Thomas G. DeLoughery, MD, FACP, FAWM

Introduction

Immune thrombocytopenia (ITP) is a common acquired autoimmune disease characterized by low platelet counts and an increased risk of bleeding. The incidence of ITP is approximately 3.3 per 100,000 adults.¹ There is considerable controversy about all aspects of the disease, with little “hard” data on which to base decisions given the lack of randomized clinical trials to address most clinical questions. This article reviews the presentation and diagnosis of ITP and its treatment options and discusses management of ITP in specific clinical situations.

Pathogenesis and Epidemiology

ITP is caused by autoantibodies binding to platelet surface proteins, most often to the platelet receptor GP IIb/IIIa.^2-4 These antibody-coated platelets then bind to Fc receptors in macrophages and are removed from circulation. The initiating event in ITP is unknown. It is speculated that the patient responds to a viral or bacterial infection by creating antibodies which cross-react with the platelet receptors. Continued exposure to platelets perpetuates the immune response. ITP that occurs in childhood appears to be an acute response to viral infection and usually resolves. ITP in adults may occur in any age group but is seen especially in young women.

Despite the increased platelet destruction that occurs in ITP, the production of new platelets often is not significantly increased. This is most likely due to lack of an increase in thrombopoietin, the predominant platelet growth factor.⁵

It had been thought that most adult patients who present with ITP go on to have a chronic course, but more recent studies have shown this is not the case. In modern series the percentage of patients who are “cured” with steroids ranges from 30% to 70%.^6–9 In addition, it has been appreciated that even in patients with modest thrombocytopenia, no therapy is required if the platelet count remains higher than 30 × 10³/µL. However, this leaves a considerable number of patients who will require chronic therapy.

Clinical Presentation

Presentation can range from a symptomatic patient with low platelets found on a routine blood count to a patient with massive bleeding. Typically, patients first present with petechiae (small bruises 1 mm in size) on the shins. True petechiae are seen only in severe thrombocytopenia. Patients will also report frequent bruising and bleeding from the gums. Patients with very low platelet counts will notice “wet purpura,” which is characterized by blood-filled bullae in the oral cavity. Life-threatening bleeding is a very unusual presenting sign unless other problems (trauma, ulcers) are present. The physical examination is only remarkable for stigmata of bleeding such as the petechiae. The presence of splenomegaly or lymphadenopathy weighs strongly against a diagnosis of ITP. Many patients with ITP will note fatigue when their platelets counts are lower.¹⁰

Diagnosis

Extremely low platelet counts with a normal blood smear and an otherwise healthy patient are diagnostic of ITP. The platelet count cutoff for considering ITP is 100 × 10³/µL as the majority of patients with counts in the 100 to 150 × 10³/µL range will not develop greater thrombocytopenia.¹¹ Also, the platelet count decreases with age (9 × 10³/µL per decade in one study), and this also needs to be factored into the evaluation.¹² The finding of relatives with ITP should raise suspicion for congenital thrombocytopenia.¹³ One should question the patient carefully about drug exposure (see Drug-Induced Thrombocytopenia), especially about over-the-counter medicines, “natural” remedies, or recreational drugs.

There is no laboratory test that rules in ITP; rather, it is a diagnosis of exclusion. The blood smear should be carefully examined for evidence of microangiopathic hemolytic anemias (schistocytes), bone marrow disease (blasts, teardrop cells), or any other evidence of a primary bone marrow disease. In ITP, the platelets can be larger than normal, but finding some platelets the size of red cells should raise the issue of congenital thrombocytopenia.¹⁴ Pseudo-thrombocytopenia, which is the clumping of platelets due to a reaction to the EDTA anticoagulant in the tube, should be excluded. The diagnosis is established by drawing the blood in a citrated (blue-top) tube to perform the platelet count. There is no role for antiplatelet antibody assay because this test lacks sensitivity and specificity. In a patient without a history of autoimmune disease or symptoms, empiric testing for autoimmune disease is not recommended.

Patients who present with ITP should be tested for both HIV and hepatitis C infection.^15,16 These are the most common viral causes of secondary ITP, and both have prognostic and treatment implications. Some authorities also recommend checking thyroid function as hypothyroidism can present or aggravate the thrombocytopenia.

The role of bone marrow examination is controversial.¹⁷ Patients with a classic presentation of ITP (young woman, normal blood smear) do not require a bone marrow exam before therapy is initiated, although patients who do not respond to initial therapy should have a bone marrow aspiration. The rare entity amegakaryocytic thrombocytopenia can present with a clinical picture similar to that of ITP, but amegakaryocytic thrombocytopenia will not respond to steroids. Bone marrow aspiration reveals the absence of megakaryocytes in this entity. It is rare, however, that another hematologic disease is diagnosed in patients with a classic clinical presentation of ITP.

In the future, measurement of thrombopoietin and reticulated platelets may provide clues to the diagnosis.⁴ Patients with ITP paradoxically have normal or only mildly elevated thrombopoietin levels. The finding of a significantly elevated thrombopoietin level should lead to questioning of the diagnosis. One can also measure “reticulated platelets,” which are analogous to red cell reticulocytes. Patients with ITP (or any platelet destructive disorders) will have high levels of reticulated platelets. These tests are not recommended for routine evaluation, but may be helpful in difficult cases.

Treatment

In general, therapy in ITP should be guided by the patient’s signs of bleeding and not by unquestioning adherence to measuring platelet levels,¹⁵ as patients tolerate thrombocytopenia well. It is unusual to have life-threatening bleeding with platelet counts greater than 5 × 10³/µL in the absence of mechanical lesions. Despite the low platelet count in patients with ITP, the overall mortality is estimated to be only 0.3% to 1.3%.¹⁸ It is sobering that in one study the rate of death from infections was twice as high as that from bleeding.¹⁹ Rare patients will have antibodies that interfere with the function of the platelet, and these patients can have profound bleeding with only modestly lowered platelet counts.²⁰ A suggested cut-off for treating newly diagnosed patients is 30 × 10³/µL.²¹

Initial Therapy

The primary therapy of ITP is glucocorticoids, either prednisone or dexamethasone. In the past prednisone at a dose of 60 to 80 mg/day was started at the time of diagnosis (Table 1).

For rapid induction of a response, there are 2 options. A single dose of intravenous immune globulin (IVIG) at 1 g/kg or intravenous anti-D immunoglobulin (anti-D) at 50 to 75 µg/kg can induce a response in more than 80% of patients in 24 to 48 hours.^21,24 IVIG has several drawbacks. It can cause aseptic meningitis, and in patients with vascular disease the increased viscosity can induce ischemia. There is also a considerable fluid load delivered with the IVIG, and it needs to be given over several hours.

The use of anti-D is limited to Rh-positive patients who have not had a splenectomy. It should not be used in patients who are Coombs positive due to the risk of provoking more hemolysis. Rarely anti-D has been reported to cause a severe hemolytic disseminated intravascular coagulation syndrome (1:20,000 patients), which has led to restrictions in its use.²⁵ Although the drug can be rapidly given over 15 minutes, due to these concerns current recommendations are now to observe patients for 8 hours after their dose and to perform a urine dipstick test for blood at 2, 4, and 8 hours. Concerns about this rare but serious side effect have led to a dramatic decrease in the use of anti-D.

For patients who are severely thrombocytopenic and do not respond to initial therapy, there are 2 options for raising the platelet counts. One is to use a combination of IVIG, methylprednisolone, vincristine, and/or anti-D.²⁶ The combination of IVIG and anti-D may be synergistic since these agents block different Fc receptors. A response of 71% has been reported for this 3- or 4-drug combination in a series of 35 patients.²⁶ The other option is to treat with a continuous infusion of platelets (1 unit over 6 hours) and IVIG 1 g/kg for 24 hours. Response rates of 62.7% have been reported with this combination, and this rapid rise in platelets can allow time for other therapies to take effect.^27,28

Patients with severe thrombocytopenia who relapse with reduction of steroids or who do not respond to steroids have several options for further management. Repeated doses of IVIG can transiently raise the platelet count, and some patients may only need several courses of therapy over the course of many months. One study showed that 60% of patients could delay or defer therapy by receiving multiple doses of anti-D. However, 30% of patients did eventually receive splenectomy and 20% of patients required ongoing therapy with anti-D.²⁹ In a randomized trial comparing early use of anti-D to steroids to avoid splenectomy, there was no difference in splenectomy rate (38% versus 42%).³⁰ Finally, an option as mentioned above is to try a 6-month course of pulse dexamethasone 40 mg/day for 4 days, repeated every 28 days.

Options for Refractory ITP

There are multiple options for patients who do not respond to initial ITP therapies. These can be divided into several broad groups: curative therapies (splenectomy and rituximab), thrombopoietin receptor agonists, and anecdotal therapies.

Splenectomy

In patients with severe thrombocytopenia who do not respond or who relapse with lower doses of prednisone, splenectomy should be strongly considered. Splenectomy will induce a good response in 60% to 70% of patients and is durable in most patients. In 2 recently published reviews of splenectomy, the complete response rate was 67% and the total response rate was 88% to 90%%.^8,31 Between 15% and 28% of patients relapsed over 5 years, with most recurrences occurring in the first 2 years. Splenectomy carries a short-term surgical risk, and the life-long risk of increased susceptibility to overwhelming sepsis is discussed below. However, the absolute magnitude of these risks is low and is often lower than the risks of continued prednisone therapy or of continued cytotoxic therapy.

Timing of splenectomy depends on the patient’s presentation. Most patients should be given a 6-month trial of steroids or other therapies before proceeding to splenectomy.³¹ However, patients who persist with severe thrombocytopenia despite initial therapies or who are suffering intolerable side effects from therapy should be considered sooner for splenectomy.³¹ In the George review, multiple factors such as responding to IVIG were found not to be predictive of response to splenectomy.⁸

Method of splenectomy appears not to matter.²¹ Rates of finding accessory spleens are just as high or higher with laparoscopic splenectomy and the patient can recover faster. In patients who are severely thrombocytopenic, open splenectomy can allow for quicker control of the vascular access of the spleen.

Rates of splenectomy in recent years have decreased for many reasons,³² including the acceptance of lower platelet counts in asymptomatic patients and the availability of alternative therapies such as rituximab. In addition, despite abundant data for good outcomes, there is a concern that splenectomy responses are not durable. Although splenectomy will not cure every patient with ITP, splenectomy is the therapy with the most patients, the longest follow-up, and the most consistent rate of cure, and it should be discussed with every ITP patient who does not respond to initial therapy and needs further treatment.

The risk of overwhelming sepsis varies by indications for splenectomy but appears to be about 1%.^33,34 The use of pneumococcal vaccine and recognition of this syndrome have helped reduce the risk. Asplenic patients need to be counseled about the risk of overwhelming infections, should be vaccinated for pneumococcus, meningococcus, and Haemophilus influenzae, and should wear an ID bracelet.^35–37 Patients previously vaccinated for pneumococcus should be re-vaccinated every 3 to 5 years. The role of prophylactic antibiotics in adults is controversial, but patients under the age of 18 should be on penicillin VK 250 mg orally twice daily.

Rituximab

Rituximab has been shown to be very active in ITP. Most studies used the standard dose of 375 mg/m² weekly for 4 weeks, but other studies have shown that 1000 mg twice 14 days apart (ie, on days 1 and 15) resulted in the same response rate and may be more convenient for patients.^38,39 The response time can vary, with patients either showing a rapid response or requiring up to 8 weeks for their counts to go up. Although experience is limited, the response seems to be durable, especially in those patients whose counts rise higher than 150 × 10³/µL; in patients who relapse, a response can be re-induced with a repeat course. Overall the response rate for rituximab is about 60%, but only approximately 20% to 40% of patients will remain in long-term remission.^40–42 There is no evidence yet that “maintenance” therapy or monitoring CD19/CD20 cells can help further the duration of remission.

Whether to give rituximab pre- or post-splenectomy is also uncertain. An advantage of presplenectomy rituximab is that many patients will achieve remission, delaying the need for surgery. Also, rituximab is a good option for patients whose medical conditions put them at high risk for complications with splenectomy. However, it is unknown whether rituximab poses any long-term risks, while the long-term risks of splenectomy are well-defined. Rituximab is the only curative option left for patients who have failed splenectomy and is a reasonable option for these patients.

There is an intriguing trial in which patients were randomly assigned to dexamethasone alone versus dexamethasone plus rituximab upon presentation with ITP; those who were refractory to dexamethasone alone received salvage therapy with dexamethasone plus rituximab.⁴³ The dexamethasone plus rituximab group had an overall higher rate of sustained remission at 6 months than the dexamethasone group, 63% versus 36%. Interestingly, patients who failed their first course of dexamethasone but then were “salvaged” with dexamethasone/rituximab had a similar overall response rate of 56%, suggesting that saving the addition of rituximab for steroid failures may be an effective option.

Although not “chemotherapy,” rituximab is not without risks. Patients can develop infusion reactions, which can be severe in 1% to 2% of patients. In a meta-analysis the fatal reaction rate was 2.9%.⁴⁰ Patients with chronic hepatitis B infections can experience reactivation with rituximab, and thus all patients should be screened before treatment. Finally, the very rare but devastating complication of progressive multifocal leukoencephalopathy has been reported.

Thrombopoietin Receptor Agonists

Although patients with ITP have low platelet counts, studies starting with Dameshek have shown that these patients also have reduced production of platelets.⁴⁴ Despite the very low circulating platelet count, levels of the platelet growth factor thrombopoietin (TPO) are not raised.⁴⁵ Seminal studies with recombinant TPO in the 1990s showed that ITP patients responded to thrombopoietin-stimulating protein, but the formation of anti-TPO antibodies halted trials with the first generation of these agents. Two TPO receptor agonists (TPO-RA) are approved for use in patients with ITP.

Romiplostim. Romiplostim is a peptibody, a combination of a peptide that binds and stimulates the TPO receptor and an Fc domain to extend its half-life.⁴⁶ It is administered in a weekly subcutaneous dose starting at 1 to 3 µg/kg. Use of romiplostim in ITP patients produces a response rate of 80% to 88%, with 87% of patients being able to wean off or decrease other anti-ITP medications.⁴⁷ In a long-term extension study, the response was again high at 87%.⁴⁸ These studies have also shown a reduced incidence of bleeding.

The major side effect of romiplostim seen in clinical trials was marrow reticulin formation, which occurred in up to 5.6% of patients.^47,48 The clinical course in these patients is the development of anemia and a myelophthisic blood smear with teardrop cells and nucleated red cells. These changes appear to reverse with cessation of the drug. The bone marrow shows increased reticulin formation but rarely, if ever, shows the collagen deposition seen with primary myelofibrosis.

Thrombosis has also been seen, with a rate of 0.08 to 0.1 cases per 100 patient-weeks,⁴⁹ but it remains unclear if this is due to the drug, part of the natural history of ITP, or expected complications in older patients undergoing any type of medical therapy. Surprisingly, despite the low platelet counts, patients with ITP in one study had double the risk of venous thrombosis, demonstrating that ITP itself can be a risk factor for thrombosis.⁵⁰ These trials have shown no long-term concerns for other clinical problems such as liver disease.

Eltrombopag. The other available TPO-RA is eltrombopag,⁵¹ an oral agent that stimulates the TPO receptor by binding the transmembrane domain and activating it. The drug is given orally starting at 50 mg/day (25 mg for patients of Asian ancestry or with liver disease) and can be dose escalated to 75 mg/day. The drug needs to be taken on an empty stomach. Eltrombopag has been shown to be effective in chronic ITP, with response rates of 59% to 80% and reduction in use of rescue medications.^47,51,52 As with romiplostim, the incidence of bleeding was also decreased with eltrombopag in these trials.^47,51

Clinical trials demonstrated that eltrombopag shares with romiplostim the risk for marrow fibrosis. A side effect unique to eltrombopag observed in these trials was a 3% to 7% incidence of elevated liver function tests.^21,52 These abnormal findings appeared to resolve in most patients, but liver function tests need to be monitored in patients receiving eltrombopag.

Clinical use. The clearest indication for the use of TPO-RAs is in patients who have failed several therapies and remain symptomatic or are on intolerable doses of other medications such as prednisone. The clear benefits are their relative safety and high rates of success. The main drawback of TPO-RAs is the need for continuing therapy as the platelet count will return to baseline shortly after these agents are stopped. Currently there is no clear indication for one medication over the other. The advantages of romiplostim are great flexibility in dosing (1–10 µg/kg week) and no concerns about drug interaction. The current drawback of romiplostim is the Food and Drug Administration’s requirement for patients to receive the drug from a clinic and not at home. Eltrombopag offers the advantage of oral use, but it has a limited dose range and potential for drug interactions. Both agents have been associated with marrow reticulin formation, although in clinical use this risk appears to be very low.⁵³

Other Options

In the literature there are numerous options for the treatment of ITP.^54,55 Most of these studies are anecdotal, enrolled small number of patients, and sometimes included patients with mild thrombocytopenia, but these therapeutic options can be tried in patients who are refractory to standard therapies and have bleeding. The agents with the greatest amount of supporting data are danazol, vincristine, azathioprine, cyclophosphamide, and fostamatinib.

Danazol 200 mg 4 times daily is thought to downregulate the macrophage Fc receptor. The onset of action may be delayed and a therapeutic trial of up to 4 to 6 months is advised. Danazol is very effective in patients with antiphospholipid antibody syndrome who develop ITP and may be more effective in premenopausal women.⁵⁶ Once a response is seen, danazol should be continued for 6 months and then an attempt to wean the patient off the agent should be made. A partial response can be seen in 70% to 90% of patients, but a complete response is rare.⁵⁴

Vincristine 1.4 mg/m² weekly has a low response rate, but if a response is going to occur, it will occur rapidly within 2 weeks. Thus, a prolonged trial of vincristine is not needed; if no platelet rise is seen in several weeks, the drug should be stopped. Again, partial responses are more common than complete response—50% to 63% versus 0% to 6%.⁵⁴Azathioprine 150 mg orally daily, like danazol, demonstrates a delayed response and requires several months to assess for response. However, 19% to 25% of patients may have a complete response.⁵⁴ It has been reported that the related agent mycophenolate 1000 mg twice daily is also effective in ITP.⁵⁷

Cyclophosphamide 1 g/m² intravenously repeated every 28 days has been reported to have a response rate of up to 40%.⁵⁸ Although considered more aggressive, this is a standard immunosuppressive dose and should be considered in patients with very low platelet counts. Patients who have not responded to single-agent cyclophosphamide may respond to multi-agent chemotherapy with agents such as etoposide and vincristine plus cyclophosphamide.⁵⁹

Fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, is currently under investigation for the treatment of ITP.⁶⁰ This agent prevents phagocytosis of antibody-coated platelets by macrophages. In early studies fostamatinib has been well tolerated at a dose of 150 mg twice daily, with 75% of patients showing a response. Large phase 3 trials are underway, and if the earlier promising results hold up fostamatinib may be a novel option for refractory patients.

A Practical Approach to Refractory ITP

One approach is to divide patients into bleeders, or those with either very low platelet counts (< 5 × 10³/µL) or who have had significant bleeding in the past, and nonbleeders, or those with platelet counts above 5 × 10³/µL and no history of severe bleeding. Bleeders who do not respond adequately to splenectomy should first start with rituximab since it is not cytotoxic and is the only other “curative” therapy (Table 2).

Nonbleeders should be tried on danazol and other relatively safe agents. If this fails, rituximab or TPO-RAs can be considered. Before one considers cytotoxic therapy, the risk of the therapy must be weighed against the risk posed by the thrombocytopenia. The mortality from ITP is fairly low (5%) and is restricted to patients with severe disease. Patients with only moderate thrombocytopenia and no bleeding are better served with conservative management. There is little justification for the use of continuous steroid therapy in this group of patients given the long-term risks of this therapy.

Special Situations

Surgery

Patients with ITP who need surgery either for splenectomy or for other reasons should have their platelet counts raised to a level greater than 20 to 30 × 10³/µL before surgery. Most patients with ITP have increased platelet function and will not have excessive bleeding with these platelet counts. For patients with platelet counts below this level, an infusion of immune globulin or anti-D may rapidly increase the platelet counts. If the surgery is elective, short-term use of TPO-RAs to raise the counts can also be considered.

Pregnancy

Up to 10% of pregnant women will develop low platelet counts during their pregnancy.^61,62 The most common etiology is gestational thrombocytopenia, which is an exaggeration of the lowered platelet count seen in pregnancy. Counts may fall as low as 50 × 10³/µL at the time of delivery. No therapy is required as the fetus is not affected and the mother does not have an increased risk of bleeding. Pregnancy complications such as HELLP syndrome and thrombotic microangiopathies also present with low platelet counts, but these can be diagnosed by history.^61,63

Women with ITP can either develop the disease during pregnancy or have a worsening of the symptoms.⁶⁴ Counts often drop dramatically during the first trimester. Early management should be conservative with low doses of prednisone to keep the count above 10 × 10³/µL.²¹ Immunoglobulin is also effective,⁶⁵ but there are rare reports of pulmonary edema. Rarely patients who are refractory will require splenectomy, which may be safely performed in the second trimester. For delivery the count should be greater than 30 × 10³/µL and for an epidural greater than 50 × 10³/µL.⁶⁴ There are reports of the use of TPO-RAs in pregnancy, and this can be considered for refractory cases.⁶⁶

Most controversy centers on management of the delivery. In the past it was feared that fetal thrombocytopenia could lead to intracranial hemorrhage, and Caesarean section was always recommended. It now appears that most cases of intracranial hemorrhage were due to alloimmune thrombocytopenia and not ITP. Furthermore, the nadir of the baby’s platelet count is not at birth but several days after. It appears the safest course is to proceed with a vaginal or C-section delivery determined by obstetrical indications and then immediately check the baby’s platelet count. If the platelet count is low in the neonate, immunoglobulin will raise the count. Since the neonatal thrombocytopenia is due to passive transfer of maternal antibody, the platelet destruction will abate in 4 to 6 weeks.

Pediatric Patients

The incidence of ITP in children is 2.2 to 5.3 per 100,000 children.¹ There are several distinct differences in pediatric ITP. Most cases will resolve in weeks, with only a minority of patients transforming into chronic ITP (5%–10%). Also, the rates of serious bleeding are lower in children than in adults, with intracranial hemorrhage rates of 0.1% to 0.5% being seen.⁶⁷ For most patients with no or mild bleeding, management now is observation alone regardless of platelet count because it is felt that the risks of therapies are higher than the risk of bleeding.²¹ For patients with bleeding, IVIG, anti-D, or a short course of steroids can be used. Given the risk of overwhelming sepsis, splenectomy is often deferred as long as possible. Rituximab is increasingly being used in children due to concerns about use of agents such a cyclophosphamide or azathioprine in children.⁶⁸ Abundant data on use of TPO-RAs in children showing high response rates and safety support their use, and these should be considered in refractory ITP before any cytotoxic agent.^69–71

Helicobacter Pylori Infection

There has been much interest in the relationship between H. pylori and ITP.^16,72,73H. pylori infections have been associated with a variety of autoimmune diseases, and there is a confusing literature on this infection and ITP. Several meta-analyses have shown that eradication of H. pylori will result in an ITP response rate of 20% to 30%, but responses curiously appear to be limited to certain geographic areas such as Japan and Italy but not the United States. In patients with recalcitrant ITP, especially in geographic areas with high incidence, it may be worthwhile to check for H. pylori infection and treat accordingly if positive.

Drug-Induced Thrombocytopenia

Patients with drug-induced thrombocytopenia present with very low (< 10 × 10³/µL) platelet counts 1 to 3 weeks after starting a new medication.^74–76 In patients with a possible drug-induced thrombocytopenia, the primary therapy is to stop the suspect drug.⁷⁷ If there are multiple new medications, the best approach is to stop any drug that has been strongly associated with thrombocytopenia (Table 3).^74,78,79

Immune globulin, corticosteroids, or intravenous anti‑D have been suggested as useful in drug‑related thrombocytopenia. However, since most of these thrombocytopenic patients recover when the agent is cleared from the body, this therapy is probably not necessary and withholding treatment avoids exposing the patients to the adverse events associated with further therapy.

Evans Syndrome

Evans syndrome is defined as the combination of autoimmune hemolytic anemia (AIHA) and ITP.^80,81 These cytopenias can present simultaneously or sequentially. Patients with Evans syndrome are thought to have a more severe disease process, to be more prone to bleeding, and to be more difficult to treat, but the rarity of this syndrome makes this hard to quantify.

The classic clinical presentation of Evans syndrome is severe anemia and thrombocytopenia. Children with Evans syndrome often have complex immunodeficiencies such as autoimmune lymphoproliferative syndrome.^82,83 In adults, Evans syndrome most often complicates other autoimmune diseases such as lupus. There are increasing reports of Evans syndrome occurring as a complication of T-cell lymphomas. Often the autoimmune disease can predate the lymphoma diagnosis by months or even years.

In theory the diagnostic approach is straightforward by showing a Coombs-positive hemolytic anemia in the setting of a clinical diagnosis of immune thrombocytopenia. The blood smear will show spherocytes and a diminished platelet count. The presence of other abnormal red cell forms should raise the possibility of an alternative diagnosis. It is unclear how vigorously one should search for other underlying diseases. Many patients will already have the diagnosis of an underlying autoimmune disease. The presence of lymphadenopathy should raise concern for lymphoma.

Initial therapy is high-dose steroids (2 mg/kg/day). IVIG should be added if severe thrombocytopenia is present. Patients who cannot be weaned off prednisone or relapse after prednisone should be considered for splenectomy, although these patients are at higher risk of relapsing.⁸⁰ Increasingly rituximab is being used with success.^84,85 For patients who fail splenectomy and rituximab, aggressive immunosuppression should be considered. Increasing data support the benefits of sirolimus, and this should be considered for refractory patients.⁸⁶ For patients with Evans syndrome due to underlying lymphoma, antineoplastic therapy often results in prompt resolution of the symptoms. Recurrence of the autoimmune cytopenias often heralds relapse.

Introduction

Immune thrombocytopenia (ITP) is a common acquired autoimmune disease characterized by low platelet counts and an increased risk of bleeding. The incidence of ITP is approximately 3.3 per 100,000 adults.¹ There is considerable controversy about all aspects of the disease, with little “hard” data on which to base decisions given the lack of randomized clinical trials to address most clinical questions. This article reviews the presentation and diagnosis of ITP and its treatment options and discusses management of ITP in specific clinical situations.

Pathogenesis and Epidemiology

ITP is caused by autoantibodies binding to platelet surface proteins, most often to the platelet receptor GP IIb/IIIa.^2-4 These antibody-coated platelets then bind to Fc receptors in macrophages and are removed from circulation. The initiating event in ITP is unknown. It is speculated that the patient responds to a viral or bacterial infection by creating antibodies which cross-react with the platelet receptors. Continued exposure to platelets perpetuates the immune response. ITP that occurs in childhood appears to be an acute response to viral infection and usually resolves. ITP in adults may occur in any age group but is seen especially in young women.

Despite the increased platelet destruction that occurs in ITP, the production of new platelets often is not significantly increased. This is most likely due to lack of an increase in thrombopoietin, the predominant platelet growth factor.⁵

It had been thought that most adult patients who present with ITP go on to have a chronic course, but more recent studies have shown this is not the case. In modern series the percentage of patients who are “cured” with steroids ranges from 30% to 70%.^6–9 In addition, it has been appreciated that even in patients with modest thrombocytopenia, no therapy is required if the platelet count remains higher than 30 × 10³/µL. However, this leaves a considerable number of patients who will require chronic therapy.

Clinical Presentation

Presentation can range from a symptomatic patient with low platelets found on a routine blood count to a patient with massive bleeding. Typically, patients first present with petechiae (small bruises 1 mm in size) on the shins. True petechiae are seen only in severe thrombocytopenia. Patients will also report frequent bruising and bleeding from the gums. Patients with very low platelet counts will notice “wet purpura,” which is characterized by blood-filled bullae in the oral cavity. Life-threatening bleeding is a very unusual presenting sign unless other problems (trauma, ulcers) are present. The physical examination is only remarkable for stigmata of bleeding such as the petechiae. The presence of splenomegaly or lymphadenopathy weighs strongly against a diagnosis of ITP. Many patients with ITP will note fatigue when their platelets counts are lower.¹⁰

Diagnosis

Extremely low platelet counts with a normal blood smear and an otherwise healthy patient are diagnostic of ITP. The platelet count cutoff for considering ITP is 100 × 10³/µL as the majority of patients with counts in the 100 to 150 × 10³/µL range will not develop greater thrombocytopenia.¹¹ Also, the platelet count decreases with age (9 × 10³/µL per decade in one study), and this also needs to be factored into the evaluation.¹² The finding of relatives with ITP should raise suspicion for congenital thrombocytopenia.¹³ One should question the patient carefully about drug exposure (see Drug-Induced Thrombocytopenia), especially about over-the-counter medicines, “natural” remedies, or recreational drugs.

There is no laboratory test that rules in ITP; rather, it is a diagnosis of exclusion. The blood smear should be carefully examined for evidence of microangiopathic hemolytic anemias (schistocytes), bone marrow disease (blasts, teardrop cells), or any other evidence of a primary bone marrow disease. In ITP, the platelets can be larger than normal, but finding some platelets the size of red cells should raise the issue of congenital thrombocytopenia.¹⁴ Pseudo-thrombocytopenia, which is the clumping of platelets due to a reaction to the EDTA anticoagulant in the tube, should be excluded. The diagnosis is established by drawing the blood in a citrated (blue-top) tube to perform the platelet count. There is no role for antiplatelet antibody assay because this test lacks sensitivity and specificity. In a patient without a history of autoimmune disease or symptoms, empiric testing for autoimmune disease is not recommended.

Patients who present with ITP should be tested for both HIV and hepatitis C infection.^15,16 These are the most common viral causes of secondary ITP, and both have prognostic and treatment implications. Some authorities also recommend checking thyroid function as hypothyroidism can present or aggravate the thrombocytopenia.

The role of bone marrow examination is controversial.¹⁷ Patients with a classic presentation of ITP (young woman, normal blood smear) do not require a bone marrow exam before therapy is initiated, although patients who do not respond to initial therapy should have a bone marrow aspiration. The rare entity amegakaryocytic thrombocytopenia can present with a clinical picture similar to that of ITP, but amegakaryocytic thrombocytopenia will not respond to steroids. Bone marrow aspiration reveals the absence of megakaryocytes in this entity. It is rare, however, that another hematologic disease is diagnosed in patients with a classic clinical presentation of ITP.

In the future, measurement of thrombopoietin and reticulated platelets may provide clues to the diagnosis.⁴ Patients with ITP paradoxically have normal or only mildly elevated thrombopoietin levels. The finding of a significantly elevated thrombopoietin level should lead to questioning of the diagnosis. One can also measure “reticulated platelets,” which are analogous to red cell reticulocytes. Patients with ITP (or any platelet destructive disorders) will have high levels of reticulated platelets. These tests are not recommended for routine evaluation, but may be helpful in difficult cases.

Treatment

In general, therapy in ITP should be guided by the patient’s signs of bleeding and not by unquestioning adherence to measuring platelet levels,¹⁵ as patients tolerate thrombocytopenia well. It is unusual to have life-threatening bleeding with platelet counts greater than 5 × 10³/µL in the absence of mechanical lesions. Despite the low platelet count in patients with ITP, the overall mortality is estimated to be only 0.3% to 1.3%.¹⁸ It is sobering that in one study the rate of death from infections was twice as high as that from bleeding.¹⁹ Rare patients will have antibodies that interfere with the function of the platelet, and these patients can have profound bleeding with only modestly lowered platelet counts.²⁰ A suggested cut-off for treating newly diagnosed patients is 30 × 10³/µL.²¹

Initial Therapy

The primary therapy of ITP is glucocorticoids, either prednisone or dexamethasone. In the past prednisone at a dose of 60 to 80 mg/day was started at the time of diagnosis (Table 1).

For rapid induction of a response, there are 2 options. A single dose of intravenous immune globulin (IVIG) at 1 g/kg or intravenous anti-D immunoglobulin (anti-D) at 50 to 75 µg/kg can induce a response in more than 80% of patients in 24 to 48 hours.^21,24 IVIG has several drawbacks. It can cause aseptic meningitis, and in patients with vascular disease the increased viscosity can induce ischemia. There is also a considerable fluid load delivered with the IVIG, and it needs to be given over several hours.

The use of anti-D is limited to Rh-positive patients who have not had a splenectomy. It should not be used in patients who are Coombs positive due to the risk of provoking more hemolysis. Rarely anti-D has been reported to cause a severe hemolytic disseminated intravascular coagulation syndrome (1:20,000 patients), which has led to restrictions in its use.²⁵ Although the drug can be rapidly given over 15 minutes, due to these concerns current recommendations are now to observe patients for 8 hours after their dose and to perform a urine dipstick test for blood at 2, 4, and 8 hours. Concerns about this rare but serious side effect have led to a dramatic decrease in the use of anti-D.

For patients who are severely thrombocytopenic and do not respond to initial therapy, there are 2 options for raising the platelet counts. One is to use a combination of IVIG, methylprednisolone, vincristine, and/or anti-D.²⁶ The combination of IVIG and anti-D may be synergistic since these agents block different Fc receptors. A response of 71% has been reported for this 3- or 4-drug combination in a series of 35 patients.²⁶ The other option is to treat with a continuous infusion of platelets (1 unit over 6 hours) and IVIG 1 g/kg for 24 hours. Response rates of 62.7% have been reported with this combination, and this rapid rise in platelets can allow time for other therapies to take effect.^27,28

Patients with severe thrombocytopenia who relapse with reduction of steroids or who do not respond to steroids have several options for further management. Repeated doses of IVIG can transiently raise the platelet count, and some patients may only need several courses of therapy over the course of many months. One study showed that 60% of patients could delay or defer therapy by receiving multiple doses of anti-D. However, 30% of patients did eventually receive splenectomy and 20% of patients required ongoing therapy with anti-D.²⁹ In a randomized trial comparing early use of anti-D to steroids to avoid splenectomy, there was no difference in splenectomy rate (38% versus 42%).³⁰ Finally, an option as mentioned above is to try a 6-month course of pulse dexamethasone 40 mg/day for 4 days, repeated every 28 days.

Options for Refractory ITP

There are multiple options for patients who do not respond to initial ITP therapies. These can be divided into several broad groups: curative therapies (splenectomy and rituximab), thrombopoietin receptor agonists, and anecdotal therapies.

Splenectomy

In patients with severe thrombocytopenia who do not respond or who relapse with lower doses of prednisone, splenectomy should be strongly considered. Splenectomy will induce a good response in 60% to 70% of patients and is durable in most patients. In 2 recently published reviews of splenectomy, the complete response rate was 67% and the total response rate was 88% to 90%%.^8,31 Between 15% and 28% of patients relapsed over 5 years, with most recurrences occurring in the first 2 years. Splenectomy carries a short-term surgical risk, and the life-long risk of increased susceptibility to overwhelming sepsis is discussed below. However, the absolute magnitude of these risks is low and is often lower than the risks of continued prednisone therapy or of continued cytotoxic therapy.

Timing of splenectomy depends on the patient’s presentation. Most patients should be given a 6-month trial of steroids or other therapies before proceeding to splenectomy.³¹ However, patients who persist with severe thrombocytopenia despite initial therapies or who are suffering intolerable side effects from therapy should be considered sooner for splenectomy.³¹ In the George review, multiple factors such as responding to IVIG were found not to be predictive of response to splenectomy.⁸

Method of splenectomy appears not to matter.²¹ Rates of finding accessory spleens are just as high or higher with laparoscopic splenectomy and the patient can recover faster. In patients who are severely thrombocytopenic, open splenectomy can allow for quicker control of the vascular access of the spleen.

Rates of splenectomy in recent years have decreased for many reasons,³² including the acceptance of lower platelet counts in asymptomatic patients and the availability of alternative therapies such as rituximab. In addition, despite abundant data for good outcomes, there is a concern that splenectomy responses are not durable. Although splenectomy will not cure every patient with ITP, splenectomy is the therapy with the most patients, the longest follow-up, and the most consistent rate of cure, and it should be discussed with every ITP patient who does not respond to initial therapy and needs further treatment.

The risk of overwhelming sepsis varies by indications for splenectomy but appears to be about 1%.^33,34 The use of pneumococcal vaccine and recognition of this syndrome have helped reduce the risk. Asplenic patients need to be counseled about the risk of overwhelming infections, should be vaccinated for pneumococcus, meningococcus, and Haemophilus influenzae, and should wear an ID bracelet.^35–37 Patients previously vaccinated for pneumococcus should be re-vaccinated every 3 to 5 years. The role of prophylactic antibiotics in adults is controversial, but patients under the age of 18 should be on penicillin VK 250 mg orally twice daily.

Rituximab

Rituximab has been shown to be very active in ITP. Most studies used the standard dose of 375 mg/m² weekly for 4 weeks, but other studies have shown that 1000 mg twice 14 days apart (ie, on days 1 and 15) resulted in the same response rate and may be more convenient for patients.^38,39 The response time can vary, with patients either showing a rapid response or requiring up to 8 weeks for their counts to go up. Although experience is limited, the response seems to be durable, especially in those patients whose counts rise higher than 150 × 10³/µL; in patients who relapse, a response can be re-induced with a repeat course. Overall the response rate for rituximab is about 60%, but only approximately 20% to 40% of patients will remain in long-term remission.^40–42 There is no evidence yet that “maintenance” therapy or monitoring CD19/CD20 cells can help further the duration of remission.

Whether to give rituximab pre- or post-splenectomy is also uncertain. An advantage of presplenectomy rituximab is that many patients will achieve remission, delaying the need for surgery. Also, rituximab is a good option for patients whose medical conditions put them at high risk for complications with splenectomy. However, it is unknown whether rituximab poses any long-term risks, while the long-term risks of splenectomy are well-defined. Rituximab is the only curative option left for patients who have failed splenectomy and is a reasonable option for these patients.

There is an intriguing trial in which patients were randomly assigned to dexamethasone alone versus dexamethasone plus rituximab upon presentation with ITP; those who were refractory to dexamethasone alone received salvage therapy with dexamethasone plus rituximab.⁴³ The dexamethasone plus rituximab group had an overall higher rate of sustained remission at 6 months than the dexamethasone group, 63% versus 36%. Interestingly, patients who failed their first course of dexamethasone but then were “salvaged” with dexamethasone/rituximab had a similar overall response rate of 56%, suggesting that saving the addition of rituximab for steroid failures may be an effective option.

Although not “chemotherapy,” rituximab is not without risks. Patients can develop infusion reactions, which can be severe in 1% to 2% of patients. In a meta-analysis the fatal reaction rate was 2.9%.⁴⁰ Patients with chronic hepatitis B infections can experience reactivation with rituximab, and thus all patients should be screened before treatment. Finally, the very rare but devastating complication of progressive multifocal leukoencephalopathy has been reported.

Thrombopoietin Receptor Agonists

Although patients with ITP have low platelet counts, studies starting with Dameshek have shown that these patients also have reduced production of platelets.⁴⁴ Despite the very low circulating platelet count, levels of the platelet growth factor thrombopoietin (TPO) are not raised.⁴⁵ Seminal studies with recombinant TPO in the 1990s showed that ITP patients responded to thrombopoietin-stimulating protein, but the formation of anti-TPO antibodies halted trials with the first generation of these agents. Two TPO receptor agonists (TPO-RA) are approved for use in patients with ITP.

Romiplostim. Romiplostim is a peptibody, a combination of a peptide that binds and stimulates the TPO receptor and an Fc domain to extend its half-life.⁴⁶ It is administered in a weekly subcutaneous dose starting at 1 to 3 µg/kg. Use of romiplostim in ITP patients produces a response rate of 80% to 88%, with 87% of patients being able to wean off or decrease other anti-ITP medications.⁴⁷ In a long-term extension study, the response was again high at 87%.⁴⁸ These studies have also shown a reduced incidence of bleeding.

The major side effect of romiplostim seen in clinical trials was marrow reticulin formation, which occurred in up to 5.6% of patients.^47,48 The clinical course in these patients is the development of anemia and a myelophthisic blood smear with teardrop cells and nucleated red cells. These changes appear to reverse with cessation of the drug. The bone marrow shows increased reticulin formation but rarely, if ever, shows the collagen deposition seen with primary myelofibrosis.

Thrombosis has also been seen, with a rate of 0.08 to 0.1 cases per 100 patient-weeks,⁴⁹ but it remains unclear if this is due to the drug, part of the natural history of ITP, or expected complications in older patients undergoing any type of medical therapy. Surprisingly, despite the low platelet counts, patients with ITP in one study had double the risk of venous thrombosis, demonstrating that ITP itself can be a risk factor for thrombosis.⁵⁰ These trials have shown no long-term concerns for other clinical problems such as liver disease.

Eltrombopag. The other available TPO-RA is eltrombopag,⁵¹ an oral agent that stimulates the TPO receptor by binding the transmembrane domain and activating it. The drug is given orally starting at 50 mg/day (25 mg for patients of Asian ancestry or with liver disease) and can be dose escalated to 75 mg/day. The drug needs to be taken on an empty stomach. Eltrombopag has been shown to be effective in chronic ITP, with response rates of 59% to 80% and reduction in use of rescue medications.^47,51,52 As with romiplostim, the incidence of bleeding was also decreased with eltrombopag in these trials.^47,51

Clinical trials demonstrated that eltrombopag shares with romiplostim the risk for marrow fibrosis. A side effect unique to eltrombopag observed in these trials was a 3% to 7% incidence of elevated liver function tests.^21,52 These abnormal findings appeared to resolve in most patients, but liver function tests need to be monitored in patients receiving eltrombopag.

Clinical use. The clearest indication for the use of TPO-RAs is in patients who have failed several therapies and remain symptomatic or are on intolerable doses of other medications such as prednisone. The clear benefits are their relative safety and high rates of success. The main drawback of TPO-RAs is the need for continuing therapy as the platelet count will return to baseline shortly after these agents are stopped. Currently there is no clear indication for one medication over the other. The advantages of romiplostim are great flexibility in dosing (1–10 µg/kg week) and no concerns about drug interaction. The current drawback of romiplostim is the Food and Drug Administration’s requirement for patients to receive the drug from a clinic and not at home. Eltrombopag offers the advantage of oral use, but it has a limited dose range and potential for drug interactions. Both agents have been associated with marrow reticulin formation, although in clinical use this risk appears to be very low.⁵³

Other Options

In the literature there are numerous options for the treatment of ITP.^54,55 Most of these studies are anecdotal, enrolled small number of patients, and sometimes included patients with mild thrombocytopenia, but these therapeutic options can be tried in patients who are refractory to standard therapies and have bleeding. The agents with the greatest amount of supporting data are danazol, vincristine, azathioprine, cyclophosphamide, and fostamatinib.

Danazol 200 mg 4 times daily is thought to downregulate the macrophage Fc receptor. The onset of action may be delayed and a therapeutic trial of up to 4 to 6 months is advised. Danazol is very effective in patients with antiphospholipid antibody syndrome who develop ITP and may be more effective in premenopausal women.⁵⁶ Once a response is seen, danazol should be continued for 6 months and then an attempt to wean the patient off the agent should be made. A partial response can be seen in 70% to 90% of patients, but a complete response is rare.⁵⁴

Vincristine 1.4 mg/m² weekly has a low response rate, but if a response is going to occur, it will occur rapidly within 2 weeks. Thus, a prolonged trial of vincristine is not needed; if no platelet rise is seen in several weeks, the drug should be stopped. Again, partial responses are more common than complete response—50% to 63% versus 0% to 6%.⁵⁴Azathioprine 150 mg orally daily, like danazol, demonstrates a delayed response and requires several months to assess for response. However, 19% to 25% of patients may have a complete response.⁵⁴ It has been reported that the related agent mycophenolate 1000 mg twice daily is also effective in ITP.⁵⁷

Cyclophosphamide 1 g/m² intravenously repeated every 28 days has been reported to have a response rate of up to 40%.⁵⁸ Although considered more aggressive, this is a standard immunosuppressive dose and should be considered in patients with very low platelet counts. Patients who have not responded to single-agent cyclophosphamide may respond to multi-agent chemotherapy with agents such as etoposide and vincristine plus cyclophosphamide.⁵⁹

Fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, is currently under investigation for the treatment of ITP.⁶⁰ This agent prevents phagocytosis of antibody-coated platelets by macrophages. In early studies fostamatinib has been well tolerated at a dose of 150 mg twice daily, with 75% of patients showing a response. Large phase 3 trials are underway, and if the earlier promising results hold up fostamatinib may be a novel option for refractory patients.

A Practical Approach to Refractory ITP

One approach is to divide patients into bleeders, or those with either very low platelet counts (< 5 × 10³/µL) or who have had significant bleeding in the past, and nonbleeders, or those with platelet counts above 5 × 10³/µL and no history of severe bleeding. Bleeders who do not respond adequately to splenectomy should first start with rituximab since it is not cytotoxic and is the only other “curative” therapy (Table 2).

Nonbleeders should be tried on danazol and other relatively safe agents. If this fails, rituximab or TPO-RAs can be considered. Before one considers cytotoxic therapy, the risk of the therapy must be weighed against the risk posed by the thrombocytopenia. The mortality from ITP is fairly low (5%) and is restricted to patients with severe disease. Patients with only moderate thrombocytopenia and no bleeding are better served with conservative management. There is little justification for the use of continuous steroid therapy in this group of patients given the long-term risks of this therapy.

Special Situations

Surgery

Patients with ITP who need surgery either for splenectomy or for other reasons should have their platelet counts raised to a level greater than 20 to 30 × 10³/µL before surgery. Most patients with ITP have increased platelet function and will not have excessive bleeding with these platelet counts. For patients with platelet counts below this level, an infusion of immune globulin or anti-D may rapidly increase the platelet counts. If the surgery is elective, short-term use of TPO-RAs to raise the counts can also be considered.

Pregnancy

Up to 10% of pregnant women will develop low platelet counts during their pregnancy.^61,62 The most common etiology is gestational thrombocytopenia, which is an exaggeration of the lowered platelet count seen in pregnancy. Counts may fall as low as 50 × 10³/µL at the time of delivery. No therapy is required as the fetus is not affected and the mother does not have an increased risk of bleeding. Pregnancy complications such as HELLP syndrome and thrombotic microangiopathies also present with low platelet counts, but these can be diagnosed by history.^61,63

Women with ITP can either develop the disease during pregnancy or have a worsening of the symptoms.⁶⁴ Counts often drop dramatically during the first trimester. Early management should be conservative with low doses of prednisone to keep the count above 10 × 10³/µL.²¹ Immunoglobulin is also effective,⁶⁵ but there are rare reports of pulmonary edema. Rarely patients who are refractory will require splenectomy, which may be safely performed in the second trimester. For delivery the count should be greater than 30 × 10³/µL and for an epidural greater than 50 × 10³/µL.⁶⁴ There are reports of the use of TPO-RAs in pregnancy, and this can be considered for refractory cases.⁶⁶

Most controversy centers on management of the delivery. In the past it was feared that fetal thrombocytopenia could lead to intracranial hemorrhage, and Caesarean section was always recommended. It now appears that most cases of intracranial hemorrhage were due to alloimmune thrombocytopenia and not ITP. Furthermore, the nadir of the baby’s platelet count is not at birth but several days after. It appears the safest course is to proceed with a vaginal or C-section delivery determined by obstetrical indications and then immediately check the baby’s platelet count. If the platelet count is low in the neonate, immunoglobulin will raise the count. Since the neonatal thrombocytopenia is due to passive transfer of maternal antibody, the platelet destruction will abate in 4 to 6 weeks.

Pediatric Patients

The incidence of ITP in children is 2.2 to 5.3 per 100,000 children.¹ There are several distinct differences in pediatric ITP. Most cases will resolve in weeks, with only a minority of patients transforming into chronic ITP (5%–10%). Also, the rates of serious bleeding are lower in children than in adults, with intracranial hemorrhage rates of 0.1% to 0.5% being seen.⁶⁷ For most patients with no or mild bleeding, management now is observation alone regardless of platelet count because it is felt that the risks of therapies are higher than the risk of bleeding.²¹ For patients with bleeding, IVIG, anti-D, or a short course of steroids can be used. Given the risk of overwhelming sepsis, splenectomy is often deferred as long as possible. Rituximab is increasingly being used in children due to concerns about use of agents such a cyclophosphamide or azathioprine in children.⁶⁸ Abundant data on use of TPO-RAs in children showing high response rates and safety support their use, and these should be considered in refractory ITP before any cytotoxic agent.^69–71

Helicobacter Pylori Infection

There has been much interest in the relationship between H. pylori and ITP.^16,72,73H. pylori infections have been associated with a variety of autoimmune diseases, and there is a confusing literature on this infection and ITP. Several meta-analyses have shown that eradication of H. pylori will result in an ITP response rate of 20% to 30%, but responses curiously appear to be limited to certain geographic areas such as Japan and Italy but not the United States. In patients with recalcitrant ITP, especially in geographic areas with high incidence, it may be worthwhile to check for H. pylori infection and treat accordingly if positive.

Drug-Induced Thrombocytopenia

Patients with drug-induced thrombocytopenia present with very low (< 10 × 10³/µL) platelet counts 1 to 3 weeks after starting a new medication.^74–76 In patients with a possible drug-induced thrombocytopenia, the primary therapy is to stop the suspect drug.⁷⁷ If there are multiple new medications, the best approach is to stop any drug that has been strongly associated with thrombocytopenia (Table 3).^74,78,79

Immune globulin, corticosteroids, or intravenous anti‑D have been suggested as useful in drug‑related thrombocytopenia. However, since most of these thrombocytopenic patients recover when the agent is cleared from the body, this therapy is probably not necessary and withholding treatment avoids exposing the patients to the adverse events associated with further therapy.

Evans Syndrome

Evans syndrome is defined as the combination of autoimmune hemolytic anemia (AIHA) and ITP.^80,81 These cytopenias can present simultaneously or sequentially. Patients with Evans syndrome are thought to have a more severe disease process, to be more prone to bleeding, and to be more difficult to treat, but the rarity of this syndrome makes this hard to quantify.

The classic clinical presentation of Evans syndrome is severe anemia and thrombocytopenia. Children with Evans syndrome often have complex immunodeficiencies such as autoimmune lymphoproliferative syndrome.^82,83 In adults, Evans syndrome most often complicates other autoimmune diseases such as lupus. There are increasing reports of Evans syndrome occurring as a complication of T-cell lymphomas. Often the autoimmune disease can predate the lymphoma diagnosis by months or even years.

In theory the diagnostic approach is straightforward by showing a Coombs-positive hemolytic anemia in the setting of a clinical diagnosis of immune thrombocytopenia. The blood smear will show spherocytes and a diminished platelet count. The presence of other abnormal red cell forms should raise the possibility of an alternative diagnosis. It is unclear how vigorously one should search for other underlying diseases. Many patients will already have the diagnosis of an underlying autoimmune disease. The presence of lymphadenopathy should raise concern for lymphoma.

Initial therapy is high-dose steroids (2 mg/kg/day). IVIG should be added if severe thrombocytopenia is present. Patients who cannot be weaned off prednisone or relapse after prednisone should be considered for splenectomy, although these patients are at higher risk of relapsing.⁸⁰ Increasingly rituximab is being used with success.^84,85 For patients who fail splenectomy and rituximab, aggressive immunosuppression should be considered. Increasing data support the benefits of sirolimus, and this should be considered for refractory patients.⁸⁶ For patients with Evans syndrome due to underlying lymphoma, antineoplastic therapy often results in prompt resolution of the symptoms. Recurrence of the autoimmune cytopenias often heralds relapse.

Introduction

Immune thrombocytopenia (ITP) is a common acquired autoimmune disease characterized by low platelet counts and an increased risk of bleeding. The incidence of ITP is approximately 3.3 per 100,000 adults.¹ There is considerable controversy about all aspects of the disease, with little “hard” data on which to base decisions given the lack of randomized clinical trials to address most clinical questions. This article reviews the presentation and diagnosis of ITP and its treatment options and discusses management of ITP in specific clinical situations.

Pathogenesis and Epidemiology

ITP is caused by autoantibodies binding to platelet surface proteins, most often to the platelet receptor GP IIb/IIIa.^2-4 These antibody-coated platelets then bind to Fc receptors in macrophages and are removed from circulation. The initiating event in ITP is unknown. It is speculated that the patient responds to a viral or bacterial infection by creating antibodies which cross-react with the platelet receptors. Continued exposure to platelets perpetuates the immune response. ITP that occurs in childhood appears to be an acute response to viral infection and usually resolves. ITP in adults may occur in any age group but is seen especially in young women.

Despite the increased platelet destruction that occurs in ITP, the production of new platelets often is not significantly increased. This is most likely due to lack of an increase in thrombopoietin, the predominant platelet growth factor.⁵

It had been thought that most adult patients who present with ITP go on to have a chronic course, but more recent studies have shown this is not the case. In modern series the percentage of patients who are “cured” with steroids ranges from 30% to 70%.^6–9 In addition, it has been appreciated that even in patients with modest thrombocytopenia, no therapy is required if the platelet count remains higher than 30 × 10³/µL. However, this leaves a considerable number of patients who will require chronic therapy.

Clinical Presentation

Presentation can range from a symptomatic patient with low platelets found on a routine blood count to a patient with massive bleeding. Typically, patients first present with petechiae (small bruises 1 mm in size) on the shins. True petechiae are seen only in severe thrombocytopenia. Patients will also report frequent bruising and bleeding from the gums. Patients with very low platelet counts will notice “wet purpura,” which is characterized by blood-filled bullae in the oral cavity. Life-threatening bleeding is a very unusual presenting sign unless other problems (trauma, ulcers) are present. The physical examination is only remarkable for stigmata of bleeding such as the petechiae. The presence of splenomegaly or lymphadenopathy weighs strongly against a diagnosis of ITP. Many patients with ITP will note fatigue when their platelets counts are lower.¹⁰

Diagnosis

Extremely low platelet counts with a normal blood smear and an otherwise healthy patient are diagnostic of ITP. The platelet count cutoff for considering ITP is 100 × 10³/µL as the majority of patients with counts in the 100 to 150 × 10³/µL range will not develop greater thrombocytopenia.¹¹ Also, the platelet count decreases with age (9 × 10³/µL per decade in one study), and this also needs to be factored into the evaluation.¹² The finding of relatives with ITP should raise suspicion for congenital thrombocytopenia.¹³ One should question the patient carefully about drug exposure (see Drug-Induced Thrombocytopenia), especially about over-the-counter medicines, “natural” remedies, or recreational drugs.

There is no laboratory test that rules in ITP; rather, it is a diagnosis of exclusion. The blood smear should be carefully examined for evidence of microangiopathic hemolytic anemias (schistocytes), bone marrow disease (blasts, teardrop cells), or any other evidence of a primary bone marrow disease. In ITP, the platelets can be larger than normal, but finding some platelets the size of red cells should raise the issue of congenital thrombocytopenia.¹⁴ Pseudo-thrombocytopenia, which is the clumping of platelets due to a reaction to the EDTA anticoagulant in the tube, should be excluded. The diagnosis is established by drawing the blood in a citrated (blue-top) tube to perform the platelet count. There is no role for antiplatelet antibody assay because this test lacks sensitivity and specificity. In a patient without a history of autoimmune disease or symptoms, empiric testing for autoimmune disease is not recommended.

Patients who present with ITP should be tested for both HIV and hepatitis C infection.^15,16 These are the most common viral causes of secondary ITP, and both have prognostic and treatment implications. Some authorities also recommend checking thyroid function as hypothyroidism can present or aggravate the thrombocytopenia.

The role of bone marrow examination is controversial.¹⁷ Patients with a classic presentation of ITP (young woman, normal blood smear) do not require a bone marrow exam before therapy is initiated, although patients who do not respond to initial therapy should have a bone marrow aspiration. The rare entity amegakaryocytic thrombocytopenia can present with a clinical picture similar to that of ITP, but amegakaryocytic thrombocytopenia will not respond to steroids. Bone marrow aspiration reveals the absence of megakaryocytes in this entity. It is rare, however, that another hematologic disease is diagnosed in patients with a classic clinical presentation of ITP.

In the future, measurement of thrombopoietin and reticulated platelets may provide clues to the diagnosis.⁴ Patients with ITP paradoxically have normal or only mildly elevated thrombopoietin levels. The finding of a significantly elevated thrombopoietin level should lead to questioning of the diagnosis. One can also measure “reticulated platelets,” which are analogous to red cell reticulocytes. Patients with ITP (or any platelet destructive disorders) will have high levels of reticulated platelets. These tests are not recommended for routine evaluation, but may be helpful in difficult cases.

Treatment

In general, therapy in ITP should be guided by the patient’s signs of bleeding and not by unquestioning adherence to measuring platelet levels,¹⁵ as patients tolerate thrombocytopenia well. It is unusual to have life-threatening bleeding with platelet counts greater than 5 × 10³/µL in the absence of mechanical lesions. Despite the low platelet count in patients with ITP, the overall mortality is estimated to be only 0.3% to 1.3%.¹⁸ It is sobering that in one study the rate of death from infections was twice as high as that from bleeding.¹⁹ Rare patients will have antibodies that interfere with the function of the platelet, and these patients can have profound bleeding with only modestly lowered platelet counts.²⁰ A suggested cut-off for treating newly diagnosed patients is 30 × 10³/µL.²¹

Initial Therapy

The primary therapy of ITP is glucocorticoids, either prednisone or dexamethasone. In the past prednisone at a dose of 60 to 80 mg/day was started at the time of diagnosis (Table 1).

For rapid induction of a response, there are 2 options. A single dose of intravenous immune globulin (IVIG) at 1 g/kg or intravenous anti-D immunoglobulin (anti-D) at 50 to 75 µg/kg can induce a response in more than 80% of patients in 24 to 48 hours.^21,24 IVIG has several drawbacks. It can cause aseptic meningitis, and in patients with vascular disease the increased viscosity can induce ischemia. There is also a considerable fluid load delivered with the IVIG, and it needs to be given over several hours.

The use of anti-D is limited to Rh-positive patients who have not had a splenectomy. It should not be used in patients who are Coombs positive due to the risk of provoking more hemolysis. Rarely anti-D has been reported to cause a severe hemolytic disseminated intravascular coagulation syndrome (1:20,000 patients), which has led to restrictions in its use.²⁵ Although the drug can be rapidly given over 15 minutes, due to these concerns current recommendations are now to observe patients for 8 hours after their dose and to perform a urine dipstick test for blood at 2, 4, and 8 hours. Concerns about this rare but serious side effect have led to a dramatic decrease in the use of anti-D.

For patients who are severely thrombocytopenic and do not respond to initial therapy, there are 2 options for raising the platelet counts. One is to use a combination of IVIG, methylprednisolone, vincristine, and/or anti-D.²⁶ The combination of IVIG and anti-D may be synergistic since these agents block different Fc receptors. A response of 71% has been reported for this 3- or 4-drug combination in a series of 35 patients.²⁶ The other option is to treat with a continuous infusion of platelets (1 unit over 6 hours) and IVIG 1 g/kg for 24 hours. Response rates of 62.7% have been reported with this combination, and this rapid rise in platelets can allow time for other therapies to take effect.^27,28

Patients with severe thrombocytopenia who relapse with reduction of steroids or who do not respond to steroids have several options for further management. Repeated doses of IVIG can transiently raise the platelet count, and some patients may only need several courses of therapy over the course of many months. One study showed that 60% of patients could delay or defer therapy by receiving multiple doses of anti-D. However, 30% of patients did eventually receive splenectomy and 20% of patients required ongoing therapy with anti-D.²⁹ In a randomized trial comparing early use of anti-D to steroids to avoid splenectomy, there was no difference in splenectomy rate (38% versus 42%).³⁰ Finally, an option as mentioned above is to try a 6-month course of pulse dexamethasone 40 mg/day for 4 days, repeated every 28 days.

Options for Refractory ITP

There are multiple options for patients who do not respond to initial ITP therapies. These can be divided into several broad groups: curative therapies (splenectomy and rituximab), thrombopoietin receptor agonists, and anecdotal therapies.

Splenectomy

In patients with severe thrombocytopenia who do not respond or who relapse with lower doses of prednisone, splenectomy should be strongly considered. Splenectomy will induce a good response in 60% to 70% of patients and is durable in most patients. In 2 recently published reviews of splenectomy, the complete response rate was 67% and the total response rate was 88% to 90%%.^8,31 Between 15% and 28% of patients relapsed over 5 years, with most recurrences occurring in the first 2 years. Splenectomy carries a short-term surgical risk, and the life-long risk of increased susceptibility to overwhelming sepsis is discussed below. However, the absolute magnitude of these risks is low and is often lower than the risks of continued prednisone therapy or of continued cytotoxic therapy.

Timing of splenectomy depends on the patient’s presentation. Most patients should be given a 6-month trial of steroids or other therapies before proceeding to splenectomy.³¹ However, patients who persist with severe thrombocytopenia despite initial therapies or who are suffering intolerable side effects from therapy should be considered sooner for splenectomy.³¹ In the George review, multiple factors such as responding to IVIG were found not to be predictive of response to splenectomy.⁸

Method of splenectomy appears not to matter.²¹ Rates of finding accessory spleens are just as high or higher with laparoscopic splenectomy and the patient can recover faster. In patients who are severely thrombocytopenic, open splenectomy can allow for quicker control of the vascular access of the spleen.

Rates of splenectomy in recent years have decreased for many reasons,³² including the acceptance of lower platelet counts in asymptomatic patients and the availability of alternative therapies such as rituximab. In addition, despite abundant data for good outcomes, there is a concern that splenectomy responses are not durable. Although splenectomy will not cure every patient with ITP, splenectomy is the therapy with the most patients, the longest follow-up, and the most consistent rate of cure, and it should be discussed with every ITP patient who does not respond to initial therapy and needs further treatment.

The risk of overwhelming sepsis varies by indications for splenectomy but appears to be about 1%.^33,34 The use of pneumococcal vaccine and recognition of this syndrome have helped reduce the risk. Asplenic patients need to be counseled about the risk of overwhelming infections, should be vaccinated for pneumococcus, meningococcus, and Haemophilus influenzae, and should wear an ID bracelet.^35–37 Patients previously vaccinated for pneumococcus should be re-vaccinated every 3 to 5 years. The role of prophylactic antibiotics in adults is controversial, but patients under the age of 18 should be on penicillin VK 250 mg orally twice daily.

Rituximab

Rituximab has been shown to be very active in ITP. Most studies used the standard dose of 375 mg/m² weekly for 4 weeks, but other studies have shown that 1000 mg twice 14 days apart (ie, on days 1 and 15) resulted in the same response rate and may be more convenient for patients.^38,39 The response time can vary, with patients either showing a rapid response or requiring up to 8 weeks for their counts to go up. Although experience is limited, the response seems to be durable, especially in those patients whose counts rise higher than 150 × 10³/µL; in patients who relapse, a response can be re-induced with a repeat course. Overall the response rate for rituximab is about 60%, but only approximately 20% to 40% of patients will remain in long-term remission.^40–42 There is no evidence yet that “maintenance” therapy or monitoring CD19/CD20 cells can help further the duration of remission.

Whether to give rituximab pre- or post-splenectomy is also uncertain. An advantage of presplenectomy rituximab is that many patients will achieve remission, delaying the need for surgery. Also, rituximab is a good option for patients whose medical conditions put them at high risk for complications with splenectomy. However, it is unknown whether rituximab poses any long-term risks, while the long-term risks of splenectomy are well-defined. Rituximab is the only curative option left for patients who have failed splenectomy and is a reasonable option for these patients.

There is an intriguing trial in which patients were randomly assigned to dexamethasone alone versus dexamethasone plus rituximab upon presentation with ITP; those who were refractory to dexamethasone alone received salvage therapy with dexamethasone plus rituximab.⁴³ The dexamethasone plus rituximab group had an overall higher rate of sustained remission at 6 months than the dexamethasone group, 63% versus 36%. Interestingly, patients who failed their first course of dexamethasone but then were “salvaged” with dexamethasone/rituximab had a similar overall response rate of 56%, suggesting that saving the addition of rituximab for steroid failures may be an effective option.

Although not “chemotherapy,” rituximab is not without risks. Patients can develop infusion reactions, which can be severe in 1% to 2% of patients. In a meta-analysis the fatal reaction rate was 2.9%.⁴⁰ Patients with chronic hepatitis B infections can experience reactivation with rituximab, and thus all patients should be screened before treatment. Finally, the very rare but devastating complication of progressive multifocal leukoencephalopathy has been reported.

Thrombopoietin Receptor Agonists

Although patients with ITP have low platelet counts, studies starting with Dameshek have shown that these patients also have reduced production of platelets.⁴⁴ Despite the very low circulating platelet count, levels of the platelet growth factor thrombopoietin (TPO) are not raised.⁴⁵ Seminal studies with recombinant TPO in the 1990s showed that ITP patients responded to thrombopoietin-stimulating protein, but the formation of anti-TPO antibodies halted trials with the first generation of these agents. Two TPO receptor agonists (TPO-RA) are approved for use in patients with ITP.

Romiplostim. Romiplostim is a peptibody, a combination of a peptide that binds and stimulates the TPO receptor and an Fc domain to extend its half-life.⁴⁶ It is administered in a weekly subcutaneous dose starting at 1 to 3 µg/kg. Use of romiplostim in ITP patients produces a response rate of 80% to 88%, with 87% of patients being able to wean off or decrease other anti-ITP medications.⁴⁷ In a long-term extension study, the response was again high at 87%.⁴⁸ These studies have also shown a reduced incidence of bleeding.

The major side effect of romiplostim seen in clinical trials was marrow reticulin formation, which occurred in up to 5.6% of patients.^47,48 The clinical course in these patients is the development of anemia and a myelophthisic blood smear with teardrop cells and nucleated red cells. These changes appear to reverse with cessation of the drug. The bone marrow shows increased reticulin formation but rarely, if ever, shows the collagen deposition seen with primary myelofibrosis.

Thrombosis has also been seen, with a rate of 0.08 to 0.1 cases per 100 patient-weeks,⁴⁹ but it remains unclear if this is due to the drug, part of the natural history of ITP, or expected complications in older patients undergoing any type of medical therapy. Surprisingly, despite the low platelet counts, patients with ITP in one study had double the risk of venous thrombosis, demonstrating that ITP itself can be a risk factor for thrombosis.⁵⁰ These trials have shown no long-term concerns for other clinical problems such as liver disease.

Eltrombopag. The other available TPO-RA is eltrombopag,⁵¹ an oral agent that stimulates the TPO receptor by binding the transmembrane domain and activating it. The drug is given orally starting at 50 mg/day (25 mg for patients of Asian ancestry or with liver disease) and can be dose escalated to 75 mg/day. The drug needs to be taken on an empty stomach. Eltrombopag has been shown to be effective in chronic ITP, with response rates of 59% to 80% and reduction in use of rescue medications.^47,51,52 As with romiplostim, the incidence of bleeding was also decreased with eltrombopag in these trials.^47,51

Clinical trials demonstrated that eltrombopag shares with romiplostim the risk for marrow fibrosis. A side effect unique to eltrombopag observed in these trials was a 3% to 7% incidence of elevated liver function tests.^21,52 These abnormal findings appeared to resolve in most patients, but liver function tests need to be monitored in patients receiving eltrombopag.

Clinical use. The clearest indication for the use of TPO-RAs is in patients who have failed several therapies and remain symptomatic or are on intolerable doses of other medications such as prednisone. The clear benefits are their relative safety and high rates of success. The main drawback of TPO-RAs is the need for continuing therapy as the platelet count will return to baseline shortly after these agents are stopped. Currently there is no clear indication for one medication over the other. The advantages of romiplostim are great flexibility in dosing (1–10 µg/kg week) and no concerns about drug interaction. The current drawback of romiplostim is the Food and Drug Administration’s requirement for patients to receive the drug from a clinic and not at home. Eltrombopag offers the advantage of oral use, but it has a limited dose range and potential for drug interactions. Both agents have been associated with marrow reticulin formation, although in clinical use this risk appears to be very low.⁵³

Other Options

In the literature there are numerous options for the treatment of ITP.^54,55 Most of these studies are anecdotal, enrolled small number of patients, and sometimes included patients with mild thrombocytopenia, but these therapeutic options can be tried in patients who are refractory to standard therapies and have bleeding. The agents with the greatest amount of supporting data are danazol, vincristine, azathioprine, cyclophosphamide, and fostamatinib.

Danazol 200 mg 4 times daily is thought to downregulate the macrophage Fc receptor. The onset of action may be delayed and a therapeutic trial of up to 4 to 6 months is advised. Danazol is very effective in patients with antiphospholipid antibody syndrome who develop ITP and may be more effective in premenopausal women.⁵⁶ Once a response is seen, danazol should be continued for 6 months and then an attempt to wean the patient off the agent should be made. A partial response can be seen in 70% to 90% of patients, but a complete response is rare.⁵⁴

Vincristine 1.4 mg/m² weekly has a low response rate, but if a response is going to occur, it will occur rapidly within 2 weeks. Thus, a prolonged trial of vincristine is not needed; if no platelet rise is seen in several weeks, the drug should be stopped. Again, partial responses are more common than complete response—50% to 63% versus 0% to 6%.⁵⁴Azathioprine 150 mg orally daily, like danazol, demonstrates a delayed response and requires several months to assess for response. However, 19% to 25% of patients may have a complete response.⁵⁴ It has been reported that the related agent mycophenolate 1000 mg twice daily is also effective in ITP.⁵⁷

Cyclophosphamide 1 g/m² intravenously repeated every 28 days has been reported to have a response rate of up to 40%.⁵⁸ Although considered more aggressive, this is a standard immunosuppressive dose and should be considered in patients with very low platelet counts. Patients who have not responded to single-agent cyclophosphamide may respond to multi-agent chemotherapy with agents such as etoposide and vincristine plus cyclophosphamide.⁵⁹

Fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, is currently under investigation for the treatment of ITP.⁶⁰ This agent prevents phagocytosis of antibody-coated platelets by macrophages. In early studies fostamatinib has been well tolerated at a dose of 150 mg twice daily, with 75% of patients showing a response. Large phase 3 trials are underway, and if the earlier promising results hold up fostamatinib may be a novel option for refractory patients.

A Practical Approach to Refractory ITP

One approach is to divide patients into bleeders, or those with either very low platelet counts (< 5 × 10³/µL) or who have had significant bleeding in the past, and nonbleeders, or those with platelet counts above 5 × 10³/µL and no history of severe bleeding. Bleeders who do not respond adequately to splenectomy should first start with rituximab since it is not cytotoxic and is the only other “curative” therapy (Table 2).

Nonbleeders should be tried on danazol and other relatively safe agents. If this fails, rituximab or TPO-RAs can be considered. Before one considers cytotoxic therapy, the risk of the therapy must be weighed against the risk posed by the thrombocytopenia. The mortality from ITP is fairly low (5%) and is restricted to patients with severe disease. Patients with only moderate thrombocytopenia and no bleeding are better served with conservative management. There is little justification for the use of continuous steroid therapy in this group of patients given the long-term risks of this therapy.

Special Situations

Surgery

Patients with ITP who need surgery either for splenectomy or for other reasons should have their platelet counts raised to a level greater than 20 to 30 × 10³/µL before surgery. Most patients with ITP have increased platelet function and will not have excessive bleeding with these platelet counts. For patients with platelet counts below this level, an infusion of immune globulin or anti-D may rapidly increase the platelet counts. If the surgery is elective, short-term use of TPO-RAs to raise the counts can also be considered.

Pregnancy

Up to 10% of pregnant women will develop low platelet counts during their pregnancy.^61,62 The most common etiology is gestational thrombocytopenia, which is an exaggeration of the lowered platelet count seen in pregnancy. Counts may fall as low as 50 × 10³/µL at the time of delivery. No therapy is required as the fetus is not affected and the mother does not have an increased risk of bleeding. Pregnancy complications such as HELLP syndrome and thrombotic microangiopathies also present with low platelet counts, but these can be diagnosed by history.^61,63

Women with ITP can either develop the disease during pregnancy or have a worsening of the symptoms.⁶⁴ Counts often drop dramatically during the first trimester. Early management should be conservative with low doses of prednisone to keep the count above 10 × 10³/µL.²¹ Immunoglobulin is also effective,⁶⁵ but there are rare reports of pulmonary edema. Rarely patients who are refractory will require splenectomy, which may be safely performed in the second trimester. For delivery the count should be greater than 30 × 10³/µL and for an epidural greater than 50 × 10³/µL.⁶⁴ There are reports of the use of TPO-RAs in pregnancy, and this can be considered for refractory cases.⁶⁶

Most controversy centers on management of the delivery. In the past it was feared that fetal thrombocytopenia could lead to intracranial hemorrhage, and Caesarean section was always recommended. It now appears that most cases of intracranial hemorrhage were due to alloimmune thrombocytopenia and not ITP. Furthermore, the nadir of the baby’s platelet count is not at birth but several days after. It appears the safest course is to proceed with a vaginal or C-section delivery determined by obstetrical indications and then immediately check the baby’s platelet count. If the platelet count is low in the neonate, immunoglobulin will raise the count. Since the neonatal thrombocytopenia is due to passive transfer of maternal antibody, the platelet destruction will abate in 4 to 6 weeks.

Pediatric Patients

The incidence of ITP in children is 2.2 to 5.3 per 100,000 children.¹ There are several distinct differences in pediatric ITP. Most cases will resolve in weeks, with only a minority of patients transforming into chronic ITP (5%–10%). Also, the rates of serious bleeding are lower in children than in adults, with intracranial hemorrhage rates of 0.1% to 0.5% being seen.⁶⁷ For most patients with no or mild bleeding, management now is observation alone regardless of platelet count because it is felt that the risks of therapies are higher than the risk of bleeding.²¹ For patients with bleeding, IVIG, anti-D, or a short course of steroids can be used. Given the risk of overwhelming sepsis, splenectomy is often deferred as long as possible. Rituximab is increasingly being used in children due to concerns about use of agents such a cyclophosphamide or azathioprine in children.⁶⁸ Abundant data on use of TPO-RAs in children showing high response rates and safety support their use, and these should be considered in refractory ITP before any cytotoxic agent.^69–71

Helicobacter Pylori Infection

There has been much interest in the relationship between H. pylori and ITP.^16,72,73H. pylori infections have been associated with a variety of autoimmune diseases, and there is a confusing literature on this infection and ITP. Several meta-analyses have shown that eradication of H. pylori will result in an ITP response rate of 20% to 30%, but responses curiously appear to be limited to certain geographic areas such as Japan and Italy but not the United States. In patients with recalcitrant ITP, especially in geographic areas with high incidence, it may be worthwhile to check for H. pylori infection and treat accordingly if positive.

Drug-Induced Thrombocytopenia

Patients with drug-induced thrombocytopenia present with very low (< 10 × 10³/µL) platelet counts 1 to 3 weeks after starting a new medication.^74–76 In patients with a possible drug-induced thrombocytopenia, the primary therapy is to stop the suspect drug.⁷⁷ If there are multiple new medications, the best approach is to stop any drug that has been strongly associated with thrombocytopenia (Table 3).^74,78,79

Immune globulin, corticosteroids, or intravenous anti‑D have been suggested as useful in drug‑related thrombocytopenia. However, since most of these thrombocytopenic patients recover when the agent is cleared from the body, this therapy is probably not necessary and withholding treatment avoids exposing the patients to the adverse events associated with further therapy.

Evans Syndrome

Evans syndrome is defined as the combination of autoimmune hemolytic anemia (AIHA) and ITP.^80,81 These cytopenias can present simultaneously or sequentially. Patients with Evans syndrome are thought to have a more severe disease process, to be more prone to bleeding, and to be more difficult to treat, but the rarity of this syndrome makes this hard to quantify.

The classic clinical presentation of Evans syndrome is severe anemia and thrombocytopenia. Children with Evans syndrome often have complex immunodeficiencies such as autoimmune lymphoproliferative syndrome.^82,83 In adults, Evans syndrome most often complicates other autoimmune diseases such as lupus. There are increasing reports of Evans syndrome occurring as a complication of T-cell lymphomas. Often the autoimmune disease can predate the lymphoma diagnosis by months or even years.

In theory the diagnostic approach is straightforward by showing a Coombs-positive hemolytic anemia in the setting of a clinical diagnosis of immune thrombocytopenia. The blood smear will show spherocytes and a diminished platelet count. The presence of other abnormal red cell forms should raise the possibility of an alternative diagnosis. It is unclear how vigorously one should search for other underlying diseases. Many patients will already have the diagnosis of an underlying autoimmune disease. The presence of lymphadenopathy should raise concern for lymphoma.

Initial therapy is high-dose steroids (2 mg/kg/day). IVIG should be added if severe thrombocytopenia is present. Patients who cannot be weaned off prednisone or relapse after prednisone should be considered for splenectomy, although these patients are at higher risk of relapsing.⁸⁰ Increasingly rituximab is being used with success.^84,85 For patients who fail splenectomy and rituximab, aggressive immunosuppression should be considered. Increasing data support the benefits of sirolimus, and this should be considered for refractory patients.⁸⁶ For patients with Evans syndrome due to underlying lymphoma, antineoplastic therapy often results in prompt resolution of the symptoms. Recurrence of the autoimmune cytopenias often heralds relapse.

INTRODUCTION

In the normal person, the process of coagulation is finely controlled at many levels to ensure the appropriate amount of hemostasis at the appropriate location. Broadly defined, disseminated intravascular coagulation (DIC) is the name given to any process that disrupts this fine tuning, leading to unregulated coagulation. Defined this way, DIC may be found in a variety of patients with a variety of disease states, and can present with a spectrum of findings ranging from asymptomatic abnormal laboratory results to florid bleeding or thrombosis. It is important to remember that DIC is always a consequence of an underlying pathological process and not a disease in and of itself. This article first reviews concepts common to all forms of DIC, and then reviews the more common disease states that lead to DIC.

PATHOGENESIS

At the most basic level, DIC is the clinical manifestation of inappropriate thrombin activation.^1–5 Inappropriate thrombin activation can be due to underlying conditions such as sepsis and obstetric disasters. The activation of thrombin leads to (1) conversion of fibrinogen to fibrin, (2) activation of platelets (and their consumption), (3) activation of factors V and VIII, (4) activation of protein C (and degradation of factors Va and VIIIa), (5) activation of endothelial cells, and (6) activation of fibrinolysis (Table 1). 

1. Conversion of fibrinogen to fibrin, which leads to the formation of fibrin monomers and excessive thrombus formation. These thrombi are rapidly dissolved by excessive fibrinolysis in most patients. In certain clinical situations, especially cancer, excessive thrombosis will occur. In patients with cancer, this is most often a deep venous thrombosis. Rare patients, especially those with pancreatic cancer, may have severe DIC with multiple arterial and venous thromboses. Nonbacterial thrombotic endocarditis can also be seen in these patients, leading to widespread embolic complications.

2. Activation of platelets and their consumption. Thrombin is the most potent physiologic activator of platelets, so in DIC there is increased activation of platelets. These activated platelets are consumed, resulting in thrombocytopenia. Platelet dysfunction is also present. Platelets that have been activated and have released their contents but still circulate are known as “exhausted” platelets; these cells can no longer function to support coagulation. The fibrin degradation products (FDP) in DIC can also bind to GP IIb/IIIa and inhibit further platelet aggregation.

3. Activation of factors V, VIII, XI, and XIII. Activation of these factors can promote thrombosis, but they are then rapidly cleared by antithrombin (XI) or activated protein C (V and VIII) or by binding to the fibrin clot (XIII). This can lead to depletion of all the prothrombotic clotting factors and antithrombin, which in turn can lead to both thrombosis and bleeding.

4. Activation of protein C further promotes degradation of factors Va and VIIIa, enhances fibrinolysis, and decreases protein C levels.

5. Activation of endothelial cells, especially in the skin, may lead to thrombosis, and in certain patients, especially those with meningococcemia, purpura fulminans. Endothelial damage will down-regulate thrombomodulin, preventing activation of protein C and leading to further reductions in levels of activated protein C.⁵6. Activation of fibrinolysis leads to the breakdown of fibrin monomers, formation of fibrin thrombi, and increased circulating fibrinogen. In most patients with DIC, the fibrinolytic response is brisk.⁶ This is why most patients with DIC present with bleeding and prolonged clotting times.

PATTERNS OF DIC

The clinical manifestations of DIC in a given patient depend on the balance of thrombin activation and secondary fibrinolysis plus the patient’s ability to compensate for the DIC. Patients with DIC can present in 1 of 4 patterns:^1–3

1. Asymptomatic. Patients can present with laboratory evidence of DIC but no bleeding or thrombosis. This is often seen in patients with sepsis or cancer. However, with further progression of the underlying disease, these patients can rapidly become symptomatic.

2. Bleeding. The bleeding is due to a combination of factor depletion, platelet dysfunction, thrombocytopenia, and excessive fibrinolysis.¹ These patients may present with diffuse bleeding from multiple sites (eg, intravenous sites, areas of instrumentation).

3. Thrombosis. Despite the general activation of the coagulation process, thrombosis is unusual in most patients with acute DIC. The exceptions include patients with cancer, trauma patients, and certain obstetrical patients. Most often the thrombosis is venous, but arterial thrombosis and nonbacterial thrombotic endocarditis have been reported.⁷

4. Purpura fulminans. This form of DIC is discussed in more detail later (see Specific DIC Syndromes section).

DIAGNOSIS

There is no one test that will diagnose DIC; one must match the test to the clinical situation (Table 2).⁸ 

SCREENING TESTS

The prothrombin time-INR and activated thromboplastin time (aPPT) are usually elevated in severe DIC but may be normal or shortened in chronic forms.⁹ One may also see a shortened aPTT in severe acute DIC due to large amounts of activated thrombin and factor X “bypassing” the contact pathway. An aPTT as short as 10 seconds has been seen in acute DIC. The platelet count is usually reduced but may be normal in chronic DIC. Serum fibrinogen and platelets are decreased in acute DIC but again may be in the “normal” range in chronic DIC.¹⁰ The most sensitive screening test for DIC is a fall in the platelet count, with low counts seen in 98% of patients and counts under 50,000 cells/μL in 50%.^9,11 The least specific test is fibrinogen, which tends to fall below normal only in severe acute DIC.⁹

SPECIFIC TESTS

This group of tests allows one to deduce that abnormally high concentrations of thrombin are present.

Ethanol Gel and Protamine Tests

Both of these older tests detected circulating fibrin monomers, whose appearance is an early sign of DIC. Circulating fibrin monomers are seen when thrombin acts on fibrinogen. Usually the monomer polymerizes with the fibrin clot, but when there is excess thrombin these monomers can circulate. Detection of circulating fibrin monomer means there is too much IIa and, ergo, DIC is present.

Fibrin(ogen) Degradation Products

Plasmin acts on the fibrin/fibrinogen molecule to cleave the molecule in specific places. The resulting degradation product levels will be elevated in situations of increased fibrin/fibrinogen destruction (DIC and fibrinolysis). The FDP are typically mildly elevated in renal and liver disease due to reduced clearance.

D-Dimers

When fibrin monomers bind to form a thrombus, factor XIII acts to bind their “D” domains together. This bond is resistant to plasmin and thus this degradation fragment is known as the “D-dimer.” High levels of D-dimer indicate that (1) IIa has acted on fibrinogen to form a fibrin monomer that bonded to another fibrin monomer, and (2) this thrombus was lysed by plasmin. Because D-dimers can be elevated (eg, with exercise, after surgery), an elevated D-dimer needs to be interpreted in the context of the clinical situation.¹¹ Currently, this is the most common specific test for DIC performed.

Other Tests

Several other tests are sometimes helpful in diagnosing DIC.

Thrombin time. This test is performed by adding thrombin to plasma. Thrombin times are elevated in DIC (FDPs interfere with polymerization), in the presence of low fibrinogen levels, in dysfibrinogenemia, and in the presence of heparin (very sensitive).

Reptilase time is the same as thrombin time but is performed with a snake venom that is insensitive to heparin. Reptilase time is elevated in the same conditions as the thrombin time, with the exception of the presence of heparin. Thrombin time and reptilase time are most useful in evaluation of dysfibrinogenemia.

Prothrombin fragment 1.2 (F_1.2). F_1.2 is a small peptide cleaved off when prothrombin is activated to thrombin. Thus, high levels of F_1.2 are found in DIC but can be seen in other thrombotic disorders. This test is still of limited clinical value.

DIC scoring system. A scoring system to both diagnose and quantify DIC has been proposed (Figure).^11,12 

MIMICKERS OF DIC

It is important to recognize coagulation syndromes that are not DIC, especially those that have specific other therapies. The syndromes most frequently encountered are thrombotic thrombocytopenic purpura (TTP) and catastrophic antiphospholipid antibody syndrome (CAPS). One important clue to both of these syndromes is that, unlike DIC, there is no primary disorder (cancer, sepsis) that is driving the coagulation abnormalities.

TTP should be suspected when any patient presents with any combination of thrombo­cytopenia, microangiopathic hemolytic anemia (schistocytes and signs of hemolysis) plus end-organ damage.^15–18 Patients with TTP most often present with intractable seizures, strokes, or sequelae of renal insufficiency. Many patients who present with TTP have been misdiagnosed as having sepsis, “lupus flare,” or vasculitis. The key diagnostic differentiator between TTP and DIC is the lack of activation of coagulation with TTP—fibrinogen is normal and D-dimers are minimally or not elevated. In TTP, lactate dehydrogenase is invariably elevated, often 2 to 3 times normal.¹⁹ The importance of identifying TTP is that untreated TTP is rapidly fatal. Mortality in the pre–plasma exchange era ranged from 95% to 100%. Today plasma exchange therapy is the foundation of TTP treatment and has reduced mortality to less than 20%.^16,20–23Rarely patients with antiphospholipid antibody syndrome can present with fulminant multiorgan system failure.^24–28 CAPS is caused by widespread microthrombi in multiple vascular fields. These patients will develop renal failure, encephalopathy, adult respiratory distress syndrome (often with pulmonary hemorrhage), cardiac failure, dramatic livedo reticularis, and worsening thrombocytopenia. Many of these patients have pre-existing autoimmune disorders and high-titer anticardiolipin antibodies. It appears that the best therapy for these patients is aggressive immunosuppression with steroids plus plasmapheresis, followed by rituximab or, if in the setting of lupus, intravenous cyclophosphamide monthly.^27,29 Early recognition of CAPS can lead to quick therapy and resolution of the multiorgan system failure.

GENERAL THERAPY

The best way to treat DIC is to treat the underlying cause that is driving the thrombin generation.^1,2,4,30,31 Fully addressing the underlying cause may not be possible or may take time, and in the meantime it is necessary to disrupt the cycle of thrombosis and/or hemorrhage. In the past, there was concern about using factor replacement due to fears of “feeding the fire,” or perpetuating the cycle of thrombosis. However, these concerns are not supported by evidence, and factors must be replaced if depletion occurs and bleeding ensues.³²

Transfusion therapy of the patient with DIC is guided by the 5 laboratory tests that reflect the basic parameters essential for both hemostasis and blood volume status:^33,34 hematocrit, platelet count, prothrombin time-INR, aPTT, and fibrinogen level. Decisions regarding replacement therapy are based on the results of these laboratory tests and the clinical situation of the patient (Table 3). 

SPECIFIC DIC SYNDROMES

SEPSIS/INFECTIOUS DISEASE

Any overwhelming infection can lead to DIC.⁴⁵ Classically, it was believed that gram-negative bacteria can lead tissue factor exposure via production of endotoxin, but recent studies indicate that DIC can be seen with any overwhelming infection.^46,47 There are several potential avenues by which infections can lead to DIC. As mentioned, gram-negative bacteria produce endotoxin that can directly lead to tissue factor exposure, resulting in excess thrombin generation. In addition, any infection can lead to expression of inflammatory cytokines that induce tissue-factor expression by endothelium and monocytes. Some viruses and Rickettsia species can directly infect the vascular endothelium, converting it from an antithrombotic to a prothrombotic phenotype.⁴⁸ When fighting infections, neutrophils can extrude their contents, including DNA, to help trap organisms. These neutrophil extracellular traps (NETS) may play an important role in promoting coagulopathy.^49,50 The hypotension produced by sepsis leads to tissue hypoxia, which results in more DIC. The coagulopathy in sepsis can range from subtle abnormalities of testing to purpura fulminans. Thrombocytopenia is worsened by cytokine-induced hemophagocytic syndrome.

As with all forms of DIC, empiric therapy targeting the most likely source of infection and maintaining hemodynamic stability is the key to therapy. As discussed below, heparin and other forms of coagulation replacement appear to be of no benefit in therapy.

PURPURA FULMINANS

DIC in association with necrosis of the skin is seen in primary and secondary purpura fulminans.^51,52 Primary purpura fulminans is most often seen after a viral infection.⁵³ In these patients, the purpura fulminans starts with a painful red area on an extremity that rapidly progresses to a black ischemic area. In many patients, acquired deficiency of protein S is found.^51,54,55 Secondary purpura fulminans is most often associated with meningococcemia infections but can be seen in any patient with overwhelming infection.^56–58 Post-splenectomy sepsis syndrome patients and those with functional hyposplenism due to chronic liver diseases are also at risk.⁵⁹ Patients present with signs of sepsis, and the skin lesions often involve the extremities and may lead to amputations. As opposed to primary purpura fulminans, those with the secondary form will have symmetrical ischemia distally (toes and fingers) that ascends as the process progresses. Rarely, adrenal infarction (Waterhouse-Friderichsen syndrome) occurs, which leads to severe hypotension.⁴⁵

Recently, Warkenten has reported on limb gangrene in critically ill patients complicating sepsis or cardiogenic shock.^60,61 These patients have DIC that is complicated by shock liver. Deep venous thrombosis with ischemic gangrene then develops, which can result in tissue loss and even amputation. The pathogenesis is hypothesized to be hepatic dysfunction leading to sudden drops in protein C and S plasma levels, which then leads to thrombophilia with widespread microvascular thrombosis. Therapy for purpura fulminans is controversial. Primary purpura fulminans, especially in those with postvaricella autoimmune protein S deficiency, has responded to plasma infusion titrated to keep the protein S level above 25%.⁵¹ Intravenous immunoglobulin has also been reported to help decrease the anti-protein S antibodies. Heparin has been reported to control the DIC and extent of necrosis.⁶² The starting dose in these patients is 5 to 8 units/kg/hr.²

Sick patients with secondary purpura fulminans have been treated with plasma drips, plasmapheresis, and continuous plasma ultrafiltration.^62–66 Heparin therapy alone has not been shown to improve survival.⁶⁶ Much attention has been given to replacement of natural anticoagulants such as protein C and antithrombin as therapy for purpura fulminans, but unfortunately randomized trials using antithrombin have shown mostly negative results.^{51,55,67–69} Trials using protein C concentrates have shown more promise in controlling the coagulopathy of purpura fulminans, but this is not widely available.^63,70–72 Unfortunately, many patients will need debridement and amputation for their necrotic limbs, with one review showing approximately 66% of patients needing amputations.⁵²

TRAUMA

Currently, the most common cause of acute DIC is trauma. The coagulation defects that occur in trauma patients are complex in origin and still controversial (including if even calling it DIC is appropriate!).^73–76 The most common etiologies are

• Generation of excess activated protein C leading to increased consumption of factor V and VIII and increased fibrinolysis;
• Tissue damage leading to generation of excess thrombin generation;
• Dilution of hemostatic factors by blood or fluid resuscitation; and
• Activation of endothelial cells leading to generation of a prothrombotic surface and shedding of glycocalyx with antithrombotic properties.

Trauma patients are prone to hypothermia, and this can be the major complicating factor in their bleeding.^77,78 Patients may be out “in the field” for a prolonged period of time and be hypothermic on arrival.⁷⁹ Packed red cells are stored at 4°C, and the infusion of 1 unit can lower the body temperature by 0.16°C.⁸⁰ Hypothermia has profound effects on the coagulation system that are associated with clinical bleeding.^77,81,82 Even modest hypothermia can greatly augment bleeding and needs to be treated or prevented.

The initial management of the bleeding trauma patient is administration of red cells and plasma (FFP) in a 1:1 ratio. This has been shown by clinical studies to lessen the risk of exsanguination in the first 24 hours and to be associated with improved clinical outcomes.^83,84 The basic set of coagulation tests should also be obtained to guide product replacement, especially as the bleeding is brought under control. Hypothermia can be prevented by several measures, including transfusing the blood through blood warmers. Devices are available that can warm 1 unit of blood per minute. An increasingly used technique is to perform “damage control” surgery. Patients are initially stabilized with control of damaged vessels and packing of oozing sites.⁸⁵ Then the patient is taken to the intensive care unit to be warmed and have coagulation defects corrected.

For trauma patients at risk of serious bleeding, the use of tranexamic acid reduced all- cause mortality (relative risk 0.91), with death due to bleeding also being reduced (relative risk 0.85).⁸⁶ There was no increase in thrombosis, but benefit was restricted to patients treated within 3 hours of the trauma. The dose of tranexamic acid was a 1-g bolus followed by a 1-g continuous infusion over 8 hours.

PREGNANCY-RELATED DIC SYNDROMES

Acute DIC of Pregnancy

Pregnancy can be associated with the rapid onset of severe DIC in 2 situations, abruption and amniotic fluid embolism.^87,88 The separation of the placenta from the uterine wall creates a space for blood to occupy. Given the richness of the placenta in tissue factor, this leads to activation of coagulation both locally and systemically. Release of blood when this space reaches the vaginal opening can lead to rapid hemorrhage, further augmenting the coagulation abnormalities. Placental insufficiency can lead to fetal demise, which can also worsen the DIC. Management depends on the size of the abruption and the clinical status of both mother and fetus.⁸⁷ For severe bleeding and DIC, blood product support is crucial to allow safe delivery. In pregnancy, the fibrinogen goal needs to be higher—200 mg/dL.⁸⁹ For smaller abruption, close observation with early delivery is indicated.

Amniotic fluid embolism is sudden, with the vascular collapse of the woman soon after delivery. Due to the presence of procoagulant rich fluid in the circulatory system, there is often overwhelming DIC. Therapy is directed at both supporting blood volume and correcting hemostatic defects.

HELLP

The acronym HELLP (hemolysis, elevated liver tests, low platelets) describes a variant of preeclampsia.⁹⁰ Classically, HELLP syndrome occurs after 28 weeks of gestation in a patient with preeclampsia, but can occur as early as 22 weeks in patients with antiphospholipid antibody syndrome.^91–93 The preeclampsia need not be severe. The first sign of HELLP is a decrease in the platelet count followed by abnormal liver function tests. Signs of hemolysis are present with abundant schistocytes on the smear and a high lactate dehydrogenase level. HELLP can progress to liver failure, and deaths are also reported due to hepatic rupture. Unlike TTP, fetal involvement is present in the HELLP syndrome, with fetal thrombocytopenia reported in 30% of cases. In severe cases, elevated D-dimers consistent with DIC are also found. Delivery of the child will most often result in cessation of the HELLP syndrome, but refractory cases will require dexamethasone and plasma exchange.⁹⁴ Patients should be closely observed for 1 to 2 days after delivery as the hematologic picture can transiently worsen before improving.⁹⁵

Acute Fatty Liver of Pregnancy

Fatty liver of pregnancy also occurs late in pregnancy and is only associated with preeclampsia in 50% of cases.^96,97 Patients first present with nonspecific symptoms of nausea and vomiting but can progress to fulminant liver failure. Patients develop thrombocytopenia early in the course, but in the later stages can develop DIC and very low fibrinogen levels. Mortality rates without therapy can be as high as 90%. Low blood glucose and high ammonia levels can help distinguish fatty liver from other pregnancy complications.⁹⁸ Treatment consists of prompt delivery of the child and aggressive blood product support.

Retained Dead Fetus Syndrome

Becoming rarer in modern practices, the presence of a dead fetus for many weeks (usually ≥ 5) can result in a chronic DIC state with fibrinogen depletion and coagulopathy. In some women, this is worsened at delivery. In a stable patient, a short trial of heparin prior to planning delivery can control the DIC to allow the coagulopathy to stabilize.

DRUG-INDUCED HEMOLYTIC-DIC SYNDROMES

A severe variant of the drug-induced immune complex hemolysis associated with DIC has been recognized. Rare patients who receive certain second- and third-generation cephalosporins (especially cefotetan and ceftriaxone) have developed this syndrome.^99–104 The clinical syndrome starts 7 to 10 days after the drug is administered. Often the patient has only received the antibiotic for surgical prophylaxis. The patient will develop severe Coombs’-positive hemolysis with hypotension and DIC. The patients are often believed to have sepsis and in the management of the supposed sepsis often are re-exposed to the cephalosporin, resulting in worsening of the clinical picture. The outcome is often fatal due to massive hemolysis and thrombosis.^{101,105–107}

Quinine is associated with a unique syndrome of drug-induced DIC.^108–111 Approximately 24 to 96 hours after quinine exposure, the patient becomes acutely ill with nausea and vomiting. The patient then develops a microangiopathic hemolytic anemia, DIC, and renal failure. Some patients, besides having antiplatelet antibodies, also have antibodies binding to red cells and neutrophils, which may lead to the more severe syndrome. Despite therapy, patients with quinine-induced TTP have a high incidence of chronic renal failure.

Treatment of the drug-induced hemolytic-DIC syndrome is anecdotal. Patients have responded to aggressive therapy, including plasma exchange, dialysis, and prednisone. Early recognition of the hemolytic anemia and the suspicion it is drug related is important for early diagnosis so that the incriminated drug can be discontinued.

CANCER

Cancers, primarily adenocarcinomas, can result in DIC. The classic Trousseau syndrome referred to the association of migratory superficial thrombophlebitis with cancer¹¹² but now refers to cancer associated with thrombotic DIC.^113,114 Highly vascular tumor cells are known to express tissue factor.^114,115 In addition, some tumor cells can express a direct activator of factor X (“cancer procoagulant”). Unlike many DIC states, cancer presents with thrombosis instead of bleeding. This may be due to the inflammatory state which accompanies cancer, or it may be a unique part of the chronic nature of cancer DIC biology that allows time for the body to compensate for loss of coagulation factors. In some patients, thrombosis is the first sign of an underlying cancer, sometimes predating the cancer diagnosis by months.¹¹⁵ Rarely, the DIC can result in nonthrombotic endocarditis with micro-emboli leading to widespread small-vessel thrombosis.¹¹³

Since effective antineoplastic therapy is lacking for many tumors associated with Trousseau syndrome, DIC therapy is aimed at suppressing thrombosis. An exception is prostate cancer, where hormonal therapy can markedly decrease the DIC.¹¹⁶ Due to the tumor directly activating coagulation factors, inhibition of active enzymes via heparin has been shown to reduce rates of recurrence compared with warfarin.^114,115 Clinical trials have demonstrated that heparin therapy is associated with a lower thrombosis recurrence rate than warfarin.^117,118 In some patients, the thrombotic process is so vigorous that new thrombosis can be seen within hours of stopping heparin.¹¹²

ACUTE PROMYELOCYTIC LEUKEMIA

There are multiple hemostatic defects in patients with acute promyelocytic leukemia (APL).¹¹⁹ Most, if not all, patients with APL have evidence of DIC at the time of diagnosis. Patients with APL have a higher risk of death during induction therapy as compared with patients with other forms of leukemia, with death most often due to bleeding. Once in remission, APL patients have a higher cure rate than most patients with leukemia. APL is also unique among leukemias in that biologic therapy with retinoic acid or arsenic is effective in inducing remission and cure in most patients. Although effective therapy is available, early death rates due to bleeding have not changed.¹¹⁹

APL patients can present with pancytopenia due to leukemic marrow replacement or with diffuse bleeding due to DIC and thrombocytopenia. Life-threatening bleeding such as intracranial hemorrhage may occur at any time until the leukemia is put into remission. The etiology of the hemostatic defects in APL is complex and is thought to be the result of DIC, fibrinolysis, and the release of prothrombotic extracellular chromatin and other procoagulant enzymes.^119,120 The diagnosis of APL can be straightforward when the leukemic cells are promyelocytes with abundant Auer rods, although some patients have the microgranular form without obvious Auer rods. The precise diagnosis requires molecular methods, including obtaining FISH for detecting the t(15;17) in PML/RARA fusion. Upon diagnosis of APL, one should obtain a complete coagulation profile, including INR, aPTT, fibrinogen, platelet count, and D-dimers. Change in fibrinogen levels tends to be a good marker of progress in treating the coagulation defects.

Therapy of APL involves treating both the leukemia and the coagulopathy. Currently, the standard treatment for APL is trans-retinoic acid (ATRA) in combination with chemotherapy or arsenic.^121,122 This approach will induce remission in more than 90% of patients, and a sizable majority of these patients will be cured of their APL. ATRA therapy will also lead to early correction of the coagulation defects, often within the first week of therapy.¹²³ This is in stark contrast to the chemotherapy era when the coagulation defects would become worse with therapy. Given the marked beneficial effect of ATRA on the coagulopathy of APL and its low toxicity profile, it should be empirically started for any patients suspected of having APL while genetic testing is being performed. Rare reports of massive thrombosis complicating therapy with ATRA exist, but the relationship to either the APL or ATRA is unknown.

Therapy for the coagulation defects consists of aggressive transfusion therapy support and possible use of other pharmacologic agents to control DIC.^124,125 The fibrinogen level should be maintained at over 150 mg/dL and the platelet count at over 50,000 cells/µL.¹²⁶ Controversy still exists over the role of heparin in therapy of APL.¹⁰⁴ Although attractive for its ability to quench thrombin, heparin use can lead to profound bleeding and its use in treating APL has fallen out of favor.

SNAKEBITES

Snake envenomation can lead to direct activation of multiple coagulation enzymes, including factors V, X, thrombin, and protein C, and lead to cleavage of fibrinogen.^127,128 Envenomation can also activate coagulation and damage vascular endothelium. The DIC can be enhanced by widespread tissue necrosis and hypotension. The key to management of snake bites is administration of specific antivenom. The role of prophylactic factor replacement is controversial, but this therapy is indicated if there is clinical bleeding.¹²⁹ One confounder is that some snake venoms, especially rattlesnake, can induce reversible platelet aggregation, which corrects with antivenom.

LOCAL VASCULAR ABNORMALITIES

Abnormal vascular structures, such as vascular tumors, vascular malformations, and aneurysms, can lead to localized areas of thrombin generation that can “spill-over” into the general circulation, leading to DIC. The diagnosis Kasabach-Merritt phenomenon should be reserved for children with vascular tumors such as angioma or hemangioendothelioma.¹³⁰ Therapy depends on the lesion. Embolization to reduce blood flow of vascular malformations can either be definitive therapy or stabilize the patient for surgery. Aneurysms can be repaired by surgery or stenting. Rare patients with aneurysms with significant coagulopathy may require heparin to raise the fibrinogen level before surgery. Kasabach-Merritt disease can respond to steroids or therapy such as vincristine or interferon.¹³⁰ Increasing data shows that use of the mTOR inhibitor sirolimus can shrink these vascular abnormalities leading to lessening of the coagulopathy.¹³¹

CONCLUSION

At the most basic level, DIC is the excess activity of thrombin. However, the clinical presentation and therapy can differ greatly depending on the primary cause. Both diagnosis and therapy involve close coordination of laboratory data and clinical assessment.

INTRODUCTION

In the normal person, the process of coagulation is finely controlled at many levels to ensure the appropriate amount of hemostasis at the appropriate location. Broadly defined, disseminated intravascular coagulation (DIC) is the name given to any process that disrupts this fine tuning, leading to unregulated coagulation. Defined this way, DIC may be found in a variety of patients with a variety of disease states, and can present with a spectrum of findings ranging from asymptomatic abnormal laboratory results to florid bleeding or thrombosis. It is important to remember that DIC is always a consequence of an underlying pathological process and not a disease in and of itself. This article first reviews concepts common to all forms of DIC, and then reviews the more common disease states that lead to DIC.

PATHOGENESIS

At the most basic level, DIC is the clinical manifestation of inappropriate thrombin activation.^1–5 Inappropriate thrombin activation can be due to underlying conditions such as sepsis and obstetric disasters. The activation of thrombin leads to (1) conversion of fibrinogen to fibrin, (2) activation of platelets (and their consumption), (3) activation of factors V and VIII, (4) activation of protein C (and degradation of factors Va and VIIIa), (5) activation of endothelial cells, and (6) activation of fibrinolysis (Table 1). 

1. Conversion of fibrinogen to fibrin, which leads to the formation of fibrin monomers and excessive thrombus formation. These thrombi are rapidly dissolved by excessive fibrinolysis in most patients. In certain clinical situations, especially cancer, excessive thrombosis will occur. In patients with cancer, this is most often a deep venous thrombosis. Rare patients, especially those with pancreatic cancer, may have severe DIC with multiple arterial and venous thromboses. Nonbacterial thrombotic endocarditis can also be seen in these patients, leading to widespread embolic complications.

2. Activation of platelets and their consumption. Thrombin is the most potent physiologic activator of platelets, so in DIC there is increased activation of platelets. These activated platelets are consumed, resulting in thrombocytopenia. Platelet dysfunction is also present. Platelets that have been activated and have released their contents but still circulate are known as “exhausted” platelets; these cells can no longer function to support coagulation. The fibrin degradation products (FDP) in DIC can also bind to GP IIb/IIIa and inhibit further platelet aggregation.

3. Activation of factors V, VIII, XI, and XIII. Activation of these factors can promote thrombosis, but they are then rapidly cleared by antithrombin (XI) or activated protein C (V and VIII) or by binding to the fibrin clot (XIII). This can lead to depletion of all the prothrombotic clotting factors and antithrombin, which in turn can lead to both thrombosis and bleeding.

4. Activation of protein C further promotes degradation of factors Va and VIIIa, enhances fibrinolysis, and decreases protein C levels.

5. Activation of endothelial cells, especially in the skin, may lead to thrombosis, and in certain patients, especially those with meningococcemia, purpura fulminans. Endothelial damage will down-regulate thrombomodulin, preventing activation of protein C and leading to further reductions in levels of activated protein C.⁵6. Activation of fibrinolysis leads to the breakdown of fibrin monomers, formation of fibrin thrombi, and increased circulating fibrinogen. In most patients with DIC, the fibrinolytic response is brisk.⁶ This is why most patients with DIC present with bleeding and prolonged clotting times.

PATTERNS OF DIC

The clinical manifestations of DIC in a given patient depend on the balance of thrombin activation and secondary fibrinolysis plus the patient’s ability to compensate for the DIC. Patients with DIC can present in 1 of 4 patterns:^1–3

1. Asymptomatic. Patients can present with laboratory evidence of DIC but no bleeding or thrombosis. This is often seen in patients with sepsis or cancer. However, with further progression of the underlying disease, these patients can rapidly become symptomatic.

2. Bleeding. The bleeding is due to a combination of factor depletion, platelet dysfunction, thrombocytopenia, and excessive fibrinolysis.¹ These patients may present with diffuse bleeding from multiple sites (eg, intravenous sites, areas of instrumentation).

3. Thrombosis. Despite the general activation of the coagulation process, thrombosis is unusual in most patients with acute DIC. The exceptions include patients with cancer, trauma patients, and certain obstetrical patients. Most often the thrombosis is venous, but arterial thrombosis and nonbacterial thrombotic endocarditis have been reported.⁷

4. Purpura fulminans. This form of DIC is discussed in more detail later (see Specific DIC Syndromes section).

DIAGNOSIS

There is no one test that will diagnose DIC; one must match the test to the clinical situation (Table 2).⁸ 

SCREENING TESTS

The prothrombin time-INR and activated thromboplastin time (aPPT) are usually elevated in severe DIC but may be normal or shortened in chronic forms.⁹ One may also see a shortened aPTT in severe acute DIC due to large amounts of activated thrombin and factor X “bypassing” the contact pathway. An aPTT as short as 10 seconds has been seen in acute DIC. The platelet count is usually reduced but may be normal in chronic DIC. Serum fibrinogen and platelets are decreased in acute DIC but again may be in the “normal” range in chronic DIC.¹⁰ The most sensitive screening test for DIC is a fall in the platelet count, with low counts seen in 98% of patients and counts under 50,000 cells/μL in 50%.^9,11 The least specific test is fibrinogen, which tends to fall below normal only in severe acute DIC.⁹

SPECIFIC TESTS

This group of tests allows one to deduce that abnormally high concentrations of thrombin are present.

Ethanol Gel and Protamine Tests

Both of these older tests detected circulating fibrin monomers, whose appearance is an early sign of DIC. Circulating fibrin monomers are seen when thrombin acts on fibrinogen. Usually the monomer polymerizes with the fibrin clot, but when there is excess thrombin these monomers can circulate. Detection of circulating fibrin monomer means there is too much IIa and, ergo, DIC is present.

Fibrin(ogen) Degradation Products

Plasmin acts on the fibrin/fibrinogen molecule to cleave the molecule in specific places. The resulting degradation product levels will be elevated in situations of increased fibrin/fibrinogen destruction (DIC and fibrinolysis). The FDP are typically mildly elevated in renal and liver disease due to reduced clearance.

D-Dimers

When fibrin monomers bind to form a thrombus, factor XIII acts to bind their “D” domains together. This bond is resistant to plasmin and thus this degradation fragment is known as the “D-dimer.” High levels of D-dimer indicate that (1) IIa has acted on fibrinogen to form a fibrin monomer that bonded to another fibrin monomer, and (2) this thrombus was lysed by plasmin. Because D-dimers can be elevated (eg, with exercise, after surgery), an elevated D-dimer needs to be interpreted in the context of the clinical situation.¹¹ Currently, this is the most common specific test for DIC performed.

Other Tests

Several other tests are sometimes helpful in diagnosing DIC.

Thrombin time. This test is performed by adding thrombin to plasma. Thrombin times are elevated in DIC (FDPs interfere with polymerization), in the presence of low fibrinogen levels, in dysfibrinogenemia, and in the presence of heparin (very sensitive).

Reptilase time is the same as thrombin time but is performed with a snake venom that is insensitive to heparin. Reptilase time is elevated in the same conditions as the thrombin time, with the exception of the presence of heparin. Thrombin time and reptilase time are most useful in evaluation of dysfibrinogenemia.

Prothrombin fragment 1.2 (F_1.2). F_1.2 is a small peptide cleaved off when prothrombin is activated to thrombin. Thus, high levels of F_1.2 are found in DIC but can be seen in other thrombotic disorders. This test is still of limited clinical value.

DIC scoring system. A scoring system to both diagnose and quantify DIC has been proposed (Figure).^11,12 

MIMICKERS OF DIC

It is important to recognize coagulation syndromes that are not DIC, especially those that have specific other therapies. The syndromes most frequently encountered are thrombotic thrombocytopenic purpura (TTP) and catastrophic antiphospholipid antibody syndrome (CAPS). One important clue to both of these syndromes is that, unlike DIC, there is no primary disorder (cancer, sepsis) that is driving the coagulation abnormalities.

TTP should be suspected when any patient presents with any combination of thrombo­cytopenia, microangiopathic hemolytic anemia (schistocytes and signs of hemolysis) plus end-organ damage.^15–18 Patients with TTP most often present with intractable seizures, strokes, or sequelae of renal insufficiency. Many patients who present with TTP have been misdiagnosed as having sepsis, “lupus flare,” or vasculitis. The key diagnostic differentiator between TTP and DIC is the lack of activation of coagulation with TTP—fibrinogen is normal and D-dimers are minimally or not elevated. In TTP, lactate dehydrogenase is invariably elevated, often 2 to 3 times normal.¹⁹ The importance of identifying TTP is that untreated TTP is rapidly fatal. Mortality in the pre–plasma exchange era ranged from 95% to 100%. Today plasma exchange therapy is the foundation of TTP treatment and has reduced mortality to less than 20%.^16,20–23Rarely patients with antiphospholipid antibody syndrome can present with fulminant multiorgan system failure.^24–28 CAPS is caused by widespread microthrombi in multiple vascular fields. These patients will develop renal failure, encephalopathy, adult respiratory distress syndrome (often with pulmonary hemorrhage), cardiac failure, dramatic livedo reticularis, and worsening thrombocytopenia. Many of these patients have pre-existing autoimmune disorders and high-titer anticardiolipin antibodies. It appears that the best therapy for these patients is aggressive immunosuppression with steroids plus plasmapheresis, followed by rituximab or, if in the setting of lupus, intravenous cyclophosphamide monthly.^27,29 Early recognition of CAPS can lead to quick therapy and resolution of the multiorgan system failure.

GENERAL THERAPY

The best way to treat DIC is to treat the underlying cause that is driving the thrombin generation.^1,2,4,30,31 Fully addressing the underlying cause may not be possible or may take time, and in the meantime it is necessary to disrupt the cycle of thrombosis and/or hemorrhage. In the past, there was concern about using factor replacement due to fears of “feeding the fire,” or perpetuating the cycle of thrombosis. However, these concerns are not supported by evidence, and factors must be replaced if depletion occurs and bleeding ensues.³²

Transfusion therapy of the patient with DIC is guided by the 5 laboratory tests that reflect the basic parameters essential for both hemostasis and blood volume status:^33,34 hematocrit, platelet count, prothrombin time-INR, aPTT, and fibrinogen level. Decisions regarding replacement therapy are based on the results of these laboratory tests and the clinical situation of the patient (Table 3). 

SPECIFIC DIC SYNDROMES

SEPSIS/INFECTIOUS DISEASE

Any overwhelming infection can lead to DIC.⁴⁵ Classically, it was believed that gram-negative bacteria can lead tissue factor exposure via production of endotoxin, but recent studies indicate that DIC can be seen with any overwhelming infection.^46,47 There are several potential avenues by which infections can lead to DIC. As mentioned, gram-negative bacteria produce endotoxin that can directly lead to tissue factor exposure, resulting in excess thrombin generation. In addition, any infection can lead to expression of inflammatory cytokines that induce tissue-factor expression by endothelium and monocytes. Some viruses and Rickettsia species can directly infect the vascular endothelium, converting it from an antithrombotic to a prothrombotic phenotype.⁴⁸ When fighting infections, neutrophils can extrude their contents, including DNA, to help trap organisms. These neutrophil extracellular traps (NETS) may play an important role in promoting coagulopathy.^49,50 The hypotension produced by sepsis leads to tissue hypoxia, which results in more DIC. The coagulopathy in sepsis can range from subtle abnormalities of testing to purpura fulminans. Thrombocytopenia is worsened by cytokine-induced hemophagocytic syndrome.

As with all forms of DIC, empiric therapy targeting the most likely source of infection and maintaining hemodynamic stability is the key to therapy. As discussed below, heparin and other forms of coagulation replacement appear to be of no benefit in therapy.

PURPURA FULMINANS

DIC in association with necrosis of the skin is seen in primary and secondary purpura fulminans.^51,52 Primary purpura fulminans is most often seen after a viral infection.⁵³ In these patients, the purpura fulminans starts with a painful red area on an extremity that rapidly progresses to a black ischemic area. In many patients, acquired deficiency of protein S is found.^51,54,55 Secondary purpura fulminans is most often associated with meningococcemia infections but can be seen in any patient with overwhelming infection.^56–58 Post-splenectomy sepsis syndrome patients and those with functional hyposplenism due to chronic liver diseases are also at risk.⁵⁹ Patients present with signs of sepsis, and the skin lesions often involve the extremities and may lead to amputations. As opposed to primary purpura fulminans, those with the secondary form will have symmetrical ischemia distally (toes and fingers) that ascends as the process progresses. Rarely, adrenal infarction (Waterhouse-Friderichsen syndrome) occurs, which leads to severe hypotension.⁴⁵

Recently, Warkenten has reported on limb gangrene in critically ill patients complicating sepsis or cardiogenic shock.^60,61 These patients have DIC that is complicated by shock liver. Deep venous thrombosis with ischemic gangrene then develops, which can result in tissue loss and even amputation. The pathogenesis is hypothesized to be hepatic dysfunction leading to sudden drops in protein C and S plasma levels, which then leads to thrombophilia with widespread microvascular thrombosis. Therapy for purpura fulminans is controversial. Primary purpura fulminans, especially in those with postvaricella autoimmune protein S deficiency, has responded to plasma infusion titrated to keep the protein S level above 25%.⁵¹ Intravenous immunoglobulin has also been reported to help decrease the anti-protein S antibodies. Heparin has been reported to control the DIC and extent of necrosis.⁶² The starting dose in these patients is 5 to 8 units/kg/hr.²

Sick patients with secondary purpura fulminans have been treated with plasma drips, plasmapheresis, and continuous plasma ultrafiltration.^62–66 Heparin therapy alone has not been shown to improve survival.⁶⁶ Much attention has been given to replacement of natural anticoagulants such as protein C and antithrombin as therapy for purpura fulminans, but unfortunately randomized trials using antithrombin have shown mostly negative results.^{51,55,67–69} Trials using protein C concentrates have shown more promise in controlling the coagulopathy of purpura fulminans, but this is not widely available.^63,70–72 Unfortunately, many patients will need debridement and amputation for their necrotic limbs, with one review showing approximately 66% of patients needing amputations.⁵²

TRAUMA

Currently, the most common cause of acute DIC is trauma. The coagulation defects that occur in trauma patients are complex in origin and still controversial (including if even calling it DIC is appropriate!).^73–76 The most common etiologies are

• Generation of excess activated protein C leading to increased consumption of factor V and VIII and increased fibrinolysis;
• Tissue damage leading to generation of excess thrombin generation;
• Dilution of hemostatic factors by blood or fluid resuscitation; and
• Activation of endothelial cells leading to generation of a prothrombotic surface and shedding of glycocalyx with antithrombotic properties.

Trauma patients are prone to hypothermia, and this can be the major complicating factor in their bleeding.^77,78 Patients may be out “in the field” for a prolonged period of time and be hypothermic on arrival.⁷⁹ Packed red cells are stored at 4°C, and the infusion of 1 unit can lower the body temperature by 0.16°C.⁸⁰ Hypothermia has profound effects on the coagulation system that are associated with clinical bleeding.^77,81,82 Even modest hypothermia can greatly augment bleeding and needs to be treated or prevented.

The initial management of the bleeding trauma patient is administration of red cells and plasma (FFP) in a 1:1 ratio. This has been shown by clinical studies to lessen the risk of exsanguination in the first 24 hours and to be associated with improved clinical outcomes.^83,84 The basic set of coagulation tests should also be obtained to guide product replacement, especially as the bleeding is brought under control. Hypothermia can be prevented by several measures, including transfusing the blood through blood warmers. Devices are available that can warm 1 unit of blood per minute. An increasingly used technique is to perform “damage control” surgery. Patients are initially stabilized with control of damaged vessels and packing of oozing sites.⁸⁵ Then the patient is taken to the intensive care unit to be warmed and have coagulation defects corrected.

For trauma patients at risk of serious bleeding, the use of tranexamic acid reduced all- cause mortality (relative risk 0.91), with death due to bleeding also being reduced (relative risk 0.85).⁸⁶ There was no increase in thrombosis, but benefit was restricted to patients treated within 3 hours of the trauma. The dose of tranexamic acid was a 1-g bolus followed by a 1-g continuous infusion over 8 hours.

PREGNANCY-RELATED DIC SYNDROMES

Acute DIC of Pregnancy

Pregnancy can be associated with the rapid onset of severe DIC in 2 situations, abruption and amniotic fluid embolism.^87,88 The separation of the placenta from the uterine wall creates a space for blood to occupy. Given the richness of the placenta in tissue factor, this leads to activation of coagulation both locally and systemically. Release of blood when this space reaches the vaginal opening can lead to rapid hemorrhage, further augmenting the coagulation abnormalities. Placental insufficiency can lead to fetal demise, which can also worsen the DIC. Management depends on the size of the abruption and the clinical status of both mother and fetus.⁸⁷ For severe bleeding and DIC, blood product support is crucial to allow safe delivery. In pregnancy, the fibrinogen goal needs to be higher—200 mg/dL.⁸⁹ For smaller abruption, close observation with early delivery is indicated.

Amniotic fluid embolism is sudden, with the vascular collapse of the woman soon after delivery. Due to the presence of procoagulant rich fluid in the circulatory system, there is often overwhelming DIC. Therapy is directed at both supporting blood volume and correcting hemostatic defects.

HELLP

The acronym HELLP (hemolysis, elevated liver tests, low platelets) describes a variant of preeclampsia.⁹⁰ Classically, HELLP syndrome occurs after 28 weeks of gestation in a patient with preeclampsia, but can occur as early as 22 weeks in patients with antiphospholipid antibody syndrome.^91–93 The preeclampsia need not be severe. The first sign of HELLP is a decrease in the platelet count followed by abnormal liver function tests. Signs of hemolysis are present with abundant schistocytes on the smear and a high lactate dehydrogenase level. HELLP can progress to liver failure, and deaths are also reported due to hepatic rupture. Unlike TTP, fetal involvement is present in the HELLP syndrome, with fetal thrombocytopenia reported in 30% of cases. In severe cases, elevated D-dimers consistent with DIC are also found. Delivery of the child will most often result in cessation of the HELLP syndrome, but refractory cases will require dexamethasone and plasma exchange.⁹⁴ Patients should be closely observed for 1 to 2 days after delivery as the hematologic picture can transiently worsen before improving.⁹⁵

Acute Fatty Liver of Pregnancy

Fatty liver of pregnancy also occurs late in pregnancy and is only associated with preeclampsia in 50% of cases.^96,97 Patients first present with nonspecific symptoms of nausea and vomiting but can progress to fulminant liver failure. Patients develop thrombocytopenia early in the course, but in the later stages can develop DIC and very low fibrinogen levels. Mortality rates without therapy can be as high as 90%. Low blood glucose and high ammonia levels can help distinguish fatty liver from other pregnancy complications.⁹⁸ Treatment consists of prompt delivery of the child and aggressive blood product support.

Retained Dead Fetus Syndrome

Becoming rarer in modern practices, the presence of a dead fetus for many weeks (usually ≥ 5) can result in a chronic DIC state with fibrinogen depletion and coagulopathy. In some women, this is worsened at delivery. In a stable patient, a short trial of heparin prior to planning delivery can control the DIC to allow the coagulopathy to stabilize.

DRUG-INDUCED HEMOLYTIC-DIC SYNDROMES

A severe variant of the drug-induced immune complex hemolysis associated with DIC has been recognized. Rare patients who receive certain second- and third-generation cephalosporins (especially cefotetan and ceftriaxone) have developed this syndrome.^99–104 The clinical syndrome starts 7 to 10 days after the drug is administered. Often the patient has only received the antibiotic for surgical prophylaxis. The patient will develop severe Coombs’-positive hemolysis with hypotension and DIC. The patients are often believed to have sepsis and in the management of the supposed sepsis often are re-exposed to the cephalosporin, resulting in worsening of the clinical picture. The outcome is often fatal due to massive hemolysis and thrombosis.^{101,105–107}

Quinine is associated with a unique syndrome of drug-induced DIC.^108–111 Approximately 24 to 96 hours after quinine exposure, the patient becomes acutely ill with nausea and vomiting. The patient then develops a microangiopathic hemolytic anemia, DIC, and renal failure. Some patients, besides having antiplatelet antibodies, also have antibodies binding to red cells and neutrophils, which may lead to the more severe syndrome. Despite therapy, patients with quinine-induced TTP have a high incidence of chronic renal failure.

Treatment of the drug-induced hemolytic-DIC syndrome is anecdotal. Patients have responded to aggressive therapy, including plasma exchange, dialysis, and prednisone. Early recognition of the hemolytic anemia and the suspicion it is drug related is important for early diagnosis so that the incriminated drug can be discontinued.

CANCER

Cancers, primarily adenocarcinomas, can result in DIC. The classic Trousseau syndrome referred to the association of migratory superficial thrombophlebitis with cancer¹¹² but now refers to cancer associated with thrombotic DIC.^113,114 Highly vascular tumor cells are known to express tissue factor.^114,115 In addition, some tumor cells can express a direct activator of factor X (“cancer procoagulant”). Unlike many DIC states, cancer presents with thrombosis instead of bleeding. This may be due to the inflammatory state which accompanies cancer, or it may be a unique part of the chronic nature of cancer DIC biology that allows time for the body to compensate for loss of coagulation factors. In some patients, thrombosis is the first sign of an underlying cancer, sometimes predating the cancer diagnosis by months.¹¹⁵ Rarely, the DIC can result in nonthrombotic endocarditis with micro-emboli leading to widespread small-vessel thrombosis.¹¹³

Since effective antineoplastic therapy is lacking for many tumors associated with Trousseau syndrome, DIC therapy is aimed at suppressing thrombosis. An exception is prostate cancer, where hormonal therapy can markedly decrease the DIC.¹¹⁶ Due to the tumor directly activating coagulation factors, inhibition of active enzymes via heparin has been shown to reduce rates of recurrence compared with warfarin.^114,115 Clinical trials have demonstrated that heparin therapy is associated with a lower thrombosis recurrence rate than warfarin.^117,118 In some patients, the thrombotic process is so vigorous that new thrombosis can be seen within hours of stopping heparin.¹¹²

ACUTE PROMYELOCYTIC LEUKEMIA

There are multiple hemostatic defects in patients with acute promyelocytic leukemia (APL).¹¹⁹ Most, if not all, patients with APL have evidence of DIC at the time of diagnosis. Patients with APL have a higher risk of death during induction therapy as compared with patients with other forms of leukemia, with death most often due to bleeding. Once in remission, APL patients have a higher cure rate than most patients with leukemia. APL is also unique among leukemias in that biologic therapy with retinoic acid or arsenic is effective in inducing remission and cure in most patients. Although effective therapy is available, early death rates due to bleeding have not changed.¹¹⁹

APL patients can present with pancytopenia due to leukemic marrow replacement or with diffuse bleeding due to DIC and thrombocytopenia. Life-threatening bleeding such as intracranial hemorrhage may occur at any time until the leukemia is put into remission. The etiology of the hemostatic defects in APL is complex and is thought to be the result of DIC, fibrinolysis, and the release of prothrombotic extracellular chromatin and other procoagulant enzymes.^119,120 The diagnosis of APL can be straightforward when the leukemic cells are promyelocytes with abundant Auer rods, although some patients have the microgranular form without obvious Auer rods. The precise diagnosis requires molecular methods, including obtaining FISH for detecting the t(15;17) in PML/RARA fusion. Upon diagnosis of APL, one should obtain a complete coagulation profile, including INR, aPTT, fibrinogen, platelet count, and D-dimers. Change in fibrinogen levels tends to be a good marker of progress in treating the coagulation defects.

Therapy of APL involves treating both the leukemia and the coagulopathy. Currently, the standard treatment for APL is trans-retinoic acid (ATRA) in combination with chemotherapy or arsenic.^121,122 This approach will induce remission in more than 90% of patients, and a sizable majority of these patients will be cured of their APL. ATRA therapy will also lead to early correction of the coagulation defects, often within the first week of therapy.¹²³ This is in stark contrast to the chemotherapy era when the coagulation defects would become worse with therapy. Given the marked beneficial effect of ATRA on the coagulopathy of APL and its low toxicity profile, it should be empirically started for any patients suspected of having APL while genetic testing is being performed. Rare reports of massive thrombosis complicating therapy with ATRA exist, but the relationship to either the APL or ATRA is unknown.

Therapy for the coagulation defects consists of aggressive transfusion therapy support and possible use of other pharmacologic agents to control DIC.^124,125 The fibrinogen level should be maintained at over 150 mg/dL and the platelet count at over 50,000 cells/µL.¹²⁶ Controversy still exists over the role of heparin in therapy of APL.¹⁰⁴ Although attractive for its ability to quench thrombin, heparin use can lead to profound bleeding and its use in treating APL has fallen out of favor.

SNAKEBITES

Snake envenomation can lead to direct activation of multiple coagulation enzymes, including factors V, X, thrombin, and protein C, and lead to cleavage of fibrinogen.^127,128 Envenomation can also activate coagulation and damage vascular endothelium. The DIC can be enhanced by widespread tissue necrosis and hypotension. The key to management of snake bites is administration of specific antivenom. The role of prophylactic factor replacement is controversial, but this therapy is indicated if there is clinical bleeding.¹²⁹ One confounder is that some snake venoms, especially rattlesnake, can induce reversible platelet aggregation, which corrects with antivenom.

LOCAL VASCULAR ABNORMALITIES

Abnormal vascular structures, such as vascular tumors, vascular malformations, and aneurysms, can lead to localized areas of thrombin generation that can “spill-over” into the general circulation, leading to DIC. The diagnosis Kasabach-Merritt phenomenon should be reserved for children with vascular tumors such as angioma or hemangioendothelioma.¹³⁰ Therapy depends on the lesion. Embolization to reduce blood flow of vascular malformations can either be definitive therapy or stabilize the patient for surgery. Aneurysms can be repaired by surgery or stenting. Rare patients with aneurysms with significant coagulopathy may require heparin to raise the fibrinogen level before surgery. Kasabach-Merritt disease can respond to steroids or therapy such as vincristine or interferon.¹³⁰ Increasing data shows that use of the mTOR inhibitor sirolimus can shrink these vascular abnormalities leading to lessening of the coagulopathy.¹³¹

CONCLUSION

At the most basic level, DIC is the excess activity of thrombin. However, the clinical presentation and therapy can differ greatly depending on the primary cause. Both diagnosis and therapy involve close coordination of laboratory data and clinical assessment.

INTRODUCTION

In the normal person, the process of coagulation is finely controlled at many levels to ensure the appropriate amount of hemostasis at the appropriate location. Broadly defined, disseminated intravascular coagulation (DIC) is the name given to any process that disrupts this fine tuning, leading to unregulated coagulation. Defined this way, DIC may be found in a variety of patients with a variety of disease states, and can present with a spectrum of findings ranging from asymptomatic abnormal laboratory results to florid bleeding or thrombosis. It is important to remember that DIC is always a consequence of an underlying pathological process and not a disease in and of itself. This article first reviews concepts common to all forms of DIC, and then reviews the more common disease states that lead to DIC.

PATHOGENESIS

At the most basic level, DIC is the clinical manifestation of inappropriate thrombin activation.^1–5 Inappropriate thrombin activation can be due to underlying conditions such as sepsis and obstetric disasters. The activation of thrombin leads to (1) conversion of fibrinogen to fibrin, (2) activation of platelets (and their consumption), (3) activation of factors V and VIII, (4) activation of protein C (and degradation of factors Va and VIIIa), (5) activation of endothelial cells, and (6) activation of fibrinolysis (Table 1). 

1. Conversion of fibrinogen to fibrin, which leads to the formation of fibrin monomers and excessive thrombus formation. These thrombi are rapidly dissolved by excessive fibrinolysis in most patients. In certain clinical situations, especially cancer, excessive thrombosis will occur. In patients with cancer, this is most often a deep venous thrombosis. Rare patients, especially those with pancreatic cancer, may have severe DIC with multiple arterial and venous thromboses. Nonbacterial thrombotic endocarditis can also be seen in these patients, leading to widespread embolic complications.

2. Activation of platelets and their consumption. Thrombin is the most potent physiologic activator of platelets, so in DIC there is increased activation of platelets. These activated platelets are consumed, resulting in thrombocytopenia. Platelet dysfunction is also present. Platelets that have been activated and have released their contents but still circulate are known as “exhausted” platelets; these cells can no longer function to support coagulation. The fibrin degradation products (FDP) in DIC can also bind to GP IIb/IIIa and inhibit further platelet aggregation.

3. Activation of factors V, VIII, XI, and XIII. Activation of these factors can promote thrombosis, but they are then rapidly cleared by antithrombin (XI) or activated protein C (V and VIII) or by binding to the fibrin clot (XIII). This can lead to depletion of all the prothrombotic clotting factors and antithrombin, which in turn can lead to both thrombosis and bleeding.

4. Activation of protein C further promotes degradation of factors Va and VIIIa, enhances fibrinolysis, and decreases protein C levels.

5. Activation of endothelial cells, especially in the skin, may lead to thrombosis, and in certain patients, especially those with meningococcemia, purpura fulminans. Endothelial damage will down-regulate thrombomodulin, preventing activation of protein C and leading to further reductions in levels of activated protein C.⁵6. Activation of fibrinolysis leads to the breakdown of fibrin monomers, formation of fibrin thrombi, and increased circulating fibrinogen. In most patients with DIC, the fibrinolytic response is brisk.⁶ This is why most patients with DIC present with bleeding and prolonged clotting times.

PATTERNS OF DIC

The clinical manifestations of DIC in a given patient depend on the balance of thrombin activation and secondary fibrinolysis plus the patient’s ability to compensate for the DIC. Patients with DIC can present in 1 of 4 patterns:^1–3

1. Asymptomatic. Patients can present with laboratory evidence of DIC but no bleeding or thrombosis. This is often seen in patients with sepsis or cancer. However, with further progression of the underlying disease, these patients can rapidly become symptomatic.

2. Bleeding. The bleeding is due to a combination of factor depletion, platelet dysfunction, thrombocytopenia, and excessive fibrinolysis.¹ These patients may present with diffuse bleeding from multiple sites (eg, intravenous sites, areas of instrumentation).

3. Thrombosis. Despite the general activation of the coagulation process, thrombosis is unusual in most patients with acute DIC. The exceptions include patients with cancer, trauma patients, and certain obstetrical patients. Most often the thrombosis is venous, but arterial thrombosis and nonbacterial thrombotic endocarditis have been reported.⁷

4. Purpura fulminans. This form of DIC is discussed in more detail later (see Specific DIC Syndromes section).

DIAGNOSIS

There is no one test that will diagnose DIC; one must match the test to the clinical situation (Table 2).⁸ 

SCREENING TESTS

The prothrombin time-INR and activated thromboplastin time (aPPT) are usually elevated in severe DIC but may be normal or shortened in chronic forms.⁹ One may also see a shortened aPTT in severe acute DIC due to large amounts of activated thrombin and factor X “bypassing” the contact pathway. An aPTT as short as 10 seconds has been seen in acute DIC. The platelet count is usually reduced but may be normal in chronic DIC. Serum fibrinogen and platelets are decreased in acute DIC but again may be in the “normal” range in chronic DIC.¹⁰ The most sensitive screening test for DIC is a fall in the platelet count, with low counts seen in 98% of patients and counts under 50,000 cells/μL in 50%.^9,11 The least specific test is fibrinogen, which tends to fall below normal only in severe acute DIC.⁹

SPECIFIC TESTS

This group of tests allows one to deduce that abnormally high concentrations of thrombin are present.

Ethanol Gel and Protamine Tests

Both of these older tests detected circulating fibrin monomers, whose appearance is an early sign of DIC. Circulating fibrin monomers are seen when thrombin acts on fibrinogen. Usually the monomer polymerizes with the fibrin clot, but when there is excess thrombin these monomers can circulate. Detection of circulating fibrin monomer means there is too much IIa and, ergo, DIC is present.

Fibrin(ogen) Degradation Products

Plasmin acts on the fibrin/fibrinogen molecule to cleave the molecule in specific places. The resulting degradation product levels will be elevated in situations of increased fibrin/fibrinogen destruction (DIC and fibrinolysis). The FDP are typically mildly elevated in renal and liver disease due to reduced clearance.

D-Dimers

When fibrin monomers bind to form a thrombus, factor XIII acts to bind their “D” domains together. This bond is resistant to plasmin and thus this degradation fragment is known as the “D-dimer.” High levels of D-dimer indicate that (1) IIa has acted on fibrinogen to form a fibrin monomer that bonded to another fibrin monomer, and (2) this thrombus was lysed by plasmin. Because D-dimers can be elevated (eg, with exercise, after surgery), an elevated D-dimer needs to be interpreted in the context of the clinical situation.¹¹ Currently, this is the most common specific test for DIC performed.

Other Tests

Several other tests are sometimes helpful in diagnosing DIC.

Thrombin time. This test is performed by adding thrombin to plasma. Thrombin times are elevated in DIC (FDPs interfere with polymerization), in the presence of low fibrinogen levels, in dysfibrinogenemia, and in the presence of heparin (very sensitive).

Reptilase time is the same as thrombin time but is performed with a snake venom that is insensitive to heparin. Reptilase time is elevated in the same conditions as the thrombin time, with the exception of the presence of heparin. Thrombin time and reptilase time are most useful in evaluation of dysfibrinogenemia.

Prothrombin fragment 1.2 (F_1.2). F_1.2 is a small peptide cleaved off when prothrombin is activated to thrombin. Thus, high levels of F_1.2 are found in DIC but can be seen in other thrombotic disorders. This test is still of limited clinical value.

DIC scoring system. A scoring system to both diagnose and quantify DIC has been proposed (Figure).^11,12 

MIMICKERS OF DIC

It is important to recognize coagulation syndromes that are not DIC, especially those that have specific other therapies. The syndromes most frequently encountered are thrombotic thrombocytopenic purpura (TTP) and catastrophic antiphospholipid antibody syndrome (CAPS). One important clue to both of these syndromes is that, unlike DIC, there is no primary disorder (cancer, sepsis) that is driving the coagulation abnormalities.

TTP should be suspected when any patient presents with any combination of thrombo­cytopenia, microangiopathic hemolytic anemia (schistocytes and signs of hemolysis) plus end-organ damage.^15–18 Patients with TTP most often present with intractable seizures, strokes, or sequelae of renal insufficiency. Many patients who present with TTP have been misdiagnosed as having sepsis, “lupus flare,” or vasculitis. The key diagnostic differentiator between TTP and DIC is the lack of activation of coagulation with TTP—fibrinogen is normal and D-dimers are minimally or not elevated. In TTP, lactate dehydrogenase is invariably elevated, often 2 to 3 times normal.¹⁹ The importance of identifying TTP is that untreated TTP is rapidly fatal. Mortality in the pre–plasma exchange era ranged from 95% to 100%. Today plasma exchange therapy is the foundation of TTP treatment and has reduced mortality to less than 20%.^16,20–23Rarely patients with antiphospholipid antibody syndrome can present with fulminant multiorgan system failure.^24–28 CAPS is caused by widespread microthrombi in multiple vascular fields. These patients will develop renal failure, encephalopathy, adult respiratory distress syndrome (often with pulmonary hemorrhage), cardiac failure, dramatic livedo reticularis, and worsening thrombocytopenia. Many of these patients have pre-existing autoimmune disorders and high-titer anticardiolipin antibodies. It appears that the best therapy for these patients is aggressive immunosuppression with steroids plus plasmapheresis, followed by rituximab or, if in the setting of lupus, intravenous cyclophosphamide monthly.^27,29 Early recognition of CAPS can lead to quick therapy and resolution of the multiorgan system failure.

GENERAL THERAPY

The best way to treat DIC is to treat the underlying cause that is driving the thrombin generation.^1,2,4,30,31 Fully addressing the underlying cause may not be possible or may take time, and in the meantime it is necessary to disrupt the cycle of thrombosis and/or hemorrhage. In the past, there was concern about using factor replacement due to fears of “feeding the fire,” or perpetuating the cycle of thrombosis. However, these concerns are not supported by evidence, and factors must be replaced if depletion occurs and bleeding ensues.³²

Transfusion therapy of the patient with DIC is guided by the 5 laboratory tests that reflect the basic parameters essential for both hemostasis and blood volume status:^33,34 hematocrit, platelet count, prothrombin time-INR, aPTT, and fibrinogen level. Decisions regarding replacement therapy are based on the results of these laboratory tests and the clinical situation of the patient (Table 3). 

SPECIFIC DIC SYNDROMES

SEPSIS/INFECTIOUS DISEASE

Any overwhelming infection can lead to DIC.⁴⁵ Classically, it was believed that gram-negative bacteria can lead tissue factor exposure via production of endotoxin, but recent studies indicate that DIC can be seen with any overwhelming infection.^46,47 There are several potential avenues by which infections can lead to DIC. As mentioned, gram-negative bacteria produce endotoxin that can directly lead to tissue factor exposure, resulting in excess thrombin generation. In addition, any infection can lead to expression of inflammatory cytokines that induce tissue-factor expression by endothelium and monocytes. Some viruses and Rickettsia species can directly infect the vascular endothelium, converting it from an antithrombotic to a prothrombotic phenotype.⁴⁸ When fighting infections, neutrophils can extrude their contents, including DNA, to help trap organisms. These neutrophil extracellular traps (NETS) may play an important role in promoting coagulopathy.^49,50 The hypotension produced by sepsis leads to tissue hypoxia, which results in more DIC. The coagulopathy in sepsis can range from subtle abnormalities of testing to purpura fulminans. Thrombocytopenia is worsened by cytokine-induced hemophagocytic syndrome.

As with all forms of DIC, empiric therapy targeting the most likely source of infection and maintaining hemodynamic stability is the key to therapy. As discussed below, heparin and other forms of coagulation replacement appear to be of no benefit in therapy.

PURPURA FULMINANS

DIC in association with necrosis of the skin is seen in primary and secondary purpura fulminans.^51,52 Primary purpura fulminans is most often seen after a viral infection.⁵³ In these patients, the purpura fulminans starts with a painful red area on an extremity that rapidly progresses to a black ischemic area. In many patients, acquired deficiency of protein S is found.^51,54,55 Secondary purpura fulminans is most often associated with meningococcemia infections but can be seen in any patient with overwhelming infection.^56–58 Post-splenectomy sepsis syndrome patients and those with functional hyposplenism due to chronic liver diseases are also at risk.⁵⁹ Patients present with signs of sepsis, and the skin lesions often involve the extremities and may lead to amputations. As opposed to primary purpura fulminans, those with the secondary form will have symmetrical ischemia distally (toes and fingers) that ascends as the process progresses. Rarely, adrenal infarction (Waterhouse-Friderichsen syndrome) occurs, which leads to severe hypotension.⁴⁵

Recently, Warkenten has reported on limb gangrene in critically ill patients complicating sepsis or cardiogenic shock.^60,61 These patients have DIC that is complicated by shock liver. Deep venous thrombosis with ischemic gangrene then develops, which can result in tissue loss and even amputation. The pathogenesis is hypothesized to be hepatic dysfunction leading to sudden drops in protein C and S plasma levels, which then leads to thrombophilia with widespread microvascular thrombosis. Therapy for purpura fulminans is controversial. Primary purpura fulminans, especially in those with postvaricella autoimmune protein S deficiency, has responded to plasma infusion titrated to keep the protein S level above 25%.⁵¹ Intravenous immunoglobulin has also been reported to help decrease the anti-protein S antibodies. Heparin has been reported to control the DIC and extent of necrosis.⁶² The starting dose in these patients is 5 to 8 units/kg/hr.²

Sick patients with secondary purpura fulminans have been treated with plasma drips, plasmapheresis, and continuous plasma ultrafiltration.^62–66 Heparin therapy alone has not been shown to improve survival.⁶⁶ Much attention has been given to replacement of natural anticoagulants such as protein C and antithrombin as therapy for purpura fulminans, but unfortunately randomized trials using antithrombin have shown mostly negative results.^{51,55,67–69} Trials using protein C concentrates have shown more promise in controlling the coagulopathy of purpura fulminans, but this is not widely available.^63,70–72 Unfortunately, many patients will need debridement and amputation for their necrotic limbs, with one review showing approximately 66% of patients needing amputations.⁵²

TRAUMA

Currently, the most common cause of acute DIC is trauma. The coagulation defects that occur in trauma patients are complex in origin and still controversial (including if even calling it DIC is appropriate!).^73–76 The most common etiologies are

• Generation of excess activated protein C leading to increased consumption of factor V and VIII and increased fibrinolysis;
• Tissue damage leading to generation of excess thrombin generation;
• Dilution of hemostatic factors by blood or fluid resuscitation; and
• Activation of endothelial cells leading to generation of a prothrombotic surface and shedding of glycocalyx with antithrombotic properties.

Trauma patients are prone to hypothermia, and this can be the major complicating factor in their bleeding.^77,78 Patients may be out “in the field” for a prolonged period of time and be hypothermic on arrival.⁷⁹ Packed red cells are stored at 4°C, and the infusion of 1 unit can lower the body temperature by 0.16°C.⁸⁰ Hypothermia has profound effects on the coagulation system that are associated with clinical bleeding.^77,81,82 Even modest hypothermia can greatly augment bleeding and needs to be treated or prevented.

The initial management of the bleeding trauma patient is administration of red cells and plasma (FFP) in a 1:1 ratio. This has been shown by clinical studies to lessen the risk of exsanguination in the first 24 hours and to be associated with improved clinical outcomes.^83,84 The basic set of coagulation tests should also be obtained to guide product replacement, especially as the bleeding is brought under control. Hypothermia can be prevented by several measures, including transfusing the blood through blood warmers. Devices are available that can warm 1 unit of blood per minute. An increasingly used technique is to perform “damage control” surgery. Patients are initially stabilized with control of damaged vessels and packing of oozing sites.⁸⁵ Then the patient is taken to the intensive care unit to be warmed and have coagulation defects corrected.

For trauma patients at risk of serious bleeding, the use of tranexamic acid reduced all- cause mortality (relative risk 0.91), with death due to bleeding also being reduced (relative risk 0.85).⁸⁶ There was no increase in thrombosis, but benefit was restricted to patients treated within 3 hours of the trauma. The dose of tranexamic acid was a 1-g bolus followed by a 1-g continuous infusion over 8 hours.

PREGNANCY-RELATED DIC SYNDROMES

Acute DIC of Pregnancy

Pregnancy can be associated with the rapid onset of severe DIC in 2 situations, abruption and amniotic fluid embolism.^87,88 The separation of the placenta from the uterine wall creates a space for blood to occupy. Given the richness of the placenta in tissue factor, this leads to activation of coagulation both locally and systemically. Release of blood when this space reaches the vaginal opening can lead to rapid hemorrhage, further augmenting the coagulation abnormalities. Placental insufficiency can lead to fetal demise, which can also worsen the DIC. Management depends on the size of the abruption and the clinical status of both mother and fetus.⁸⁷ For severe bleeding and DIC, blood product support is crucial to allow safe delivery. In pregnancy, the fibrinogen goal needs to be higher—200 mg/dL.⁸⁹ For smaller abruption, close observation with early delivery is indicated.

Amniotic fluid embolism is sudden, with the vascular collapse of the woman soon after delivery. Due to the presence of procoagulant rich fluid in the circulatory system, there is often overwhelming DIC. Therapy is directed at both supporting blood volume and correcting hemostatic defects.

HELLP

The acronym HELLP (hemolysis, elevated liver tests, low platelets) describes a variant of preeclampsia.⁹⁰ Classically, HELLP syndrome occurs after 28 weeks of gestation in a patient with preeclampsia, but can occur as early as 22 weeks in patients with antiphospholipid antibody syndrome.^91–93 The preeclampsia need not be severe. The first sign of HELLP is a decrease in the platelet count followed by abnormal liver function tests. Signs of hemolysis are present with abundant schistocytes on the smear and a high lactate dehydrogenase level. HELLP can progress to liver failure, and deaths are also reported due to hepatic rupture. Unlike TTP, fetal involvement is present in the HELLP syndrome, with fetal thrombocytopenia reported in 30% of cases. In severe cases, elevated D-dimers consistent with DIC are also found. Delivery of the child will most often result in cessation of the HELLP syndrome, but refractory cases will require dexamethasone and plasma exchange.⁹⁴ Patients should be closely observed for 1 to 2 days after delivery as the hematologic picture can transiently worsen before improving.⁹⁵

Acute Fatty Liver of Pregnancy

Fatty liver of pregnancy also occurs late in pregnancy and is only associated with preeclampsia in 50% of cases.^96,97 Patients first present with nonspecific symptoms of nausea and vomiting but can progress to fulminant liver failure. Patients develop thrombocytopenia early in the course, but in the later stages can develop DIC and very low fibrinogen levels. Mortality rates without therapy can be as high as 90%. Low blood glucose and high ammonia levels can help distinguish fatty liver from other pregnancy complications.⁹⁸ Treatment consists of prompt delivery of the child and aggressive blood product support.

Retained Dead Fetus Syndrome

Becoming rarer in modern practices, the presence of a dead fetus for many weeks (usually ≥ 5) can result in a chronic DIC state with fibrinogen depletion and coagulopathy. In some women, this is worsened at delivery. In a stable patient, a short trial of heparin prior to planning delivery can control the DIC to allow the coagulopathy to stabilize.

DRUG-INDUCED HEMOLYTIC-DIC SYNDROMES

A severe variant of the drug-induced immune complex hemolysis associated with DIC has been recognized. Rare patients who receive certain second- and third-generation cephalosporins (especially cefotetan and ceftriaxone) have developed this syndrome.^99–104 The clinical syndrome starts 7 to 10 days after the drug is administered. Often the patient has only received the antibiotic for surgical prophylaxis. The patient will develop severe Coombs’-positive hemolysis with hypotension and DIC. The patients are often believed to have sepsis and in the management of the supposed sepsis often are re-exposed to the cephalosporin, resulting in worsening of the clinical picture. The outcome is often fatal due to massive hemolysis and thrombosis.^{101,105–107}

Quinine is associated with a unique syndrome of drug-induced DIC.^108–111 Approximately 24 to 96 hours after quinine exposure, the patient becomes acutely ill with nausea and vomiting. The patient then develops a microangiopathic hemolytic anemia, DIC, and renal failure. Some patients, besides having antiplatelet antibodies, also have antibodies binding to red cells and neutrophils, which may lead to the more severe syndrome. Despite therapy, patients with quinine-induced TTP have a high incidence of chronic renal failure.

Treatment of the drug-induced hemolytic-DIC syndrome is anecdotal. Patients have responded to aggressive therapy, including plasma exchange, dialysis, and prednisone. Early recognition of the hemolytic anemia and the suspicion it is drug related is important for early diagnosis so that the incriminated drug can be discontinued.

CANCER

Cancers, primarily adenocarcinomas, can result in DIC. The classic Trousseau syndrome referred to the association of migratory superficial thrombophlebitis with cancer¹¹² but now refers to cancer associated with thrombotic DIC.^113,114 Highly vascular tumor cells are known to express tissue factor.^114,115 In addition, some tumor cells can express a direct activator of factor X (“cancer procoagulant”). Unlike many DIC states, cancer presents with thrombosis instead of bleeding. This may be due to the inflammatory state which accompanies cancer, or it may be a unique part of the chronic nature of cancer DIC biology that allows time for the body to compensate for loss of coagulation factors. In some patients, thrombosis is the first sign of an underlying cancer, sometimes predating the cancer diagnosis by months.¹¹⁵ Rarely, the DIC can result in nonthrombotic endocarditis with micro-emboli leading to widespread small-vessel thrombosis.¹¹³

Since effective antineoplastic therapy is lacking for many tumors associated with Trousseau syndrome, DIC therapy is aimed at suppressing thrombosis. An exception is prostate cancer, where hormonal therapy can markedly decrease the DIC.¹¹⁶ Due to the tumor directly activating coagulation factors, inhibition of active enzymes via heparin has been shown to reduce rates of recurrence compared with warfarin.^114,115 Clinical trials have demonstrated that heparin therapy is associated with a lower thrombosis recurrence rate than warfarin.^117,118 In some patients, the thrombotic process is so vigorous that new thrombosis can be seen within hours of stopping heparin.¹¹²

ACUTE PROMYELOCYTIC LEUKEMIA

There are multiple hemostatic defects in patients with acute promyelocytic leukemia (APL).¹¹⁹ Most, if not all, patients with APL have evidence of DIC at the time of diagnosis. Patients with APL have a higher risk of death during induction therapy as compared with patients with other forms of leukemia, with death most often due to bleeding. Once in remission, APL patients have a higher cure rate than most patients with leukemia. APL is also unique among leukemias in that biologic therapy with retinoic acid or arsenic is effective in inducing remission and cure in most patients. Although effective therapy is available, early death rates due to bleeding have not changed.¹¹⁹

APL patients can present with pancytopenia due to leukemic marrow replacement or with diffuse bleeding due to DIC and thrombocytopenia. Life-threatening bleeding such as intracranial hemorrhage may occur at any time until the leukemia is put into remission. The etiology of the hemostatic defects in APL is complex and is thought to be the result of DIC, fibrinolysis, and the release of prothrombotic extracellular chromatin and other procoagulant enzymes.^119,120 The diagnosis of APL can be straightforward when the leukemic cells are promyelocytes with abundant Auer rods, although some patients have the microgranular form without obvious Auer rods. The precise diagnosis requires molecular methods, including obtaining FISH for detecting the t(15;17) in PML/RARA fusion. Upon diagnosis of APL, one should obtain a complete coagulation profile, including INR, aPTT, fibrinogen, platelet count, and D-dimers. Change in fibrinogen levels tends to be a good marker of progress in treating the coagulation defects.

Therapy of APL involves treating both the leukemia and the coagulopathy. Currently, the standard treatment for APL is trans-retinoic acid (ATRA) in combination with chemotherapy or arsenic.^121,122 This approach will induce remission in more than 90% of patients, and a sizable majority of these patients will be cured of their APL. ATRA therapy will also lead to early correction of the coagulation defects, often within the first week of therapy.¹²³ This is in stark contrast to the chemotherapy era when the coagulation defects would become worse with therapy. Given the marked beneficial effect of ATRA on the coagulopathy of APL and its low toxicity profile, it should be empirically started for any patients suspected of having APL while genetic testing is being performed. Rare reports of massive thrombosis complicating therapy with ATRA exist, but the relationship to either the APL or ATRA is unknown.

Therapy for the coagulation defects consists of aggressive transfusion therapy support and possible use of other pharmacologic agents to control DIC.^124,125 The fibrinogen level should be maintained at over 150 mg/dL and the platelet count at over 50,000 cells/µL.¹²⁶ Controversy still exists over the role of heparin in therapy of APL.¹⁰⁴ Although attractive for its ability to quench thrombin, heparin use can lead to profound bleeding and its use in treating APL has fallen out of favor.

SNAKEBITES

Snake envenomation can lead to direct activation of multiple coagulation enzymes, including factors V, X, thrombin, and protein C, and lead to cleavage of fibrinogen.^127,128 Envenomation can also activate coagulation and damage vascular endothelium. The DIC can be enhanced by widespread tissue necrosis and hypotension. The key to management of snake bites is administration of specific antivenom. The role of prophylactic factor replacement is controversial, but this therapy is indicated if there is clinical bleeding.¹²⁹ One confounder is that some snake venoms, especially rattlesnake, can induce reversible platelet aggregation, which corrects with antivenom.

LOCAL VASCULAR ABNORMALITIES

Abnormal vascular structures, such as vascular tumors, vascular malformations, and aneurysms, can lead to localized areas of thrombin generation that can “spill-over” into the general circulation, leading to DIC. The diagnosis Kasabach-Merritt phenomenon should be reserved for children with vascular tumors such as angioma or hemangioendothelioma.¹³⁰ Therapy depends on the lesion. Embolization to reduce blood flow of vascular malformations can either be definitive therapy or stabilize the patient for surgery. Aneurysms can be repaired by surgery or stenting. Rare patients with aneurysms with significant coagulopathy may require heparin to raise the fibrinogen level before surgery. Kasabach-Merritt disease can respond to steroids or therapy such as vincristine or interferon.¹³⁰ Increasing data shows that use of the mTOR inhibitor sirolimus can shrink these vascular abnormalities leading to lessening of the coagulopathy.¹³¹

CONCLUSION

At the most basic level, DIC is the excess activity of thrombin. However, the clinical presentation and therapy can differ greatly depending on the primary cause. Both diagnosis and therapy involve close coordination of laboratory data and clinical assessment.

Patients with cancer can have many hematologic complications. One of the most serious is bleeding, which can range in severity from laboratory abnormalities to life-threatening hemorrhage. The bleeding can be due to complications of the cancer, its therapy, or treatment for complications of cancer such as thrombosis. This manual discusses an approach to the cancer patient with bleeding, with a specific focus on issues such as coagulation defects, thrombocytopenia, and platelet dysfunction. Bleeding complications of specific cancers and their treatment will be discussed as well.

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Patients with cancer can have many hematologic complications. One of the most serious is bleeding, which can range in severity from laboratory abnormalities to life-threatening hemorrhage. The bleeding can be due to complications of the cancer, its therapy, or treatment for complications of cancer such as thrombosis. This manual discusses an approach to the cancer patient with bleeding, with a specific focus on issues such as coagulation defects, thrombocytopenia, and platelet dysfunction. Bleeding complications of specific cancers and their treatment will be discussed as well.

To read the full article in PDF:

Click here

Patients with cancer can have many hematologic complications. One of the most serious is bleeding, which can range in severity from laboratory abnormalities to life-threatening hemorrhage. The bleeding can be due to complications of the cancer, its therapy, or treatment for complications of cancer such as thrombosis. This manual discusses an approach to the cancer patient with bleeding, with a specific focus on issues such as coagulation defects, thrombocytopenia, and platelet dysfunction. Bleeding complications of specific cancers and their treatment will be discussed as well.

To read the full article in PDF:

Click here