PRACTICE RECOMMENDATIONS
• Testing for inherited hypercoagulable disorders should focus on the identification of individuals most likely to benefit from it. C
• Avoid testing asymptomatic individuals for the sole purpose of initiating long-term prophylactic therapy. C
• Long-term anticoagulant therapy may be warranted for patients with antithrombin III, protein C, or protein S deficiency, who may be at increased risk of recurrent thrombosis. C
• A definitive diagnosis of antiphospholipid antibody syndrome requires a history of either vascular thrombosis or pregnancy morbidity. C
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
Each year, venous thrombosis develops in approximately 1 in 1000 people.1 The cause: An alteration in blood composition, venous stasis, or vascular damage—commonly known as Virchow’s triad. Changes in blood composition are associated with hereditary thrombophilias, such as factor V Leiden mutation or a deficiency in protein C or S or antithrombin III (AT). Changes in blood flow (stasis) and vessel damage stem from acquired conditions that commonly lead to hypercoagulability—pregnancy, malignancy, and estrogen use among them.
Regardless of the reason a patient is at elevated risk, however, the goal is the same: to prevent the development of thrombi, thereby reducing the increased morbidity and mortality associated with thromboembolism. Achieving that goal requires an understanding of both inherited and acquired risk factors, familiarity with diagnostic tools, and knowledge of appropriate treatment. This review, which begins with hereditary hypercoagulable states before turning to acquired conditions associated with hypercoagulability, will help toward that end.
Keep these thrombophilias on your radar screen
Factor V Leiden mutation is the most common inherited hypercoagulable disorder, and the most common form of activated protein C resistance. The mutation is found in an estimated 5% to 10% of the general population.2 Among patients with thromboembolic disorders, however, the incidence is considerably higher, with estimates ranging from 21% to 60%.3,4 Factor V Leiden mutation is more prevalent among Caucasian populations, and rarely found in people of Asian or African descent.2
Prothrombin G20210A mutation, an autosomal-dominant disorder, is the second most common inherited hypercoagulable state.4 This mutation is associated with an increase in prothrombin levels, causing an elevation in thrombin and, in turn, a heightened risk of thrombosis.
Although prothrombin G20210A mutation is found in only 1% to 2% of the general population, its prevalence among those with a history of thromboembolic events is estimated at 5% to 19%.4 This disorder, too, varies significantly by ethnicity: People from southern Europe are twice as likely to be affected as northern Europeans, and the mutation is rarely found in people of Asian or African descent.2,5
Protein C deficiency. Protein C, a vitamin K-dependent anticoagulant produced in the liver, is activated when thrombomodulin binds with thrombin in the presence of protein S, which serves as the cofactor. Protein C is required to inactivate clotting factors V and VIII.2 The deficiency is an autosomal-dominant disorder, and is more likely to result in venous than arterial thrombosis.2
Protein C deficiency affects 1 in every 200 to 500 people in the general population; among patients with a history of venous thrombosis, its prevalence is 2% to 9%.2,3 Generally, people with a protein C deficiency begin developing thrombi in their late teens, and about 75% suffer from 1 or more thrombotic events during the course of their lives.2
There are 2 types of protein C deficiency: Patients with type I have a decreased production of protein C, while those with type II have normal levels of the protein, but in a form that is dysfunctional.6
AT deficiency. AT, a natural anticoagulant synthesized by the liver and endothelial cells, is responsible for inactivating several clotting factors, including thrombin and factors IXa, Xa, XIa, and XIIa. Like protein C deficiency, AT deficiency is an autosomal-dominant disorder with 2 subtypes. Individuals with type I deficiency have normal plasma levels of AT, but the anticoagulant has reduced biological activity or is dysfunctional; those with type II deficiency have decreased plasma levels of fully functional AT.2 Both types are more likely to lead to venous than arterial thrombosis.
AT deficiency affects approximately 1 in 2000 to 5000 people, including 2.8% of patients who develop venous thrombosis.7 Nearly two-thirds of those with AT deficiency develop thrombi before the age of 35.2
Protein S deficiency. Endothelial cells are responsible for the synthesis of protein S, which, like protein C (for which it serves as a cofactor), is vitamin K-dependent. Protein S deficiency, also an autosomal-dominant disorder, has 3 subtypes: Type I, also known as classical deficiency, is characterized by reduced free and total levels of functional protein S; type II patients have a normal total level of protein S, but a decreased amount of free protein; and type III patients have normal levels of both free and total protein S, but the available proteins are dysfunctional.2,6