Patients having gynecologic surgery for benign conditions benefit from the twice-daily regimen, and those undergoing gynecologic oncology surgery or other high-risk procedures seem to benefit from thrice-daily dosing.26
These regimens also significantly reduced DVT and fatal pulmonary emboli in general surgery patients.27 The LDUH regimen is now used to judge the efficacy of other prophylactic measures.
Low molecular weight heparin
This form of heparin acts primarily by inhibiting factor Xa, which is higher in the coagulation cascade than antithrombin. Thus, low molecular weight heparin (LMWH) is more efficient than unfractionated heparin.
LMWH has a molecular weight of 3,000 to 6,000 daltons and is produced by concentrating the low molecular component of heparin. Because the molecular configuration of antithrombin III is not altered by LMWH, thrombin conversion is minimally inhibited and aPTT is not appreciably affected.
Half-life is approximately 4 hours, by any route of administration. The longer half-life provides a longer dosing interval. Bioavailability is more consistent than that of LDUH, approaching 90% to 95%. The excellent bioavailability allows dosing to be based on lean body mass. Less heparin-induced thrombocytopenia is another plus.
Use in pregnancy. LMWH does not cross the placenta and is safe to use during pregnancy.
What the data show. No randomized trials have compared LMWH therapy with no therapy, with efficacy assessed by venography or fibrinogen uptake. An uncontrolled series28 of 2,030 patients did show that LMWH reduced the incidence of thromboembolic disease.
A randomized controlled trial29 comparing 2,500 U and 5,000 U daily of dalteparin (an LMWH) found greater efficacy in the higher-dose group (6.6% versus 12.7% incidence of DVT), but bleeding complications also were higher (4.7% versus 2.7%). In a subgroup of patients with malignancy, the high-dose therapy remained superior in preventing DVT, and the bleeding risk was equal.
Dosing options. Once a day dosing is normally adequate for prophylaxis; twice-daily dosing is needed for therapy. Enoxaparin is an LMWH that is readily available in the United States and commonly prescribed when use of LMWH is desired. For prophylaxis, it can be given in daily doses of 20 mg, 30 mg, 40 mg, or 60 mg. None of these doses has proven superior to the others. The typical regimen for moderate risk is 20 mg per day; for high risk, 40 mg per day. Enoxaparin appears to convey the same degree of protection as 5,000 units of LDUH every 8 hours.
2 heparins compared
Randomized controlled trials comparing LDUH and LMWH have found them to be similarly effective. In addition, within the LMWH class, all compounds appear to have similar benefits. However, it remains unclear which form of heparin is associated with fewer bleeding complications.
In theory, LMWH would be associated with an increase in these complications due to its longer half-life and increased bioavailability.30 However, studies have not consistently identified excess bleeding in any group.31 Fortunately, excess postoperative bleeding requiring transfusion is uncommon.
Complications of heparin
Heparin-induced thrombocytopenia is a recognized complication, seen in as many as 20% of LDUH patients. The diagnosis is made when the platelet count falls below the lower limits of normal or when the platelet count falls by 50% but remains in the normal range. Two forms of heparin-induced thrombocytopenia have been described.
• Type 1 thrombocytopenia is initially mild, rarely dropping below 100,000 platelets per milliliter. Platelet count monitoring is important, but therapy usually can continue, since the platelet count returns to normal even with continued use. Type 1 thrombocytopenia appears to directly result from platelet activation and is not immune-mediated.
• Type 2 thrombocytopenia occurs 7 to 14 days after starting therapy. Platelet counts frequently drop to 20,000 per milliliter. Type 2 is an immune response caused by antibodies to the heparin-platelet factor 4 complex. Patients are at risk for venous and arterial thrombosis, but often the diagnosis is made only after a complicating thrombotic event.
The risk of type 2 thrombocytopenia appears to be related to the molecular weight of the compound being administered, its dose, and the duration of therapy. Therefore, unfractionated heparin—if given in full anticoagulation doses and beyond 14 days—seems to have the greatest potential for this complication.
Paradoxically, these patients also are at risk for severe hemorrhage. Because mortality and morbidity are high, immediate withdrawal of all forms of heparin—including LMWH—is mandatory.32 Catastrophic hemorrhage or thrombosis may be the first sign. Often a fall in platelet concentration precedes serious complications. Thus, platelet concentration should be monitored at least every 2 days.
Hematoma with conduction anesthesia. Use of major conduction anesthesia in patients who also need LMWH, LDUH, or oral anticoagulants is controversial. LMWH may pose a risk of hematoma if initiated preoperatively, intraoperatively, or within 3 hours of surgery in patients who have a continuous epidural. Hematoma formation seems to occur immediately following catheter withdrawal.