Recombinant Factor VIIA in the Treatment of Bleeding

Madhu V. Midathada, MD; Paulette Mehta, MD; Milton Waner, MD; Louis M. Fink, MD


Am J Clin Pathol. 2004;121(1) 

In This Article

Drug-Induced Coagulopathy

Patients receiving oral anticoagulant treatment have abnormally low levels of functional vitamin K—dependent coagulation proteins and, consequently, an increased risk of hemorrhagic complications.[41,42] Drug-induced hemorrhagic events have been associated with warfarin. The incidence of hemorrhage has been reported around 0.6% to 0.7% per month at a therapeutic INR. Plasma or PCCs have been used to treat bleeding associated with oral anticoagulants, but these products have been associated with an increased risk of infections and thromboembolic complications, respectively. rFVIIa has been tested in rats and humans treated with anti—vitamin K drugs, and it completely normalized the PT in animals and humans with acquired deficiencies of the vitamin K—dependent factors.[43]

Girard et al[44] evaluated the effect of different doses of intravenous rFVIIa in healthy volunteers who had an INR greater than 2 while taking acenocoumarol. They also studied a population pharmacokinetics model for rFVIIa clotting activity after injection of rFVIIa in 28 healthy volunteers who were undergoing anticoagulation therapy with acenocoumarol. The volume of distribution at steady state seemed to be significantly dose-dependent; the estimated clearance was 2.4 L/h. The dose of rFVIIa that produced a 50% drop of INR was estimated to be 2.2 µg/kg.[44]

Muleo et al[45] reported completely satisfactory results with the use of rFVIIa in 4 patients, 3 with liver disease and 1 receiving oral anticoagulant therapy before surgery. In a similar type of study, Deveras and Kessler[46] used rFVIIa to treat 13 patients with critically high INRs who required immediate reversal of warfarin-induced anticoagulation. Indications for the use of rFVIIa included an INR of more than 10 in 5 high-risk patients, 4 with clinical hemorrhage, and 4 undergoing diagnostic or therapeutic procedures. The PT and INR were measured before and after administration of rFVIIa. The investigators concluded that rFVIIa was safe and effective for correcting critically prolonged INRs and that it can reverse warfarin-induced bleeding.

An open, multicenter pilot trial is underway to determine the effect of rFVIIa administered to patients experiencing a bleeding episode due to vitamin K antagonists.[41] Veshchev et al[47] describe a 52-year-old man, a mechanical valve recipient with warfarin-induced coagulopathy, who had an acute subdural hematoma and needed urgent neurosurgical intervention. He was given rFVIIa preoperatively with rapid correction of the coagulation parameters to a level that permitted safe intervention without delay.[47] rFVIIa might be effective for treating bleeding associated with α IIb β 3 inhibitors.[48] Stepinska et al[49] describe a 59-year-old man who received tirofiban, a IIb/IIIa inhibitor in the management of coronary occlusion complicated by cardiac arrest. A nosebleed and oropharyngeal, pulmonary, and gastrointestinal bleeding subsequently developed. He was treated with transfusion of packed RBCs, platelets, and FFP and was given 2 boluses of rFVIIa, after which the bleeding stopped. No adverse effects of rFVIIa were observed, and there was no reocclusion of the implanted stent.[49]

The newer anticoagulant fondaparinux is being used postoperatively to prevent venous thrombosis. Bijsterveld et al[50] studied the effect of rFVIIa in neutralizing the anticoagulant effects of subcutaneous fondaparinux. In a randomized, placebo-controlled study of 16 healthy volunteers, rFVIIa normalized the prolonged PT, aPTT, and thrombin time induced by fondaparinux. The baseline PT, which was 13.2 seconds, was prolonged to 14.3 seconds with fondaparinux and corrected to 9.2 seconds following administration of rFVIIa. The baseline PTT, which was 33.5 seconds, was prolonged to 38.8 seconds with fondaparinux and corrected to baseline following rFVIIa administration. The duration of this effect ranged from 2 to 6 hours after rFVIIa injection. The authors concluded that rFVIIa effectively normalizes coagulation times and is useful for reversing the anticoagulant effect of fondaparinux in cases of serious bleeding complications.[50]


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