Recombinant Factor VIIA in the Treatment of Bleeding

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

Disclosures

Am J Clin Pathol. 2004;121(1) 

In This Article

Abstract and Introduction

Abstract

Recombinant factor VIIa (rFVIIa) has become available for treating people with hemophilia with inhibitors who experience bleeding or require surgery. It has become apparent that rFVIIa is useful in controlling bleeding in a variety of clinical situations. This review attempts to collate and summarize the nonhemophilia applications of rFVIIa. The theoretical mechanism for the coagulation and hemostatic effects of rFVIIa are discussed. The dosage and clinical administration are described.

The potential uses for patients with liver disease, anticoagulation-induced bleeding, surgery, thrombocytopenia, thrombasthenia, von Willebrand disease, and other bleeding disorders are reviewed. The use of rFVIIa is evolving, and the indications, dosage, and precautions or contraindications need to be further described and defined. It is an expensive therapy and needs to be prescribed judiciously. This review is meant to be an introduction to this new hemostatic reagent. The uses for rFVIIa will evolve as more studies are published.

Introduction

New advances in medicine are evaluated by their efficacy in clinical trials. However, in certain areas, the numbers of specific patients or the heterogeneity of the patients make prospective clinical trials difficult. In the area of bleeding, the clinical situations often are so varied and multifactorial that physicians have accepted the investigational use of agents to treat life-threatening hemorrhage. This has become the case for treatment of hemorrhage with recombinant factor VIIa (rFVIIa).

Originally, rFVIIa was developed for the treatment of bleeding complications in patients with hemophilia with alloantibodies (inhibitors) against exogenous factor VIII or IX.[1,2,3,4,5,6,7,8,9,10,11] In 1988, rFVIIa was used successfully in patients with inhibitors to these factors.[12] Recently, the effectiveness and safety of rFVIIa in patients with hemophilia with inhibitors has been reported in the hemophilia research society registry.[13] rFVIIa has become available as a recombinant preparation and also has been used in nonhemophiliac conditions. At present, the only US Food and Drug Administration—approved use of rFVIIa is for the treatment of patients with hemophilia with inhibitors. We describe the uses of rFVIIa in conditions unrelated to hemophilia and the treatment of acquired inhibitors of factors VIII and IX. Some of the limitations in the use of rFVIIa at present are related to the cost of the drug. As clinical use and experience increase and the cost of rFVIIa decreases, the indications for the use of rFVIIa may change drastically. rFVIIa might become the treatment of choice in selected cases of massive hemorrhage, but more data are needed before this occurs.

Hemostasis is a physiologic mechanism that maintains blood in a fluid state within the circulation. The coagulation of blood is maintained by cellular components and soluble plasma proteins. In response to vascular injury, circulating platelets adhere, aggregate, and provide cell surface phospholipids for the assembly of blood clotting enzyme complexes, thrombin activation, and fibrin formation. Simultaneously fibrinolysis is initiated.

At the site of injury, tissue factor (TF) and factor VIIa activate factors X and IX. Thrombin is generated, and fibrin is formed.[14,15] When there are low levels of factor VIII or IX, the formation of thrombin is slow (Figure 1). When pharmacologic doses of rFVIIa are given, there is a marked enhancement of thrombin formation. This increase in the thrombin burst occurs after direct rFVIIa activation of factors IX and X on the surface of activated platelets (even in the absence of factor VIII or IX). It is postulated that the thrombin-generating capacity of rFVIIa is enhanced substantially by platelets accumulating at the site of vascular damage (Figure 2). This increase in the rate of thrombin formation with large doses of rFVIIa permits the formation of fibrin, which is less susceptible to lysis. The decrease in fibrinolysis might be due to an increase in thrombin-activatable fibrinolysis inhibitor and an increase in factor XIIIa. The rFVIIa seems to work in a TF-independent manner directly on factors IX and X on the phospholipid surface of activated platelets. rFVIIa is able to activate factor X on phospholipid vesicles, activated platelets, or monocytes independent of TF, although the TF-independent generation of thrombin is much less efficient than the TF-dependent thrombin generation by rFVIIa.[16] Impaired thrombin formation caused by a low number of platelets with functional defects or defects due to consumptive or dilutional processes might be overcome by treatment with rFVIIa (Figure 1).

Figure 1.

Tissue factor—dependent action of recombinant factor VIIa. The tissue factor—dependent pathway is shown by gray shading. Dashed lines represent site of major inhibitors. AP, α-antiplasmin; APC, activated protein C; FDP, fibrin split products; PAI, plasminogen activator inhibitor; PC, protein C; PS, protein S; TAFI, thrombin-activatable fibrinolysis inhibitor; TFPI, tissue factor pathway inhibitor; TM, thrombomodulin; TPA, tissue plasminogen activator; UK, urokinase.

Figure 2.

Tissue factor—independent mechanism of recombinant factor VIIa (rFVIIa)-enhanced hemostasis.

It is important to note that although global tests such as the prothrombin time (PT) are shortened by in vivo treatment with rFVIIa, there is little evidence to suggest that substantial fibrin is formed or remains anywhere except where there is tissue trauma.

rFVIIa has become available as a recombinant preparation and has been used in hemophilia and in nonhemophilia conditions. A large number of case reports and studies show that rFVIIa might be effective for prevention and treatment of bleeding in patients with inherited and acquired hemophilia, overanticoagulation, renal failure, liver disease, liver transplantation, intractable bleeding, platelet disorders, and congenital severe factor VII deficiency.[17] However, most are anecdotal case reports and small series. This review attempts to collate these reports and discuss the reported uses of rFVIIa ( Table 1 ).

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