Optimal use of recombinant factor VIIa in the control of bleeding episodes in hemophilic patients

Abstract

One of the last remaining clinical hurdles in the treatment of people with hemophilia is the development of inhibitors. Alloantibodies or autoantibodies directed at coagulation factors render the infusion of coagulation factor concentrates ineffective, and alternative means must be used to achieve hemostasis. Recombinant factor VIIa (rFVIIa) was developed to control bleeding episodes in hemophilic patients with inhibitors. Clinical efficacy in achieving hemostasis in inhibitor patients was demonstrated by a compassionate-use protocol, as well as in randomized controlled trials. To date, over 1.5 million doses of rFVIIa have been given to inhibitor patients, with an excellent efficacy and safety record. Because of its short half-life, alternative means of dosing and infusing rFVIIa have been explored and are reviewed here.

Keywords: factor VIIa; hemophilia; inhibitor; inhibitors; recombinant.

Figure 1

Tissue factor initiated blood coagulation. During the initiation phase, blood becomes exposed to TF-bearing cells. Inactivated Factor VII and VIIa compete for binding with TF. Once the TF: VIIa complex is formed, X is activated to factor Xa. Factor Xa and Va form the prothrombinase complex which converts prothrombin (II) to thrombin (IIa). The nanomolar amount of thrombin generated can activate platelets, Factor V, VIIIa, and XIa. Small amounts of fibrinogen are converted to fibrin by thrombin, but not enough to form a stable clot. The initiation phase is rapidly inhibited by TFPI. In order to form a stable clot, a burst in thrombin activity is required, which occurs through the propagation phase. XIa can activate IXa, with the resulting IXa: VIIIa forming the Xase complex. This complex can form Xa. Additional prothrombinase is formed, which activates thrombin which can feed back and generate more XIa, thus creating a burst in thrombin activity. In addition to generating a sufficient amount of fibrin for stable clot formation, the burst in thrombin activity also generates TAFI which inhibits fibrinolysis. Fibrin is cross-linked by XIIIa, which is activated by thrombin. Solid arrows indicate activation. Dashed arrows indicate inhibition. Blue equals the initiation phase. Red equals the propagation phase. Purple equals both. Green arrows indicate substances activated by thrombin. Brown indicates inhibitors of coagulation. Abbreviations: TAFI, thrombin-activatable fibrinolysis inhibitor; TF, tissue factor; TFPI, tissue factor pathway inhibitor; VIIa, activated factor VII; X, factor X; Va, factor Va; VIIIa, activated factor VIII; XIa, activated factor XI; IXa, activated factor IX.

Figure 2a

Cell-mediated model of normal coagulation. The TF: VIIa complex forms on a TF-bearing cell. Prothrombinase then forms on this cell membrane to generate thrombin. Additional thrombin is propagated through XIa and the Xase and prothrombinase complexes formed on the surface of activated platelets. Abbreviations: TF, tissue factor; VIIa, activated factor VII; XIa, activated factor XI.

Figure 2b

Cell-mediated model in a hemophilic patient with an inhibitor. The TF:VIIa complex and prothrombinase complex can generate thrombin, however the propagation phase cannot occur due to the absence of factors VIII or IX. TFPI rapidly inhibits the TF:VIIa complex. Abbreviations: TF, tissue factor; VIIa, activated factor VII; TFPI, tissue factor pathway inhibitor.

Figure 2c

Cell-mediated model with supraphysiologic VIIa. rVIIa can outcompete factor VII for TF binding. Thrombin is generated by the TF: rFVIIa complex and prothrombinase as above. This can be inhibited by TFPI. In addition, a burst in thrombin activity is restored by the activation of factor X by rFVIIa present on the surface of activated platelets. Abbreviations: VIIa, activated Factor VII; rVIIa, recombinant activated Factor VII; TF, tissue factor; TFPI, tissue factor pathway inhibitor.