Clinical use of recombinant human activated factor VII (rFVIIa) in the prevention and treatment of bleeding episodes in patients with Glanzmann's thrombasthenia

Abstract

Glanzmann's thrombasthenia (GT) is a congenital qualitative platelet disorders due to the deficiency or defect of platelet membrane GPIIb/IIIa (integrin alpha(IIb)beta3). The standard treatment for bleeding is platelet transfusion but repeated transfusion may result in the development of anti-platelet antibodies (to HLA and/or GPlIbIIIa) rendering future platelet transfusion ineffective. Alternative effective agent(s) are needed. There are increasing reports documenting efficacy of high dose rFVIIa in GT patients with adverse events uncommon. The efficacy is supported by evidence that high concentration FVIIa binds to activated platelet surface and improves thrombin generation to enhance deposition (adhesion) and aggregation of platelets lacking GPIIb/IIIa. While there are increasing clinical experiences, evidence-based clinical data are not available. There is a need for more clinical studies, particularly clinical trials, to further assess the efficacy, safety (particularly thrombotic events) and optimal regimen ofrFVIIa in GT patients, either singly or in combination with other hemostatic agents such as platelet transfusion. In the absence of this data, for treatment of severe bleeding in GT patients with platelet antibodies and platelet refractoriness, rFVIIa at dose 90 microg/kg every 2 h for 3 or more doses could be considered. This more "optimal regimen" derived from a recent International Survey needs confirmation with larger studies. What the optimal regimen for surgical coverage is remains unresolved.

Figure 1

Schematic tissue factor-independent, platelet-dependent model of primary hemostatic plug formation in Glanzmann’s thrombasthenia (GT) platelets deficient in membrane glycoprotein (GP) IIb-IIIa (integrin a_IIbβ₃). FVIIa-tissue factor (TF) complex on TF-bearing cells at the site of vascular injury activates FX to FXa, which in turn complexes with FVa on the TF-bearing cells to initiate generation of a small amount of thrombin (FIIa) from prothrombin (FII). This initially generated thrombin is not sufficient to allow fibrin formation, but is sufficient to activate the GT platelets, causing degranulation and release of FV. FVIIa binds to activated platelets weakly. At high concentration (eg, high dose rFVIIa therapy), the bound FVIIa can directly activate FX to FXa to mediate generation of high concentration of thrombin (thrombin burst). The augmented thrombin generation results in increased number of activated platelets deposited (adhesion) to the wound site, and increased available platelet procoagulant surface to facilitate more thrombin generation and more platelet activation. The augmented thrombin generated also converts fibrinogen to fibrin. Activated GT platelets cannot utilize fibrinogen for aggregation reaction as they lack the fibrinogen receptor integrin a_IIbβ₃. However, binding of fibrin/polymeric fibrin to an as yet unidentified platelet surface receptor can mediate aggregation of the GT platelets at the wound site (even though less potent than fibrinogen mediated aggregation of normal platelets) resulting in primary hemostatic plug formation. Adapted from Poon (2006).