Glanzmann thrombasthenia (GT) is a rare inherited autosomal recessive
bleeding disorder of platelet function caused by a quantitative or qualitative defect of
platelet membrane glycoprotein IIb/IIIa (
integrin αIIbβ3), a
fibrinogen receptor required for platelet aggregation. Bleeds in GT are variable and may be severe and unpredictable.
Bleeding not responsive to local and adjunctive measures, as well as
surgical procedures, is treated with platelets, recombinant
activated factor VII (
rFVIIa), or
antifibrinolytics, alone or in combination. Although platelets are the standard treatment for GT, their use is associated with the risk of
blood-borne infection transmission and may also cause the development of platelet
antibodies (to
human leukocyte antigens and/or αIIbβ3), potentially resulting in platelet refractoriness. Currently, where
rFVIIa is approved for use in GT, this is mostly for patients with platelet
antibodies and/or a history of platelet refractoriness. However, data from the prospective Glanzmann's
Thrombasthenia Registry (829 bleeds and 206 procedures in 218 GT patients) show that
rFVIIa was frequently used in nonsurgical and surgical bleeds, with high efficacy rates, irrespective of platelet
antibodies/refractoriness status. The mechanisms underpinning
rFVIIa effectiveness in GT have been studied. At therapeutic concentrations,
rFVIIa binds to activated platelets and directly activates FX to FXa, resulting in a burst of
thrombin generation.
Thrombin converts
fibrinogen to
fibrin and also enhances GT platelet adhesion and aggregation mediated by the newly converted (polymeric)
fibrin, leading to primary hemostasis at the
wound site. In addition,
thrombin improves the final clot structure and activates
thrombin-activatable fibrinolysis inhibitor to decrease clot lysis.