The Quebec platelet disorder (QPD) is a rare, autosomal dominant bleeding disorder that was characterized initially by a deficiency of platelet-associated factor V (Tracy et al, J Clin Invest. 1984;74:1221-1228). Subsequent studies revealed that QPD is associated with proteolytic degradation of multiple platelet alpha-granule proteins (Janeway et al, Blood. 1996;87:3571-3578) and that urinary-type plasminogen activator (u-PA) levels within platelet alpha-granules are markedly elevated in QPD patients compared to normal controls (Kahr et al, Blood. 2001;98:257-265). In addition to compromising hemostasis by catalyzing degradation of factor V and other alpha-granule proteins, such as von Willebrand factor (vWF), overexpression of platelet u-PA could cause bleeding by promoting fibrinolysis as platelets are activated and release their contents at sites of clot formation.
In this issue, Kufrin and colleagues (page 926) have shed light on this interesting platelet disorder by generating transgenic mice with platelet-specific u-PA overexpression. As with QPD patients, transgenic mice exhibited a bleeding diathesis that was corrected with orally administered fibrinolysis inhibitors. Lysates of transgenic platelets rapidly degraded factor V. Platelet von Willebrand factor and fibrinogen were degraded in transgenic mice, while there was no evidence of a fibrinolytic state in plasma. Platelet-specific u-PA expression protected mice against thrombosis, and transfusion experiments revealed that overexpression of u-PA within only a minor population of the total pool of circulating platelets was sufficient to confer an antithrombotic effect.
These detailed studies demonstrate that platelet-specific overexpression of u-PA recapitulates the phenotype of QPD and suggest that the abnormal bleeding in this disorder may result predominantly from u-PA-induced hyperfibrinolysis within the environment of the hemostatic plug, as opposed to proteolytic degradation of platelet alpha-granule components. The studies by Kufrin and colleagues also support the intriguing potential of targeting expression of fibrinolytic and hemostatic proteins to the platelet alpha-granule as a strategy to treat thrombotic and bleeding disorders.
