Blood, 15 July 2001, Vol. 98, No. 2, pp. 255-255
Questions from Quebec
Platelets promote hemostasis by releasing plasminogen activator
inhibitor 1 (PAI-1), which protects the clot against premature lysis.
Platelet-rich arterial clots require high concentrations of plasminogen
activators to be lysed. What would happen if platelets began to express
antithrombotic or fibrinolytic activity?
Patients with the Quebec platelet disorder (QPD) have a hemorrhagic
disorder. Bleeding is typically delayed and responds to antifibrinolytic therapy, but not to platelet transfusions. The Hamilton group previously discovered that several constituents of QPD
platelet 
-granules
including fibrinogen, von Willebrand factor
(vWF), and factor Vare degraded, whereas membrane and dense granule
proteins are spared. QPD serum contains elevated levels of fibrinogen
degradation products, but the plasma content is normal. These findings
suggest that QPD platelets contain a protease with broad substrate specificity.
The studies of Kahr and colleagues (page 257) represent another step
toward unraveling the pathogenesis of this uncommon, but informative,
disease. They demonstrate that QPD -granules contain increased
amounts of urokinase, which overwhelms platelet PAI-1 and proteolyzes
several coagulation-related proteins stored in these granules. The
presence of uPA mRNA in QPD but not normal platelets
suggests the abnormality results from increased synthesis.
In addition to addressing the pathophysiology of the QPD defect, these
sentinel observations raise several interesting scientific questions.
Is the ectopic expression due to a mutation in the promoter sequence of
the urokinase gene or to a modifier gene, as has been described
for vWF (Cell. 1999;96:111)? Is the urokinase activated by
another protease, as may occur in plasminogen deficient mice, or might
autoactivation (J Biol Chem. 1998;273:7457) occur in the granule
milieu? Are the granular proteins proteolyzed by urokinase, by
activation of plasminogen taken up by megakaryocytes, or by activating
another protease? These studies also raise the notion of targeting
proteins to the platelet granules as a means to deliver fibrinolytic
agents to platelet-rich clots.
Douglas B. Cines
University of Pennsylvania
