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 α-granules—including fibrinogen, von Willebrand factor (vWF), and factor V—are 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 α-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.