More to TTP than VWFCP

Recent advances in understanding thrombotic thrombocytopenic purpura (TTP) have been remarkable, but several important questions about pathogenesis remain unanswered. Most adult patients with “idiopathic” TTP have acquired deficiency of plasma von Willebrand factor (VWF) cleaving protease (VWFCP, ADAMTS13), caused by an autoantibody that inhibits the enzyme. VWFCP has been cloned, and mutations in the VWFCP gene have been characterized that cause a congenital form of TTP. The relationship between VWFCP deficiency and TTP is clear. But a substantial number of patients with thrombotic microangiopathy have normal levels of VWFCP. These conditions may be clinically indistinguishable from “classic” idiopathic TTP, and the pathophysiology of these disorders is not understood.

Raife and colleagues (page 437) now have identified factor V Leiden as a distinct genetic risk factor for thrombotic microangiopathy. Factor V Leiden is associated with an increased incidence of venous thrombosis, which is not common in TTP. Blood clotting tests are normal in most cases of idiopathic TTP, indicating that consumption of clotting factors is not a conspicuous feature of the disease. Therefore, factor V Leiden may seem an unlikely candidate to promote thrombotic microangiopathy. But it is clear that disorders of diverse cause converge on a clinical phenotype that includes thrombotic microangiopathy. For example, VWFCP levels are normal in patients with TTP caused by certain chemotherapeutic agents or cyclosporin or by infection with verotoxin-producing bacteria. Some patients with idiopathic TTP and many patients with the clinically similar hemolytic uremic syndrome have normal VWFCP levels.

The mechanism of idiopathic TTP appears to affect platelet thrombus formation by altering VWF-platelet dynamics, and the microvascular lesions contain platelets and VWF but scant fibrin. The possible involvement of factor V Leiden suggests that other mechanisms of TTP may depend on fibrin deposition. If so, perhaps the histopathology of thrombotic microangiopathies should be reexamined.