Thrombosis in patients with paroxysmal noctural hemoglobinuria is associated with markedly elevated plasma levels of leukocyte-derived tissue factor.

Thromboembolism is a frequent complication of paroxysmal nocturnal hemoglobinuria (PNH) and contributes significantly to patient morbidity and mortality. A number of mechanisms have been proposed to explain the increased incidence of this complication of PNH. Increased platelet activation with platelet microparticle formation and depression of cell surface-mediated fibrinolysis has been demonstrated in patients with PNH. We have studied two patients with hemolytic PNH who had recurrent and refractory venous thromboembolic events despite therapeutic anticoagulation. Plasma samples from both patients demonstrated marked hemostatic activation as determined by elevated plasma thrombin-antithrombin complexes (TAT) and D-dimers. Plasma samples from both patients were also shown to contain markedly elevated levels of circulating tissue factor (TF), which was shown to be predominantly derived from monocytes and macrophages. In one patient, a successful allogeneic bone marrow transplant resulted in a reduction in hemostatic activation associated with a marked decrease in circulating tissue factor to near normal levels. We propose that thrombosis in PNH results from increased tissue factor expression by complement injured CD55- and CD59-deficient monocytes and macrophages.