Clinical Pearls & Morning Reports
Published January 23, 2019
Over the past two decades, despite a better understanding of the pathophysiological characteristics of thrombotic thrombocytopenic purpura (TTP), treatment outcomes have not changed substantially, with recent mortality rates reported to be as high as 20%. Scully et al. conducted a randomized, double-blind, placebo-controlled trial to assess the potential role of caplacizumab in the treatment of TTP with respect to the time to normalization of the platelet count, as well as other outcomes. Read the NEJM Original Article here.
Q: Describe the pathophysiology of immune-mediated TTP.
A: Acquired or immune-mediated TTP is a rare thrombotic microangiopathy that is characterized by thrombocytopenia and hemolytic anemia. Autoantibodies inhibit activity of the von Willebrand factor–cleaving protease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), which leads to platelet consumption in von Willebrand factor–platelet aggregates and microvascular thrombosis. The ensuing tissue ischemia and multiorgan dysfunction may result in thromboembolic events and death. Death occurs primarily during the acute phase, as a result of uncontrolled formation of microvascular thrombi.
Q: What is caplacizumab?
A: The current treatments for TTP — plasma exchange and immunosuppression — replenish functional ADAMTS13 enzyme and control the underlying autoimmune disease but do not directly address the microvascular thrombosis. Caplacizumab, an anti–von Willebrand factor humanized, bivalent variable-domain-only immunoglobulin fragment, inhibits interaction between von Willebrand factor multimers and platelets, a step in the formation of thrombi.
A: In the phase 3 trial by Scully et al., the time to normalization of the platelet count was shorter among patients who had received caplacizumab than among those who had received placebo, presumably because caplacizumab prevented the consumption of platelets in microthrombi. The trial also showed that treatment with caplacizumab resulted in a lower incidence of a composite of TTP-related death, recurrence of TTP, or a major thromboembolic event during the trial treatment period and a lower incidence of recurrence during the overall trial period than placebo. Refractory disease developed in no patients in the caplacizumab group and in three patients in the placebo group (P=0.06). The effect of treatment with caplacizumab on the time to normalization of the platelet count and on the incidence of recurrence was also reflected in the fewer number of days of plasma exchange and the shorter stays in the hospital and in the intensive care unit among patients who received caplacizumab than among those who received placebo.
A: Safety results in the trial by Scully et al. were consistent with those reported previously, including an increased risk of bleeding. Bleeding-related adverse events were reported in 46 patients (65%) in the caplacizumab group and in 35 patients (48%) in the placebo group. The most common such events were epistaxis and gingival bleeding; all these events resolved, most without intervention. Serious adverse events of bleeding were reported in 8 patients (11%) in the caplacizumab group and in 1 patient (1%) in the placebo group. The most commonly reported serious adverse event of bleeding was epistaxis, which occurred in 4 patients in the caplacizumab group.