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Improved survival with plasma exchange in patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome
CORRESPONDENCE IMPROVED SURVIVAL WITH PLASMA EXCHANGE IN PATIENTS WITH THROMBOTIC THROMBOCYTOPENIC PURPURA-HEMOLYTIC UREMIC SYNDROME To the Editor: We read with interest the recent article by Lara et al (1), in which they purported to show an improved prognosis in patients with so-called thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) treated with plasmapheresis. While we agree that this is an important issue, we have five concerns about the validity of the authors’ approach and conclusions. First, the study population is very heterogeneous and includes patients with different types of HUS and TTP. Although these two syndromes are phenotypically similar, they have different causes, pathogeneses, treatments, and outcomes; and it is unwise to group them together. The commonest type of HUS, caused by Escherichia coli, is now called Shiga toxin HUS (Stx HUS) (2). There is no evidence whatsoever that this condition requires treatment with plasmapheresis. TTP itself is now known to consist of several different conditions based on the presence of autoantibodies to von Willebrand factor– cleaving protease in some cases (3,4) and a constitutional defect in these proteases in others (5). Patients who develop TTP after treatment with the antiplatelet drugs ticlopidine or clopidogrel also have autoantibodies to von Willebrand factor– cleaving protease (6 – 8). By removing these autoantibodies, plasmapheresis may benefit some patients with TTP. No abnormalities in von Willebrand factor–cleaving protease have been found in patients with HUS (4,5). This recent evidence for the importance of abnormal activity of cleaving 156
䉷2001 by Excerpta Medica, Inc. All rights reserved.
protease responsible for the degradation of very large von Willebrand factor multimers in TTP suggests that incorporation of this new diagnostic test will be vital for proper assessment of any proposed treatment modality for TTP. Second, the study had no controls, and in view of the variable courses of these syndromes, it may be unwarranted to conclude that plasmapheresis exerted any benefit. Third, there are serious problems of ascertainment because these cases were referred to an apheresis center. Fourth, different regimens were used over the long retrospective period of the study. Fifth, the study end points are poorly defined and the duration of follow-up may not be adequate to accurately gauge the utility of plasmapheresis in TTP. We recognize the serious nature of TTP and the severity of the morbidity and long-term sequelae of this syndrome. However, until a carefully planned randomized clinical trial is performed that incorporates stateof-the-art diagnostic tools and more precise case definitions, we think that it is premature to conclude that plasmapheresis is beneficial for patients with TTP. As for Stx HUS, there is not a shred of evidence that it is of any value. Thousands of children with Stx HUS have been treated successfully all over the world without using this expensive and potentially dangerous treatment. Bernard S. Kaplan, MD Children’s Hospital of Philadelphia Philadelphia, Pennsylvania Howard Trachtman, MD Schneider Children’s Hospital of the North Shore-LIJ Health System New Hyde Park, New York 1. Lara PN Jr, Coe TL, Zhou H, et al. Improved survival with plasma exchange in patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Am J Med. 1999;107:573–579. 2. Kaplan BS, Meyers KW, Schulman SL. The
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pathogenesis and treatment of hemolytic uremic syndrome. J Am Soc Nephrol. 1998; 9:1126 –1133. Moake IL. Moschcowitz, multimers, and metalloprotease. N Engl I Med. 1998;339: 1629 –1631. Tsai JIM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med. 1998;339:1585–1594. Furlan M, Robles R, Galbusera M, et al. Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med. 1998;339:1578 –1584. Gerritsen HE, Turecek PL, Schwarz HP, et al. Assay of von Willebrand factor (vWF)cleaving protease based on decreased collagen binding affinity of degraded vWF: a tool for the diagnosis of thrombotic thrombocytopenic purpura. Thromb Haemost. 1999; 82:1386 –1389. Tsai JIM, Rice L, Sarode R, et al. Antibody inhibitors to von Willebrand factor metalloproteinase and increased binding of von Willebrand factor to platelets in ticlopidineassociated thrombotic thrombocytopenic purpura. Ann Intern Med. 2000;132:794 – 799. Bennett CL, Connors JM, Carwile JM, et al. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med. 2000;342:1773–1777.
The Reply: Kaplan and Trachtman raise several issues regarding our recent retrospective study on plasma exchange in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) (1). While we agree that HUS and TTP may indeed be different (based on recent data about the lack of von Willebrand factor– cleaving protease activity in TTP and not in HUS), most hematologists treating adults over the last 2 decades have approached TTP and HUS as a continuum of the same disorder (2). This is different from the approach by pediatricians, who often do not treat HUS with plasma exchange. There is no evidence that being able to distinguish the two entities pathogenetically will mean that the treatment approach will change. Incorporating a test for von Willebrand factor– cleaving protease activity should help sort out the 0002-9343/01/$–see front matter PII S0002-9343(00)00696-3
䉷2001 by Excerpta Medica, Inc. All rights reserved.
protease responsible for the degradation of very large von Willebrand factor multimers in TTP suggests that incorporation of this new diagnostic test will be vital for proper assessment of any proposed treatment modality for TTP. Second, the study had no controls, and in view of the variable courses of these syndromes, it may be unwarranted to conclude that plasmapheresis exerted any benefit. Third, there are serious problems of ascertainment because these cases were referred to an apheresis center. Fourth, different regimens were used over the long retrospective period of the study. Fifth, the study end points are poorly defined and the duration of follow-up may not be adequate to accurately gauge the utility of plasmapheresis in TTP. We recognize the serious nature of TTP and the severity of the morbidity and long-term sequelae of this syndrome. However, until a carefully planned randomized clinical trial is performed that incorporates stateof-the-art diagnostic tools and more precise case definitions, we think that it is premature to conclude that plasmapheresis is beneficial for patients with TTP. As for Stx HUS, there is not a shred of evidence that it is of any value. Thousands of children with Stx HUS have been treated successfully all over the world without using this expensive and potentially dangerous treatment. Bernard S. Kaplan, MD Children’s Hospital of Philadelphia Philadelphia, Pennsylvania Howard Trachtman, MD Schneider Children’s Hospital of the North Shore-LIJ Health System New Hyde Park, New York 1. Lara PN Jr, Coe TL, Zhou H, et al. Improved survival with plasma exchange in patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Am J Med. 1999;107:573–579. 2. Kaplan BS, Meyers KW, Schulman SL. The
3.
4.
5.
6.
7.
8.
pathogenesis and treatment of hemolytic uremic syndrome. J Am Soc Nephrol. 1998; 9:1126 –1133. Moake IL. Moschcowitz, multimers, and metalloprotease. N Engl I Med. 1998;339: 1629 –1631. Tsai JIM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med. 1998;339:1585–1594. Furlan M, Robles R, Galbusera M, et al. Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med. 1998;339:1578 –1584. Gerritsen HE, Turecek PL, Schwarz HP, et al. Assay of von Willebrand factor (vWF)cleaving protease based on decreased collagen binding affinity of degraded vWF: a tool for the diagnosis of thrombotic thrombocytopenic purpura. Thromb Haemost. 1999; 82:1386 –1389. Tsai JIM, Rice L, Sarode R, et al. Antibody inhibitors to von Willebrand factor metalloproteinase and increased binding of von Willebrand factor to platelets in ticlopidineassociated thrombotic thrombocytopenic purpura. Ann Intern Med. 2000;132:794 – 799. Bennett CL, Connors JM, Carwile JM, et al. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med. 2000;342:1773–1777.
The Reply: Kaplan and Trachtman raise several issues regarding our recent retrospective study on plasma exchange in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) (1). While we agree that HUS and TTP may indeed be different (based on recent data about the lack of von Willebrand factor– cleaving protease activity in TTP and not in HUS), most hematologists treating adults over the last 2 decades have approached TTP and HUS as a continuum of the same disorder (2). This is different from the approach by pediatricians, who often do not treat HUS with plasma exchange. There is no evidence that being able to distinguish the two entities pathogenetically will mean that the treatment approach will change. Incorporating a test for von Willebrand factor– cleaving protease activity should help sort out the 0002-9343/01/$–see front matter PII S0002-9343(00)00696-3