The reply:

Abstract

Kaplan and Trachtman raise several issues regarding our recent retrospective study on plasma exchange in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) (1Lara P.N. Coe T.L. Zhou H. et al.Improved survival with plasma exchange in patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.Am J Med. 1999; 107: 573-579Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar). 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 (2George J.N. How I treat patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.Blood. 2000; 96: 1223-1229Crossref PubMed Google Scholar). 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 diagnosis, but this was obviously unavailable during the 20-year period of our study. Interestingly, in the 1991 study by Bell et al (3Bell W. Braine H.G. Ness P. Kickler T.S. Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome clinical experience in 108 patients.N Engl J Med. 1991; 325: 398-403Crossref PubMed Scopus (702) Google Scholar), patients with clinically defined HUS were successfully treated with plasma exchange. At that time, those patients were thought to be resistant to conservative treatment. We clearly stated that the study was a retrospective cohort analysis in 126 consecutive patients and, therefore, was not a controlled trial. The survival improvement was based on comparisons with published historic controls. Before widespread plasma exchange, a review by Amorosi and Ultmann (4Amorosi E.L. Ultman J.E. Thrombotic thrombocytopenic purpura report of 16 cases and review of literature.Medicine. 1966; 45: 139-159Crossref Scopus (757) Google Scholar) showed that the mortality rate was 90%. We found a 30-day mortality rate of 10% in the 122 patients who received plasma exchange as the principal treatment. This is an advance over the reported outcomes 30 years ago. We acknowledge the ascertainment bias; however, all patients diagnosed in our region with TTP-HUS were treated. One always has an ascertainment bias based on a proper diagnosis. We also acknowledged the variation in regimens over the 2-decade period as a limitation that must be considered when interpreting the results of the study. This is clearly indicated in our discussion section. We disagree that our study end points were “poorly defined.” On the contrary, the study end points (or outcome variables) were clearly defined by laboratory and mortality criteria. The median follow-up is likewise clearly stated and is commensurate with other studies. We also disagree that there are insufficient data to conclude that plasmapheresis is beneficial for TTP, as clinically defined. The efficacy of plasma exchange compared with plasma infusion has already been confirmed in a prospective randomized trial conducted by the Canadian Apheresis Study Group (5Rock G.A. Shumak K.H. Buskard N.A. et al.Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura.N Engl J Med. 1991; 325: 393-397Crossref PubMed Scopus (1509) Google Scholar). With regard to HUS, until there is a clearly defined separation between TTP and HUS (especially in adult patients) that has been shown in a prospective study to be able to separate patients requiring plasma exchange from those who do not, we believe it is hazardous to withhold potentially life-saving therapy from adult patients with clinically defined HUS. The seminal work of Furlan et al (6Furlan 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: 1578-1584Crossref PubMed Scopus (1465) Google Scholar) and Tsai and Lian (7Tsai H.M. Lian E.C. Antibodies to Von Willebrand factor cleaving protease in acute thrombotic thrombocytopenic purpura.N Engl J Med. 1998; 339: 1585-1594Crossref PubMed Scopus (1461) Google Scholar) has indeed brought hope that these entities, which are clinically similar and oftentimes difficult to separate, can indeed be distinguished. However, this notion must first be tested in a rigorous fashion, and we believe that it is too early to base clinical decisions on the presence or absence of von Willebrand factor–cleaving protease activity.