The role of pulse dexamethasone in acquired idiopathic thrombotic thrombocytopenic purpura.

Abstract

Thrombotic thrombocytopenic purpura (TTP) was characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia and neurological deficits. Acquired idiopathic TTP is usually associated with inhibitory autoantibody to von Willebrand factor (VWF)‐cleaving metalloprotease, ADAMTS13 [1Furlan M. Robles R. Galbusera M. Remuzzi G. Kyrle P.A. Brenner B. Krause M. Scharrer I. Aumann V. Mittler U. Solenthaler M. Lammle B. Willebrand factor‐cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic‐uremic syndrome.N Engl J Med. 1998; 339: 1578-84Crossref PubMed Scopus (1484) Google Scholar, 2Tsai H.M. Lian E.C. Antibodies to von Willebrand factor‐cleaving protease in acute thrombotic thrombocytopenic purpura.N Engl J Med. 1998; 339: 1585-94Crossref PubMed Scopus (1492) Google Scholar, 3Rieger M. Mannucci P.M. Kremer Hovinga J.A. Herzog A. Gerstenbauer G. Konetschny C. Zimmermann K. Scharrer I. Peyvandi F. Galbusera M. Remuzzi G. Bohm M. Plaimauer B. Lammle B. Scheiflinger F. ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases.Blood. 2005; 106: 1262-7Crossref PubMed Scopus (241) Google Scholar]. Ensuing severe deficiency of this enzyme allows endothelium‐derived unusually large VWF (uLVWF) to agglutinate platelets forming platelet‐rich thrombi under high shear stress. The mortality rate of TTP decreased from 90% to as low as 10% by the introduction of plasma exchange that not only removes the autoantibody, but also replenishes the ADAMTS‐13 [4Rock G.A. Shumak K.H. Buskard N.A. Blanchette V.S. Kelton J.G. Nair R.C. Spasoff R.A. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group.N Engl J Med. 1991; 325: 393-7Crossref PubMed Scopus (1550) Google Scholar]. However, a subset of patients is dependent on or, refractory to, prolonged repeated plasma exchanges. In addition, TTP with severely deficient ADAMTS‐13 due to autoantibody frequently relapses requiring repeated treatments [5Vesely S.K. George J.N. Lammle B. Studt J.D. Alberio L. El‐Harake M.A. Raskob G.E. ADAMTS13 activity in thrombotic thrombocytopenic purpura‐hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients.Blood. 2003; 102: 60-8Crossref PubMed Scopus (577) Google Scholar, 6Zheng X.L. Kaufman R.M. Goodnough L.T. Sadler J.E. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura.Blood. 2004; 103: 4043-9Crossref PubMed Scopus (385) Google Scholar, 7Veyradier A. Obert B. Houllier A. Meyer D. Girma J.P. Willebrand factor‐cleaving protease in thrombotic microangiopathies: a study of 111 cases.Blood. 2001; 98: 1765-72Crossref PubMed Scopus (365) Google Scholar]. Because plasma products pose a risk for transfusion‐transmitted infections, immunosuppressive agents, such as steroid, vincristine, rituximab and cyclosporine, have been investigated for their adjunctive roles in this autoimmune disorder. In one study, rituximab was found to induce clinical remission in six acute refractory TTP patients with undetectable ADAMTS‐13 by suppressing autoantibody production [8Fakhouri F. Vernant J.P. Veyradier A. Wolf M. Kaplanski G. Binaut R. Rieger M. Scheiflinger F. Poullin P. Deroure B. Delarue R. Lesavre P. Vanhille P. Hermine O. Remuzzi G. Grunfeld J.P. Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13‐deficient thrombotic thrombocytopenic purpura: a study of 11 cases.Blood. 2005; 106: 1932-7Crossref PubMed Scopus (231) Google Scholar]. However, in addition to the high cost of treatment, the reported responses were slow, 4–6 weeks after initiation, and patients still required plasma infusion during that period [8Fakhouri F. Vernant J.P. Veyradier A. Wolf M. Kaplanski G. Binaut R. Rieger M. Scheiflinger F. Poullin P. Deroure B. Delarue R. Lesavre P. Vanhille P. Hermine O. Remuzzi G. Grunfeld J.P. Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13‐deficient thrombotic thrombocytopenic purpura: a study of 11 cases.Blood. 2005; 106: 1932-7Crossref PubMed Scopus (231) Google Scholar]. Although commonly used, the efficacy of corticosteroid in TTP remains to be confirmed. In a large series by Bell et al. [9Bell W.R. Braine H.G. Ness P.M. 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 (718) Google Scholar], a very high dose of steroid alone (200 mg day−1 prednisolone) could induce remission in 30 of 54 mild TTP‐hemolytic uremic syndrome patients who did not present with neurological deficits. Interestingly, the responses were usually within 48–72 h of treatment [9Bell W.R. Braine H.G. Ness P.M. 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 (718) Google Scholar]. In addition, another case report demonstrated the efficacy of 1 g day−1 of methylprednisolone with dipyridamole [10Toyoshige M. Zaitsu Y. Okafuji K. Inoue Y. Hiroshige Y. Matsumoto N. Kaku K. Kaneko T. Successful treatment of thrombotic thrombocytopenic purpura with high‐dose corticosteroid.Am J Hematol. 1992; 41: 69Crossref PubMed Scopus (15) Google Scholar]. As pulse dexamethasone had been shown to be very effective in idiopathic thrombocytopenic purpura (ITP), another autoantibody‐mediated disorder [11Cheng Y. Wong R.S. Soo Y.O. Chui C.H. Lau F.Y. Chan N.P. Wong W.S. Cheng G. Initial treatment of immune thrombocytopenic purpura with high‐dose dexamethasone.N Engl J Med. 2003; 349: 831-6Crossref PubMed Scopus (246) Google Scholar], we tried it in two TTP cases with severe ADAMTS‐13 deficiency and prolonged courses. They could promptly be withdrawn from plasma therapy using pulse dexamethasone as a sole treatment. A 75‐year‐old woman presented with multiple ecchymoses without any neurological deficit or fever. Her complete blood count (CBC) showed hemoglobin (Hb) 8.3 g dL−1, normal WBC, platelet 39 × 109 L−1, and lactate dehydrogenase (LDH) was 3520 U L−1 (normal 230–460). Blood smear revealed frank MAHA. ADAMTS‐13 activity using the residual collagen‐binding assay [12Mannucci P.M. Canciani M.T. Forza I. Lussana F. Lattuada A. Rossi E. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor.Blood. 2001; 98: 2730-5Crossref PubMed Scopus (425) Google Scholar] was <3% with 1.4 U mL−1 of inhibitor. Platelet counts and treatments were illustrated in Fig. 1A. After 5‐day plasma infusion, the platelet count rose to 343 × 109 L−1, ADAMTS‐13 to 30% but LDH was 1321 U L−1. She refused further plasma infusion and went home with 40 mg day−1 prednisolone. Two weeks later, she was asymptomatic but the platelet count fall to 20 × 109 L−1 and LDH 3560 U L−1. After five sessions of plasma exchange in 10 days, platelet count and LDH were normalized. Two weeks later, her platelet count was 16 × 109 L−1, but she insisted to go home against advice. Dexamethasone 40 mg day−1 was given orally for 4 days, followed by prednisolone 10 mg day−1. She came 2 weeks later with platelet count of 373 × 109 L−1 and 565 U L−1 LDH. Prednisolone 5 mg day−1 was given. Three weeks later, Hb, platelet count and LDH was 9.5 g dL−1, 24 × 109 L−1 and 2556 U L−1, respectively. The second pulse dexamethasone was prescribed, followed by 15 mg day−1 prednisolone. She, again, showed a dramatic improvement. Seven months after TTP diagnosis, she developed right hemiparesis and aphasia from a small cerebral infarction. Her platelet count was 14 × 109 L−1 and LDH was 1030 U L−1. She received pulse dexamethasone for 4 days and two units of cryosupernatant plasma infusion once daily for 2 days. Her symptoms were markedly improved with only minimal weakness of the hand and the platelet count became normal within 4 days but serum LDH was still high. The muscle power was completely recovered in 1–2 weeks. Pulse dexamethasone was then given every month for 3 months. At 7 months after the second episode, platelet count and LDH were normal with 10 mg day−1 prednisolone. However, the ADAMTS‐13 activity was still undetectable. A 44 year old, previously healthy man was hospitalized with fever, dizziness, tiredness and petechiae. The platelet count and LDH were 9 × 109 L−1, and 1790 U L−1, respectively. Blood smear showed MAHA with 9% ADAMTS‐13 without detectable inhibitor. Anti‐HIV was negative. Plasma exchange was initiated and continued five times per week for 4 weeks (Fig. 1B). He was asymptomatic. His platelet count and LDH were normal, but started falling after withdrawing exchange. From the dramatic results in case 1, we stopped plasma exchange and started pulse dexamethasone for 4 days, followed by prednisolone 30 mg day−1. The sustained platelet response occurred. Within 4 days, platelet count and LDH changed from 64 × 109 L−1 and 429 U L−1 to 153 × 109 L−1 and 340 U L−1, respectively. At 7 months after diagnosis, his platelet count is still normal with prednisolone 5 mg on alternate day. ADAMTS‐13 is 15%. The rapid hematological responses of TTP to pulse dexamethasone within a few days suggest that the mechanism of action is not the inhibition of antibody production. Notably, lower doses of steroid were not helpful in our first case and the previous successful reports used very high doses of steroid [9Bell W.R. Braine H.G. Ness P.M. 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 (718) Google Scholar, 10Toyoshige M. Zaitsu Y. Okafuji K. Inoue Y. Hiroshige Y. Matsumoto N. Kaku K. Kaneko T. Successful treatment of thrombotic thrombocytopenic purpura with high‐dose corticosteroid.Am J Hematol. 1992; 41: 69Crossref PubMed Scopus (15) Google Scholar]. Interestingly, our two cases displayed low ADAMTS‐13 activity long after recovery, although platelet counts and LDH were normal. The persistent ADAMTS‐13 deficiency in apparently healthy patients is a well‐known phenomenon [5Vesely S.K. George J.N. Lammle B. Studt J.D. Alberio L. El‐Harake M.A. Raskob G.E. ADAMTS13 activity in thrombotic thrombocytopenic purpura‐hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients.Blood. 2003; 102: 60-8Crossref PubMed Scopus (577) Google Scholar, 6Zheng X.L. Kaufman R.M. Goodnough L.T. Sadler J.E. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura.Blood. 2004; 103: 4043-9Crossref PubMed Scopus (385) Google Scholar, 7Veyradier A. Obert B. Houllier A. Meyer D. Girma J.P. Willebrand factor‐cleaving protease in thrombotic microangiopathies: a study of 111 cases.Blood. 2001; 98: 1765-72Crossref PubMed Scopus (365) Google Scholar]. This suggests that precipitating factors other than the ADAMTS defect are required to develop clinical TTP. Various cytokines can stimulate vascular endothelium to secrete uLVWF [13Bernardo A. Ball C. Nolasco L. Moake J.F. Dong J.F. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell‐derived ultralarge von Willebrand factor multimers under flow.Blood. 2004; 104: 100-6Crossref PubMed Scopus (398) Google Scholar]. In the absence of ADAMTS‐13, uLVWF that still attaches to cells and agglutinates platelets in situ causes idiopathic TTP. On the other hand, secondary TTP associated with transplantation, cancer or drugs often retains some ADAMTS‐13 activity [5Vesely S.K. George J.N. Lammle B. Studt J.D. Alberio L. El‐Harake M.A. Raskob G.E. ADAMTS13 activity in thrombotic thrombocytopenic purpura‐hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients.Blood. 2003; 102: 60-8Crossref PubMed Scopus (577) Google Scholar, 6Zheng X.L. Kaufman R.M. Goodnough L.T. Sadler J.E. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura.Blood. 2004; 103: 4043-9Crossref PubMed Scopus (385) Google Scholar], and may be caused by severe endothelial injury releasing great amount of uLVWF. Consistent with this hypothesis, various cytokines have been shown to be elevated in acute episode of TTP and correlated with disease activity [14Wada H. Kaneko T. Ohiwa M. Tanigawa M. Tamaki S. Minami N. Takahashi H. Deguchi K. Nakano T. Shirakawa S. Plasma cytokine levels in thrombotic thrombocytopenic purpura.Am J Hematol. 1992; 40: 167-70Crossref PubMed Scopus (54) Google Scholar, 15Shariatmadar S. Nassiri M. Vincek V. Effect of plasma exchange on cytokines measured by multianalyte bead array in thrombotic thrombocytopenic purpura.Am J Hematol. 2005; 79: 83-8Crossref PubMed Scopus (45) Google Scholar]. In multiple sclerosis, the main mechanism of action of pulse steroid is to down regulate various cytokines and chemokines [16Wandinger K.P. Wessel K. Trillenberg P. Heindl N. Kirchner H. Effect of high‐dose methylprednisolone administration on immune functions in multiple sclerosis patients.Acta Neurol Scand. 1998; 97: 359-65Crossref PubMed Scopus (42) Google Scholar]. Therefore, the mode of action of high‐dose steroid in TTP is possibly via suppression of endothelial activation. However, cytokine measurements are required to prove this hypothesis. Immunosuppressive agents are recommended only for TTP patients who are refractory to or dependent on plasma exchange [17George J.N. How I treat patients with thrombotic thrombocytopenic purpura – hemolytic uremic syndrome.Blood. 2000; 96: 1223-9Crossref PubMed Google Scholar]. We used pulse steroid as a sole treatment because both never had severe neurological symptoms. One refused plasma exchange and the other was treated until all symptoms disappeared with very close follow ups. In our opinion, plasma exchange is still the key treatment of TTP. However, our data suggested that pulse dexamethasone probably has a significant adjunctive role in shortening the course of disease and reducing blood component exposure, at least in a subset of TTP with severe ADAMTS‐13 deficiency. Studies in more patients are required to confirm our results and elucidate the mechanisms of action.