Diagnosis and Treatment of Thrombotic Thrombocytopenic Purpura: A Single Institution Experience

Transcription

1 J Med Sci 2012;32(3): Copyright 2012 JMS Diagnosis and Treatment of Thrombotic Thrombocytopenic Purpura: A Single Institution Experience Ping-Ying Chang 1, Ching-Liang Ho 1, Tsu-Yi Chao 1, Woei-Yau Kao 1, Ming-Shen Dai 1, Tzong-Shi Chiueh 2, Hsiang-Lin Wan 3, and Yeu-Chin Chen 1* 1 Division of Hematology and Oncology, Department of Internal Medicine; 2 Department of Clinical Pathology, Blood Bank, Tri-Service General Hospital, National Defense Medical Center, Taipei; 3 Department of Hematology and Oncology, Taipei Tzu Chi General Hospital, Taipei, Taiwan, Republic of China Background: Thrombotic thrombocytopenic purpura (TTP) is an urgent, life-threatening hematologic disorder. It can result in a high fatality rate without early identification and prompt plasma exchange (PE) therapy. We report our experience of clinical manifestations, laboratory abnormalities, diagnosis, treatment and outcome of patients with TTP at our institution. Patients and Methods: Medical records of 13 patients diagnosed with TTP at our institution from 1997 to 2009 were reviewed. Relevant information including age, gender, clinical presentation, predisposing factors, laboratory abnormalities, treatment, complications, and outcome of each patient were analyzed. Results: The median age of the patients was 47 years with a range of Five of the 13 (38%) patients presented with the full pentad of all clinical features. The median hemoglobin and platelet count at diagnosis was 8.3 g/dl and /μl, respectively. The median time from onset of symptoms to diagnosis was 14 days. Nine of the 13 patients (70%) had the sporadic or idiopathic form of TTP. The other cases of TTP were associated with ticlopidine, breast cancer and autoimmune diseases. The median number of PE was 11 (range: 6-37). Nine of 13 patients (70%) were treated successfully with the combination of PE and corticosteroids, and the remaining 4 patients who failed to respond to this therapy eventually died of multi-organ failure. Conclusion: Our study showed 38% of such patients presented with the full pentad of clinical features but the median time from symptom onset to diagnosis and initiation of therapy was 14 days for the entire cohort. Treatment with a combination of corticosteroids and PE resulted in a 70% success rate in achieving long term remission. Key words: thrombotic thrombocytopenic purpura, thrombocytopenia, plasma exchange INTRODUCTION Received: November 29, 2011; Revised: March 26, 2012; Accepted: April 13, 2012 * Corresponding author: Yeu-Chin Chen, Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, No 325, Sec. 2. Cheng-gong Road, Taipei 114, Taiwan, Republic of China. Tel: ; Fax: ; yeuchin99@gmail.com Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition caused by formation of microvascular thrombi in multiple sites as a result of highly procoagulant ultra large multimers of von Willebrand Factor (VWF) in the circulation which in turn results in microangiopathic hemolysis as well as end organ damage from the thrombotic occlusions. The reason for the appearance of the abnormally large and pathogenic VWF multimers is now known to be an acquired or inherited deficiency of A disintegrin and metalloproteinase family with thrombospondin type 1 repeat, number 13 ( AD- AMTS13 ) which is a cleaving protease for von Willebrand factor (VWF) multimers as described by Tsai et al. and Furlan et al. independently in ,2 Clinically this disorder is characterized by the classically described pentad of thrombocytopenia, microangiopathic hemolytic anemia (MAHA), fever, neurological abnormalities and renal dysfunction. However, the triad of thrombocytopenia, schistocytosis, and elevation of LDH level in the absence of alternative explanations such as malignant hypertension is usually sufficient to establish the diagnosis and initiate plasma exchange (PE) therapy. 3 A variety of conditions including pregnancy, autoimmune diseases, drugs such as ticlopidine, clopidogrel and mitomycin-c, as well as cancer and allogeneic bone marrow transplan- 121

2 Thrombotic thrombocytopenic purpura tation have all been described to be associated with TTP. 4 Additionally, the presence of autoantibodies inhibiting ADAMTS13 in patients with non-familial TTP has also been well reported in the literature and is generally considered to be the most common form of this disease. 3 TTP is usually fatal if early identification and prompt intervention with PE are not done. PE can reduce the mortality from 90% to 10-25%. 5 The therapeutic efficacy of PE with fresh frozen plasma (FFP) has been attributed to removal of neutralizing auto- antibodies and the restoration of ADAMTS13 activity. 1,6 There has been very limited information available on TTP in patients from Taiwan with most of them being in the form of single case reports Because little is known about the patterns of presentation, diagnosis and outcome of TTP in Taiwan, we conducted a retrospective study of 13 patients with TTP at our institution to address these specific questions. PATIENTS AND METHODS Patients This study was performed by retrospective chart review of TTP patients diagnosed between 1997 and 2009 at our institution. The essential diagnostic criteria included demonstration of MAHA with schistocytosis in the peripheral blood along with elevated lactate dehydrogenase (LDH) and thrombocytopenia ( all patients platelet counts were < /μL). Further, the presence of additional clinical features known to occur with TTP including fever (>38.0 o C), neurological abnormalities (headaches, behavior change, mental status change, seizures or focal deficits) and renal dysfunction (proteinuria, hematuria or acute renal failure) were also recorded. Patients with other causes of MAHA such as malignant hypertension and acute disseminated intravascular coagulation were excluded. Treatment protocol PE was performed once daily with FFP using approximately fold of predicted total plasma volume. All procedures were performed on the Baxter Fenwal CS plus blood cell separator (Baxter, Deerfield, IL, USA). All the 13 patients were treated with corticosteroids (methylprednisolone, dexamethasone or prednisolone) and PE as front-line therapies. Some alternative therapies including chemotherapy with vincristine or cyclophosphamide and immunotherapy with Rituximab were used for patients with refractory and relapsed diseases. None of the 13 patients underwent splenectomy for treatment of refractory TTP. Definitions for clinical outcomes Definitions for clinical outcomes were adapted from a study described previously by Vesely et al. 12 (1) Response to treatment: normalization of the platelet count ( 150x10 3 /μl) (2) Remission: durable response without PE treatment for equal to or more than 30 days. (3) Treatment failure: no improvement at all or progressive deterioration in clinical symptoms and laboratory values or death (4) Relapse: recurrence of the initial symptoms and abnormal laboratory values after PE was stopped for more than 30 days (5) Exacerbation: deterioration of the clinical symptoms and laboratory values after initial improvement during the treatment period or within 30 days after PE ADAMTS13 activity assay ADAMTS13 activity was measured by enzyme linked immunosorbent assay (ELISA) with a commercial kit (ATS-13, GTI Diagnostics, Waukesha, WI, USA) according to the manufacturer s instructions. We retrospectively measured the ADAMTS13 activities before and after PE in some patients from our cohort. RESULTS Patient characteristic and clinical presentation There were a total of 13 patients, eight of whom (61%) were female. The median age was 47 years old with a range of years. The demographic and clinical characteristics of these patients are shown in Table 1. Five patients (38%) presented with the classic pentad, six (46%) had a tetrad and two (16%) had a triad of clinical features. Nine patients (69%) had fever, ten (77%) had neurological presentation and eight (61.5%) had renal presentation. Nine patients (70%) were considered to have idiopathic TTP. Two patients (No.#3 and #7) had a known diagnosis of autoimmune disease, No.#4 was on ticlopidine and No.#13 had advanced breast cancer. The median values of hemoglobin, platelet counts and serum LDH at disease diagnosis were 8.3 g/dl (range: g/dl), /μl (range: /μl), 1549 U/ L (range: U/L), respectively. The median time from symptoms to diagnosis was 2 weeks with a range from two days to one month. 122

3 Table 1 Patient characteristics and clinical features No Sex/Age Predisposing factor Fever Neuro Renal Time to diagnosis Hgb (g/dl) PLT (10 3 /μl) LDH* (U/L) 1 M/73 Unknown days F/31 Unknown days M/41 MCTD days F/72 Ticlopidine days M/78 Unknown days F/40 Unknown days F/14 suspected SLE days M/75 Unknown days F/36 Unknown days F/47 Unknown days M/71 Unknown days F/44 Unknown days F/47 breast cancer days MV days MCTD: mixed connective tissue disease, SLE: systemic lupus erythematosus, Neuro: neurological, MV: median value, *normal range of LDH:( U/L) Treatment response and outcome as listed in Table 2 Three patients (No.#2, #10, #12) had platelet transfusion before TTP diagnosis. Two of them (No.#2, #12) developed conscious disturbance, but the other one (No.#10) had no deterioration of neurological symptoms. Patient No.#12 got complete recovery without neurological sequelae after treatment. None of the 13 patients received platelet transfusion during the plasma exchange treatment after TTP diagnosis. The median number and volume of PE were 11 (range: 7-38) and 220 units (range: ), respectively. Ten patients (77%) responded to treatment which was sustained long term in eight (80%) of them. Eight of 9 (88.9%) idiopathic TTP patients had response to PE and 6 of the 8 (75%) patients had remission. Two of 4 (50%) secondary TTP patients had response to PE and both of them achieved remission. No.#1 had response to treatment but died of undetermined cause one year later. Five patients (No.#5, #8, #9, #11, #12) experienced exacerbation during treatment defined by worsening of any disease related parameter as outlined in the clinical outcomes criteria described above. Two of them (No.#8, #11) achieved remission with continuation of PE and steroid therapy. Patient No.#9 was treated with vincristine and patient No.#12 was treated with vincristine followed by oral cyclophosphamide after they failed initial treatment. Both these patients ultimately achieved remission. Rituximab 375mg/m2/week was administered for the patient No.#2 (1 dose) who failed PE and corticosteroid therapy and for the patient No.#5 (2 doses) who experienced exacerbation and had poor response to PE and corticosteroid retreatment. Neither of them responded and eventually succumbed to their disease. Two other patients (No.#7 and #13) who also failed the combination of PE and corticosteroid therapy subsequently died of multi-organ failure. No.#6 experienced relapse of disease up to 6 times after initial treatment and was successfully managed with PE each time. Two patients (No.#2 and #7) developed severe hyperglycemia in association with TTP related acute pancreatitis. With regard to treatment related complications, there were four patients with infection, including two with pneumonia (No.#8, #11), one with a catheter related infection (No.#4) and one with CMV pneumonitis 123

4 Thrombotic thrombocytopenic purpura Table 2 Patient treatment outcomes No PE number PE volume (unit) Adjuvant therapy Complications Time to Response Outcome Steroid No 6 days Death Steroid, rituximab PE, AP, hyperglycemia - Death (9 days after treatment) Steroid Transfusion allergy 7 days Remission (+), alive Steroid Catheter infection 5 days Remission (+), alive Steroid, rituximab No 20 days Exacerbation(+), death (23 days after treatment) Steroid Transfusion allergy 9 days (first treatment) Relapse (+), remission (+), alive Steroid AP, myocardial muscle necrosis, hyperglycemia - Death (13 days after treatment) Steroid DVT, pneumonia 18 days Exacerbation (+), remission (+), alive Steroid, vincristine No 7 days Exacerbation (+), remission (+), alive Steroid No 11 days Remission (+), alive Steroid PCP, PU bleeding 9 days Exacerbation (+), remission (+), alive Steroid, vincristine, endoxan Catheter occlusion, PU bleeding 5 days Exacerbation (+), remission (+), alive Steroid CMV pneumonitis, fungemia - Death (15 days after treatment) MV MV: median value, NA: not available, time to CR: time to complete response, AP: acute pancreatitis, PE: pulmonary embolism, DVT: deep vein thrombosis, PJP: pneumocystis jiroveci pneumonia, PU: peptic ulcer, CMV: cytomegalovirus, endoxan: cyclophosphamide. Time to response: duration from treatment start day to treatment response day (No.#13). Two patients had peptic ulcers with bleeding (No.#11, #12), one patient (No.#8) experienced catheter related deep venous thrombosis and one (No.#12) developed catheter occlusion for which re-insertion of a new catheter was required. Finally, eight patients (61.5%) had sustained remission and remained free of disease till present time. ADAMTS13 activity results Four patients ADAMTS13 activities were assayed. No.#8 had low ADMATS13 activity before corticosteroid and PE treatment and this increased from 10% to 84% (normal range: 12-44%) after treatment. The patient achieved remission. Another patient s (No.#13) ADAMTS13 activity was also improved from 5% to 28%, but she finally died of TTP in spite of ongoing PE although her course was additionally complicated by CMV pneumonitis and fungemia. No.#10 had normal ADAMTS13 activity during follow-up and did not experience disease relapse while No.#6 who also had normal ADAMTS 13 activity during the follow-up period, developed multiple disease relapses. DISCUSSION Clinical and biological studies on Taiwanese patients with TTP have been very limited in the past. A retrospective study of Chinese patients with TTP was published 124

5 recently, but the majority of patients in it had secondary TTP. 13 In a registry of thrombotic microangiography across Japan ( ), 919 patients had confirmed thrombotic microangiopathy. Most of the patients had secondary thrombotic microangiopathy (50%, 464 patients) and the percentage of idiopathic TTP was 31% (284 patients). 14 In a Korean TTP Registry ( ), 66 patients had the diagnosis TTP which revealed higher percentage of idiopathic TTP 59% (39 patients). 15 In the present study, our patients presented with several clinical manifestations and associated diseases but most of them (70%) had the idiopathic, sporadic form of the disease. A variety of response rates (55-89%), relapse rates (8-32%) and mortality rates (15-22%) with the use of PE for TTP have been reported in the literature. 12,13,15-21 In this study, the response rate (77%) and relapse rate (7.7%) were relatively similar to those reported from Western countries. There was a higher mortality (38%) in this study however, which may be attributed to delayed diagnosis and thus delayed treatment of our patients. Our institution is a tertiary referral center and some patients were only transferred into our hospital when they were in advanced stages of disease. The median time from onset of symptoms to disease diagnosis was 14 days. Although ADAMTS 13 plays an important role in the pathogenesis of TTP and around 60% of TTP patients have severe ADAMTS 13 deficiency 5,22, secondary TTP patients almost never have severe ADAMTS13 deficiency 22 and the clinical value of measuring ADAMTS13 activity and inhibitor detection remains undetermined. 22 This assay is not necessary for the diagnosis of TTP because not all patients have ADAMTS 13 deficiency, but its measurement may be helpful for monitoring of relapse. 22 In the present study, 2 patients (No.#8 and #10) with normal follow-up ADAMTS13 activity did not have relapse. This finding supports the previous clinical observation 22 although the patient number in our study was very limited. Routine measurement of ADAMTS13 activity during remission is generally not recommended because severe deficiency during remission is not clearly associated with clinical TTP recurrence. 23 Tsai et al and Furlan et al have reported independently that circulating inhibitory IgG subtype antibodies inhibit ADAMTS13 and lead to functional deficiency of its activity. 1,2 This may provide the rationale for steroid use as immunosuppressive therapy, but its efficacy, dosage and duration remain undetermined. 4 The usual dose of methylprednisolone is 1-2 mg/kg/day until remission or 1 gm/day intravenously daily for three consecutive days. 4 There are potentially serious adverse effects related to steroids including immune suppression, peptic ulceration, hyperglycemia and others which warrant caution in their use. In our study, 7 of 13 (54%) patients developed complications related to steroid usage (Table 2). Laboratory data (platelet and LDH) are usually used to monitor efficacy of TTP treatment. The guideline of the British Society of Hematology defined refractory TTP as persistent thrombocytopenia or LDH elevation after a total of seven daily PE. 4 Because systemic infection may cause thrombocytopenia and high LDH, it is critical to evaluate for possible infection in patients labeled as being treatment-refractory who have indwelling catheters or are on immunosuppressive therapy. 6 Carefully monitoring can help to avoid over-treatment and prevent treatment related complications. Most TTP patients present with severe thrombocytopenia and clinicians may give them platelet transfusion before disease diagnosis. It has been believed that platelet transfusion may lead to deterioration and death in TTP patients. Swisher et al reviewed platelets transfusion on TTP patients in the literatures and the data of Oklahoma TTP-HUS Registry, and they found whether platelet transfusion is harmful for TTP patients is controversial. 24 George JN proposed that platelet transfusion may be given for some TTP patients with hemorrhage, but this should be very cautious. 23 Therefore, platelet transfusion on TTP patients needs judicious evaluation. Though PE is the standard treatment of choice for TTP, it does carry risk of complications, including catheter related infection/thrombosis, transfusion related allergy, citrate toxicity, and others. In one cohort of 249 consecutive patients treated for TTP, the treatment related mortality was 2.8% and 26% had major complications such as systemic infection, venous thrombosis and hypotension. 25 In the present study, two patients (No.#3, #6) had transfusion related allergy and 3 patients (No.#4, #8, #12) had catheter related complications. The major overall complication rate (23%) of our cohort of patients was very similar to that report. 25 Approximately one third of TTP patients relapse after initial successful treatment with PE. 16 Rescue therapies such as splenectomy and immunosuppressive agents like rituximab, cyclosporine, vincristine or cyclophosphamide can be considered for patients with refractory or relapsed TTP. 4,6,26-30 The use of immunosuppressive agents has not been standardized because most studies have been small retrospective case series with limited data. 4 In our study, two patients (No.#9 and #12) treated with vincristine with/without oral cyclophosphamide (100 mg/day) achieved remission. Rituximab is a monoclonal antibody directly against 125

6 Thrombotic thrombocytopenic purpura the CD20 antigen presenting on B lymphocytes and has been demonstrated to be effective and well tolerated for refractory and relapsed TTP patients with or without ADAMTS 13 antibodies. 28 The usual dose is 375 mg/m 2 / week for four consecutive weeks. In this study, No.#2 received 1 dose of rituximab and No.#5 received 2 weekly doses for their refractory disease. Unfortunately, both failed to respond to this treatment and eventually died. The poor response may have been due to late rituximab use when patients had already developed advanced multiorgan dysfunction. In summary, our study demonstrates that Taiwanese patients with TTP had similar clinical characteristics as those reported in Western studies. The combination of PE and corticosteroid was effective (70% remission rate) treatment for these patients although it is conceivable that we may have seen even better responses if had there not been a median delay of two weeks in diagnosis and initiation of therapy. Mortality rate of the patients with a diagnosis within 2 weeks and beyond 2 weeks was 33.3% (2/6) and 42.9% (3/7) respectively. Furthermore, 3 patients with their diagnosis within one week were all alive. We intend to use this data as an educational tool for primary care and other non-hematology clinicians in Taiwan to increase awareness of TTP and its presentation with particular emphasis on the life threatening nature of the disease and the consequences of diagnostic delay on patient outcomes. It is our hope that such education can serve to ultimately reduce these delays. There was a 30% rate of refractory and relapsed disease with PE and steroid treatment in our study and some of these patients could be salvaged with therapies such as vincristin and cyclophosphamide. It was also apparent that there can be significant complications (23 % in this study) related to the use of PE and steroids which one needs to bear in mind. Finally, ADAMTS13 activity assay may be helpful for monitoring of disease relapse although its use in this context is controversial and not universally accepted. DISCLOSURE All authors declare no competing financial interests. REFERENCES 1. Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpurar. N Engl J Med 1998 Nov 26;339: Furlan M, Robles R, Galbusera M, Remuzzi G, Kyrle PA, Brenner B, Krause M, Scharrer I, Aumann V, Mittler U, Solenthaler M, Lämmle B. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 1998 Nov 26;339: Moake JL. Thrombotic microangiopathies. N Engl J Med 2002 Aug 22;347: Allford SL, Hunt BJ, Rose P, Machin SJ; Haemostasis and Thrombosis Task Force, British Committee for Standards in Haematology. Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias. Br J Haematol 2003 Feb;120: Lammle B, Kremer Hovinga JA, Alberio J. Thrombotic thormbocytopenic purpura. J Thromb Haemost 2005;3: George JN. Clinical practice. Thrombotic thrombocytopenic purpura. N Engl J Med 2006 May 4;354: Yang CW, Chen YC, Dunn P, Chang MY, Fang JT, Huang CC. Ticlopidine-induced thrombotic thrombocytopenic purpura: two case reports treated with plasma exchange plus steroids. Ren Fail 2001 Nov;23: Yang CW, Chen YC, Dunn P, Chang MY, Fang JT, Huang CC.Thrombotic thrombocytopenic purpura (TTP): initial treatment with plasma exchange plus steroids and immunosuppressive agents for relapsing cases. Ren Fail 2003 Jan;25: Chen YC, Chen HS, Shen CJ, Chang HM, Tsai EM. Delayed postpartum hemorrhage--a rare clinical presentation of thrombotic thrombocytopenic purpurahemolytic uremic syndrome: a case report. Kaohsiung J Med Sci 2005 Nov;21: Lin CY, Lin SH. Fatal thrombotic throbmocytopenic purpura coexisting with bacterial infection: a case report. Acta Neurol Taiwan 2008 Mar;17: Lee CH, Chen CL, Lin CC, Yang CH, Cheng YF, Wang MC, Eng HL, Liu PP, Chuang FR. Plasma exchange therapy for thrombotic thrombocytopenic purpura in pediatric patients with liver transplantation. Transplant Proc 2008 Oct;40: Ves ely SK, George JN, Lämmle B, Studt JD, Alberio L, El-Harake MA, Raskob GE. 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 Jul 1;102: Zhang W, Shi H, Ren H, Shen PY, Pan XX, Li X, Chen YX, Xu YW, Chen XN, Zhu P, Chen N. 126

7 Clinicopathological characteristics and outcome of Chinese patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: a 9-year retrospective study. Nephron Clin Pract 2009;112:c Fujimura Y, Matsumoto M. Registry of 919 patients with thrombotic microangiopathies across Japan: database of Nara Medical University during Intern Med 2010;49: Jang MJ, Chong SY, Kim IH, Kim JH, Jung CW, Kim JY, Park JC, Lee SM, Kim YK, Lee JE, Jang SS, Kim JS, Jo DY, Zang DY, Lee YY, Yhim HY, Oh D. Clinical features of severe acquired ADAMTS13 deficiency in thrombotic thrombocytopenic purpura: the Korean TTP registry experience. Int J Hematol 2011 Feb;93: George JN. The thrombotic thrombocytopenic purpura and hemolytic uremic syndromes: evaluation, management, and long-term outcomes experience of the Oklahoma TTP-HUS Registry, Kidney Int Suppl 2009 Feb;112:S Dervenoulas J, Tsirigotis P, Bollas G, Pappa V, Xiros N, Economopoulos T, Pappa M, Mellou S, Kostourou A, Papageorgiou E, Raptis SA. Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS): treatment outcome, relapses, prognostic factors. A single-center experience of 48 cases. Ann Hematol 2000 Feb;79: Shamseddine A, Saliba T, Aoun E, Chahal A, El- Saghir N, Salem Z, Bazarbachi A, Khalil M, Taher A. Thrombotic thrombocytopenic purpura: 24 years of experience at the American University of Beirut Medical Center. J Clin Apher 2004;19: Altuntas F, Aydogdu I, Kabukcu S, Kocyigit I, Cikim K, Sari I, Erkut MA, Eser B, Ozturk A, Kaya E, Cetin M, Keskin A, Unal A. Therapeutic plasma exchange for the treatment of thrombotic thrombocytopenic purpura: a retrospective multicenter study. Transfus Apher Sci 2007 Feb;36: Forzley BR, Sontrop JM, Macnab JJ, Chen S, Clark WF. Treating TTP/HUS with plasma exchange: a single centre s 25-year experience. Br J Haematol 2008 Sep;143: Levandovsky M, Harvey D, Lara P, Wun T. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS): a 24-year clinical experience with 178 patients. J Hematol Oncol 2008 Dec 1;1: Sadler JE. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood 2008 Jul 1;112: George JN. How I treat patients with thrombotic thrombocytopenic purpura: Blood 2010 Nov18; 116: Swisher KK, Terrell DR, Vesely SK, Kremer Hovinga JA, Lämmle B, George JN. Clinical outcomes after platelet transfusions in patients with thrombotic thrombocytopenic purpura. Transfusion 2009 May;49: Nguyen L, Terrell DR, Duvall D, Vesely SK, George JN. Complications of plasma exchange in patients treated for clinically suspected thrombotic thrombocytopenic purpura. IV. An additional study of 43 consecutive patients, 2005 to Transfusion 2009 Feb;49: Fontana S, Kremer Hovinga JA, Lämmle B, Mansouri Taleghani B. Treatment of thrombotic thrombocytopenic purpura. Vox Sang 2006 May;90: Kappers-Klunne MC, Wijermans P, Fijnheer R, Croockewit AJ, van der Holt B, de Wolf JT, Löwenberg B, Brand A. Splenectomy for the treatment of thrombotic thrombocytopenic purpura. Br J Haematol 2005 Sep;130: Elliott MA, Heit JA, Pruthi RK, Gastineau DA, Winters JL, Hook CC. Rituximab for refractory and or relapsing thrombotic thrombocytopenic purpura related to immune-mediated severe ADAMTS13-deficiency: a report of four cases and a systematic review of the literature. Eur J Haematol 2009 Oct;83: Ziman A, Mitri M, Klapper E, Pepkowitz SH, Goldfinger D. Combination vincristine and plasma exchange as initial therapy in patients with thrombotic thrombocytopenic purpura: one institution s experience and review of the literature. Transfusion 2005 Jan;45: Hertzberg MS, Koutts J. Oral cyclophosphamide for refractory or relapsing thrombotic thrombocytopenic purpura (TTP). Aust N Z J Med 1997 Aug;27: