The thrombotic thrombocytopenic purpura and hemolytic uremic syndromes: evaluation, management, and long-term outcomes experience of the Oklahoma TTP-HUS Registry, 1989–2007
Authors: James N George
Journal: Kidney International (2009)

The Oklahoma thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) Registry, an inception cohort of 382 consecutive patients with TTP–HUS, provides a complete community perspective of these syndromes. TTP, as defined by thrombocytopenia and microangiopathic hemolytic anemia without an alternative etiology, is the appropriate term for all adults. These limited diagnostic criteria are supported by the presenting features of patients with ADAMTS13 deficiency, in whom both neurologic and renal abnormalities are uncommon. HUS is the appropriate term for children who fulfill these diagnostic criteria and who also have renal failure. These definitions are consistent with current management: plasma exchange is the essential treatment for most adults; supportive care is sufficient for children with HUS. Plasma exchange treatment has decreased the mortality of TTP from 90 to 10%. Patients with acquired autoimmune ADAMTS13 deficiency may also require immunosuppressive treatment to achieve a durable remission. Recovery has revealed previously unrecognized long-term risks. Recurrent acute episodes occur in approximately 40% of patients with acquired ADAMTS13 deficiency; most relapses occur within the first year and most patients have only one relapse. Adults with TTP of any etiology have a high risk for persistent minor cognitive abnormalities. The Oklahoma thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) Registry, an inception cohort of 382 consecutive patients with TTP–HUS, provides a complete community perspective of these syndromes. TTP, as defined by thrombocytopenia and microangiopathic hemolytic anemia without an alternative etiology, is the appropriate term for all adults. These limited diagnostic criteria are supported by the presenting features of patients with ADAMTS13 deficiency, in whom both neurologic and renal abnormalities are uncommon. HUS is the appropriate term for children who fulfill these diagnostic criteria and who also have renal failure. These definitions are consistent with current management: plasma exchange is the essential treatment for most adults; supportive care is sufficient for children with HUS. Plasma exchange treatment has decreased the mortality of TTP from 90 to 10%. Patients with acquired autoimmune ADAMTS13 deficiency may also require immunosuppressive treatment to achieve a durable remission. Recovery has revealed previously unrecognized long-term risks. Recurrent acute episodes occur in approximately 40% of patients with acquired ADAMTS13 deficiency; most relapses occur within the first year and most patients have only one relapse. Adults with TTP of any etiology have a high risk for persistent minor cognitive abnormalities. Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) describe disorders of multiple etiologies. The experience of the Oklahoma TTP-HUS Registry provides a basis for evaluation and management and for anticipating long-term outcomes. In the era before effective treatment, TTP was defined by a pentad of clinical features, namely thrombocytopenia, microangiopathic hemolytic anemia, neurologic abnormalities, renal failure, and fever.1Amorosi E.L. Ultmann J.E. Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature.Medicine. 1966; 45: 139-159Crossref Scopus (767) Google Scholar The availability of effective treatment with plasma exchange required urgency for diagnosis and decreased stringency of diagnostic criteria. The current diagnostic criteria are only thrombocytopenia and microangiopathic hemolytic anemia, without an apparent alternative etiology.2Rock 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 (1541) Google Scholar, 3George J.N. Thrombotic thrombocytopenic purpura.N Engl J Med. 2006; 354: 1927-1935Crossref PubMed Scopus (443) Google Scholar The validity of these limited criteria is supported by the presenting features of patients whose diagnosis of TTP was supported by the presence of severe ADAMTS13 deficiency: neurologic and renal abnormalities were uncommon, fever was rare, and no patients had the complete pentad of clinical features (Table 1).4Vesely S.K. George J.N. Lämmle B. et al.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; 101: 60-68Crossref Scopus (572) Google Scholar The availability of effective treatment and the limited diagnostic criteria have resulted in an 8- to 10-fold increase in patients treated with plasma exchange for TTP.5Clark W.F. Garg A.X. Blake P.G. et al.Effect of awareness of a randomized controlled trial on use of experimental therapy.JAMA. 2003; 290: 1351-1355Crossref PubMed Scopus (45) Google Scholar, 6George J.N. Kremer Hovinga J.A. Terrell D.R. et al.The Oklahoma thrombotic thrombocytopenic purpura-hemolytic uremic syndrome Registry: the Swiss connection.Eur J Haematol. 2008; 80: 277-286Crossref PubMed Scopus (36) Google ScholarTable 1Presenting clinical features of the initial 18 patients in the Oklahoma TTP-HUS Registry whose diagnosis was supported by ADAMTS13 activity <5%4Vesely S.K. George J.N. Lämmle B. et al.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; 101: 60-68Crossref Scopus (572) Google ScholarClinical featuresPatients (n)Presenting symptomsaThe number of presenting symptoms exceeds 18 because some patients had more than one prominent presenting symptom. Thrombocytopenia and microangiopathic hemolytic anemia were required criteria for diagnosis of TTP and inclusion in the Registry. Abdominal pain6 Nausea, vomiting, diarrhea5 Minor neurologic abnormalitiesbConfusion, disorientation (4 patients), ataxia (1), and headache (1).5 Severe neurologic abnormalitiescFocal abnormalities (4 patients), seizure (2), and aphasia (2).3 Fever4 Weakness, dyspnea3 Chest pain3 Hematuria2Laboratory abnormalities Thrombocytopenia18 Microangiopathic hemolytic anemia18 Renal function abnormalities Acute renal failuredIncreased serum creatinine ≥44 μmol/l on 2 consecutive days or creatinine ≥354 μmol/l and dialysis within 7 days of diagnosis.41 Minor renal insufficiencyeSerum creatinine ≥133 μmol/l within 7 days of diagnosis.7 Normal renal functionfSerum creatinine values all <133 μmol/l.10Complete pentad of clinical featuresgThrombocytopenia, microangiopathic hemolysis, neurologic and renal abnormalities, and fever. present0TTP-HUS, thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.a The number of presenting symptoms exceeds 18 because some patients had more than one prominent presenting symptom. Thrombocytopenia and microangiopathic hemolytic anemia were required criteria for diagnosis of TTP and inclusion in the Registry.b Confusion, disorientation (4 patients), ataxia (1), and headache (1).c Focal abnormalities (4 patients), seizure (2), and aphasia (2).d Increased serum creatinine ≥44 μmol/l on 2 consecutive days or creatinine ≥354 μmol/l and dialysis within 7 days of diagnosis.4Vesely S.K. George J.N. Lämmle B. et al.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; 101: 60-68Crossref Scopus (572) Google Scholare Serum creatinine ≥133 μmol/l within 7 days of diagnosis.f Serum creatinine values all <133 μmol/l.g Thrombocytopenia, microangiopathic hemolysis, neurologic and renal abnormalities, and fever. Open table in a new tab TTP-HUS, thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. As the diagnosis of TTP requires consideration of plasma exchange treatment, and because almost all adults who fulfill the diagnostic criteria for TTP may benefit from plasma exchange, we use the diagnostic term TTP for almost all adults. We restrict the term HUS to children who fulfill the diagnostic criteria of thrombocytopenia and microangiopathic hemolytic anemia and who also have renal failure. Overall 90% of children with HUS have a diarrhea prodrome, caused mostly by Escherichia coli O157:H7;7Tarr P.I. Gordon C.A. Chandler W.L. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome.Lancet. 2005; 365: 1073-1086Abstract Full Text Full Text PDF PubMed Scopus (1381) Google Scholar their mortality is 3% with supportive care;8Karpac C.A. Li X. Terrell D.R. et al.Sporadic bloody diarrhoea-associated thrombotic thrombocytopenic purpura-haemolytic uraemic syndrome: an adult and paediatric comparison.Br J Haematol. 2008; 141: 696-707Crossref PubMed Scopus (47) Google Scholar therefore, plasma exchange is rarely requested. As children with HUS are not treated with plasma exchange, the use of the term HUS in adults may imply that plasma exchange is unnecessary. Therefore, we avoid the term HUS for adults, even adults with acute renal failure. As the diagnostic criteria for TTP are not specific, multiple systemic disorders can mimic TTP, resulting in mistaken diagnosis. These include disseminated malignancies,9Francis K.K. Kojouri K. George J.N. Occult systemic carcinoma masquerading as thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.Community Oncol. 2005; 2: 339-343Crossref Scopus (16) Google Scholar, 10Francis K.K. Kalyanam N. Terrell D.R. et al.Disseminated malignancy misdiagnosed as thrombotic thrombocytopenic purpura: a report of 10 cases and a systematic review of the literature.Oncologist. 2007; 12: 11-19Crossref PubMed Scopus (116) Google Scholar systemic infections,11Robboy S.J. Salisbury K. Ragsdale B. et al.Mechanism of Aspergillus-induced microangiopathic hemolytic anemia.Arch Intern Med. 1971; 128: 790-793Crossref PubMed Scopus (22) Google Scholar, 12George J.N. Vesely S.K. Terrell D.R. The Oklahoma thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) Registry: a community perspective of patients with clinically diagnosed TTP-HUS.Semin Hematol. 2004; 41: 60-67Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 13Selleng K. Warkentin T.E. Greinacher A. et al.Very severe thrombocytopenia and fragmentation hemolysis mimicking thrombotic thrombocytopenic purpura associated with a giant intracardiac vegetation infected with Staphylococcus epidermidis: role of monocyte procoagulant activity induced by bacterial supernatant.Amer J Hematol. 2006; 82: 766-771Crossref Scopus (8) Google Scholar, 14Dwyre D.M. Bell A.M. Siechen K. et al.Disseminated histoplasmosis presenting as thrombotic microangiopathy.Transfusion. 2006; 46: 1221-1225Crossref PubMed Scopus (18) Google Scholar malignant hypertension,15Egan J.A. Bandarenko N. Hay S.N. et al.Differentiating thrombotic microangiopathies induced by severe hypertension from anemia and thrombocytopenia seen in thrombotic thrombocytopenic purpura.J Clin Apheresis. 2004; 19: 125-129Crossref PubMed Scopus (30) Google Scholar, 16Brain M.C. Dacie J.V. Hourihane O.B. Microangiopathic hemolytic anemia: the possible role of vascular lesions in pathogenesis.Br J Haematol. 1962; 8: 358-374Crossref PubMed Scopus (278) Google Scholar systemic lupus erythematosus,17George J.N. Vesely S.K. James J.A. Overlapping features of thrombotic thrombocytopenic purpura and systemic lupus erythematosus.South Med J. 2007; 100: 512-514Crossref PubMed Scopus (40) Google Scholar and other renal disorders.16Brain M.C. Dacie J.V. Hourihane O.B. Microangiopathic hemolytic anemia: the possible role of vascular lesions in pathogenesis.Br J Haematol. 1962; 8: 358-374Crossref PubMed Scopus (278) Google Scholar Therefore, physicians must maintain continued vigilance for alternative disorders even after a diagnosis of TTP is apparently established and plasma exchange treatment has begun. ADAMTS13 measurements may not assist initial diagnosis and management decisions but are important for prognosis. Although most patients with severe ADAMTS13 deficiency have no renal insufficiency, causing initial reports to suggest that ADAMTS13 activity measurements may distinguish TTP from HUS,18Furlan 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 (1473) Google Scholar some patients with severe ADAMTS13 deficiency have acute renal failure (Table 1). ADAMTS13 activity <5% appears to be specific for TTP but does not identify all patients who may relapse; ADAMTS13 activity <10% essentially identifies all patients who are at risk for relapse but is not specific; patients with sepsis19Ono T. Mimuro J. Madoiwa S. et al.Severe secondary deficiency of von Willebrand factor-cleaving protease (ADAMTS13) in patients with sepsis-induced disseminated intravascular coagulation: its correlation with development of renal failure.Blood. 2006; 107: 528-534Crossref PubMed Scopus (299) Google Scholar, 20Nguyen T.C. Liu A. Liu L. et al.Acquired ADAMTS13 deficiency in pediatric patients with severe sepsis.Haematologia. 2007; 92: 121-124Crossref Scopus (117) Google Scholar and liver cirrhosis21Uemura M. Fujimura Y. Matsumoto M. et al.Comprehensive analysis of ADAMTS13 in patients with liver cirrhosis.Thromb Haemost. 2008; 99: 1019-1029Crossref PubMed Scopus (106) Google Scholar may also have ADAMTS13 activity <10%. Reproducible definitions are required to accurately analyze the clinical outcomes of patients with TTP.4Vesely S.K. George J.N. Lämmle B. et al.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; 101: 60-68Crossref Scopus (572) Google Scholar Response is defined as the achievement of a normal platelet count; other parameters seem less important. Exacerbation of a continuing episode is defined as the recurrence of TTP within 30 days of stopping plasma exchange treatment. Remission is defined as a normal platelet count for 30 days after stopping plasma exchange treatment. Relapse, a distinct new episode of TTP, is defined as recurrent TTP occurring more than 30 days after stopping plasma exchange. The 30-day interval is important because patients with ADAMTS13 deficiency commonly have exacerbations of continuing disease when plasma exchange treatment is stopped. Plasma exchange is the essential treatment for all patients who are diagnosed with TTP, with or without renal failure,2Rock 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 (1541) Google Scholar, 22Rock G.A. Shumak K. Kelton J. et al.Thrombotic thrombocytopenic purpura: outcome in 24 patients with renal impairment treated with plasma exchange.Transfusion. 1992; 32: 710-714Crossref PubMed Scopus (75) Google Scholar but the number of plasma exchange treatments to achieve a remission is extremely variable. Among our patients with severe ADAMTS13 deficiency, the number of plasma exchange treatments required to achieve a remission ranged from 3 to 89.4Vesely S.K. George J.N. Lämmle B. et al.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; 101: 60-68Crossref Scopus (572) Google Scholar A hypothesis for the efficacy of plasma exchange is that ADAMTS13 deficiency is corrected by plasma infusion and that ADAMTS13 inhibitor is removed by apheresis.23Moake J.L. Thrombotic microangiopathies.N Engl J Med. 2002; 347: 589-600Crossref PubMed Scopus (1131) Google Scholar However, the majority of adults diagnosed with TTP do not have severe ADAMTS13 deficiency, and many also appear to respond to plasma exchange, such as patients who present with bloody diarrhea or who have quinine-induced TTP.4Vesely S.K. George J.N. Lämmle B. et al.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; 101: 60-68Crossref Scopus (572) Google Scholar, 8Karpac C.A. Li X. Terrell D.R. et al.Sporadic bloody diarrhoea-associated thrombotic thrombocytopenic purpura-haemolytic uraemic syndrome: an adult and paediatric comparison.Br J Haematol. 2008; 141: 696-707Crossref PubMed Scopus (47) Google Scholar, 24Kojouri K. Vesely S.K. George J.N. Quinine-associated thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: frequency, clinical features, and long-term outcomes.Ann Int Med. 2001; 135: 1047-1051Crossref PubMed Scopus (124) Google Scholar The mechanism of possible plasma exchange efficacy in these patients is unknown. The decision to initiate plasma exchange treatment must balance potential complications with confidence in the diagnosis of TTP. Among 206 consecutive patients over 9 years in the Oklahoma Registry, 57 (28%) had major complications and 5 (2.4%) deaths were attributed to plasma exchange.25Rizvi M.A. Vesely S.K. George J.N. et al.Complications of plasma exchange in 71 consecutive patients treated for clinically suspected thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.Transfusion. 2000; 40: 896-901Crossref PubMed Scopus (148) Google Scholar, 26McMinn J.R. Thomas I.A. Terrell D.R. et al.Complications of plasma exchange in patients treated for clinically suspected thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: an additional study of 78 consecutive patients.Transfusion. 2003; 43: 415-416Crossref PubMed Scopus (66) Google Scholar, 27Howard M.A. Williams L.A. Terrell D.R. et al.Complications of plasma exchange in patients treated for clinically suspected thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. III. An additional study of 57 consecutive patients, 2002–2005.Transfusion. 2006; 46: 154-156Crossref PubMed Scopus (105) Google Scholar Deaths were caused by hemorrhagic or pneumothorax complications of central venous catheter insertion (two patients) or sepsis attributed to the central venous catheter (three patients). Two additional patients had cardiac arrests with pulseless electrical activity: one caused by an anaphylactic reaction to plasma and the other caused by cardiac tamponade related to catheter insertion. Treatment with immunosuppressive agents is reserved for patients with suspected autoimmune ADAMTS13 deficiency. Corticosteroids are the initial immunosuppressive agents; other agents, such as rituximab28George J.N. Woodson R.D. Kiss J.E. et al.Rituximab therapy for thrombotic thrombocytopenic purpura: a proposed study of the Transfusion Medicine/Hemostasis Clinical Trials Network with a systematic review of rituximab therapy for immune-mediated disorders.J Clin Apheresis. 2006; 21: 49-56Crossref PubMed Scopus (92) Google Scholar and cyclosporine,29Cataland S.R. Jin M. Ferketich A.K. et al.An evaluation of cyclosporine and corticosteroids individually as adjuncts to plasma exchange in the treatment of thrombotic thrombocytopenic purpura.Br J Haematol. 2007; 132: 146-149Crossref Scopus (66) Google Scholar are used for patients with a more critical course. Aspirin is not used as adjunctive treatment but is appropriate for patients who have a standard cardiac or neurologic indication and do not have severe thrombocytopenia. In spite of optimal management, mortality among patients with TTP remains approximately 15%. However, half of these deaths may be attributed to complications of plasma exchange treatment or hospitalization, such as sepsis, hemorrhage, and thrombosis. Among patients with severe ADAMTS13 deficiency, the risk for relapse is approximately 40%. The value of maintenance immunosuppressive treatment or measurement of ADAMTS13 activity during remission is unknown. Patients may have severe ADAMTS13 deficiency for many years with no evidence of TTP. The critical element of continuing care is to insist that patients obtain a platelet count immediately when any acute symptoms occur, as any symptom may indicate recurrent TTP. Although relapse may be the greatest concern, other problems affect many more patients. After recovery, patients have significantly abnormal health-related quality of life;30Lewis Q.F. Terrell D.R. Vesely S.K. et al.Long-term abnormalities of patient-reported outcomes after recovery from thrombotic thrombocytopenic purpura (TTP) using health-related quality-of-life (QOL) measurements.Blood. 2006; 108: 139a-140aGoogle Scholar neurocognitive studies have documented deficits of attention, processing speed and memory, and also fatigue.31Lewis Q.F. Scott J.G. Kremer Hovinga J.A. et al.Neurocognitive impairment following recovery from ADAMTS13-deficient thrombotic thrombocytopenic purpura.Blood. 2007; 110: 395aGoogle Scholar The author has declared no financial interests. This study is supported by The Hematology Research Fund (University of Oklahoma).