Acquired TTP: Clinical manifestations and diagnosis
- James N George, MD
James N George, MD
- Professor of Medicine
- University of Oklahoma Health Sciences Center
- Adam Cuker, MD, MS
Adam Cuker, MD, MS
- Assistant Professor of Medicine, Assistant Professor of Pathology & Laboratory Medicine
- Perelman School of Medicine University of Pennsylvania
Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by severely reduced activity of the von Willebrand factor-cleaving protease ADAMTS13. It is characterized by small-vessel platelet-rich thrombi that cause thrombocytopenia, microangiopathic hemolytic anemia, and sometimes organ damage. TTP is a medical emergency that is almost always fatal if appropriate treatment is not initiated promptly. With appropriate treatment, survival rates of up to 90 percent are possible.
TTP can be acquired, due to an autoantibody inhibitor, or hereditary, due to inherited mutations in ADAMTS13. This topic reviews the clinical manifestations and our approach to the diagnosis of acquired autoimmune TTP. Our approach to evaluating patients with other suspected thrombotic microangiopathies (including hereditary TTP) is presented in separate topic reviews:
●Suspected TTP or hemolytic uremic syndrome (HUS), diagnosis unclear – (See "Approach to the patient with suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
●Suspected hereditary TTP – (See "Hereditary thrombotic thrombocytopenic purpura (TTP)".)
●Suspected drug-induced thrombotic microangiopathy (also called drug-induced TTP) – (See "Drug-induced thrombotic microangiopathy".)
- George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med 2014; 371:654.
- Reese JA, Muthurajah DS, Kremer Hovinga JA, et al. Children and adults with thrombotic thrombocytopenic purpura associated with severe, acquired Adamts13 deficiency: comparison of incidence, demographic and clinical features. Pediatr Blood Cancer 2013; 60:1676.
- Terrell DR, Vesely SK, Kremer Hovinga JA, et al. Different disparities of gender and race among the thrombotic thrombocytopenic purpura and hemolytic-uremic syndromes. Am J Hematol 2010; 85:844.
- Scully M, Yarranton H, Liesner R, et al. Regional UK TTP registry: correlation with laboratory ADAMTS 13 analysis and clinical features. Br J Haematol 2008; 142:819.
- Griffin D, Al-Nouri ZL, Muthurajah D, et al. First symptoms in patients with thrombotic thrombocytopenic purpura: what are they and when do they occur? Transfusion 2013; 53:235.
- Nokes T, George JN, Vesely SK, Awab A. Pulmonary involvement in patients with thrombotic thrombocytopenic purpura. Eur J Haematol 2014; 92:156.
- Page EE, Kremer Hovinga JA, Terrell DR, et al. Thrombotic thrombocytopenic purpura: diagnostic criteria, clinical features, and long-term outcomes from 1995 through 2015. Blood Advances 2017; 1:590.
- Hawkins BM, Abu-Fadel M, Vesely SK, George JN. Clinical cardiac involvement in thrombotic thrombocytopenic purpura: a systematic review. Transfusion 2008; 48:382.
- Amorosi EL, Ultmann JE. Thrombotic thrombocytopenic purpura: Report of 16 cases and review of the literature. Medicine (Baltimore) 1966; 45:139.
- Routh JK, Koenig SC. Severe vitamin B12 deficiency mimicking thrombotic thrombocytopenic purpura. Blood 2014; 124:1844.
- Noël N, Maigné G, Tertian G, et al. Hemolysis and schistocytosis in the emergency department: consider pseudothrombotic microangiopathy related to vitamin B12 deficiency. QJM 2013; 106:1017.
- BRAIN MC, DACIE JV, HOURIHANE DO. Microangiopathic haemolytic anaemia: the possible role of vascular lesions in pathogenesis. Br J Haematol 1962; 8:358.
- Cohen JA, Brecher ME, Bandarenko N. Cellular source of serum lactate dehydrogenase elevation in patients with thrombotic thrombocytopenic purpura. J Clin Apher 1998; 13:16.
- George JN. How I treat patients with thrombotic thrombocytopenic purpura: 2010. Blood 2010; 116:4060.
- Burns ER, Lou Y, Pathak A. Morphologic diagnosis of thrombotic thrombocytopenic purpura. Am J Hematol 2004; 75:18.
- Fava S, Galizia AC. Thrombotic thrombocytopenic purpura-like syndrome in the absence of schistocytes. Br J Haematol 1995; 89:643.
- George JN. Clinical practice. Thrombotic thrombocytopenic purpura. N Engl J Med 2006; 354:1927.
- Sadler JE, Moake JL, Miyata T, George JN. Recent advances in thrombotic thrombocytopenic purpura. Hematology Am Soc Hematol Educ Program 2004; :407.
- Hawley JS, Ney JP, Swanberg MM. Thrombotic thrombocytopenic purpura-induced posterior leukoencephalopathy in a patient without significant renal or hypertensive complications. J Postgrad Med 2004; 50:197.
- Bakshi R, Shaikh ZA, Bates VE, Kinkel PR. Thrombotic thrombocytopenic purpura: brain CT and MRI findings in 12 patients. Neurology 1999; 52:1285.
- Burrus TM, Wijdicks EF, Rabinstein AA. Brain lesions are most often reversible in acute thrombotic thrombocytopenic purpura. Neurology 2009; 73:66.
- Vesely SK, George JN, 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; 102:60.
- Zafrani L, Mariotte E, Darmon M, et al. Acute renal failure is prevalent in patients with thrombotic thrombocytopenic purpura associated with low plasma ADAMTS13 activity. J Thromb Haemost 2015; 13:380.
- Remuzzi G. HUS and TTP: variable expression of a single entity. Kidney Int 1987; 32:292.
- Eknoyan G, Riggs SA. Renal involvement in patients with thrombotic thrombocytopenic purpura. Am J Nephrol 1986; 6:117.
- Gami AS, Hayman SR, Grande JP, Garovic VD. Incidence and prognosis of acute heart failure in the thrombotic microangiopathies. Am J Med 2005; 118:544.
- Patschan D, Witzke O, Dührsen U, et al. Acute myocardial infarction in thrombotic microangiopathies--clinical characteristics, risk factors and outcome. Nephrol Dial Transplant 2006; 21:1549.
- Ridolfi RL, Hutchins GM, Bell WR. The heart and cardiac conduction system in thrombotic thrombocytopenic purpura. A clinicopathologic study of 17 autopsied patients. Ann Intern Med 1979; 91:357.
- Podolsky SH, Zembowicz A, Schoen FJ, et al. Massive myocardial necrosis in thrombotic thrombocytopenic purpura: a case report and review of the literature. Arch Pathol Lab Med 1999; 123:937.
- Wajima T, Johnson EH. Sudden cardiac death from thrombotic thrombocytopenic purpura. Clin Appl Thromb Hemost 2000; 6:108.
- Hughes C, McEwan JR, Longair I, et al. Cardiac involvement in acute thrombotic thrombocytopenic purpura: association with troponin T and IgG antibodies to ADAMTS 13. J Thromb Haemost 2009; 7:529.
- George JN, Chen Q, Deford CC, Al-Nouri Z. Ten patient stories illustrating the extraordinarily diverse clinical features of patients with thrombotic thrombocytopenic purpura and severe ADAMTS13 deficiency. J Clin Apher 2012; 27:302.
- Downes KA, Yomtovian R, Tsai HM, et al. Relapsed thrombotic thrombocytopenic purpura presenting as an acute cerebrovascular accident. J Clin Apher 2004; 19:86.
- Sarode R. Atypical presentations of thrombotic thrombocytopenic purpura: a review. J Clin Apher 2009; 24:47.
- Imanirad I, Rajasekhar A, Zumberg M. A case series of atypical presentations of thrombotic thrombocytopenic purpura. J Clin Apher 2012; 27:221.
- Tsai HM, Shulman K. Rituximab induces remission of cerebral ischemia caused by thrombotic thrombocytopenic purpura. Eur J Haematol 2003; 70:183.
- Jamme M, Rondeau E. The PLASMIC score for thrombotic thrombocytopenic purpura. Lancet Haematol 2017; 4:e148.
- Bendapudi PK, Hurwitz S, Fry A, et al. Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: a cohort study. Lancet Haematol 2017; 4:e157.
- George JN. Measuring ADAMTS13 activity in patients with suspected thrombotic thrombocytopenic purpura: when, how, and why? Transfusion 2015; 55:11.
- Froehlich-Zahnd R, George JN, Vesely SK, et al. Evidence for a role of anti-ADAMTS13 autoantibodies despite normal ADAMTS13 activity in recurrent thrombotic thrombocytopenic purpura. Haematologica 2012; 97:297.
- Rieger M, Mannucci PM, Kremer Hovinga JA, et al. ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases. Blood 2005; 106:1262.
- Kremer Hovinga JA, Vesely SK, Terrell DR, et al. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood 2010; 115:1500.
- Meyer SC, Sulzer I, Lämmle B, Kremer Hovinga JA. Hyperbilirubinemia interferes with ADAMTS-13 activity measurement by FRETS-VWF73 assay: diagnostic relevance in patients suffering from acute thrombotic microangiopathies. J Thromb Haemost 2007; 5:866.
- Hassan S, Westwood JP, Ellis D, et al. The utility of ADAMTS13 in differentiating TTP from other acute thrombotic microangiopathies: results from the UK TTP Registry. Br J Haematol 2015; 171:830.
- Bendapudi PK, Li A, Hamdan A, et al. Impact of severe ADAMTS13 deficiency on clinical presentation and outcomes in patients with thrombotic microangiopathies: the experience of the Harvard TMA Research Collaborative. Br J Haematol 2015; 171:836.
- Cataland SR, Wu HM. How I treat: the clinical differentiation and initial treatment of adult patients with atypical hemolytic uremic syndrome. Blood 2014; 123:2478.
- 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.
- Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998; 339:1585.
- Shah N, Sarode R. Thrombotic thrombocytopenic purpura-what is new? J Clin Apher 2013; 28:30.
- Wu N, Liu J, Yang S, et al. Diagnostic and prognostic values of ADAMTS13 activity measured during daily plasma exchange therapy in patients with acquired thrombotic thrombocytopenic purpura. Transfusion 2015; 55:18.
- Shah N, Rutherford C, Matevosyan K, et al. Role of ADAMTS13 in the management of thrombotic microangiopathies including thrombotic thrombocytopenic purpura (TTP). Br J Haematol 2013; 163:514.
- Page EE, Kremer Hovinga JA, Terrell DR, et al. Clinical importance of ADAMTS13 activity during remission in patients with acquired thrombotic thrombocytopenic purpura. Blood 2016; 128:2175.
- Grillberger R, Casina VC, Turecek PL, et al. Anti-ADAMTS13 IgG autoantibodies present in healthy individuals share linear epitopes with those in patients with thrombotic thrombocytopenic purpura. Haematologica 2014; 99:e58.
- Deford CC, Reese JA, Schwartz LH, et al. Multiple major morbidities and increased mortality during long-term follow-up after recovery from thrombotic thrombocytopenic purpura. Blood 2013; 122:2023.
- Hassell KL, Eckman JR, Lane PA. Acute multiorgan failure syndrome: a potentially catastrophic complication of severe sickle cell pain episodes. Am J Med 1994; 96:155.
- TERMINOLOGY AND DISEASE DEFINITIONS
- CLINICAL AND LABORATORY FINDINGS
- Overview of presentation
- - MAHA and thrombocytopenia
- - Neurologic and other organ involvement
- - Reduced ADAMTS13 activity
- Atypical presentations
- DIAGNOSTIC TESTING
- Overview of our approach
- Diagnostic evaluation
- ADAMTS13 testing
- - ADAMTS13 activity
- - ADAMTS13 inhibitor
- Presumptive diagnosis
- Confirmed diagnosis
- DIFFERENTIAL DIAGNOSIS
- SUMMARY AND RECOMMENDATIONS