Pathophysiology of acquired TTP and other primary thrombotic microangiopathies (TMAs)
- 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 microangiopathy (TMA) describes a specific pathologic lesion in which abnormalities in the vessel wall of arterioles and capillaries lead to microvascular thrombosis. TMA is a pathologic diagnosis made by tissue biopsy. However, it is commonly inferred from the observation of microangiopathic hemolytic anemia (MAHA) and thrombocytopenia in the appropriate clinical setting. Acquired thrombotic thrombocytopenic purpura (TTP) was the first of the primary TMAs to be described and is perhaps the best understood of the TMAs pathophysiologically. TTP is unique among the primary TMAs for minimal abnormalities of kidney function, despite microthrombi observed throughout the kidney.
The pathophysiology of acquired (autoimmune) TTP, complement-mediated TMA, Shiga toxin-induced TMA (hemolytic uremic syndrome [ST-HUS]), and some of the rare inherited TMAs will be reviewed here.
The pathophysiology of hereditary TTP and drug-induced TMA (also called drug-induced TTP) is presented separately. (See "Hereditary thrombotic thrombocytopenic purpura (TTP)", section on 'Genetics' and "Drug-induced thrombotic microangiopathy", section on 'Pathophysiology'.)
Separate topic reviews also discuss the general approach to the patient with a suspected TMA (see "Approach to the patient with suspected TTP, HUS, or other thrombotic microangiopathy (TMA)"), and diagnosis and management of specific conditions:
●Acquired TTP – (See "Acquired TTP: Clinical manifestations and diagnosis" and "Acquired TTP: Initial treatment".)
- George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med 2014; 371:654.
- Laszik ZG, Kambham N, Silva FG. Thrombotic microangiopathies. In: Heptinstall's Pathology of the Kidney, Jennett JC, D'Agati VD, Olson JL, Silva FG (Eds), Lippincott-Raven, Philadelphia 2014.
- Sethi S, Fervenza FC. Pathology of renal diseases associated with dysfunction of the alternative pathway of complement: C3 glomerulopathy and atypical hemolytic uremic syndrome (aHUS). Semin Thromb Hemost 2014; 40:416.
- Nokes T, George JN, Vesely SK, Awab A. Pulmonary involvement in patients with thrombotic thrombocytopenic purpura. Eur J Haematol 2014; 92:156.
- George JN. Clinical practice. Thrombotic thrombocytopenic purpura. N Engl J Med 2006; 354:1927.
- George JN. Systemic malignancies as a cause of unexpected microangiopathic hemolytic anemia and thrombocytopenia. Oncology (Williston Park) 2011; 25:908.
- Zander CB, Cao W, Zheng XL. ADAMTS13 and von Willebrand factor interactions. Curr Opin Hematol 2015; 22:452.
- Fujimura Y, Matsumoto M, Isonishi A, et al. Natural history of Upshaw-Schulman syndrome based on ADAMTS13 gene analysis in Japan. J Thromb Haemost 2011; 9 Suppl 1:283.
- Moatti-Cohen M, Garrec C, Wolf M, et al. Unexpected frequency of Upshaw-Schulman syndrome in pregnancy-onset thrombotic thrombocytopenic purpura. Blood 2012; 119:5888.
- Kremer Hovinga JA, Vesely SK, Terrell DR, et al. Survival and relapse in patients with thrombotic thrombocytopenic purpura. Blood 2010; 115:1500.
- George JN. Measuring ADAMTS13 activity in patients with suspected thrombotic thrombocytopenic purpura: when, how, and why? Transfusion 2015; 55:11.
- Tersteeg C, de Maat S, De Meyer SF, et al. Plasmin cleavage of von Willebrand factor as an emergency bypass for ADAMTS13 deficiency in thrombotic microangiopathy. Circulation 2014; 129:1320.
- Chauhan AK. Degradation of platelet-von Willebrand factor complexes by plasmin: an alternative/backup mechanism to ADAMTS13. Circulation 2014; 129:1273.
- Nguyen TC, Liu A, Liu L, et al. Acquired ADAMTS-13 deficiency in pediatric patients with severe sepsis. Haematologica 2007; 92:121.
- Uemura M, Fujimura Y, Matsumoto M, et al. Comprehensive analysis of ADAMTS13 in patients with liver cirrhosis. Thromb Haemost 2008; 99:1019.
- George JN. Clinical insights from observations on ADAMTS13 deficiency in liver cirrhosis. Thromb Haemost 2008; 99:987.
- Mannucci PM, Canciani MT, Forza I, et al. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood 2001; 98:2730.
- Mannucci PM, Parolari A, Canciani MT, et al. Opposite changes of ADAMTS-13 and von Willebrand factor after cardiac surgery. J Thromb Haemost 2005; 3:397.
- Sánchez-Luceros A, Farías CE, Amaral MM, et al. von Willebrand factor-cleaving protease (ADAMTS13) activity in normal non-pregnant women, pregnant and post-delivery women. Thromb Haemost 2004; 92:1320.
- Reiter RA, Knöbl P, Varadi K, Turecek PL. Changes in von Willebrand factor-cleaving protease (ADAMTS13) activity after infusion of desmopressin. Blood 2003; 101:946.
- Studt JD, Kremer Hovinga JA, Antoine G, et al. Fatal congenital thrombotic thrombocytopenic purpura with apparent ADAMTS13 inhibitor: in vitro inhibition of ADAMTS13 activity by hemoglobin. Blood 2005; 105:542.
- Blombery P, Scully M. Management of thrombotic thrombocytopenic purpura: current perspectives. J Blood Med 2014; 5:15.
- 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.
- Coppo P, Busson M, Veyradier A, et al. HLA-DRB1*11: a strong risk factor for acquired severe ADAMTS13 deficiency-related idiopathic thrombotic thrombocytopenic purpura in Caucasians. J Thromb Haemost 2010; 8:856.
- 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.
- Plaimauer B, Kremer Hovinga JA, Juno C, et al. Recombinant ADAMTS13 normalizes von Willebrand factor-cleaving activity in plasma of acquired TTP patients by overriding inhibitory antibodies. J Thromb Haemost 2011; 9:936.
- Isonishi A, Bennett CL, Plaimauer B, et al. Poor responder to plasma exchange therapy in acquired thrombotic thrombocytopenic purpura is associated with ADAMTS13 inhibitor boosting: visualization of an ADAMTS13 inhibitor complex and its proteolytic clearance from plasma. Transfusion 2015; 55:2321.
- Luken BM, Turenhout EA, Hulstein JJ, et al. The spacer domain of ADAMTS13 contains a major binding site for antibodies in patients with thrombotic thrombocytopenic purpura. Thromb Haemost 2005; 93:267.
- Klaus C, Plaimauer B, Studt JD, et al. Epitope mapping of ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura. Blood 2004; 103:4514.
- Pos W, Luken BM, Sorvillo N, et al. Humoral immune response to ADAMTS13 in acquired thrombotic thrombocytopenic purpura. J Thromb Haemost 2011; 9:1285.
- Varadi K, Schreiner J, Plaimauer B, et al. ADAMTS13 autoantibody detection by quantitative immunoblotting. Blood 2003; 102:1932.
- Shah N, Sarode R. Thrombotic thrombocytopenic purpura-what is new? J Clin Apher 2013; 28:30.
- Makou E, Herbert AP, Barlow PN. Functional anatomy of complement factor H. Biochemistry 2013; 52:3949.
- Noris M, Mescia F, Remuzzi G. STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat Rev Nephrol 2012; 8:622.
- Hofer J, Giner T, Józsi M. Complement factor H-antibody-associated hemolytic uremic syndrome: pathogenesis, clinical presentation, and treatment. Semin Thromb Hemost 2014; 40:431.
- Turner N, Sartain S, Moake J. Ultralarge von Willebrand factor-induced platelet clumping and activation of the alternative complement pathway in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndromes. Hematol Oncol Clin North Am 2015; 29:509.
- Turner NA, Moake J. Assembly and activation of alternative complement components on endothelial cell-anchored ultra-large von Willebrand factor links complement and hemostasis-thrombosis. PLoS One 2013; 8:e59372.
- Turner N, Nolasco L, Nolasco J, et al. Thrombotic microangiopathies and the linkage between von Willebrand factor and the alternative complement pathway. Semin Thromb Hemost 2014; 40:544.
- Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet 2005; 365:1073.
- Kovacs MJ, Roddy J, Grégoire S, et al. Thrombotic thrombocytopenic purpura following hemorrhagic colitis due to Escherichia coli O157:H7. Am J Med 1990; 88:177.
- Bell BP, Goldoft M, Griffin PM, et al. A multistate outbreak of Escherichia coli O157:H7-associated bloody diarrhea and hemolytic uremic syndrome from hamburgers. The Washington experience. JAMA 1994; 272:1349.
- Buchholz U, Bernard H, Werber D, et al. German outbreak of Escherichia coli O104:H4 associated with sprouts. N Engl J Med 2011; 365:1763.
- Maki DG. Don't eat the spinach--controlling foodborne infectious disease. N Engl J Med 2006; 355:1952.
- George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med 2014; 371:1847.
- Lemaire M, Frémeaux-Bacchi V, Schaefer F, et al. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet 2013; 45:531.
- Quaggin SE. DGKE and atypical HUS. Nat Genet 2013; 45:475.
- Ozaltin F, Li B, Rauhauser A, et al. DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN. J Am Soc Nephrol 2013; 24:377.
- Bruneau S, Néel M, Roumenina LT, et al. Loss of DGKε induces endothelial cell activation and death independently of complement activation. Blood 2015; 125:1038.
- Westland R, Bodria M, Carrea A, et al. Phenotypic expansion of DGKE-associated diseases. J Am Soc Nephrol 2014; 25:1408.
- Sinibaldi S, Guzzo I, Piras R, et al. Post-transplant recurrence of atypical hemolytic uremic syndrome in a patient with thrombomodulin mutation. Pediatr Transplant 2013; 17:E177.
- Fan X, Yoshida Y, Honda S, et al. Analysis of genetic and predisposing factors in Japanese patients with atypical hemolytic uremic syndrome. Mol Immunol 2013; 54:238.
- Russo P, Doyon J, Sonsino E, et al. A congenital anomaly of vitamin B12 metabolism: a study of three cases. Hum Pathol 1992; 23:504.
- Geraghty MT, Perlman EJ, Martin LS, et al. Cobalamin C defect associated with hemolytic-uremic syndrome. J Pediatr 1992; 120:934.
- Cornec-Le Gall E, Delmas Y, De Parscau L, et al. Adult-onset eculizumab-resistant hemolytic uremic syndrome associated with cobalamin C deficiency. Am J Kidney Dis 2014; 63:119.
- Grangé S, Bekri S, Artaud-Macari E, et al. Adult-onset renal thrombotic microangiopathy and pulmonary arterial hypertension in cobalamin C deficiency. Lancet 2015; 386:1011.
- George JN. Cobalamin C deficiency-associated thrombotic microangiopathy: uncommon or unrecognised? Lancet 2015; 386:1012.
- HISTOPATHOLOGY OF TMA
- Endothelial changes and microthrombi
- Hematologic findings
- TTP PATHOGENESIS
- Deficient ADAMTS13 activity
- Causes of ADAMTS13 deficiency
- - Inhibitory antibodies to ADAMTS13
- - ADAMTS13 gene mutations
- COMPLEMENT-MEDIATED TMA PATHOGENESIS
- Consequences of excessive complement activity
- Inhibitory antibodies to complement factor H
- Complement gene mutations
- Interactions between VWF and the alternative complement pathway
- SHIGA TOXIN-INDUCED TMA (ST-HUS)
- OTHER PRIMARY TMA PATHOGENESIS
- Mutations in coagulation regulators
- - DGKE
- - Thrombomodulin
- Vitamin B12 metabolism/MMACHC mutations
- Drug-induced TMA