Hereditary thrombotic thrombocytopenic purpura (TTP)
- 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 and microangiopathic hemolytic anemia (MAHA). Some patients may have neurologic abnormalities, mild renal insufficiency, and low-grade fever. Most cases of TTP are acquired, caused by autoantibody inhibition of ADAMTS13 activity. Hereditary TTP, caused by ADAMTS13 gene mutations, is much less common.
This topic discusses our approach to the diagnosis and management of hereditary TTP.
Our general approach to the patient with suspected TTP, HUS, or related syndromes is presented in detail separately. (See "Approach to the patient with suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
Separate topic reviews also present the diagnosis, management, and pathophysiology of acquired TTP and hemolytic uremic syndrome (HUS):
●Acquired TTP diagnosis – (See "Acquired TTP: Clinical manifestations and diagnosis".)
- 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.
- Lotta LA, Wu HM, Mackie IJ, et al. Residual plasmatic activity of ADAMTS13 is correlated with phenotype severity in congenital thrombotic thrombocytopenic purpura. Blood 2012; 120:440.
- von Krogh AS, Quist-Paulsen P, Waage A, et al. High prevalence of hereditary thrombotic thrombocytopenic purpura in central Norway: from clinical observation to evidence. J Thromb Haemost 2016; 14:73.
- 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.
- Fuchs WE, George JN, Dotin LN, Sears DA. Thrombotic thrombocytopenic purpura. Occurrence two years apart during late pregnancy in two sisters. JAMA 1976; 235:2126.
- Barbot J, Costa E, Guerra M, et al. Ten years of prophylactic treatment with fresh-frozen plasma in a child with chronic relapsing thrombotic thrombocytopenic purpura as a result of a congenital deficiency of von Willebrand factor-cleaving protease. Br J Haematol 2001; 113:649.
- Scully M, Thomas M, Underwood M, et al. Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes. Blood 2014; 124:211.
- Epperla N, Hemauer K, Friedman KD, et al. Congenital thrombotic thrombocytopenic purpura related to a novel mutation in ADAMTS13 gene and management during pregnancy. Am J Hematol 2016; 91:644.
- Jiang Y, McIntosh JJ, Reese JA, et al. Pregnancy outcomes following recovery from acquired thrombotic thrombocytopenic purpura. Blood 2014; 123:1674.
- Raval JS, Padmanabhan A, Kremer Hovinga JA, Kiss JE. Development of a clinically significant ADAMTS13 inhibitor in a patient with hereditary thrombotic thrombocytopenic purpura. Am J Hematol 2015; 90:E22.
- 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.
- Plaimauer B, Scheiflinger F. Expression and characterization of recombinant human ADAMTS-13. Semin Hematol 2004; 41:24.
- Levy GG, Nichols WC, Lian EC, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001; 413:488.
- SCHULMAN I, PIERCE M, LUKENS A, CURRIMBHOY Z. Studies on thrombopoiesis. I. A factor in normal human plasma required for platelet production; chronic thrombocytopenia due to its deficiency. Blood 1960; 16:943.
- George JN. Congenital thrombotic thrombocytopenic purpura: Lessons for recognition and management of rare syndromes. Pediatr Blood Cancer 2008; 50:947.
- Mise K, Ubara Y, Matsumoto M, et al. Long term follow up of congenital thrombotic thrombocytopenic purpura (Upshaw-Schulman syndrome) on hemodialysis for 19 years: a case report. BMC Nephrol 2013; 14:156.
- Bennett M, Chubar Y, Gavish I, et al. Experiences in a family with the Upshaw-Schulman syndrome over a 44-year period. Clin Appl Thromb Hemost 2014; 20:296.
- De Meyer SF, Savchenko AS, Haas MS, et al. Protective anti-inflammatory effect of ADAMTS13 on myocardial ischemia/reperfusion injury in mice. Blood 2012; 120:5217.
- Gandhi C, Motto DG, Jensen M, et al. ADAMTS13 deficiency exacerbates VWF-dependent acute myocardial ischemia/reperfusion injury in mice. Blood 2012; 120:5224.
- CLINICAL FEATURES
- Acute episode presenting features
- Laboratory findings
- - Acute episode
- - After recovery
- - Unaffected siblings
- Differential diagnosis
- Overview of approach
- Acute episode
- - Plasma infusion
- - Expected recovery
- Routine monitoring
- Prevention of recurrences
- Complications of plasma infusion
- Genetic counseling and testing of siblings
- THERAPIES UNDER DEVELOPMENT
- SUMMARY AND RECOMMENDATIONS