Thrombotic Thrombocytopenic Purpura: Etiopathogenesis, Diagnostics and Basic Principles of Treatment

Željko Todorović 1 , 2 , Milena Jovanovic 3 , Dusan Todorovic 4 , Dejan Petrovic 3 ,  and Predrag Djurdjevic 5
  • 1 Faculty of Medical Sciences, University of Kragujevac, Serbia
  • 2 Radnička 24/2, 34000 Kragujevac, Serbia
  • 3 Center of Nephrology and Dialysis, Clinic for Urology and Nephrology, Clinical Center “Кragujevac”, Serbia
  • 4 Faculty of Medical Sciences, University of Kragujevac, Serbia
  • 5 Clinic for Hematology, Clinical Center “Kragujevac”, Serbia


Thrombotic thrombocytopenic purpura (TTP) is a clinical syndrome that manifests with thrombocytopenia, microangiopathic haemolytic anaemia and symptoms and signs of kidney and brain damage, but it rarely involves other organs. The main pathophysiological cause of TTP is diminished metalloproteinase ADAMTS13 activity; the main function of ADAMTS13 is to degrade large multimers of the von Willebrand factor. Diminished activity of ADAMTS13 is caused either by a genetic mutation in the gene that codes ADAMTS13 (congenital TTP) or by antibodies that block ADAMTS13 enzyme activity or accelerate the degradation of ADAMTS13 (acquired TTP). Clinically, TTP presents most frequently with signs and symptoms of brain and kidney damage with concomitant haemorrhagic syndrome. TTP is suspected when a patient presents with a low platelet count, microangiopathic haemolytic anaemia (negative Coombs tests, low haptoglobine concentration, increased serum concentration of indirect bilirubin and lactate dehydrogenase, increased number of schysocytes in peripheral blood) and the typical clinical presentation. A definitive diagnose can be made only by measuring the ADAMTS13 activity. The differential diagnosis in such cases includes both typical and atypical haemolytic uremic syndrome, disseminated intravascular coagulation, HELLP syndrome in pregnant women and other thrombotic microangiopathies. The first line therapy for TTP is plasma exchange. In patients with acquired TTP, in addition to plasma exchange, immunosuppressive medications are used (corticosteroids and rituximab). In patients with hereditary TTP, the administration of fresh frozen plasma is sometimes required.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1. Petrović D. Akutno oštećenje bubrega: etiologija, dijagnostika i lečenje. Medicinska Istraživanja. 2011;45(3):7-13.

  • 2. Said A, Haddad RY, Stein R, Lerma EV. Thrombotic thrombocytopenic purpura. Dis Mon. 2014;60(10):500-4.

  • 3. Crawley JT, Scully MA. Thrombotic thrombocytopenic purpura: basic pathophysiology and therapeutic strategies. Hematology Am Soc Hematol Educ Program. 2013;2013(1):292-9.

  • 4. Barbour T, Johnson S, Cohney S, Hughes P. Thrombotic microangiopathy and associated renal disorders. Nephrol Dial Transplant. 2012;27(7):2673-85.

  • 5. Kremer Hovinga JA, Lammle B. Role of ADAMTS13 in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. Hematology Am Soc Hematol Educ Program. 2012;2012(1):610-6.

  • 6. Giblin JP, Hewlett LJ, Hannah MJ. Basal secretion of von Willebrand factor from human endothelial cells. Blood. 2008;112(4):957-964.

  • 7. Springer TA. Biology and physics of von Willebrand factor concatamers. J Thromb Haemost. 2011;9(Suppl 1):130-143.

  • 8. Zhou YF, Eng ET, Zhu J, et al. Sequence and structure relationships within von Willebrand factor. Blood. 2012;120(2):449-458.

  • 9. Zhang X, Halvorsen K, Zhang CZ, et al. Mechanoenzymatic cleavage of the ultralarge vascular protein von Willebrand factor. Science. 2009;324(5932):1330-1334.

  • 10. Siedlecki CA, Lestini BJ, Kottke-Marchant KK, et al. Shear-dependent changes in the three-dimensional structure of human von Willebrand factor. Blood. 1996;88(8):2939-2950.

  • 11. Bianchi V, Robles R, Alberio L, et al. Von Willebrand factor-cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura. Blood. 2002;100:710-13.

  • 12. 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(5):819-826.

  • 13. Ferrari S, Mudde GC, Rieger M, et al. IgG subclass distribution of anti-ADAMTS13 antibodies in patients with acquired thrombotic thrombocytopenic purpura. J Thromb Haemost. 2009;7(10):1703-1710.

  • 14. Ferrari S, Scheiflinger F, Rieger M, et al. Prognostic value of 614 American Society of Hematology anti- ADAMTS 13 antibody features (Ig isotype, titer, and inhibitory effect) in a cohort of 35 adult French patients undergoing a first episode of thrombotic microangiopathy with undetectable ADAMTS 13 activity. Blood. 2007;109(7):2815-2822.

  • 15. Hunt BJ, Lämmle B, Nevard CH, et al. von Willebrand factor-cleaving protease in childhood diarrhoeaassociated haemolytic uraemic syndrome. Thromb Haemost. 2001;85(6):975-978.

  • 16. Terrell DR, Williams LA, Vesely SK, et al. The incidence of thrombotic thrombocytopenic purpurahemolytic uremic syndrome: all patients, idiopathic patients, and patients with severe ADAMTS-13 deficiency. J.Thromb.Haemost 2005;3(7):1432-1436.

  • 17. Tsai HM. The kidney in thrombotic thrombocytopenic purpura. Minerva Med. 2007;98(6):731-47.

  • 18. Bennett CL, Davidson CJ, Raisch DW, et al. Thrombotic thrombocytopenic purpura associated with ticlopidine in the setting of coronary artery stents and stroke prevention. Arch.Intern.Med 1999;159(21):2524-2528.

  • 19. Tsai HM, Rice L, Sarode R, et al. Antibody inhibitors to von Willebrand factor metalloproteinase and increased binding of von Willebrand factor to platelets in ticlopidineassociated thrombotic thrombocytopenic purpura. Ann Intern.Med 2000;132(10):794-799.

  • 20. Lattuada A, Rossi E, Calzarossa C, et al. Mild to moderate reduction of a von Willebrand factor cleaving protease (ADAMTS-13) in pregnant women with HELLP microangiopathic syndrome. Haematologica 2003;88(9):1029-1034.

  • 21. 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(5):819-826.

  • 22. Jiang Y, McIntosh JJ, Reese JA, et al. Pregnancy outcomes following recovery from acquired thrombotic thrombocytopenic purpura. Blood. 2014;123(11):1674-80.

  • 23. Levy GG, Nichols WC, Lian EC, et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature. 2001;413(6855):488-494.

  • 24. Schneppenheim R, Kremer Hovinga JA, Becker T, et al. A common origin of the 4143insA ADAMTS13 mutation. Thromb Haemost. 2006;96(1):3-6.

  • 25. Camilleri RS, Cohen H, Mackie IJ, et al. Prevalence of the ADAMTS-13 missense mutation R1060W in late onset adult thrombotic thrombocytopenic purpura. J Thromb Haemost. 2008;6(2):331-338.

  • 26. Takimoto T, Nakao M, Nakajo T, et al. Acute myocardial infarction as the initial thrombotic event of thrombotic thrombocytopenic purpura. Blood Coagul Fibrinolysis. 2016 Jan 11. [Epub ahead of print]

  • 27. Yamamoto K, Hattori Y, Shimada K, et al. Sudden death associated with myocardial damage caused by microthrombi in a patient with thrombotic thrombocytopenic purpura. Rinsho Ketsueki. 2015;56(11):2336-40.

  • 28. Duffy SM, Coyle TE. Platelet transfusions and bleeding complications associated with plasma exchange catheter placement in patients with presumed thrombotic thrombocytopenic purpura. J Clin Apher. 2013;28(5):356-8..

  • 29. Blombery P, Scully M. Management of thrombotic thrombocytopenic purpura: current perspectives. J Blood Med. 2014;5:15-23.

  • 30. Shelat SG, Ai J, Zheng XL. Molecular biology of ADAMTS13 and diagnostic utility of ADAMTS13 proteolytic activity and inhibitor assays. Semin Thromb Hemost. 2005;31(6):659-72.

  • 31. Franchini M, Mannucci PM. Advantages and limits of ADAMTS13 testing in thrombotic thrombocytopenic purpura. Blood Transfus. 2008;6(3):127-35.

  • 32. Kokame K, Nobe Y, Kokubo Y, et al. FRETS-VWF73, a first fluorogenic substrate for ADAMTS13 assay. Br J Haematol. Br J Haematol. 2005;129(1):93-100.

  • 33. Gerritsen HE, Turecek PL, Schwarz HP, et al. Assay of von Willebrand factor (vWF)-cleaving protease based on decreased collagen binding affinity of degraded vWF: a tool for the diagnosis of thrombotic thrombocytopenic purpura (TTP) Thromb Haemost. Thromb Haemost. 1999;82(5):1386-9.

  • 34. Rick ME, Moll S, Taylor MA, et al. Clinical use of a rapid collagen binding assay for von Willebrand factor cleaving protease in patients with thrombotic thrombocytopenic purpura. Thromb Haemost. Thromb Haemost. 2002;88(4):598-604.

  • 35. Bohm M, Vigh T, Scharrer I. Evaluation and clinical application of a new method for measuring activity of von Willebrand factor-cleaving metalloprotease (ADAMTS13) Ann Hematol. Ann Hematol. 2002;81(8):430-5.

  • 36. Whitelock JL, Nolasco L, Bernardo A, et al. ADAMTS-13 activity in plasma is rapidly measured by a new ELISA method that uses recombinant VWF-A2 domain as substrate. J Thromb Haemost. 2004;2(3):485-91.

  • 37. Rieger M, Mannucce P, Kremer Hovinga JA, et al. ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases. Blood. Blood. 2005;106(4):1262-7.

  • 38. Petrović D, Čanović P, Mijailović Ž, Popovska-Jovičić B, Jaćović S. Hemolitičko-uremijski sindrom: etiopatogeneza, dijagnostika i osnovni principi lečenja. Med Čas 2015; 49(2):(in print).

  • 39. Diaz-Cremades J, Fernandez-Fuertes F, Ruano JA et al. Concurrent thrombotic thrombocytopenic purpura and antiphospholipid syndrome: a rare and severe clinical combination. Br J Haematol. 2009;147(4):584-5.

  • 40. Ahmed I, Majeed A, Powell R. Heparin induced thrombocytopenia: diagnosis and management update. Postgrad Med J. 2007;83(983):575-82.

  • 41. McCrae KR. Thrombocytopenia in pregnancy. Hematology Am Soc Hematol Educ Program. 2010; 2010(1):397-402.

  • 42. Soucemarianadin M, Benhamou Y, Delmas Y, et al. Twice-daily therapeutical plasma exchange-based salvage therapy in severe autoimmune thrombotic thrombocytopenic purpura: the French TMA Reference Center experience. Eur J Haematol. 2015 Nov 26. [Epub ahead of print]

  • 43. Scully M, Hunt BJ, Benjamin S, et al. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol. 2012;158(3):323-35.

  • 44. Balduini CL, Gugliotta L, Luppi M, et al; Italian TTP Study Group. High versus standard dose methylprednisolone in the acute phase of idiopathic thrombotic thrombocytopenic purpura: a randomized study. Ann Hematol. 2010;89(6):591-596.

  • 45. Scully M, McDonald V, Cavenagh J, et al. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura. Blood. 2011;118(7):1746-1753.

  • 46. Froissart A, Buffet M, Veyradier A, et al. Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center. Crit Care Med. 2012;40(1):104-11.

  • 47. Scully M, Cohen H, Cavenagh J, et al. Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13. Br J Haematol. 2007;136(3):451-61.

  • 48. Jasti S, Coyle T, Gentile T, et al. Rituximab as an adjunct to plasma exchange in TTP: a report of 12 cases and review of literature. J Clin Apher. 2008;23(5):151-6.

  • 49. Ling HT, Field JJ, Blinder MA. Sustained response with rituximab in patients with thrombotic thrombocytopenic purpura: a report of 13 cases and review of the literature. Am J Hematol. 2009;84(7):418-21.

  • 50. Chemnitz JM, Uener J, Hallek M, Scheid C. Long-term follow-up of idiopathic thrombotic thrombocytopenic purpura treated with rituximab. Ann Hematol. 2010;89(10):1029-33.

  • 51. de la Rubia J, Moscardo F, Gomez MJ, et al. Efficacy and safety of rituximab in adult patients with idiopathic relapsing or refractory thrombotic thrombocytopenic purpura: results of a Spanish multicenter study. Transfus Apher Sci. 2010;43(3):299-303.

  • 52. Goyal J, Adamski J, Lima JL, Marques MB. Relapses of thrombotic thrombocytopenic purpura after treatment with rituximab. J Clin Apher. 2013;28(6):390-4.

  • 53. Yates S, Matevosyan K, Rutherford C, et al. Bortezomib for chronic relapsing thrombotic thrombocytopenic purpura: a case report. Transfusion. 2014;54(8):2064-7.

  • 54. Shortt J, Oh DH, Opat SS. ADAMTS13 antibody depletion by bortezomib in thrombotic thrombocytopenic purpura. N Engl J Med. 2013;368(1):90-2.

  • 55. Patel PP, Becker J, Freyer C, et al. Rituximab-refractory thrombotic thrombocytopenic purpura responsive to intravenous but not subcutaneous bortezomib. Transfusion. 2016 Jan 18. [Epub ahead of print]

  • 56. Hie M, Gay J, Galicier L, et al. Preemptive rituximab infusions after remission efficiently prevent relapses in acquired thrombotic thrombocytopenic purpura. Blood. 2014;124(2):204-10.

  • 57. Westwood JP, Webster H, McGuckin S, et al. Rituximab for thrombotic thrombocytopenic purpura: benefit of early administration during acute episodes and use of prophylaxis to prevent relapse. J Thromb Haemost. 2013;11(3):481-90.

  • 58. Plaimauer B, Kremer Hovinga JA, Juno C, et al. Recombinant ADAMTS13 normalizes von Willebrand factorcleaving activity in plasma of acquired TTP patients by overriding inhibitory antibodies. J Thromb Haemost. 2011;9(5):936-944.

  • 59. Callewaert F, Roodt J, Ulrichts H, et al. Evaluation of efficacy and safety of the anti-VWF Nanobody ALX-0681 in a preclinical baboon model of acquired thrombotic thrombocytopenic purpura. Blood. 2012;120(17): 3603-3610.

  • 60. Ulrichts H, Silence K, Schoolmeester A, et al. Antithrombotic drug candidate ALX-0081 shows superior preclinical efficacy and safety compared with currently marketed antiplatelet drugs. Blood. 2011;118(3):757-765.


Journal + Issues