Thrombotic Thrombocytopenic Purpura (TTP) Clinical Presentation
- Author: Theodore Wun, MD, FACP; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP more...
Patients with thrombotic thrombocytopenic purpura (TTP) typically report an acute or subacute onset of the following symptoms related to neurologic dysfunction, anemia, or thrombocytopenia:
Neurologic manifestations include alteration in mental status, seizures, hemiplegia, paresthesias, visual disturbance, and aphasia
Fatigue may accompany the anemia
Severe bleeding from thrombocytopenia is unusual, although petechiae are common
Clinical manifestations may also include the following:
Fever occurs in approximately 50% of patients
Patients may notice dark urine from hemoglobinuria.
Clinical differentiation of hemolytic-uremic syndrome (HUS) and TTP can be problematic. Differentiation is often based on the presence of central nervous system involvement in TTP and the more severe renal involvement in HUS. In HUS, an antecedent history of diarrheal illness is more often present. In fact, some investigators suggest a clinical classification of HUS based on the presence or absence of diarrhea.
In children, the distinction between HUS and TTP may be of more importance, as general supportive measures (with dialysis as needed) are the standard therapy for HUS, versus plasma exchange for TTP. However, albeit somewhat controversial, plasma exchange is performed in adults with HUS so the differentiation has less therapeutic implications at present.
Patients with TTP or HUS have no characteristic physical findings. Findings upon examination depend on the severity of involvement of the target organ systems.
Hemolytic anemia and thrombocytopenia cause pallor, jaundice, and petechiae. Abnormal findings upon neurologic examination consist of mental status changes and/or focal neurologic deficits. These defects can be evanescent and, thus, present as transient ischemic attacks. Organomegaly is not typical.
The exact etiology of HUS and TTP is not clear, although much recent data are available on the role of bacterial Shiga toxin in HUS and of a deficiency in a protease designated ADAMTS13 in TTP. HUS, and to some extent TTP, commonly occur following a diarrheal illness with enterohemorrhagic Escherichia coli O157:H7 and Shigella dysenteriae serotype I. These bacteria, besides causing bloody diarrhea, are able to secrete an exotoxin called Shiga toxin (in the case of Shigella) or Shigalike toxin (in the case of E coli).
These toxins can bind to certain cell membrane globotriaosylceramide receptors, which, depending on the cell in question, can lead to chemokine or cytokine secretion (colonic and renal epithelial cells), cellular activation (monocytes and platelets), or secretion of unusually large von Willebrand multimers (glomerular endothelial cells). Evidence for activation of the coagulation cascade in HUS also exists. The relative specificity of the toxin for renal endothelial cells versus other types of endothelial cells is unknown.
Drugs such as mitomycin, cyclosporin A, cisplatin, bleomycin, quinine, and ticlopidine have been associated with HUS and TTP. Whether the drugs and/or their metabolites have a direct effect on the vascular endothelium or whether alteration of the endothelial cells results in a neoantigen that leads to autoantibody formation remains unknown.
Formation of endothelial cell autoantibodies may underlie the association of thrombotic microangiopathies and pregnancy.
Most sporadic cases of TTP appear to be associated with severe deficiency of ADAMTS13 activity due to autoantibodies against this protease. Normally, ADAMTS13 cleaves the large multimers of von Willebrand factor when they are secreted from endothelial cells. In most patients with active TTP, unusually large von Willebrand multimers are found in plasma. These multimers can bind to platelets in the absence of physiologic stimulus, and this mechanism might underlie the white clot seen in pathologic specimens from patients with TTP.
Congenital TTP results from mutations in the gene for ADAMTS13. Why such patients do not always have clinically apparent TTP remains unknown.
Pregnancy can precipitate TTP. Onset of TTP during pregnancy may represent acute acquired TTP or the first episode of congenital TTP. In a prospective study of pregnancy-associated TTP from the United Kingdom, TTP presented primarily in the third trimester or postpartum.
Tsai HM. Thrombotic thrombocytopenic purpura and the atypical hemolytic uremic syndrome: an update. Hematol Oncol Clin North Am. 2013 Jun. 27(3):565-84. [Medline].
Ferrari S, Mudde GC, Rieger M, Veyradier A, Kremer Hovinga JA, Scheiflinger F. IgG-subclass distribution of anti-ADAMTS13 antibodies in patients with acquired thrombotic thrombocytopenic purpura. J Thromb Haemost. 2009 Aug 11. [Medline].
Mariotte E, Azoulay E, Galicier L, Rondeau E, Zouiti F, Boisseau P, et al. Epidemiology and pathophysiology of adulthood-onset thrombotic microangiopathy with severe ADAMTS13 deficiency (thrombotic thrombocytopenic purpura): a cross-sectional analysis of the French national registry for thrombotic microangiopathy. Lancet Haematol. 2016 May. 3 (5):e237-45. [Medline].
Lowes R. FDA Okays Blood Plasma Product for Clotting Disorders. Medscape Medical News. January 17, 2013. Available at http://www.medscape.com/viewarticle/777822. Accessed: January 31, 2013.
Vesely SK, George JN, Lammle 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 Jul 1. 102(1):60-8. [Medline].
Miller DP, Kaye JA, Shea K, Ziyadeh N, Cali C, Black C, et al. Incidence of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. Epidemiology. 2004 Mar. 15 (2):208-15. [Medline].
Scully M, Thomas M, Underwood M, Watson H, Langley K, Camilleri RS, et al. Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes. Blood. 2014 Jul 10. 124(2):211-9. [Medline].
Bouw MC, Dors N, van Ommen H, Ramakers-van Woerden NL. Thrombotic thrombocytopenic purpura in childhood. Pediatr Blood Cancer. 2009 Jun 18. 53(4):537-542. [Medline].
Wu N, Liu J, Yang S, Kellett ET, Cataland SR, Li H, et al. Diagnostic and prognostic values of ADAMTS13 activity measured during daily plasma exchange therapy in patients with acquired thrombotic thrombocytopenic purpura. Transfusion. 2014 Jun 23. [Medline].
Coppo P, Veyradier A. Current management and therapeutical perspectives in thrombotic thrombocytopenic purpura. Presse Med. 2012 Mar. 41(3 Pt 2):e163-76. [Medline].
[Guideline] Scully M, Hunt BJ, Benjamin S, Liesner R, Rose P, Peyvandi F, et al. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Br J Haematol. 2012 Aug. 158 (3):323-35. [Medline]. [Full Text].
Shah N, Rutherford C, Matevosyan K, Shen YM, Sarode R. Role of ADAMTS13 in the management of thrombotic microangiopathies including thrombotic thrombocytopenic purpura (TTP). Br J Haematol. 2013 Nov. 163 (4):514-9. [Medline].
Connell NT, Cheves T, Sweeney JD. Effect of ADAMTS13 activity turnaround time on plasma utilization for suspected thrombotic thrombocytopenic purpura. Transfusion. 2015 Oct 12. [Medline].
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 May 30. [Medline].
Marn Pernat A, Buturovic-Ponikvar J, Kovac J, et al. Membrane plasma exchange for the treatment of thrombotic thrombocytopenic purpura. Ther Apher Dial. 2009 Aug. 13(4):318-21. [Medline].
Michael M, Elliott EJ, Craig JC, Ridley G, Hodson EM. Interventions for hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: a systematic review of randomized controlled trials. Am J Kidney Dis. 2009 Feb. 53(2):259-72. [Medline].
Fakhouri F, Vernant JP, Veyradier A, et al. Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic purpura: a study of 11 cases. Blood. 2005 Sep 15. 106(6):1932-7. [Medline].
Froissart A, Buffet M, Veyradier A, Poullin P, Provôt F, Malot S, 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 Jan. 40(1):104-11. [Medline].
Becerra E, Scully MA, Leandro MJ, Heelas EO, Westwood JP, De La Torre I, et al. Effect of rituximab on B-cell phenotype and serum B-cell activating factor levels in patients with Thrombotic Thrombocytopenic Purpura. Clin Exp Immunol. 2014 Oct 22. [Medline].
Patriquin CJ, Thomas MR, Dutt T, McGuckin S, Blombery PA, Cranfield T, et al. Bortezomib in the treatment of refractory thrombotic thrombocytopenic purpura. Br J Haematol. 2016 Mar 24. [Medline].
Zhou A, Mehta RS, Smith RE. Outcomes of platelet transfusion in patients with thrombotic thrombocytopenic purpura: a retrospective case series study. Ann Hematol. 2014 Oct 7. [Medline].
Gringauz I, Carmel-Neiderman NN, Mangel T, Portnoy O, Segal G, Goren I. Marked Improvement in Refractory TTP Directly after H. pylori Eradication Therapy. Case Rep Hematol. 2016. 2016:1568586. [Medline]. [Full Text].
Peyvandi F, Scully M, Kremer Hovinga JA, Cataland S, Knöbl P, Wu H, et al. Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura. N Engl J Med. 2016 Feb 11. 374 (6):511-22. [Medline]. [Full Text].
Phase III Trial With Caplacizumab in Patients With Acquired Thrombotic Thrombocytopenic Purpura (HERCULES). ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT02553317. March 17, 2016; Accessed: May 13, 2016.
Jhaveri KD, Scheuer A, Cohen J, Gordon B. Treatment of refractory thrombotic thrombocytopenic purpura using multimodality therapy including splenectomy and cyclosporine. Transfus Apher Sci. 2009 Aug. 41(1):19-22. [Medline].
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 Aug 18. 118(7):1746-53. [Medline].
Shumak KH, Rock GA, Nair RC. Late relapses in patients successfully treated for thrombotic thrombocytopenic purpura. Canadian Apheresis Group. Ann Intern Med. 1995 Apr 15. 122(8):569-72. [Medline].
Roriz M, Landais M, Desprez J, et al; French Thrombotic Microangiopathies Reference Center. Risk Factors for Autoimmune Diseases Development After Thrombotic Thrombocytopenic Purpura. Medicine (Baltimore). 2015 Oct. 94 (42):e1598. [Medline]. [Full Text].