Thrombotic Thrombocytopenic Purpura (TTP)
- Author: Theodore Wun, MD, FACP; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP more...
Thrombotic thrombocytopenic purpura (TTP) is a rare blood disorder characterized by clotting in small blood vessels of the body (thromboses), resulting in a low platelet count. In its full-blown form, the disease consists of the pentad of microangiopathic hemolytic anemia, thrombocytopenic purpura, neurologic abnormalities, fever, and renal disease.
To make an accurate diagnosis, the clinician must recognize the similarity between thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS). In addition to HUS, the differential diagnosis also includes immune thrombocytopenic purpura (ITP) and disseminated intravascular coagulation (DIC), two entities with very different modes of therapy (see the image below).
Secondary TTP has been associated with the use of certain drugs, including chemotherapy drugs such as gemcitabine and mitomycin and antiplatelet agents such as clopidogrel and ticlopidine. If secondary TTP is suspected, the offending drug should be discontinued.
See Cancer Chemotherapy: Keys to Diagnosing Common Toxicities, a Critical Images slideshow, to help recognize some of the more common complications of chemotherapy.
Signs and symptoms
Patients with TTP typically report an acute or subacute onset of 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
TTP can affect any organ system, but involvement of the peripheral blood, the central nervous system, and the kidneys causes the clinical manifestations.
See Clinical Presentation for more detail.
The exact etiology of TTP is unknown. Most sporadic cases of TTP appear to be associated with severe deficiency of ADAMTS13 activity due to autoantibodies against this protease.[2, 3] Measuring ADAMTS13 activity level may aid in diagnosis.
Laboratory studies for suspected TTP include a CBC, platelet count, blood smears, coagulation studies, BUN creatinine, and serum bilirubin and lactate dehydrogenase.
Imaging studies and biopsies are not required for diagnosis.
See Workup for more detail.
The therapy of choice for TTP is plasma exchange with fresh frozen plasma. Only the minority of TTP patients (20-30%) present with the classic pentad. The presence of microangiopathic hemolytic anemia (schistocytes, elevated LDH, and indirect hyperbilirubinemia) and thrombocytopenia in the absence of other obvious causes (DIC, malignant hypertension) is justification to begin total plasma exchange.
Octaplas (Octapharma), a blood plasma product extensively used in Europe, was approved by the FDA in January 2013 for use in the United States. The product is a sterile, frozen solution of pooled human plasma from several donors. It is a viable alternative to single-donor plasma, and it is treated with a solvent detergent process, which reduces the risk of infection. The FDA based approval on clinical studies of patients with liver disease, liver transplant, heart surgery, and TTP.
In those patients refractory to plasma exchange, using cryopoor plasma (or cryosupernatant) has sometimes led to a response. This is fresh frozen plasma that has had the cryoprecipitate removed and is thus depleted of high-molecular-weight von Willebrand multimers, which have a pathogenic role in TTP. Corticosteroids may also be used in refractory TTP. Rituximab, although not approved for use in TTP, is increasingly recommended for use in refractory cases.
TTP can affect any organ system, but involvement of the peripheral blood, the central nervous system, and the kidneys causes the clinical manifestations. The classic histologic lesion is one of bland thrombi in the microvasculature of affected organs. These thrombi consist predominantly of platelets with little fibrin and red cells compared with thrombi that occur secondary to intravascular coagulation. The ultimate cause of TTP is unknown; however, research has uncovered some clues about the pathophysiology.
Patients with TTP have unusually large multimers of von Willebrand factor (vWF) in their plasma. Patients with TTP lack a plasma protease that is responsible for the breakdown of these ultralarge vWF multimers. In the congenital form of TTP, mutations in the gene encoding this protease have been described. In the more common sporadic form, an antibody inhibitor can be isolated in most patients. This protease has been isolated and cloned and is designated ADAMTS13 (A Disintegrinlike And Metalloprotease with ThromboSpondin type 1 motif 13). The activity of this protease is normal in most patients with classic HUS, suggesting differing pathogenesis of these closely related entities.
In 1924, Eli Moschowitz, MD, described a girl who presented with an abrupt onset of petechiae and pallor followed rapidly by paralysis, coma, and death. Upon pathologic examination, the small arterioles and capillaries of the patient were found to have thrombi consisting mostly of platelets. Dr. Moschowitz hypothesized a "powerful poison which had both agglutinative and hemolytic properties" as the cause of the disease. The syndrome described by Moschowitz is now known as thrombotic thrombocytopenic purpura (TTP).
In its full-blown form, the disease consists of the following pentad:
Microangiopathic hemolytic anemia
A closely related disorder, hemolytic-uremic syndrome (HUS), shares many clinical characteristics of TTP but is more common in children. Renal abnormalities tend to be more severe in HUS. Although once considered variants of a single syndrome, recent evidence suggests differing pathogenic mechanisms of TTP and HUS. The mortality of TTP is greatly reduced with the routine use of aggressive high-volume total plasma exchange (TPE). The effect of TPE on the outcome of patients with HUS is more controversial.
Exact incidence figures for the United States are not available, although TTP is thought to be a rare disease. One series showed that the frequency was one in approximately 50,000 hospital admissions. In a 25-year period in the Sacramento, California region (population at risk, 1.2 million), at least 176 documented cases of TTP were reported. In another 1-year study, 20 institutions reported 115 patients with TTP.
Analysis of a French national registry found that the rate of TTP in France was 13 cases per million population. The age-sex standardized incidence of TTP and hemolytic uremic syndrome in the United Kingdom has been estimated at 2.2 cases per million population per year in the United Kingdom and 3.2 cases per million population per year in Saskatchewan, Canada.
Untreated, TTP has a mortality rate of as high as 90%. With plasma exchange, the mortality rate is reduced to 10-20%.
Acute morbidities include ischemic events such as stroke, transient ischemic attacks, myocardial infarction and arrhythmia, bleeding, and azotemia. TTP during pregnancy may precipitate fetal loss.
In general, survivors have no long-term sequelae, with the exception of residual neurologic deficits in a minority of patients. However, relapses are not uncommon, occurring in 13-36% of patients.
Racial, Sexual, and Age-Related Disparities
An ethnic predisposition to TTP is not established. In the larger series reported, a female predominance of approximately 2:1 has been noted.
In several large studies, the median age at diagnosis is approximately 40 years. However, in the authors' series of 126 consecutive patients, the median age was 52 years.
In general, HUS is diagnosed in children and TTP is diagnosed in adults; 90% of cases of HUS occur in children. Bouw et al have presented a review article of TTP in children.
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].