Thrombotic Thrombocytopenic Purpura Clinical Presentation

  • Author: Theodore Wun, MD, FACP; Chief Editor: Emmanuel C Besa, MD   more...
 
Updated: Oct 3, 2011
 

History

  • Patients with thrombotic thrombocytopenic purpura (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.
  • Fever occurs in approximately 50% of patients.
  • Patients also may notice dark urine from hemoglobinuria.
  • Clinical differentiation of HUS and TTP can be problematic and differentiation is often based on the presence of CNS 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 are suggesting 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, is the standard therapy versus plasma exchange. However, albeit somewhat controversial, plasma exchange is performed in adults with HUS so the differentiation has less therapeutic implications at present.
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Physical

  • 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.
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Causes

  • 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.
  • HUS, and to some extent TTP, commonly occur following a diarrheal illness with enterohemorrhagic Escherichia coli O 157: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, and, 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.[3] 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.
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Contributor Information and Disclosures
Author

Theodore Wun, MD, FACP  Professor of Medicine, Professor of Pathology and Laboratory Medicine, University of California Davis School of Medicine; Chief of Hematology/Oncology, Program Director, Veterans Affairs Northern California Health Care System; Medical Director, University of California Davis CCRC

Theodore Wun, MD, FACP is a member of the following medical societies: American Association of Blood Banks, American College of Physicians, American Federation for Medical Research, American Society for Blood and Marrow Transplantation, American Society of Hematology, and Southwest Oncology Group

Disclosure: Nothing to disclose.

Coauthor(s)

Wadie F Bahou, MD  Chief, Division of Hematology, Hematology/Oncology Fellowship Director, Professor, Department of Internal Medicine, State University of New York at Stony Brook

Wadie F Bahou, MD is a member of the following medical societies: American Society of Hematology

Disclosure: Nothing to disclose.

Specialty Editor Board

Wadie F Bahou, MD  Chief, Division of Hematology, Hematology/Oncology Fellowship Director, Professor, Department of Internal Medicine, State University of New York at Stony Brook

Wadie F Bahou, MD is a member of the following medical societies: American Society of Hematology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Marcel E Conrad, MD  Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group

Disclosure: No financial interests None None

Rajalaxmi McKenna, MD, FACP  Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD  Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences

Disclosure: Nothing to disclose.

References

  1. Sauna ZE, Okunji C, Hunt RC, et al. Characterization of conformation-sensitive antibodies to ADAMTS13, the von Willebrand cleavage protease. PLoS One. Aug 5 2009;4(8):e6506. [Medline]. [Full Text].

  2. Bouw MC, Dors N, van Ommen H, Ramakers-van Woerden NL. Thrombotic thrombocytopenic purpura in childhood. Pediatr Blood Cancer. Jun 18 2009;53(4):537-542. [Medline].

  3. 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. Aug 11 2009;[Medline].

  4. Marn Pernat A, Buturovic-Ponikvar J, Kovac J, et al. Membrane plasma exchange for the treatment of thrombotic thrombocytopenic purpura. Ther Apher Dial. Aug 2009;13(4):318-21. [Medline].

  5. Jhaveri KD, Scheuer A, Cohen J, Gordon B. Treatment of refractory thrombotic thrombocytopenic purpura using multimodality therapy including splenectomy and cyclosporine. Transfus Apher Sci. Aug 2009;41(1):19-22. [Medline].

  6. 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. Aug 18 2011;118(7):1746-53. [Medline].

  7. Bell WR, Braine HG, Ness PM, Kickler TS. Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. N Engl J Med. Aug 8 1991;325(6):398-403. [Medline].

  8. 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. Sep 15 2005;106(6):1932-7. [Medline].

  9. Furlan M, Robles R, Galbusera M, et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med. Nov 26 1998;339(22):1578-84. [Medline].

  10. Lara PN, Coe TL, Zhou H, et al. Improved survival with plasma exchange in patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Am J Med. Dec 1999;107(6):573-9. [Medline].

  11. Lau DH, Wun T. Early manifestation of thrombotic thrombocytopenic purpura. Am J Med. Nov 1993;95(5):544-5. [Medline].

  12. Moake JL. Haemolytic-uraemic syndrome: basic science. Lancet. Feb 12 1994;343(8894):393-7. [Medline].

  13. Neild GH. Haemolytic-uraemic syndrome in practice. [published erratum appears in Lancet 1994 Feb 26;343(8896):552]. Lancet. Feb 12 1994;343(8894):398-401. [Medline].

  14. Rock GA, Shumak KH, Buskard NA, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med. Aug 8 1991;325(6):393-7. [Medline].

  15. Shumak KH, Rock GA, Nair RC. Late relapses in patients successfully treated for thrombotic thrombocytopenic purpura. Canadian Apheresis Group. Ann Intern Med. Apr 15 1995;122(8):569-72. [Medline].

  16. Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med. Nov 26 1998;339(22):1585-94. [Medline].

  17. 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. Jul 1 2003;102(1):60-8. [Medline].

 
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Differential diagnosis of thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome.
Peripheral smear from a patient with thrombotic thrombocytopenic purpura: Red blood cells are fragmented and appear as schistocytes. Certain schistocytes have the appearance of helmet cells (H). Spheroidal cells often are present (S). Occasional nucleated erythroid precursors may be present.
 
 
 
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