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Thrombotic Thrombocytopenic Purpura

http://emedicine.medscape.com/article/206598-overview

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Thrombotic Thrombocytopenic Purpura


Author: Theodore Wun, MD, FACP; Chief Editor: Emmanuel C Besa, MD more... Updated: Feb 4, 2013

Practice Essentials
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.

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.

Diagnosis
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.[1] 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.

Management
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

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Thrombotic Thrombocytopenic Purpura

http://emedicine.medscape.com/article/206598-overview

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. [2] 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 patients. See Treatment and Medication for more detail.

Image library

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.

Background
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). See image below.

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.

In its full-blown form, the disease consists of the pentad of microangiopathic hemolytic anemia, thrombocytopenic purpura, neurologic abnormalities, fever, and renal disease. 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.

Pathophysiology

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Thrombotic Thrombocytopenic Purpura

http://emedicine.medscape.com/article/206598-overview

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 to thrombi that occur secondary to intravascular coagulation. The ultimate cause of TTP is unknown; however, recent 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.[3]

Frequency
United States
Exact incidence figures are not available, although TTP is thought to be a rare disease. One series showed the frequency was 1 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.

International
International incidence figures are not available.

Mortality/Morbidity
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. 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.

Race
An ethnic predisposition to TTP is not established.

Sex
In the larger series reported, a female predominance of approximately 2:1 was noted.

Age
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. Ninety percent of cases of HUS occur in children. Bouw et al recently presented a review article of TTP in children.[4]

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

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Thrombotic Thrombocytopenic Purpura

http://emedicine.medscape.com/article/206598-overview

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 and Hematopoietic Stem Cell Transplantation, 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. 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]. 2. Lowes R. FDA Okays Blood Plasma Product for Clotting Disorders. Medscape Medical News. January 17,

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Thrombotic Thrombocytopenic Purpura

http://emedicine.medscape.com/article/206598-overview

2013. Available at http://www.medscape.com/viewarticle/777822. Accessed January 31, 2013. 3. 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]. 4. 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]. 5. 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]. 6. 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]. 7. 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]. 8. Bell WR, Braine HG, Ness PM, Kickler TS. Improved survival in thrombotic thrombocytopenic purpurahemolytic uremic syndrome. Clinical experience in 108 patients. N Engl J Med. Aug 8 1991;325(6):398-403. [Medline]. 9. 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]. 10. 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]. 11. 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]. 12. Lau DH, Wun T. Early manifestation of thrombotic thrombocytopenic purpura. Am J Med. Nov 1993;95(5):544-5. [Medline]. 13. Moake JL. Haemolytic-uraemic syndrome: basic science. Lancet. Feb 12 1994;343(8894):393-7. [Medline]. 14. 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]. 15. 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]. 16. 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]. 17. 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]. 18. Vesely SK, George JN, Lammle B, et al. ADAMTS13 activity in thrombotic thrombocytopenic purpurahemolytic 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]. Medscape Reference 2011 WebMD, LLC

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