eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

Thrombotic Thrombocytopenic Purpura

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
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
Contributor Information and Disclosures

Updated: Aug 27, 2009

Introduction

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).

Pathophysiology

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.¹

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.²

Clinical

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.

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.

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.

• Search for CME/CE on This Topic »

• Thrombotic Thrombocytopenic Purpura (Neurology)
• Thrombocytopenic Purpura (Emergency Medicine)
• Dermatologic Manifestations of Hematologic Disease (Dermatology)
• Anemia, Chronic (Pediatrics: General Medicine)

• Antiphospholipid Antibodies: Paradigm in Transition
• Effectiveness and Safety of Generic Fixed-Dose Combination of Tenofovir/Emtricitabine/Efavirenz in HIV-1-Infected Patients in Western India
• Morbidity and Mortality in the Antiphospholipid Syndrome