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Definition, Etiology, PathogenesisTop
Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy with thrombocytopenia caused by the formation of intravascular platelet aggregates, which develop due to endothelial injury and the presence of ultra large von Willebrand factor (vWF) molecules in plasma (in healthy persons these are degraded by a plasma metalloproteinase: ADAMTS-13 [vWF-cleaving protease]). Hemolytic anemia and schistocytes result from red blood cell damage related to platelet aggregates in microcirculation.
Chronic TTP is associated with an inherited ADAMTS-13 deficiency, while acute TTP can be caused by autoantibodies to ADAMTS-13. In some patients, particularly those with a history of organ transplantation, the etiology is unknown (ADAMTS-13 levels are normal). TTP may also develop in patients with bacterial infections; HIV infection; in the course of treatment with various drugs, including calcineurin inhibitors, quinine, interferon α, ticlopidine, clopidogrel, simvastatin, trimethoprim, gemcitabine, and bleomycin; in pregnancy; or in patients with cancer. Platelet aggregates present in microcirculation cause hemolytic anemia with schistocytes in peripheral blood smears and features of ischemia of various organs and systems, most frequently the central nervous system. Thrombi form in capillaries and arterioles in all organs, with particularly extensive involvement of the vessels of the brain, heart, kidneys, pancreas, and adrenal glands.
Clinical Features and Natural HistoryTop
TTP is more prevalent in women, usually between the ages of 30 to 40 years. The onset is acute and may be preceded by a mild upper respiratory tract infection. Manifestations include signs and symptoms of thrombocytopenia, hemolysis (anemia and jaundice), neurologic symptoms (in ~65% of patients; these may include behavioral abnormalities, headache, visual disturbances, paresthesias, aphasia, coma), fever, abdominal pain, myalgia (frequent), and enlargement of the liver and spleen (in ~50% of patients).
1. Complete blood count: Normocytic anemia, erythroblasts and schistocytes present in peripheral blood smears, thrombocytopenia, increased reticulocyte counts.
2. Blood biochemical tests: Elevated serum unconjugated bilirubin and lactate dehydrogenase (LDH) levels. Features of impaired renal function in some patients.
3. Urinalysis: Proteinuria, microscopic hematuria, casts.
4. Other studies: Markedly decreased concentrations and decreased activity of ADAMTS-13 (<10%) as well as positive antibodies to ADAMTS-13 may be seen. Coombs test results are negative.
Diagnosis is usually based on clinical features. Confirmation of microangiopathic hemolytic anemia and thrombocytopenia without an identifiable cause is sufficient for establishing the diagnosis. Documenting reduced ADAMTS-13 levels and positive antibodies to ADAMTS-13 may be performed if available.
Disseminated intravascular coagulation, Evans syndrome, catastrophic antiphospholipid syndrome, bacterial sepsis, hemolytic-uremic syndrome.
1. Plasmapheresis (plasma exchange) of 1 to 1.5 total plasma volume per day (the most effective treatment). Until plasmapheresis administer fresh-frozen plasma (FFP) 30 mL/kg/d. Continue plasmapheresis until the resolution of neurologic symptoms and normalization of platelet counts and LDH levels. If no improvement is observed, consider the administration of cryoprecipitate-reduced plasma (with reduced concentrations of vWF, fibrinogen, fibronectin, and factor XIII).
2. Rituximab 375 mg/m2 once weekly for 4 to 8 weeks, particularly in patients not responding to plasmapheresis or glucocorticoids, or with relapse. Rituximab is being used with increasing frequency in newly presenting patients, as it may reduce the risk of relapse.
3. Immunosuppressive drugs: These are used in patients who deteriorate despite other treatments. Steroids are frequently used; however, there is little evidence of efficacy. From day 4 of treatment agents may include intravenous vincristine 1.4 mg/kg every 3 days, cyclophosphamide, or azathioprine.
4. Splenectomy may lead to improvement in some patients. Optimally, it should be performed in remission after the first relapse.
5. Packed red blood cell transfusions are used to control anemia.
6. Platelet concentrates are administered only in patients with life-threatening hemorrhages.
7. Chronic TTP: Administer FFP 20 mL/kg every 3 to 4 weeks.
Mortality rates are 90% in untreated patients and 10% to 20% in patients treated with plasma exchange. TTP relapses in 30% of patients, and in half of these cases relapse occurs within 2 months of the first episode. Rituximab therapy may reduce the rate of relapse.