Pathogenesis: Thought to be secondary to production and accumulation of unusually large von Willebrand factor (ULvWf) multimers, which attach to platelets and promote platelet aggregation and clumping, resulting in microvascular occlusion and hemolysis. Normally, a specific protease cleaves these ULvWf multimers; in inherited TTP, these is a deficiency of this protease, while in acquired forms of the disease autoantibodies are produced against this protease.

• TTP has been associated with mucinous GI adenocarcinomas, SLE, antiphospholipid antibodies, high-dose chemotherapy, immunosuppressive agents, quinine, ticlodipine/clopidogrel, and HIV.

Diagnostic Criteria: Presence of thrombocytopenia and microangiopathic hemolytic anemia in the absence of other clinically apparent causes makes the diagnosis. Classically, patients may also show evidence of neurologic and renal abnormalities.

• Important to exclude DIC (typically has prolongation of PT/PTT with ¯ fibrinogen and ­ dimers), vasculitis (usually associated with systemic signs/symptoms, normal platelet count, and peripheral rather than central neurologic symptoms), and malignant hypertension (associated with DBP > 130 mmHg and abnormal retinal exam).

Classic pentad

• Hematologic: Anemia & thrombocytopenia with schistocytes on peripheral blood smear; markedly elevated LDH; low haptoglobin; high reticulocyte count; indirect hyperbilirubinemia.
• Neurologic (present in ~60%): Fluctuating nonfocal abnormalities, including headache, confusion, lethargy, seizures, coma. Focal motor/sensory deficits are less common.
• Mild-to-moderate renal insufficiency (present in ~40%), frequently with proteinuria or microscopic hematuria.
• Fever is nonspecific and is usually low-grade, typically not associated with chills.

Treatment: Plasma exchange is the mainstay of treatment. Prior to plasma exchange, mortality from TTP was ~90%; now, with effective treatment, survival is > 90%!!!

• Plasma infusion is thought to replace the missing protease that normally breaks down the ULvWf multimers; plasma exchange can remove both the multimers as well as the anti-protease antibodies (in acquired TTP).
• Plasma exchange with FFP – goal is to exchange 1 to 1.5 times the predicted plasma volume with FFP daily or twice daily until the platelet count is at least 100K. Can then slowly wean the frequency of exchange transfusions as long as the platelet count is stable.
• Other therapies: none of the other therapies for TTP other than plasma exchange have proven benefit.
• Antiplatelet agents: aspirin (100 mg/day) and dipyridamole (300 mg/day) are of uncertain benefit in TTP. May be of benefit when used in conjunction with plasma exchange.
• Steroids: Prednisone (100 to 200 mg/day) – probably effective in acquired TTP. Taper slowly over several weeks.
• Vincristine: indicated in refractory TTP and/or life-threatening TTP (severe renal or neurologic dysfunction).
• IVIG, cyclosporine, cyclophosphamide, and Prosorbicolumn (Staph protein A immunoadsorption column) are investigational therapies.
• Splenectomy – indicated only in low operative risk patients who have frequent relapses, when platelet count is normal. May decrease relapse rate.
• Platelet transfusions are contraindicated except in the face of life-threatening hemorrhage.
• 10-year relapse rate has been estimated at 36%! Therefore, it is important to monitor this disease indefinitely once diagnosed.

D. Suh 10/24/00