thrombotic thrombocytopenic purpura
Summary
Thrombotic thrombocytopenic purpura (TTP) is a life-threatening microangiopathy caused by deficiency or inhibition of ADAMTS13, leading to accumulation of ultra-large vWF multimers and platelet microthrombi. It classically presents with the pentad: fever, microangiopathic hemolytic anemia, thrombocytopenia, renal dysfunction, and neurologic symptoms (though full pentad is rare). It is a medical emergency treated with plasma exchange (TPE), not platelet transfusion.
Detail
Pathophysiology: TTP results from severe deficiency (<10%) of ADAMTS13, a metalloprotease that cleaves ultra-large von Willebrand factor (vWF) multimers. This deficiency is most commonly acquired via autoantibodies (immune-mediated TTP) but can be hereditary (Upshaw-Schulman syndrome, congenital ADAMTS13 mutation). Without ADAMTS13 activity, ultra-large vWF multimers persist in circulation, promoting spontaneous platelet aggregation and formation of platelet-rich microthrombi in small vessels throughout the body—particularly in the brain, kidneys, and heart.
Clinical features: Classic pentad (fever, MAHA, thrombocytopenia, renal dysfunction, neurologic abnormalities) is present in a minority of cases; most patients present with MAHA and thrombocytopenia plus variable organ involvement. MAHA produces schistocytes on peripheral smear due to mechanical shearing of RBCs as they pass through platelet thrombi. Neurologic symptoms range from headache to seizures and altered mental status. Renal involvement is typically milder than in hemolytic uremic syndrome (HUS).
Lab findings: Thrombocytopenia, anemia with schistocytes, elevated LDH, low haptoglobin, indirect hyperbilirubinemia, elevated reticulocyte count, normal PT/PTT (distinguishes from DIC), and severely decreased ADAMTS13 activity (<10%) with or without inhibitor antibodies.
Differential diagnosis: Important to distinguish from DIC (abnormal coagulation studies), HUS (more prominent renal failure, often preceded by Shiga toxin-producing E. coli diarrhea in children), and HELLP syndrome in pregnancy.
Treatment: Plasma exchange (plasmapheresis) is first-line, removing autoantibodies and ultra-large vWF multimers while replenishing ADAMTS13. Corticosteroids are often added for immune-mediated TTP. Rituximab (anti-CD20) is used for refractory or relapsing cases to target antibody-producing B cells. Caplacizumab, a nanobody that blocks vWF-platelet interaction, may be used in acute episodes to reduce microthrombi formation. Platelet transfusions are generally avoided unless life-threatening hemorrhage occurs, as they can exacerbate microthrombi formation and worsen ischemic organ damage.
High-yield board points: TTP vs HUS distinction, pentad presentation, schistocytes on smear, normal coagulation studies (distinguishing from DIC), ADAMTS13 deficiency mechanism, and plasma exchange as definitive treatment.
Sources
- First Aid for the USMLE Step 1
- Pathoma - Fundamentals of Pathology
- Harrison's Principles of Internal Medicine
- UpToDate: Thrombotic thrombocytopenic purpura
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