Thrombotic Thrombocytopenic Purpura (TTP)

ADAMTS13 deficiency, the thrombotic microangiopathy emergency treated with urgent plasma exchange, caplacizumab, and immunosuppression

Key Points

• TTP is a thrombotic microangiopathy (TMA) caused by severe ADAMTS13 deficiency (activity <10%), leading to ultra-large von Willebrand factor multimers that drive platelet-rich microthrombi.
• It is a hematologic emergency: untreated mortality exceeds 90%, but prompt plasma exchange reduces it to ~10–20%. Never wait for the ADAMTS13 result to start treatment.
• The classic pentad (microangiopathic hemolytic anemia, thrombocytopenia, neurologic signs, renal impairment, fever) is present in a minority — MAHA plus thrombocytopenia without another cause is enough to act.
• The PLASMIC score helps estimate the probability of severe ADAMTS13 deficiency at the bedside while confirmatory testing is pending.
• Immune (acquired) TTP is treated with plasma exchange, corticosteroids, caplacizumab (anti-vWF nanobody), and rituximab; congenital TTP (Upshaw-Schulman syndrome) is treated with plasma or recombinant ADAMTS13.
• Do NOT transfuse platelets except for life-threatening hemorrhage — platelet transfusion can fuel microthrombosis and worsen outcomes.

Pathophysiology

Thrombotic thrombocytopenic purpura is caused by a severe deficiency of ADAMTS13, the plasma metalloprotease that cleaves ultra-large von Willebrand factor (vWF) multimers into smaller, less adhesive forms. When ADAMTS13 activity falls below ~10%, ultra-large vWF multimers accumulate on the endothelial surface and spontaneously bind platelets, forming platelet-rich (vWF-rich) microthrombi in the microcirculation. These microthrombi consume platelets (thrombocytopenia) and shear passing red cells against the partially occluded vessels, producing schistocytes and microangiopathic hemolytic…

Clinical Presentation and the PLASMIC Score

The historically taught **pentad** — MAHA, thrombocytopenia, neurologic abnormalities, renal dysfunction, and fever — is complete in fewer than 10% of patients and should NOT be required to make the diagnosis. Waiting for the full pentad delays life-saving therapy. **In practice, suspect TTP when there is:** microangiopathic hemolytic anemia (anemia + schistocytes on smear + elevated LDH + low haptoglobin + negative direct antiglobulin test) together with thrombocytopenia, and no alternative explanation (e.g. DIC, malignant hypertension, or another TMA). **Common features:** -…

Treatment of Immune TTP

Immune TTP is a medical emergency. Treatment combines removal of the autoantibody and ultra-large vWF (plasma exchange), replacement of ADAMTS13 (plasma), immunosuppression, and blockade of the vWF–platelet interaction. **1. Therapeutic plasma exchange (TPE):** The cornerstone. Begin urgently — ideally within 4–8 hours of suspicion. TPE removes anti-ADAMTS13 antibodies and ultra-large vWF multimers while replacing functional ADAMTS13 via fresh frozen plasma. Perform daily (typically 1–1.5 plasma volumes) until the platelet count normalizes (>150 × 10⁹/L) for at least 2 consecutive days and…

Congenital TTP and Long-Term Follow-Up

**Congenital TTP (Upshaw-Schulman syndrome):** Caused by inherited ADAMTS13 deficiency without an autoantibody. Because the problem is absent enzyme rather than an antibody, treatment centers on ADAMTS13 replacement rather than immunosuppression: - **Plasma infusion** (fresh frozen plasma) supplies ADAMTS13 and is used both to treat acute episodes and as scheduled prophylaxis in patients with frequent events or during high-risk periods such as pregnancy. - **Recombinant ADAMTS13 (apadamtase alfa):** FDA-approved for congenital TTP, providing targeted enzyme replacement for prophylaxis and…