Thrombotic Thrombocytopenic Purpura (TTP) / Hemolytic Uremic Syndrome (HUS)

Risk factors

• TTP: female sex, pregnancy/postpartum, autoimmune disease (lupus), HIV, drugs (ticlopidine, clopidogrel, quinine, cyclosporine, tacrolimus, gemcitabine), recent infection
• STEC-HUS: ingestion of contaminated food (ground beef, leafy greens, unpasteurized dairy, petting zoo exposure), young children
• aHUS: genetic complement mutations (factor H, factor I, MCP, C3, factor B), pregnancy/postpartum triggers, transplantation
• Secondary TMA: malignancy, HSCT, drugs (calcineurin inhibitors, VEGF inhibitors), severe HTN

Pathophysiology

TTP: ADAMTS13 (von Willebrand factor-cleaving protease) deficient — acquired autoantibody (most common) or congenital (Upshaw-Schulman). Ultralarge vWF multimers accumulate, bind platelets, and form microvascular thrombi causing organ ischemia and red cell shear (schistocytes). STEC-HUS: Shiga toxin from E. coli O157:H7 (or Shigella dysenteriae) damages endothelial cells, especially in renal glomeruli, triggering platelet activation and microvascular thrombosis. aHUS: uncontrolled alternative complement activation on endothelial surfaces.

Clinical presentation

Differential diagnosis

• DIC — Thrombocytopenia + prolonged PT/PTT + low fibrinogen + high D-dimer; underlying sepsis/trauma/malignancy; TTP/HUS have normal coags
• HELLP syndrome — Pregnancy/postpartum, hypertension, elevated LFTs, thrombocytopenia, microangiopathic hemolysis; resolves with delivery
• Severe preeclampsia / eclampsia — Hypertension, proteinuria, end-organ injury; overlap with HELLP
• ITP — Isolated thrombocytopenia without hemolysis, schistocytes, or organ dysfunction
• Evans syndrome — Warm AIHA + ITP, positive DAT, no schistocytes
• Malignant hypertension — BP >180/120 with end-organ damage; can cause microangiopathic hemolysis
• Catastrophic antiphospholipid syndrome — Multiorgan thrombosis, antiphospholipid antibodies
• Drug-induced TMA — Quinine, gemcitabine, calcineurin inhibitors, VEGF inhibitors; temporal relation
• Transplant-associated TMA — Post-HSCT or solid organ transplant; calcineurin inhibitors, GVHD

Diagnostic workup

Diagnostic algorithm

Treatment

Complications

• TTP untreated: ~90% mortality; with PLEX ~10-20% mortality
• Neurologic sequelae: cognitive impairment, focal deficits, seizures
• Acute kidney injury — may require dialysis; STEC-HUS often recovers, aHUS often progresses to ESRD
• Cardiac involvement — myocardial microthrombi, troponin elevation, arrhythmia, sudden cardiac death
• Relapse of acquired TTP — ~30-50%; lifelong monitoring
• aHUS post-transplant recurrence without complement blockade — common
• Eculizumab risks: meningococcal infection (give MenACWY + MenB vaccines + antibiotic prophylaxis), other encapsulated organisms

PANCE pearls

• Microangiopathic hemolytic anemia + thrombocytopenia = treat as TTP/HUS until proven otherwise. Do not wait for the full pentad — most patients have only 2 or 3 features.
• Plasma exchange must be initiated within hours of suspicion in TTP — mortality halves with prompt treatment.
• DO NOT give platelet transfusion in TTP unless life-threatening bleeding — fuels thrombosis. (Contrast with ITP where platelet transfusion is acceptable for severe bleeding.)
• PLASMIC score: high probability of severe ADAMTS13 deficiency predicts TTP — useful when ADAMTS13 result delayed.
• STEC-HUS: AVOID ANTIBIOTICS — may worsen outcomes by triggering Shiga toxin release from dying bacteria. Aggressive IV fluids early reduce HUS risk in confirmed STEC infection.
• Eculizumab (aHUS) requires meningococcal vaccination 2 weeks before initiation plus penicillin prophylaxis — patients are at high risk of meningococcal sepsis.
• Pregnancy can precipitate both TTP and aHUS, and HELLP/severe preeclampsia mimic them — ADAMTS13 testing and delivery trial distinguish.
• Caplacizumab (HERCULES trial) is a relatively new agent — anti-vWF nanobody — that reduces time to platelet normalization and refractoriness when added to standard TTP therapy.

References

• ISTH 2020 — ISTH guidelines for the diagnosis and treatment of thrombotic thrombocytopenic purpura (Zheng et al., J Thromb Haemost 2020)
• HERCULES Trial — Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura (Scully et al., NEJM 2019)
• ASH 2020 — American Society of Hematology 2020 guidelines on thrombotic thrombocytopenic purpura (Zheng et al.)
• Tarr et al. — Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome (Tarr, Lancet 2005)
• Legendre et al. — Terminal Complement Inhibitor Eculizumab in Atypical Hemolytic-Uremic Syndrome (NEJM 2013)