Thrombotic microangiopathy: TTP, HUS, and aHUS in ICU

1. Recognise — thrombocytopenia + microangiopathic haemolytic anaemia (MAHA: schistocytes, high LDH, low haptoglobin, high indirect bilirubin). Organ ischaemia (neurological, renal, cardiac, GI)
2. Exclude DIC (different): DIC has prolonged PT/aPTT, low fibrinogen, positive D-dimer (consumption coagulopathy). TMA has NORMAL PT/aPTT, normal fibrinogen (localised, not systemic)
3. Differentiate TTP/HUS/aHUS — send: ADAMTS13 (TTP <10%), stool Shiga toxin / culture (HUS positive), complement (aHUS abnormal). DON'T WAIT for results if TTP suspected
4. If TTP suspected (any TMA with neurological symptoms or ADAMTS13 pending) — START PLASMA EXCHANGE within 4-8h. Also: steroids (prednisolone 1 mg/kg or methylprednisolone), caplacizumab (anti-vWF). Mortality 90% untreated
5. If HUS (diarrhoea + STEC positive) — supportive. NO antibiotics (may increase toxin). NO plasma exchange. Dialysis if needed
6. If aHUS (no STEC, normal ADAMTS13, complement abnormal) — eculizumab (complement C5 inhibitor). Vaccinate against meningococcus (complement deficiency risk)
7. Supportive ICU — transfusion (platelets AVOID in TTP unless life-threatening bleeding), renal replacement therapy, seizure prophylaxis, cardiac monitoring

1. RECOGNISE and ACT FAST. Any thrombocytopenia + MAHA (schistocytes, high LDH, low haptoglobin) with neurological symptoms or PLASMIC score ≥6 → treat as TTP. Mortality increases with every hour of delay. PLASMA EXCHANGE within 4–8 hours of suspicion. Do NOT wait for ADAMTS13 result (24–48h turnaround).[5] }
2. DRAW BLOOD BEFORE PLEX (if possible). Send: ADAMTS13 activity + anti-ADAMTS13 IgG, CBC, reticulocytes, LDH, haptoglobin, bilirubin, creatinine, PT/INR, aPTT, fibrinogen, D-dimer, DAT (direct antiglobulin test — to exclude autoimmune haemolysis), stool Shiga toxin + culture, complement C3/C4, ANA, anti-dsDNA, anti-cardiolipin, lupus anticoagulant, HIV, HBV, HCV, β-hCG (pregnancy). ADAMTS13 must be drawn BEFORE first PLEX — donor plasma in PLEX confounds the assay.[1] }
3. LARGE-BORE CENTRAL VENOUS ACCESS. Dual-lumen dialysis/apheresis catheter (right internal jugular preferred; femoral if coagulopathic or urgent). Ultrasound-guided insertion. Note: central line placement is an acceptable reason for prophylactic platelet transfusion in severe TTP (platelets often <20).[5] }
4. PLASMA EXCHANGE — START DAILY. Exchange 1.0–1.5 plasma volumes daily (~40–60 mL/kg per session). Replacement fluid: FFP (fresh frozen plasma) or cryosupernatant (cryopoor plasma — lower vWF content, theoretically superior). Citrate anticoagulation (ACD-A) with calcium replacement. Continue daily PLEX until: platelet count >150 × 10⁹/L AND haemolysis resolving (LDH falling, haptoglobin rising) AND maintained for 2 consecutive days → then begin taper (alternate-day × 3 sessions, then stop if stable).[5] }
5. CORTICOSTEROIDS — START IMMEDIATELY. Prednisolone 1 mg/kg/day orally OR methylprednisolone 1 g IV daily × 3 days then 0.75 mg/kg/day. Rationale: suppresses autoantibody-producing B cells (acquired TTP). Taper as ADAMTS13 recovers. Caplacizumab does NOT replace steroids — it targets vWF, not the immune mechanism.[1] }
6. CAPLACIZUMAB — START IF AVAILABLE. Anti-vWF nanobody; blocks vWF A1 domain → prevents platelet adhesion. Dose: 11 mg SC daily (first dose may be IV bolus). HERCULES trial: faster platelet recovery, reduced recurrence. Start at diagnosis (ideally before first PLEX). Continue for ≥30 days after PEX stops. CAUTION: caplacizumab increases bleeding risk (especially mucocutaneous) — monitor. If bleeding: temporarily hold, consider platelet transfusion.[2] }
7. RITUXIMAB — FOR REFRACTORY OR HIGH-RELAPSE-RISK. Anti-CD20 monoclonal antibody; depletes B cells producing anti-ADAMTS13. Dose: 375 mg/m² IV weekly × 4 (started within first week). Indications: refractory TTP (no platelet recovery by day 5 of PLEX), exacerbation during taper, or preemptive (high anti-ADAMTS13 IgG titre). Reduces relapse rate from ~40% to ~10% at 1 year. Onset of action ~1–2 weeks (slower than PLEX/caplacizumab).[1] }
8. DAILY MONITORING. CBC (platelet trend — most sensitive marker of response), LDH, haptoglobin, creatinine, neuro exam (GCS, focal deficits), cardiac troponin (cardiac TTP can cause MI), ECG. Platelet count should rise within 3–5 days of starting PLEX. If platelets do NOT rise by day 5 → refractory TTP → escalate (increase PLEX intensity to 1.5 volumes, add rituximab, reconsider diagnosis — could be aHUS or secondary TMA).[11] }
9. SUPPORTIVE CARE. Folate supplementation (haemolysis → folate depletion). PPI prophylaxis (with steroids). VTE prophylaxis (TMA is prothrombotic but platelets low — use mechanical prophylaxis until platelets >50, then LMWH). Avoid NSAIDs. Transfuse red cells for Hb <70 (target 70–80). AVOID platelet transfusion unless life-threatening bleeding or procedural requirement.[5] }
10. DISCONTINUATION CRITERIA (stop PLEX). Platelets >150 × 10⁹/L for 2 consecutive days, LDH near-normal, no neurological symptoms, haemolysis markers resolving. Taper: alternate-day PLEX × 3, then stop. Continue caplacizumab for ≥30 days after PLEX stops. Taper steroids over 4–6 weeks. Monitor ADAMTS13 every 2–4 weeks during first 6 months — falling titre signals relapse risk → preemptive rituximab.[1] }

1. SUSPECT aHUS when: TMA (thrombocytopenia + MAHA) with AKI, negative Shiga toxin, ADAMTS13 >10% (or not yet available but clinical picture not TTP — renal predominant, minimal neurology), no alternative diagnosis (no DIC, no malignant HTN, no post-transplant). Common triggers: pregnancy (postpartum), infection (pneumococcal, influenza), drugs (CNI, mTOR inhibitors), surgery, malignancy.[10] }
2. EXCLUDE STEC-HUS. Stool culture for STEC (O157 and non-O157), Shiga toxin PCR (Stx1, Stx2). Seroconversion (anti-LPS IgM). Note: antibiotic use before stool sample may reduce stool culture sensitivity — Shiga toxin PCR is preferred. STEC-HUS treated supportively (no eculizumab routinely, no PLEX).[3] }
3. EXCLUDE TTP. ADAMTS13 activity: <10% → TTP (not aHUS). >10% with renal-dominant TMA → consistent with aHUS. BUT: if ADAMTS13 not back within 24h and clinical picture is TTP-like (neurology prominent) → start PLEX empirically (PLEX provides some benefit in aHUS and is life-saving in TTP — safer to treat as TTP initially).[11] }
4. EXCLUDE SECONDARY TMA. Malignant HTN (BP >180/120 + retinopathy/LVH — but malignant HTN and aHUS can coexist and be hard to distinguish). SLE/APS (ANA, anti-dsDNA, anti-cardiolipin, lupus anticoagulant). Pregnancy-related (HELLP, AFLP, TTP, aHUS — all in differential). Post-transplant (CNI toxicity, recurrent aHUS, AMR). Malignancy-associated.[10] }
5. COMPLEMENT WORKUP. Serum C3 (low in ~50% of aHUS), C4 (usually normal — alternative pathway), factor H, factor I levels. Anti-factor H autoantibody (10–15% of aHUS). Genetic testing (factor H, factor I, MCP/CD46, C3, factor B, thrombomodulin) — results take weeks → do NOT delay treatment. Genetic results guide prognosis and family screening but should NOT delay eculizumab.[10] }
6. ECULIZUMAB — START IF aHUS CONFIRMED OR HIGHLY SUSPECTED. Anti-C5 monoclonal antibody. Dose (adults ≥18 kg): 900 mg IV weekly × 4 doses, then 1200 mg IV every 2 weeks. Continue long-term (indefinite in most cases; some patients with identifiable reversible trigger may attempt withdrawal under specialist supervision). ONSET: within 7–14 days (platelet recovery, LDH fall, renal improvement).[4] }
7. MENINGOCOCCAL PROPHYLAXIS — MANDATORY BEFORE OR WITH FIRST DOSE. Vaccinate: MenACWY (conjugate quadrivalent) AND MenB (Bexsero/Trumenba) — ideally ≥2 weeks before eculizumab. If eculizumab cannot be delayed → give vaccines + start antibiotic prophylaxis (penicillin V 500 mg BD or ciprofloxacin 250 mg BD) until ≥2 weeks post-vaccination. Continue antibiotic prophylaxis for duration of eculizumab therapy (and 2–3 months after stopping). Document vaccination in notes.[4] }
8. PLASMA EXCHANGE IN aHUS — LIMITED ROLE. PLEX was standard before eculizumab; provides factor H/I (replaces deficient regulators) and removes mutant proteins. Now reserved for: anti-factor H autoantibody aHUS (PLEX removes antibody + provides factor H), or when eculizumab unavailable, or bridging to eculizumab. Once eculizumab started → PLEX typically stopped (PLEX also removes eculizumab — if concurrent, need supplemental eculizumab dosing).[10] }
9. MONITORING ON ECULIZUMAB. CBC, LDH, haptoglobin, creatinine (weekly initially → monthly). Complement: CH50 / AH50 (should be undetectable/low — confirms complement blockade; if CH50 detectable → inadequate blockade → increase dose or shorten interval). Renal recovery: 60–80% of aHUS patients have improvement with eculizumab; 30–40% come off dialysis. Monitor for infection (encapsulated organisms — meningococcus, pneumococcus, Haemophilus).[4] }
10. DURATION AND WITHDRAWAL. Most aHUS patients continue eculizumab indefinitely. Withdrawal may be considered in: patients with complement factor H/I/MCP mutations → high relapse risk → lifelong. Patients with isolated anti-factor H antibody → treat antibody (PLEX + immunosuppression) → may withdraw eculizumab once antibody cleared. Patients with pregnancy-triggered aHUS and no genetic mutation → may attempt withdrawal 6–12 months postpartum. All withdrawals under nephrology/haematology supervision with close monitoring.[10] }

Pregnancy/postpartum TMA is a high-yield exam topic. Five conditions overlap and each requires different treatment. [1]

1. RECOGNISE TMA IN PREGNANCY. Thrombocytopenia + MAHA (schistocytes, high LDH) + organ dysfunction in pregnancy or postpartum (especially third trimester or first 6 weeks postpartum). The differential includes FIVE conditions: TTP, aHUS, HELLP syndrome, AFLP (acute fatty liver of pregnancy), and severe pre-eclampsia.[12] }
2. SEND ADAMTS13 IMMEDIATELY. TTP in pregnancy: ADAMTS13 <10%. TTP tends to occur throughout pregnancy (not just postpartum). TTP is the most dangerous of the pregnancy TMAs (90% mortality untreated). If neurological symptoms present → start PLEX empirically.[12] }
3. CHECK LIVER FUNCTION. HELLP (Haemolysis, Elevated Liver enzymes, Low Platelets): AST >70, LDH >600, platelets <100. AFLP: jaundice, hypoglycaemia, coagulopathy (PT prolonged, INR >1.5), high ammonia. HELLP and AFLP → deliver the baby (definitive treatment). TTP and aHUS → delivery does NOT resolve the TMA.[13] }
4. DIFFERENTIATE TTP FROM aHUS (POSTPARTUM). TTP: neurological predominant, ADAMTS13 <10%, may occur antepartum. aHUS: renal predominant, postpartum (classic presentation: 2–6 weeks postpartum, severe AKI, dialysis-requiring), ADAMTS13 >10%, complement abnormal. Treatment differs critically: TTP → PEX + steroids + caplacizumab. aHUS → eculizumab. Getting it wrong = ongoing organ damage.[13] }
5. TIMING CLUES. Pre-eclampsia/HELLP: antepartum or immediate postpartum, resolves within 48–72h of delivery. AFLP: third trimester. TTP: any trimester (often first–second). aHUS: classically postpartum (days to weeks after delivery). Postpartum TMA with severe AKI and normal ADAMTS13 → aHUS until proven otherwise.[12] }
6. IF TTP (ADAMTS13 <10%) → PLEX + steroids + caplacizumab. PLEX is safe in pregnancy. Do NOT deliver for TTP alone (delivery does not treat TTP and adds risk). Continue PLEX through delivery and postpartum. Caplacizumab safety in pregnancy not established — discuss with MDT (benefit vs risk).[12] }
7. IF aHUS (POSTPARTUM, ADAMTS13 >10%, RENAL PREDOMINANT) → eculizumab. Vaccinate (MenACWY + MenB) + antibiotic prophylaxis. Eculizumab is considered safe in pregnancy (IgG2/4 backbone, minimal placental transfer). Early eculizumab prevents permanent renal damage (postpartum aHUS has high ESRF rate without treatment).[13] }
8. IF HELLP / PRE-ECLAMPSIA → deliver the baby (if ≥34 weeks or severe features: uncontrolled BP, deteriorating LFTs, falling platelets, neuro symptoms, AFLP co-existing). Magnesium sulphate for seizure prophylaxis. BP control (labetalol, hydralazine, nifedipine). HELLP usually resolves within 72h of delivery. If platelets still falling or MAHA persists >72h postpartum → reconsider TTP/aHUS.[13] }
9. BREASTFEEDING. PEX: safe to breastfeed. Steroids: safe (low levels in breast milk). Eculizumab: minimal excretion in breast milk — generally considered safe. Caplacizumab: unknown — discuss. Rituximab: avoid (excreted in breast milk, immunosuppressive to infant).[12] }

1. CONFIRM STEC-HUS. Preceding bloody diarrhoea (5–10 days before), positive stool Shiga toxin PCR/culture, AKI + thrombocytopenia + MAHA. Typically children 1–5 years but adults also affected (especially O104:H4 outbreak strain).[3] }
2. FLUID MANAGEMENT — EARLY AND AGGRESSIVE. The most impactful intervention. Early IV fluids (within first 4 days of diarrhoea onset) reduce progression to oliguric AKI and dialysis. Use balanced crystalloid. Target euvolaemia. Monitor urine output — if oliguric/anuric → fluid restriction + prepare for RRT.[3] }
3. AVOID ANTIBIOTICS. Antibiotics (especially fluoroquinolones, TMP-SMX) induce SOS response → ↑ Shiga toxin production → worse HUS. Exception: life-threatening sepsis (then use azithromycin — least toxin-inducing). A meta-analysis of 9 RCTs showed no benefit and potential harm. Azithromycin was studied in the O104:H4 outbreak — neutral effect on HUS but reduced STEC carriage.[3] }
4. AVOID ANTI-MOTILITY AGENTS. Loperamide, opioids slow gut transit → prolonged toxin exposure. Also avoid narcotics, NSAIDs (nephrotoxic), ACE inhibitors/ARBs (can worsen AKI in acute phase).[3] }
5. RENAL REPLACEMENT THERAPY. ~40–60% of children with STEC-HUS need dialysis (usually temporary — 1–4 weeks). Indications: standard AKI indications (hyperkalaemia, acidosis, volume overload, uraemia). Prefer PD in children (haemodynamically stable, simpler access); HD/CVVHDF in haemodynamically unstable or adults. Most recover renal function within 2–4 weeks.[3] }
6. TRANSFUSION SUPPORT. Red cell transfusion for symptomatic anaemia (Hb <60–70 g/L). Platelet transfusion only for active bleeding or procedural need (thrombocytopenia in HUS is less severe than TTP — typically 30–80 — and platelet transfusion does not carry the same absolute contraindication as in TTP).[3] }
7. NO PLASMA EXCHANGE. PLEX does not improve outcomes in STEC-HUS. Studied in multiple trials (including the 2011 O104:H4 outbreak) — no mortality or renal benefit. Reserved for: atypical presentation (neurological predominant — overlapping with TTP), or severe refractory disease after discussion with specialist centre.[3] }
8. NO ECULIZUMAB (ROUTINELY). Eculizumab was used in severe STEC-HUS (especially with neurological involvement) during the O104:H4 outbreak — results were inconclusive (no clear benefit, some signal of harm). Not recommended routinely. May be considered in: severe neurological HUS (coma, seizure, stroke) on case-by-case basis after specialist consultation.[3] }
9. MONITOR FOR COMPLICATIONS. Neurological (seizures, coma, stroke — in 20–30% of severe cases), cardiac (MI, heart failure, arrhythmia), pancreatic (diabetes insipidus, pancreatitis), intestinal (intussusception, perforation, colonic strictures). ICU admission for severe neurological, cardiac, or multi-organ involvement.[3] }
10. LONG-TERM FOLLOW-UP. Most children recover completely. BUT long-term risk: hypertension (10–30%), proteinuria (15–30%), CKD (5–10%), ESRF (3–5%). Annual BP + urinalysis + creatinine for life. Adults have worse outcomes than children. Recurrence is rare (unlike TTP relapse) unless recurrent STEC infection.[3] }