Pregnancy-Associated Thrombotic Microangiopathy

Pregnancy associated thrombotic microangiopathy (P-TMA) covers thrombotic microangiopathies presenting in pregnancy or the puerperium, defined by microangiopathic haemolytic anaemia, thrombocytopenia and organ injury (kidney, brain, heart, gut). Entities:

• Thrombotic thrombocytopenic purpura (TTP): congenital or acquired ADAMTS13 deficiency with activity below 10%; often presents in the second or third trimester
• Complement mediated TMA (atypical haemolytic uraemic syndrome, aHUS): usually postpartum, driven by complement dysregulation (CFH, CFI, MCP, C3, CFB variants or anti-factor H antibodies)
• HELLP syndrome and severe pre-eclampsia
• Acute fatty liver of pregnancy
• Catastrophic antiphospholipid syndrome
• Shiga toxin haemolytic uraemic syndrome
• Secondary TMA: sepsis, lupus, malignant hypertension, drugs

TTP occurs in about 1 per 25,000 pregnancies, with maternal mortality of 10 to 20% and high fetal loss without treatment.

• Fever, fatigue, pallor, jaundice, petechiae and bruising
• Neurological: headache, confusion, seizures, focal deficits, visual change (TTP)
• Renal: oliguria, haematuria, proteinuria, acute kidney injury (aHUS)
• Cardiac: chest pain, arrhythmia, myocardial infarction
• Gastrointestinal: abdominal pain, diarrhoea
• Hypertension, malignant in aHUS and in overlap with pre-eclampsia
• TTP presents most often in the second or third trimester with neurological features and severe thrombocytopenia; aHUS within days of delivery with severe renal failure; HELLP and acute fatty liver have prominent liver involvement and improve after delivery

• Blood film for schistocytes; full blood count (platelets under 30,000 to 100,000/microlitre), reticulocytes, LDH (very high), haptoglobin (low), bilirubin (indirect), negative direct Coombs test, and normal PT, aPTT and fibrinogen (no DIC in TTP or aHUS)
• ADAMTS13 activity (below 10% is diagnostic of TTP; send before plasma exchange) with inhibitor antibodies; a pretest probability score (PLASMIC) helps
• Creatinine and eGFR, urinalysis, liver tests (HELLP, fatty liver), uric acid, glucose
• Complement studies: C3, C4, factor H, factor I, MCP expression, anti-factor H antibody and genetic analysis of complement genes; a low soluble sFlt-1 to PlGF ratio argues against pre-eclampsia-related HELLP
• Stool culture and Shiga toxin PCR; antiphospholipid antibodies, ANA, HIV and hepatitis tests
• Brain MRI for neurological features; placental and fetal ultrasound

Refer urgently to a centre with haematology, nephrology, critical care and obstetrics.

• Suspected TTP (ADAMTS13 below 10% or high pretest probability): start daily therapeutic plasma exchange immediately (1 to 1.5 plasma volumes with fresh frozen plasma replacement) until platelets exceed 150,000/microlitre for at least 2 days and LDH normalises. Add prednisolone 1 mg/kg/day, and rituximab 375 mg/m2 weekly for 4 doses for refractory or relapsing disease. Caplacizumab (10 mg IV bolus, then 10 mg SC daily during exchange and for 30 days afterwards) is used in specialist units. Delivery does not cure TTP. Congenital TTP: prophylactic plasma infusion 10 to 15 mL/kg every 1 to 3 weeks through pregnancy, or recombinant ADAMTS13
• Suspected aHUS (normal ADAMTS13, severe renal injury, postpartum): complement inhibition with eculizumab 900 mg IV weekly for 4 doses, then 1,200 mg at week 5 and every 2 weeks (or ravulizumab by weight, 2,400 to 3,000 mg then every 8 weeks), after meningococcal vaccination and with antibiotic prophylaxis (penicillin V 500 mg twice daily); plasma exchange as a bridge; dialysis for renal failure
• HELLP and severe pre-eclampsia: deliver after maternal stabilisation, magnesium sulfate 4 to 6 g IV loading then 1 to 2 g/hour for 24 hours after delivery, control severe hypertension (labetalol 20 mg IV then 40 to 80 mg every 10 minutes to 300 mg, or nifedipine 10 to 20 mg orally every 20 minutes, or hydralazine 5 to 10 mg IV every 20 minutes). If there is no improvement 72 hours after delivery, suspect TTP or complement mediated disease and start plasma exchange
• Aspirin 75 mg and enoxaparin 40 mg daily when platelets are above 50,000/microlitre; avoid platelet transfusion in TTP unless bleeding is life threatening
• Pregnancy in remission: ADAMTS13 monthly with plasma infusion if activity falls below 20%, low dose aspirin, fetal growth surveillance, and delivery at 36 to 38 weeks
• Long term: renal and cardiovascular follow up, and counselling that recurrence in future pregnancies is up to 50% for TTP and aHUS