Thrombotic Microangiopathy
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Direct answer
Microangiopathic haemolysis with thrombocytopenia and a normal INR defines the thrombotic microangiopathies — TTP and the haemolytic uraemic syndromes — in which platelet-rich microthromi occlude arterioles and capillaries while coagulation is spared, separating them from DIC at the laboratory bench. Thrombotic thrombocytopenic purpura follows severe ADAMTS13 deficiency (activity under 10 per cent): ultra-large von Willebrand factor multimers accumulate and shred passing erythrocytes, producing the pentad of thrombocytopenia, microangiopathic haemolysis, neurologic signs, renal impairment and fever. Typical HUS follows shiga toxin-producing Escherichia coli (O157:H7) dysentery damaging glomerular endothelium, with children dominant and renal failure prominent; atypical HUS arises from complement dysregulation (factor H or I mutations, anti-factor H antibodies) and responds to eculizumab. Plasma exchange saves TTP; supportive care and dialysis carry typical HUS.
What you must remember
- Core laboratory triad: schistocytes and helmet cells on the smear, thrombocytopenia, and a normal or near-normal PT/INR with normal D-dimer rise — DIC shows the opposite coagulation pattern.
- TTP mechanism: acquired autoantibody (or rare congenital Upshaw-Schulman syndrome) against ADAMTS13, the metalloprotease that cleaves ultra-large vWF multimers; activity under 10 per cent is diagnostic; platelet count is often below 20,000 with neurologic features fluctuating from headache to seizures.
- Typical (STEC) HUS: shiga toxin (Stx1, Stx2) from Escherichia coli O157:H7 (undercooked beef, unpasteurised milk, and person-to-person spread) binds Gb3 receptors on glomerular endothelium; prodromal bloody diarrhoea, then oliguria, hypertension and haemolysis; children under five and the elderly (with higher mortality) at risk; antibiotics and antimotility drugs may worsen outcomes.
- Atypical HUS: complement-mediated, from factor H or I deficiency, membrane cofactor abnormalities or anti-factor H antibodies; no diarrhoea prodrome, relapsing course, family history; eculizumab (anti-C5) transformed outcomes, and unchecked disease progresses to end-stage renal disease.
- Secondary causes: pregnancy, malignant hypertension, lupus, antiphospholipid syndrome, calcineurin inhibitors, quinine, clopidogrel, ticlopidine, HIV and cobalamin C deficiency — the exam's drug-and-disease list.
- Treatment mapping: TTP — urgent plasma exchange with corticosteroids (and caplacizumab, an anti-vWF nanobody, where available); typical HUS — supportive with dialysis, no exchange; atypical HUS — eculizumab with meningococcal vaccination.
- Untreated TTP mortality: historically near-universal before plasma exchange; suspected TTP gets exchange before ADAMTS13 results return — treatment starts on suspicion.
- Indian context: STEC HUS is reported less often than shigella-associated HUS in Indian series, and typhoid, malaria and dengue dominate the broader fever-with-haemolysis differential — but the schistocyte smear and INR check apply regardless of the local pathogen list.
TTP versus HUS versus DIC in one reasoned pass
A 28-year-old pregnant woman has confusion, pallor and petechiae: haemoglobin 7, platelets 15,000, LDH over 1500, creatinine mildly raised, INR normal, smear full of schistocytes. Normal coagulation excludes DIC; prominent neurology with mild renal injury favours TTP over HUS; pregnancy is a classic trigger. Start plasma exchange immediately and send ADAMTS13 — the test confirms later, treatment cannot wait. Contrast a four-year-old with five days of bloody diarrhoea, now pale, oliguric and hypertensive with the same schistocyte picture but marked azotaemia: STEC HUS — fluids carefully managed, dialysis as needed, no antibiotics, no exchange; most children recover renal function, unlike atypical HUS. A third patient, an adult with recurrent episodes and a family history of renal failure without diarrhoea, fits atypical HUS: complement studies and eculizumab. Finally the DIC patient — sepsis or obstetric catastrophe — shows prolonged PT and aPTT, low fibrinogen, raised D-dimers, and bleeding with oozing puncta: the coagulation profile, not the smear, sorts them out.
Where candidates slip
The first slip is waiting for ADAMTS13 before treating: suspected TTP is a medical emergency in which plasma exchange starts on clinical grounds, since assays take days. Second, antibiotics in STEC HUS — candidates reflexively treat bloody diarrhoea, but antibiotics and antimotility agents may increase toxin release and HUS risk; management is supportive. Third, using the pentad as a gate: full pentads are rare; the dyad of schistocytic haemolysis plus thrombocytopenia with normal coagulation is enough to act. Fourth, forgetting secondary TMA: a hypertensive emergency or antiphospholipid syndrome can produce an identical smear, and treating the trigger matters as much as exchange. Fifth, eculizumab requires meningococcal vaccination before or alongside therapy — an exam-tested safety pairing.
Frequently asked questions
What distinguishes TMA from DIC in the laboratory?
Both show microangiopathic haemolysis and thrombocytopenia, but TMA keeps PT, aPTT and fibrinogen normal with modest D-dimer, whereas DIC prolongs coagulation times, consumes fibrinogen and markedly raises D-dimers.
What causes thrombotic thrombocytopenic purpura?
Severe deficiency of ADAMTS13 (under 10 per cent activity), usually from autoantibodies, leaving uncleaved ultra-large von Willebrand factor multimers that aggregate platelets in microvasculature.
How does shiga toxin cause haemolytic uraemic syndrome?
Toxin from STEC binds Gb3 receptors on glomerular and renal tubular endothelium, causing endothelial injury and platelet-fibrin microthrombi, haemolysis and acute kidney injury after bloody diarrhoea.
Why is plasma exchange urgent in suspected TTP?
Untreated TTP carries historically very high mortality, and exchange replaces the missing ADAMTS13 while removing the autoantibody — outcomes depend on starting before confirmatory results.
What is atypical HUS and its specific therapy?
Complement-mediated TMA from factor H or I mutations, complement regulatory defects or anti-factor H antibodies, treated with the anti-C5 monoclonal antibody eculizumab alongside meningococcal vaccination.