Nephrology emergency · KIMS Secunderabad
Thrombotic Microangiopathy — When Small Vessel Clots Destroy Blood Cells and the Kidneys
Thrombotic microangiopathy (TMA) is a clinical syndrome — not a single disease — characterised by microangiopathic haemolytic anaemia (MAHA: mechanical destruction of red blood cells as they pass through small vessels occluded by platelet-fibrin thrombi), thrombocytopenia (platelet consumption in the thrombi), and end-organ ischaemia from the small vessel occlusion — most commonly the kidneys and brain. The blood film is the essential diagnostic bedside tool: fragmented red cells (schistocytes — helmet cells, triangular cells) on peripheral blood smear confirm MAHA and immediately direct the clinician toward TMA as the unifying diagnosis.
The critical point about TMA is that the treatment depends entirely on the underlying cause — and the causes have completely different mechanisms and specific therapies. A TMA that is TTP (from ADAMTS13 deficiency) is treated with plasma exchange. A TMA that is aHUS (from complement dysregulation) is treated with eculizumab. A TMA that is STEC-HUS (from E. coli Shiga toxin) is managed supportively. Getting the cause wrong and giving the wrong treatment can be fatal. The diagnostic workup must proceed in parallel with initial supportive treatment.
The TMA causes — a diagnostic framework
| TMA cause | Mechanism | Key distinguishing test | Treatment |
|---|---|---|---|
| TTP (Thrombotic thrombocytopenic purpura) | Deficiency of ADAMTS13 (the enzyme that cleaves ultra-large von Willebrand factor multimers) — from autoantibodies (acquired TTP) or genetic mutation (hereditary TTP) — causing platelet aggregation in small vessels | ADAMTS13 activity: below 10% (severe deficiency) · Anti-ADAMTS13 antibody: positive in acquired TTP | Plasma exchange (replaces ADAMTS13 and removes the autoantibody) + immunosuppression (rituximab, steroids) for acquired TTP · Caplacizumab (anti-vWF nanobody) for acute TTP |
| STEC-HUS (Shiga toxin-producing E. coli HUS) | Shiga toxin from E. coli O157:H7 (or other STEC strains) binds to glomerular endothelial cells, causing localised TMA predominantly in the kidney | Clinical context: bloody diarrhoea 5–10 days before HUS onset in a child · Stool culture for STEC or PCR for Shiga toxin · ADAMTS13 normal · Complement normal | Supportive — dialysis for AKI, avoid antibiotics (may increase toxin release), avoid anti-motility agents |
| aHUS (atypical HUS) | Complement alternative pathway dysregulation from CFH, CFI, MCP, C3, CFB, CFHR mutations or anti-CFH antibodies — causing uncontrolled C3 and C5 activation in glomerular endothelium | ADAMTS13 normal (above 10%) · Complement studies: reduced C3, elevated sC5b-9 · CFH, CFI, MCP, C3, CFB, CFHR5 genetic panel | Eculizumab (anti-C5 complement inhibitor) — started immediately without waiting for genetic results if clinical TMA with normal ADAMTS13 |
| Secondary TMA | TMA triggered by a systemic condition — malignant hypertension, preeclampsia/HELLP, SLE, antiphospholipid syndrome, scleroderma renal crisis, drugs (quinine, mitomycin, tacrolimus, gemcitabine), pregnancy, HIV, bone marrow transplant | Clinical context (pregnancy, BP measurement, drug history) · ANA, antiphospholipid antibodies for autoimmune causes · ADAMTS13 usually above 10% · Complement usually normal | Treat the underlying cause — BP control for malignant hypertension, ACE inhibitors for scleroderma renal crisis |
The blood film — the essential bedside test
Any patient presenting with acute kidney injury or AKI + anaemia + thrombocytopenia must have a peripheral blood film examined for schistocytes. Schistocytes (red cell fragments — helmet cells, triangular cells, bite cells) confirm MAHA and indicate that the haemolysis is mechanical — from red cells being sheared as they pass through small vessels partially occluded by platelet-fibrin thrombi. This finding is pathognomonic of TMA and is the trigger for the TMA diagnostic workup. At KIMS, peripheral blood film with schistocyte quantification (above 1% schistocytes is significant) is performed as an emergency investigation in any patient with the AKI + anaemia + thrombocytopenia triad.
Initial management while awaiting results
Plasma exchange
Started immediately in all TMA patients where TTP cannot be excluded (ADAMTS13 result not yet available). Plasma exchange is life-saving in TTP — delaying it while awaiting test results is dangerous. In aHUS and STEC-HUS, plasma exchange is ineffective but not harmful.
CRRT
For AKI management. Available 24/7 at KIMS ICU.
Platelet transfusion
Avoid in TTP and TMA (platelet transfusion in TTP adds substrate for further microvascular thrombosis and may worsen neurological outcome). Indicated only for life-threatening haemorrhage.
Eculizumab
Started immediately in clinically suspected aHUS (TMA with normal ADAMTS13 and without STEC trigger) without waiting for genetic results. Meningococcal vaccination before eculizumab (or prophylactic penicillin if vaccination cannot be given before urgent eculizumab).
Emergency Nephrology at KIMS — 24/7 for TMA, AKI, and Haemolytic Uraemic Syndrome
Frequently Asked Questions — Thrombotic Microangiopathy
TTP and HUS are both forms of TMA — but with different dominant organ involvement and different mechanisms. In TTP, the predominant organ affected is the brain — neurological manifestations (confusion, seizures, stroke) are prominent and AKI is usually mild. The mechanism is ADAMTS13 deficiency causing platelet aggregation in cerebral small vessels. ADAMTS13 activity is severely reduced (below 10%). In HUS, the predominant organ affected is the kidney — AKI is severe and often requires dialysis, while neurological features are typically absent or mild. The mechanism is either Shiga toxin (STEC-HUS) or complement dysregulation (aHUS) causing renal endothelial TMA. ADAMTS13 activity is normal in HUS.
The peripheral blood smear in TMA shows schistocytes — fragmented red blood cells formed when normal red cells are mechanically sheared as they pass through small vessels partially occluded by platelet-fibrin thrombi. Schistocytes appear as helmet-shaped cells, triangular fragments, or small irregularly shaped red cell pieces — completely different from the normal smooth, biconcave disc shape of a red cell. Their presence confirms that haemolysis is mechanical (intravascular, from small vessel pathology) rather than immune-mediated (which would show spherocytes instead). At KIMS, the haematology laboratory quantifies schistocytes as a percentage of red cells — above 1% is clinically significant.
Plasma exchange is immediately life-saving in TTP and should be started without delay in any TMA patient where TTP cannot be excluded. In STEC-HUS (from bloody diarrhoea with positive STEC culture), plasma exchange is not indicated — supportive care and dialysis are the treatments. In aHUS, plasma exchange has limited efficacy — eculizumab is the definitive treatment. The clinical challenge is that STEC-HUS, TTP, and aHUS can all present identically at the time of initial assessment. The KIMS protocol: start plasma exchange immediately while ADAMTS13 and STEC testing are in progress. If ADAMTS13 is normal (above 10%) and STEC is negative, the diagnosis shifts toward aHUS and eculizumab is added.
Yes — numerous drugs cause secondary TMA by different mechanisms. The most important in India: quinine (an antimalarial — immune-mediated endothelial damage causing TMA, sometimes after a single dose in sensitised individuals), mitomycin C (a chemotherapy agent — cumulative dose-related endothelial toxicity), tacrolimus and cyclosporine (calcineurin inhibitors used in transplant patients — cause direct endothelial toxicity and TMA, manageable by dose reduction or switch to a different immunosuppressant), and gemcitabine. Drug-induced TMA is a secondary TMA — ADAMTS13 and complement are typically normal. Treatment: stop the offending drug and provide supportive care.
KIMS Secunderabad — Dr. E. Ravi (Senior Consultant Nephrologist, critical care nephrology lead), peripheral blood film schistocyte quantification, ADAMTS13 activity and anti-ADAMTS13 antibody, complement studies and genetic panel for aHUS, STEC culture and PCR, plasma exchange, eculizumab for aHUS, CRRT for severe AKI, 24/7 emergency nephrology. NABH and NABL accredited. Emergency line: 040-4488-5000.