Thrombotic Microangiopathy — Advanced

This presentation is classical for thrombotic thrombocytopenic purpura (TTP): severe thrombocytopenia, MAHA with schistocytes, neurological symptoms and critically low ADAMTS13 activity (<10%). The immediate, life‑saving therapy for acquired TTP is urgent plasma exchange together with immunosuppression (commonly high‑dose corticosteroids) while further antibody testing is obtained. Eculizumab targets complement-mediated TMA (aHUS) and is not first‑line for TTP. Platelet transfusion is contraindicated unless there is life‑threatening bleeding because it may exacerbate microvascular thrombosis. Renal biopsy is unnecessary and potentially hazardous in the acute unstable thrombocytopenic patient and will not change the urgent need for plasma exchange. Waiting to repeat ADAMTS13 delays critical treatment and is inappropriate in suspected TTP.

This clinical picture (TMA with AKI, ADAMTS13 not severely deficient, negative STEC) is typical of complement‑mediated aHUS. The disease can progress rapidly to organ failure; targeted therapy with terminal complement blockade (eculizumab or similar agents) is indicated in aHUS after excluding active infection and providing meningococcal vaccination and appropriate antibiotic prophylaxis. Plasma exchange has limited efficacy in typical complement‑mediated aHUS and is not preferred as sole long‑term therapy. Genetic testing is important but should not delay urgent initiation of complement blockade when clinically indicated. High‑dose steroids alone are ineffective as monotherapy in aHUS.

In pregnancy, thrombocytopenia with haemolysis and schistocytes can reflect pregnancy‑associated TMA syndromes. Normal coagulation studies and an ADAMTS13 activity that is not severely deficient (58%) make acquired TTP unlikely. HELLP (Haemolysis, Elevated Liver enzymes, Low Platelets) or severe pre‑eclampsia commonly present around this gestation with hypertension, elevated liver enzymes and MAHA; these are pregnancy‑related TMAs. Warm autoimmune haemolysis is typically Coombs (direct antiglobulin) positive and does not cause schistocytes or thrombocytopenia. Vitamin B12 deficiency causes macrocytosis and hypersegmented neutrophils, not schistocytes. DIC would usually show abnormal PT/APTT and hypofibrinogenaemia. Mechanical haemolysis from a prosthetic valve is unlikely in this context.

An ADAMTS13 activity around 10–20% is strongly suggestive of TTP in the right clinical context; many guidelines use a threshold <10% as diagnostic of severe deficiency, but values around 10–20% still warrant treatment as TTP if clinical features match. The correct action is to treat as TTP with plasma exchange and immunosuppression while further testing for inhibitor and secondary causes continues. ADAMTS13 does not 'exclude' TTP at 12% — rather it supports it. Steroids do not invalidate the measurement to the point of withholding therapy. Platelet transfusion is generally avoided unless there is life‑threatening haemorrhage. Eculizumab is not first‑line in TTP.

Kidney biopsy can provide useful diagnostic and prognostic information in TMA (e.g. distinguishing chronic changes, thrombi, complement deposition) but it is not required in every acute case and is often impractical or unsafe while the patient is thrombocytopenic or haemodynamically unstable. Biopsy is most appropriate after initial stabilisation if the diagnosis is unclear, if renal disease persists or to determine chronicity and guide long‑term management. It should not routinely precede urgent life‑saving therapy (e.g. plasma exchange or complement blockade), nor is an absolute platelet threshold of 150 x10^9/L required. Immediate biopsy in all dialysis patients is unnecessary.

Genetic and functional complement testing in suspected complement‑mediated aHUS is important for prognosis, recurrence risk assessment and transplant planning (e.g. recurrence risk post‑renal transplant differs by mutation). These investigations should be arranged early once the patient is stabilised but must not delay urgent therapy (e.g. eculizumab). Genetic abnormalities occur in both adults and children and can meaningfully influence long‑term decisions. Lack of an identifiable mutation does not exclude complement dysregulation. Genetic results do not reliably predict immediate response to plasma exchange.

Postpartum TMA with normal ADAMTS13 and persistent renal failure despite delivery suggests complement‑mediated aHUS. Complement blockade (eculizumab) is indicated in this scenario, with appropriate meningococcal vaccination and prophylaxis. Plasma exchange is not reliably effective for aHUS and is not the preferred definitive therapy. Corticosteroids alone are not effective. Immediate kidney transplantation is inappropriate in the acute setting. Lifelong anticoagulation is not an accepted therapy for TMA and is not indicated to treat microvascular thrombosis in this context.

Post‑transplant TMA has multiple potential causes: calcineurin inhibitor toxicity (tacrolimus), antibody‑mediated rejection, infections (e.g. CMV), recurrence of primary disease or de novo complement dysregulation. The initial appropriate step is to address reversible causes — reduce or change the calcineurin inhibitor and evaluate/treat antibody‑mediated rejection and infectious triggers. Dialysis may be required if severe but stopping all immunosuppression permanently risks graft loss and infection. High‑dose steroids alone without addressing the likely trigger are inadequate. Splenectomy is not standard. Eculizumab may be considered if complement‑mediated disease is confirmed or if TMA persists despite addressing reversible causes, but it should not automatically replace evaluation of reversible causes.

Patients with a history of acquired TTP are at risk of relapse. Regular clinical follow‑up with periodic measurement of ADAMTS13 activity is recommended because falling ADAMTS13 activity often precedes clinical relapse; pre‑emptive rituximab in patients with persistent or recurrent severe ADAMTS13 deficiency can reduce relapse risk. Routine annual complement genetic testing is not relevant for acquired TTP. Lifelong plasma exchange is unnecessary and impractical. Low‑dose aspirin has not been shown to prevent TTP relapses.

Recurrence risk of complement‑mediated aHUS after kidney transplant depends on the underlying complement abnormality; some mutations (e.g. factor H) confer high recurrence risk. Best practice is to perform complement genetic/functional testing and use that information to plan transplant strategy. In high‑risk patients, prophylactic complement blockade with eculizumab around the time of transplant reduces recurrence and preserves graft function. Plasma exchange alone is often insufficient as prophylaxis. Saying transplant only if genetic testing is negative is overly restrictive — many patients can be transplanted with peri‑transplant complement blockade. Altering immunosuppression to high‑dose steroids is not evidence‑based for preventing aHUS recurrence.