Thrombotic microangiopathy, HUS and TTP

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Unusually large von Willebrand-factor multimers are normally cleaved by ADAMTS13. In TTP, profound loss of that protease permits platelet-rich microthrombi, causing cerebral and cardiac ischaemia even when creatinine is only mildly abnormal. Plasma exchange removes inhibitor and supplies enzyme; immunosuppression suppresses antibody production, while caplacizumab blocks platelet binding to von Willebrand factor during the dangerous early phase.

HUS has overlapping blood-film findings but often greater kidney involvement. Shiga toxin damages endothelium after enteric infection; treatment is supportive and includes careful fluid, electrolyte, blood-pressure and dialysis management. Complement-mediated HUS reflects dysregulated alternative complement activation and may require a specialist complement inhibitor. These pathways cannot be separated by creatinine or diarrhoea alone because diarrhoea can occur in TTP and complement-mediated disease may be triggered by infection.

The safe initial approach is parallel rather than sequential: confirm genuine MAHA, send ADAMTS13 before plasma, investigate STEC and pregnancy or secondary causes, assess brain, heart and kidney injury, and involve regional haematology and nephrology early. A scoring tool may support probability when ADAMTS13 turnaround is delayed, but British Society for Haematology guidance favours early measurement over reliance on a score.

Key points

Thrombotic microangiopathy is a clinicopathological syndrome of small-vessel endothelial injury, microangiopathic haemolytic anaemia, thrombocytopenia and organ ischaemia; it is not a final aetiological diagnosis.
The laboratory pattern is falling haemoglobin and platelets, schistocytes, raised LDH and indirect bilirubin, reticulocytosis and low haptoglobin. The direct antiglobulin test is usually negative and coagulation may be relatively preserved in TTP.
Do not wait for the historical pentad of fever, neurological change, renal impairment, anaemia and thrombocytopenia. Many patients have only MAHA and thrombocytopenia when life-saving treatment should start.
Immune TTP results from severe ADAMTS13 deficiency, generally activity below 10 IU/dL, caused by an autoantibody; congenital TTP has severe deficiency without inhibitor and pathogenic ADAMTS13 variants.
Take ADAMTS13 activity and inhibitor samples before plasma infusion or exchange whenever possible, but never postpone urgent plasma exchange when clinical probability is high.
Acute immune TTP is managed in a designated regional centre with daily plasma exchange, corticosteroid immunosuppression, caplacizumab and usually early rituximab under the current specialist protocol.
STEC-HUS typically follows bloody diarrhoea, especially in children, and is managed with meticulous supportive renal care, stool Shiga-toxin testing and public-health notification; antibiotics and antimotility drugs are not routine treatment.
Complement-mediated HUS is considered after urgent exclusion of severe ADAMTS13 deficiency, STEC and a compelling secondary cause. Complement levels can be normal, so a normal C3 does not exclude it.
Pregnancy, malignant hypertension, transplantation, drugs, autoimmune disease, cancer, infection and DIC can produce secondary TMA; removing or treating the driver is essential and TTP can still coexist.
Avoid prophylactic platelet transfusion in TTP because additional platelets may feed microvascular thrombosis; reserve it for life-threatening bleeding or an essential high-risk procedure after specialist advice.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Severe ADAMTS13 deficiency

Immune autoantibody or inherited ADAMTS13 deficiency permits unusually large von Willebrand factor multimers to drive platelet-rich microthrombi characteristic of TTP.

Shiga-toxin HUS

Shiga-toxin-producing gastrointestinal infection, often with bloody diarrhoea, injures endothelium and commonly produces prominent renal involvement, especially in children.

Complement-mediated HUS

Acquired or inherited alternative-complement dysregulation causes uncontrolled endothelial injury; diagnosis follows assessment for severe ADAMTS13 deficiency, STEC and convincing secondary triggers.

Secondary endothelial injury

Pregnancy, severe hypertension, transplantation, medicines, autoimmune disease, cancer, infection and disseminated coagulation can generate a secondary TMA phenotype.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Endothelial activation and injury
ADAMTS13 failure, toxin, complement or systemic stress activates and damages the microvascular endothelium, especially in renal and cerebral beds.
2
Platelet-rich microthrombi
Exposed and activated endothelial surfaces recruit platelets, narrowing arterioles and capillaries while consuming circulating platelets across organs.
3
Mechanical haemolysis
Erythrocytes fragment while traversing narrowed microvessels, producing schistocytes, raised LDH, indirect bilirubin and low haptoglobin during acute illness.
4
Organ ischaemia
Microvascular occlusion deprives kidneys, brain, heart and gut of perfusion, with the dominant organ pattern varying by cause.
5
Amplifying vascular dysfunction
Ischaemia, hypertension and complement or coagulation activation reinforce endothelial damage, allowing rapid clinical deterioration without the historical full symptom pentad.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Microangiopathic haemolysisRed flag

Anaemia, thrombocytopenia and fragmented red cells occur with high LDH, low haptoglobin, indirect hyperbilirubinaemia and a marrow reticulocyte response. Severe hypertension and mechanical valves can mimic parts of this pattern.

Immune TTP phenotypeRed flag

Fluctuating confusion, headache, seizure, focal deficit, chest pain or abdominal symptoms accompany marked thrombocytopenia and MAHA, often with less severe renal failure than HUS, but no single feature safely excludes it.

STEC-associated HUSRed flag

Abdominal cramps and usually bloody diarrhoea precede pallor, bruising, reduced urine, oedema or hypertension by several days, most characteristically in a child but also in vulnerable adults.

Complement-mediated HUSRed flag

Severe or persistent renal TMA occurs without severe ADAMTS13 deficiency or confirmed STEC, sometimes triggered by infection, surgery or pregnancy and sometimes with a personal or family history of recurrence.

Pregnancy-associated TMARed flag

Thrombocytopenia, haemolysis, hypertension, liver injury or AKI develops antenatally or postpartum. TTP, complement-mediated HUS, pre-eclampsia and HELLP overlap and need immediate obstetric-haematology-renal assessment.

Secondary TMARed flag

The syndrome follows calcineurin or VEGF-pathway drugs, transplant, cancer, systemic autoimmunity, malignant hypertension, severe infection or DIC; the trigger pattern guides treatment but does not negate urgent ADAMTS13 testing.

Congenital TTP clue

Recurrent unexplained thrombocytopenia and haemolysis begin in childhood or are provoked by pregnancy, with persistently severe ADAMTS13 deficiency but no inhibitor and possible neonatal jaundice in the history.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
FBC, blood film and haemolysis profileFirst step
Why
Demonstrate thrombocytopenia and non-immune red-cell fragmentation quickly and trend severity.
Interpretation and limitations
Request urgent expert film review, LDH, reticulocytes, haptoglobin, bilirubin and DAT. Schistocyte number can be modest early; a negative DAT supports non-immune haemolysis but does not name the TMA.
02
ADAMTS13 activity and inhibitor before plasma
Why
Identify severe protease deficiency and distinguish immune from congenital TTP.
Interpretation and limitations
Activity below 10 IU/dL strongly supports TTP. Draw before plasma exchange or infusion, label timing precisely and do not wait for the result to treat a high-probability presentation.
03
Urea, electrolytes, urinalysis and urine ACR or PCR
Why
Quantify AKI, potassium, acid-base risk and glomerular endothelial injury.
Interpretation and limitations
Severe renal dysfunction increases the likelihood of HUS or secondary TMA but can occur in TTP. Protein and blood are common; urine findings do not replace causal testing.
04
Coagulation, fibrinogen and D-dimer
Why
Separate a relatively preserved TTP coagulation pattern from consumptive coagulopathy and detect bleeding risk.
Interpretation and limitations
Marked PT, APTT and fibrinogen disturbance favours DIC, severe liver disease or another process, although overlap is possible in sepsis and pregnancy.
05
ECG, troponin and neurological assessment
Why
Find clinically silent cardiac and cerebral microvascular injury that changes monitoring intensity.
Interpretation and limitations
Troponin elevation in TTP is a high-risk finding even without classic chest pain. New focal deficit, seizure or reduced consciousness prompts emergency brain imaging and critical-care review.
06
Stool culture or PCR for Shiga toxin
Why
Confirm STEC when diarrhoea or an epidemiological link makes infection plausible and enable public-health action.
Interpretation and limitations
Send early and liaise with microbiology because yield falls after the diarrhoeal phase. HUS is notifiable in England, and a negative late specimen does not automatically prove complement-mediated disease.
07
Pregnancy and targeted secondary-cause screen
Why
Identify obstetric, drug, transplant, autoimmune, infectious, malignant and hypertensive drivers.
Interpretation and limitations
Check pregnancy status, BP, liver profile, medication chronology, cultures and disease-specific tests. Complement C3/C4 and genetics can support specialist CM-HUS evaluation but normal levels do not exclude dysregulation.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Disseminated intravascular coagulation

Markedly abnormal coagulation, fibrinogen consumption and an obvious septic or obstetric trigger favour systemic coagulation activation, though DIC and TMA can coexist.

Autoimmune haemolytic anaemia

A positive direct antiglobulin test and spherocytes favour immune red-cell destruction rather than fragmentation through platelet-rich microvessels.

Severe hypertension with secondary TMA

Extreme blood pressure and retinal or cardiac target-organ injury may drive endothelial damage; ADAMTS13 testing and the wider trajectory help exclude concurrent TTP.

Pregnancy-associated HELLP syndrome

Pregnancy timing, hepatic enzyme elevation and placental disease support HELLP, while persistent postpartum microangiopathy may require complement-mediated or TTP reassessment.

Isolated thrombocytopenia or bleeding

Immune thrombocytopenia, marrow disease and drug effects lower platelets without schistocytes or biochemical evidence of microangiopathic haemolysis.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Probable TTPSample, call and exchangeFirst stepAlternativeMAHA and thrombocytopenia have no immediately dominant alternative, especially with cerebral or cardiac features.

1Send citrate plasma for ADAMTS13 activity and inhibitor before any plasma if this causes no delay, plus urgent haemolysis, renal, coagulation, troponin and infection tests.
2Contact the designated regional TTP centre immediately and begin daily plasma exchange, corticosteroid and caplacizumab treatment under its protocol while arranging monitored transfer.
3Add early B-cell-directed immunosuppression as directed, trend platelets, LDH and organ injury, and revise the pathway promptly when ADAMTS13 and causal results return.

02Diarrhoeal HUSSupport kidneys and protect the publicTMA follows acute diarrhoea, particularly bloody diarrhoea or a shared food or contact exposure.

1Send stool for STEC testing, notify the appropriate public-health team and use infection-control precautions while recording fluid losses, weight, urine output and blood pressure.
2Provide careful isotonic fluid only to correct verified deficit, then manage overload, electrolytes, anaemia and uraemia with paediatric or adult nephrology; dialyse for standard clinical indications.
3Avoid routine antibiotics and antimotility drugs for suspected STEC, review the diagnosis if tests are negative or disease persists, and continue to exclude TTP in parallel.

03Possible CM-HUSExclude mimics and access complement expertiseRenal-predominant TMA persists without severe ADAMTS13 deficiency or confirmed STEC and no secondary driver fully explains it.

1Involve a specialist renal-complement service urgently, preserve pre-treatment complement and genetic samples, and document infection, pregnancy, transplant and medicine triggers.
2Continue organ support while the expert team determines whether eculizumab or ravulizumab is indicated through the commissioned pathway and arranges meningococcal prevention.
3Monitor haematological and renal response, reassess competing diagnoses and let the specialist service determine treatment duration because relapse risk and genetic context vary.

04Secondary TMARemove the driver without missing TTPSevere hypertension, pregnancy, sepsis, transplantation, cancer, autoimmunity or a culprit medicine accompanies the TMA.

1Stabilise organ injury and treat the cause, including controlled BP reduction, obstetric delivery decisions, infection treatment or withdrawal of a suspected toxic medicine with specialist oversight.
2Send ADAMTS13 before plasma and assess whether the severity or pattern exceeds the apparent trigger; use renal biopsy only when safe and likely to change a later decision.
3EscalationEscalate ongoing haemolysis, thrombocytopenia or renal failure to the regional TMA team so TTP or complement-mediated disease is not falsely closed off.

Key medicines and prescribing safety5 treatments · regimens, roles and cautions

Removes pathogenic anti-ADAMTS13 antibody and supplies functional ADAMTS13 during an acute immune TTP episode.

Therapeutic plasma exchange

Exchange approximately one to one-and-a-half plasma volumes daily using the regional TTP centre protocol.

Start urgently but obtain the diagnostic sample first when feasible; central access, citrate hypocalcaemia, allergic reactions, infection, haemodynamic instability and plasma choice require an experienced apheresis service.

Blocks von Willebrand-factor platelet binding and rapidly reduces ongoing microvascular platelet consumption in acute immune TTP.

Caplacizumab

Give 10 mg intravenously before first plasma exchange, then 10 mg subcutaneously after each exchange and daily for 30 days after exchange ends, with specialist extension if needed.

Use only with plasma exchange and immunosuppression through the specialist pathway; assess mucosal or major bleeding, invasive procedures and concomitant antiplatelet or anticoagulant therapy, and follow current SmPC timing.

Suppresses the autoimmune process producing anti-ADAMTS13 antibody while plasma exchange and caplacizumab control the acute syndrome.

Corticosteroid immunosuppression

Use high-dose intravenous methylprednisolone or oral prednisolone according to the regional acute TTP regimen and taper plan.

Monitor glucose, blood pressure, delirium, infection, gastric and bone risk; route and dose depend on severity, and steroids must not be the sole urgent treatment for probable TTP.

Depletes B cells, speeds durable ADAMTS13 recovery and reduces relapse risk in immune TTP.

Rituximab

A common acute regimen is 375 mg/m² intravenously weekly for four doses, scheduled by the TTP centre around plasma exchange.

Screen hepatitis B and relevant infection risks, premedicate and monitor infusion reactions; plasma exchange affects timing, vaccines may be less effective, and specialist alternatives are needed after serious intolerance.

Inhibits terminal complement when complement-mediated HUS is confirmed or strongly suspected after urgent differential assessment.

Eculizumab or ravulizumab

Use licensed weight-based loading and maintenance schedules only through the specialist complement-mediated HUS service and current commissioning protocol.

Life-threatening meningococcal and other encapsulated infection risk requires vaccination, antibiotic prevention and emergency fever advice; do not substitute complement blockade for immediate TTP treatment while ADAMTS13 is unresolved.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Neurological and cardiac ischaemia

TTP can cause fluctuating confusion, seizures, stroke, arrhythmia or myocardial injury through widespread platelet-rich microvascular occlusion.

Acute kidney injury

HUS and secondary TMA often cause severe renal endothelial injury, with hypertension, haematuria, proteinuria and temporary or permanent filtration loss.

Mesenteric and multiorgan injury

Gut, pancreas and other organs may become ischaemic, producing abdominal pain, inflammation and escalating systemic instability.

Bleeding and procedural risk

Severe thrombocytopenia increases bleeding risk, while prophylactic platelet transfusion in TTP may add substrate for microvascular thrombosis.

Relapse or chronic renal damage

Immune TTP can relapse, while complement-mediated and secondary TMA may leave persistent hypertension, proteinuria and chronic kidney impairment.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

During acute TTP, check platelet count, haemoglobin, LDH, bilirubin, neurological state, ECG or troponin risk and renal function at least daily, with higher-frequency observations when unstable.
Judge response by sustained platelet and haemolysis recovery plus organ improvement; caplacizumab can normalise platelets before the ADAMTS13 autoimmune process is controlled.
After immune TTP remission, the regional centre should monitor ADAMTS13 activity and inhibitor, relapse symptoms, cognition, mood and cardiovascular risk and offer pre-emptive therapy when indicated.
For HUS, use strict fluid balance, daily weight, urine output, blood pressure, potassium, bicarbonate, creatinine and haemoglobin to guide fluids, transfusion and kidney replacement therapy.
On complement inhibition, follow the commissioned service schedule for haemolysis, kidney function, infection prevention, vaccination and treatment continuation or withdrawal decisions.
Notify suspected STEC and HUS according to UKHSA and local public-health arrangements and document household, food, childcare and occupational implications.
Reconsider the aetiology when platelets or haemolysis fail to respond as expected, renal injury progresses or a new drug, pregnancy, transplant or malignant-hypertension trigger emerges.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

The pentad is historical

Waiting for five classic manifestations loses time; otherwise unexplained MAHA and thrombocytopenia are enough to activate urgent TTP assessment.

Take plasma before plasma

Infused donor ADAMTS13 can obscure diagnostic activity, so the pre-exchange citrate sample and exact collection time are pivotal.

Kidney severity is directional

Profound AKI makes HUS more likely, but neither severe renal failure excludes TTP nor mild impairment rules out complement-mediated disease.

Normal complement can mislead

Serum C3 and C4 are screening context, not a rule-out test for alternative-pathway dysregulation; expert phenotyping and genetics take longer.

Platelets can harm

Transfusing platelets into active TTP without major bleeding may add substrate to platelet-rich microthrombi and is therefore avoided.

Diarrhoea is not ownership

Gastrointestinal symptoms occur in several TMAs, so stool testing and ADAMTS13 should proceed together when the phenotype is uncertain.

Remission is not discharge from risk

TTP survivors can have relapse, cognitive symptoms, depression and vascular risk even with a normal platelet count, warranting specialist longitudinal care.

11Common pitfallsFrequent interpretation and management errors.

01
Delaying regional TTP-centre contact until the ADAMTS13 result becomes available.
02
Ruling out TTP because fever, renal failure or a focal neurological deficit is absent.
03
Calling every thrombocytopenic AKI a TMA without confirming haemolysis and examining the blood film.
04
Giving prophylactic platelets for a low count in active TTP without major bleeding or procedural necessity.
05
Treating suspected STEC diarrhoea routinely with antibiotics or loperamide despite UKHSA advice.
06
Using a normal C3 result to exclude complement-mediated HUS.
07
Attributing pregnancy or malignant hypertension as the complete cause without sending pre-plasma ADAMTS13.