Thrombotic thrombocytopenic purpura

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

ADAMTS13 normally trims ultra-large von Willebrand factor released from endothelium. Severe deficiency permits platelet-rich microthrombi to form under high shear. Platelets are consumed and erythrocytes fragment across partially occluded arterioles and capillaries. Tissue ischaemia particularly affects brain, heart and gut; kidney injury occurs but often is less dominant than in HUS. The platelet count and haemolysis can change quickly, so a patient with transient neurological symptoms and normal coagulation can be critically ill.

Diagnosis begins before confirmation. Repeat count, urgent film, LDH, bilirubin, haptoglobin, reticulocytes, renal function, coagulation, ECG and troponin establish TMA and organ involvement. Send citrate plasma for ADAMTS13 before plasma exchange or infusion, following the reference laboratory instructions. Exclude pregnancy microangiopathy, DIC, malignant hypertension, STEC-HUS, complement-mediated HUS, drugs and transplantation, but treatment of a high-probability immune TTP proceeds in parallel.

Therapy is delivered by a specialist TTP network. Plasma exchange continues daily until durable platelet and haemolysis response under protocol. Caplacizumab prevents new VWF-mediated microthrombi quickly but increases mucocutaneous and procedural bleeding; it generally continues beyond exchange until immune disease is controlled. Corticosteroid and rituximab reduce autoantibody. Platelets are avoided unless life-threatening bleeding or an exceptional procedure demands them. Survivorship includes cognition, mood, fatigue, cardiovascular risk, pregnancy planning and ADAMTS13 surveillance, not merely a normal count.

Key points

TTP is a thrombotic microangiopathy caused by severe ADAMTS13 deficiency, usually from an acquired autoantibody and rarely from biallelic inherited variants.
Without ADAMTS13 cleavage, ultra-large von Willebrand factor multimers capture platelets in small vessels, causing organ ischaemia, thrombocytopenia and red-cell fragmentation.
Most patients do not present with the historic pentad; thrombocytopenia and microangiopathic haemolytic anaemia without another clear cause should trigger immediate action.
Schistocytes, raised LDH, low haptoglobin, indirect bilirubin and reticulocytosis support haemolysis, while routine coagulation is often normal unlike DIC.
Neurological fluctuation, headache, confusion, seizure, focal deficit, myocardial injury and abdominal pain can occur despite only modest creatinine elevation.
A pre-treatment ADAMTS13 activity below 10% strongly confirms TTP; inhibitor or antibody studies distinguish acquired immune disease from congenital deficiency.
Use a validated clinical score such as PLASMIC to estimate severe ADAMTS13 deficiency while awaiting the assay, but never let scoring delay the TTP centre.
Daily plasma exchange replaces ADAMTS13 and removes antibody, corticosteroid suppresses autoimmunity, and caplacizumab rapidly blocks von Willebrand factor–platelet interaction.
Rituximab is commonly added early in immune TTP to suppress antibody production and reduce relapse; hepatitis B screening and infection planning are required.
After clinical remission, serial ADAMTS13 activity can identify biochemical relapse before thrombocytopenia and guide pre-emptive specialist treatment.

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

Immune ADAMTS13 inhibition

Autoantibodies reduce ADAMTS13 activity through inhibition or accelerated clearance, sometimes associated with pregnancy, autoimmune disease, infection or no identifiable trigger.

Congenital ADAMTS13 deficiency

Biallelic pathogenic variants cause hereditary TTP with variable age at presentation, episodic triggers and a different long-term replacement strategy.

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

1
Uncleaved von Willebrand factor
Ultra-large multimers persist on activated endothelium and bind platelets avidly under shear, creating disseminated platelet-rich arteriolar microthrombi.
2
Mechanical red-cell injury
Erythrocytes crossing narrowed fibrin- and platelet-lined vessels fragment into schistocytes, producing intravascular haemolysis and tissue oxygen loss.
3
Organ microischaemia
Intermittent obstruction injures brain, myocardium, gut and kidneys, explaining fluctuating symptoms and troponin rise without large-vessel thrombosis.

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

Core dyad

Unexplained thrombocytopenia and microangiopathic haemolytic anaemia with schistocytes are enough to suspect TTP before every organ feature appears.

Fluctuating neurology

Transient speech change, weakness, confusion, headache or seizure can reflect cerebral microthrombi and should not be dismissed after spontaneous improvement.

Cardiac involvement

Troponin elevation, chest pain, ECG change or arrhythmia may be silent organ TMA and increases monitoring need.

TTP emergency patternRed flag

Thrombocytopenia, fragments and haemolysis with normal routine coagulation requires immediate TTP service contact and treatment.

Relapse signal

New bruising, fatigue, neurological symptoms or biochemical haemolysis after remission requires urgent count, film, LDH and ADAMTS13 review.

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
Full count and urgent blood filmFirst step
Why
Confirm platelet consumption and red-cell fragmentation.
Interpretation and limitations
Schistocytes support TMA; their early absence does not exclude high-probability TTP and warrants expert repeat film.
02
LDH, bilirubin, haptoglobin and reticulocytes
Why
Establish evidence of intravascular microangiopathic haemolysis.
Interpretation and limitations
Marked LDH may also reflect organ ischaemia; interpret with film, haemoglobin and transfusion timing.
03
ADAMTS13 activity and inhibitor
Why
Confirm severe protease deficiency and immune mechanism.
Interpretation and limitations
Activity below 10% strongly supports TTP; draw before plasma where feasible but do not postpone exchange or caplacizumab.
04
PT, APTT, fibrinogen and D-dimer
Why
Distinguish disseminated intravascular coagulation from TTP.
Interpretation and limitations
Near-normal routine coagulation fits TTP, while a consumption pattern raises DIC; mixed critical illness can complicate this separation.
05
Renal profile, urinalysis and blood pressure
Why
Measure kidney involvement and alternate TMA phenotype.
Interpretation and limitations
Severe dominant renal failure may favour HUS but does not by itself exclude TTP; integrate ADAMTS13.
06
ECG and troponin
Why
Identify clinically silent myocardial microvascular injury.
Interpretation and limitations
An elevated troponin changes monitoring and critical-care risk even without classic coronary symptoms.
07
PLASMIC score
Why
Estimate probability of severe ADAMTS13 deficiency before assay return.
Interpretation and limitations
Use validated components accurately as a decision support; a score never substitutes for urgent specialist judgement in an unstable TMA.

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

Disseminated intravascular coagulation

Sepsis, trauma or cancer can cause fragments and thrombocytopenia but usually consumes coagulation factors, prolongs clotting times and lowers fibrinogen.

STEC-associated HUS

Bloody diarrhoea followed by dominant acute kidney injury, especially in children, supports Shiga-toxin disease; stool testing and epidemiology guide classification.

Complement-mediated HUS

Severe renal TMA with ADAMTS13 above the TTP range and no STEC may reflect alternative-complement dysregulation requiring a specialist complement pathway.

Pregnancy microangiopathy

HELLP, pre-eclampsia and acute fatty liver overlap with TTP; gestation, hypertension, liver tests, ADAMTS13 and post-delivery trajectory guide multidisciplinary decisions.

Malignant hypertension

Extreme blood pressure with retinal and renal injury can generate secondary TMA, though TTP itself may also raise blood pressure and requires ADAMTS13 assessment.

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

01RecognitionTreat the dyad, not the pentadFirst stepAlternativeThrombocytopenia and microangiopathic haemolysis occur without a clear alternative cause.

1Call the regional TTP team, assess brain, heart, kidneys, abdomen and bleeding and calculate a validated probability score without delaying transfer.
2Send pre-plasma ADAMTS13, inhibitor and TMA samples according to the reference laboratory instructions while preserving treatment urgency.
3Start daily plasma exchange, corticosteroid and caplacizumab under the specialist pathway and avoid prophylactic platelet transfusion.

02Acute controlStop microthrombi and suppress antibodyImmune TTP treatment is underway and platelet or organ response is being assessed.

1Continue exchange and caplacizumab on schedule, monitor neurological and cardiac status and treat line, allergic, citrate and bleeding complications.
2Add early rituximab for immune disease after hepatitis screening and coordinate dose timing around plasma exchange to avoid immediate removal.
3Investigate refractory platelet or LDH response for ongoing immune activity, infection, missed treatment, alternate TMA or organ ischaemia with the TTP centre.

03RemissionWatch the enzyme before the countPlatelets and haemolysis recover after an acute immune episode.

1Complete caplacizumab and immunosuppression according to ADAMTS13 recovery and specialist protocol, planning procedures around residual bleeding effect.
2Measure ADAMTS13 serially and consider pre-emptive rituximab when activity falls through the TTP service before clinical relapse.
3Assess cognition, fatigue, mood, cardiovascular risk, pregnancy and return to activity and provide a written route for urgent relapse symptoms.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Blocks von Willebrand factor binding to platelets, rapidly preventing new TTP microthrombi while immunosuppression restores ADAMTS13.

Caplacizumab

Give the licensed 10 mg intravenous dose before plasma exchange then 10 mg subcutaneously after each exchange and daily after exchange for the protocol-defined period, extended if immune activity persists.

Mucocutaneous and major bleeding, procedures and concomitant antithrombotics require review; continuing after exchange depends on ADAMTS13 and specialist assessment.

Depletes B cells producing anti-ADAMTS13 antibody and reduces refractory disease and relapse in immune TTP.

Rituximab

The TTP centre uses an intravenous induction regimen scheduled around plasma exchange, commonly 375 mg/m² weekly for four doses, with premedication and infection screening.

Screen hepatitis B, immunoglobulins and vaccine needs; infusion reaction, infection, late neutropenia and impaired vaccine response require follow-up.

Suppresses the autoimmune inhibitor while plasma exchange and caplacizumab provide immediate disease control.

Corticosteroid

Use high-dose oral prednisolone or intravenous methylprednisolone under the acute TTP protocol, then taper according to clinical and ADAMTS13 response.

Hyperglycaemia, infection, psychiatric symptoms, hypertension, gastrointestinal and bone toxicity require active prevention and a clear taper.

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

Cerebral ischaemia

Fluctuating confusion, focal deficits, seizure and coma result from microvascular occlusion and can recur while the platelet count is improving.

Cardiac injury

Microvascular myocardial ischaemia causes troponin elevation, arrhythmia, heart failure or sudden death, making ECG and monitored care important.

Relapse

Immune ADAMTS13 deficiency can recur after apparent clinical recovery, and falling activity may precede thrombocytopenia sufficiently for pre-emptive review.

Treatment bleeding

Caplacizumab impairs VWF-dependent primary haemostasis, increasing epistaxis, bruising, procedural and occasionally major bleeding during acute treatment.

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

Measure platelets, haemoglobin, LDH, bilirubin, reticulocytes, renal function and clinical organ status at least daily during acute exchange.
Use ECG monitoring and serial troponin for cardiac involvement and repeat neurological assessment because symptoms can fluctuate.
Track caplacizumab bleeding, injection sites, procedures and concurrent anticoagulants or antiplatelets, coordinating interruption with the TTP centre.
Monitor exchange-line infection, thrombosis, citrate-related calcium symptoms, allergy and volume balance during daily procedures.
After remission measure ADAMTS13 at specialist intervals and act on biochemical decline before the platelet count necessarily falls.
Review cognition, fatigue, depression, blood pressure and vascular risk because recovery extends beyond normalisation of laboratory haemolysis.

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

The pentad delays care

Most patients lack fever, severe renal failure or every neurological feature, so the haemolysis-thrombocytopenia dyad carries the emergency decision.

ADAMTS13 sample precedes plasma

Donor enzyme changes the assay, but preserving a perfect sample must never delay plasma exchange in high-probability disease.

Caplacizumab is a bridge

It stops VWF-platelet binding quickly while corticosteroid and rituximab address the slower autoimmune source of deficiency.

Remission has two levels

A normal count marks clinical recovery, while persistently low ADAMTS13 indicates ongoing biological relapse risk.

11Common pitfallsFrequent interpretation and management errors.

01
Waiting for the historic five-feature pentad.
02
Waiting for ADAMTS13 before plasma exchange.
03
Calling normal routine coagulation falsely reassuring.
04
Giving prophylactic platelets to correct the count.
05
Stopping follow-up when platelets normalise.
06
Missing myocardial injury without chest pain.