Thrombotic Thrombocytopenic Purpura (TTP)

Immune TTP (iTTP) is a life-threatening thrombotic microangiopathy caused by autoantibodies against ADAMTS13, resulting in accumulation of ultra-large von Willebrand factor multimers, platelet-rich microthrombi, and ischemic organ injury. Untreated mortality approaches 90%; with modern triple therapy (therapeutic plasma exchange + corticosteroids + rituximab ± caplacizumab), 30-day survival exceeds 93%. [1-2] Annual incidence is 2–6 cases per million, with higher rates in females (IRR 3.19), Black individuals (IRR 7.09), and adults. [1]

The following figure illustrates the diagnostic and initial management workflow:

1. History

Key HPI questions: Onset and progression of fatigue, bruising/petechiae, headache, confusion, visual changes, chest pain, abdominal pain, dark urine, fever
Symptom characterization: Neurologic symptoms are the most common presenting feature (39–80%), including headache, confusion, vision changes, and seizures; abdominal pain/nausea in 35–39%; fever in 10–35% [1]
Timing/triggers: Acute onset over days; may be triggered by infection (HIV in 13%), pregnancy (7%), autoimmune disease (SLE, antiphospholipid syndrome in 14%), or rarely drugs (1%) [1]
Important negatives: Absence of bloody diarrhea (argues against Shiga toxin HUS), absence of recent transplant or active malignancy, no recent heparin exposure

2. Alarm Features

Neurologic deterioration: Seizures, focal deficits, stupor, coma — independent predictor of 30-day mortality [1]
Cardiac involvement: Troponin elevation (present in 54–68% of patients), chest pain, heart failure, cardiogenic shock — elevated troponin above ULN associated with 6-fold increase in mortality (12.1% vs 2.0%) [3-4]
Glasgow Coma Scale ≤14: 9-fold increase in mortality (20% vs 2.2%) [3]
LDH >10× ULN: Independent predictor of 30-day mortality [1]
Refractory disease: Lack of platelet count doubling after ≥5 TPE sessions with persistently elevated LDH [1]

3. Medications

Relevant medication contributors (drug-induced TMA):

Definite causal association: quinine (most common), cyclosporine, tacrolimus, ticlopidine, gemcitabine, mitomycin [1][5]
Other reported associations: clopidogrel, oxaliplatin, interferon-β, quetiapine, vancomycin [6-7]

Core treatments:

Therapeutic plasma exchange (TPE): Daily, 1–1.5 plasma volumes
Corticosteroids: Prednisone 1 mg/kg/day PO or methylprednisolone 1000 mg IV daily × 3 days for severe features [1]
Rituximab: 375 mg/m² weekly × 4 doses (off-label for TTP) [1]
Caplacizumab: 11 mg IV bolus before first TPE, then 11 mg SC daily for ≥30 days after TPE cessation [8]

Contraindicated medications:

Platelet transfusions are generally avoided unless life-threatening hemorrhage (theoretical concern for fueling microvascular thrombosis) [9]
Avoid re-exposure to any suspected causative drug

4. Diet

No specific dietary triggers for iTTP
Ensure adequate hydration, particularly during TPE
Monitor for electrolyte derangements during plasma exchange (hypocalcemia from citrate anticoagulant)

5. Review of Systems

Neurologic: Headache, confusion, vision changes, seizures, focal weakness, speech difficulty
Cardiac: Chest pain, dyspnea, palpitations, syncope
GI: Abdominal pain, nausea, vomiting
Hematologic: Easy bruising, petechiae, mucosal bleeding, dark urine (hemoglobinuria)
Renal: Decreased urine output (though severe renal failure is uncommon — only 5% develop kidney failure) [1]
Constitutional: Fever, fatigue, malaise

6. Collateral History and Family History

Prior episodes of TTP or unexplained thrombocytopenia/anemia (relapse occurs in ~30% at 5-year follow-up) [1]
Family history of TTP (rare congenital TTP from biallelic ADAMTS13 mutations — 3–5% of cases) [1]
History of autoimmune disease (SLE, antiphospholipid syndrome)
HIV status, pregnancy status
Medication history with focus on quinine, calcineurin inhibitors, ticlopidine, gemcitabine

7. Risk Factors

Female sex (IRR 3.19) [1]
Black race (IRR 7.09) [1]
Adult age (peak incidence in 30s–50s) [1]
Autoimmune disease (SLE, antiphospholipid syndrome — 14%) [1]
HIV infection (13%) [1]
Pregnancy (7%, particularly second/third trimester) [1]
Obesity — associated with higher relapse risk in some cohorts
Prior TTP episode — 16% clinical relapse rate, 13% ADAMTS13 relapse only at 5 years [1]

8. Differential Diagnosis

9. Past Medical History

Prior TTP episodes (relapse risk is significant — 40% at 5-year follow-up in UK registry) [12]
Autoimmune conditions (SLE, antiphospholipid syndrome, thyroid disease)
HIV/AIDS
Prior pregnancy-related TMA
History of splenectomy
Transplant history (solid organ or stem cell)
Active malignancy

10. Physical Exam

Vitals: Fever (10–35%), tachycardia, hypo- or hypertension
Skin: Petechiae, purpura, ecchymoses, jaundice/scleral icterus
Neurologic: Altered mental status, confusion, focal deficits, seizures, visual field deficits — perform thorough neurologic exam including GCS
Cardiac: Tachycardia, signs of heart failure (JVD, crackles, S3), arrhythmias
Abdominal: Tenderness (often diffuse), hepatosplenomegaly (uncommon)
Note: Less than 10% present with the classic "pentad" (hemolytic anemia, thrombocytopenia, fever, renal dysfunction, neurologic dysfunction) [1]

11. Lab Studies

Diagnostic labs:

CBC with peripheral smear: Thrombocytopenia (typically <30 × 10⁹/L), anemia, schistocytes ≥1% (may be absent initially — repeat daily) [1]
ADAMTS13 activity: <10% confirms diagnosis; draw before initiating TPE if possible [1]
Anti-ADAMTS13 antibody (IgG ELISA and/or functional inhibitor assay) [1]
Hemolysis panel: LDH (markedly elevated), indirect bilirubin (elevated), haptoglobin (undetectable), reticulocyte count (elevated)
Direct Coombs test (DAT): Negative (distinguishes from autoimmune hemolytic anemia)
Coagulation studies: PT/INR and aPTT typically normal or mildly prolonged (helps distinguish from DIC) [1]
BMP: Creatinine typically <2 mg/dL (distinguishes from aHUS)
Troponin: Elevated in 54–68%; prognostic marker — cTnI >0.25 μg/L associated with 3-fold increase in death/refractoriness [4][13]

Rule-out labs:

Blood cultures (if febrile, to exclude sepsis)
HIV testing, hepatitis B panel (before rituximab)
ANA, antiphospholipid antibodies (if autoimmune etiology suspected)
Pregnancy test in women of childbearing age
Stool studies if diarrhea present (Shiga toxin)

12. Imaging

CT head without contrast: If focal neurologic deficits or seizures — evaluate for stroke, hemorrhage
MRI brain: More sensitive for ischemic changes from microvascular thrombosis; consider if CT is negative with persistent neurologic symptoms
Echocardiogram: If troponin elevated or signs of heart failure — assess for wall motion abnormalities, reduced EF, pericardial effusion [14-15]
Chest X-ray: If respiratory symptoms or heart failure suspected
Routine imaging is not required for diagnosis

13. Special Tests

PLASMIC Score (most commonly used clinical prediction tool): [1]

Score 0–4: Low risk → TTP unlikely
Score 5: Intermediate risk → consider empiric treatment, urgent hematology consult
Score 6–7: High risk → initiate empiric treatment immediately
Sensitivity of score ≥5: 99% (95% CI, 91–100%); specificity: 57% [1][16]

Rapid ADAMTS13 assays (e.g., HemosIL AcuStar): Turnaround <1 hour, sensitivity 98%, specificity 99% — may avert unnecessary empiric TPE in non-TTP patients [17]

14. ECG

Obtain ECG on all patients with suspected TTP
Findings may include: ST-segment changes (depression or elevation), T-wave inversions, repolarization abnormalities — present in 62% of patients with elevated troponin [13]
Non-ST elevation pattern is the predominant presentation of myocardial injury in TTP [15]
Conduction abnormalities: AV block (microthrombi in AV node and His bundle on autopsy) [18]
Arrhythmias: Atrial tachyarrhythmias (5.9%), ventricular tachyarrhythmias (2.0%) [14]
Cardiac arrest reported in 1.9% of TTP hospitalizations [14]

15. Assessment

iTTP is a hematologic emergency — mortality approaches 90% without treatment [2]
The classic pentad (MAHA, thrombocytopenia, fever, neurologic dysfunction, renal dysfunction) is present in <10% of cases; do not wait for the full pentad to initiate treatment [1]
Severity stratification based on: neurologic features, troponin elevation, GCS, LDH level, ADAMTS13 antibody burden [1][3][19]
Cardiovascular complications occur in 25% of hospitalizations and are associated with significantly higher in-hospital mortality (19.7% vs 4.1%) [14]
Long-term survivors have elevated cardiovascular mortality and a 5-fold higher rate of ischemic stroke compared to the general population [1]

16. Treatment Plan

Initial stabilization:

Emergent hematology consultation
Large-bore IV access; central venous catheter for apheresis

First-line therapy (ISTH 2020 guidelines, reaffirmed 2025): [1][20]

Therapeutic plasma exchange (TPE): Daily, 1–1.5 plasma volumes with FFP replacement. Continue until sustained platelet normalization (≥150 × 10⁹/L for ≥2 days) and declining LDH
Corticosteroids: Prednisone 1 mg/kg/day PO or methylprednisolone 1 g IV daily × 3 days for severe neurologic/cardiac features [1]
Rituximab: 375 mg/m² IV weekly × 4 doses (conditional recommendation). Screen for hepatitis B before initiation [1]
Caplacizumab: 11 mg IV bolus before first TPE, then 11 mg SC daily. Continue for 30 days after last TPE or until ADAMTS13 recovery >10%. May extend up to additional 28 days if ADAMTS13 remains severely deficient [1][8]

Key outcomes with triple/quadruple therapy:

JAMA[1]

Refractory TTP (no response after ≥5 TPE sessions):

Escalate to twice-daily TPE
Add rituximab and/or caplacizumab if not already initiated
Consider cyclosporine, cyclophosphamide, vincristine, bortezomib, daratumumab, or splenectomy [1]

17. Disposition

All patients with suspected TTP require hospital admission, typically to the ICU or a monitored setting with apheresis capability [21]
Transfer to a center with TPE capability if not available locally
Admission criteria: Any patient with MAHA + thrombocytopenia and PLASMIC ≥5 or high clinical suspicion
Discharge criteria: Sustained platelet count normalization (≥150 × 10⁹/L for ≥2 consecutive days), declining LDH, no new organ injury, transition to outpatient caplacizumab (if applicable)
Hematology consultation is mandatory and should be obtained emergently [1]

18. Follow Up / Return Precautions

Monitoring in remission:

ADAMTS13 activity should be monitored regularly (e.g., every 1–3 months initially, then every 3–6 months) — declining ADAMTS13 <20% warrants preemptive rituximab [1]
Preemptive rituximab for ADAMTS13 relapse (activity <10–20% without clinical symptoms) reduces clinical relapse from 0.5 episodes/year to 0 episodes/year (OR 0.09) [1][22]
CBC, LDH, haptoglobin at follow-up visits
Cardiovascular risk assessment: Survivors have elevated long-term cardiovascular mortality; ischemic stroke occurs in 13% during remission (5-fold higher than expected) [1]

Return precautions — instruct patients to seek immediate care for:

New or worsening headache, confusion, vision changes, weakness
Chest pain, shortness of breath, palpitations
New bruising, petechiae, dark urine
Fever

Expected course:

16% of patients experience at least one clinical relapse; ~30% have clinical or ADAMTS13 relapse at 5 years [1]
Long-term follow-up with hematology is essential for relapse surveillance, cardiovascular risk management, and psychosocial support [1][23]

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