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Thrombotic Thrombocytopenic Purpura

Chirag N. Shah, MD
Grant Wei, MD, FACEP
Jay Patel, DO

BASICS

DESCRIPTION

  • Acute syndrome of microangiopathic hemolytic anemia (MAHA) and consumptive thrombocytopenia

  • Hyaline thrombi in terminal arterioles/capillaries → ischemic multiorgan damage

  • TTP: MAHA (schistocytes on smear) + thrombocytopenia (<30,000)

  • May present with/without: neurologic symptoms, renal dysfunction, fever

  • Pentad (historic): MAHA, thrombocytopenia, renal dysfunction, neurologic symptoms, fever (rare in modern treatment)

EPIDEMIOLOGY

  • First episode: mostly adulthood (90%), median age 41; 10% childhood/adolescence

  • Female > male (2:1), higher relapse in females

  • Blacks > whites (7:1)

  • Increased risk: high BMI, pregnancy

  • Incidence: 3/million/year; Prevalence: 10/million/year

ETIOLOGY AND PATHOPHYSIOLOGY

  • UL vWF multimers (ultra-large) drive platelet thrombi

  • ADAMTS13 metalloprotease cleaves UL vWF; deficiency (congenital/acquired) → TTP

  • Acquired idiopathic TTP: autoantibodies against ADAMTS13

  • Familial TTP: mutation in ADAMTS13 gene (chromosome 9q34, autosomal recessive)

  • Secondary TTP: endothelial injury (drug/toxin, platelet/neutrophil activation)

  • Upshaw-Schulman syndrome: congenital TTP, presents infancy/childhood, more renal impairment

RISK FACTORS

  • Pregnancy, OCPs, AIDS/HIV, infection/sepsis, acute pancreatitis

  • Autoimmune disease: APS, SLE, scleroderma

  • Cancer, stem cell/organ transplant

  • Drugs of abuse: MDMA, cocaine, oxymorphone ER

  • Drug toxicity: antimicrobials (trimethoprim, ciprofloxacin), chemotherapy (mitomycin C, gemcitabine, pentostatin, vincristine, bleomycin, cisplatin, oxaliplatin, bevacizumab, sunitinib, adalimumab, bortezomib), calcineurin inhibitors, immune-mediated (quinine, quinidine, ticlopidine, clopidogrel)

COMMONLY ASSOCIATED CONDITIONS

  • TTP/HUS/atypical HUS: similar—MAHA, thrombocytopenia, multiorgan involvement

    • TTP: minimal renal, possible neurologic

    • HUS: more renal, less neuro

    • ADAMTS13 <10%: TTP (adults); normal: HUS (children)

DIAGNOSIS

  • Screening: ADAMTS13 activity <10% (draw before plasma exchange); >20% makes TTP less likely

  • Do not delay therapy for results

  • Symptoms (nonspecific):

    • Thrombocytopenia: bruising, purpura, petechiae, epistaxis, menorrhagia, bleeding gums, GI bleeding, ICH, visual changes (retinal hemorrhage)

    • Hemolytic anemia: jaundice, fatigue, end-organ ischemia

    • Neurologic: 60%—headache, AMS, seizures, stroke

    • Cardiac: arrhythmia, MI, heart failure

    • Renal: hematuria, proteinuria, oliguria/anuria

PLASMIC Score (1 point each):

  • Platelet count <30,000/µL

  • Hemolysis (retic >2.5%, low haptoglobin, indirect bili >2)

  • No active cancer

  • No organ/stem cell transplant

  • MCV <90 fL

  • INR <1.5

  • Creatinine <2 mg/dL
    Score 6–7 = predictive of ADAMTS13 <10%

HISTORY

  • Acute (most), subacute (25%)

  • ~50%: identifiable trigger/risk

PHYSICAL EXAM

  • Fever

  • Neuro: confusion, coma, stupor, weakness

  • HEENT: retinal hemorrhage, scleral icterus, epistaxis

  • Abdomen/GI: nonspecific

  • Skin: jaundice, petechiae, purpura, ecchymoses

DIFFERENTIAL DIAGNOSIS

  • HUS/atypical HUS

  • APS (prolonged PTT, lupus anticoagulant)

  • SLE

  • Malignant hypertension

  • Pregnancy-associated preeclampsia/eclampsia, HELLP

  • DIC

  • ITP (no hemolysis, normal LDH/bili, antiplatelet Ab)

  • Malignancy-associated microangiopathy

  • Evan syndrome (Coombs+)

  • Sclerodermal kidney

DIAGNOSTIC TESTS & INTERPRETATION

  • CBC: ↓hemoglobin (avg 8–10), ↓platelets (10–30,000)

  • Reticulocyte count: high (>120×10⁹/L)

  • Haptoglobin: undetectable

  • Peripheral smear: schistocytes (>1%), helmet cells, RBC fragments, nucleated RBCs, polychromasia

  • Coag studies: usually normal (mild elevation in 15%)

  • Coombs test: negative

  • BUN/Cr: mild ↑ (Cr <3)

  • LFTs: ↑indirect bilirubin

  • LDH: 5–10x normal

  • Urinalysis: proteinuria, microscopic hematuria

  • ECG: sinus tach, heart block (10%)

  • Stool for Shiga toxin

  • Troponin: ↑ in 60% (>0.1 µg/L)

  • HIV, hepatitis A/B/C

  • Pregnancy test (women)

  • Head CT/MRI if mental status changes

TREATMENT

# ALERT: Prompt treatment is essential (untreated mortality ~90%)

  • Start treatment for TTP if MAHA + thrombocytopenia and no other cause

  • Plasma exchange (PEX) is the cornerstone (start immediately)

    • PEX with FFP replaces ADAMTS13, removes vWF/autoantibodies

    • Continue PEX until platelets >150k x2 days + LDH/clinical recovery; then taper

    • FFP: temp use if PEX delayed or bleeding

MEDICATION

  • First Line

    • Glucocorticoids: adjunctive, all patients; e.g., prednisone 1 mg/kg/day (taper in remission) or methylprednisolone 1 g/day IV x3d

    • Rituximab: anti-CD20, reduce relapse with PEX/steroids; 375 mg/m² IV weekly x4

  • Second Line (refractory)

    • Caplacizumab: anti-vWF–GP1b, speeds platelet normalization, ↓PEX/hospital stay

    • IVIG

    • Splenectomy (acute phase, severe/refractory)

REFERRAL

  • Hematology/blood bank (PEX)

  • Nephrology (dialysis), cardiology (arrhythmia/ischemia), neurosurgery (hemorrhage)

ADDITIONAL THERAPIES

  • Recombinant ADAMTS13 (investigational)

SURGERY/PROCEDURES

  • Splenectomy: reserved for severe, refractory cases

ADMISSION/INPATIENT CARE

  • ABCs, O₂, IV access, telemetry

  • Volume resuscitation if hypotensive/bleeding

  • PRBC transfusion (safe), platelets only if hemorrhage

  • Discharge: stable neurologic status, LDH, platelets, renal function

ONGOING CARE

  • Monitor blood counts/ADAMTS13 activity for months post-PEX (relapse risk)

  • Patient education: self-monitor for relapse (fever, headache, bruising, fatigue)

NHLBI info: https://www.nhlbi.nih.gov/health/thrombotic-thrombocytopenic-purpura

PROGNOSIS

  • Prompt treatment: 30-day mortality 10% (with PEX)

  • 70% respond in 14 days, 90% in 28 days, 80% survival idiopathic TTP (PEX)

  • Pre-PEX era: 90% mortality

  • Initial LDH/platelets not predictive of response or relapse

  • Low ADAMTS13 during remission = higher relapse risk

  • Autoimmune TTP: ~40% relapse

COMPLICATIONS

  • Cognitive impairments: attention, concentration, memory (after ≥1 episode)

  • PEX complications: central line infection, hemorrhage, citrate toxicity, hypersensitivity, electrolyte issues

REFERENCES

  1. Joly BS, Coppo P, Veyradier A. Thrombotic thrombocytopenic purpura. Blood. 2017;129(21):2836-2846.

  2. Michael M, Elliott EJ, Ridley GF, et al. Interventions for HUS and TTP. Cochrane Database Syst Rev. 2009;2009(1):CD003595.

  3. Zheng XL, Vesely SK, Cataland SR, et al. ISTH guidelines for treatment of TTP. J Thromb Haemost. 2020;18(10):2496-2502.

Codes:

  • ICD10: M31.1 Thrombotic microangiopathy, D69.42 Congenital/hereditary thrombocytopenic purpura, D69.3 Immune thrombocytopenic purpura

Clinical Pearls

  • Diagnosis is clinical: nonspecific symptoms—abdominal pain, fatigue, fever, bruising, purpura, petechiae

  • Pentad rarely present; dyad of MAHA (schistocytes) + severe thrombocytopenia (<30,000) = start treatment

  • Do not wait for ADAMTS13 results to treat

End of note