Antibody-mediated platelet activation by heparin-PF4 complexes causing paradoxical thrombosis with thrombocytopenia.
Also known as: HIT, HIT II, heparin-induced thrombocytopenia and thrombosis, HITT
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Risk factors
- Unfractionated heparin > LMWH > fondaparinux (very rare)
- Cardiac surgery, orthopedic surgery (especially total knee/hip)
- Therapeutic-dose > prophylactic-dose heparin
- Female sex
- Duration of heparin exposure >4 days
Pathophysiology
Heparin binds platelet factor 4 forming a neoantigen. IgG antibodies bind heparin-PF4 complexes; the immune complexes crosslink FcγRIIa receptors on platelets, causing platelet activation, granule release, and microparticle generation. Activated platelets are consumed (thrombocytopenia) while procoagulant microparticles and tissue-factor expression on monocytes/endothelium drive thrombin generation and thrombosis (venous more often than arterial, but both occur).
Clinical presentation
Symptoms
- Often asymptomatic platelet drop noticed on routine CBC 5-10 days after starting heparin
- Rapid-onset HIT (within hours) in patients with heparin exposure within prior 100 days
- New thrombosis: DVT, PE, limb ischemia, stroke, MI, adrenal vein thrombosis (bilateral adrenal hemorrhage)
- Skin necrosis or erythematous plaques at heparin injection sites
- Acute systemic reaction (fever, chills, dyspnea, hypotension) within 30 min of IV heparin bolus
Signs / physical exam
- Platelet count drop ≥50% from baseline, typically nadir 30-80 × 10⁹/L (severe thrombocytopenia uncommon)
- Signs of new venous or arterial thrombosis
- Skin necrosis or hemorrhagic infarcts at injection sites
- Bilateral adrenal hemorrhage → hypotension, abdominal/flank pain
Classic findings
Platelet count fall 5-10 days after starting heparin with new thrombosis — the 'paradoxical' picture of thrombocytopenia with clotting rather than bleeding.
Differential diagnosis
- Non-immune (type I) heparin effect — Mild thrombocytopenia within 1-2 days; nadir >100k; resolves despite continued heparin; no antibodies
- Sepsis/DIC — Consumptive coagulopathy with elevated D-dimer, low fibrinogen, prolonged PT/PTT; clinical context
- Drug-induced thrombocytopenia (non-heparin) — Quinine, vancomycin, beta-lactams, GP IIb/IIIa inhibitors; temporal relationship to culprit drug
- Post-transfusion purpura — Severe thrombocytopenia 5-10 days after transfusion; anti-HPA-1a antibodies
- Immune thrombocytopenia (ITP) — Isolated thrombocytopenia without heparin exposure or thrombosis
- Thrombotic microangiopathy (TTP, HUS, aHUS) — Schistocytes, hemolysis, renal/neuro involvement
Diagnostic workup
Diagnostic criteria
4Ts score 0-3 (low) → HIT unlikely; 4-5 (intermediate) and 6-8 (high) → stop heparin, start non-heparin anticoagulant, send PF4 ELISA and confirmatory functional assay. Diagnosis = clinical probability + positive functional assay.
Labs
- Calculate 4Ts score: Thrombocytopenia, Timing, Thrombosis, oTher causes (each 0-2 points)
- Anti-PF4/heparin ELISA (immunoassay) — high sensitivity, lower specificity; optical density correlates with clinical probability
- Functional assay — serotonin release assay (SRA) or heparin-induced platelet activation (HIPA) — gold standard confirmatory test
- CBC with platelet trend, coagulation studies, fibrinogen, D-dimer
- Doppler US lower extremities to screen for clinically silent DVT once HIT suspected
Imaging
- Lower extremity venous duplex Doppler in all patients diagnosed with HIT
- CT/CTA or other vascular imaging guided by clinical signs of thrombosis
- CT abdomen if adrenal hemorrhage suspected
Treatment
First-line
- STOP all heparin immediately (including flushes, LMWH, heparin-coated catheters)
- Start non-heparin anticoagulant at therapeutic dose — argatroban (direct thrombin inhibitor, hepatic clearance) or bivalirudin (DTI, predominantly enzymatic/proteolytic clearance with minor renal component) for inpatients; fondaparinux acceptable for non-acute scenarios
- Avoid warfarin until platelets recover (>150 × 10⁹/L) — early warfarin causes warfarin-induced skin necrosis and venous limb gangrene from protein C depletion
- Do NOT give prophylactic platelet transfusions (may exacerbate thrombosis); reserve for active bleeding
Isolated HIT (no thrombosis)
- Therapeutic non-heparin anticoagulation for minimum 4 weeks
- Screen for occult DVT with bilateral lower-extremity duplex
HIT with thrombosis (HITT)
- Therapeutic anticoagulation for at least 3 months
- Transition to warfarin or DOAC (rivaroxaban, apixaban) once platelets >150 × 10⁹/L with bridging from parenteral agent
Need for urgent cardiac surgery / catheterization in HIT patient
- Bivalirudin for cardiopulmonary bypass or PCI
- Delay surgery if possible until anti-PF4 antibodies have cleared (months)
Second-line / adjunct
- DOACs (rivaroxaban, apixaban, dabigatran) — increasingly used after initial parenteral phase or even as initial therapy in stable patients
- IVIG and therapeutic plasma exchange for severe refractory HIT or 'spontaneous' HIT variants
Complications
- Venous thromboembolism (most common) — DVT, PE
- Arterial thrombosis — limb ischemia/gangrene, stroke, MI
- Bilateral adrenal hemorrhage and adrenal insufficiency
- Cerebral venous sinus thrombosis
- Venous limb gangrene from early warfarin use
- Heparin-induced skin necrosis at injection sites
- Mortality 5-10%; amputation risk 5-10%
PANCE pearls
- The classic timing is days 5-10 after first heparin exposure; rapid-onset HIT (<24 h) occurs with re-exposure within ~100 days.
- A 4Ts score of 0-3 has high negative predictive value — further testing usually unnecessary.
- Never use warfarin alone in acute HIT — overlap with non-heparin parenteral anticoagulation until platelets recover.
- LMWH cross-reacts with HIT antibodies — switching from UFH to enoxaparin is NOT a valid strategy.
- Argatroban prolongs the INR — use chromogenic factor X or higher INR target (3-4) when bridging to warfarin.
- Spontaneous (autoimmune) HIT can occur without recent heparin, often after orthopedic surgery, viral infection, or COVID-19 vaccination.
References
- ASH 2018 Guidelines — Cuker A et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv 2018; 2:3360-3392.
- ISTH SSC — Greinacher A. CLINICAL PRACTICE. Heparin-induced thrombocytopenia. N Engl J Med 2015; 373:252-261.
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