24  HIT & Other Anti-PF4 Disorders

Key Points
  • HIT: IgG vs PF4-heparin complex → plt activation → thrombosis (50%)
  • 4Ts score (0-8): Thrombocytopenia, Timing, Thrombosis, oTher causes → low (≤3): NPV 97-99%
  • Dx: PF4-ELISA (screen, 100% sensitivity) → SRA (confirm, gold std)
  • Tx: Stop ALL heparin (incl flushes) → non-heparin AC (argatroban/bivalirudin/fondaparinux/DOAC)
  • NO warfarin until plt ≥150K (protein C depletion → skin necrosis)
  • VITT: Post-adenoviral vaccine, ↑↑↑ thrombosis (>90%) → IVIG + anticoagulation
  • MGTS: Paraproteinemia + anti-PF4 Ab → BTK inhibitor or myeloma tx

24.1 Pathophysiology

  • Anti-PF4 antibodies + PF4/heparin complex → Fc receptor binding (plt, monocytes)
    • Cellular activation, microparticle ↑, NETosis by neutrophils
    • Intensely prothrombotic state
  • Incidence: 0.2%-5% UFH exposure; varies by group
    • Postop: 1%-5% UFH vs 0.1%-1% LMWH
    • Cardiac surgery: 1%-3%
    • Cancer: 1%, ICU: 0.4%, OB: <0.1%
  • LMWH risk 5-10× lower than UFH; negligible w/ fondaparinux
  • Prevention: LMWH or alternative AC preferred

24.2 HIT Types

  • Classic HIT: Onset d5-14, plt drop ≥50% (median ~75%)
  • Rapid-Onset: Prior heparin exposure ≤30d → onset within hours
  • Autoimmune (Delayed-Onset): Post-dc thrombosis, autoreactive Ab (recognize PF4 alone), plt improve over weeks-mo
  • Spontaneous: No heparin exposure, endogenous polyanions (LPS, surgery) trigger Ab
  • Non-Immune (Type I): Transient, no Ab, resolves despite heparin
  • VITT & VITT-Like: Post-vaccine/viral, thrombosis at unusual sites, ↑↑↑ D-dimer

24.3 Clinical Presentation

HIT: Clinicopathological syndrome = Ab + clinical (plt drop ≥50% OR new thrombosis)

  • Timing: d5-14 post-heparin (or hours w/ prior exposure)
  • Thrombosis: ~50% at dx, ~40% develop if untreated
    • Venous > arterial (2:1)
    • Unusual sites: cerebral sinuses, splanchnic, visceral
    • Skin necrosis at injection site (beware warfarin)
    • Phlegmasia, adrenal infarction, DIC if severe
  • Plt nadir: 40-80 K (not <150 K required; ≥50% drop is key)
  • Postop: Plt ↑ by d8-10 (rises post-surgery normally)
  • Epidemiology: Rare peds, 2× female, 3× surgical > medical

24.4 Diagnosis

24.4.1 4Ts Scoring System

High negative predictive value; low score (≤3) makes HIT unlikely in 97%-98% of patients, but HIT can still occur in 2%-3% (usually from missing clinical information). Combination of low score + negative PF4-heparin ELISA essentially rules out HIT.

Caption
4Ts 2 Points 1 Point 0 Points
Thrombocytopenia Platelet ↓ >50% & nadir ≥20 × 10^9/L Platelet ↓ 30%-50% OR nadir 10-19 × 10^9/L Platelet ↓ <30% OR nadir <10 × 10^9/L
Timing Clear onset days 5-10 after heparin; or ↓ within 1 day w/ prior exposure ≤30 days Consistent w/ days 5-10 (not clear) or ≥day 10; or ↓ within 1 day w/ prior exposure 30-100 days Onset <4 days w/o recent exposure
Thrombosis/Sequelae New thrombosis (confirmed); skin necrosis at injection site; acute systemic reaction after IV UFH bolus Progressive/recurrent thrombosis; non-necrotizing skin lesions; suspected (not proven) thrombosis None
Other Causes None apparent Possible Definite
  • Limitations: Low PPV, ↓ interobserver agreement, poor in ICU (0.5% HIT, ↑ plt drop)

24.5 Laboratory Testing

  • PF4-ELISA: 100% sensitivity, negative = excludes HIT
    • OD >2.0: activating IgG likely, may skip functional assay
    • OD <1.0: rarely functional assay+
    • IgG-specific > polyspecific (↑ specificity)
  • Automated: HemosIL HIT-Ab or AcuStar HIT-IgG (~90-95% sens, ↑ specificity)
  • Functional (SRA = gold std, HIPA): ↑ specificity, limited availability, not real-time
  • Approach: Clinical suspicion + correlative testing; monitor plt ≥q2d if risk >1%
  • Caution: Overdiagnosis → ↑ bleeding from unnecessary AC

24.6 Treatment

Immediate Actions 1. Stop ALL heparin (incl flushes) when suspected 2. Labs: HIT Ab, D-dimer, aPTT, fibrinogen, INR 3. Start non-heparin AC (therapeutic dose) immediately 4. 4-limb doppler (↑ silent DVT) 5. Avoid: PLT transfusion, IV lines, LMWH, warfarin pre-plt recovery

Duration: No thrombosis = 4-6 wk; w/ thrombosis = ≥3 mo

Anticoagulation Options - Argatroban: Hepatic clearance, ↑ aPTT/PT, use dTT if confounded - Bivalirudin: t½ 25 min, short-acting, aPTT confounding in severe illness - Fondaparinux: t½ 20 hr (caution acute hospital), no RCTs - DOACs: FXa or dabigatran, fixed dose, but peak-trough variation (use post-acute phase) - Warfarin: Contraindicated acutely (protein C depletion → skin necrosis, phlegmasia) - Start only after plt ≥150 K & hypercoagulability controlled, w/ parenteral overlap - If on warfarin at dx: D/C, give 10 mg IV vit K, start alternative AC

Autoimmune HIT: IVIG 1 g/kg × 2d → rapid plt ↑ (blocks Fc receptor)

Heparin Re-exposure: Ab vanish 3 mo → safe if functional assay neg (intraop only)

Clinical Pearls
  • No LMWH in established HIT (cross-reactivity)
  • Warfarin + acute HIT = skin necrosis/phlegmasia → wait for plt recovery
  • 4Ts low (≤3) + ELISA neg = rules out HIT (NPV 97-99%), but 2-3% still have HIT

24.7 Acute & Chronic VITT

Overview - VITT: Post-adenoviral vaccine (AZ, J&J) or viral (adenovirus, CMV, RSV) - Non-heparin-dependent anti-PF4 IgG (vs HIT) - Incidence: Rare (1:25K-200K); younger risk, vaccines still used outside US

Clinical: Onset d5-20, thrombosis >90%, unusual sites (cerebral/splanchnic), plt 20-80K, ↑↑ D-dimer

Dx: Microtiter PF4-ELISA only (rapid assays unreliable)

Tx 1. Non-heparin AC (therapeutic) 2. IVIG 1 g/kg × 2d (blocks Fc receptor) 3. TPE if refractory 4. Rule out CVST & splanchnic thrombosis (unusual headache = treat as CVST) 5. Avoid PLT transfusion, IV lines, warfarin pre-recovery

VITT-Like Disorders - Viral infections or paraproteinemia → anti-PF4 Ab - MGTS (monoclonal gammopathy of thrombotic significance): Recurrent thrombosis + paraproteinemia - Tx: AC + BTK inhibitor (ibrutinib) or myeloma tx (eliminate clone)