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Heparin-Induced Thrombocytopenia (HIT)

Note on sources: Davidson's Principles and Practice of Medicine is not available in this library's collection. The answer below draws primarily from Harrison's Principles of Internal Medicine, 22nd Edition (2025), supplemented by Goldman-Cecil Medicine and The Washington Manual of Medical Therapeutics - all authoritative standard internal medicine references.

Definition

• Harrison's 22e, Ch. 123: "HIT is an antibody-mediated process triggered by antibodies directed against neoantigens on PF4 that are exposed when heparin binds to this protein."

Epidemiology

• More common in surgical patients than medical patients
• More common in women than men (like many autoimmune conditions)
• Goldman-Cecil: "It is seen in 2 to 5% of patients exposed to unfractionated heparin and in 0.7% of patients given LMWH."

Pathophysiology

1. Heparin binds PF4 (platelet factor 4, secreted by platelets), forming a heparin-PF4 complex and exposing neoantigens on PF4.
2. IgG antibodies form against these neoantigens. These antibodies simultaneously bind to the heparin-PF4 complex AND to platelet Fc receptors (FcγRIIA).
3. Platelet activation cascade: Fc receptor binding activates platelets → release of more PF4 → generation of platelet microparticles → microparticles expose anionic phospholipids → binding of clotting factors → massive thrombin generation → thrombosis + thrombocytopenia.

• Harrison's 22e: "Circulating microparticles are procoagulant because they express anionic phospholipids on their surface and can bind clotting factors and promote thrombin generation."
• Goldman-Cecil: "Large complexes of antibodies directed against heparin-bound PF4 accumulate on the surface of platelets... leading to activation of the coagulation cascade, likely through exposure of tissue factor on the surface of activated macrophages."

Clinical Features (Harrison's Table 123-3)

Key Clinical Points:

• HIT rarely causes severe thrombocytopenia (platelet <20 × 10⁹/L) and rarely causes bleeding
• Thrombotic complications occur in 30-75% of HIT patients
• Patients without thrombosis at diagnosis still have a 20-30% chance of developing thrombosis within the next month (Goldman-Cecil)
• Venous thrombosis: DVT, PE, skin necrosis at injection sites
• Arterial thrombosis: ischemic stroke, acute MI, limb ischemia (aortic/iliac thrombi)
• Skin necrosis at heparin injection sites (even in the absence of thrombocytopenia)
• Systemic reactions after IV heparin bolus: fever, hypotension, dyspnea, cardiac arrest

Diagnosis

Step 1: 4T Scoring System (Clinical Pre-test Probability)

Step 2: Laboratory Testing

• Low 4T score → No testing needed
• Intermediate/High 4T score → PF4 ELISA first; if positive → confirmatory SRA/HIPA
• A negative ELISA effectively rules out HIT
• Do NOT defer urgent clinical decisions pending lab results
• Harrison's 22e: "The most specific diagnostic test for HIT is the serotonin release assay... Enzyme-linked assays are sensitive but can be positive in the absence of any clinical evidence of HIT."

Management

Immediate Steps (Harrison's Table 123-4):

1. Stop ALL heparins immediately - including subcutaneous "minidose" heparin, LMWH, and heparin-coated IV catheters
2. Start an alternative anticoagulant (mandatory - stopping heparin alone is insufficient)
3. Do NOT give platelet transfusions (may fuel thrombosis)
4. Do NOT give warfarin acutely (risk of venous limb gangrene due to protein C depletion)
5. Screen for thrombosis - especially DVT (compression ultrasound)

Alternative Anticoagulants:

• Goldman-Cecil: "Low-molecular-weight heparins should never be used in the treatment of HIT because this drug can cross-react with the pathologic HIT antibodies."

Transitioning to Warfarin (if needed):

• Only initiate warfarin AFTER platelet count normalizes to >150 × 10⁹/L
• Start at no more than 5 mg/day
• Overlap with a DTI for at least 5 days (to prevent protein C-depletion-mediated skin necrosis / venous limb gangrene)
• Alternatively, switch directly to a DOAC

Duration of Anticoagulation (Washington Manual):

• Isolated HIT (no thrombosis): 4-6 weeks
• HIT with thrombosis: 3 months

Special Scenario: Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT)

• Occurs 4-28 days post-vaccination
• Presents with cerebral/splanchnic vein thrombosis, DVT, or PE
• Diagnosis: antibodies against PF4 + positive SRA with added PF4
• Treatment: IV immunoglobulin, steroids, plasma exchange + argatroban/fondaparinux/rivaroxaban

Summary Mnemonic: HIT "4 Nots"

1. Not a bleeding disorder - it's thrombotic
2. Not treated with platelet transfusions
3. Not treated with warfarin acutely
4. Not treated by stopping heparin alone - must add alternative anticoagulation

• Harrison's Principles of Internal Medicine, 22e (2025) - Chapter 123 (Anticoagulant, Fibrinolytic, and Antiplatelet Therapy)
• Goldman-Cecil Medicine - Chapter 158 (Thrombocytopenia)
• The Washington Manual of Medical Therapeutics - Chapter 20 (HIT)

Heparin-Induced Thrombocytopenia (HIT)

Causes / Risk Factors

• Unfractionated heparin (UFH) - highest risk (2-5%)
• Low-molecular-weight heparin (LMWH) - lower risk (~0.7%)
• Fondaparinux - extremely rare / almost never
• Higher risk in: surgical patients (esp. cardiothoracic), women, cancer patients
• Any route of heparin exposure counts - including IV flushes and heparin-coated catheters

Pathophysiology

Heparin + PF4 (platelet factor 4)
        ↓
Heparin-PF4 complex exposes neoantigens
        ↓
IgG antibodies form against heparin-PF4
        ↓
IgG binds heparin-PF4 complex AND platelet FcγRIIA receptors
        ↓
Platelet activation → releases more PF4 (positive feedback loop)
        ↓
Platelet microparticles generated
        ↓
Microparticles expose anionic phospholipids → bind clotting factors
        ↓
Massive thrombin generation → THROMBOSIS + THROMBOCYTOPENIA

Investigations

Step 1 - Clinical Scoring: 4T Score

• 0-3 = Low → HIT unlikely, no testing needed
• 4-5 = Intermediate → send labs
• 6-8 = High → treat empirically, send labs

Step 2 - Lab Tests

• ELISA first → if positive → confirm with SRA
• Do NOT wait for results before acting in high clinical probability

Management

Immediate (all suspected/confirmed HIT):

Alternative Anticoagulants:

Never use LMWH in HIT treatment - it cross-reacts with HIT antibodies.

Transitioning to Warfarin (if needed):

• Only after platelets normalize to >150 × 10⁹/L
• Overlap DTI + warfarin for ≥5 days before stopping DTI
• Starting dose ≤5 mg/day

Duration:

• HIT without thrombosis → anticoagulate for 4-6 weeks
• HIT with thrombosis → anticoagulate for 3 months

Quick Memory Aid

"HIT = High clots, Low platelets, No heparin, No warfarin, No platelets"