Heparin-Induced Thrombocytopenia (HIT)

A 62-year-old man is hospitalized for treatment of a pulmonary embolism and is started on intravenous unfractionated heparin. On hospital day 6, he develops new-onset pain and swelling of the left leg. He is afebrile and hemodynamically stable. Laboratory studies show a decrease in platelet count from 240,000/µL on admission to 100,000/µL. Hemoglobin and leukocyte counts are within normal limits. Doppler ultrasound of the left lower extremity shows a new deep vein thrombosis. There is no evidence of bleeding. He was hospitalized 2 months ago and received heparin at that time. Diagnosis?

Diagnosis is Heparin-Induced Thrombocytopenia (HIT).

1. Definition

HIT is an immune-mediated adverse drug reaction in which IgG antibodies form against PF4–heparin complexes, leading to platelet activation, thrombocytopenia, and a hypercoagulable state.

2. Types

1. Type I (HAT)
• Non-immune
• Occurs within 1–4 days
• Mild thrombocytopenia
• No thrombosis
• Platelets normalize even if heparin is continued
2. Type II (True HIT)
• Immune-mediated (IgG)
• Occurs 5–10 days (range 5–14 days) after exposure
• Can occur within hours if prior exposure (<100 days)
• Causes thrombosis
• Clinically significant

3. Pathophysiology

1. PF4 released from platelets binds heparin
2. IgG antibodies form against PF4–heparin complex
3. Immune complexes bind Fcγ receptors on platelets
4. Platelet activation and aggregation occur
5. Thrombin generation → hypercoagulable state
6. Platelet consumption + macrophage clearance → thrombocytopenia

4. Clinical Features

4.1 Core Features

1. Platelet fall >50% from baseline
2. Occurs 5–10 days (range 5–14 days) after heparin exposure
3. Thrombosis (venous > arterial)

4.2 Associated Features

1. DVT, PE (most common)
2. Arterial thrombosis (stroke, MI, limb ischemia)
3. Skin necrosis (especially if warfarin given early)
4. Acute systemic reaction after IV heparin
5. Platelet count typically 20,000–100,000/µL (rarely <10,000/µL)
6. Hemoglobin usually stable

5. Diagnosis

5.1 Clinical Assessment

1. 4T Score (first step)
• Thrombocytopenia
• Timing
• Thrombosis
• oTher causes

Interpretation:

• 0–3 → HIT unlikely
• 4–5 → intermediate probability
• 6–8 → high probability

➡ Score ≥4 → stop heparin and initiate treatment immediately

5.2 Laboratory Testing

1. PF4–heparin ELISA
• High sensitivity, high negative predictive value
• Detects IgG/IgA/IgM → false positives possible
• Negative test → HIT very unlikely
2. Serotonin Release Assay (SRA)
• Gold standard functional test
• Confirms diagnosis

6. Management

6.1 Immediate Management (Critical)

1. Stop ALL heparin immediately
• IV, SQ, flushes, coated catheters, dialysate
2. Do NOT wait for lab confirmation

6.2 Anticoagulation

1. Start non-heparin anticoagulation (therapeutic dosing in most patients):
• Argatroban (preferred in critically ill; hepatic clearance)
• Bivalirudin (PCI/cardiac surgery)
• Fondaparinux (does not cause HIT and does not cross-react with HIT antibodies; avoid if CrCl <30 mL/min)
• DOACs (guideline-supported, especially in clinically stable patients)
2. Consider prophylactic dosing only if high bleeding risk

6.3 Warfarin

1. Contraindicated in acute HIT
2. If already started → stop and reverse with vitamin K
3. Start only when:
• Platelets ≥150k or baseline
• Patient therapeutically anticoagulated
• Overlap ≥5 days

7. Duration of Treatment

1. HIT with thrombosis (HITT): ~3 months
2. Isolated HIT: ~1 month
• Continue at least until platelet recovery
• Do not exceed 3 months unless ongoing HIT

8. Complications

1. Venous thrombosis (DVT, PE)
2. Arterial thrombosis
3. Limb ischemia
4. Skin necrosis
5. Mortality up to ~30% if untreated

9. Key Clinical Insight

Patient on heparin with >50% platelet drop at day 5–10 ± thrombosis should be treated as HIT immediately, stop heparin and start alternative anticoagulation without waiting for labs

10. Exam-Level Pearls

1. HIT = thrombosis + thrombocytopenia
2. Platelet drop >50% is more important than absolute count
3. Platelets rarely <20k
4. Stop heparin first, confirm later
5. Early warfarin → skin necrosis / limb gangrene
6. Negative ELISA → HIT very unlikely
7. Prothrombotic risk persists ~30 days after stopping heparin