Heparin-Induced Thrombocytopenia (HIT)

 Definition

Heparin-Induced Thrombocytopenia (HIT) is an immune-mediated adverse drug reaction to heparin characterized by:

  • Thrombocytopenia (drop in platelet count by >50% from baseline)
  • Prothrombotic state, paradoxically leading to thrombosis (venous or arterial)

There are two types:

Key Points for Exams

Feature

Type I HIT

Type II HIT

Mechanism

Non-immune, direct platelet aggregation effect of heparin

Immune-mediated, IgG antibodies against PF4-heparin complex

Onset

<2 days

5–10 days (earlier if prior exposure)

Platelet fall

Mild

>50%

Thrombosis risk

None

High

Management

Continue heparin

Stop heparin, start alternative anticoagulant

 

Pathophysiology

Key Mechanism:

  1. Heparin binds to Platelet Factor 4 (PF4) → forms Heparin–PF4 complex.
  2. This complex is immunogenic, leading to formation of IgG antibodies.
  3. The IgG–PF4–Heparin immune complex binds to FcγIIa receptors on platelets.
  4. → Platelet activation, microparticle release, and thrombin generation.
  5. Result: Widespread thrombosis despite low platelets (a prothrombotic thrombocytopenia).

Additional effects:

  • Activated monocytes and endothelial cells release tissue factor, enhancing coagulation.
  • Platelet consumption → thrombocytopenia.


# Timing of Onset

Situation

Typical Onset

First exposure to heparin

5–10 days after start

Previous heparin exposure (<100 days ago)

Rapid onset (within 24 hours)

Delayed onset (after stopping heparin)

Up to 2 weeks post-discontinuation


#Clinical Features

1. Thrombocytopenia

  • Usually platelet count falls >50% from baseline.
  • Nadir: 20,000–100,000 /µL (rarely <20,000).

2. Thrombosis (in ~50% of HIT)

  • Venous (commoner): DVT, PE, adrenal vein thrombosis.
  • Arterial: limb ischemia, stroke, MI.
  • Microvascular thrombosis → skin necrosis, organ ischemia.

3. Other manifestations

  • Skin necrosis at heparin injection site.
  • Acute systemic reaction: fever, chills, dyspnea, chest pain after heparin bolus.
  • Adrenal hemorrhagic necrosis (bilateral) → acute adrenal insufficiency.


# Diagnosis

Step 1: Clinical Probability — 4Ts Score

Parameter

2 Points

1 Point

0 Points

Thrombocytopenia

>50% fall & nadir ≥20,000

30–50% fall or nadir 10–19k

<30% fall or nadir <10k

Timing

5–10 days, or ≤1 day if prior exposure

Consistent with days 10+ or unclear

<4 days without prior exposure

Thrombosis or other sequelae

Proven thrombosis, skin necrosis

Suspected thrombosis

None

Other causes for thrombocytopenia

None apparent

Possible

Definite

Interpretation:

  • 6–8 points: High probability
  • 4–5: Intermediate
  • 0–3: Low probability (HIT unlikely)

# If 4Ts ≤3, do not test for HIT antibodies.
# If ≥4, proceed to confirmatory tests.


Step 2: Laboratory Tests

1. Immunoassays

  • Detect anti–PF4–heparin antibodies (IgG, IgA, IgM) by ELISA.
  • High sensitivity (≈99%), but low specificity.
  • OD value >1.0 increases likelihood.

2. Functional Assays (Confirmatory)

  • Detect platelet activation in presence of heparin.

Test

Principle

Comments

Serotonin Release Assay (SRA)

Measures serotonin release from donor platelets

Gold standard

Heparin-Induced Platelet Activation (HIPA)

Measures platelet aggregation

Less available


# Management

1. Immediate Steps

  • STOP all heparin immediately (including flushes, LMWH, heparin-coated catheters).
  • Avoid platelet transfusions unless life-threatening bleeding.

2. Start Non-Heparin Anticoagulant

Continue even if thrombosis not yet confirmed.

Drug

Class

Comments

Argatroban

Direct thrombin inhibitor

Preferred in renal impairment

Bivalirudin

Direct thrombin inhibitor

Common in cardiac surgery

Fondaparinux

Factor Xa inhibitor

Off-label but effective

DOACs (e.g., rivaroxaban, apixaban)

Factor Xa inhibitors

For stable, subacute HIT

Warfarin is contraindicated initially!

  • Because early use can cause microvascular thrombosis & skin necrosis due to protein C depletion.
  • Start warfarin only after platelet count >150,000/µL.


3. Duration of Therapy

Situation

Duration

HIT with thrombosis (HITT)

At least 3 months

HIT without thrombosis

4–6 weeks (to prevent delayed thrombosis)




# Differential Diagnosis

Condition

Key Feature

DIC

Prolonged PT/aPTT, low fibrinogen

Sepsis-associated thrombocytopenia

Clinical infection, no PF4 antibodies

Drug-induced thrombocytopenia

No thrombosis, normal coagulation

Pseudothrombocytopenia

Platelet clumping artifact in EDTA


# References

  1. Harrison’s Principles of Internal Medicine, 21st Edition.
  2. Warkentin TE, Greinacher A. Heparin-Induced Thrombocytopenia, N Engl J Med 2015;373:252–261.
  3. ASH 2018 Guidelines for Management of HIT.
  4. UpToDate: Clinical features and diagnosis of heparin-induced thrombocytopenia.