What is Heparin-induced thrombocytopenia (HIT)?

Heparin-Induced Thrombocytopenia (HIT)

Heparin-induced thrombocytopenia (HIT) is a serious antibody-mediated adverse drug reaction to heparin that can lead to devastating thromboembolic complications and is characterized by the development of antibodies against platelet factor 4-heparin complexes, resulting in platelet activation, thrombocytopenia, and potentially life-threatening thrombosis. 1

Pathophysiology

HIT is caused by IgG antibodies that recognize multimolecular complexes of platelet factor 4 (PF4) and heparin that form on platelet surfaces. These key mechanisms occur:

• Antibodies bind to PF4/heparin complexes on platelet surfaces
• This binding activates platelets via FcIIa (IgG) receptors
• Activated platelets release procoagulant microparticles
• Massive thrombin generation occurs
• Multi-cellular activation involves platelets, endothelial cells, neutrophils, and monocytes
• Monocytes express tissue factor, contributing to hypercoagulability 2

Types and Classification

Two distinct types of thrombocytopenia can occur with heparin therapy:

1. Type I (Non-immune HIT):

   • Benign, early-onset thrombocytopenia
   • Non-immune mediated
   • No thrombotic complications
   • Platelet count recovers despite continued heparin therapy

2. Type II (Immune HIT):

   • Delayed-onset thrombocytopenia (typically 5-10 days after heparin initiation)
   • Immune-mediated
   • Associated with thrombosis
   • Potentially life-threatening 2

Additionally, several HIT subtypes have been identified:

• Typical-onset HIT: Platelet count fall 5-10 days after heparin initiation
• Rapid-onset HIT: Abrupt platelet count fall within 24 hours in patients with recent heparin exposure
• Delayed-onset HIT: Thrombocytopenia occurring up to 3 weeks after heparin cessation
• Spontaneous autoimmune HIT: Clinical features of HIT without heparin exposure
• Persistent autoimmune HIT: Failure to recover platelets within 1 week of heparin discontinuation
• Treatment-refractory HIT: Progression despite heparin discontinuation and alternative anticoagulation 2

Risk Factors

The risk of developing HIT varies based on:

1. Type of heparin:

   • Unfractionated heparin (UFH): Higher risk (10x greater than LMWH)
   • Low molecular weight heparin (LMWH): Lower risk
   • Fondaparinux: Minimal risk

2. Patient population:

   • Surgical patients (especially cardiac or orthopedic): 1-5%
   • Medical or obstetric patients: 0.1-1%
   • Women have approximately twice the risk of men 2

3. Duration of exposure:

   • Risk decreases with heparin treatments lasting beyond one month 2

Clinical Presentation

The hallmark clinical features include:

• Thrombocytopenia: Occurs in 85-90% of patients

  • Defined as platelet count <150 × 10⁹/L or
  • 30-50% fall in platelet count even if nadir remains >150 × 10⁹/L

• Thrombosis: Venous and/or arterial thrombosis occurs in 50-60% of HIT patients

  • Deep vein thrombosis
  • Pulmonary embolism
  • Cerebral vein thrombosis
  • Limb ischemia
  • Stroke
  • Myocardial infarction
  • Mesenteric thrombosis
  • Renal arterial thrombosis
  • Skin necrosis
  • Gangrene of extremities 3, 4

• Timing: Typically 5-10 days after heparin initiation, but can occur earlier with recent heparin exposure or later as delayed-onset HIT 2

Diagnosis

Diagnosis requires both clinical assessment and laboratory confirmation:

1. Clinical Probability Assessment: The 4Ts score evaluates:

   • Thrombocytopenia severity
   • Timing of platelet count fall
   • Thrombosis or other sequelae
   • Other causes of thrombocytopenia 5

2. Laboratory Testing:

   • Immunoassays: Detect anti-PF4/heparin antibodies

     • High sensitivity but modest specificity
     • Negative result can exclude HIT

   • Functional Assays: Detect platelet-activating antibodies

     • Serotonin release assay (SRA)
     • Heparin-induced platelet activation assay (HIPA)
     • Heparin-induced multi-electrode aggregometry (HIMEA)
     • More specific for confirming HIT diagnosis 2

Management

Immediate actions upon suspecting HIT:

1. Discontinue all heparin products including heparin flushes 1

2. Initiate alternative non-heparin anticoagulation:

   • For normal renal function: argatroban, lepirudin, or danaparoid
   • For renal insufficiency: argatroban is preferred
   • For urgent cardiac surgery: bivalirudin
   • Direct oral anticoagulants (DOACs): Growing evidence supports rivaroxaban and apixaban use even before platelet recovery 2, 1

3. Avoid platelet transfusions unless life-threatening bleeding occurs 1

4. Avoid warfarin in acute HIT until platelet count recovers to >150 × 10⁹/L to prevent venous limb gangrene 1

5. Consider IVIg in special situations:

   • Spontaneous HIT (85.4% expert agreement)
   • Persistent HIT (83.7% expert agreement)
   • Treatment-refractory HIT (87.4% expert agreement)
   • Cases needing immediate correction of thrombocytopenia (78.4% expert agreement) 2

Monitoring

Platelet count monitoring based on risk level:

• Low risk (<0.1%): No monitoring needed
• Intermediate risk (0.1-1.0%): Monitor every 2-3 days from day 4-14
• High risk (>1.0%): Monitor at least every other day from day 4-14 1

Common Pitfalls and Caveats

1. Overdiagnosis: The modest specificity of immunoassays leads to false positives, unnecessary treatments, increased costs, and bleeding risk 2, 6

2. Delayed diagnosis: Failure to recognize HIT can lead to catastrophic thrombotic complications

3. Warfarin monotherapy: Using warfarin alone in HIT can activate coagulation and hasten venous limb gangrene 4

4. Inadequate transition to warfarin: When transitioning to warfarin, overlap with non-heparin anticoagulant for minimum 5 days and until INR is therapeutic 1

5. Failure to recognize HIT subtypes: Autoimmune HIT variants may require specialized management approaches including IVIg 2

6. Reexposure to heparin: Patients with history of HIT should avoid future heparin exposure when possible

By maintaining a high index of clinical suspicion, promptly discontinuing heparin, and initiating appropriate alternative anticoagulation, the morbidity and mortality associated with this potentially devastating condition can be significantly reduced.