What causes Heparin-Induced Thrombocytopenia (HIT)?

Causes of Heparin-Induced Thrombocytopenia (HIT)

Heparin-induced thrombocytopenia is caused by an immune-mediated mechanism where IgG antibodies recognize complexes of heparin and platelet factor 4 (PF4), leading to intense platelet activation, thrombin generation, and paradoxical thrombosis despite thrombocytopenia. 1

Primary Pathophysiological Mechanism

• HIT occurs when heparin binds to platelet factor 4 (PF4), forming multimolecular complexes that undergo conformational changes, creating immunogenic epitopes 2, 1
• These PF4-heparin complexes form on the surface of platelets, triggering the formation of IgG antibodies against them 2
• The immune complexes (IgG antibodies bound to PF4-heparin) bind to the FcγIIa (IgG) receptors on platelets, resulting in massive platelet activation 1
• Activated platelets release procoagulant, platelet-derived microparticles, leading to marked thrombin generation and paradoxical thrombosis 2, 1

Molecular Requirements

• A minimum of 12-14 saccharides (molecular weight >4000 Da) are required to form the antigenic PF4/heparin complex 1
• This explains why unfractionated heparin (UFH) with larger molecules carries a 10-fold higher risk of causing HIT than low molecular weight heparin (LMWH) with smaller molecules 2, 1

Cellular Activation Cascade

• The binding of immune complexes to platelets triggers a cascade of events: 1
  1. Massive platelet activation and aggregation
  2. Release of procoagulant microparticles
  3. Amplification of the coagulation cascade
  4. Thrombin generation
  5. Formation of venous and arterial thromboses

Thrombocytopenia Mechanism

• The thrombocytopenia in HIT results from two main processes: 1
  • Massive activation and consumption of platelets in developing thrombi
  • Clearance of antibody-coated platelets by the mononuclear phagocyte system

Risk Factors

• Type of heparin: Unfractionated heparin (UFH) carries a 10-fold higher risk than low molecular weight heparin (LMWH) 2
• Patient population: Patients who undergo cardiac or orthopedic surgery have a higher risk (1-5%) than medical or obstetric patients (0.1-1%) 2
• Gender: Women have approximately twice the risk of developing HIT compared to men 2, 1
• Duration of heparin exposure: Longer exposure increases risk 2

Clinical Presentation Timeline

• Typical-onset HIT: Platelet count fall occurs 5-10 days after initiation of heparin, particularly when administered perioperatively 2
• Rapid-onset HIT: Abrupt platelet count fall within 24 hours in patients with recent heparin exposure (usually within the past month) due to pre-existing circulating HIT antibodies 2
• Delayed-onset HIT: Thrombocytopenia occurring up to 3 weeks after cessation of heparin 2

Thrombotic Complications

• Venous thrombosis (including DVT and PE) occurs in 17-55% of untreated patients with HIT 2, 1
• Arterial thrombosis (limb ischemia, stroke, myocardial infarction) occurs in 3-10% of cases 2, 1
• Less common manifestations include venous limb gangrene, necrotizing skin lesions at heparin injection sites, adrenal hemorrhagic necrosis, and acute systemic reactions 2

Important Distinctions

• Type 2 HIT (immune-mediated) must be distinguished from Type 1 HIT, which is a benign, non-immune mediated thrombocytopenia that occurs early and resolves despite continued heparin therapy 1
• HIT antibodies are typically transient, disappearing within weeks to months after heparin exposure 1
• Despite the name "thrombocytopenia," platelet counts often remain above 50,000/mm³, with a typical decrease of ≥50% from baseline 1

Clinical Relevance

• HIT is diagnosed in approximately 0.4% of all patients exposed to heparin at tertiary care hospitals 3
• The risk is significantly lower in those treated with LMWH only compared to those who receive unfractionated heparin 3
• Higher antibody titers are associated with increased risk of thrombosis 3