What is the pathophysiology of Type 2 Heparin-Induced Thrombocytopenia (HIT)?

Pathophysiology of Type 2 Heparin-Induced Thrombocytopenia (HIT)

Type 2 HIT occurs through 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

Immunological Mechanism

• HIT is triggered when heparin binds to platelet factor 4 (PF4), forming multimolecular complexes that undergo conformational changes, creating immunogenic epitopes 1
• IgG antibodies develop against these PF4/heparin complexes, typically 5-10 days after heparin exposure (or earlier with recent prior exposure) 1
• These immune complexes (PF4/heparin/IgG) bind to FcγIIA receptors on platelet surfaces, causing platelet activation 1

Cellular Activation Cascade

• The binding of immune complexes to platelets triggers massive platelet activation and aggregation 1
• Activated platelets release procoagulant microparticles, further amplifying the coagulation cascade 1
• Beyond platelets, HIT involves multi-cellular activation including:
  • Endothelial cells becoming activated and prothrombotic 1
  • Neutrophils contributing to the inflammatory response 1
  • Monocytes expressing tissue factor, a potent initiator of coagulation 1

Thrombocytopenia Mechanism

• Thrombocytopenia in HIT results from two main processes:
  • Massive activation and consumption of platelets in developing thrombi 1
  • Clearance of antibody-coated platelets by the mononuclear phagocyte system 1
• Despite the name "thrombocytopenia," platelet counts often remain above 50,000/mm³, with a typical decrease of ≥50% from baseline 1, 2

Thrombotic Complications

• The hallmark of Type 2 HIT is the paradoxical development of thrombosis despite low platelet counts 1
• Venous thrombosis (including DVT and PE) occurs in 17-55% of untreated patients with HIT 1
• Arterial thrombosis (limb ischemia, stroke, myocardial infarction) occurs in 3-10% of cases 1
• The hypercoagulable state results from explosive thrombin generation triggered by the cellular activation cascade 1

Risk Factors and Incidence

• The risk of developing Type 2 HIT varies by:
  • Type of heparin: Unfractionated heparin (UFH) carries 10-fold higher risk than low molecular weight heparin (LMWH) 1
  • Clinical setting: Higher risk in surgical patients (1-5%) than medical patients (0.1-1%) 1
  • Gender: Women have approximately twice the risk of developing HIT compared to men 1
  • Duration of therapy: Risk decreases after prolonged therapy (>1 month) 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 (larger molecules) has a higher risk of causing HIT than LMWH (smaller molecules) 1

Clinical Considerations

• Type 2 HIT 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
• The thrombotic risk in HIT persists even after heparin discontinuation, necessitating alternative anticoagulation 2
• HIT antibodies are typically transient, disappearing within weeks to months after heparin exposure 1

Understanding the complex immunopathology of Type 2 HIT explains why immediate heparin cessation and alternative anticoagulation are essential to prevent the devastating thrombotic complications of this condition.