What is the pathophysiology of Heparin-induced thrombocytopenia (HIT)?

Pathophysiology of Heparin-Induced Thrombocytopenia (HIT)

Heparin-induced thrombocytopenia (HIT) is an immune-mediated prothrombotic disorder characterized by antibody formation against platelet factor 4 (PF4)-heparin complexes, leading to intense platelet activation and explosive thrombin generation that results in thrombocytopenia and potentially catastrophic thrombosis. 1

Core Immunological Mechanism

• HIT is caused by IgG isotype antibodies that recognize heparin-modified platelet factor 4 (PF4/H) complexes 1
• Heparin binds to endogenous PF4, forming multimolecular complexes that become immunogenic in susceptible individuals 1
• These complexes form on the surface of platelets, creating the primary antigen that triggers the immune response 1

Cellular Activation Cascade

• The antibody-PF4-heparin immune complexes bind to FcγIIa (IgG) receptors on platelets, triggering platelet activation 1, 2
• Activated platelets release procoagulant microparticles, further amplifying the thrombotic process 1
• The immune complexes also activate endothelial cells, neutrophils, and monocytes 1
• Monocytes express tissue factor, contributing significantly to the hypercoagulable state 1

Molecular Requirements

• A minimum of 12-14 saccharides (molecular weight >4000 Da) are required to form the antigenic complex with PF4 1
• This explains why HIT occurs less commonly with low molecular weight heparin (LMWH) than with unfractionated heparin (UFH) 1

Clinical Manifestations

• Thrombocytopenia occurs in 85-90% of patients with HIT, defined as platelet count <150 x 10^9/L 1
• If the definition includes a proportional fall in platelet count (30-50% fall even if nadir remains >150 x 10^9/L), this increases to 90-95% of cases 1
• Thrombocytopenia results from massive platelet activation and elimination by the mononuclear phagocyte system 1
• The most severe consequence is thrombosis, with venous thrombosis (17-55% of cases) being more common than arterial thrombosis (3-10%) 1

Timing of HIT Development

• Typical-onset HIT: Platelet count fall occurs 5-10 days after starting heparin, particularly when administered perioperatively 1
• Rapid-onset HIT: Abrupt platelet count fall within 24 hours in patients with recent heparin exposure (within past month, occasionally up to 100 days) 1
• Delayed-onset HIT: Thrombocytopenia develops up to 3 weeks after stopping heparin 1

Risk Factors

• Type of heparin: Higher risk with unfractionated heparin compared to LMWH (10-fold difference) 1
• Patient population: Surgical patients (especially cardiac and orthopedic) have higher risk (1-5%) than medical or obstetric patients (0.1-1%) 1
• Gender: Women have approximately twice the risk of developing HIT compared to men 1
• Duration of exposure: Longer exposure increases risk 1

Diagnostic Considerations

• Laboratory diagnosis involves two main classes of assays: activation assays and antigen assays 1
• Activation assays (like serotonin release assay or heparin-induced platelet activation) detect platelet-activating antibodies and are considered the gold standard 1
• Antigen assays detect anti-PF4/heparin antibodies but have lower specificity as they detect both pathogenic and non-pathogenic antibodies 1

Clinical Implications

• Without early recognition and treatment, HIT carries a mortality rate of approximately 20% 2
• The thrombotic risk in untreated HIT is substantial, with deep vein thrombosis and pulmonary embolism being most common 1
• In up to 25% of patients with HIT, thrombosis precedes the development of thrombocytopenia 1

Understanding this complex pathophysiology is crucial for early recognition, diagnosis, and appropriate management of this potentially devastating condition.