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Pathogenesis

• Heparin-induced thrombocytopenia is caused by antibodies that activate platelets in the presence of heparin (Figure 1).



• The predominant platelet-activating immunoglobulin subclass is usually IgG1.



• Antibodies recognize a multi-molecular complex of heparin and platelet factor 4 (PF4)^8-9.



• PF4 is a heparin-binding tetrameric protein produced by platelet a-granules that are released during activation by heparin or other agonists. An in-situ immune complex forms consisting of heparin, PF4, and the antibody²¹⁰



• Platelet activation occurs by complexing with platelet FcgIIa receptors⁴. This causes release of additional PF4 from platelet a-granules, leading to formation of more heparin-PF4 complexes.



• Therefore, even more platelet-activating immune complexes are made, creating a vicious cycle of progressive platelet activation.



• Although the predominant pathogenic anti-platelet antibodies in patients with HIT are IgG, a few patients had IgM and/or IgA antibodies detectable against heparin-PF4 complexes¹³. How these classes of antibodies might cause platelet activation and thrombosis is not known.



• In addition, a small minority of HIT patients develop anti-platelet antibodies that recognise proteins other than PF4, such as interleukin-8 or neutrophil-activating peptide-2¹⁴.


Figure 1




• Heparin produces mild platelet activation, resulting in release of platelet factor 4 (PF4) from platelets a-granules, and formation of immunogenic heparin-PF4 complexes¹⁰.



• B-Lymphocytes generate IgG that recognizes heparin-PF4 complexes; Fc tails of IgG bind to platelet FcgII receptors, resulting in Fc receptor clustering and consequent strong platelet activation¹⁰.



• Platelet-derived microparticles are generated that accelerate thrombin generation¹⁵.



• The HIT antibodies also recognize PF4 bound to endothelial heparin sulphate, leading to immune mediated injury that causes endothelial cell activation.



• Tissue factor expressed on the endothelial surface further produces thrombin generation¹⁶.



• This model helps explain some unusual clinical manifestations of HIT (venous limb gangrene, DIC and skin necrosis) and provides a rationale for treatment that reduces thrombin generation (danaparoid, recombinant hirudin).

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