Mechanistic basis of heparin-induced thrombocytopenia.
Heparin-induced thrombocytopenia (HIT) occurs in 1% to 5% of patients treated with unfractionated high-molecular weight heparin and often results in limb- and/or life-threatening thrombotic complications. This disorder involves the formation of antibodies to a complex of Platelet Factor 4 (PF4) with the heparin. We believe that the pathogenesis of this disease begins with having an excess of platelet PF4 release. The freed PF4 is bound to platelet and other vascular membrane surfaces and has three critical roles in the initiation of HIT. (1) Infused heparin neutralizes a portion of excess surface PF4, directly enhancing local thrombosis. (2) The excess PF4 is mobilized into PF4/heparin complexes that stimulates HIT antibody production. (3) The remaining PF4 complexed to heparanoids and heparin on the vascular surfaces now bind to these HIT antibodies and through surface Fc gammaRII receptors leads to more platelet activation and removal, thrombus formation, and inflammation. These events, in turn, further stimulate PF4 release, perpetuating repetitive cycle that results in the clinical manifestations of this disorder.
Poncz
Mortimer
M
Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, 34th Street & Civic Center Blvd., Philadelphia, PA 19104, USA. poncz@email.chop.edu
D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000473:pathology / Q000648:ultrastructure; D005260:Female; D006495:Heparin, Low-Molecular-Weight / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D015539:Platelet Activation / Q000502:physiology; D010978:Platelet Factor 4 / Q000187:drug effects / Q000378:metabolism*; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000276:immunology / Q000503:physiopathology*; D013927:Thrombosis / Q000503:physiopathology
D006495:Heparin, Low-Molecular-Weight; D010978:Platelet Factor 4