Newer insights on the mechanism of heparin-induced thrombocytopenia.
Heparin-induced thrombocytopenia (HIT) type II is a complex clinical syndrome. It is an immune reaction to heparin in which the formation of antibodies targeted against the heparin-platelet factor 4 complex results in platelet activation. Platelet activation plays a central role in HIT; however, platelet activation does not occur as an isolated physiologic response. To elucidate further the mechanism of thrombogenesis in HIT, we undertook studies to determine the effect of heparin antibodies on endothelial cells, leukocytes, and the inflammatory state. We summarize our previous and new findings. For endothelial cells: Antiheparin antibodies bind to and directly activate microvascular endothelial cells, whereas binding to and activating macrovascular endothelial cells requires preactivation by platelets or tumor necrosis factor alpha (TNFalpha). Increased circulating levels of hemostatic activation factors as observed with thrombosis, particularly soluble P-selectin, plasminogen activator inhibitor type 1 (PAI-1), tissue factor, and thrombomodulin, were associated with endothelial cell activation and were also found in the blood circulation of patients with HIT. For the inflammatory state: Neutrophils and monocytes (but not lymphocytes) bind to and form complexes with platelets in the presence of HIT antibodies. Activated monocytes bind to endothelial cells and produce a procoagulant state. Patients with HIT have an increased level of cytokines in their blood circulation. For HIT antibodies: Only heparin fractions larger than 5 kd interacted with HIT antibodies, explaining why low-molecular-weight heparin (LMWH) usually does not generate antibodies. HIT antibodies are heterogeneous in structure, affinity, and specificity. These data suggest that, in addition to the platelet component, several other mechanisms are associated with the pathophysiology of HIT. These include an inflammatory state, endothelial cell remodeling, and the known procoagulant state. Differences between patients in the levels of the inflammatory markers may relate to various stages of the inflammatory/procoagulant state that exists in patients with HIT. The variations within the HIT antibodies may influence their ability to activate platelets, endothelial cells, and leukocytes, and thus contribute further to the variations in the pathogenicity of HIT.
Walenga
Jeanine M
JM
Departments of Thoracic & Cardiovascular Surgery, Loyola University Medical Center, Maywood, Illinois 60153, USA. jwaleng@lumc.edu
Jeske
Walter P
WP
Prechel
M Margaret
MM
Bakhos
Mamdouh
M
D001323:Autoantibodies / Q000097:blood; D015815:Cell Adhesion Molecules / Q000097:blood; D004730:Endothelium, Vascular / Q000473:pathology; D006493:Heparin / Q000009:adverse effects* / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000276:immunology / Q000473:pathology; D007962:Leukocytes / Q000473:pathology; D010978:Platelet Factor 4 / Q000276:immunology; D013921:Thrombocytopenia / Q000139:chemically induced*
D001323:Autoantibodies; D015815:Cell Adhesion Molecules; D010978:Platelet Factor 4; D006493:Heparin