Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells.

Abstract

Heparin-induced thrombocytopenia/thrombosis (HITP) is thought to be mediated by immunoglobulins that activate platelets in the presence of pharmacologic concentrations of heparin, but the molecular basis for this relatively common and often serious complication of heparin therapy has not been established. We found that plasma from each of 12 patients with HITP contained high titer (. 1:200) Invest. 1994. 93:81-88.)

Heparin‐induced thrombocytopenia and thrombosis

“…enzyme-linked, Ig-specific secondary reagent to detect antibody binding (solid phase ELISA) [29][30][31][32]37]. Linear polyanions such as polyvinylsulfonate can be substituted for heparin without loss of sensitivity or specificity [35].…”

“…However, the test is designed only to detect antibodies reactive with heparin/PF4 complexes. In that respect, it is both highly sensitive [37] and specific, because positive reactions are extremely rare in patients not exposed to heparin [30]. In various studies, 2-13% of patients thought to have HIT on clinical grounds were antibody-negative [40][41][42][43], but it is impossible to know how many of them may have had some other cause for their thrombocytopenia.…”

“…Such reports, together with concerns about legal liability, have led some centers to require that HIT antibody testing be done prior to starting heparin, especially in patients undergoing open heart surgery (OHS), most of whom have had recent heparin exposure incident to diagnostic testing. Several studies have shown that a positive PF4 ELISA result does not predict the development of HIT in a patient given heparin during cardiac surgery (6,30) but leave open the question of whether, on rare occasions, unusually strong antibodies stimulated by previous heparin treatment may put patients at risk. Prospective studies to address this issue seem indicated.…”

Warfarin-Induced Skin Necrosis Following Heparin-Induced Thrombocytopenia

“…Th e generation of procoagulant, plateletderived microparticles observed in HIT is postulated to accelerate the rate of protein C consumption, thus contributing to the early warfarin-induced protein C defi ciency and an increased state of hypercoagulability (7,12,13). Th ese microparticles, along with the procoagulant HIT antibodies, may also contribute to an increase in thrombin, which predisposes the patient to the development of microvascular thrombosis during warfarin treatment (7,14). Th e combination of these factors can lead to catastrophic hypercoagulable consequences, as noted in our patient.…”

Pathogenicity of human anti-platelet factor 4 (PF4)/heparin in vivo: generation of mouse anti-PF4/heparin and induction of thrombocytopenia by heparin

“…However, it has not yet been established that cross-linking these receptors occurs in vivo or is unique to HIT. Others have invoked the possibility that HIT antibodies recognize PF4 bound to heparin or proteoglycans containing heparin-like sequences expressed by endothelial cells [7,17]. It has also been proposed that monocytes exposed to PF4 and HIT antibody may contribute to thrombosis through increased expression of P selectin and tissue factor [17,21].…”