Induction of monocyte tissue factor expression by antibodies to heparin-platelet factor 4 complexes developed in heparin-induced thrombocytopenia

The pathogenesis of thrombosis in heparin-induced thrombocytopenia (HIT) wa s studied by investigating whether antibodies to heparin-platelet factor 4 (H-PF4) induced tissue factor (TF) synthesis by monocytes. Plasma from 5 pa tients with HIT containing IgG to H-PF4 was incubated with peripheral blood mononuclear cells without or with purified PF4 and heparin. Significant TF -dependent procoagulant activity (PCA) expressed by monocytes, measured wit h a factor Xa-based chromogenic assay, was induced after incubation of each HIT plasma sample. This monocyte PCA required the presence of PF4 and was inhibited by high concentrations of heparin. Furthermore, purified HIT IgG added to whole blood with PF4 and heparin also provoked significant synthes is of TF mRNA by monocytes, demonstrated by RT-PCR, and this effect was not observed with normal IgG. These findings strongly support the hypothesis t hat antibodies to PF4 developed in HIT trigger the production of tissue fac tor by monocytes, and this effect could account in vivo for hypercoagulabil ity and thrombotic complications in affected patients. (Blood. 2001; 97:330 0-3302) (C) 2001 by The American Society of Hematology.