CYCLOSPORINE AND CREMAPHOR MODULATE VON-WILLEBRAND-FACTOR RELEASE FROM CULTURED HUMAN ENDOTHELIAL-CELLS

Cyclosporine has been associated with microangiopathic hemolysis (MAHA ) and other thrombotic complications of bone marrow and renal transpla ntation. MAHA is characterized by intravascular platelet aggregation, which, in some situations, is thought to be mediated by hyperactive hi gh molecular weight von Willebrand factor (vWF). We have hypothesized that transplant-related MAHA may be caused by CsA-mediated release of von Willebrand factor from endothelial cells. This hypothesis was test ed by studying vWF release from human umbilical vein endothelial cells primed with either CsA or cremophor EL. CsA and cremophor alone did n ot increase vWF release until toxic concentrations were reached (50-10 0 mu g/ml). However, at therapeutic concentrations (0.1-5 mu g/ml) vWF release by cells stimulated with thrombin, histamine, PMA, and the ca lcium ionophore A23187 was enhanced by both CsA and cremophor in a con centration-dependent manner. In single isolated endothelial cells, the thrombin-induced increase in cytosolic free calcium was enhanced by b oth CsA and cremophor. Preincubation for 24 hr with CsA but not cremop hor suppressed vWF release after thrombin stimulation. These observati ons were mirrored by a concentration-dependent suppression of [H-3]thy midine uptake by CsA. We conclude that CsA vehicle, cremophor, enhance s stimulated vWF release in vitro, probably by processes dependent upo n increased cytosolic free calcium. This suggests a possible mechanism for thrombotic transplant complications.