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 transplantation. MAHA is characterized by intravascular platelet aggregation, which, in some situations, is thought to be mediated by hyperactive high 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 tested by studying vWF release from human umbilical vein endothelial cells primed with either CsA or cremophor EL. CsA and cremophor alone did not increase vWF release until toxic concentrations were reached (50-100 micrograms/ml). However, at therapeutic concentrations (0.1-5 micrograms/ml) vWF release by cells stimulated with thrombin, histamine, PMA, and the calcium ionophore A23187 was enhanced by both CsA and cremophor in a concentration-dependent manner. In single isolated endothelial cells, the thrombin-induced increase in cytosolic free calcium was enhanced by both CsA and cremophor. Preincubation for 24 hr with CsA but not cremophor suppressed vWF release after thrombin stimulation. These observations were mirrored by a concentration-dependent suppression of [3H]thymidine uptake by CsA. We conclude that CsA vehicle, cremophor, enhances stimulated vWF release in vitro, probably by processes dependent upon increased cytosolic free calcium. This suggests a possible mechanism for thrombotic transplant complications.
Collins
P
P
Department of Haematology, Royal London Hospital, United Kingdom.
Wilkie
M
M
Razak
K
K
Abbot
S
S
Harley
S
S
Bax
C
C
Zaidi
M
M
Blake
D
D
Cunningham
J
J
Newland
A
A
D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D014677:Pharmaceutical Vehicles / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism; D014471:Umbilical Veins; D014841:von Willebrand Factor / Q000378:metabolism*
D014677:Pharmaceutical Vehicles; D014841:von Willebrand Factor; C022131:cremophor; D011092:Polyethylene Glycols; D016572:Cyclosporine; D002118:Calcium; D013936:Thymidine