Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator.

Abstract

Vascular endothelium possesses multiple procoagulant properties, including synthesis and expression of Factor V. We studied the effects of homocysteine on the regulation of endothelial cell Factor V activity. Elevated levels of homocysteine are associated with the congenital thrombotic disorder homocystinuria. Treatment of cultured endothelial cells with 0.5-10 mM homocysteine had no effect on cell morphology, but did increase Factor V activity and prothrombin activation by Factor Xa. A radioimmunoassay for endothelial cell Factor V demonstrated that homocysteine treatment did not increase Factor V antigen levels. 125I-prothrombin was activated by treated endothelial cells and Factor Xa in the presence of thrombin inhibitors. Exogenous 125I-Factor V was cleaved by homocysteine-treated but not control endothelial cells. 125I-Factor V cleavage products distinct from those generated by thrombin and Factor Xa were identified. These data provide evidence for regulation of endothelial cell Factor V activity, and indicate that increased Factor V activity associated with homocysteine-treated vascular endothelium results primarily from induction of an activator of Factor V.

Relationship between Plasma Homocysteine Levels and Saphenous Vein Graft Disease after Coronary Artery Bypass Grafts.

“…28,29) Although the exact mechanisms of homocysteine leading to atherosclerosis have not been fully elucidated, experimental studies have demonstrated that high homocysteine levels lead to endothelial dysfunction and thrombus formation. [30][31][32][33][34][35] These mechanisms of homocysteine may be related to SVG disease after CABG.…”

Central retinal vein occlusion and thrombophilia

“…49,50 Although the exact mechanism(s) by which hyperhomocysteinaemia causes thrombosis are unknown, it has been shown to be directly toxic to endothelial cells, impair thrombomodulin expression, directly activate factor V and inhibit protein C activation. [51][52][53][54] There are many causes for hyperhomocysteinaemia including vitamin deficiencies (pyridoxine, folic acid, vitamin B12) chronic illnesses (chronic renal failure, diabetes, cancer), drugs (methotrexate, anti-epileptic agents), as well as the rare enzyme deficiencies mentioned above. In 1988 however a mild form of hyperhomocysteinaemia was identified due to a thermolabile variant of MTHFR.…”

Nutritional aspects and possible pathological mechanisms of hyperhomocysteinaemia: an independent risk factor for vascular disease

“…Also, work by several authors suggests that lipid peroxidation, as a result of elevated homocysteine levels, may then cause decreased expression of the enzyme nitric oxide synthase and directly degrade NO (Heinecke et al 1987;Chin et al 1992;Liao et al 1995;Blom et al 1995;Domagala et al 1997) Thrombotic mechanisms Coagulant pathway. Elevated homocysteine levels in vitro have been shown to upset the balance of certain factors within the coagulation pathway, including activation of factors V and X11 (Ratnoff, 1968;Rodgers & Kane, 1986).…”