A Rabbit Model of Hyperhomocysteinemia:The Effect of Homocysteine on Blood Clot Structure and Stability
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Date
2004-04-29
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Abstract
Hyperhomocysteinemia(Hhcys) is a condition that several epidemiological studies have shown to be associated with atherosclerosis and thrombosis, due to an elevation of plasma homocysteine levels. Plasma homocysteine(hcys) levels have a tendency to rise with age and changes in nutrition. Hcys can affect coagulation proteins, altering the formation of blood clots. The mechanism(s) by which hcys might cause modification of coagulation proteins "in vivo" is not understood. My hypothesis is that adult and juvenile animals could respond differently to chronic administration of hcys, and elevated plasma levels of hcys might lead to modification of fibrinogen "in vivo". Methodology: Six months old (juvenile, n=6) and 12 month old (adult, n=6) New Zealand White rabbits were divided into control (n=3) and homocysteine-treated (hcys-trt) (n=3) groups and injected for seven weeks; afterwards, they were given a bolus injection of hcys. Blood was drawn to evaluate plasma clearance of hcys. At the end, rabbits were exsanguinated by cardiac puncture and blood was collected for coagulation studies. Results: Juvenile hcys-trt rabbits adapted to chronic administration of hcys, however, adult hcys-trt rabbits developed Hhcys. Adult hcys-trt rabbits had higher levels of malonaldehyde in liver tissue, which is evidence of oxidative stress. Juvenile hcys-trt rabbits had similar malonaldehyde levels as juvenile control rabbits. Plasma elimination of hcys was impaired in adult hcys-trt rabbits. Adult hcys-trt rabbits had increased fibrinogen levels, longer reptilase times, and shorter thrombin clotting times versus adult control rabbits. Clots formed from purified fibrinogen obtained from hcys-trt rabbits lysed slower than comparable clots formed from control rabbits purified fibrinogen. Some congenital dysfibrinogenemias have clots that are abnormally resistant to fibrinolysis due to alterations in fibrinogen structure, and lead to recurrent thrombosis. Clotting results for adult hcys-trt rabbits suggest that hyperhomocysteinemia leads to a similar acquired dysfibrinogenmia. Therefore, the prolonged reptilase times and formation of clots that are abnormally resistant to fibrinolysis could directly contribute to increased risk of thrombosis in hyperhomocysteinemia.
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Keywords
homocysteine, fibrinogen, fibrinolysis, blood clots, rabbits
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Degree
PhD
Discipline
Nutrition
