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Nutrient Metabolism

Hyperhomocysteinemia Due to Folate Deficiency Is Thrombogenic in Rats

Liselotte Sabroe Ebbesen^*,,3, Kirsten Christiansen and Jørgen Ingerslev

^* Institute of Experimental Clinical Research and Center for Hemophilia & Thrombosis, Department of Clinical Biochemistry, University Hospital of Aarhus/Skejby, Brendstrupgaardsvej, DK-8200 Aarhus N, Denmark

³To whom correspondence should be addressed. E-mail: lse{at}dadlnet.dk.

Although hyperhomocysteinemia (HH) appears to be an independent risk factor for thrombosis, the pathophysiologic mechanisms seen in thrombus formation are largely unresolved. The aim of the present study was to investigate whether HH is accompanied by thrombogenic alterations as assessed by whole blood thromboelastographic profiles. Severe (111 µmol/L) and intermediate (42 µmol/L) HH were induced in two series of rats by feeding them a folate-depleted diet. Each group was compared with a separate control group. In rats suffering severe HH (n = 30), initiation of the coagulation was protracted, with a clotting time of 79.7 s (95% CI, 76.2–83.4) compared with 70.4 s (95% CI, 66.5–74.6) in controls (P = 0.001). The velocity of the propagation of coagulation was increased, reaching 0.119 mm/s (95% CI, 0.111–0.127) in HH rats compared with 0.104 mm/s (95% CI, 0.099–0.108) in controls (P < 0.001). The maximum clot firmness also was increased, i.e., 41.9 mm (95% CI, 40.5–43.4) in HH rats compared with 37.6 mm (95% CI, 36.5–38.7) in controls (P < 0.001). The resting thrombin-antithrombin complex concentration in plasma tended to be lower in HH rats [5.60 µg/L (95% CI, 3.76–8.34) than in controls [8.56 µg/L (95% CI, 6.44–11.37)] (P = 0.074). In the series of rats with intermediate HH (n = 16), the changes in the whole blood coagulation profile (WBCP) were similar to those in rats with severe HH although only the prolongation of the initiation phase was significant. In conclusion, our study revealed that the WBCP was influenced by high plasma homocysteine by 1) prolonging the initiation phase, 2) increasing the velocity of the coagulation propagation and 3) increasing the maximum clot firmness. These changes in WBCP may contribute to the increased risk of thrombosis in hyperhomocysteinemic individuals.

KEY WORDS: • blood coagulation • folic acid deficiency • homocysteine • thromboelastography • rats

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