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Biochemical and Molecular Actions of Nutrients

Folate Deficiency-Induced Hyperhomocysteinemia Attenuates, and Folic Acid Supplementation Restores, the Functional Activities of Rat Coagulation Factors XII, X, and II^1,2

Clinical Institute and Center for Hemophilia and Thrombosis, Department of Clinical Biochemistry, University Hospital of Aarhus (Skejby Sygehus), DK-8200 Aarhus N, Denmark

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

Hyperhomocysteinemia (HH) constitutes a risk marker for thrombosis, but the pathophysiological mechanisms in thrombus formation are still unresolved. We investigated the influence of HH on single coagulation factor functions and evaluated the platelet GpIIb/IIIa receptor function in HH-induced changes in whole-blood coagulation profiles (WBCP). Three groups of 12 rats were investigated: control rats, folate deficient-HH (FD-HH) rats, and treated rats. Plasma total homocysteine was 7.1 µmol/L in controls, 31.3 µmol/L in FD-HH rats, and 7.6 µmol/L in treated rats. Factor (F) II:C, FX:C, and FXII:C were reduced in FD-HH rats compared with controls and normalized in treated rats (P < 0.05). FVII:C activity did not differ among the groups. Factor VIII:C activity was greater in FD-HH rats than in controls (P < 0.05). Blockage of the platelet GpIIb/IIIa receptor by Integrilin (Schering-Plough A/S) did not abolish the FD-HH–induced increase in whole-blood coagulation velocity, irrespective of the dosage of Integrilin. In conclusion, FD-HH reduced the functional activities of FXII:C, FX:C and FII:C, whereas FVII:C was unchanged and FVIII:C increased. These findings may partially explain the prolonged initiation phase of WBCP in FD-HH rats. The changes in single coagulation factor functions and WBCPs in FD-HH rats were reversed by treatment with folic acid.

KEY WORDS: • homocysteine • folic acid deficiency • blood coagulation factors • thrombelastography