Environmental and genetic determinants of the hypercoagulable state and cardiovascular disease in renal transplant recipients

Background. Fibrinogen and factor VII coagulant activity (VIIc), risk factors for cardiovascular disease (CVD) in the general population, could contribute to CVD risk in renal transplant recipients (RTR). Methods. We measured fibrinogen and VIIc in 38 RTR and 31 controls, along with prothrombin fragment F1 + 2 and D-Dimer (markers of coagulation and fibrinolytic activation), plasma lipids and the acute phase response cytokine, interleukin 6. The effect of genetic polymorphisms of beta-fibrinogen (G/A(-455)) and factor VII (Arg/Gln(353)) was explored. Results. F1 + 2, D-Dimer, and fibrinogen were increased in all RTR, indicating a chronic prothrombotic state. Fibrinogen correlated with age, F1 + 2, and trough cyclosporin A (CsA). RTR carriers of the A(-455) allele had greater increment in plasma fibrinogen concentration and correlation with CsA than homozygotes for the G(-455) allele. Interleukin 6 was increased in RTR confirming that a persistent low-grade acute-phase response could contribute to increased fibrinogen. Differences in plasma VIIc were associated with factor VII genotype, disease status, and blood lipids. Carriers of the Gln(353) allele had 30% lower VIIc when compared with Arg(353) homozygotes, which could confer a reduced thrombotic risk. The 12 RTR with CVD or metabolic complications (RTR+) were more hyperlipidaemic and had higher fibrinogen and VIIc than the 26 RTR free of disease complications (RTR-), or the controls. Conclusions. Long-term RTR manifest features of a chronic prothrombotic and persistent inflammatory state. Alterations in fibrinogen and VIIc in RTR arise in part as a result of interactions between common genetic and environmental factors, and these changes could contribute to the increased risk of CVD in RTR.