Single Nucleotide Variants in the Protein C Pathway and Mortality in Dialysis Patients

Background: The protein C pathway plays an important role in the maintenance of endothelial barrier function and in the inflammatory and coagulant processes that are characteristic of patients on dialysis. We investigated whether common single nucleotide variants (SNV) in genes encoding protein C pathway components were associated with all-cause 5 years mortality risk in dialysis patients. Methods: Single nucleotides variants in the factor V gene (F5 rs6025; factor V Leiden), the thrombomodulin gene (THBD rs1042580), the protein C gene (PROC rs1799808 and 1799809) and the endothelial protein C receptor gene (PROCR rs867186, rs2069951, and rs2069952) were genotyped in 1070 dialysis patients from the NEtherlands COoperative Study on the Adequacy of Dialysis (NECOSAD) cohort) and in 1243 dialysis patients from the German 4D cohort. Results: Factor V Leiden was associated with a 1.5-fold (95% CI 1.1-1.9) increased 5-year all-cause mortality risk and carriers of the AG/GG genotypes of the PROC rs1799809 had a 1.2-fold (95% CI 1.0-1.4) increased 5-year all-cause mortality risk. The other SNVs in THBD, PROC, and PROCR were not associated with 5-years mortality. Conclusion: Our study suggests that factor V Leiden and PROC rs1799809 contributes to an increased mortality risk in dialysis patients

Type of arteriovenous vascular access and association with patency and mortality

There are only a few risk factors known for primary patency loss in patients with an arteriovenous graft or fistula. Furthermore, a limited number of studies have investigated the association between arteriovenous access modality and primary patency loss and mortality. The aim of this study was to investigate risk factors for patency loss and to investigate the association between graft versus fistula use and outcomes (patency loss and mortality). We prospectively followed 919 incident hemodialysis patients and calculated hazard ratios (HRs) for putative risk factors of primary patency loss using Cox regression. Furthermore, HRs were calculated to study the association between graft versus fistula use and two-year primary patency loss and two-year mortality. Cardiovascular disease, prior catheter use, lowest tertile of albumin, highest tertile of hsCRP, and lowest tertile of fetuin-A were associated with primary patency loss in both patients with grafts and fistulas. Increased age, female sex, and diabetes mellitus were only associated with primary patency loss in patients with a fistula. We did not observe an association between primary patency loss and BMI, residual GFR, levels of calcium, phosphorus, and total cholesterol. Furthermore, graft use as compared with fistula use was associated with an 1.4-fold (95% CI 1.0-1.9) increased risk of primary patency loss and with an 1.5-fold(95% CI 1.0-2.2) increased mortality risk. Cardiovascular disease, prior catheter use, albumin, hsCRP, and fetuin-A are risk factors for patency loss. Graft use as compared with fistula use was associated with an increased risk of patency loss and mortalit

Identification of coagulation gene 3′UTR variants that are potentially regulated by microRNAs

MicroRNAs have been recognized as critical regulators of gene expression and might affect the risk of venous thrombosis. We aimed to identify 3′ untranslated region (UTR) variants in coagulation genes that influence coagulation factor levels and venous thrombosis risk. The 3′UTR of coagulation genes were sequenced in subjects with extremely high or low plasma levels of these factors in two case-control studies. In total, 28 variants were identified. Five single nucleotide polymorphisms (SNPs) were predominantly present in one extreme level group (F2 rs1799963, F8 rs1050705 and F11 rs4253429, rs4253430 and rs1062547). Additional to F2 rs1799963, F8 rs1050705 (in men) and F11 rs4253430 were associated with an increased risk of venous thrombosis albeit confidence intervals were wide. The three F11 SNPs were in high linkage disequilibrium with functional variants rs2289252 and rs2036914. Rs1062547 and rs4253430 were associated with a significant increase of plasma FXI activity in heterozygotes and homozygotes in wild-type controls. In silico prediction revealed that these SNPs might disturb the binding sites of miR-544 and miR-513a-3p. Only miR-544 provoked a significant decrease of the luciferase activity that was not observed with a rs4253430 mutated vector. In conclusion, these results reinforce that microRNAs are candidates to play a role in haemostasis and complex disorders, such as thrombosis

Identification of coagulation gene 3′UTR variants that are potentially regulated by microRNAs

MicroRNAs have been recognized as critical regulators of gene expression and might affect the risk of venous thrombosis. We aimed to identify 3′ untranslated region (UTR) variants in coagulation genes that influence coagulation factor levels and venous thrombosis risk. The 3′UTR of coagulation genes were sequenced in subjects with extremely high or low plasma levels of these factors in two case-control studies. In total, 28 variants were identified. Five single nucleotide polymorphisms (SNPs) were predominantly present in one extreme level group (F2 rs1799963, F8 rs1050705 and F11 rs4253429, rs4253430 and rs1062547). Additional to F2 rs1799963, F8 rs1050705 (in men) and F11 rs4253430 were associated with an increased risk of venous thrombosis albeit confidence intervals were wide. The three F11 SNPs were in high linkage disequilibrium with functional variants rs2289252 and rs2036914. Rs1062547 and rs4253430 were associated with a significant increase of plasma FXI activity in heterozygotes and homozygotes in wild-type controls. In silico prediction revealed that these SNPs might disturb the binding sites of miR-544 and miR-513a-3p. Only miR-544 provoked a significant decrease of the luciferase activity that was not observed with a rs4253430 mutated vector. In conclusion, these results reinforce that microRNAs are candidates to play a role in haemostasis and complex disorders, such as thrombosis

Flow-simulated thrombin generation profiles as a predictor of thrombotic risk among pre-menopausal women

BACKGROUND: A large number of individuals are at risk for deep venous thrombosis (DVT) due to alterations in multiple coagulation factors and inhibitors secondary to malignancy, drug interactions, or other general medical conditions. Traditional metrics of haemostasis such as prothrombin time, partial thromboplastin time, and bleeding time, generally estimate anticoagulation status and bleeding risk rather than thrombosis risk. OBJECTIVE: The objective of this study was to correlate a novel, systems-based metric of clotting potential to risk of DVT from a database derived from the Leiden Thrombophilia Study (LETS). METHODS: We utilized a computational model of blood coagulation, which addresses the interplay between biochemical factors, blood flow, and physiologic surface initiation of coagulation, to calculate an individualized, systems-based metric of clotting potential, termed the flow simulated thrombin generation (FSTG), for 210 pre-menopausal women in LETS. RESULTS: Both DVT and oral contraceptive (OC) use were associated with higher values of FSTG. We demonstrated a nearly 3-fold increased risk of DVT for each standard deviation increase above the mean in FSTG determined under venous flow conditions, which remained highly predictive after adjustment for age and OC status (adjusted OR 2.66; 95% CI 1.69–4.19; P<0.0001). CONCLUSIONS: A systems-based screening approach that integrates biochemical factors and flow haemodynamics identifies small subgroups of patients at risk of thrombosis that may benefit from oral anticoagulants

Venous and arterial thrombosis in dialysis patients

Whether the risk of both venous and arterial thrombosis is increased in dialysis patients as compared to the general population is unknown. In addition, it is unknown which subgroups are at highest risk. Furthermore, it is unknown whether having a history of venous thrombosis or arterial thrombosis prior to dialysis treatment increases mortality risk. A total of 455 dialysis patients were followed for objectively verified symptomatic thrombotic events between January 1997 and June 2009. The incidence rates in dialysis patients as compared to the general population was 5.6-fold (95% CI 3.1-8.9) increased for venous thrombosis, 11.9-fold (95% CI 9.3-14.9) increased for myocardial infarction, and 8.4-fold (95% CI 5.7-11.5) increased for ischaemic stroke. The combination of haemodialysis, lowest tertile of albumin, history of venous thrombosis, and malignancy was associated with subsequent venous thrombosis. Increased age, renal vascular disease, diabetes, high cholesterol levels, history of venous thrombosis, and history of arterial thrombosis were associated with subsequent arterial thrombosis. The all-cause mortality risk was 1.9-fold (95% CI 1.1-3.3) increased for patients with a history of venous thrombosis and 1.9-fold (95% CI 1.4-2.6) increased for patients with a history of arterial thrombosis. A potential limitation of this study was that in some risk categories associations with venous thrombosis did not reach statistical significance due to small numbers. In conclusion, dialysis patients have clearly elevated risks of venous thrombosis and arterial thrombosis and occurrence of venous thrombosis or arterial thrombosis prior to the start of dialysis is associated with an increased mortality ris