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Transforming growth factor–β1 (TGF-β1) and plasminogen activator inhibitor–type 1 (PAI-1) might play a role in the development of fibrosis and stenosis of hemodialysis vascular accesses. We studied polymorphisms in the TGFβ1 (869T>C; 915G>C), and PAI-1 (4G/5G) genes in 416 hemodialysis patients (107 access thrombosis cases, 309 controls), to determine if they are related to vascular access thrombosis. Three TGF-β1 production haplotypes (low, intermediate, and high) were defined according to the combination of polymorphisms found. The adjusted odds ratio (OR) and 95% confidence interval (CI) for access thrombosis in low TGF-β1 producers was 7.31 (2.15-24.88; P = .001). The interaction between low TGF-β1 production haplotype and the 4G/4G PAI-1 genotype was strongly associated with access thrombosis (adjusted OR 19.3; 95% CI 2.82-132.40; P = .003). Mean access thrombosis–free survival times in years (95% CI) were 14.65 (12.05-17.25), 11.96 (8.67-15.25), and 4.94 (3.06-6.83) in high, intermediate, and low TGF-β1 producers, respectively (P = .044). Analysis of the synergy index and the case-only cross-product supported the presence of an interaction. We concluded that low TGF-β1 production haplotype is a risk factor for hemodialysis access thrombosis and that in the presence of the 4G/4G PAI-1 genotype there is an additional increase in risk.

Abstract 1142 Background Pregnancy is associated with a hypercoagulable state, with the highest risk of venous thromboembolism (VTE) occurring during the postpartum period. This risk is further increased by the presence of inherited thrombophilic states, including Factor V Leiden (FVL) or the prothrombin gene variant (PGV), such that many clinicians provide routine postpartum thromboprophylaxis for this group. Publications examining the absolute incidence of pregnancy associated VTE in carriers of FVL and PGV report a rate of only 0–1% over the combined antepartum and 6–12 week postpartum periods. However, given that at least 50% of pregnancy associated VTE occur postpartum, the daily risk of VTE may be sufficiently high to warrant thromboprophylaxis during this period. Objectives 1. To determine the absolute rate of postpartum VTE among a prospectively enrolled cohort of FVL or PGV positive women. 2. To determine the pooled proportion of postpartum VTE in this population through a systematic review of published prospective cohort studies. Methods We performed a substudy analysis of the prospective Ottawa and Kingston (OaK) birth cohort study, in which women presenting for routine antenatal care were followed throughout pregnancy until delivery. Genotyping for FVL and PGV by polymerase chain reaction was performed for all participants after completion of the postpartum period. 336 women who enrolled through the participating Ottawa hospitals and identified as FVL or PGV positive were eligible for the current analysis. Data relating to the occurrence of VTE during the 6-week post partum period were obtained for 201/336 women through medical record review or direct contact by a study investigator. The main outcome measure was the proportion of objectively confirmed VTE within 6 weeks of delivery among participants with heterozygous FVL or PGV. Eligible articles were identified through a comprehensive search of the MEDLINE database. Inclusion criteria included a) prospective cohort design of women completing pregnancy during the study period; b) assessment of all participants for FVL and/or PGV; c) observation of participants throughout the postpartum period; d) report of objectively confirmed VTE during the postpartum period. Studies limited to women with previous pregnancy complications or previous VTE were excluded. The pooled proportion of postpartum VTE was calculated from combination of reported postpartum VTE rates and the current study results. Results No postpartum VTE occurred among the 188 participants heterozygous for FVL or PGV alone. The proportion of VTE among the population with isolated heterozygous FVL and/or PGV was 0% (95% CI 0 to 2.0). One postpartum event was documented in a heterozygous PGV carrier with coexisting protein C deficiency. No events were documented among 12 women with homozygous or compound heterozygous defects. Superficial vein thrombosis was diagnosed in two carriers of FVL. Ten publications examining the rate of postpartum VTE among FVL or PGV carriers were identified in the systematic review. ( Table 1 ) The pooled proportion of postpartum VTE among those who did not receive postpartum prophylaxis was 0.6% (95% CI 0.2 to 1.3) for heterozygous carriers of FVL and 0% (95% CI 0 to 1.6) for PGV heterozygotes. Conclusion The absolute risk of VTE among asymptomatic carriers of FVL or PGV appears sufficiently low to withhold postpartum prophylaxis. Table 1 . Pooled Proportions of Postpartum VTE Study Proportion Receiving Prophylaxis VTE Proportion: No prophylaxis (95% CI) VTE Proportion: Prophylaxis or unknown prophylaxis (95% CI) FVL - Heterozygous Dizon-Townson 1997 NR – 0/13 Lindqvist 1999 4/263 2/259 1/4 Eichinger 1999 None 0/11 – Murphy 2000 NR – 0/16 Middledorp 2001 9/17 0/8 0/9 Salomen 2004 None 0/23 – Dizon-Townson 2005 None 0/134 – Clark 2008 NR – 0/142 Kjellberg 2010 128/472 3/344 0/128 Current Study 14/139 0/125 0/14 Pooled Proportion 5/904 = 0.6% (0.2–1.3) 1/326 = 0.3% (0.1–1.7) PGV - Heterozygous Salomen 2004 None 0/27 – Silver 2010 None 0/156 – Current Study * 1/48 0/47 0/1 Pooled Proportion 0/230 = 0% (0–1.6) Insufficient data for pooled proportion FVL: factor V Leiden, PGV: prothrombin gene variant, NR: not reported. * Data regarding postpartum prophylaxis unavailable in one case. Disclosures: Ramsay: Heart and Stroke Foundation of Canada: Research Funding; Canadian Institutes of Health Research: Research Funding. Rodger: Canadian Institutes of Health Research: Research Funding; Heart and Stroke Foundation of Canada: Research Funding.

Background. Transforming growth factor-β1 (TGF-β1) is involved in cell growth and differentiation and it plays an important role in the genesis of fibrosis through the stimulation of neointima proliferation and accumulation of components of the extracellular matrix and it has been suggested that polymorphisms (polym) in its gene contribute to determining the patency of the vascular access (VA) in patients (pts) on hemodialysis (HD) by contributing to both atherogenesis and VA thrombosis. On the other hand it has been demonstrated that polym in the gene encoding the plasminogen activator inhibitor type-1 (PAI-1) are a risk factor for ischemic heart disease and possibly stroke although their role in other vascular territories is unknown. It is also known that TGF-β1 is an important up-regulator of the PAI-1 gene. Methods. We conducted a case-control study to determine the relationship between TGF-β1 polym of the signal sequence (869 T>C; 915 G>C) and VA thrombosis in 416 HD pts. (107 with VA thrombosis, 309 controls had no thrombosis). We also explored for possible interactions with the 4G/5G polym of the PAI-1 gene. TGF-β1 and PAI-1 polym were amplified using PCR and genotyped using an ABI PRISM 3100 Genetic Analyzer. TGF-β1 producing haplotypes (haplo) were defined as low, intermediate or high as previously reported. All pts were also tested for thrombophilia. Statistical analysis was done using univariate and multivariate logistic regression adjusted for thrombophilia, age, access type, etc. Results. Frequencies for low, intermediate and high TGF-β1 producing haplo were 9.3, 26.2 and 64.5% in cases and 2.6, 22.3 and 75.1% in controls. Odds of thrombosis for TGF-β1 haplotypes Haplotype Crude OR (95% CI) p Adjusted OR (95% CI) p High producing haplotype is reference category Low 5.11 (1.93, 13.5) 0.001 7.31 (2.15, 24.88) 0.001 Intermediate 1.30 (0.74, 2.29) 0.36 1.39 (0.70, 2.75) 0.35 Figure Figure Frequencies for 5G/5G, 4G/5G and 4G/4G PAI-1 polym. were 21.5, 56.1 and 22.4% in cases and 25.6, 50.2 and 24.3% in controls respectively. When we explored the interaction between both gene polym we found a highly significant result for the interaction between the low TGF-β1 producers and the 4G/4G PAI-1 polym (adjusted OR 19.3; 95% CI 2.82, 132.40; p=0.003). Conclusions. Our results show that intermediate and high producing TGF-β1 haplo have a protective effect against VA thrombosis in HD patients that is not modified by PAI-1 polym and also suggest that the interaction between low TGF-β1 producing haplo and the 4G/4G PAI-1 polym might be an important contributor to thrombosis of the VA in HD pts. Further studies are ongoing to determine the relationship between TGF-β1 haplo, TGF-β1 level, and PAI-1 polym with thrombosis in this and other populations as well as to clarify the mechanisms underlying this apparently paradoxical effect.