Hypercoagulability resulting from opposite effects of lupus anticoagulants is associated strongly with thrombotic risk.
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Interference of antiphospholipid antibodies (aPL) with coagulation was investigated in 40 aPL-patients (24 with thrombosis) using thrombography. Impairment of the activated protein C anticoagulant pathway was partially offset by the genuine anticoagulant effect. The net result, a procoagulant phenotype, was associated with a 7-fold increased risk of thrombosis in aPL-patients. (+info)
Endothelial protein C receptor is overexpressed in rheumatoid arthritic (RA) synovium and mediates the anti-inflammatory effects of activated protein C in RA monocytes.
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OBJECTIVES: (1) To investigate whether inflammatory synovial tissues from patients with rheumatoid arthritis (RA) express endothelial protein C receptor (EPCR) and (2) to determine the major cell type(s) that EPCR is associated with and whether EPCR functions to mediate the effects of activated protein C (APC) on these cells. METHODS: EPCR, CD68 and PC/APC in synovial tissues were detected by immunostaining and in situ PCR. Monocytes were isolated from peripheral blood of patients with RA and treated with APC, lipopolysaccharide (LPS), and/or EPCR blocking antibody RCR252. Cells and supernatants were collected for RT-PCR, western blotting, enzyme-linked immuosorbent assay and chemotaxis assay. RESULTS: EPCR was expressed by both OA and RA synovial tissues but was markedly increased in RA synovium. EPCR was colocalised with PC/APC mostly on CD68 positive cells in synovium. In RA monocytes, APC upregulated EPCR expression and reduced monocyte chemoattractant protein-1-induced chemotaxis of monocytes by approximately 50%. APC also completely suppressed LPS-stimulated NF-kappaB activation and attenuated TNF-alpha protein by more than 40% in RA monocytes. The inhibitory effects of APC were reversed by RCR252, indicating that EPCR is required. CONCLUSIONS: Our results demonstrate for the first time that EPCR is expressed by synovial tissues, particularly in RA, where it co-localises with PC/APC on monocytes/macrophages. In addition, APC inhibits the migration and activation of RA monocytes via EPCR. These inhibitory effects on RA monocytes suggest that PC pathway may have a beneficial therapeutic effect in RA. (+info)
Genetic polymorphisms on the factor V gene in women with recurrent miscarriage and acquired APCR.
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BACKGROUND: Recurrent miscarriage (RM) has been associated with the thrombophilia, activated protein C resistance (APCR). The factor V Leiden mutation located on the B domain of the factor V gene, causes 95% of APCR and since the B domain is pivotal to APCR, it seemed plausible that other mutations or polymorphisms affecting this active domain may instigate acquired APCR. The objective of this study was to determine whether other polymorphisms exist on the parts of the gene encoding the B domain of the factor V in women with acquired APCR and RM. METHODS: There were 51 women with RM and acquired APCR, 24 parous women (with no history of miscarriage and at least one normal full-term delivery) and 15 women with a history of idiopathic RM, who formed the study and two control groups, respectively. Six exons of the B domain of the factor V gene were intensely analysed using polymerase chain reactions, single-strand conformation polymorphism, genetic sequencing and restriction enzyme digestion analysis to identify single-nucleotide polymorphisms (SNPs). RESULTS: A significantly increased frequency of some SNPs on the factor V gene were observed in the women with acquired APCR and RM when compared with the control groups. CONCLUSIONS: The presence of some of these SNPs may predispose these women to acquired APCR and RM. (+info)
The risk of recurrent venous thromboembolism among heterozygous carriers of factor V Leiden or prothrombin G20210A mutation. A systematic review of prospective studies.
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Factor V Leiden (FVL) and prothrombin G20210A mutation (PTM) are the two most common genetic polymorphisms known to predispose to a first episode of venous thromboembolism (VTE). However, whether these thrombophilic abnormalities are also risk factors for recurrent VTE is unclear. We conducted a systematic review of prospective studies to assess the risk of recurrent VTE associated with heterozygous carriage of each of these mutations. All randomized controlled trials and prospective cohort studies that reported the incidence of recurrent VTE in patients with and without FVL and PTM after discontinuation of anticoagulant treatment were collected and analyzed. The risk ratios (RR) and their 95% confidence intervals (CI) for recurrent VTE were calculated in heterozygous carriers of FVL or PTM and compared to those of non-carriers. Eleven studies fulfilled the inclusion criteria. Recurrent VTE occurred in 114 out of 557 heterozygous carriers of FVL (20.5%) as compared to 382 out of 2,646 non-carriers (14.4%); and in 38 out of 212 heterozygous carriers of PTM (17.9%) compared to 428 of 2,996 non-carriers (14.3%). The RR of VTE recurrence conferred by the heterozygous carriage of FVL and PTM was 1.39 (95% CI, range 1.15 to 1.67) and 1.20 (range 0.89 to 1.61), respectively, using the Mantel-Haenszel fixed-effects model; 1.45 (1.13 to 1.85) and 1.36 (1.02 to 1.82), respectively, using the Der Simonian and Laird random effects method. In symptomatic patients with VTE, heterozygous carriage of FVL is clearly associated with a definitely increased risk of recurrent thromboembolism. The risk is lower with PTM and is difficult to interpret since it varies according to the assessment method used. (+info)
Fibrinogen Columbus: a novel gamma Gly200Val mutation causing hypofibrinogenemia in a family with associated thrombophilia.
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Fibrinogen is an essential component of the coagulation cascade and the acute phase response. The native 340 kDa molecule has a symmetrical trinodular structure composed of a central E-domain connected to outer D-domains by triple helical coiled-coils.1 Several mutations known to cause hypofibrinogenemia occur within the C-terminal gammaD-domain and have helped to elucidate the structurally and functionally important areas of this domain.2-5 Here we report the identification of a novel point mutation gammaG200V (fibrinogen Columbus) causing hypofibrinogenemia and co-segregating with three genetic thrombophilia risk factors. (+info)
Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism: report from the Women's Health Study.
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BACKGROUND: Supplementation with vitamin E may antagonize vitamin K in healthy adults, but it is unclear whether intake of vitamin E decreases the risk of venous thromboembolism (VTE). METHODS AND RESULTS: The Women's Health Study randomized 39,876 women > or = 45 years of age to receive 600 IU of natural source vitamin E or placebo on alternate days. Before randomization, 26,779 participants gave blood samples, which were used to determine factor V Leiden, G20210A prothrombin, and 677C>T MTHFR polymorphisms. Documented VTE (including deep vein thrombosis or pulmonary embolism) and unprovoked VTE (no recent surgery, trauma, or cancer diagnosis) were prospectively evaluated, secondary end points of the trial. During a median follow-up period of 10.2 years, VTE occurred in 482 women: 213 in the vitamin E group and 269 in the placebo group, a significant 21% hazard reduction (relative hazard, 0.79; 95% CI, 0.66 to 0.94; P=0.010). For unprovoked VTE, the hazard reduction was 27% (relative hazard, 0.73; 95% CI, 0.57 to 0.94; P=0.016). In subgroup analyses, the 3% of participants who reported VTE before randomization had a 44% hazard reduction (relative hazard, 0.56; 95% CI, 0.31 to 1.00; P=0.048), whereas women without prior VTE had an 18% hazard reduction (relative hazard 0.82; 95% CI, 0.68 to 0.99; P=0.040). Women with either factor V Leiden or the prothrombin mutation had a 49% hazard reduction associated with vitamin E treatment (relative hazard, 0.51; 95% CI, 0.30 to 0.87; P=0.014). CONCLUSIONS: These data suggest that supplementation with vitamin E may reduce the risk of VTE in women, and those with a prior history or genetic predisposition may particularly benefit. (+info)
The role of thrombophilia and thyroid autoimmunity in unexplained infertility, implantation failure and recurrent spontaneous abortion.
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BACKGROUND: The role of thrombophilia and thyroid autoimmunity in unexplained infertility (UI), implantation failure (IF) and recurrent spontaneous abortion (RSA) is controversial and poorly understood. METHODS: From March, 2004 to January, 2007, 119 women were prospectively included: 32 oocyte donors, 31 patients with UI, 26 with IF and 30 with RSA. The IF and RSA groups presented normal preimplantation genetic screening. Protein C, protein S, antithrombin III, lupus anticoagulant, activated protein C resistance (APCR), immunoglobulin M and G anticardiolipin antibodies, homocystine, Factor V Leiden, prothrombin G20210A mutation, methylentetrahydrofolate reductase C677T mutation, thyroid-stimulating hormone (TSH), free thyroxine, anti-thyroid peroxidase (TPO) and anti-thyroglobulin (TG) antibodies were assessed. RESULTS: The prevalence of thrombophilia was high and similar among groups. In the IF group, the prevalence of APCR (15.4%), lupus anticoagulant (11.5%) and combined thrombophilia (19.2%) was higher, but not significantly different, than the other three groups. The prevalence of thyroid autoimmunity in women with IF (anti-TPO antibodies, P = 0.009; anti-TPO plus anti-TG antibodies,P = 0.04) and UI (anti-TPO, P = 0.002; anti-TG, P = 0.019; anti-TPO plus anti-TG antibodies, P = 0.005) was significantly increased in comparison to those with RSA. There was also a trend towards a higher prevalence of thyroid autoimmunity in the UI and IF groups than in the control group. TSH and free thyroxine levels all remained within a normal range. CONCLUSIONS: When embryo aneuploidy is ruled out, thrombophilia could constitute an etiologic factor in IF. Furthermore, thyroid autoimmunity is strongly related to UI and IF. (+info)
SV-IV Peptide1-16 reduces coagulant power in normal Factor V and Factor V Leiden.
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Native Factor V is an anticoagulant, but when activated by thrombin, Factor X or platelet proteases, it becomes a procoagulant. Due to these double properties, Factor V plays a crucial role in the regulation of coagulation/anticoagulation balance. Factor V Leiden (FVL) disorder may lead to thrombophilia. Whether a reduction in the activation of Factor V or Factor V Leiden may correct the disposition to thrombophilia is unknown. Therefore we tested SV-IV Peptide 1-16 (i.e. a peptide derived by seminal protein vescicle number IV, SV-IV) to assess its capacity to inhibit the procoagulant activity of normal clotting factor V or Factor V Leiden (FVL). We found that SV-IV protein has potent anti-inflammatory and immunomodulatory properties and also exerts procoagulant activity. In the present work we show that the SV-IV Peptide 1-16, incubated with plasma containing normal Factor V or FVL plasma for 5 minutes reduces the procoagulant capacity of both substances. This is an anticoagulant effect whereas SV-IV protein is a procoagulant. This activity is effective both in terms of the coagulation tests, where coagulation times are increased, and in terms of biochemical tests conducted with purified molecules, where Factor X activation is reduced. Peptide 1-16 was, in the pure molecule system, first incubated for 5 minutes with purified Factor V then it was added to the mix of phosphatidylserine, Ca2+, Factor X and its chromogenic molecule Chromozym X. We observed a more than 50% reduction in lysis of chromogenic molecule Chromozym X by Factor Xa, compared to the sample without Peptide 1-16. Such reduction in Chromozym X lysis, is explained with the reduced activation of Factor X by partial inactivation of Factor V by Peptide 1-16. Thus our study demonstrates that Peptide 1-16 reduces the coagulation capacity of Factor V and Factor V Leiden in vitro, and, in turn, causes factor X reduced activation. (+info)