Factor V Leiden Carriers Research Articles

Variable plasma levels of Factor V Leiden correlate with circulating platelet microparticles in carriers of Factor V Leiden

Introduction Inheritance of Factor V Leiden (FVL) is associated with an increased but variable level of risk for thrombosis. We have previously shown that FVL heterozygotes have elevated levels of circulating pro-coagulant microparticles (MP). Here we sought to determine if these subjects differed in their plasma levels of FVL and if this was related to MP concentrations and/or history of thrombosis. Materials and Methods The Hemoclot Quanti. V-L clotting assay was used to specifically measure FVL in plasma samples from 44 known carriers (12 M, 32 F; aged 46 ± 13 years). Circulating MP were quantified by flow cytometry using fluorochrome conjugated antibodies to platelet (CD41a), leukocyte (CD45), and endothelial (CD62e) surface markers, and MP prothrombinase activity was determined by ELISA. Results The cohort was found to have a mean FVL of 49.5 ± 5.6% and this was positively correlated to the total number of circulating CD41a + MP (R = 0.31, p = 0.03) but not to other MP subsets or to MP prothrombinase activity. The amount of FVL relative to normal factor V (FVL/FV clotting ratio) was calculated and found to be highly variable, ranging from 0.37 to 0.69, and significantly correlated with a history of thrombosis (n = 14; p = 0.04). Conclusions This is the first study to investigate the relationship between varying levels of FVL and plasma derived MP. These results are consistent with our previous findings of an increase in MP levels in carriers of FVL as compared to controls, and suggest a role for FVL/FV ratio in predicting risk of thrombosis in carriers of FVL.

Thrombomodulin-dependent effect of factor VLeiden mutation on factor XIII activation

IntroductionFactor V Leiden mutation (FVLeiden) is associated with impaired down-regulation of activated FV procoagulant activity and loss of FV anticoagulant function that result in an increased risk of venous thromboembolism. As the downstream effects of FVLeiden on clot formation and fibrinolyis have only partially been revealed, we investigated its effect on the activation of factor XIII (FXIII) and the cross-linking of fibrin. MethodsIn the plasma samples of fifteen healthy individuals with known FV genotypes coagulation was initiated by recombinant human tissue factor and phospholipids with or without recombinant human thrombomodulin (rhTM). FV deficient plasma supplemented with purified wild type FV or FVLeiden were also investigated. Clots were recovered and analyzed by SDS-PAGE and quantitative densitometric evaluation of Western blots. ResultsrhTM considerably delayed the activation of FXIII in the plasma from FV wild type individuals. This effect of rhTM was significantly impaired in the plasma from FVLeiden carriers. The results were confirmed in experiments with FV deficient plasma supplemented by FV prepared from wild type individuals or FVLeiden homozygotes. Fibrin γ-chain dimerization was also considerably delayed by rhTM in plasma samples from individuals without Leiden mutation, but not in plasma samples from FVLeiden heterozygotes or homozygotes. The difference between heterozygotes and homozygotes was not statistically significant. ConclusionThe highly diminished delaying effect of TM on FXIII activation and on the cross-linking of fibrin in FVLeiden carriers might represent a novel mechanism contributing to the increased thrombosis risk of these individuals.

Low but sustained coagulation activation ameliorates glucose-induced podocyte apoptosis: protective effect of factor V Leiden in diabetic nephropathy

AbstractWhereas it is generally perceived to be harmful, enhanced coagulation activation can also convey salutary effects. The high prevalence of the prothrombotic factor V Leiden (FVL) mutation in whites has been attributed to a positive selection pressure (eg, resulting from reduced blood loss or improved survival in sepsis). The consequences of enhanced coagulation activation, as observed in FVL carriers, on microvascular diabetic complications remain unknown. We therefore investigated the role of FVL in diabetic nephropathy. In heterozygous or homozygous diabetic FVL mice, albuminuria and indices of diabetic nephropathy were reduced compared with diabetic wild-type mice. This was associated with reduced glomerular apoptosis and preservation of podocytes in diabetic FVL-positive mice. In vitro, low-dose thrombin (50pM) prevented, whereas high-dose thrombin (20nM) aggravated, glucose-induced apoptosis in podocytes. In diabetic patients, the FVL mutation, but not the plasminogen activator inhibitor-1 4G/5G polymorphism, is associated with reduced albuminuria, which is consistent with a nephroprotective role of low but sustained thrombin generation. Consistently, anticoagulation of diabetic FVL-positive mice with hirudin abolished the nephroprotective effect. These results identify a nephroprotective function of low but sustained thrombin levels in FVL carriers, supporting a dual, context-dependent function of thrombin in chronic diseases.

Factor V Leiden Mutation and Pregnancy-Related Complications

Objective The objective of the study was to determine the prevalence of the factor V Leiden (FVL) mutation and its association with obstetric complications, blood loss during delivery, and venous thromboembolism (VTE). Study Design This was a prospective, observational, case-cohort study of 491 FVL carriers and 1055 controls derived from 6003 screened women. Data were analyzed with a Student t test and cross-tabulation. Results FVL carriership prevalence was 8.3%. Gestational age at delivery, birthweight deviation, gestational hypertension, and preeclampsia incidences did not differ between groups. The incidences of placental abruption, neonatal asphyxia, eclampsia, intrauterine fetal death, intrapartum death, and unexplained late miscarriage were low. The incidence of major blood loss at delivery was lower in carriers. There were 3 VTEs among carriers and none among controls. Conclusion FVL carriership did not influence pregnancy-induced hypertension, birthweight, or prematurity but raised the risk of venous thromboembolism and lowered the risk of major blood loss.

Are inherited thrombotic risk factors associated with fibrostenosis in Crohnʼs disease?

Fibrostenotic lesions are common complications in Crohn's disease (CD) often requiring surgery. Inherited thrombotic risk factors are associated with fibrosis in other chronic inflammatory diseases. The aim of the study was to assess whether inherited thrombotic risk factors are associated with fibrostenosis in CD. Clinical data on 529 CD patients were collected retrospectively. Subjects were tested for and grouped according to the presence of factor V Leiden (FVL), the prothrombin G20210A, and the methylenetetrahydrofolate reductase C677T mutation (MTHFR). Patients who underwent CD-related intestinal surgery were assessed for the presence of fibrostenosis, which was the primary endpoint. The diagnosis of fibrostenosis was based on surgical, pathological, and histopathological reports. A Cox proportional hazards model was used for statistical analysis. Thirty-two (6.1%, heterozygous 30, homozygous 2) patients were carriers of FVL, 19 (3.6%, all heterozygous) carried the prothrombin variant, and 318 (60.1%) the MTHFR variant (243 heterozygous, 75 homozygous). In all, 303 (57.3%) patients underwent intestinal surgery. Fibrostenosis was identified in 219 (72.3%) surgical specimens. The rate of first intestinal surgeries with fibrostenosis tended to be more frequent in patients with the homozygous 677TT MTHFR mutation (hazard ratio, HR 1.39; 95% confidence interval [CI]: 0.98-1.97; P = 0.067). After adjustment for potential confounders homozygous 677TT MTHFR mutation did not remain a risk factor for intestinal surgery with fibrostenosis (HR 1.23; 95% CI: 0.77-1.98; P = 0.387). FVL and the prothrombin variant had no influence on the primary endpoint. The MTHFR 677TT mutation, factor V Leiden, and the prothrombin G20210A mutation are not associated with fibrostenosis in CD.

FV Leiden Mutation and Deep Venous Thrombosis in Vojvodina: A Case-Control Study

FV Leiden Mutation and Deep Venous Thrombosis in Vojvodina: A Case-Control StudyBetween September 2007 and February 2010, the occurrence of symptomatic deep venous thrombosis (DVT) was investigated in a cohort of 79 consecutive patients. A case-control study inclu ded 71 healthy controls matched with cases for sex and age. The prevalence of factor V G1691A mutation genotype was analyzed. Eighteen cases (22.79%; 95% confidence interval (CI) 13.53% to 32.03%) and four controls (5.63%; 95% CI 0.27% to 10.99%) were heterozygous carriers of FV Leiden (p= 0.025). The odds ratio for DVT was 4.94 (95% CI 1.58 to 15.42) and the relative risk 4.04 (95% CI 1.44-11.38) compared with FV 1691G carriers. Four cases were homozygous carriers of FV Leiden, giving a prevalence of 5.06% (95% CI 0.23 to 9.89%) and no controls, therefore OR and RR calculation was based on the prevalence of homozygotes in the general Caucasian population. The OR for DVT was 47.28 (95% CI 0.04 - 52167.3) and the RR 45.57 (95% CI 0.04 to 49540.77; p=0.025) compared with FV 1691 G carriers. Our study confirms that factor V Leiden carriers in Vojvodina, as in similar studies previously carried out in other populations, have an increased risk of developing DVT. The evaluated risk of DVT in heterozygous carriers of the mutation is four- to five-fold higher, whereas for homozygous carriers it is 45- to 48-fold higher than in non-carriers. These results confirm that patients with DVT and their relatives should undergo screening for FV Leiden mutation.

Factor V Leiden mutation and pregnancy-related complications

The objective of the study was to determine the prevalence of the factor V Leiden (FVL) mutation and its association with obstetric complications, blood loss during delivery, and venous thromboembolism (VTE). This was a prospective, observational, case-cohort study of 491 FVL carriers and 1055 controls derived from 6003 screened women. Data were analyzed with a Student t test and cross-tabulation. FVL carriership prevalence was 8.3%. Gestational age at delivery, birthweight deviation, gestational hypertension, and preeclampsia incidences did not differ between groups. The incidences of placental abruption, neonatal asphyxia, eclampsia, intrauterine fetal death, intrapartum death, and unexplained late miscarriage were low. The incidence of major blood loss at delivery was lower in carriers. There were 3 VTEs among carriers and none among controls. FVL carriership did not influence pregnancy-induced hypertension, birthweight, or prematurity but raised the risk of venous thromboembolism and lowered the risk of major blood loss.

Factor V Leiden in Chioggia: a prevalence study in patients with venous thrombosis, their blood relatives and the general population.

Factor V Leiden (FVL) is the most common genetic polymorphism known to predispose to episodes of venous thromboembolism (VTE) in western countries; heterozygosity for FVL occurs in 3–8%, and the rate of homozygosity is around 1/5,000 in the general population in Italy1. As previously reported, we observed a very high prevalence of FVL carriers in patients with deep venous thrombosis in Chioggia. Among 292 consecutive patients attending our Laboratory for investigation of thrombophilic risk factors after an episode of venous thrombosis we observed 168 (57.5%) normal subjects and 124 (42.5%) FVL carriers: 13 (4.5%) of whom were homozygous for the polymorphism and 111 (38.0%) heterozygous2,3. The high prevalence of FVL carriers among patients with venous thrombosis should be due to case selection but may also reflect a high diffusion of this particular mutation in Chioggia. The aim of this study was to establish the correct prevalence of FVL carriers in our area by evaluating patients, their blood relatives and the general population.

Tamoxifen and the Factor V Leiden Mutation

Both tamoxifen and the factor V Leiden (FVL) mutations are wellestablished risk factors for thromboembolic events (TE). Tamoxifen has been shown to increase risk by two- to fourfold in both adjuvant and preventive trials (1). The FVL mutation is well-established as a risk factor for TE in the general population, with a three- to sixfold relative risk compared with persons without the mutation (2), and it also confers risk in persons in whom excess estrogen stimulation has occurred, such as in women using hormone replacement therapy or high-dose oral contraceptives and in pregnant women (3). Thus, it came as a surprise that among women who took tamoxifen in two major breast cancer prevention trials, FVL carriers carried no excess risk of thromboembolism, despite the fact that tamoxifen itself was a clear and strong risk factor (4,5). In fact for the International Breast Cancer Intervention Study-I (IBIS-I) prevention trial, among 35 women with an available blood sample who developed a TE (29 of whom received tamoxifen), none were positive for the FVL mutation as compared with eight (5.0%) of the 159 matched control women (6). In addition, none of the women with a TE had the prothrombin G2010A mutation, which is also known to lead to an increased risk of TE (7), as opposed to three women in the control group (1.9%). Similar results were seen in the National Surgical Adjuvant Breast and Bowel Project P1 breast cancer prevention trial (NSABP-P1[BCPT]) (8), in which, again, neither the FVL mutation nor the prothrombin mutation was related to TE risk in tamoxifen users. In this trial, 48 women with a TE were compared with 189 matched controls. Again, tamoxifen was a risk factor for TE, with a relative risk of 1.9 (P = .006). An analysis in breast cancer patients taking tamoxifen that is presented in this issue by Garber et al. (9) found the prevalence of an FVL mutation to be almost fivefold higher in women who had a TE (18.5%) compared with matched control subjects (4.5%) and strongly supports an effect of FVL mutation on risk of TE among tamoxifen users, at least in the adjuvant setting. From these data, it was not possible to determine whether the effects of tamoxifen and the FVL mutation were multiplicative (ie, did not interact) or whether the effect of FVL was stronger or weaker among tamoxifen users than among women who did not take this drug. The incidence of a serious TE during 5 years of treatment with tamoxifen is about 2.4% in adjuvant trials (10), so based on these data, the risk would be more than 10% among FVL carriers and would be clinically relevant. In the prevention setting, the TE risk is substantially less, that is, about 0.6% during 5 years of active tamoxifen treatment in women older than 50 years and even less in younger women (1). Why are the results so apparently different in these two contexts? It could still be due to chance. There were 74 case subjects in the tamoxifen arms of the prevention trials and 124 evaluated case subjects here, and an interaction test gives P = .10. An obvious difference is that the women in this study all had breast cancer, and about 50% had also received chemotherapy, which has been found to be a risk factor for TEs in many other studies (11), but curiously not in the presented article. However, why FVL would predict TE in this setting, but not when tamoxifen is used for prevention, remains a mystery. The issue for breast cancer treatment with tamoxifen is now less important than a few years ago because newer, generally more effective treatments, such as aromatase inhibitors in the postmenopausal setting and luteinizing hormone–releasing hormone agonists in the premenopausal setting, are now available. However, because these newer treatments are not without their own side effects (eg, bone loss and arthralgia), tamoxifen remains a valuable option for some women. In the adjuvant setting, it may be prudent to test for FVL and prothrombin G2010A mutations before starting treatment with tamoxifen. However, the lack of an association between tamoxifen use and TE risk in the prevention trials makes this decision less clear when tamoxifen is used prophylactically. In postmenopausal women, raloxifene is another option for breast cancer prevention, and it does not appear to confer as much risk of TE as tamoxifen (12), but recent evidence also indicates that it is only 75% as effective in preventing breast cancer as tamoxifen (13). Aromatase inhibitors are also being evaluated for breast cancer prevention in high-risk postmenopausal women (14). Continued follow-up and research on the relationship between the FVL mutation and tamoxifen, especially in the prevention setting, will be the only way to clarify these apparently contradictory findings.

The Association of Factor V Leiden and Prothrombin Gene Mutation and Placenta-Mediated Pregnancy Complications: A Systematic Review and Meta-analysis of Prospective Cohort Studies

Factor V Leiden (FVL) and prothrombin gene mutation (PGM) are common inherited thrombophilias. Retrospective studies variably suggest a link between maternal FVL/PGM and placenta-mediated pregnancy complications including pregnancy loss, small for gestational age, pre-eclampsia and placental abruption. Prospective cohort studies provide a superior methodologic design but require larger sample sizes to detect important effects. We undertook a systematic review and a meta-analysis of prospective cohort studies to estimate the association of maternal FVL or PGM carrier status and placenta-mediated pregnancy complications. A comprehensive search strategy was run in Medline and Embase. Inclusion criteria were: (1) prospective cohort design; (2) clearly defined outcomes including one of the following: pregnancy loss, small for gestational age, pre-eclampsia or placental abruption; (3) maternal FVL or PGM carrier status; (4) sufficient data for calculation of odds ratios (ORs). We identified 322 titles, reviewed 30 articles for inclusion and exclusion criteria, and included ten studies in the meta-analysis. The odds of pregnancy loss in women with FVL (absolute risk 4.2%) was 52% higher (OR = 1.52, 95% confidence interval [CI] 1.06-2.19) as compared with women without FVL (absolute risk 3.2%). There was no significant association between FVL and pre-eclampsia (OR = 1.23, 95% CI 0.89-1.70) or between FVL and SGA (OR = 1.0, 95% CI 0.80-1.25). PGM was not associated with pre-eclampsia (OR = 1.25, 95% CI 0.79-1.99) or SGA (OR 1.25, 95% CI 0.92-1.70). Women with FVL appear to be at a small absolute increased risk of late pregnancy loss. Women with FVL and PGM appear not to be at increased risk of pre-eclampsia or birth of SGA infants. Please see later in the article for the Editors' Summary.

Antiphospholipid antibodies and pregnancy outcomes in women heterozygous for Factor V Leiden

Antiphospholipid antibodies are associated with a spectrum of pregnancy complications, including preeclampsia and small for gestational age (SGA) fetuses. We sought to assess anticardiolipin and anti-beta2-glycoprotein I (anti-beta2-GPI) IgG and IgM antibody prevalence and the relationship of these antibodies to pregnancy complications in women with the Factor V Leiden (FVL) mutation. The study comprised a secondary analysis of a multicenter, prospective observational study of FVL prevalence among 5188 asymptomatic pregnant women. A subset of 362 women (117 FVL heterozygotes, 245 matched controls) had serum collected at the time of the original study and underwent serum analysis for anticardiolipin and anti-beta2-GPI IgG and IgM as a part of this analysis. The primary outcome was preeclampsia and/or SGA (<10%). The overall prevalence of anticardiolipin and anti-beta2-GPI IgG and IgM antibodies was low and did not vary with FVL status. Forty-seven women (13.0%) developed preeclampsia and/or SGA. There were no differences in primary outcome rates between women with and without aPL antibodies, regardless of FVL mutation status. Among FVL carriers, the presence of antiphospholipid antibodies does not appear to contribute to adverse pregnancy outcome.

Impact of the factor V Leiden mutation on the outcome of pneumococcal pneumonia: a controlled laboratory study

IntroductionStreptococcus (S.) pneumoniae is the most common cause of community-acquired pneumonia. The factor V Leiden (FVL) mutation results in resistance of activated FV to inactivation by activated protein C and thereby in a prothrombotic phenotype. Human heterozygous FVL carriers have been reported to be relatively protected against sepsis-related mortality. We here determined the effect of the FVL mutation on coagulation, inflammation, bacterial outgrowth and outcome in murine pneumococcal pneumonia.MethodsWild-type mice and mice heterozygous or homozygous for the FVL mutation were infected intranasally with 2*106 colony forming units of viable S. pneumoniae. Mice were euthanized after 24 or 48 hours or observed in a survival study. In separate experiments mice were treated with ceftriaxone intraperitoneally 24 hours after infection and euthanized after 48 hours or observed in a survival study.ResultsThe FVL mutation had no consistent effect on activation of coagulation in either the presence or absence of ceftriaxone therapy, as reflected by comparable lung and plasma levels of thrombin-antithrombin complexes and fibrin degradation products. Moreover, the FVL mutation had no effect on lung histopathology, neutrophil influx, cytokine and chemokine levels or bacterial outgrowth. Remarkably, homozygous FVL mice were strongly protected against death due to pneumococcal pneumonia when treated with ceftriaxone, which was associated with more pronounced FXIII depletion; this protective effect was not observed in the absence of antibiotic therapy.ConclusionsHomozygosity for the FVL mutation protects against lethality due to pneumococcal pneumonia in mice treated with antibiotics.

Different risk of deep vein thrombosis and pulmonary embolism in carriers with factor V Leiden compared with non-carriers, but not in other thrombophilic defects. Results from a large retrospective family cohort study

The term factor V Leiden (FVL) paradox is used to describe the different risk of deep vein thrombosis and pulmonary embolism that has been found in carriers of FVL. In a thrombophilic family-cohort, we estimated differences in absolute risks of deep vein thrombosis and pulmonary embolism for various thrombophilic defects. Of 2,054 relatives, 1,131 were female, 41 had pulmonary embolism and 126 deep vein thrombosis. Annual incidence for deep vein thrombosis in non-carriers of FVL was 0.19% (95%CI, 0.16-0.23), and 0.41% (95%CI, 0.28-0.58) in carriers; relative risk (RR) 2.1 (95%CI, 1.4-3.2). For pulmonary embolism these incidences were similar in carriers and non-carriers 0.07%, respectively; RR 1.0 (95% CI, 0.4-2.5). When co-inheritance of other thrombophilic defects was excluded the RR for deep vein thrombosis in FVL carriers was 7.0 (95%CI, 2.3-21.7) compared to non-carriers and 2.8 (95%CI, 0.5-14.4) for pulmonary embolism. For other thrombophilic defects no such effect was observed. Thus the FVL paradox was confirmed in our study. However, a similar paradox in carriers of other thrombophilic defects was not observed.

Increased sperm count may account for high population frequency of factor V Leiden.

Factor V Leiden (FVL) increases the risk of venous thrombosis and pregnancy loss in carriers. Nevertheless, this relatively old mutation is prevalent in Caucasion populations, which could be explained by positive selection pressure. Men with FVL have previously been found to have higher fecundity (the time between marriage and first pregnancy). Whether this is caused by increased sperm counts in men with FVL is unknown. To assess whether men with factor V Leiden have increased sperm counts. We performed a prospective cohort study among 1139 consecutively included male partners of subfertile couples presenting at our university hospital for fertility workup between January 2000 and July 2007. All potential candidates who gave informed consent were included, irrespective of their fertility workup. In this retrospective analysis, we excluded participants with known causes of spermatogenic function or azoospermia. Subsequently, we genotyped all participants and compared sperm counts between FVL carriers and non-carriers. We identified 37 FVL carriers and 921 non-carriers. FVL carriers had higher total sperm counts and total motile sperm counts than non-carriers: 236 x 10(6) (95% CI 158-292 x 10(6)) vs. 163 x 10(6) (95% CI 147-178 x 10(6)) and 81 x 10(6) (95% CI 54-105 x 10(6)) vs. 52 x 10(6) (95% CI 48-57 x 10(6)), respectively. To our knowledge, this is the first study that indicates that an increased incidence of a genotype may be controlled by increased sperm counts. However, the finding that men with FVL had higher total (motile) sperm counts was not statistically significant and needs confirmation in other studies.

The Risk of Venous Thrombosis Related to Increase in Body Mass Index Is Mediated by Factor VIII Induced APC-Resistance.

Abstract 453 Background:The reason why a high BMI predisposes to venous thrombosis is not clarified. People with overweight or obesity tend to be more immobile which may lead to clot formation through stasis. It is also possible that these subjects acquire a prothrombotic state. Factor (F) VIII can be released by adipose tissue through inflammatory cytokines, which consequently might induce APC-resistance. This APC-resistance could be aggravated in case FV Leiden is also present. In addition, presence of high levels of FVIII in non-O blood group subjects could worsen this further. Objective:To determine whether an association exists between BMI and APC-resistance, and whether the combination of both high BMI and APC-resistance increased the risk of venous thrombosis in the Leiden Trombophilia Study (LETS). Whether increasing FVIII levels induced APC-resistance was also studied. In a pooled analysis of LETS and a Norwegian case-cohort study (TROL), we verified if FV Leiden modified the risk of increasing BMI on the occurence of venous thrombosis and whether these risks were further increased by blood group non-O. Methods:Linear regression was used to determine the relation between increasing APC-resistance and BMI, increasing FVIII levels and BMI, increasing APC-resistance and FVIII levels, and between increasing APC-resistance and BMI adjusted for FVIII levels. Cut-off points needed to create tertile categories of APC-resistance were derived from the control-group of the LETS and the TROL population separately. Logistic regression was used to calculate odds ratios and their 95% confidence intervals, adjusted for age and sex. To make the TROL and LETS population more similar for the current analysis, we restricted the analysis in the TROL subjects to those who were younger than 70 and to those who had a DVT only (n=183 cases and n=696 controls). Results:APC-resistance increased linearly with increasing BMI. A same phenomenon was observed for FVIII, i.e. an increase of BMI led to higher FVIII levels. Increased APC-resistance was in its turn associated with an increase of FVIII levels. FVIII explained part of the relation between APC and BMI, as the slope of the regression line of APC-resistance on BMI levels decreased after adjustment for FVIII. To examine the effect of increasing BMI, independent of existing APC-resistance, on the risk of venous thrombosis, we restricted the analysis to subjects from the LETS in whom APC-resistance was not related to other factors such as FV Leiden or oral contraceptive use. In these subjects (n=237 cases and n=369 controls), the risk of venous thrombosis increased 1.4-fold for those with a BMI in the median tertile (odds ratio 1.4; 95% CI, 0.9-2.3) and 2.5-fold for those in the upper tertile (odds ratio 2.5; 95% CI, 1.6-3.9), as compared to subjects in the lowest tertile. Adjustment for APC-resistance or FVIII led to a slight decrease in these relative risk estimates. Non-FV Leiden-carriers with blood group O were only at risk of venous thrombosis when they had a BMI in the upper tertile compared to non-FV Leiden-carriers with blood group O and a BMI in the lowest tertile; (adjusted odds ratio 1.9). This risk was modestly increased when non FV Leiden carriers with non-O blood group were compared with this reference group, with adjusted odds ratios of 1.5, 2.4 and 3.4, respectively, within the BMI tertiles. This risk was strongly increased when FV Leiden carriers with blood group O were compared to the reference group, with adjusted odds ratios of 3.0, 8.3 and 9.7, respectively, within the BMI tertiles. Risk of FV Leiden carriers with non-O blood group showed the highest risk of venous thrombosis compared to the reference group, no longer in a dose-response way, with adjusted odds ratios of 40.6, 23.3 and 25.2, respectively, within the BMI tertiles. Conclusion:The increased risk of venous thrombosis in subjects with high BMI is mediated by FVIII induced APC-resistance. Subjects with FV Leiden and increasing BMI had a higher risk of venous thrombosis compared to non-carriers, and this risks was more than 20 fold increased in carriers of blood group non-O and FV Leiden. Future studies are needed to show if these risks can be downgraded by weight loss. Disclosures:No relevant conflicts of interest to declare.

Procarboxypeptidase U (TAFI) contributes to the risk of thrombosis in patients with hereditary thrombophilia

Introduction It is considered that high plasma levels of procarboxypeptidase U (proCPU or TAFI) can promote the development of thrombosis, but data comparing proCPU levels in thrombophilia carriers and healthy subjects are rather scarce. Moreover, the results of previous studies on the risk of thrombosis related to high proCPU concentration in this population were not consistent. Although the 325 polymorphism of proCPU has a significant effect on the CPU half-life, it's influence on the risk of thrombosis or spontaneous pregnancy loss in carriers of hereditary thrombophilia is not clear. Materials and Methods The study population consisted of 144 thrombophilic patients (94 heterozygous and 10 homozygous carriers of FV Leiden, 26 heterozygous carriers of the prothrombin G20210A variation and 14 double carriers of FV Leiden and FII variation) and 69 healthy controls. Results The results show that patients with inherited thrombophilia have a tendency toward lower mean proCPU plasma levels compared to healthy controls, however, this difference was only significant in carriers of FII G20210A (p = 0.014). A higher frequency of the most stable Ile325Ile proCPU was seen among carriers of FII G20210A mutation compared to the control group (19% vs 7%; p = 0.186). In the second part of the study proCPU as a risk factor for thrombosis was evaluated. In heterozygous carriers of FV Leiden or FII G20210A high levels of proCPU conferred to an almost 4-fold increased risk for spontaneous onset thrombosis. The more stable Ile325Ile proCPU seems to impose a higher risk for clinical manifestation of the thrombophilic condition. Finally, a significant positive correlation between F1+2 and proCPU concentration was seen. Conclusion The increased risk of thrombosis in thrombophilia patients is not only ascribable to an increased thrombin generation, but also high levels of proCPU and the presence of the 325Ile genotype tip the balance towards thrombotic tendency even further.

519: Do antiphospholipid antibodies affect pregnancy outcomes in women heterozygous for Factor V Leiden?

Antiphospholipid antibodies are associated with a spectrum of pregnancy complications, including preeclampsia (PE) and small for gestational age (SGA) fetuses. Our goals were to assess the frequency of elevated levels of anticardiolipin (aCL) and anti-2-glycoprotein I (anti-2-GPI) IgG and IgM antibodies in women with and without the Factor V Leiden (FVL) mutation and to examine if interactions between the FVL mutation and aCL and anti-2-GPI antibodies alter the rates of PE and SGA. Secondary analysis of a multicenter, prospective observational study of FVL prevalence among 5188 pregnant women. 371 women (120 cases of FVL heterozygotes and 251 FVL mutation negative randomly selected controls [matched for clinical center, maternal age, and race/ethnicity]) underwent serum analysis for the presence of aCL and anti-2-GPI IgG and IgM. The primary outcome was development of PE and/or SGA (<10%). Forty seven women (12.7%) developed the primary outcome; there were no differences in primary outcome rates between women with and without antiphospholipid antibodies, regardless of FVL mutation status. Among FVL carriers, antiphospholipid antibody status does not appear to contribute to adverse pregnancy outcome.

Type and Location of Venous Thromboembolism in Carriers of Factor V Leiden or Prothrombin G20210A Mutation Versus Patients With No Mutation

Factor V Leiden (FVLeiden) and prothrombin G20210A are the most common genetic causes of thrombophilia and established risk factors for different clinical manifestations of venous thromboembolism (VTE). This study investigated whether the clinical manifestation of VTE, the extension of deep vein thrombosis (DVT) and the presence of transient risk factors at the time of the first VTE, differed among patients with mutations (97 with FVLeiden; 33 with prothrombin G20210A) and in 109 patients without thrombophilia. Isolated pulmonary embolism (PE) was less prevalent in patients with FVLeiden (6%) and no thrombophilia (6%) than in those with prothrombin G20210A (15%). No difference was found in the incidence of distal DVT. Regarding the extension of proximal DVT, the lowest incidence for isolated popliteal vein and the highest for iliofemoral vein were observed in patients with prothrombin G20210A. No difference was observed between groups of patients with or without thrombophilia by unprovoked VTE. The pregnancy/puerperium was the most prevalent risk factor in carriers of prothrombin G20210A. Among FVLeiden carriers, the most prevalent risk factor was surgery, and in patients without thrombophilia, it was trauma (P < .05). Thrombosis of the upper limb was more frequent in a group without thrombophilia than in patients with mutations (P < .01). Transverse sinus venous thrombosis was present only in patients with prothrombin G20210A. Carriers of prothrombin G20210A have an increased risk of developing isolated PE and more severe clinical manifestations than those with FVLeiden or without thrombophilia.

Carriership of Factor V Leiden and Evolutionary Selection Advantage

Historically, lethal exsanguinations and severe infections have been two major causes of maternal death. Gene mutations that lower the risk of profuse hemorrhage or severe infections would give a survival advantage. A single mutation of coagulation factor V, known as FV Leiden (FVL), can be such a beneficial mutation. FVL is common among Caucasians and today confers an increased risk of thromboembolism. However, the high prevalence of FVL (up to 15%) in the general population suggests that it has given an evolutionary advantage. In this review, we discuss possible mechanisms of the evolutionary survival advantage associated with FVL. In women, FVL confers lower risk of blood loss and profuse hemorrhage in association with delivery and improves the hemoglobin status. In addition, FVL carriers possibly have a survival advantage during sepsis. In conclusion, the high prevalence of FVL may be the result of one or more evolutionary selection advantages.

Should female relatives of factor V Leiden carriers be screened prior to oral contraceptive use?

Venous thromboembolism (VTE) is three-fold higher among FV Leiden (FVL) carriers receiving oral contraceptives (OCPs) than in the general population. FVL screening, however, is not routinely performed before prescribing OCP, and the cost-effectiveness of this strategy is unknown. A decision tree model was constructed to evaluate FVL screening and prophylactic anticoagulation (AC) strategies in female relatives of FVL carriers. In the model, AC was low molecular weight heparin, given warfarin embryopathy risks. VTE morbidity, mortality, and other clinical parameters were obtained from published studies. Drug costs were based on average wholesale price, and counseling included VTE risk with OCP use and FVL status. Outcomes included medical costs, effectiveness measured as quality-adjusted-life-years (QALY), and the incremental cost-effectiveness ratio (ICER) over 30 years, with cost and effectiveness discounted at 3%/year. FVL screening and counselling without prophylactic AC cost less and was more effective than no screening in this population, but was less effective than screening, counselling, and prophylaxis during high-risk periods, which gained 0.083 QALY, for an ICER of $147/QALY gained. Screening with counselling and long-term AC cost $3,536 with minimal QALY gain and an ICER >$600,000/QALY. Screening, OCP counseling, and prophylactic AC during high-risk periods was favoured and cost <$20,000/QALY, unless: (a) high-risk prophylaxis cost >$4,231 (base $932), (b) long-term prophylaxis cost <$1199 (base $6,546), or (c) VTE relative risk reduction with prophylaxis was <21% (base 90%). In conclusion, screening, counselling and prophylactic AC during high-risk periods in female relatives of FVL carriers is an economically favourable strategy.