The association of the JAK2 46/1 haplotype with non-splanchnic venous thrombosis

Background

The inherited JAK2 46/1 haplotype is strongly associated with the development of myeloproliferative neoplasms (MPNs), and its increased frequency has also been reported in splanchnic venous thrombosis (SVT). In the present study, the role of the JAK2 46/1 haplotype in non-splanchnic venous thrombosis (non-SVT) was investigated.

Methods and Results

We genotyped 438 patients with non-SVT, 226 patients with MPNs and 459 healthy controls for three single nucleotide polymorphisms (SNPs) which tag the JAK2 46/1 haplotype (rs12342421 G > C, rs12343867 T > C and rs10974944 C > G). We found statistically significant association of the rs12342421 GC + CC genotypes (OR = 1.40; p = 0.023) and the rs12343867 TC + CC genotypes (OR = 1.83; p = 7.02x10^- 5) with non-SVT. We also found that the CC haplotype of these two SNPs was associated with an increased risk of the disease (OR = 1.68; p = 0.009). Stratification analysis indicated that the observed association of the JAK2 46/1 haplotype with non-SVT was probably largely free of confounding effect of thrombophilic risk factors. In addition, we established a strong association of SNPs rs12342421 and rs10974944 and their CG haplotype with MPNs and with JAK2 V617F-positive MPNs.

Conclusions

This study provides statistical evidence that SNPs rs12342421 and rs12343867 are associated with an increased risk of non-SVT. Consistently, haplotypes of the SNPs were also associated with non-SVT risk, suggesting that inherited genetic variation in the JAK2 gene may play a role in the pathogenesis of non-SVT. Furthermore, the reported associations of the JAK2 46/1 haplotype with MPNs as well as with the occurrence of the JAK2 V617F mutation in MPNs were confirmed.     

TAFI gene polymorphisms in patients with cerebral venous thrombosis

Gene polymorphisms of thrombin activatable fibrinolysis inhibition (TAFI) factor have been investigated in various studies in terms of etiology (recurrence) and treatment (fibrinolytic effect) of thrombus formation. Cerebral venous thrombosis (CVT) is a life-threatening disease observed in young persons. Fifty-nine patients with CVT and 100 healthy control subjects were enrolled in the case/control study. The association between TAFI gene polymorphisms ?438G>A, +505A>G and +1040C>T and cerebral venous thrombosis was investigated. It was found that frequencies of polymorphic genotype and allele were not different in patients than in control group and that they were not significant for cerebral venous thrombosis.     

Association between the plasminogen activator inhibitor-1 4G/5G polymorphism and risk of venous thromboembolism: A meta-analysis

Introduction

The plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism was considered to be associated with risk of venous thromboembolism (VTE), while evidence remains inadequate. To provide a more accurate estimation of this relationship, we performed an updated meta-analysis of all eligible studies.

Materials and Methods

A systematical search was performed in PubMed, EMBASE, Wanfang, China National Knowledge Infrastructure (CNKI) and Cqvip databases to identify relevant studies published before March 6^th 2014. The odds ratios (ORs) with 95% confidence intervals (CIs) were pooled using the fixed/random-effects model using Review Manager 5.1 and STATA 12.0.

Results

A total of 34 studies with 3561 cases and 5693 controls were analyzed. Overall, significant association between the PAI-1 4G/5G variant and VTE risk in total population (dominant model: OR = 1.32, 95%CI: 1.13-1.54) was observed. And this variant was also related to the deep vein thrombosis risk (dominant model: OR = 1.60, 95%CI: 1.24-2.06, P = 0.0003). In the subgroup analyses on ethnicity, significant results were obtained in both Asians (dominant model: OR = 2.08, 95%CI: 1.29-3.35, P = 0.003) and Caucasians (dominant model: OR = 1.31, 95%CI: 1.10-1.56, P = 0.003). However, no significant association was found in patients with provoked VTE. In terms of subgroup analyses on co-existence of other thrombotic risk factors, the PAI-1 4G/5G polymorphism was significantly associated with VTE risk in patients with factor V Leiden mutation (dominant model: OR = 1.72, 95%CI: 1.17-2.53), but not in patients with cancer or surgery.

Conclusion

Our findings demonstrate the role of PAI-1 4G/5G polymorphism being a risk candidate locus for VTE susceptibility, especially in patients with other genetic thrombophilic disorders.     

Influence of CYP2C9 polymorphism and phenytoin co-administration on acenocoumarol dose in patients with cerebral venous thrombosis

Background

The study aimed at evaluating the contribution of genetic variations in the drug metabolizing enzyme, CYP2C9, and the influence of co-medication with the antiepileptic drug, phenytoin, to variability in acenocoumarol response, in patients with cerebral venous thrombosis (CVT).

Methods

476 acenocoumarol-treated CVT patients (153 males and 323 females) were genotyped for CYP2C9*2 and CYP2C9*3 polymorphisms by PCR-RFLP method. Mean acenocoumarol dose required for achieving and maintaining a stable international normalized ratio (INR) was calculated for different genotypes. The effect of co-administration with phenytoin was determined.

Results

Genotype distributions of CYP2C9 were as follows: 83%CYP2C9*1/*1, 8.6%CYP2C9*1/*3, 5.9%CYP2C9*1/*2, 1.9%CYP2C9*3/*3, 0.4%CYP2C9*2/*3 and 0.2%CYP2C9*2/*2. During the initiation phase of anticoagulation the CYP2C9*2 allele was independently associated with low acenocoumarol dose requirement (Adjusted OR 5.38; 95%CI 1.65-17.49; p = 0.005). Similarly, the adjusted odds ratio for requiring a low dose during the induction phase in patients bearing the CYP2C9*3 allele was 12.79 (95%CI 4.74-34.57; p < 0.0001). During the maintenance phase, CYP2C9*2 and CYP2C9*3 alleles were associated with 19-fold (Adjusted OR 19.67; 95%CI 2.46-157.19; p = 0.005) and 11.9-fold odds (Adjusted OR 11.98; 95%CI 2.61-55.08; p = 0.001) of requiring a low dose. Clinical covariates such as age, alcohol consumption, postpartum state and oral contraceptive intake also influenced acenocoumarol dosage. Co-medication with phenytoin was associated with lower dose requirement across genotypes during the initiation phase. However, during the maintenance phase, phenytoin-treated patients of all genotypes required higher doses of acenocoumarol.

Conclusion

This study emphasizes the fact that polymorphisms in CYP2C9 gene and co-medication with phenytoin alter the anticoagulant effect of acenocoumarol.     

The Methylenetetrahydrofolate Reductase Polymorphism (MTHFR c.677C > T) and Elevated Plasma Homocysteine Levels in a U.S. Pediatric Population with Incident Thromboembolism

Objective

Elevated plasma homocysteine (tHcy) and the MTHFR c.677C > T variant have been postulated to increase the risk of venous thromboembolism (VTE), although mechanisms and implications to pediatrics remain incompletely understood. The objectives of this study were to determine the prevalences of elevated tHcy and MTHFR variant in a pediatric population with VTE or arterial ischemic stroke (AIS), and to determine associations with thrombus outcomes.

Study Design

Subjects were enrolled in an institution-based prospective cohort of children with VTE or AIS. Inclusion criteria consisted of objectively confirmed thrombus, ≤ 21 years at diagnosis, tHcy measured and MTHFR c.677C > T mutation analysis. Clinical and laboratory data were collected. Frequencies for elevated tHcy and MTHFR variant were compared with NHANES values for healthy US children and also between study groups (VTE vs AIS, provoked vs idiopathic) and by age.

Results

The prevalences of hyperhomocysteinemia or MTHFR variant were not increased in comparison to NHANES. tHcy did not differ between those with wild-type MTHFR versus either c.677C > T heterozygotes or homozygotes. There was no association between tHcy or MTHFR variant and thrombus outcomes.

Conclusion

In this cohort of US children with VTE or AIS, neither the prevalence of hyperhomocysteinemia nor that of MTHFR variant was increased relative to reference values, and adverse thrombus outcomes were not definitively associated with either. While it is important to consider that milder forms of pyridoxine-responsive classical homocystinuria will be detected only by tHcy, we suggest that routine testing of MTHFR c.677C > T genotype as part of a thrombophilia evaluation in children with incident thromboembolism is not warranted until larger studies have been performed in order to establish or refute a link between MTHFR and adverse outcomes.     

Association of F11 polymorphism rs2289252 with deep vein thrombosis and related phenotypes in population of Latvia

Introduction

Deep vein thrombosis (DVT) has a strong inherited predisposition that is partly explained by the strong genetic risk factors such as mutations in factor V, prothrombin, antithrombin III, protein C and S genes. Only recently the first GWAS have been performed on DVT resulting in discovery of novel genetic variants, however, the information on the common polymorphisms predisposing to the risk of DVT is still scarce.

Materials and Methods

Here we selected six SNPs (rs5361 in SELE, rs2066865 in FGG, rs2227589 in SERPINC1, rs1613662 in GP6, rs13146272 in CYP4V2, rs2289252 in F11) reported to be associated with venous thrombosis conditions and studied the association of these common variants in selected case (n = 177) and control (n = 235) groups from population of Latvia. Genotyping was performed using TaqMan hybridization probe SNP genotyping assay.

Results

Patients with DVT had a significantly higher frequency of F11 rs2289252 polymorphism (p = 0.001; OR [95%CI] = 1.61 [1.20-2.14]). When stratified by recurrence of DVT the tendency was observed that the same SNP had higher OR value in group of DVT patients with repeated episodes of DVT compared to patients with single DVT episode (p = 0.009; OR [95%CI] = 2.27[1.22-4.21] and p = 0.009; OR [95%CI] = 1.52[1.11-2.08] respectively), but due to limited group of cases this finding should be replicated.

Conclusion

We conclude that F11 gene variant rs2289252 contribute to inherited forms of DVT incidence and correlation of other analysed SNPs should be explored in populations with greater sample size and associated with various thrombosis related traits.     

The role of inherited thrombophilia in patients with isolated pulmonary embolism: A systematic review and a meta-analysis of the literature

Introduction

Venous thromboembolism (VTE) is a common vascular disease that results in deep venous thrombosis (DVT) and pulmonary embolism (PE). Factor V Leiden mutation (FVL) and G20210A prothrombin mutation (PTM) are associated with an increased risk of VTE. Recent studies have reported a lower prevalence of FVL in patients with isolated PE than in patients with DVT with or without PE, suggesting the possibility that the prevalence of FVL in patients with isolated PE may be not significantly different from that of the general population. To address this issue, we performed a systematic review and a meta-analysis of published studies that assessed the prevalence of FVL and/or PTM in patients with isolated PE and in controls without VTE.

Methods

MEDLINE and EMBASE databases were searched up to October 2013. Pooled odds Ratios (OR) and 95% confidence intervals (CIs) were calculated using a random-effects model. Statistical heterogeneity was evaluated using the Cochran Q and I² statistics.

Results

Eighteen studies totalling more than 11,000 patients were included. FVL was found significantly more often in patients presenting isolated PE than in controls (OR 2.06; 95% CI 1.66, 2.56; p < 0.0001). The prevalence of PTM was also significantly different in patients presenting with isolated PE than in controls (OR 2.64, 95% CI 1.92, 3.63; p < 0.0001). Heterogeneity among studies was low.

Conclusion

FVL and PTM are both associated with isolated PE. However, the association magnitude between PE and FVL mutation appeared to be lower compared to that observed in the general population of VTE patients.     

FGB mutations leading to congenital quantitative fibrinogen deficiencies: An update and report of four novel mutations

Introduction

Causative mutations leading to congenital quantitative fibrinogen are frequently clustered in FGA encoding the fibrinogen Aα-chain. Mutations of FGB encoding the Bβ-chain are less common and of interest since the Bβ-chain is considered the rate-limiting factor in the hepatic production of the fibrinogen hexamer.

Method

Four novel FGB mutations were identified in two afibrinogenemic (one new-born and one 30 years old male) and hypofibrinogenemic (a 49 years old female) patient, with heterogeneous thrombotic and bleeding phenotype. The human fibrinogen beta chain precursor protein sequence (P02675) was obtained from the UniProt database. The resulting models were analysed in SwissPdbViewer 4.1 and POV-Ray 3.7.

Results

The FGB c.895 T>C p.Y299H (numbering from the initiator Met) and the FGB c.1415G>T p.G472V were predicted to be deleterious by SIFT analysis. The first replaces an uncharged aromatic amino acid side chain by a positively charged side chain modifying the balance in the distribution of hydrophobic and hydrophilic of the 10 Å neighbourhood residues. The second replaces one non-charged aliphatic side chain by another without any changes for the 10 Å surrounding region. The FGB c.352C>T p.Q118X leads to a severe premature termination codon and the FGB intron 4: IVS4-1G>C (c719-1G>C) leads to skipping of exon 5 or usage of a cryptic acceptor site located upstream or downstream of the normal site.

Conclusions

The continuous characterization of novel molecular defects responsible for fibrinogen deficiency combined with modelling of mutant proteins will continue to provide a better comprehension of the complexity of fibrinogen synthesis and physiology.     

Predictors of attempted inferior vena cava filters retrieval in a tertiary care centre

Background

Retrieval rates of optional recovery inferior vena cava (IVC) filters in US hospitals range from 11 - 70%. We conducted a retrospective study in a Canadian tertiary care centre to determine retrieval rates and predictors of filter removal.

Methods

Consecutive patients who had a retrievable IVC filter inserted or removed between January 2007 and December 2010 were identified. Data collected included baseline demographics, indications for filter insertion and removal, documentation of an IVC filter management plan, reasons for non-retrieval, complications, and death.

Results

275 patients with a median age of 60 years were followed in hospital for a median of 17 patient-days (range 1–876). Indications for filter placement were acute or prior VTE with contraindication to anticoagulation (72.4%), high risk of PE (11.3%) and primary prophylaxis (13.8%). Retrieval was attempted in 165 patients (60%) and was successful in 146 patients (53.1%). The most common reason for failed retrieval was filter thrombus. Predictors of attempted retrieval included documentation of filter plan (odds ratio [OR] 16.7; p < 0.001), surgical indication for IVC filter insertion (OR 4.8; p = 0.002), age ≤ 70 years (OR 3.8; p = 0.001), Hematology service involvement (OR 3.0; p = 0.006), and presence of metastatic cancer (OR 0.2; p = 0.001). Thrombotic complications occurred in 48 patients, including 3 patients who died of fatal PE.

Conclusion

Our filter retrieval rate is suboptimal. Improvements in follow-up documentation or a dedicated clinical service may help increase retrieval rates.     

The impact of co-morbid conditions on family history of venous thromboembolism in Whites and Blacks

Introduction

Our objectives were to compare the magnitude of family history as a risk factor for venous thromboembolism (VTE) risk between Blacks and Whites, and to assess the impact of co-morbid conditions on familial risk for VTE.

Materials and methods

We used data from the Genetic Attributes Thrombosis Epidemiology (GATE) study, a matched case-control study which enrolled Blacks and Whites aged 18-70 years in Atlanta, Georgia. A total of 1,094 case patients with a deep vein thrombosis (DVT) or pulmonary embolism (PE) and 1,264 control patients were interviewed about their family history.

Results

Family history of VTE was a statistically significant risk factor for VTE among Blacks (odds ratio (OR) = 2.9, 95% confidence interval (CI) 2.0-4.1; P value < 0.0001) and among Whites (OR = 2.7, 95% CI 1.9-3.7; P value < 0.0001); among Blacks and Whites who were obese or had hypertension; among Blacks who had diabetes mellitus or cancer; as well as among males and females, and across all age categories. Family history of VTE increased the risk of VTE among Blacks with cancer by about 6-fold, whereas among Blacks without cancer the increased risk due to a positive family history was about 3-fold; a 2-fold relative difference. In addition, family history was a risk factor for VTE among case patients with DVT only or with PE only. The effect of family history generally was stronger among those with recurrent episodes of VTE compared with a first episode of VTE. For example, family history of any VTE was a strong risk factor among Black females with recurrent VTE compared with Black females with first VTE (OR = 3.9, 95% CI 2.0-7.5; P value < 0.0001).

Conclusion

Our study indicated that the adjusted attributable fraction for VTE was 16.9% among Blacks vs. 18.3% among Whites, and certain co-morbid conditions could further increase the risk of VTE associated with a positive family history of VTE.     

Who are at risk for thromboembolism after arthroplasty? A systematic review and meta-analysis

Background

Thromboembolism, including deep venous thrombosis and pulmonary embolism, is a grave threat to patients undergoing total joint replacement. Using a systematic review and meta-analysis we asked whether gene mutations or polymorphisms could be risk factors for thrombosis after arthroplasty.

Methods

We performed a comprehensive search of Medline, PubMed, Embase, Cochrane databases, China National Knowledge Infrastructure (CNKI), and Google Scholar, and identified 19 studies detailing genetic investigations of patients with thromboembolism following joint replacement.

Results

Our meta-analyses included 5149 patients who underwent arthroplasty surgery. Significant associations with venous thromboembolism were identified for factor G1691A (odds ratio (OR) 1.41, 95% confidence interval (CI) 1.03 - 1.94, p = 0.03), prothrombin G20210A (OR 2.16, 95% CI, 1.27- 3.69, p = 0.005), and MTHFR/C677T/TT (OR 2.36, 95% CI 1.03 - 5.42, p = 0.04) in Caucasian populations. No significant gene mutation was identified in Asian populations.

Conclusion

This study suggests a way to identify patients scheduled for arthroplasty who are at higher risk of thrombosis, enabling individualized treatment.     

Circulating microparticles and risk of venous thromboembolism

Introduction

Circulating microparticles (MPs) may trigger a hypercoagulable state, leading to thrombotic complications. Data on their association with venous thromboembolism (VTE) are few and inconsistent.

Materials and methods

To investigate whether or not high levels of MPs are associated with an increased risk of VTE, we carried out a case-control study on 186 patients with a first, objectively diagnosed, episode of VTE and 418 healthy controls. Plasma levels of circulating MPs were measured by flow cytometry.

Results

Patients had higher median plasma levels of total MPs than controls (2184 per μL vs 1769 per μL, p < 0.0001). The risk of VTE increased progressively with increasing MPs, with a linear dose-response effect in the log odds. Individuals with MPs above the 90th percentile of the controls’ distribution (P₉₀ = 3263 per μL) had a 5-fold increased risk of VTE than those with MPs below the 10th percentile of controls (P₁₀ = 913 per μL), independently of sex, age, body mass index, thrombophilia, and plasma factor VIII levels [adjusted odds ratio: 5.30 (95%CI: 2.05-13.7)]. Using the 95th percentile of controls as cut-off (P₉₅ = 4120 per μL), the adjusted odds ratio was 2.20 (1.01-4.79) for individuals with MPs > P₉₅ compared with those having MPs ≤ P₉₅. After exclusion of individuals with antiphospholipid antibodies and hyperhomocysteinemia, the interaction between MPs > P₉₅ and thrombophilia increased the VTE risk from 1.63 (0.60-4.50) to 6.09 (1.03-36.1).

Conclusions

High levels of circulating MPs are a possible independent risk factor for VTE.     

Thromboprophylaxis patterns,risk factors,and outcomes of care in the medically ill patient population

Introduction

Medically ill, hospitalized patients are at increased risk for venous thromboembolism (VTE) after discharge. This study aimed to examine thromboprophylaxis patterns, risk factors, and post-discharge outcomes.

Methods

This was a retrospective claims analysis involving administrative claims data and in-patient data abstracted from a sample of hospital charts. Patients aged ≥ 40 years hospitalized for ≥ 2 days for nonsurgical reasons between 2005 and 2009 were included. Hospital chart data were abstracted for a random sample of patients without evidence of anticoagulant use at 30 days post-discharge. The combined data determined whether in-patient thromboprophylaxis (anticoagulant or mechanical prophylaxis) reduces risk of VTE at 90 days post-discharge. Hazard ratios (HR) and odds ratios (OR) were calculated using Cox proportional hazard models and logistic regression.

Results

Of 141,628 patients in the claims analysis, 3.9% received anticoagulants (3.6% warfarin). VTE, rehospitalization, and mortality rates were 1.9%, 17.2%, and 6.2%, respectively. The strongest predictors of post-discharge VTE were history of VTE (HR = 4.0, 95% confidence interval [CI]: 3.3-4.8), and rehospitalization (HR = 3.9, 95% CI: 3.6-4.3). Of 504 medical charts, 209 (41.5%) reported in-patient thromboprophylaxis. There was no statistically significant difference in post-discharge VTE rates between patients who did and did not receive in-patient thromboprophylaxis. All-cause mortality was greater among patients without use of VTE prophylaxis.

Conclusion

Utilization rates of in-hospital and post-discharge VTE prophylaxis were low. In-hospital VTE prophylaxis did not reduce the risk of post-discharge VTE in the absence of post-discharge anticoagulation. Combined in-patient and post-discharge thromboprophylaxis lowered the odds of short-term, all-cause post-discharge mortality.     

Meta-Analysis to Assess the Quality of International Normalized Ratio Control and Associated Outcomes in Venous Thromboembolism Patients

Introduction

Patients with venous thromboembolism (VTE) frequently require vitamin K antagonists (VKAs) to prevent recurrent events, but their use increases hemorrhage risk. We performed a meta-analysis to assess the quality of international normalized ratio (INR) control, identify study-level predictors of poor control and to examine the relationship between INR control and adverse outcomes in VTE patients.

Materials and Methods

We searched bibliographic databases (1990-June 2013) for studies of VTE patients receiving adjusted-dose VKAs that reported time in range (2.0-3.0) or proportion of INRs in range and/or reported INR measurements coinciding with thromboembolic or hemorrhagic events. Meta-analysis and meta-regression analysis was performed.

Results

Upon meta-analysis, studies found 59% (95%CI: 54-64%) of INRs measured and 61% (95%CI: 59-63%) of the time patients were treated were spent outside the target range of 2.0-3.0; with a tendency for under- versus over-anticoagulation. Moreover, this poor INR control resulted in a greater chance of recurrent VTE (beta-coefficient = -0.46, p = 0.01) and major bleeding (beta-coefficient = -0.30, p = 0.02). Patients with an INR < 2.0 made up 58% (95%CI: 39-77%) of VTE cases, while those with an INR > 3.0 made up 48% (95%CI: 34-61%) of major hemorrhage cases. Upon meta-regression, being VKA-naïve (-14%, p = 0.04) and treated in the community (-7%, p < 0.001) were associated with less time in range, while being treated in Europe/United Kingdom (compared to North America) was associated with (11%, p = 0.003) greater time.

Conclusions

Strategies to improve INR control or alternative anticoagulants, including the newer oral agents, should be widely implemented in VTE patients to reduce the rate of recurrent events and bleeding.     

Incidental venous thromboembolism detected by PET-CT in patients with cancer: Prevalence and impact on survival rate

Introduction

People with cancer are at increased risk of incidental venous thromboembolism (VTE) and PET-CT imaging is commonly used in this population. However, the prevalence of incidental VTE detected by PET-CT in patients with cancer and its impact on survival are unknown.

Materials and Methods

This retrospective study was approved by the local Institutional Review Board. 1331 consecutive adult patients with cancer who underwent PET-CT examination between 2009 and 2012 were included in the study (mean age: 57 ± 15 years). PET-CT reports were reviewed to identify patients with incidental VTE at the time of examination. Survival rates were assessed with Kaplan-Meier curves. The Cox proportional hazards model was used to determine the association between incidental VTE and overall survival, after controlling for clinical variables.

Results

Incidental VTE was detected in 19 patients (1.4%). Patients with genitourinary malignancies, colorectal cancer and lung cancer had the highest rates of incidental VTE at PET-CT. At multivariate analysis, incidental VTE detected by PET-CT was associated with worse overall survival independently of patient age, hospitalization status at time of PET-CT examination, and the presence of metastatic disease (Hazard ratio = 2.03; 95% confidence interval = 1.08-3.81, p = 0.028).

Conclusion

Incidental VTE was detected in 1.4% of adult patients with cancer undergoing PET-CT imaging. Diagnosis of incidental VTE at PET-CT imaging was associated with worse overall survival in this population.     

Red cell distribution width and risk for venous thromboembolism: A population-based cohort study

Introduction

Red cell distribution width (RDW) has been associated with venous thromboembolism (VTE), but whether RDW is a predictor of first event of VTE is unknown. We investigated the association between RDW and incidence of first event of VTE in a population-based cohort.

Materials and Methods

RDW was measured in 27 042 subjects (aged 45–73 years, 60.6% women), without previous history of VTE or cancer within 5 years before follow-up, who participated in the Malmö Diet and Cancer study during 1991–1996. Incidence of VTE was identified from the patient register and the cause of death register during a mean follow-up of 13.8 years and studied in relation to RDW.

Results

During follow-up, 991 subjects (57.5% women) were affected by VTE (pulmonary embolism or deep venous thrombosis of the lower limbs). After adjustment for potential confounding factors the hazard ratios (HR) for VTE for the second, third and fourth RDW quartiles 1.15 (95% confidence interval 0.94–1.41), 1.41 (1.14–1.73), 1.74 (1.38–2.21), respectively, were compared with the bottom quartile of RDW. In the multivariate model subjects with the top 5% of RDW values compared with the bottom quartile had an even higher risk (HR = 2.51, 1.78–2.54). In receiver operating characteristic (ROC) analysis, the male specific area under the ROC curve (AUC) for RDW was 0.57 (95% CI 0.54–0.59). The female specific AUC was 0.56 (95% CI 0.53–0.58).

Conclusions

RDW was found to be associated with long-term incidence of first event of VTE among middle-aged subjects.     

VASP phosphorylation and genetic polymorphism for clopidogrel resistance in Chinese patients with non-cardioembolic ischemic stroke

Background

Clopidogrel resistance(CR)is found in non-cardioembolic ischemic stroke (NCIS) patients. However, it is still largely unknown how to identify CR in NCIS patients by laboratory and genetic characteristics.

Methods

A total of 95 patients with acute NCIS were recruited. Phosphorylation of the vasodilator stimulated phosphoprotein (VASP) was detected using flow cytometry, and genes(CYP2C19,CYP3A4) were detected using the Sanger method. The baseline of platelet reactivity index (BPRI) before clopidogrel treatment and the platelet reactivity index with clopidogrel treatment (CPRI) for 7 days were measured. Laboratory clopidogrel resistance (LCR) was defined as CPRI of ≥ 50%.Clinical clopidogrel resistance (CCR) was defined as the presence of progressive stroke during hospitalization, stroke recurrence or occurrence of other ischemic vascular events within 6 months.

Results

The incidence of LCR was 41.05% and 18.95% developed CCR. The incidence of LCR was significantly higher in GA/AA patients with CYP2C19 (681G > A) (χ2 = 11.16, P = 0.001) and CYP2C19 (636G > A) (χ2 = 4.829, P = 0.028) than in wildtype GG patients. CYP2C19 (681G > A) (OR 6.272, 95%CI 2.162,18.199,P = 0.001) and CYP2C19 (636G > A) (OR: 5.625,95%CI 1.439, 21.583,P = 0.013) were risk factors for LCR. patients with LCR were more likely to develop CCR (χ2 = 6.021, P = 0.014). The probability of CCR was markedly increased in GA/AA patients with CYP2C19 (681G > A) (χ2 = 10.341, P = 0.001). We identified CYP2C19 (681G > A) (OR 7.814, 95%CI 1.816, 33.618 P = 0.006), Essen score (OR 8.351, 95%CI 1.848, 37.745 P = 0.006), and LCR (OR 5.881, 95%CI 1.373, 25.192, P = 0.017) as risk factors for CCR.

Conclusion

In clinical practice,LCR and CYP2C19 gene polymorphism should be assessed in NCIS patients receiving clopidogrel treatment.The Chinese Clinical Trial Registry number: ChiCTR-ONC-13003406     

Influence of coronary artery disease-associated genetic variants on risk of venous thromboembolism

Introduction

We investigated whether genetic variations robustly associated with coronary artery disease are also associated with risk of venous thromboembolism in a well-defined, female case–control study (n = 2753) from Sweden.

Materials and Methods

39 single nucleotide polymorphisms in 32 loci associated with coronary artery disease in genome-wide association studies were identified in a literature search and genotyped in the ThromboEmbolism Hormone Study (TEHS). Association with venous thromboembolism was assessed by logistic regression.

Results

Only rs579459 in the ABO locus demonstrated a significant association with VTE. A tentative association between ANRIL and VTE in the discovery analysis failed to replicate in a meta-analysis of 4 independent cohorts (total n = 7181).

Conclusions

It appears that only the ABO locus is a shared risk factor for coronary artery disease and VTE.     

Antithrombin deficiency in three Japanese families: One novel and two reported point mutations in the antithrombin gene

Introduction

Inherited antithrombin (AT) deficiency is associated with a predisposition to familial venous thromboembolic disease. We analyzed the AT gene in three unrelated patients with an AT deficiency who developed thrombosis.

Materials and Methods

We analyzed the SERPINC1 gene in three patients. Additionally, we expressed the three mutants in the COS-1 cells and compared their secretion rates and levels of AT activity with those of the wild-type (WT).

Results

We identified three distinct heterozygous mutations of c.2534C>T: p.56Arginine → Cysteine (R56C), c.13398C>A: p.459Alanine → Aspartic acid (A459D) and c.2703C>G: p.112 Proline → Arginine (P112R). In the in vitro expression experiments, the AT antigen levels in the conditioned media (CM) of the R56C mutant were nearly equal to those of WT. In contrast, the AT antigen levels in the CM of the A459D and P112R mutants were significantly decreased. The AT activity of R56C was decreased in association with a shorter incubation time in a FXa inhibition assay and a thrombin inhibition-based activity test. However, the AT activity of R56C was comparable to that of WT when the incubation time was increased.

Conclusions

We concluded that the R56C mutant is responsible for type II HBS deficiency. We considered that the A459D and P112R mutants can be classified as belonging to the type I AT deficiency.