Risk factors for venous thromboembolism in women under combined oral contraceptive. The PILl Genetic RIsk Monitoring (PILGRIM) Study.

Identifying women at risk of venous thromboembolism (VTE) is a major public health issue. The objective of this study was to identify environmental and genetic determinants of VTE risk in a large sample of women under combined oral contraceptives (COC). A total of 968 women who had had one event of VTE during COC use were compared to 874 women under COC but with no personal history of VTE. Clinical data were collected and a systematic thrombophilia screening was performed together with ABO blood group assessment. After adjusting for age, family history, and type and duration of COC use, main environmental determinants of VTE were smoking (odds ratio [OR] =1.65, 95% confidence interval [1.30-2.10]) and a body mass index higher than 35 kg.m⁻² (OR=3.46 [1.81-7.03]). In addition, severe inherited thrombophilia (OR=2.13 [1.32-3.51]) and non-O blood groups (OR=1.98 [1.57-2.49]) were strong genetic risk factors for VTE. Family history poorly predicted thrombophilia as its prevalence was similar in patients with or without first degree family history of VTE (29.3% vs 23.9%, p=0.09). In conclusion, this study confirms the influence of smoking and obesity and shows for the first time the impact of ABO blood group on the risk of VTE in women under COC. It also confirms the inaccuracy of the family history of VTE to detect inherited thrombophilia.

[Antiphospholipids antibodies and hemodialysis: a frequent association linked to arteriovenous fistula thrombosis]. / Anticorps antiphospholipides et hémodialyse: une association fréquente corrélée à la thrombose de l'abord vasculaire.

Antiphospholipid antibodies (APL) are a heterogeneous family of auto-antibodies that recognize phospholipoproteins bound antigenic epitopes. APL prevalence in patients on chronic hemodialysis ranges from 11 to 37% in the literature. The association of APL with hemodialysis vascular access (VA) thrombosis has already been reported in small studies. In this single center and retrospective study, we defined the APL prevalence and APL risk factors in a large cohort of 192 hemodialysis patients. The association between history of VA thrombosis and APL presence was also analyzed. At least one type of APL was found in 38 patients (19.8%) of which 74% (n=28) had only lupus anticoagulant. Median age of APL positive patients was 68.1years vs. 71.3years in APL negative patients (P=0.02). Smoking history was associated with APL presence: 35.5% of APL positive patients had a smoking history vs only 18.3% of APL negative patients (P=0.04). The multivariate analysis showed an association between the history of VA thrombosis and patient age (HR [IC 95%]=1.04 [1.02-1.06]; P=0.001) or APL presence (HR [IC 95%]=3.03 [1.69-4.42]; P<10(-3)). In conclusion, the prevalence of APL in hemodialysis patients remains high despite hemodialysis techniques improvement: hemodiafiltration, biocompatibility improvements, ultrapure dialysis water. We report that a younger age and past history of smoking are associated with an increased risk of APL presence. The presence of APL, especially lupus anticoagulant, is associated to VA thrombosis in hemodialysis patients.

ABO blood group and von Willebrand factor levels partially explained the incomplete penetrance of congenital thrombophilia.

OBJECTIVE: We aimed to study the association among ABO blood group, von Willebrand factor, factor VIII plasma levels, and the risk of venous thrombosis (VT) in a cohort of 1774 relatives from 500 families with inherited thrombophilia. METHODS AND RESULTS: One hundred sixty-one of the 1774 relatives had a VT. Different risk groups were formed: no, low-(factor V Leiden or F2G20210A heterozygous carriers), and high-risk thrombophilia (antithrombin, protein C, protein S, factor V Leiden, or F2G20210A homozygous carriers and combined defects). Compared with group O, AB blood group was associated with increased risk of VT: hazard ratio (HR)=3.8 (2.0-7.2). The effect of blood group A and B was milder (HR=1.6 [1.1-2.5] and 1.8 [1.0-3.3], respectively). An increased risk of VT was observed with increasing levels of von Willebrand factor and factor VIII plasma levels (HR=2.96 [1.92-4.56] and HR=2.60 [1.92-4.56] for third versus first tertile of von Willebrand factor and factor VIII plasma levels, respectively). In multivariate analysis, AB group (HR=2.3 [1.1-4.8]), high-risk thrombophilia (HR=2.8 [1.6-4.6]), and high von Willebrand factor levels (HR=2.3 [1.3-4.0]) were significantly associated with increased risk of VT. The risk of VT in individuals with high-risk thrombophilia and AB group was 14.4× higher than in those without thrombophilia and O group (5.0-41.4). CONCLUSIONS: ABO blood group modifies the risk of VT in families with hereditary thrombophilia. Phenotyping of the ABO blood group should be performed to better assess the risk of VT in asymptomatic individuals from thrombophilic families.

Detection and characterisation of large SERPINC1 deletions in type I inherited antithrombin deficiency.

Methods routinely used for investigating the molecular basis of antithrombin (AT) deficiency do not detect large SERPINC1 rearrangements. Between 2000 and 2008, 86 probands suspected of having AT-inherited type I deficiency were screened for SERPINC1 mutations in our laboratory. Mutations causally linked to the deficiency were identified by sequencing analysis in 63 probands. We present here results of multiplex ligation-dependent probe amplification (MLPA) analysis performed in 22 of the 23 remaining probands, in whom sequencing had revealed no mutation. Large deletions, present at the heterozygous state, were detected in 10 patients: whole gene deletions in 5 and partial deletions removing either exon 6 (n = 2), exons 1-2 (n = 1) or exons 5-7 (n = 2) in 5 others. Exon 6 partial deletions are a 2,769-bp deletion and a 1,892-bp deletion associated with a 10-bp insertion, both having 5' and/or 3' breakpoints located within Alu repeat elements. In addition, we identified the 5' breakpoint of a previously reported deletion of exons 1-2 within an extragenic Alu repeat. Distinct mutational mechanisms explaining these Alu sequence-related deletions are proposed. Overall, in this series, large deletions detected by MLPA explain almost half of otherwise unexplained type I AT-inherited deficiency cases.

Comparison of skin microvascular reactivity with hemostatic markers of endothelial dysfunction and damage in type 2 diabetes.

AIM: Patients with non-insulin-dependent diabetes mellitus (NIDDM) are at increased cardiovascular risk due to an accelerated atherosclerotic process. The present study aimed to compare skin microvascular function, pulse wave velocity (PWV), and a variety of hemostatic markers of endothelium injury [von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (t-PA), tissue factor pathway inhibitor (TFPI), and the soluble form of thrombomodulin (s-TM)] in patients with NIDDM. METHODS: 54 patients with NIDDM and 38 sex- and age-matched controls were studied. 27 diabetics had no overt micro- and/or macrovascular complications, while the remainder had either or both. The forearm skin blood flow was assessed by laser-Doppler imaging, which allowed the measurement of the response to iontophoretically applied acetylcholine (endothelium-dependent vasodilation) and sodium nitroprusside (endothelium-independent vasodilation), as well as the reactive hyperemia triggered by the transient occlusion of the circulation. RESULTS: Both endothelial and non-endothelial reactivity were significantly blunted in diabetics, regardless of the presence or the absence of vascular complications. Plasma vWF, TFPI and s-TM levels were significantly increased compared with controls only in patients exhibiting vascular complications. Concentrations of t-PA and PAI-1 were significantly increased in the two groups of diabetics versus controls. CONCLUSION: In NIDDM, both endothelium-dependent and -independent microvascular skin reactivity are impaired, whether or not underlying vascular complications exist. It also appears that microvascular endothelial dysfunction is not necessarily associated in NIDDM with increased circulating levels of hemostatic markers of endothelial damage known to reflect a hypercoagulable state.

Multicenter evaluation of a bilayer polymer blood collection tube for coagulation testing: effect on routine hemostasis test results and on plasma levels of coagulation activation markers.

We compared the results of different hemostasis tests obtained in an evacuated bilayer polymer tubes (Vacuette, Greiner Bio-One) and in a siliconized glass tubes containing the same citrate concentrations (0.109 M and 0.129 M). For that purpose, blood was collected in five centers from 60 untreated patients and from patients on oral anticoagulant (n = 168), unfractionated heparin (n = 111) or a low molecular weight derivative (n = 108). Test results obtained in polymer tubes were not significantly different from those in glass tubes, except for INR when a high ISI thromboplastin was used (p < 0.0001 for tubes containing 0.129 M sodium citrate) and for APTT (p < 0.05 for both citrate concentrations). However, these differences had no clinical relevance (Bland-Altman analysis). In addition, no effect of aging of the polymer tubes on the test results could be demonstrated. The plasma levels of F1+2 and TAT, measured in a subset of 30 untreated patients, were significantly lower when blood was collected in polymer than in glass tubes, for both citrate concentrations. These results suggest that samples collected into the Vacuette polymer tubes allow accurate routine hemostasis testing both in untreated patients and in patients on traditional anticoagulant treatment during the whole shelf-life indicated by the manufacturer.

FcgammaRIIIb and complement component C7 codeficiency in a patient with recurrence of fulminant meningococcal septic shock.

Individuals with deficiencies of the late components of complement exhibit a susceptibility to the recurrence of meningococcal disease with a usually mild clinical presentation. We report the recurrence of fulminant meningococcal disease in a complement component C7-deficient patient. We found a total deficiency of FcgammaRIIIb on neutrophils, which could partially explain the unusually severe clinical presentation.

Plasma fibrinogen concentration predicts the risk of myocardial infarction differently in various parts of Europe: effects of beta-fibrinogen genotype and environmental factors. The HIFMECH Study.

The propensity to atherothrombotic disease differs in Europe, with high-risk regions located in the North of Europe and lowrisk regions in the South of Europe. The HIFMECH study (Hypercoagulability and Impaired Fibrinolytic function MECHanisms predisposing to myocardial infarction (MI) study) was undertaken to elucidate genetic and environmental mechanisms underlying MI based on investigations of postinfarction patients and healthy individuals recruited from Stockholm, Sweden, London, England (North of Europe), Marseille, France and San Giovanni Rotondo, Italy (South of Europe). In the present report, emphasis was placed on fibrinogen, a multifunctional protein, widely recognized as an independent predictor of atherothrombotic disease. The adjusted plasma fibrinogen concentration was an independent discriminator between cases and controls in London (SOR 3.58; 95% CI 1.31; 9.83), but not in the other centres. Genotyping for six beta-fibrinogen promoter single nucleotide polymorphisms was performed of which -249C/T, -455G/A and -854G/A were used in analysis as a consequence of the linkage disequilibrium pattern. Four haplotypes, with similar distribution across Europe, were detected: CGG (46.7%), CAG (20.3%), TGG (18.2%) and CGA (14.8%). A significant haplotype effect on plasma fibrinogen concentration was observed in patients (p < 0.001) but not in controls (p = 0.08). The -455G/A genotype related to plasma fibrinogen concentration amongst patients along with centre and IL-6 concentration (together explaining 11.5% of the variation), whereas predictors amongst controls included centre, body mass index, IL-6 and smoking habit (explaining 15.7%). Thus, plasma fibrinogen concentration contributes differently to MI across Europe, and a disease-related stimulus is required to evoke allele-specific regulation of fibrinogen synthesis.