Background: Neutrophils Extracellular Traps (NETs) are emerging biomarkers for their key role in immunothrombosis, including in the context of the recent COVID-19 epidemic. Aims: With the aim of characterizing novel molecular determinants associated with the inter individual variability of NET plasma levels, NETs were measured using a MPO-DNA ELISA assay in 657 participants of the FARIVE study, a French case-control study (372-285) for venous thrombosis. FARIVE participants were typed for genome wide polymorphisms using an Illumina DNA array. Methods: Using a compound poisson-gamma modeling of the NETs distribution characterized by a mixture of excess of 0 values and of positive values, a genome wide association analysis of 8,866,687 imputed polymorphisms was performed. Results: The analysis revealed a significant association peak ( P = 1.7 × 10-8 ) on chromosome 21q21.3. Carriers of the A allele at the lead polymorphism (rs57502213) exhibited increased NETs levels (β=+0.97 ± 0.16) than non carriers, homogeneously in VTE cases (β=+1.20 ± 0.21, N = 372) and in controls (β=+0.73 ± 0.25, N = 285). This polymorphism explained ∼2% of the variability of NETs plasma levels. Rs57502213 maps to microRNA MIR155HG but exhibits very strong linkage disequilibrium with several others polymorphisms covering the MRPL29, JAM2, GABPA and APP genes. Interestingly, GABPA codes for a transcription factor that has been demonstrated in vitro to play a role in the nuclear maturation of neutrophils from which NETs are derived, while APP has been demonstrated to control NET formation in mice. Conclusions: To our knowledge, this work is the first genome-wide association study on NETs and provides the first epidemiologic evidence that the chr21q21.3 locus participates to the regulation of NETs in humans. The association that we observed deserves to be further validated in independent samples (a call will be launched during the ISTH presentation to encourage collaboration) and further investigations will be needed to fine map the genetic regulation of NETs at this locus.

Objective Arterial thrombosis is common during SARS-CoV-2 infection suggesting possible role of platelet activation.

À l’heure actuelle, le bilan de thrombophilie biologique constitutionnelle comprend la recherche de cinq anomalies : les déficits en inhibiteurs naturels de la coagulation (antithrombine, protéine C et protéine S) ainsi que la recherche du facteur V Leiden et du variant G20210A de la prothrombine. Ce bilan est figé depuis le début des années 1990. Cependant, des découvertes technologiques importantes en termes de génotypage et de séquençage de l’ADN au début des années 2000 ont permis des avancées majeures dans l’identification des facteurs génétiques associés à la maladie thromboembolique veineuse (MTEV). Ainsi les études pangénomiques dites GWAS, utilisant des puces ADN, ont permis d’identifier au moins 30 nouveaux variants génétiques fréquents associés au risque de MTEV. L’avènement du séquençage à haut débit, permettant à présent de séquencer l’ensemble du génome d’un individu a permis aussi d’identifier des variants beaucoup plus rares sur des gènes non impliqués dans la cascade de la coagulation comme MAST2. L’ensemble de ces nouvelles approches technologiques a permis ainsi d’identifier de nombreux nouveaux facteurs de risque génétiques de MTEV. Il est nécessaire à présent de développer de nouvelles stratégies permettant d’implémenter ces nouvelles découvertes en clinique.

Factor V serves an important role in the regulation of blood coagulation. The rs6025 (R534Q) and rs4524 (K858R) polymorphisms in the F5 gene, are known to influence the risk of venous thrombosis. While the rare Q534 (factor V Leiden) allele is associated with an increased risk of venous thrombosis, the minor R858 allele is associated with a lower risk of disease. However, no study has deeply examined the cumulative impact of these two variations on venous thrombosis risk. We study the association of these polymorphisms with the risk of venous thrombosis in 4 French case-control populations comprising 3719 patients and 4086 controls. We demonstrate that the Q534 allele has a dominant effect over R858. Besides, we show that in individuals not carrying the Q534 allele, the protective effect of the R858 allele acts in a dominant mode. Thrombin generation-based normalized activated protein C sensitivity ratio was lower in the 858R/R homozygotes than in the 858K/K homozygotes (1.92 ± 1.61 vs 2.81 ± 1.57, p = 0.025). We demonstrate that the R858 allele of the F5 rs4524 variant protects from venous thrombosis only in non-carriers of the Q534 allele of the F5 rs6025. Its protective effect is mediated by reduced factor VIII levels and reduced activated protein C resistance.

Hormonal exposure in young women increases the risk of venous thromboembolic disease (VTE). Thrombophilia testing is often proposed in women of childbearing age before the initiation of contraception. However, the presence of a familial history of VTE has the potential to be more accurate than the presence of inherited thrombophilia.To demonstrate an association between the risk of VTE in young women with hormonal exposure (pregnancy or oral contraceptive use) and the presence of a previous episode of VTE in their first-degree relatives, according to whether or not a detectable inherited thrombophilia was present.We will perform a multicenter case-control cross-sectional study. The main risk factor is defined by the presence of a symptomatic VTE in young women with hormonal exposure. The principle variable is the presence of an objectively diagnosed episode of VTE in first-degree relatives. We will need to include 2,200 family members in 440 cases.We expect to improve understanding of the thrombotic risk in first-degree relatives of patients in hormonal context with or without a past history of VTE.

La thrombose veineuse (TV) est une maladie multifactorielle commune dont la forte composante genetique a ete suspectee il y a pres de 60 ans. Durant cette lecture, nous decrirons les determinants genetiques de la maladie et mettrons a jour les resultats recents obtenus par l’application de technologies de genotypage et de sequencage a haut debit. A ce jour, 17 genes ont ete clairement identifies comme presentant des variations genetiques associees au risque de TV : ABO, F2, F5, F9, F11, FGG, GP6, KNG1, PROC, PROCR, PROS1, SERPINC1, SLC44A2, STXBP5, THBD, TSPAN15 et VWF. Cependant, les polymorphismes communs identifies dans ces genes sont estimes ne representer qu’une partie modeste (∼ 5 %) de l’heritabilite de la TV. Il reste donc beaucoup a faire pour demeler completement l’architecture genetique (et epigenetique) exacte de la maladie. A present, une vaste gamme d’outils puissants et de strategies de recherche peut etre deployee sur des grandes collections de patients atteints de TV deja rassemblees dans le cadre de reseaux nationaux (comme INNOVTE) ou internationaux.

La trombosis venosa es una patología compleja que se debe a la interacción entre factores genéticos y factores ambientales. Entre los factores genéticos de riesgo, hay cinco anomalías constitucionales de la hemostasia que suelen identificarse y buscarse en un estudio de trombofilia: los déficits de antitrombina, proteína C y proteína S, así como dos mutaciones (factor V Leiden y mutación G20210A del gen de la protrombina). La trombosis venosa tiene un fuerte componente de heredabilidad, pues alcanza casi el 60%, pero estas cinco anomalías no permiten explicar más que una pequeña parte de esta heredabilidad. En los 10 últimos años, se han multiplicado los enfoques y los estudios genéticos para la identificación de nuevos marcadores genéticos de riesgo. También se han identificado muchos polimorfismos asociados a la trombosis venosa. En comparación con las anomalías del estudio de una trombofilia, estos polimorfismos confieren un incremento moderado del riesgo de trombosis venosa, pero su frecuencia es muy elevada en la población general.

Hormonal exposure in young women increases the risk of venous thromboembolic disease (VTE). Thrombophilia testing is often proposed in women of childbearing age before the initiation of contraception. However, the presence of a familial history of VTE has the potential to be more accurate than the presence of inherited thrombophilia. OBJECTIVE:To demonstrate an association between the risk of VTE in young women with hormonal exposure (pregnancy or oral contraceptive use) and the presence of a previous episode of VTE in their first-degree relatives, according to whether or not a detectable inherited thrombophilia was present. METHODS:We will perform a multicenter case-control cross-sectional study. The main risk factor is defined by the presence of a symptomatic VTE in young women with hormonal exposure. The principle variable is the presence of an objectively diagnosed episode of VTE in first-degree relatives. We will need to include 2,200 family members in 440 cases. EXPECTED RESULTS:We expect to improve understanding of the thrombotic risk in first-degree relatives of patients in hormonal context with or without a past history of VTE.

The TOPIC trial showed that switching dual antiplatelet (DAPT) from aspirin plus a newer P2Y12 blocker (prasugrel or ticagrelor) to aspirin plus clopidogrel led to a reduction in bleeding complications with similar risk of ischemic recurrence. The objective of this analysis was to evaluate the impact of diabetes on the benefit of switched strategy. TOPIC study randomized patients admitted for an ACS without adverse event at 1 month on aspirin and a newer P2Y12 blocker, to aspirin and clopidogrel (switched DAPT) or continuation of their drug regimen (unchanged DAPT). Three hundred and twenty-two patients were randomized to switched DAPT and 323 to unchanged DAPT. The primary endpoint of this analysis aimed to evaluate the impact of diabetes on clinical outcomes (composite of cardiovascular death, urgent revascularization, stroke and bleeding BARC classification ≥ 2) at 1 year. Hundred and seventy-seven patients were diabetics corresponding to 84 (26%) in the switched arm and 93 (29%) in the unchanged. No differences in primary outcome incidence was observed in the unchanged arm between diabetic and non-diabetic (25.8% vs. 26.5%, HR 95% CI 0.96 (0.60–1.54), P = 0.88) while in the switched arm, primary endpoint occurred significantly more in diabetics (22.6% vs. 10.1%, 95% CI 2.72 (1.37–5.42), P < 0.01). Benefit of switched strategy was maintained in non-diabetic patients (HR 95% CI 0.37 (0.34–0.56), P < 0.01) while no significant differences were observed in diabetic patients (HR 95% CI 0.83 (0.45–1.50), P = 0.53). This lack of benefit in the diabetic arm was related to increased risk of recurrent ischemic events (HR 95% CI 1.52 (0.70–3.27), P = 0.29) (Fig. 1) despite reduction in bleedings BARC ≥ 2 (HR 0.37, P = 0.04) (Fig. 1). Switching DAPT proved its benefit after ACS in terms of bleeding prevention. However, in diabetic patients switching DAPT was associated with excess of ischemic events despite bleeding prevention. Switching DAPT strategy should be preferred in non-diabetic patients.

Venous thrombosis (VT) is a complex pathology involving both environmental and genetic causes. Although its heritability is estimated to be ⁓ 50%, identifying the genetic background of the disease remains a major challenge. Some genetic variants that contribute to the risk have been identified in candidate genes, such as the factor V Leiden mutation. Other susceptibility single‐nucleotide polymorphisms (SNPs) have been identified in unsuspected genes, such as SLC44A2 or TSPAN15, through high‐throughput genotyping strategies, mostly in genome‐wide association studies (GWASs) 1.Trégouët D.A. Morange P.E. What is currently known about the genetics of venous thromboembolism at the dawn of next generation sequencing technologies.Br J Haematol. 2018; 180: 335-45Crossref PubMed Scopus (27) Google Scholar. However, even though those approaches have been successful in identifying new genes, much remains to be done to identify the missing heritability of VT, as known genetic variants explain only 5% of the heritability component. In addition, the incomplete penetrance of the identified VT‐related mutations/polymorphisms is still a challenge to overcome. The FV Leiden variant (F5L) was identified years ago, and, despite being well known as a genetic risk factor for VT, is still not completely understood. Indeed, despite an allele frequency of ~ 5% in the general population of European descent, only 10% of F5L heterozygotes will develop VTs, with various degrees of severity, in their lifetimes. Scientists have attempted to explain the incomplete penetrance and the variable clinical picture of VT in F5L patients, leading to the identification of genetic interactions with other known thrombotic risk factors (antithrombin deficiency, protein C or protein S deficiency, and the prothrombin G20210A mutation). However, because < 2% of F5L heterozygotes are expected to carry one of these mutations, other genetic modifiers of the F5L phenotype are yet to be discovered. Identifying the genetic environment surrounding F5L that enhances or decreases its associated thrombotic phenotype appears to be an important challenge. Ginsburg's group, in a recent and impressive mouse study, tried to identify genetic modifiers of the F5L phenotype 2.Westrick R.J. Tomberg K. Siebert A.E. Zhu G. Winn M.E. Dobies S.L. Manning S.L. Brake M.A. Cleuren A.C. Hobbs L.M. Mishack L.M. Johnston A.J. Kotnik E. Siemieniak D.R. Xu J. Li J.Z. Saunders T.L. Ginsburg D. Sensitized mutagenesis screen in factor V Leiden mice identifies thrombosis suppressor loci.Proc Natl Acad Sci USA. 2017; 114: 9659-64Crossref PubMed Scopus (9) Google Scholar. Mice have a high degree of conservation of the R504/R506 activated protein C cleavage site within FV, and thus provide a good model for studying what happens in humans with F5L. The authors have previously described tissue factor (TF) pathway inhibitor (TFPI) deficiency as an F5L‐associated risk factor for venous thromboembolism in mice. They crossed mice carrying F5L with mice in which the Tfpi gene was knocked out, and identified a lethal perinatal phenotype for the F5L/L Tfpi+/− genotype. They combined this observation with random mutagenesis to correct the sensitized phenotype, and, once the protective genotype had been transmitted to new generations, they tried to identify the mutations that allowed the correction of the phenotype. The authors used F5L/L males (G0) treated with N‐ethyl‐N‐nitrosourea (ENU), and crossed them with F5L/+ Tfpi+/− females, leading to the generation of F5L/L Tfpi+/− mice (G1). As the F5L/L Tfpi+/− genotype is lethal, the mice who survived to weaning were carrying putative suppressor mutants. Once these mutants had been identified, the heritability of these mutations was tested. After two generations of crossing with F5L/L mice, only 16 of the initial 44 mutants produced living F5L/L Tfpi+/− progeny. Several generations have been produced from these 16 mutant lines, and they were backcrossed on a 129S1/SvIMJ (129S1) or a C57BL/6 (B6) background. Hundreds of offspring have been genotyped for 800 markers for gene mapping, in order to identify a genomic region responsible for survival. Only one mutant line gave a locus with a sufficiently high logarithm of the odds score (4.49) on chromosome 3. The identified chromosome 3 region contains 43 genes, including F3, encoding TF, which is known to initiate the coagulation cascade and whose function is inhibited by TFPI. Because of its importance in thrombosis, the authors chose to test F3 as a candidate suppressor of the F5L/L Tfpi+/− phenotype. Triple‐heterozygous F5L/+ Tfpi+/− F3+/− mice were crossed with F5L/L B6 mice. Of 273 progenies genotyped at weaning, 13 F5L/L Tfpi+/− F3+/− mice and one F5L/L Tfpi+/− F3+/+ mouse survived. Haploinsufficiency for F3 thus suppressed the lethal phenotype. On the basis of these findings, F3, which was included in the region of interest identified by gene mapping, seemed to be a great candidate as a modifier gene of F5L. However, neither whole exome sequencing, Sanger sequencing of F3 introns and exons nor F3 mRNA level analysis allowed identification of an ENU‐induced mutation. This suggested the existence of a mutation outside the sequenced segment, or a regulatory mutation in another gene. Forty‐three genes have been mentioned as being present in the identified region. Genes such as Slc44a3, which is a paralog of Slc44a2 recently identified in a GWAS as a potential genetic risk factor for VT in humans, could also be important 3.Germain M. Chasman D.I. de Haan H. Tang W. Lindström S. Weng L.C. de Andrade M. de Visser M.C.H. Wiggins K.L. Suchon P. Saut N. Smadja D.M. Le Gal G. van Hylckama Vlieg A. Di Narzo A. Hao K. Nelson C.P. Rocanin‐Arjo A. Folkersen L. Monajemi R. et al.Meta‐analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism.Am J Hum Genet. 2015; 96: 532-42Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar. The use of an existing phenotype as a sensitizer to highlight new modifier genes has already given successful results when applied to ENU mutagenesis in mice 4.Buchovecky C.M. Turley S.D. Brown H.M. Kyle S.M. McDonald J.G. Liu B. Pieper A.A. Huang W. Katz D.M. Russell D.W. Shendure J. Justice M.J. A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome.Nat Genet. 2013; 45: 1013-20Crossref PubMed Scopus (146) Google Scholar. Some of the mutations that have been generated seem to successfully prevent a lethal phenotype, whereas others do not, suggesting the existence of modifier genes of great importance in the F5L/L genotype. Interestingly, concerning the F5L/L phenotype, the authors observed that the B6 and 129S1 backgrounds are not equal. This implies the presence of strain‐specific modifier genes that directly impact on the clinical consequences of F5L. In order not to miss a possible gene modifier, whole exome sequencing was performed on eight mutant lines with large pedigrees, including the four lines used previously for gene mapping. Forty‐seven ENU‐induced variants were identified as potential suppressor mutations. Only one variant conferred a significant survival advantage: a non‐synonymous SNP in the actin‐related protein 2 (ARP2) gene (Actr2), which has not yet been reported to be associated with VT. ARP2 is part of the ARP2–actin‐related protein 3 complex, which plays a key role in cytoskeleton function as an initiator of formation of the branched actin network in a broad range of cells, including platelets. To explore this, the authors generated an independent Actr2 knock‐in allele by using CRISPR/Cas9 genome editing. However, no surviving pups with this allele were obtained, suggesting that heterozygous loss of function for Actr2 results in a loss of viability. Actr2 haploinsufficiency has not been reported in humans, consistent with the lethal phenotype in mice. The mutant line that rescued the lethal F5L/L Tfpi genotype caused by the ENU‐induced Actr2 variant must have either a hypomorphic or a unique gain‐of‐function mutation, not a haploinsufficiency. It would be interesting to further assess the function of this protein, in order to elucidate how the mutation can affect thrombosis. Conditional platelet‐specific knock‐in mice or bone marrow transplants from Actr2‐mutated fetuses in irradiated wild‐type mice could, for instance, provide more insights into the story. Because the ENU‐induced mutations were generated in males, study of the possible ENU‐induced mutation on chromosome X on the male progeny was impossible. However, as F8, which is relevant in thrombosis, is located on this chromosome, the authors decided to independently check whether an X‐linked hemophilia A caused by a mutation in F8 affected survival in their model. They found that it did: F5L/L Tfpi+/− lethality was genetically suppressed by F8 deficiency, as the mice carrying the mutation survived. This result is consistent with what is found in humans, as studies have demonstrated that F8 levels constitute an important VT risk factor. However, is there another possible gene modulator of F5L in chromosome X? This question remains unanswered. Despite the discovery of a region of interest on chromosome 3, no genes related to VT in previous GWAS studies were identified here 1.Trégouët D.A. Morange P.E. What is currently known about the genetics of venous thromboembolism at the dawn of next generation sequencing technologies.Br J Haematol. 2018; 180: 335-45Crossref PubMed Scopus (27) Google Scholar. Are the SNPs identified in humans found in mice? Is this mouse model pertinent? It is indeed possible that regions of interest could be located in intronic and/or regulatory regions. Exons are much easier to study than introns, and the latter remain a dark area of the genome waiting to be better understood. TFPI is an important protein in regulating the initiation of coagulation through inhibition of the TF pathway. The authors have observed an interesting effect of TF mutation on the F5L/L Tfpi+/− phenotype, but, except in the context of cancer‐associated thrombosis 5.Thomas G.M. Brill A. Mezouar S. Crescence L. Gallant M. Dubois C. Wagner D.D. Tissue factor expressed by circulating cancer cell‐derived microparticles drastically increases the incidence of deep vein thrombosis in mice.J Thromb Haemost. 2015; 13: 1310-19Crossref PubMed Scopus (100) Google Scholar, a role of TF in the risk of VT has not yet been demonstrated. However, this work suggests that a imbalance in TF/TFPI activity, such as is observed in cancer, may affect the F5L phenotype. TF or TFPI knock‐out mice both show lethal intrauterine hemorrhage or widespread thrombosis. It might be that the thrombotic effect of the TFPI haploinsufficiency is too strong to study specific genetic modifiers of the F5L mutation. The outcome of the genotype studied is lethality, but, owing to its duality (F5L and Tfpi), we cannot assess whether the protective mutations identified, such as the Actr2 mutation, play roles as modifiers of one gene or the other gene. The protective effect of the Actr2 mutation may therefore be completely independent of F5L. Taken together, the results show that there is still much to discover in the field of VT genetics. By identifying an interesting chromosome 3 region and a novel gene that is potentially associated with the variable expression of VT in F5L carriers, the authors have opened new paths that are waiting to be explored. Given the evolution of molecular technologies and the widespread use of next‐generation sequencing at low cost, whole genome sequencing in large groups of individuals with VT has begun. It will be interesting to see whether rare mutations associated with VT will be identified in humans at the loci identified in this interesting study. P. Fautrad, G. M. Thomas and P. E. Morange contributed intellectually to this manuscript and wrote the manuscript. All authors have approved the final version. The authors state that they have no conflict of interest. The authors thank the ANR (grant ANR‐17‐CE14‐0003‐01 to G. M. Thomas) for funding.ANRANR‐17‐CE14‐0003‐01

La maladie thromboembolique veineuse (MTEV) et les maladies cardiovasculaires (MCV) sont historiquement considérées comme deux maladies distinctes avec des différences en termes de physiopathologie et de traitement. Il existe de plus en plus d’études mettant en évidence une association entre ces deux maladies mais leur corrélation reste inexpliquée. L’objectif de ce travail était de mettre en évidence les facteurs de risque de survenue d’évènements cardiovasculaires chez les patients présentant une MTEV, à 1 an et à 5 ans. Nous avons réalisé une étude rétrospective, monocentrique, comprenant des patients d’au moins 18 ans, présentant une MTEV, hospitalisés entre le 1er janvier 2009 et le 31 décembre 2010. Les patients atteints de cancer, dialysés, greffés, présentant un filtre cave ou une thrombose veineuse profonde (TVP) distale seule ont été exclus. Le critère de jugement principal était d’évaluer la survenue d’un infarctus du myocarde (IDM), d’un accident vasculaire cérébral (AVC) ischémique ou d’une artériopathie chronique oblitérante des membres inférieurs (AOMI) revascularisée à 1 an et à 5 ans. Les données ont été extraites à partir des dossiers médicaux informatisés puis les patients ont été contactés par téléphone. Cent quatre-vingt-dix patients ont été inclus dans l’étude. L’âge médian était de 69 ans. Au total, 21 évènements ont été observés comprenant à 1 an : 3 AVC ischémiques, 3 IDM et 3 AOMI et à 5 ans : 6 AVC ischémiques, 5 IDM et 1 AOMI. Notre étude met en évidence qu’un antécédent personnel d’IDM, chez les patients présentant une MTEV, est associé à une augmentation significative du risque d’apparition d’un nouvel événement cardiovasculaire (p = 0,0003), quel que soit le type d’événement cardiovasculaire. Ce risque est majoré la première année (p = 0,008) et reste significatif à 5 ans (p = 0,017). Un antécédent personnel d’AOMI, le haut risque cardiovasculaire et la dyslipidémie sont également associés à une augmentation significative du risque d’athérothrombose ultérieure. Les différentes caractéristiques de l’épisode thromboembolique veineux n’ont pas été associées à une augmentation du risque cardiovasculaire, de même pour les autres FDRCV majeurs. Nos résultats sont en accord avec la littérature et mettent en évidence une potentielle association entre MTEV et athérothrombose. Ils ouvrent des retombées pratiques sur le risque cardiovasculaire en cas de MTEV et aussi thérapeutiques.

HaemophiliaVolume 23, Issue 6 p. e533-e535 LETTER TO THE EDITOR Peripartum bleeding management in a patient with CalDAG-GEFI deficiency M. Canault, Corresponding Author M. Canault matthias.canault@univ-amu.fr orcid.org/0000-0002-7880-5250 Aix Marseille Univ, INSERM, INRA, NORT, Marseille, France Correspondence Matthias Canault, UMR Inserm 1062, INRA 1260, Aix-Marseille Univ Nutrition, Obesity and Risk of Thrombosis (NORT) laboratory, Faculté de Médecine Timone, Marseille, France. Email: matthias.canault@univ-amu.frSearch for more papers by this authorP. Saultier, P. Saultier Aix Marseille Univ, INSERM, INRA, NORT, Marseille, FranceSearch for more papers by this authorS. Fauré, S. Fauré Aix Marseille Univ, INSERM, INRA, NORT, Marseille, FranceSearch for more papers by this authorM. Poggi, M. Poggi Aix Marseille Univ, INSERM, INRA, NORT, Marseille, FranceSearch for more papers by this authorA. T Nurden, A. T Nurden Institut-Hospitalo-Universitaire LIRYC, Plateforme Technologique et d'Innovation Biomédicale, Pessac, FranceSearch for more papers by this authorP. Nurden, P. Nurden Institut-Hospitalo-Universitaire LIRYC, Plateforme Technologique et d'Innovation Biomédicale, Pessac, FranceSearch for more papers by this authorP. E. Morange, P. E. Morange Aix Marseille Univ, INSERM, INRA, NORT, Marseille, France APHM, CHU Timone, French Reference Centre for Rare Platelet Disorders, Marseille, FranceSearch for more papers by this authorM-C. Alessi, M-C. Alessi Aix Marseille Univ, INSERM, INRA, NORT, Marseille, France APHM, CHU Timone, French Reference Centre for Rare Platelet Disorders, Marseille, FranceSearch for more papers by this authorJ-C. Gris, J-C. Gris Laboratoire d'hématologie, Groupe Hospitalo-Universitaire Caremeau, Nîmes, FranceSearch for more papers by this author M. Canault, Corresponding Author M. Canault matthias.canault@univ-amu.fr orcid.org/0000-0002-7880-5250 Aix Marseille Univ, INSERM, INRA, NORT, Marseille, France Correspondence Matthias Canault, UMR Inserm 1062, INRA 1260, Aix-Marseille Univ Nutrition, Obesity and Risk of Thrombosis (NORT) laboratory, Faculté de Médecine Timone, Marseille, France. Email: matthias.canault@univ-amu.frSearch for more papers by this authorP. Saultier, P. Saultier Aix Marseille Univ, INSERM, INRA, NORT, Marseille, FranceSearch for more papers by this authorS. Fauré, S. Fauré Aix Marseille Univ, INSERM, INRA, NORT, Marseille, FranceSearch for more papers by this authorM. Poggi, M. Poggi Aix Marseille Univ, INSERM, INRA, NORT, Marseille, FranceSearch for more papers by this authorA. T Nurden, A. T Nurden Institut-Hospitalo-Universitaire LIRYC, Plateforme Technologique et d'Innovation Biomédicale, Pessac, FranceSearch for more papers by this authorP. Nurden, P. Nurden Institut-Hospitalo-Universitaire LIRYC, Plateforme Technologique et d'Innovation Biomédicale, Pessac, FranceSearch for more papers by this authorP. E. Morange, P. E. Morange Aix Marseille Univ, INSERM, INRA, NORT, Marseille, France APHM, CHU Timone, French Reference Centre for Rare Platelet Disorders, Marseille, FranceSearch for more papers by this authorM-C. Alessi, M-C. Alessi Aix Marseille Univ, INSERM, INRA, NORT, Marseille, France APHM, CHU Timone, French Reference Centre for Rare Platelet Disorders, Marseille, FranceSearch for more papers by this authorJ-C. Gris, J-C. Gris Laboratoire d'hématologie, Groupe Hospitalo-Universitaire Caremeau, Nîmes, FranceSearch for more papers by this author First published: 04 October 2017 https://doi.org/10.1111/hae.13352Citations: 4 Alessi and Gris are equally contributed to this study. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume23, Issue6November 2017Pages e533-e535 RelatedInformation

Hereditary Protein S (PS) deficiency is a rare coagulation disorder associated with an increased risk of venous thrombosis (VT). The PS Heerlen (PSH) mutation is a rare S501P mutation that was initially considered to be a neutral polymorphism. However, it has been later shown that PSH has a reduced half-life in vivo which may explain the association of PSH heterozygosity with mildly reduced levels of plasma free PS (FPS). Whether the risk of VT is increased in PSH carriers remains unknown. We analyzed the association of PSH (rs121918472 A/G) with VT in 4,173 VT patients and 5,970 healthy individuals from four independent case-control studies. Quantitative determination of FPS levels was performed in a subsample of 1257 VT patients. In the investigated populations, the AG genotype was associated with an increased VT risk of 6.57 [4.06–10.64] (p = 1.73 10 −14 ). In VT patients in whom PS deficiency was excluded, plasma FPS levels were significantly lower in individuals with PSH when compared to those without [72 + 13 vs 91 + 21 UI/dL; p = 1.86 10 −6 , mean + SD for PSH carriers (n = 21) or controls (n = 1236) respectively]. We provide strong evidence that the rare PSH variant is associated with VT in unselected individuals.

La thrombose veineuse est une maladie multifactorielle commune qui représente la troisième cause de mortalité cardiovasculaire dans les pays industrialisés. Elle présente une composante génétique qui a été soupçonnée il y a déjà plus de 60 ans. Ces dernières années, l’application des nouvelles technologies basées sur le génotypage et le séquençage à haut débit a identifié de nombreux nouveaux déterminants génétiques de la maladie. À ce jour, dix-sept gènes présentent des variations génétiques associées au risque de thrombose veineuse : ABO, F2, F5, F9, F11, FGG, GP6, KNG1, PROC, PROCR, PROS1, SERPINC1, SLC44A2, STXBP5, THBD, TSPAN15 et VWF. Cependant, l’ensemble des polymorphismes communs présents sur ces gènes ne représentent qu’une part modeste (environ 5 %) de l’héritabilité de la thrombose veineuse. Il reste donc encore beaucoup à faire pour démêler entièrement l’architecture génétique (et épigénétique) exacte de la thrombose veineuse. À l’heure actuelle, un large panel d’outils puissants et de stratégies de recherche peut être déployé sur les grandes collections de patients afin d’identifier l’héritabilité manquante de la thrombose veineuse.

Essentials Patients with α‐1‐antitrypsin (α1‐AT) Pittsburgh exhibit a mild bleeding tendency. A new case of α1‐AT Pittsburgh with suspected high antifibrinolytic potential was studied. We showed that α1‐AT Pittsburgh inhibits tissue plasminogen activator and plasmin. The antifibrinolytic potential of the variant contributes to explaining the mild bleeding phenotype.

Essentials Tissue factor pathway inhibitor (TFPI) regulates the blood coagulation cascade. We replicated previously reported linkage of TFPI plasma levels to the chromosome 2q region. The putative causal locus, rs62187992, was associated with TFPI plasma levels and thrombosis. rs62187992 was marginally associated with TFPI expression in human aortic endothelial cells.

Background: Through a meta-analysis of 12 genome-wide association studies, the International Network against VENous Thrombosis (INVENT) consortium identified two novel susceptibility loci for venous thromboembolism (VTE). This project has also generated other candidates that need to be confirmed.Objectives: To assess the association with VTE of common single-nucleotide polymorphisms (SNPs) that demonstrated strong statistical, but not genome-wide, significance in the INVENT cohorts.Patients/methods: Eleven SNPs were genotyped and tested for association with VTE in three case-control studies totaling 3019 patients and 2605 healthy individuals.Results and conclusions: None of the tested SNPs showed evidence for association with VTE. Different strategies are needed to decipher the whole spectrum of common and rare genetic variations associated with VTE risk.