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• W3040596983 abstract "Deep vein thrombosis (DVT) is a major cause of worldwide mortality and morbidity, and its incidence continues to increase.1.Wendelboe A.M. Raskob G.E. Global burden of thrombosis: epidemiologic aspects.Circ Res. 2016; 118: 1340-1347Crossref PubMed Scopus (476) Google Scholar DVT is a multifactorial disease with many acquired (eg, age, surgery, malignancy, certain drugs, obesity, sedentary lifestyle, stasis, smoking) and inherited (eg, protein S, protein C, antithrombin deficiencies, prothrombin 20210A, factor V Leiden) risk factors.2.Rosendaal F.R. Causes of venous thrombosis.Thromb J. 2016; 14: 24Crossref PubMed Scopus (47) Google Scholar Understanding the early molecular and cellular events that contribute to disease development, as well as identifying improved prophylactic therapies, are essential if we are to diminish the burden of this disease. These represent major ongoing research challenges. Current DVT therapies rely primarily upon anticoagulation to reduce thrombus growth. However, although anticoagulant therapy is effective, it comes at the cost of elevated risk of serious bleeding.3.Chan N.C. Eikelboom J.W. Weitz J.I. Evolving treatments for arterial and venous thrombosis: role of the direct oral anticoagulants.Circ Res. 2016; 118: 1409-1424Crossref PubMed Scopus (75) Google Scholar, 4.Schulman S. RE‐MEDYRE‐SONATE Trial InvestigatorsExtended anticoagulation in venous thromboembolism.N Engl J Med. 2013; 368: 2329PubMed Google Scholar, 5.Wolberg A.S. Rosendaal F.R. Weitz J.I. et al.Venous thrombosis.Nat Rev Dis Primers. 2015; 1: 15006Crossref PubMed Scopus (167) Google Scholar Consequently, identification of novel ways to diminish DVT incidence without the collateral damage of increased bleeding are essential if we are to improve patient care. Genome‐wide association studies (GWAS) on venous thromboembolism (VTE) have identified a panel of susceptibility genes with comparatively well‐characterized/understood effects coagulation (ie ABO, F2, F5, F11, FGG, PROCR, PROS, PROC, SERPINC1).6.Germain M. Chasman D.I. de Haan H. 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: 532-542Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 7.Hinds D.A. Buil A. Ziemek D. et al.Genome‐wide association analysis of self‐reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis.Hum Mol Genet. 2016; 25: 1867-1874Crossref PubMed Scopus (78) Google Scholar These associations corroborate the observed efficacy of therapeutic anticoagulation for prevention of DVT. Intriguingly, these GWAS studies have also identified two new susceptibility loci for VTE, TSPAN15 and SLC44A2, both of which currently have no defined role in thrombosis/coagulation.6.Germain M. Chasman D.I. de Haan H. 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: 532-542Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar If these genes have causal links to DVT that are independent of hemostasis, this may not only provide much needed mechanistic insight into disease development, but also identify potential (adjunctive) therapeutic targets for thromboprophylaxis that do not modify bleeding risk. In this issue of the Journal of Thrombosis and Haemostasis, Tilburg et al8.Tilburg J. Coenen D.M. Zirka G. et al.SLC44A2 deficient mice have a reduced response in stenosis but not in hypercoagulability driven venous thrombosis.J Thromb Haemost. 2020; 18: 1714-1727Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar present extensive and compelling data that demonstrate a role for SLC44A2 in venous thrombosis. The authors reveal that SLC44A2 deficiency appreciably diminishes thrombus formation in the murine stenosis model. This model bears many of the hallmarks of the human disease and appears to mimic some of the immunothrombotic mechanisms that, in recent years, have been associated with DVT.9.von Bruhl M.L. Stark K. Steinhart A. et al.Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo.J Exp Med. 2012; 209: 819-835Crossref PubMed Scopus (1185) Google Scholar Also known as choline transporter‐like protein‐2, SLC44A2 is transmembrane protein with 10 membrane‐spanning domains.10.Nair T.S. Kommareddi P.K. Galano M.M. et al.SLC44A2 single nucleotide polymorphisms, isoforms, and expression: association with severity of Meniere's disease?.Genomics. 2016; 108: 201-208Crossref PubMed Scopus (12) Google Scholar Both the N‐ and C‐terminal regions are intracellular. The N‐terminus contains several putative phosphorylation sites and, although their importance is not known, they suggest a role of SLC44A2 in cellular signalling. The transmembrane domains are interconnected via four intracellular loops and five extracellular loops of different lengths (178a.a., 38a.a., 72a.a., 38a.a., and 18a.a., respectively). By homology with choline‐transporter protein 1, SLC44A2 is predicted to adopt a pore‐like structure in the plasma membrane, and has been speculated to have a transporter function, although this has not been formally demonstrated.11.Nair T.S. Kozma K.E. Hoefling N.L. et al.Identification and characterization of choline transporter‐like protein 2, an inner ear glycoprotein of 68 and 72 kDa that is the target of antibody‐induced hearing loss.J Neurosci. 2004; 24: 1772-1779Crossref PubMed Scopus (102) Google Scholar At this time, the molecular and cellular function of SLC44A2 is not well‐defined. Its deficiency has been associated with hair cell loss, spiral ganglion degeneration, and hearing loss in mice,12.Kommareddi P. Nair T. Kakaraparthi B.N. et al.Hair cell loss, spiral ganglion degeneration, and progressive sensorineural hearing loss in mice with targeted deletion of Slc44a2/Ctl2.J Assoc Res Otolaryngol. 2015; 16: 695-712Crossref PubMed Scopus (20) Google Scholar and with Meniere disease and transfusion‐related acute lung injury in humans.10.Nair T.S. Kommareddi P.K. Galano M.M. et al.SLC44A2 single nucleotide polymorphisms, isoforms, and expression: association with severity of Meniere's disease?.Genomics. 2016; 108: 201-208Crossref PubMed Scopus (12) Google Scholar, 13.Bayat B. Tjahjono Y. Berghofer H. et al.Choline transporter‐like protein‐2: new von Willebrand factor‐binding partner involved in antibody‐mediated neutrophil activation and transfusion‐related acute lung injury.Arterioscler Thromb Vasc Biol. 2015; 35: 1616-1622Crossref PubMed Scopus (28) Google Scholar Despite these associations, mechanistic insight into how these phenotypes are manifest remains poor. The identification of SLC44A2 as a susceptibility locus for VTE has generated heightened interest in the role of this gene/protein.6.Germain M. Chasman D.I. de Haan H. 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: 532-542Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 7.Hinds D.A. Buil A. Ziemek D. et al.Genome‐wide association analysis of self‐reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis.Hum Mol Genet. 2016; 25: 1867-1874Crossref PubMed Scopus (78) Google Scholar, 14.Apipongrat D. Numbenjapon T. Prayoonwiwat W. Arnutti P. Nathalang O. Association between SLC44A2 rs2288904 polymorphism and risk of recurrent venous thromboembolism among Thai patients.Thromb Res. 2019; 174: 163-165Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar GWAS have identified a polymorphism in SLC44A2 (rs2288904‐G/A), which is linked to protection against VTE. This SNP in codon 461 of the gene, based on a substitution (G>A) that causes a missense mutation (R154Q) with a minor allele frequency of 0.22.6.Germain M. Chasman D.I. de Haan H. 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: 532-542Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 7.Hinds D.A. Buil A. Ziemek D. et al.Genome‐wide association analysis of self‐reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis.Hum Mol Genet. 2016; 25: 1867-1874Crossref PubMed Scopus (78) Google Scholar, 14.Apipongrat D. Numbenjapon T. Prayoonwiwat W. Arnutti P. Nathalang O. Association between SLC44A2 rs2288904 polymorphism and risk of recurrent venous thromboembolism among Thai patients.Thromb Res. 2019; 174: 163-165Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar This substitution affects the first and longest extracellular loop of SLC44A2. R154, and indeed the surrounding amino acids in this loop, are very highly conserved between species suggestive of their functional importance. In the GWAS reports, the common or wild‐type sequence represents the risk allele (odds ratio = 1.19).6.Germain M. Chasman D.I. de Haan H. 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: 532-542Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar However, it is perhaps easier to appreciate the protective nature of the rs2288904‐A SNP by considering that the frequency of VTE in individuals homozygous for this SNP is 30%‐50% lower than in those homozygous for the wild‐type allele. These intriguing findings highlight the importance of elucidating the mechanistic link between SLC44A2 and DVT. In the present study, Tilburg et al8.Tilburg J. Coenen D.M. Zirka G. et al.SLC44A2 deficient mice have a reduced response in stenosis but not in hypercoagulability driven venous thrombosis.J Thromb Haemost. 2020; 18: 1714-1727Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar used Slc44a2+/+, Slc44a2+/−, and Slc44a2−/− mice in the hypercoagulability model and the stenosis model of thrombosis. In the stenosis model following 90% flow restriction of the inferior vena cava, they observed that Slc44a2−/− mice exhibit significantly reduced (~50%) thrombus size at 48 hours.8.Tilburg J. Coenen D.M. Zirka G. et al.SLC44A2 deficient mice have a reduced response in stenosis but not in hypercoagulability driven venous thrombosis.J Thromb Haemost. 2020; 18: 1714-1727Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar A more profound effect is observed after 6 hours, with Slc44a2−/− mice exhibiting much smaller thrombi (>80% reduced weight and length) at this early time point.8.Tilburg J. Coenen D.M. Zirka G. et al.SLC44A2 deficient mice have a reduced response in stenosis but not in hypercoagulability driven venous thrombosis.J Thromb Haemost. 2020; 18: 1714-1727Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar This perhaps points to an involvement of SLC44A2 in the initial events of DVT. Using the hypercoagulability model, Tilburg et al also induced thrombosis by knockdown of both antithrombin and protein C. In this coagulation‐driven model induced by loos of hemostatic control, they observed no significant differences in thrombosis between Slc44a2−/− and Slc44a2+/+ mice,8.Tilburg J. Coenen D.M. Zirka G. et al.SLC44A2 deficient mice have a reduced response in stenosis but not in hypercoagulability driven venous thrombosis.J Thromb Haemost. 2020; 18: 1714-1727Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar perhaps supporting the contention that lack of SLC44A2 does not exert a protective effect by diminishing coagulation cascade and/or platelet function. Within the vasculature, SLC44A2 is expressed in neutrophils, endothelial cells, and platelets. Proteomic data suggest >300‐fold greater expression in neutrophils compared with platelets (http://immprot.org). Given the multitude of factors that contribute to the development of DVT, which includes platelets, neutrophils, and the endothelium, Slc44a2−/− mice may be protected against DVT because of the lack of SLC44A2 from one or more of these cellular compartments. However, given that SLC44A2 deficiency has no effect in the hypercoagulability model of thrombosis, this may imply that SLC44A2 in platelets unlikely accounts for the protective phenotype in the stenosis model. This is also suggested by the normal activation and aggregation of platelets from Slc44a2−/− mice, and the prior study by Tilburg et al15.Tilburg J. Adili R. Nair T.S. et al.Characterization of hemostasis in mice lacking the novel thrombosis susceptibility gene Slc44a2.Thromb Res. 2018; 171: 155-159Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar showing that Slc44a2−/− mice exhibit essentially normal hemostatic responses in the laser‐induced injury model. The authors elude to a role of SLC44A2 in neutrophils because they noticed a trend of reduction in citrullinated H3 staining within the venous thrombi of Slc44a2−/− mice, indicative of diminished release of neutrophil extracellular traps (NETs). NETs are known to be crucial for the pathogenesis of DVT. The importance of immunothrombotic mechanisms associated with experimental DVT is highlighted by protective effects associated with either depletion of neutrophils, administration of DNase (to dissolve NETs), or prevention of NETosis (by genetic ablation of Pad4).9.von Bruhl M.L. Stark K. Steinhart A. et al.Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo.J Exp Med. 2012; 209: 819-835Crossref PubMed Scopus (1185) Google Scholar, 16.Fuchs T.A. Brill A. Wagner D.D. Neutrophil extracellular trap (NET) impact on deep vein thrombosis.Arterioscler Thromb Vasc Biol. 2012; 32: 1777-1783Crossref PubMed Scopus (377) Google Scholar, 17.Martinod K. Demers M. Fuchs T.A. et al.Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice.Proc Natl Acad Sci USA. 2013; 110: 8674-8679Crossref PubMed Scopus (340) Google Scholar NETs can contribute to DVT in many ways, including entrapment of red blood cells and platelets, activation of the contact pathway and by conferring resistance to fibrinolysis.16.Fuchs T.A. Brill A. Wagner D.D. Neutrophil extracellular trap (NET) impact on deep vein thrombosis.Arterioscler Thromb Vasc Biol. 2012; 32: 1777-1783Crossref PubMed Scopus (377) Google Scholar, 18.Brill A. Fuchs T.A. Savchenko A.S. et al.Neutrophil extracellular traps promote deep vein thrombosis in mice.J Thromb Haemost. 2012; 10: 136-144Crossref PubMed Scopus (633) Google Scholar, 19.Fuchs T.A. Brill A. Duerschmied D. et al.Extracellular DNA traps promote thrombosis.Proc Natl Acad Sci USA. 2010; 107: 15880-15885Crossref PubMed Scopus (1569) Google Scholar How SLC44A2 contributes to either the recruitment and/or activation of neutrophils/NETosis remains to be determined, although the recent suggestion that neutrophil SLC44A2 may interact directly with platelets via activated integrin αIIbβ3 and induce flow‐dependent NETosis may provide some mechanistic insight into this, but this requires further investigation.20.Constantinescu‐Bercu A. Grassi L. Frontini M. Salles‐Crawley I.I. Woollard K. Crawley J.T. Activated αIIbβ3 on platelets mediates flow‐dependent NETosis via SLC44A2.Elife. 2020; 9Crossref PubMed Scopus (40) Google Scholar The exciting study by Tilburg et al provides new mechanistic insights into the link between SLC44A2 and DVT, demonstrating a role for this transmembrane protein in the initial events leading to thrombus formation. This, together with the importance of SLC44A2 outlined by GWAS, highlights SLC44A2 as a potential therapeutic target for venous thrombosis, and certainly one that warrants formal investigation. The major challenges ahead consist of determining the cellular compartment responsible for protection against DVT associated with SLC44A2 deficiency, ascertaining the molecular basis of the protection conferred by the rs2288904‐A SNP, and identifying means of potentially blocking SLC44A2 to protect against venous thrombosis without causing any of the phenotypes associated with SLC44A2 deficiency in humans. Considering that SLC44A2‐deficiency does not appear to impair hemostasis, this promising target may provide an opportunity to develop an adjunctive therapy that, alongside established thromboprophylaxis, may further diminish the incidence of VTE without further modifying bleeding risk. All authors declare that they have no conflicts of interest to declare. Adela Constantinescu‐Bercu, Isabelle I. Salles‐Crawley, and James T. B. Crawley all developed, wrote, and proofread this commentary. British Heart FoundationPG/17/22/32868" @default.
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• W3040596983 title "SLC44A2 – A novel therapeutic target for venous thrombosis?" @default.
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