Association between SLC44A2 rs2288904 polymorphism and risk of recurrent venous thromboembolism among Thai patients

Apipongrat, Dollapak; Numbenjapon, Tontanai; Prayoonwiwat, Wichai; Arnutti, Pasra; Nathalang, Oytip

doi:10.1016/j.thromres.2019.01.001

Cited by 9 publications

(15 citation statements)

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“…Using transcriptomic and proteomic data, we identified 30 transmembrane candidates that were preferentially expressed in neutrophils (or T-cells) over monocytes. From this list, SLC44A2 stood out due to its recent identification as a risk locus for both VTE and stroke, but with as yet unknown functional association with these pathologies (Apipongrat et al, 2019;Germain et al, 2015;Hinds et al, 2016). As plateletleukocyte interactions are involved in both of these thrombotic disorders, we hypothesized that SLC44A2 functions as the neutrophil counter receptor for activated α IIb β 3 .…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, alternative targets that inhibit DVT disease processes, but that do not modify bleeding risk may provide new adjunctive therapies to further protect against the development or recurrence of DVT. GWAS studies have also identified additional risk loci for VTE, but with no known role in coagulation (Apipongrat et al, 2019;Germain et al, 2015;Hinds et al, 2016). This provides encouragement that alternative therapeutic targets may exist with the potential to modify the disease process without affecting bleeding risk.…”

Section: Introductionmentioning

confidence: 96%

“…This provides encouragement that alternative therapeutic targets may exist with the potential to modify the disease process without affecting bleeding risk. These loci include SLC44A2 and TSPAN15 genes (Apipongrat et al, 2019;Germain et al, 2015;Hinds et al, 2016). Despite the identification of these loci, the function of these cell surface proteins with respect to their involvement in the pathogenesis of venous thrombosis remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Activated α_IIbβ₃on platelets mediates flow-dependent NETosis via SLC44A2

Constantinescu‐Bercu

Grassi

Frontini

et al. 2018

Preprint

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Platelet-leukocyte interactions are important for innate immune responses, but also contribute to the pathogenesis of thrombotic disorders, such as deep vein thrombosis. How these interactions are manifest and how they influence leukocyte function remains poorly understood. Here, we demonstrate that binding to von Willebrand factor under flow through glycoprotein Ib 'primes' platelets resulting in intracellular Ca 2+ release and  IIb  3 activation. This priming enables platelets to bind leukocytes via a mechanism that is largely independent of P-selectin, but that is inhibited by blocking  IIb  3 . We show that neutrophils and T-cells bind directly to activated  IIb  3 under flow, identifying this platelet integrin as a novel leukocyte receptor. Binding of neutrophils to  IIb  3 under flow causes rapid intracellular Ca 2+ release, and initiates Ca 2+ -and NADPH oxidase-dependent signaling leading to production of neutrophil extracellular traps (NETs). NET production is itself dependent upon a mechanosensitive mechanism, as NETosis is markedly diminished if neutrophils are captured by  IIb  3 under static conditions. Takentogether, these data demonstrate a novel mechanism for platelet-neutrophil cross-talk and mechanosensitive NET production.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Activated α_IIbβ₃on platelets mediates flow-dependent NETosis via SLC44A2

Constantinescu‐Bercu

Grassi

Frontini

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2

Constantinescu‐Bercu

Grassi

Frontini

et al. 2020

eLife

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Platelet-neutrophil interactions are important for innate immunity, but also contribute to the pathogenesis of deep vein thrombosis, myocardial infarction and stroke. Here we report that, under flow, von Willebrand factor/glycoprotein Ibα-dependent platelet ‘priming’ induces integrin αIIbβ3 activation that, in turn, mediates neutrophil and T-cell binding. Binding of platelet αIIbβ3 to SLC44A2 on neutrophils leads to mechanosensitive-dependent production of highly prothrombotic neutrophil extracellular traps. A polymorphism in SLC44A2 (rs2288904-A) present in 22% of the population causes an R154Q substitution in an extracellular loop of SLC44A2 that is protective against venous thrombosis results in severely impaired binding to both activated αIIbβ3 and VWF-primed platelets. This was confirmed using neutrophils homozygous for the SLC44A2 R154Q polymorphism. Taken together, these data reveal a previously unreported mode of platelet-neutrophil crosstalk, mechanosensitive NET production, and provide mechanistic insight into the protective effect of the SLC44A2 rs2288904-A polymorphism in venous thrombosis.

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