rs78707713 — TSPAN15

TSPAN15 — The Molecular Scissor That Controls Your Platelet Collagen Receptor

When a blood vessel tears, platelets¹¹ platelets
Small, disc-shaped blood cells that aggregate at injury sites to form the initial clot plug rush to seal the breach. Their primary sensor for collagen — the structural protein exposed in damaged vessel walls — is a receptor called GPVI (glycoprotein VI). Without GPVI, platelets cannot recognize and grip collagen, and the clotting response stalls. But GPVI activity needs to be tightly regulated: too much collagen sensing and platelets clump inappropriately, forming venous clots that can travel to the lungs.

TSPAN15 sits at the center of this regulatory mechanism. It is a member of the tetraspanin superfamily²² tetraspanin superfamily
Transmembrane proteins that form scaffold complexes on the cell surface, organizing other proteins into functional signaling platforms and acts as an essential co-factor for ADAM10, a membrane-bound enzyme that cleaves GPVI from the platelet surface. The rs78707713 variant — an intronic change in TSPAN15 — alters the gene's regulatory output, affecting how efficiently GPVI is shed. The C allele³³ C allele
The minor, less common allele; the reference T allele is carried by ~92% of people globally has been associated with a 31% increased risk of venous thromboembolism⁴⁴ 31% increased risk of venous thromboembolism
OR 1.31, p=1.67×10⁻¹⁶ in a meta-analysis of 65,734 individuals across multiple European cohorts.

The Mechanism

TSPAN15 functions as a "molecular scaffold" within the TspanC8 family⁵⁵ TspanC8 family
A sub-group of tetraspanins — including TSPAN5, TSPAN10, TSPAN14, TSPAN15, TSPAN17, and TSPAN33 — that specifically regulate ADAM10 trafficking and activity that escorts ADAM10 to the cell surface and positions it precisely above its cleavage target. For GPVI specifically, Tspan15 bears the primary regulatory role⁶⁶ Tspan15 bears the primary regulatory role
Koo et al. showed that knocking out Tspan15 in platelets reduced GPVI shedding more than knocking out any other TspanC8 family member, with Tspan33 providing a compensatory backup.

The intronic rs78707713 variant does not change the TSPAN15 protein sequence but likely affects splicing efficiency or gene expression levels, altering the abundance of the TSPAN15/ADAM10 complex on the platelet surface. The net result is a change in the rate at which GPVI is shed — with the C allele apparently reducing GPVI clearance (or otherwise shifting platelet collagen reactivity), creating conditions more favorable for venous thrombus formation.

The Evidence

The original discovery came from a meta-analysis of 65,734 individuals⁷⁷ meta-analysis of 65,734 individuals
Germain M et al. Meta-analysis identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism. Am J Hum Genet. 2015 that identified rs78707713 as the lead signal at the TSPAN15 locus with an odds ratio of 1.31 (p=1.67×10⁻¹⁶). Notably, this association was independent of conventional hemostatic biomarkers — prothrombin levels, fibrinogen, D-dimer, or von Willebrand factor — placing TSPAN15 in a class of "unexpected actors" outside the classical coagulation cascade.

The association has since been replicated across ancestries. The Thibord et al. cross-ancestry GWAS⁸⁸ Thibord et al. cross-ancestry GWAS
81,669 VTE cases across 30 studies including European, African, and Hispanic populations; Circulation 2022 confirmed platelet function as a major contributor to genetic VTE risk, while the Ghouse et al. Nature Genetics 2023 mega-analysis⁹⁹ Ghouse et al. Nature Genetics 2023 mega-analysis
Over 81,000 cases and 1.4 million controls; polygenic score derived from 93 loci matched monogenic thrombophilia risk strata incorporated the TSPAN15 locus into a validated polygenic risk framework. More recently, a multi-population GWAS with zebrafish validation¹⁰¹⁰ multi-population GWAS with zebrafish validation
Wolford et al. Blood Advances 2025; 9 international biobanks; CRISPR/Cas9 knockdown of TSPAN15 in zebrafish produced suggestive pro-thrombotic phenotype provided experimental functional evidence for the TSPAN15-thrombosis link using a laser endothelial injury model.

Practical Actions

For C allele carriers, the primary implication is awareness of an elevated background VTE risk that compounds with acquired triggers. The OR of 1.31 per C allele is in the moderate range — meaningful in absolute terms when combined with other risk factors (surgery, immobility, hormonal contraceptives, pregnancy, cancer) but not a standalone indication for anticoagulation in otherwise healthy individuals.

The VTE prevention measures most relevant to C allele carriers are those that specifically target provoked situations: immobility during long-haul travel, perioperative periods, and hormonal changes. Compression during travel and disclosure to healthcare providers before surgery are the most immediately actionable steps.

TSPAN15 also has emerging pharmacogenomic relevance. Because it controls GPVI availability, variants that affect TSPAN15 expression could influence both baseline platelet collagen reactivity and the response to anti-GPVI therapies. Two GPVI-blocking agents — glenzocimab¹¹¹¹ glenzocimab
Humanized anti-GPVI Fab fragment; in Phase 2/3 trials for ischemic stroke and acute coronary syndrome and revacept¹²¹² revacept
Dimeric GPVI-Fc fusion protein that blocks collagen binding; studied in PCI and coronary artery disease — are in active clinical development. Whether TSPAN15 genotype should inform dosing for these agents is not yet established, but the biology warrants monitoring as trial data mature.

Interactions

The most clinically important interactions for C allele carriers involve co-inheritance with other thrombophilia variants. Carrying both rs78707713 C and Factor V Leiden rs6025¹³¹³ Factor V Leiden rs6025
F5 R506Q, the most common inherited thrombophilia at ~5% European frequency; each additional thrombophilic variant compounds absolute VTE risk multiplicatively rather than additively would be expected to produce substantially higher combined risk than either alone, though large formal interaction studies for this specific combination have not been published. The same applies to co-inheritance with prothrombin G20210A rs1799963¹⁴¹⁴ prothrombin G20210A rs1799963
The second most common inherited thrombophilia; also in the heart-inflammation category of the GeneOps platform.

Acquired thrombophilic states — combined oral contraceptive use, pregnancy, post-surgical immobility, active malignancy — multiply the background risk conferred by TSPAN15 C alleles through separate, additive mechanisms.