rs78707713 — TSPAN15

Intronic TSPAN15 variant; the C allele is associated with a 31% increased risk of venous thromboembolism

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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). 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 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 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.

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 rs60251111 Factor V Leiden rs6025
F5 R506Q, the most common inherited thrombophilia at ~5% European frequency 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 rs17999631212 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.

Genotype Interpretations

What each possible genotype means for this variant.

TT Typical GPVI Regulation Normal

Common genotype — typical TSPAN15 activity and baseline VTE risk

You carry two copies of the common T allele at rs78707713. This is the most common genotype globally, found in approximately 84% of people across ancestries — and in about 77% of Europeans (where the C allele is more common). You do not carry the TSPAN15 C allele associated with elevated VTE risk in GWAS studies.

CT One C Allele Intermediate

One C allele — modest increase in venous thromboembolism risk

TSPAN15 regulates how efficiently the platelet collagen receptor GPVI is cleaved from the platelet surface by the ADAM10 enzyme complex.

The OR of 1.31 per allele means your absolute annual VTE risk (approximately 0.1% for the general population) increases to roughly 0.13-0.14% per year under typical circumstances. This becomes more clinically meaningful when combined with acquired risk factors: - Long-haul air travel (immobility) roughly doubles VTE risk in the general population - Surgery with post-operative immobility is a major provoked VTE trigger - Estrogen-containing oral contraceptives independently increase VTE risk 3-5 fold - Pregnancy and the postpartum period are the highest per-month VTE risk windows

You do not need anticoagulation based on this variant alone, but knowing this result means you can take targeted precautions during high-risk windows.

CC Two C Alleles High Risk

Two C alleles — elevated VTE risk from impaired GPVI regulation

The GWAS effect size (OR 1.31 per allele) applied twice yields a combined OR in the 1.5-1.7 range — meaningful but well below the 5-10 fold ORs of high-penetrance variants like Factor V Leiden or prothrombin G20210A. Nevertheless, CC homozygotes should consider a full thrombophilia evaluation, especially if there is a personal or family history of VTE, to determine whether co-existing high-penetrance thrombophilia variants also contribute.

Thrombosis triggers to manage proactively: - Surgical procedures — major VTE risk window requiring prophylaxis planning - Pregnancy and postpartum — discuss thromboprophylaxis with an obstetrician - Estrogen-containing hormonal therapies — avoid if possible - Extended immobility (hospitalization, long journeys, cast immobilization)