rs28673647 — ADAMTS13

ADAMTS13 — The Enzyme That Keeps Your Blood Clots in Check

Every time a blood vessel is damaged, von Willebrand factor (VWF)¹¹ von Willebrand factor (VWF)
a large adhesive protein stored in endothelial cells and platelets that uncoils upon vascular injury to capture circulating platelets floods the injury site, unfurling into enormous multimers that recruit platelets to form the initial clot. Left unchecked, these ultra-large VWF multimers would persist in the circulation and trigger dangerous spontaneous platelet aggregation. The enzyme that prevents this is ADAMTS13²² ADAMTS13
ADAM metallopeptidase with thrombospondin type 1 motif 13, encoded by ADAMTS13 on chromosome 9q34.2 — a VWF-specific protease produced mainly in the liver and released into the bloodstream, where it continuously trims VWF multimers to safe sizes. The balance between VWF production and ADAMTS13-mediated cleavage is a critical dial for thrombotic risk. rs28673647 is an intronic ADAMTS13 variant that shifts this dial.

The Mechanism

rs28673647 sits in an intron of ADAMTS13 and does not alter the protein sequence. Its effect is regulatory: by modifying gene expression, splicing efficiency, or mRNA stability within the ADAMTS13 locus on 9q34.2, the G allele increases the amount of functional ADAMTS13 enzyme circulating in plasma. The A allele produces the lower, population-baseline ADAMTS13 level. Because each G allele adds approximately 6.7% to plasma concentration, the three genotypes form a gradient: AA (lowest) < AG (intermediate) < GG (highest).

When ADAMTS13 activity is insufficient relative to VWF release — whether because of low ADAMTS13 protein, inhibitory antibodies (as in immune TTP), or acute-phase consumption — ultra-large VWF multimers³³ ultra-large VWF multimers
multimers that are far more adhesive than processed VWF and bind platelet GPIbα with very high affinity under shear stress accumulate in the microvasculature. These hyper-reactive multimers anchor platelets indiscriminately, forming platelet-rich thrombi in small vessels. The clinical spectrum runs from subclinical thrombotic propensity at mild reductions, through elevated CHD and DVT risk at moderate deficiency, to full thrombotic thrombocytopenic purpura (TTP) when activity falls below 10%.

The Evidence

The genetic association was established by Ma et al. 2017⁴⁴ Ma et al. 2017
Ma Q, Jacobi PM, Emmer BT et al. Genetic variants in ADAMTS13 as well as smoking are major determinants of plasma ADAMTS13 levels. Blood Adv. 2017;1(18):1375-1388. in a GWAS of healthy individuals. The rs28673647 G allele was the top intronic signal, with a β of +6.7% for plasma ADAMTS13 concentration and a p-value of 1.3×10⁻⁵² — one of the most significant genetic associations for any plasma enzyme level. Common variants across the ADAMTS13 locus collectively explained 20% of the variance in plasma ADAMTS13 levels. The same study found that tobacco smoking independently reduced plasma ADAMTS13 by a clinically meaningful amount — a modifiable environmental factor acting on the same pathway as the A allele.

The downstream clinical consequences of low ADAMTS13 were quantified in the Rotterdam Study⁵⁵ Rotterdam Study
Sonneveld MA et al. Low ADAMTS-13 activity and the risk of coronary heart disease. J Thromb Haemost. 2016;14(11):2114-2120. — a prospective cohort of 5,688 participants aged 55+ with 456 incident CHD events over 9.7 years. ADAMTS13 activity in the lowest quartile conferred a hazard ratio of 1.42 (95% CI 1.07–1.89) for CHD compared to the highest quartile, independent of VWF levels and traditional cardiovascular risk factors. For venous thrombosis, Pagliari et al. 2021⁶⁶ Pagliari et al. 2021
Pagliari MT et al. ADAMTS13 activity, high VWF and FVIII levels in the pathogenesis of deep vein thrombosis. Thromb Res. 2021;198:92-98. showed that ADAMTS13 activity below the first quartile (≤86%) gave a 1.6-fold increased DVT risk (OR 1.6, 95% CI 1.05–2.55) in 657 Italian subjects; the combination of low ADAMTS13 with high VWF amplified DVT risk 15-fold (95% CI 7.80–33.80).

In stable coronary artery disease, an elevated vWF/ADAMTS13 antigen ratio — reflecting the same imbalance — predicted an adjusted OR of 1.86 (95% CI 1.45–2.82) for MI, stroke, or death at two-year follow-up in 999 aspirin-treated patients (Warlo et al. 2017)⁷⁷ (Warlo et al. 2017).

Practical Actions

For AA homozygotes — the genotype with the lowest ADAMTS13 levels — the most actionable intervention is eliminating tobacco exposure. Smoking is the largest modifiable environmental determinant of ADAMTS13 levels (Ma et al. 2017), and for AA individuals there is no genetic buffer from a G allele. Measuring the VWF:ADAMTS13 ratio directly quantifies the ADAMTS13-VWF balance and is clinically useful when additional thrombotic risk factors are present.

For AG and GG carriers, the same smoking-avoidance principle applies: the environmental ADAMTS13-lowering effect of tobacco is independent of genotype and can neutralize the genetic advantage from G alleles.

Interactions

ADAMTS13 does not act in isolation. The VWF-cleaving axis interacts directly with VWF levels, which are determined partly by rs1063856 (VWF gene variant) and ABO blood group (O blood group is associated with ~25% lower VWF). An AA individual with high VWF levels — from a VWF-increasing variant, non-O blood group, or inflammatory state — faces a particularly adverse ADAMTS13:VWF ratio. The 15-fold DVT risk observed with combined low ADAMTS13 + high VWF in Pagliari et al. 2021 illustrates this interaction's clinical magnitude. rs3739893 is a second major independent ADAMTS13 signal (β = −22.3%, p = 1.2×10⁻³⁰) with a much larger negative effect on ADAMTS13 levels; the combination of rs3739893 risk genotype with AA at rs28673647 would substantially compound the ADAMTS13-lowering effect.