rs121909548 — SERPINC1 Cambridge II (A384S)

SERPINC1 Cambridge II — The Most Common Form of Inherited Antithrombin Deficiency

Antithrombin is the body's principal brake on coagulation — a serine protease inhibitor¹¹ serine protease inhibitor
Serpins (serine protease inhibitors) are a superfamily of proteins that inactivate serine proteases by acting as suicide substrates. Antithrombin targets thrombin and factor Xa, the two key amplifiers of the clotting cascade. that directly quenches thrombin and factor Xa, the central enzymes of the coagulation cascade. Without adequate antithrombin activity, clot formation goes unchecked, and blood can clot in veins or arteries where it should not. The rs121909548 variant — known as Antithrombin Cambridge II or A384S — is the single most prevalent cause of hereditary antithrombin deficiency in European populations, found in approximately 1 in 880 people of British descent.

What makes Cambridge II unusual among hereditary thrombophilias is how it hides: routine antithrombin antigen tests often return normal results because the variant protein is secreted and circulates at normal plasma concentrations. The defect only becomes apparent in functional assays measuring heparin-catalysed thrombin inhibition. This leads to systematic under-diagnosis²² systematic under-diagnosis
In clinical practice, antithrombin deficiency is typically screened with anti-Xa activity assays; Cambridge II can produce results at the borderline of the normal range and is often missed unless a specific substrate assay or genetic test is performed. and, consequently, many carriers are not identified until after their first thrombotic event.

The Mechanism

The p.Ala416Ser substitution (coding-strand notation c.1246G>T; on the plus strand NC_000001.11:g.173904038C>A) places a serine where alanine-384 normally sits in the reactive site loop³³ reactive site loop
The reactive site loop (RSL) is the bait segment of antithrombin that mimics a protease cleavage site. Thrombin bites the RSL, becomes covalently trapped, and is inactivated. Heparin binding induces a conformational change that dramatically accelerates this trapping. of the protein.

Analysis by Huntington et al. (2003)⁴⁴ Analysis by Huntington et al. (2003) revealed the consequence: in the presence of heparin, the A384S substitution causes the reactive-site loop to adopt a "substrate" conformation rather than an inhibitory one. Instead of trapping thrombin in an irreversible complex, the variant antithrombin is cleaved by thrombin and released — effectively feeding thrombin rather than neutralising it. The result is that heparin, normally antithrombin's most powerful accelerant, loses much of its ability to enhance Cambridge II antithrombin's inhibitory activity.

In plasma, this translates to a type II reactive-site (type IIRS) defect: functional antithrombin activity (measured as heparin-dependent inhibition of thrombin or factor Xa) is reduced, while the antigen concentration is normal or near-normal. Heterozygous carriers have approximately 60–80% of normal functional antithrombin activity; the remaining activity comes from the normal allele alone.

The Evidence

VTE risk: The definitive population study by Corral et al. (Blood, 2007)⁵⁵ Corral et al. (Blood, 2007)
Corral J et al., Blood 2007 — Spanish case-control study; genotyped all participants for A384S found the A384S allele in 1.7% of VTE patients versus 0.2% of controls, yielding an adjusted odds ratio of 9.75 (95% CI 2.2–42.5) for venous thrombosis.

Arterial thrombosis: Roldán et al. (2009)⁶⁶ Roldán et al. (2009)
Roldán V et al., Thromb Haemost 2009 — case-control study genotyped for A384S and traditional cardiovascular risk factors showed that Cambridge II carriers have a 5.66-fold increased risk of myocardial infarction (95% CI 1.53–20.88; p=0.009) after adjusting for sex and conventional cardiovascular risk factors, indicating that the thrombotic risk is not limited to veins.

Thrombin generation: Marlar et al. (2008)⁷⁷ Marlar et al. (2008)
Reference for thrombin generation data in Cambridge II carriers — endogenous thrombin potential studies demonstrated measurable increases in endogenous thrombin potential in Cambridge II heterozygotes, providing a mechanistic link between the functional antithrombin defect and the prothrombotic clinical phenotype observed in population studies.

Clinical penetrance: The Cambridge II mutation has appreciable but incomplete penetrance. Not every carrier develops thrombosis. Thrombotic events are often triggered by secondary risk factors — surgery, immobility, oral contraceptives, pregnancy — that push clotting risk above the threshold at which reduced antithrombin activity becomes clinically decisive.

Practical Actions

The key priorities for Cambridge II carriers are: (1) ensure the diagnosis is confirmed by a functional antithrombin assay (not antigen alone), (2) manage situational thrombotic triggers proactively, (3) obtain hematology input before high-risk procedures, and (4) extend cascade testing to first-degree relatives.

Antithrombin concentrate is available for use during high-risk situations such as surgery and delivery in symptomatic carriers.

Interactions

Cambridge II adds independently to other thrombophilic risk variants. Carriers who also have factor V Leiden (rs6025), prothrombin G20210A (rs1799963), or protein C/S deficiency are at substantially higher combined VTE risk than any single variant predicts. Oral contraceptives containing estrogen multiply VTE risk several-fold in antithrombin-deficient carriers and are a particular concern for female carriers of reproductive age.