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
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-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 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.

Crystallographic analysis by Huntington et al. (2003) | Huntington JA et al.,
Blood 2003 — X-ray crystal structures of Cambridge II antithrombin in complex
with heparin and a heparin mimetic; showed the A384S substitution repositions
the reactive centre loop P14 residue, favouring insertion into the A-sheet rather
than trapping thrombin revealed the
structural 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) |
Corral J et al., Blood 2007 — Spanish case-control study of 479 unselected VTE
patients and 477 matched controls; genotyped all participants for A384S; also
surveyed 9,669 West Scotland blood donors for population prevalence
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. In
their survey of 9,669 West Scotland blood donors, 10 carriers were identified —
a prevalence of 1.14 per 1,000 — establishing Cambridge II as the most frequent
single cause of hereditary antithrombin deficiency in the British population.

Arterial thrombosis: Roldán et al. (2009) | Roldán V et al., Thromb Haemost
2009 — case-control study of 303 myocardial infarction patients and 303 matched
controls in southern Spain; 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) | 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.

Standard anticoagulants (heparin, warfarin, DOACs) remain effective, though
unfractionated heparin and LMWH require larger-than-usual doses to achieve
therapeutic effect in some carriers because their circulating Cambridge II
antithrombin is heparin-resistant. 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 — this is one of the best-studied gene-gene interactions
in thrombophilia. Oral contraceptives containing estrogen multiply VTE risk
several-fold in antithrombin-deficient carriers and are a particular concern
for female carriers of reproductive age.