• Prevalence in the general population is approximately 0.02–0.2% (1 in 500 to 1 in 5,000) ^[1][2].
• Among patients presenting with a first unprovoked VTE, inherited AT deficiency accounts for roughly 1–2% of cases.
• AT deficiency is the rarest but most thrombogenic of the three classic inherited thrombophilias (AT deficiency, protein C deficiency, protein S deficiency) ^[1][2].

• In the Chinese population, inherited thrombophilias (AT, protein C, protein S deficiency) are very rare causes of VTE ^[1][3].
• Factor V Leiden is NOT found in Chinese — this is a Caucasian-predominant mutation ^[1][2]. This is critical for HKUMed exams: do not include Factor V Leiden in the differential for thrombophilia in a Chinese patient.
• Prothrombin G20210A mutation is also virtually absent in East Asians.
• Despite rarity, AT deficiency should still be considered in young Chinese patients with unprovoked or recurrent VTE, VTE at unusual sites, or family history of thrombosis.

Antithrombin (AT) is a single-chain glycoprotein of ~58 kDa, belonging to the serpin superfamily (serine protease inhibitor). It circulates in plasma at a concentration of approximately 150 µg/mL (functional level ~80–120%).

• Antithrombin is synthesised by the liver ^[1]. This is why severe liver disease also leads to acquired AT deficiency — the failing liver simply cannot make enough.

• SERPINC1 gene, located on chromosome 1q25.1 ^[2].
• "SERPIN" = serine protease inhibitor; "C1" = complement/coagulation inhibitor subfamily, member 1.

AT acts as a suicide substrate inhibitor (a "molecular trap"): it binds covalently to the active site of target serine proteases and forms an irreversible 1:1 complex, permanently inactivating them.

Antithrombin is a protease that neutralises (inactivates) the following clotting factors: ^[1]

• Thrombin (factor IIa) — the most important target
• Factor Xa — the second most important target
• Factor IXa
• Factor XIa
• Factor XIIa

"Basically some common pathway, then most of the intrinsic pathway" ^[1]

Think of it this way: AT polices the middle and end of the coagulation cascade. It does NOT significantly inhibit factor VIIa (the initiator of the extrinsic pathway — that's the job of tissue factor pathway inhibitor / TFPI).

Under physiological conditions, AT's inhibitory activity is slow. The endogenous heparan sulphate proteoglycans on the endothelial cell surface (and therapeutically administered heparin) accelerate AT's activity by ~1,000–4,000 fold.

Heparin relies on antithrombin to exert its activities — hence, without antithrombin, heparin has nothing to enhance, and thus cannot inhibit anything. ^[1]

"If your patient has a homozygous deficiency of the [antithrombin] gene, then they will have primary resistance towards heparin." ^[1]

The lecture analogy is apt: "Antithrombin is the army, heparin is the king — without an army, no matter how smart the king is, cannot defeat the enemy." ^[1]

How heparin works mechanistically:

1. Heparin (a negatively charged glycosaminoglycan) binds to a specific pentasaccharide sequence on AT, inducing a conformational change in AT.
2. This conformational change exposes the reactive centre loop of AT, drastically accelerating its binding to thrombin and factor Xa.
3. For thrombin inhibition specifically, heparin must be long enough (≥18 saccharide units) to simultaneously bind both AT and thrombin (a "ternary bridging complex"). This is why unfractionated heparin (UFH) inhibits both thrombin and Xa, while low-molecular-weight heparin (LMWH) primarily inhibits factor Xa (shorter chains cannot bridge).
4. Fondaparinux (a synthetic pentasaccharide = the minimal heparin sequence needed to bind AT) activates AT selectively against factor Xa only.

AT deficiency sits within the broader framework of the body's three major natural anticoagulant pathways:

This is the form most commonly discussed in the thrombophilia context.

Inheritance: Autosomal dominant with variable penetrance ^[1][2]

• Heterozygous deficiency: the clinically relevant form. AT levels typically 40–60% of normal. Symptomatic with variable expressivity.
• Homozygous Type I deficiency: essentially incompatible with life (lethal in utero or neonatal period) — very rare, almost never seen clinically.
• Homozygous Type II (heparin-binding site) deficiency: rare but can be viable, though severely prothrombotic.

Classification of Hereditary AT Deficiency

The risk of thrombosis depends on the type of antithrombin deficiency: ^[1]

Why does this classification matter?

• Type I and Type II-RS have the highest thrombotic risk because the AT molecule is either absent or functionally dead at its critical business end.
• Type II-HBS has a lower thrombotic risk in heterozygotes because the AT molecule can still inhibit thrombin/Xa (just more slowly without heparin enhancement). However, homozygous Type II-HBS individuals lose the heparin-augmentation entirely and are at significant risk.

Acquired causes are far more common than hereditary causes and must be excluded before labelling a patient as having inherited AT deficiency.

The pathophysiology is straightforward once you understand AT's role:

1. Normal state: AT continuously patrols the blood, neutralising any thrombin and factor Xa that are generated. This prevents inappropriate clot propagation. Endothelial heparan sulphate potentiates this on vessel walls, creating an anticoagulant surface.

2. AT deficiency: With reduced AT quantity or function, the "braking system" on coagulation is impaired:

   • Thrombin accumulates → converts more fibrinogen to fibrin → clot grows
   • Factor Xa accumulates → generates more thrombin via prothrombinase complex → positive feedback amplification
   • Factor IXa, XIa, XIIa accumulate → further amplification of intrinsic pathway
   • Net result: unopposed thrombin generation → hypercoagulable state → VTE

3. Why venous thrombosis predominantly?

   • Venous flow is slow (stasis), allowing coagulation factors to accumulate locally
   • The coagulation cascade (thrombin/fibrin-driven) is the dominant mechanism in venous thrombosis (as opposed to arterial thrombosis, which is more platelet-driven)
   • AT deficiency specifically impairs the coagulation cascade inhibition → preferentially predisposes to venous clots

4. Heparin resistance:

   • Since heparin's mechanism of action is to potentiate AT, patients with AT deficiency may show VTE often resistant to normal doses of heparin ^[2]
   • This manifests as failure to achieve therapeutic APTT prolongation despite adequate/escalating UFH doses
   • Or subtherapeutic anti-Xa levels despite adequate LMWH dosing

AT deficiency alone (in heterozygotes) is often not sufficient to cause thrombosis — most affected individuals need an additional provocation (Virchow's triad):

• Stasis: immobilisation, long-haul flights, post-operative period
• Endothelial injury: surgery, trauma, central venous catheters
• Additional hypercoagulability: pregnancy (physiological increase in procoagulant factors II, VII, VIII, X, fibrinogen + decreased protein S), oral contraceptive pills, concurrent malignancy

This explains why ~70% have VTE before age 60 ^[2] — over a lifetime, the cumulative exposure to "second hits" eventually triggers an event.

Common inherited thrombophilias (all autosomal dominant) ^[1][2]:

Indications for thrombophilia screening (which would detect AT deficiency) ^[3]:

• Young patients with idiopathic venous thrombosis
• Suspected antiphospholipid syndrome, e.g. recurrent miscarriage
• Unusual sites of thrombosis (mesenteric, renal, portal vein, cerebral venous sinus)
• Warfarin-induced skin necrosis (protein C/S deficiency, but screen full panel)
• First-degree relative with documented inherited thrombophilia
• Recurrent VTE despite adequate anticoagulation
• Heparin resistance

On standard coagulation testing (PT and APTT), antithrombin deficiency does NOT cause any abnormality: ^[5]

• PT: Normal (extrinsic pathway intact)
• APTT: Normal (all intrinsic pathway factors are present; AT is not a clotting factor but an inhibitor)
• Fibrinogen: Normal
• Platelet count: Normal

This is a critical teaching point: a normal PT and APTT do NOT exclude a hypercoagulable state. Standard clotting tests only detect factor deficiencies (bleeding tendency). They do not detect deficiencies of natural anticoagulants. Specific assays (AT activity, protein C, protein S) are needed.

The only scenario where AT deficiency might indirectly affect the APTT is when heparin is administered — you would expect UFH to prolong the APTT, but in AT deficiency, the APTT fails to prolong adequately (heparin resistance).

"Heparin can inhibit the intrinsic pathway (prolonging APTT), as well as inhibits thrombin (factor IIa, in common pathway) — antithrombin activated, inactivates thrombin-induced activation of factors V, VIII, and XI" ^[5]

In DIC, there is widespread activation of the coagulation cascade → massive consumption of clotting factors AND natural anticoagulants including AT ^[3][6]. This creates a vicious cycle:

• Reduced AT → less inhibition of thrombin → more thrombin generation → more fibrin deposition → more consumption of AT
• This is why AT levels are measured in DIC and why AT concentrate has been studied (though not standard therapy) as adjunctive treatment

Pregnancy is a physiological prothrombotic state. In women with AT deficiency:

• Baseline thrombotic risk is already elevated
• Pregnancy further increases procoagulant factors and reduces protein S
• Risk of VTE during pregnancy is estimated at 30–50% per pregnancy in untreated AT-deficient women
• Prophylaxis is required in pregnancy, surgery, or post-VTE ^[2]

Both cause hypercoagulability but through different mechanisms:

• AT deficiency: loss of a natural anticoagulant → reduced inhibition of coagulation cascade
• APS: autoantibodies against phospholipids/β2-glycoprotein I → complex mechanism involving endothelial activation, complement activation, and platelet activation → both venous AND arterial thrombosis
• APS paradoxically prolongs APTT in vitro (lupus anticoagulant interferes with phospholipid-dependent clotting tests) but causes thrombosis in vivo
• AT deficiency does NOT affect APTT

These causes are extremely uncommon in Chinese. Do not include these as differential diagnosis in Chinese patients. ^[2]

Common inherited thrombophilias ^[1][2][7]:

"Warfarin-induced skin necrosis in the first few days" occurs in protein C deficiency because protein C has the shortest half-life (~6–8 hours) of the vitamin K-dependent factors — it drops first when warfarin is started, creating a transient prothrombotic window → cutaneous microvascular thrombosis. AT deficiency does NOT cause this because AT is not vitamin K-dependent. ^[2][7]

Indications for thrombophilia screening (which would detect AT deficiency) ^[3]:

• Young patients with idiopathic venous thrombosis
• Suspected APLS, e.g. recurrent miscarriage
• Unusual sites of thrombosis (mesenteric, renal, portal vein, cerebral venous sinus)
• Warfarin-induced skin necrosis (protein C/S deficiency, but screen full panel)

Additional clinical triggers specific to AT deficiency:

• Heparin resistance — heparin relies on antithrombin to exert its activities; hence, without antithrombin, heparin has nothing to enhance, and thus cannot inhibit anything ^[1] — this is a near-pathognomonic clue
• Recurrent VTE despite adequate anticoagulation
• Strong family history of VTE (especially if multiple first-degree relatives affected before age 50)
• VTE in pregnancy or puerperium without other obvious risk factors

The diagnosis of hereditary AT deficiency requires:

Classification scheme based on lab results:

Why do we need both an activity assay AND an antigen assay? Because the activity assay tells you "how well does the AT work?" while the antigen assay tells you "how much AT protein is present?" If both are low proportionally, you have a quantitative deficiency (Type I — not enough protein). If the antigen is normal but activity is low, you have a qualitative deficiency (Type II — enough protein but it doesn't work properly). This distinction matters because Type I and Type II-RS carry the highest thrombotic risk.

When thrombophilia screening is indicated, the standard panel includes:

These are done in any patient presenting with VTE, not specific to AT deficiency, but critical for context:

"You can do well only on platelet count, PT and APTT" ^[5] — these are the bread-and-butter first-line haemostasis tests. But remember: they are tests of FACTOR DEFICIENCY (bleeding tendency), NOT tests of INHIBITOR DEFICIENCY (thrombotic tendency). A completely normal PT, APTT, and platelet count can coexist with severe AT deficiency.

Before labelling a patient as having hereditary AT deficiency, the following must be assessed:

Since AT deficiency presents through its thrombotic complications, you also need to diagnose and characterise the VTE:

Interpretation of clotting profile ^[8][9]:

"Can see that you can do well only on platelet count, PT and APTT" ^[5] — but for thrombophilia, these three tests are all NORMAL. You need the specific inhibitor assays.

Patient on unfractionated heparin — how is PT/APTT affected? ^[5]:

• No change in PT
• Increase in APTT
• Antithrombin activated, inactivates thrombin-induced activation of factors V, VIII, and XI

This tells you: if you give UFH and the APTT does NOT rise, the AT that heparin needs to activate is not there → think AT deficiency.

The recommended approach to avoid false positives and false negatives:

1. First measurement: AT activity (heparin cofactor assay) in a stable patient, off anticoagulants
2. If low: Repeat AT activity + add AT antigen level, at a separate time point ≥ 2–4 weeks later
3. If persistently low: Exclude all acquired causes (LFT, urinalysis, DIC screen, drug history)
4. If no acquired cause: Screen first-degree family members
5. If family members concordantly affected: Hereditary AT deficiency confirmed clinically
6. Optional: SERPINC1 gene sequencing for definitive molecular diagnosis

Heparin relies on antithrombin to exert its activities — hence, without antithrombin, heparin has nothing to enhance, and thus cannot inhibit anything. ^[1]

This means standard-dose heparin may not achieve therapeutic anticoagulation. The approach differs depending on severity:

"Basically anti-thrombin is the army, heparin is the king → without an army, no matter how smart the king is, cannot defeat the enemy" ^[1]

How to Recognise and Manage Heparin Resistance in Practice

1. Start UFH infusion → target APTT 1.5–2.5× baseline ^[12][13]
2. Monitor APTT at 6 hours after initiation or dose change
3. If APTT fails to reach target despite dose escalation (e.g. > 35,000 U/day):
   • Check anti-Xa level (more reliable than APTT in this context) — if anti-Xa is subtherapeutic despite high UFH dose, confirms true heparin resistance
   • Measure AT activity — if low, this is the cause
   • Administer AT concentrate to raise AT level to > 80% → then re-attempt heparin dosing
   • OR switch to a direct thrombin inhibitor (argatroban, bivalirudin) which does not require AT

This is the specific treatment for AT deficiency — it directly replaces the missing protein.

These bypass the AT pathway entirely and are increasingly used:

Why are direct inhibitors attractive in AT deficiency? Because the entire problem is that AT-dependent drugs (heparin, LMWH, fondaparinux) cannot work without their cofactor. Direct inhibitors sidestep this completely — they grab thrombin or Xa directly without needing any intermediary.

For protein C deficiency, the notes explicitly state "anticoagulation in VTE → should continue indefinitely" ^[2]. The same principle applies even more strongly to AT deficiency, which carries a higher thrombotic risk (16.3× vs 7×).

DOAC Dosing for VTE (for reference) [15]:

Conditions not suitable for DOAC ^[12]:

• Valvular AF / mechanical prosthetic heart valves — must use warfarin
• Severe renal impairment (CrCl < 15 mL/min for most DOACs; < 30 mL/min for dabigatran)
• Pregnancy and breastfeeding — use LMWH instead
• Antiphospholipid syndrome (APS) — DOACs shown to be inferior to warfarin in triple-positive APS (TRAPS trial)
• Active pathological bleeding

Contraindications to anticoagulation ^[12]:

• Recent major surgery
• Uncontrolled hypertension / haemorrhagic stroke
• Major bleeding diathesis
• Active bleeding
• Severe thrombocytopenia (platelet < 50 × 10⁹/L)

If the patient is already on long-term anticoagulation:

• Stop warfarin 5 days before elective surgery (or stop 2 days + oral vitamin K) ^[16]
• Bridging with LMWH when INR becomes subtherapeutic → discontinue LMWH 12 hours before surgery ^[16]
• Indications for bridging: known hypercoagulability e.g. protein C/S deficiency ^[16] — AT deficiency falls into this same high-risk category requiring bridging

Pregnancy in AT-deficient women is high-risk — VTE risk estimated at 30–50% per pregnancy without prophylaxis.

"Pregnancy: switch to LMWH when 1st trimester (↓ teratogenicity) and > 36 weeks (avoid PPH); cover up to 6 weeks postpartum (highest risk as blood returns from uterus)" ^[13]

In AT deficiency specifically, LMWH doses may need to be higher than standard prophylactic doses (e.g. ≥ 100 U/kg/day ^[2]), and AT concentrate should be readily available for delivery.

Not all individuals with hereditary AT deficiency will develop VTE. For asymptomatic carriers (identified through family screening) who have never had a thrombotic event:

• No routine long-term anticoagulation is recommended — the bleeding risk of lifelong anticoagulation outweighs the benefit in someone who has never clotted
• Lifestyle counselling: avoid prolonged immobilisation, maintain hydration during travel, avoid oestrogen-containing contraceptives
• Situational prophylaxis: LMWH for surgery, pregnancy, prolonged immobilisation
• Education: recognise symptoms of DVT/PE and seek immediate medical attention
• Genetic counselling: explain AD inheritance, 50% transmission risk to offspring

The management differs fundamentally from hereditary AT deficiency because the primary goal is to treat the underlying cause:

This is the chronic sequela of DVT and affects up to 20–50% of DVT patients, including those with AT deficiency.

AT deficiency can cause thrombosis in sites less commonly seen with typical provoked VTE:

AT deficiency in pregnancy carries the highest VTE risk among the inherited thrombophilias:

While not a "complication" in the traditional sense, heparin resistance is arguably the most clinically important consequence of AT deficiency because it directly impacts acute treatment:

"Heparin relies on antithrombin to exert its activities — hence, without antithrombin, heparin has nothing to enhance, and thus cannot inhibit anything" ^[1]

The universal risk of all anticoagulants. The trade-off is always: preventing thrombosis vs. causing haemorrhage.

Reversal agents ^[12]:

HIT is doubly dangerous in AT deficiency: the patient already has a prothrombotic state from AT deficiency, and now HIT adds a second prothrombotic mechanism on top. These patients can develop catastrophic thrombosis.

Often overlooked but clinically important: