antithrombin III deficiency

**Physiology:** Antithrombin III (SERPINC1 gene, chromosome 1q) is a serine protease inhibitor (serpin) made in the liver. It inactivates thrombin (IIa), factor Xa, and also IXa, XIa, and XIIa. Heparin and heparan sulfate bind ATIII and cause a conformational change that increases its activity about 1000-fold.

**Genetics/Types:** - Inherited: autosomal dominant, usually heterozygous (homozygous is usually lethal in utero). - Type I (quantitative): low antigen and low activity. - Type II (qualitative): normal antigen, low activity (for example, defects in the heparin-binding site or reactive site). - Acquired causes (low ATIII from loss or decreased production): - Nephrotic syndrome (urinary loss), a classic board association. - Liver disease (decreased synthesis). - DIC and sepsis (consumption). - Major surgery, trauma, or large thrombosis (consumption). - Asparaginase (decreased synthesis). - Heparin therapy (a modest decrease). - Pregnancy and estrogen or oral contraceptives (may mildly decrease levels).

**Pathophysiology:** Less inhibition of thrombin and Xa causes a hypercoagulable state. The result is venous thrombosis, most often in the lower-extremity deep veins, with PE. Unusual sites (mesenteric, cerebral venous sinus, portal) can be involved. Arterial clots are less common. Thrombosis often starts in young adults (<50 years), recurs, and may be triggered by pregnancy, surgery, immobilization, or estrogen. Recurrent pregnancy loss can occur.

**Key clinical pearl, heparin resistance:** - Unfractionated heparin (UFH) does not raise the aPTT adequately, even at high doses, because there is not enough ATIII for heparin to activate. - Management of acute thrombosis: higher heparin doses, ATIII concentrate (recombinant or plasma-derived), or a direct thrombin inhibitor (argatroban, bivalirudin) or direct Xa inhibitor, which do not need ATIII. - Fresh frozen plasma is a source of ATIII if concentrate is unavailable.

**Diagnosis:** - Functional (activity) ATIII assay is the initial test. Antigen assays then distinguish type I from type II. - Test when the patient is not acutely thrombosed and is off heparin if possible, because acute thrombosis and heparin lower levels (false positives). Also exclude acquired causes. - Baseline PT, aPTT, and platelet count are normal.

**Treatment/Prevention:** - Acute VTE: anticoagulation as above. - Long-term: warfarin or a DOAC. Duration is often indefinite after an unprovoked or recurrent event. - Prophylaxis: ATIII concentrate in high-risk settings (surgery, delivery). - Pregnancy: use LMWH. Avoid warfarin because it is teratogenic. - Warfarin overlap: start it only after therapeutic heparin is established, but protein C and S deficiency are the ones classically linked to warfarin-induced skin necrosis, not ATIII.

**Comparison with other thrombophilias (high-yield):** - Factor V Leiden is the most common inherited thrombophilia (activated protein C resistance). - Prothrombin G20210A mutation. - Protein C and S deficiency causes warfarin skin necrosis. - ATIII deficiency is the rarest of these but has the strongest thrombotic risk, and it is the one that causes heparin resistance.

**Exam buzzwords:** young patient with recurrent DVT/PE, a failure of heparin to increase the PTT (aPTT), nephrotic syndrome (urinary ATIII loss), and treatment with ATIII concentrate or a direct thrombin inhibitor.