[MIM 613 118]

(Hereditary thrombophilia due to congenital antithrombin 3 deficiency)

Rare: 2/10,000 approximately. Cause of thrombophilia diagnosed in 1 to 2 % of patients who have presented a thromboembolic accident. Autosomal dominant transmission with variable penetrance of a mutation of the SERPINC1 (1q23-25) gene. 

Antithrombin (AT) is a glycoprotein (serine protease inhibitor) produced by the liver, endothelial cells, and megakaryocytes. It is not dependent on vitamin K. It exerts its anticoagulant effect by inactivating thrombin (Xa) and factors IXa, and XIIa. The inhibitory action of AT is fast and powerful in the presence of heparin; in vivo, the glycosaminoglycans of the endothelial membranes accelerate and potentiate the action of ATIII. A deficiency of ATIII therefore causes some resistance to the effects of heparin.

Different types:

-         type I ((80 %): quantitative deficiency: the concentration is close to 50 % of normal (80-120 %) and is genotypically heterozygous. It is likely that the homozygous forms are lethal. There also exists a Ib form with a low level of normal ATIII, associated with low level of variants.

-         type II: qualitative deficiency: the protein is dysfunctional. 

There are some subtypes:

-            subtype II-RS (Reactive Site) (rare and highly thrombogenic) due to a mutation in the  thrombin-binding site,

-            subtype II-HBS (Heparin Binding Site) (most frequent) due to an anomaly of the binding to heparin; in case of homozygous form, the risk of venous thrombosis is similar or even higher than type I and there is a risk of arterial thrombosis

-            subtype II-PE that affects the binding sites of both thrombin, and heparin.

Usually, the first clinical manifestations appear during the 2nd or 3rd decade: recurrentsuperficial or deep venous thrombosis, of the limbs, sometimes resulting in pulmonary embolism in case of immobilization (plaster) , of estroprogestative contraception or pregnancy. Sometimes the renal, mesenteric or cerebral veins are involved. Type II-HBS cases have been described in newborns and infants.

Treatment: 

1)         acute phase: heparin is generally effective in case of type I or IIa; in case of HBS form , heparin alone is ineffective and should be associated at AT of human origin or recombinant (AT ©, Aclotine ©) at a dose of 30-50 IU/kg IV slowly (in principle: every 2 days) to get a plasma level of greater than 80 % AT.

2)         long term prophylaxis: vitamin K antagonists to keep the INR between 2 and 3 in heterozygous patients after a thrombotic event and in homozygous patients (BHS) even if asymptomatic.

An acquired antithrombin deficiency can be observed in case of:

-        pregnancy and estroprogetative contraception

-        reduced synthesis: severe liver failure, malnutrition, L-asparaginase

-        increased urinary, digestive and cutaneous losses: nephrotic syndrome, Crohn's disease or ulcero-hemorrhagic rectocolitis, extensive burns

-        increased consumption: extensive thrombosis, DIC, sepsis, heparin at therapeutic doses

Anesthetic implications: 

major risk of venous thrombosis: thromboprophylaxis. If already under vitamin K antagonists, ensure the transition to heparin with the advice of a specialist in hemostasis

References : 

-        Kok V, Sclacmeulder M, Joghmans K, Ninane J. 
Déficit en antithrombine et thromboses chez le jeune enfant. 
Arch Pédiatr 1999 ; 6 : 279-82.

-         Meyer Samama M, Horellou M-H, Conard J. 
Déficit constitutionnel en antithrombine. 
Sang Thrombose Vaisseaux 2005 ; 17 : 289-91.

-         Guermazi S, Elloumi-Zghal H, Ben Hassine L, Romani S et al. 
Déficit homozygote en antithrombine de type HBS : à propos d’une famille. 
Pathologie Biologie 2007 ; 55 : 256-61.

-         Hougardy L, Stéphenne X, Reding R, Sokal E, Smets F, Lambert C, Hermans C. 
Acquired antithrombin type IIb deficiency after liver transplantation: a case report. 
Am J Transplant 2012: 12: 1329-32.

-        Piper BJ, Farrell PT. 
Hereditary antithrombin III deficiency and neuraxial anaesthesia. 
Anaesth Intensive Care 2015 ; 43 : 782-5  

-        VanDyck K, Dunn IF, Yates C, Robbs C,Tanaka KA.
Hereditary Antithrombin Deficiency: a balancing act of perioperative hemostasis and thromboprophylaxis : a case report.
A&A Practice 2021;15:e01550

Updated: June 2023