Antithrombin III (ATIII) is a potent inhibitor of the coagulation cascade. It is a nonvitamin K-dependent protease that inhibits coagulation by lysing thrombin and factor Xa. ATIII activity is markedly potentiated by heparin; potentiation of its activity is the principle mechanism by which both heparin and low molecular weight heparin result in anticoagulation.

Congenital ATIII deficiency

• Congenital ATIII deficiency is an autosomal dominant disorder in which an individual inherits 1 copy of a defective gene.
• This condition leads to increased risk of venous and arterial thrombosis, with an onset of clinical manifestations typically appearing in young adulthood. 
• This form is commonly diagnosed during childhood by screening after an affected family member has been identified or after a child has had a thrombotic event.

Severe congenital ATIII deficiency

• Severe congenital ATIII deficiency, in which the individual inherits 2 defective genes, is a rare autosomal recessive condition associated with increased thrombogenesis, typically noted in the neonatal period or early infancy.

Acquired ATIII deficiency

Acquired ATIII deficiency is a deficiency of antithrombin primarily due to consumption. It is observed in situations in which activation of the coagulation system is inappropriate.

Common conditions that result in acquired ATIII deficiency

• Disseminated intravascular coagulation (DIC)
• Microangiopathic hemolytic anemias due to endothelial damage (ie, hemolytic uremic syndrome),
• Venoocclusive disease (VOD) in patients undergoing bone marrow transplant

Causes

Two types of ATIII deficiency have been described. 

• Type I is a simple deficiency of the enzyme, and both antigen and activity levels are similarly low. 
• Type II is also known as "unclassified ATIII deficiency," in which the enzyme activity is reduced.

 

Two defects, wibble and wobble, have been characterized as resulting in substitutions of a single amino acid at the beginning of the beta sheet of the peptide

Women of childbearing age are of special concern

• ATIII deficiency, like other congenital procoagulant defects, may contribute to an increased risk of spontaneous abortions.
• Particularly in cases of fetal or umbilical thrombosis as the cause of the miscarriage, consider ATIII deficiency, along with protein C or protein S deficiency and AP antibody syndrome.
• Oral contraceptives (OCs) contain large doses of estrogen, which is a stimulator of coagulation.
• Women who are ATIII-deficient heterozygotes are at an increased risk of thrombosis when taking OCs.
• Parents of newborns who have a thrombotic event are at increased risk of having a procoagulant disorder themselves.
• These individuals should be referred for further assessment of their own risk factors.

Clinical features

Antithrombin III (ATIII) deficiency is most commonly associated with venous thrombosis.

Other risk factors

• Presence of a central line currently or in the past (an especially common risk factor for thrombosis in infants and small children where the lumen of the vessel is small, and blood flow around the catheter is no longer laminar.)
• Medications known to be procoagulant or medications that nonspecifically impair protein synthesis (eg, L-asparaginase)
• Other diseases associated with procoagulant states (systemic lupus erythematosus [SLE], nephrotic syndrome, bone marrow transplantation, and trauma)
• Communicating heart defects (atrial septal defect [ASD], ventriculoseptal defect [VSD], truncus arteriosus)
• Patients with congenital ATIII deficiency who have had one unprovoked thrombotic event (particularly in the mesenteric or splanchnic systems) are much more likely to have recurrent clots.

Tests and diagnosis

• AT III levels
• PT and aPTT
• Protein C and protein S
• Factor V Leiden testing
• Homocysteine level: Increased levels of homocysteine are associated with an increased risk of thrombosis in adults, but this is rarely seen in children.
• Anticardiolipin antibodies (both IgG and IgM class) should be measured by ELISA or other physical means to rule out coexisting thrombotic risk from this source.
• 2D- echo
• Venous duplex doppler

Treatment

Three congenital conditions are discussed:

• Homozygous ATIII deficiency discovered in neonates
• Heterozygous ATIII deficiency in patients with their first thrombosis
• Heterozygous ATIII deficiency in patients with previous thrombosis

Managment of venous thrombosis

• In neonates who are homozygote deficient, both arterial and venous thrombosis is seen, particularly if vascularly invasive procedures (eg, extracorporeal membrane oxygenation [ECMO], umbilical vessel catheterization) are performed.
• In these patients, replacement of ATIII using ATIII concentrates or fresh frozen plasma is recommended. 
• Enoxaparin a low molecular weight heparin (LMWH) is frequently used to prevent thrombi as well as to prevent thrombi that have already occurred from propagating.
• Congenital ATIII deficiency has developed thrombosis, anticoagulation is indicated. Warfarin (Coumadin) is the principal anticoagulant used. This vitamin K antagonist is administered at a dose to maintain an international normal ratio (INR) on PT of 1.5-2.5.
• The duration of warfarin therapy in children with acquired or heterozygous congenital ATIII deficiency experiencing their first clot is controversial, but therapy is generally continued for at least 3-6 months before stopping anticoagulation is considered.
• ATIII-deficient heterozygotes experiencing a second clot, particularly in mesenteric or splanchnic beds, are at significant risk of further life-threatening or organ-threatening thrombosis. These patients are candidates for indefinite warfarin therapy.
• Acquired ATIII deficiency is due to decreased production or increased consumption. In either case, treatment of the underlying disease and replacement of ATIII using ATIII concentrates is the common approach used.

Surgical care

• ATIII concentrates have been used in the preoperative period for surgical prophylaxis in patients with a known deficiency.
• Should ATIII concentrates not be available, fresh frozen plasma at a dose of 20 mL/kg can raise the ATIII level by approximately 20%