Excerpt from Antithrombin III Deficiency

Please click here to view the full topic text: Antithrombin III Deficiency

Background

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 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, 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 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 include disseminated intravascular coagulation (DIC), microangiopathic hemolytic anemias due to endothelial damage (ie, hemolytic uremic syndrome), and venoocclusive disease (VOD) in patients undergoing bone marrow transplant.

Pathophysiology

Heterozygous ATIII deficiency results in venous thrombosis, most commonly starting in the third decade of life.

The defect is autosomal dominant, and several different genetic abnormalities have been identified in separate kindreds. The defects are most often translational or postprocessing errors that result in decreased functional ATIII.

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. Numerous discrete point mutations of the antithrombin gene have been identified. The type I deficiency is the most common phenotype.

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. Substitutions that result in polar amino acids in this location result in decreased activity and survival of the enzyme (Wibble), whereas others cause amino acid substitutions and result in less severe decreases. Clinically, the Wibble gene is associated with a greater risk of thrombosis early in life (second decade).

Other regions of the gene (eg, the "shutter" region) are also associated with clinically significant thrombosis.

Acquired deficiencies are commonly due to increased coagulation secondary to endothelial injury or the presence of antiphospholipid (AP) antibodies (eg, lupus anticoagulant). In both of these situations, ATIII is consumed at increased rates because of excessive activation of the coagulation pathway. Other reported mechanisms of acquired ATIII deficiency include chronic liver disease, with resultant synthetic failure, and protein loss due to ascites or nephrotic syndrome.

Race

Congenital ATIII deficiency is recognized in all racial and ethnic groups.

Sex

No sex-related difference is noted in terms of the prevalence of congenital ATIII deficiency. 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.

Age

Patients who are homozygotes often present in the neonatal period; individuals who are heterozygotes may remain asymptomatic well into middle age.

• A thrombotic challenge, such as placement of a central venous catheter or other vascular catheter, frequently unmask heterozygotes. Individuals who have multiple catheter-related thrombotic events, or life/organ threatening events with no other risk factor, should be evaluated for an underlying procoagulant condition.

Please click here to view the full topic text: Antithrombin III Deficiency