eMedicine Specialties > Pediatrics: General Medicine > Hematology
Antithrombin III Deficiency
Updated: Aug 16, 2007
Introduction
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.
Clinical
History
- Antithrombin III (ATIII) deficiency is most commonly associated with venous thrombosis. History should focus on current symptoms, defining the patient's personal medical history in terms of thrombosis and thrombotic symptoms, as well as determining if other procoagulant risk factors are present.
- Other risk factors include the following:
- 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, trauma)
- Communicating heart defects (atrial septal defect [ASD], ventriculoseptal defect [VSD], truncus arteriosus)
- Personal history of thrombosis is particularly important in terms of treatment. 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. These patients are usually treated with indefinite anticoagulant therapy, so careful review of this area is wise.
- Family history may be helpful. However, owing to a late onset of venous thrombosis and a relatively recent development of the ability to accurately screen for specific defects, many patients have family histories that are negative for the condition, even in affected kindreds. Family history topics should include venous thrombosis of the splanchnic system, thrombosis in any vessel without evident cause of local etiology, and recurrent miscarriages.
Physical
No physical stigmata are associated with congenital ATIII deficiency.
- Homozygote deficient newborns may have purpura fulminans-type presentation with embolic lesions in the skin. Heterozygote newborns are typically normal in appearance and do not commonly develop purpura fulminans unless other problems are coexistent.
Causes
- Deficiency may be due to several different genetic defects associated with differing degrees of enzyme production, enzymatic activity, and chemical stability (see Pathophysiology).
- Certain abnormal alleles have been associated with specific clinical features (Wibble and Wobble, mutations in the "shutter" region of the enzyme), while others have yet to be studied.
- Acquired ATIII deficiency is usually due to abnormal activation of a coagulation pathway or synthetic defect, often from medication (eg, L-asparaginase) or liver disease.
- ATIII may be lost in third spaces when it redistributes into edematous tissues. ATIII may also be lost as part of increased protein losses seen in nephrotic syndrome, and this should be suspected if clotting occurs.
More on Antithrombin III Deficiency |
 Overview: Antithrombin III Deficiency |
| Differential Diagnoses & Workup: Antithrombin III Deficiency |
| Treatment & Medication: Antithrombin III Deficiency |
| Follow-up: Antithrombin III Deficiency |
| References |
| Next Page » |
References
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Further Reading
Keywords
antithrombin III deficiency, acquired antithrombin deficiency, congenital antithrombin deficiency, AT-III deficiency, ATIII deficiency, AT III deficiency, heterozygous antithrombin deficiency, heparin, low molecular weight heparin, thrombin disorder, anticoagulation, anti-coagulation, venous thrombosis, arterial thrombosis, clotting disorder, blood clots, hematologic disorder, increased thrombogenesis, inappropriate activation of the clotting system, inappropriate coagulation, coagulopathy, disseminated intravascular coagulation, DIC, microangiopathic hemolytic anemias due to endothelial damage, hemolytic uremic syndrome, veno-occlusive disease, venoocclusive disease, VOD, protein C deficiency, protein S deficiency, liver disease, nephrotic syndrome
