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COAGULATION CORNER: JULY 2011

COAGULATION AND ANTI-THROMBIN 

Antithrombin (AT) is a potent inhibitor of the reactions of the coagulation cascade.  This is a serine protease inhibitor which primary enzymes it inhibits are factor Xa, factor IXa and thrombin (factor IIa). It also has inhibitory actions on factor XIIa, factor XIa and the complex of factor VIIa and tissue factor. Its ability to limit coagulation through multiple interactions makes it one of the primary natural anticoagulant proteins. The interaction between thrombin and antithrombin could be accelerated by as much as 2000 times by heparin.

Antithrombin is synthesized in the liver and secreted into plasma  containing 432 amino acids with a molecular weight of 58,200, with a plasma half life of 3 days. Normal levels are between 80-150%. A 50% reduction in AT levels is sufficient to result in thrombosis. Neonates have reduced level of AT at birth (30%-50%) which rise to 60% of adult levels 1 month after birth.

Five types of antithrombin were classified by Seegers in 1962 with the first family identified by Olav Egeberg in 1965.  The most recent research has described novel mutations in the antithrombin gene. This has been described as the most severe of the inherited conditions with an odds ratio for thrombosis of 10-20 fold however the incident of venous thrombosis is ~ 1 per 2000-5000 people.  AT deficiency is the most serious disorder of the inherited deficiencies of protein C or S. 85% of people with congenital AT deficiency experience thrombotic episodes by age 55, initially with presentation at between 20-30 years of age having multiple events throughout lifetime

Laboratory Testing:

Patients suspected with AT deficiency will have normal screening tests for PT, APTT, Fibrinogen and D-dimer.  First line of testing is activity which is perfomed by a chromogenic assay. The principle uses excess amount of Factor Xa added to sample in the Presence of heparin, portion of enzyme is complexed, and  inactivated by AT in sample. Excess uninhibited Xa cleaves a specific chromogenic substrate releasing a dye. The change is measured by increase in absorbance. Result is inversely proportional to inhibiting activity of Antithrombin. If this test is abnormal, it can suggest either a dysfunctional (qualitative) disorder or a quantitative disorder.  In order to distinguish between the two types an antigen test should be performed.

AT deficiency can be congenital or acquired. There are 2 types of deficiencies, Type 1 deficiency is a quantitative deficiency where patients present with reduced activity and antigen levels

Congenital Antithrombin deficiency:

Type I antithrombin deficiency are heterozygous mutations which lead to a complete loss of the mutant antithrombin protein result in immunologic and functional levels that are 50% or less than normal. The genetic basis  includes major gene deletions or point mutations causing a quantitative reduction in antithrombin synthesis by various processes, including premature termination of translation, aberrant RNA processing, and production of unstable antithrombin molecules that have short plasma half lives.   Twenty two novel mutations of which 9 missense mutations resulted in type I deficiency and led to low antithrombin activity and antigen levels. Clinically these mutations were associated with venous thrombosis occurring before the age of 32 years. Homozygous type I antithrombin deficiency (AT deficiency) is almost always fatal in utero.

Type II antithrombin deficiency states are usually the result of single amino acid changes that result in functional deficits in a molecule that is otherwise synthesized and secreted into the plasma in a normal fashion. The variant antithrombin molecules may have abnormalities at the reactive site or the heparin binding site. Most cases of type II antithrombin deficiency are also heterozygous, although rare cases of homozygous type II deficiency have been described.

There also exists a third category of type II antithrombin deficiency in which multiple or "pleiotropic" abnormalities affect the reactive site, the heparin binding site, or the plasma concentration. Type II heparin binding site variants are not associated with a high risk of thrombosis unless the affected individual is a homozygote.

Acquired Antithrombin deficiency:

There are several conditions which can cause an acquired AT deficience

-  Liver failure: Since AT is synthesized in the liver, disorders of the liver result in decreased production. The more severe the condition the greater the impact on the levels of AT (such as liver cirrhosis)

-  Nephrotic syndrome: antithrombin is in the urine, resulting in reduced plasma levels, and these patients are at higher risk for thrombotic events. Conversely, patients with inherited antithrombin deficiency (AT deficiency) may develop renal failure due to renal vein thrombosis or due to fibrin deposition in the glomeruli.

-  Acute respiratory distress syndrome is a known secondary cause of antithrombin deficiency (AT deficiency), and this is a major cause of both morbidity and mortality in the newborn. Extracorporeal membrane oxygenation used in the treatment of respiratory failure can be associated with reduced antithrombin and thrombotic events.  

-  Pregnancy: Although it is widely believed that no substantial reduction of antithrombin occurs during normal pregnancy,  antithrombin levels were lower during the third trimester of pregnancy and in the postpartum period. Pregnancy-induced antithrombin deficiency (AT deficiency) is more likely to be seen in twin and triplet pregnancies.

-  Sepsis: antithrombin deficiency (AT deficiency) in the setting of sepsis appears to be a correlation between the severity of illness and the degree of antithrombin reduction. .

-  Consumptive coagulopathies such as DIC, thrombotic microangiopathy, and acute hemolytic transfusion reactions are associated with antithrombin depletion.

Treatment:

Patients who have had an episode of DVT and whose antithrombin deficiency has been recognized should receive lifelong oral anticoagulation to protect them from recurrent VTE. Patients with AT deficiency may present with atypical site thrombosis, such as mesenteric or hepatic vein thrombosis, and should be placed on lifelong anticoagulation immediately.

Antithrombin supplementation has been suggested to be useful in patients with the following conditions or those undergoing the following procedures.

• Malignancies
• Sepsis
• Shock
• Open heart surgery
• Orthopedic procedures

Each unit of FFP obtained from a blood bank contains normal levels of antithrombin. If a patient requires 3000 U of antithrombin, that patient would require 3000 mL of FFP given rapidly to raise the level of antithrombin in the recipient. Volume overload becomes a problem in such patients, FFP replacement is not a reasonable source of repeated antithrombin replacement and a choice only when no concentrate is available. .

Antithrombin is an important part of the coagulation cascade.  Although AT is a rare deficiency, consumption of AT is more common. AT testing is important to complete a thrombophia workup.

Donna Castellone

About the Author

Donna Castellone,
MS, MT(ASCP)SH
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