Laboratory for Molecular Diagnostics
Center for Nephrology and Metabolic Disorders

Antithrombin 3

Antithrombin 3 deficiency, a an autosomal dominant disorder causing hypercoagulability and recurrent thrombosis. Although easily measured in plasma, further subclassification and family counselling is available through molecular genetic analysis.

Epidemiology

Initially, the prevalence of antithrombin deficiency in the general population was estimated one in 2000 to 5000. These estimated were based on immunological measurements of the circulating protein. Then, functional assays revealed a much higher prevalence of antithrombin deficiency, one in 150 to 500. These assays also allowed for a further subclassification of antithromin deficiency.[Error: Macro 'ref' doesn't exist]

In patients with venous thromboembolism, the prevalence of antithrombin deficiency is about 0.5%.[Error: Macro 'ref' doesn't exist]

Gene Structure

The gene spans about 14kb on chromosome 1 (1q23-q25) and consists of seven exons.

Protein Structure

The gene product is a glycoprotein that belongs to the alpha-2-globuline fraction. The mature protein of 432 amino acids is secreted by the liver after splitting off the signal peptide (32 amino acids) and further biochemical processing in the endoplasmatic reticulum.

Two functional active sites can be separated in the mature protein. The reactive center, Arg393-Ser394, cleaves thrombin, and the heparin binding site at the amino terminus. Binding heparin increases inactivating function of antithrombin by 4000 fold.

Expression

Antithrombin is a plasma protein that exists in two forms: the active monomer and an inactive heterodimer. One active molecule can inactivate an other by cleaving it and forming a heterodimer, which is also called the latent form.

Phenotype

Antithrombin deficiency is classified in type 1, with functional activity and concentration reduced simultaneously, and type 2, in which the immunologically measurable concentration of the protein is normal despite a significantly reduced functional activity. Type 2 might be further divided into heparin binding site defects (Type 2c), thrombin binding and cleavage site defects (2b), and pleiotropic defects (2c). Heparin binding site defects account for most of antithrombin deficiencies. In these patients, pharmacological reaction to standard heparin therapy is altered, while the effect of low molecular weight heparin therapy is unchanged. Also, the risk of thromboembolic diseases at physiological conditions appears not to be increased.

Furthermore there exist unstable variants of antithrombin that in fever, acid base disorders, or other pathophysiological conditions exhibit an accelerated antithrombin activity without heparin, which explains thrombophilia in these patients, when seriously ill.

Gene Regulation

Independent of vitamin K, antithrombin is synthesized and secreted by the liver. It plays a major role in inactivation of thrombin and other activated coagulation serine proteases, including factor Xa and IXa.

In the absence of heparin, antithrombin slowly inactivates thrombin. This process is called progressive antithrombin activity, and as opposed to that, heparin cofactor activity of antithrombin account for rapid thrombin inactivation in the presence of heparin.

Interpretation

In type 1 antithrombin deficiency the underlying mutation might be nonsense or splice mutations in one of the first exons. These mutations can be found by direct sequencing the entire coding region, but a significant portion might be caused by large deletions, duplications or rearrangement, which usually cannot be detected by sequencing.

Direct sequencing allows to differentiate among type 2 subtypes. As most often point mutations at the specific sites of the molecule account for these functional alterations, the detection rate is much higher in these cases.

Genetests:

Clinic Method Carrier testing
Turnaround 5
Specimen type genomic DNA
Clinic Method Multiplex Ligation-Dependent Probe Amplification
Turnaround 20
Specimen type genomic DNA
Clinic Method Genomic sequencing of the entire coding region
Turnaround 20
Specimen type genomic DNA
Clinic Method Massive parallel sequencing
Turnaround 25
Specimen type genomic DNA

Related Diseases:

Thromboembolic diseases
Autosomal dominant protein C deficiency
PROC
Autosomal dominant protein S deficiency
PROS1
Autosomal recessive protein C deficiency
PROC
Autosomal recessive protein S deficiency
PROS1
F2
F5
Factor XII deficiency
F12
HABP2
Hypoplasminogenemia
Dysplasminogenemia
PLG
Hypoplasminogenemia
PLG
MTHFR
PAI transcription modulator
SERPINE1
Protein Z deficiency
PROZ
SERPINA10
SERPINC1
THBD
Thrombophilia due to heparin cofactor 2 deficiency
SERPIND1
VKORC1

References:

1.

Picard V et al. (2006) Molecular bases of antithrombin deficiency: twenty-two novel mutations in the antithrombin gene.

[^]
2.

Meade TW et al. (1990) Antithrombin III and procoagulant activity: sex differences and effects of the menopause.

[^]
3.

Odegård OR et al. (1978) Antithrombin III: critical review of assay methods. Significance of variations in health and disease.

[^]
4.

Tait RC et al. (1994) Prevalence of antithrombin deficiency in the healthy population.

[^]
5.

Perry DJ et al. (1996) Molecular genetics of human antithrombin deficiency.

[^]
6.

Mateo J et al. (1997) Laboratory evaluation and clinical characteristics of 2,132 consecutive unselected patients with venous thromboembolism--results of the Spanish Multicentric Study on Thrombophilia (EMET-Study).

[^]
Update: Sept. 26, 2018