Hereditary antithrombin III deficiency

Introduction to hereditary antithrombin III deficiency Hereditary antithrombin III deficiency is an autosomal dominant hereditary disease. The chances of men and women are equal. It is more common in heterozygotes and has no clinical symptoms. Only 4% of patients with venous thrombosis are patients with ATIII deficiency. basic knowledge The proportion of illness: 0.005% Susceptible people: no special people Mode of infection: non-infectious complication:

Causes of hereditary antithrombin III deficiency

(1) Causes of the disease

Autosomal dominant antithrombin III deficiency.

(two) pathogenesis

The ATIII gene is located on the long arm of chromosome 1 (1q23~25). It is a single copy in the haploid chromosome genome and contains 7 exons. The full length of the DNA is 14kb. It has been obtained from ATIII mRNA using the human liver RNA promoter extension assay. The initial map, ATIII transcription starts at the 5' end of the ATG starter coding vector 72bp, the 3' end is 49bp away from the terminal coding sequence, containing AATKAA sequence, the downstream 224bp of this sequence is enzymatic or polyadenylation At the locus, gene expression is tissue-specific, but its regulatory mechanism is cis-regulatory or retro-regulatory. It is not known. Two regulatory elements have been found, but common TATA, CCAAT cannot be found in the 5' region. Or regulatory elements such as GC.

Hereditary antithrombin III deficiency prevention

Asymptomatic ATIII deficiency asymptomatic patients do not need prophylactic anticoagulant therapy, because retrospective analysis data show that the disease thrombosis rate and mortality are not high, but because the incidence of thrombosis varies from family to family, currently 15 40 years old ATIII deficiency, high-risk thrombosis, such as pregnancy, surgery, it is recommended to give anticoagulation to prevent thrombosis complications, the use of ATIII concentrate or low-dose heparin subcutaneous administration during surgery, there have been many successful reports.

Hereditary antithrombin III deficiency complications Complication

Generally no complications.

Hereditary antithrombin III deficiency symptoms Common symptoms Venous thrombosis pulmonary embolism

The main manifestation of this disease is venous thrombosis (60%), some patients may be accompanied by pulmonary embolism (40%), more than 50% of patients have more than one clinical manifestation of thrombosis, although all ages can occur, but 67% The initial onset age of the patients is 10 to 35 years old (median 20 years old), of which about 1/3 of the thrombosis occurs without incentives, commonly induced because of pregnancy, childbirth, prolonged bed rest, oral estrogen contraceptives, surgery, trauma, infection, etc. Common sites of thrombosis are deep veins of the lower extremities, iliac veins, femoral veins and superficial veins, followed by pelvic veins, superior vena cava, mesenteric vein, hepatic vein and portal vein (the latter two can produce Budd-Chiari syndrome). Kidney, sputum, sputum, brain and retinal vein thrombosis, and arterial thrombosis are also reported.

Examination of hereditary antithrombin III deficiency

For young patients with thrombosis, whether recurrent thrombosis or family tendencies are worthy of laboratory screening, there is no consensus. Only 30% of patients with venous thrombosis with these three clinical features can be found to be ATIII. Or protein C or protein S deficiency, on the contrary, only 13% of ATIII or protein C or protein S deficiency present the above clinical features, the British Society of Hematology recommends venous thrombosis, recurrent venous thrombosis or thrombosis in the age of 40 to 45 years old Phlebitis, abnormal thrombosis, family history of significant thrombosis or repeated habitual abortion, the cause of low ATIII activity has diagnostic value,

1 immunological test to measure plasma ATIII antigen;

2 cross-immunoelectrophoresis assay to determine abnormal molecules, the presence of slow peaks in the presence of heparin suggests that ATIII-heparin binding site variation;

3 functional tests, including ATIII heparin cofactor activity test and progressive ATIII inhibition test, cofactor activity test is the best screening test for this disease, all deficiencies show abnormalities, progressive ATIII inhibition test is based on lack of heparin acceleration conditions The egg of ATIII is reacted with the target protease by the enzyme inhibitory activity. This test can screen out patients with impaired ATIII-heparin, which shows that the ATIII progressive inhibitory activity is normal, but the heparin cofactor activity is low.

ATIII deficiency classification: More than 50 variants of ATIII deficiency are known, and the classification method is not yet perfect, and can be divided into 2 types (Table 1).

1. Type I (ATIII deficiency) is a classic deficiency, the patient can not synthesize ATIII, so the plasma ATIII antigen and activity are reduced, Ia type can not detect the variant protein, cross immunoelectrophoresis migration and peak shape is normal, but the peak is reduced Ib type with a small amount of variant protein, the antigenicity is not proportional to the decrease of activity, the antigen level is higher than the activity level, the cross-immunoelectrophoresis shows a slow peak, the affinity of these variant proteins with heparin is reduced, and thrombin does not react, the molecular basis A small type Ia is a large gene deletion or rearrangement leading to a non-functional allele. Most type I patients have point-like changes in the exon region, such as single base substitutions, insertions or deletions, resulting in: translational framework migration;

2 prematurely generating a termination code;

3 produces unstable proteins;

4 affecting the mechanism of RNA processing and other mechanisms involved in the formation of molecular diseases.

2. Type II (ATIII deficiency) Half of the ATIII in this type of plasma is a variant protein, so the amount of antigen is normal but the activity is weakened. In the cross-immunoelectrophoresis, a slow peak (high molecular weight) is observed, and the complex formed with heparin is inactive, and some The nature of the molecular structure defects of functionally defective individuals is not yet clear.

Type IIa: The test showed that the ATIII-heparin binding site and the ATIII reaction site were abnormal.

Type IIb: only the reaction site is abnormal.

Type IIc: only the heparin binding site is abnormal.

Both type IIa and IIb variants produce a non-functional protein, mainly due to a single base substitution, making the reaction site dysfunctional, such as ATIII North Wick Park Arg393Cys.

The single base substitution of IIc makes the ATIII heparin binding site dysfunctional, such as ATIII Toyama, sperm 47cysteine without heparin acceleration, ATIII activity, ATIII Rouen-1 fine 47 group and ATIII Rouen-2 fine 47 silk The heparin affinity is reduced, and the thrombocytosis tendency of the type IIc-only heparin-binding site (cofactor) is decreased.

According to the condition, clinical manifestations, symptoms, signs, choose to do B-ultrasound, X-ray, CT, electrocardiogram, hematuria routine and biochemical examination.

Diagnosis and identification of hereditary antithrombin III deficiency

According to medical history, clinical manifestations and laboratory tests confirmed.

Generally not confused with other diseases.

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