Genetic factors associated with predisposition for thrombosis

Orzu YuldashevaMUA Fall 2015

1854 Rudolph VirchowFactors precipitating hypercoagulable state/ Thrombophilias I. Decreased blood flow (venous stasis)II. Inflammation of or near the blood vessels

(vascular endothelial injury) III. Intrinsic alterations in the nature of the

blood itself

Background Information

Hypercoagulable states

Etiology • Inherited• Aquired• Both

Types• -venous thrombosis

(most common)• -arterial thrombosis• -both

Acquired

Advanced age prolonged immobilization Surgery Fractures use of oral contraceptives hormone replacement

therapy Pregnancy/puerperium Cancer And many more

VENOUS THROMBOSISRisk factors

Inherited

Mutation in genes encoding foro protein C o protein So factor V Leideno MTHFR (methylene

tetrahydrofolate reductase) Hyperhomocysteinemia elevated concentrations of

factors II, VIII, IX, XI and fibrinogen

Purpose of study

• To identify mutation in genes coding for coagulation cascade proteins

• Identify the frequency of those mutations in population of Uzbekistan.

Materials and Methods

Subjects of study -158 patients aged from 17 to 65 Step I - Identify presence of mutations in genes coding for proteins of coagulation cascade. Step II- Statistical analysis of the mutations discoveredFactor V LeidenFII (Prothrombin) MTHFR (methylene tetrahydrofolate reductase)

Results

Total number of subject in study -158

1.7% were carriers of genes coding for Prothrombin1.7 % subjects had mutation in genes coding for Factor V 50% -carriers of gene coding for mutant MTHFR

From those43.1% were heterozygotes 6.9% were homozygotes

Statistical analysis 1.70% 1.70%

46.60%

6.90%

43.10%Prothrombin

Factor V

Unidentified

Homozygous MTHFR

Heterozygous MTHFR

*Unidentified- no know mutations associated with Hypercoagulability were identified

Distribution of most frequent mutations leading to thrombophilias in USA. *Data obtained from Cleveland Medical Clinic

MTHFR mutation

• It was identified that this mutation follows autosomal-recessive pattern of inheritance, therefore clinical symptoms were only observed in homozygotes.

• Altered enzyme, determined by mutant MTHFR is thermolabile, and characterized by decreased enzymatic activity which leads to deffierent degrees of hyperhomocysteinemia resulting in hypercoagulability and vascular events.

Cytogenetic Location: 1p36.3

Molecular Location on chromosome 1: base pairs 11,785,729 to 11,806,102

Single point mutation in the coding region for the MTHFR binding site (exon 4) is autosomal recessive, leads to the substitution of a valine for an alanine, and results in a thermolabile variant of the MTHFR (tlMTHFR)

Conclusion

• As the results of study show the most common mutation is MTHFR, which leads to increased level of homocysteine, development of blood clots and cardiovascular abnormalities. Whereas, Factor V Leiden and Prothrombin mutations are more common in Western regions, especially in Europe and USA.

Thank You