الفهرس 
Title pageOnly 14 pages are availabe for public view
 |  | from | 87 |  |  |
| | | from | 87 | | |
Abstract
Venous thromboembolism (VTE) including deep venous thrombosis (DVT) and pulmonary embolism (PE), is a common and potentially life threatening disease. Venous thromboembolism is thought to start in the calf veins, can progress to the proximal veins, and may break free to cause the potentially fatal condition of PE. VTE is associated with acute symptoms and long-term complications, including post-thrombotic syndrome and chronic pulmonary hypertension.
Warfarin is the most commonly used oral anticoagulant medication given as a prophylaxis and/or treatment of venous thromboembolic disorders. Warfarin functions as a vitamin k antagonist and thus inhibits the activity of vitamin K-dependent coagulation proteins by inhibiting vitamin K epoxide reductase.
Warfarin doses vary up to 10-fold among patients due to pharmacokinetics, pharmacodynamics and pharmacogenomics factors. In addition, Warfarin has a narrow therapeutic index with the risk of developing serious side effects such as severe bleeding or failure of therapy. Therefore, the main challenge to achieve the therapeutic goal in warfarin treatment is estimating the appropriate dose for each patient.
Several studies have revealed genetic components that influence the dose of warfarin necessary for a therapeutic response. A polymorphism within the promoter region of VKORC1 gene, encoding the subunit 1 of the vitamin K epoxide reductase complex; the target of warfarin, specifically a guanine to adenine conversion at position -1639, decreased the production of VKORC1 mRNA and reduced expression of the enzyme. As a result, patients with the AA genotype require lower initial doses of the drug than those with the AG or GG genotype. The -1639G>A allele frequency varies among different ethnic groups. It is the major allele in Asian populations. It is also common in Caucasians.
This study aimed to determine the frequency of VKORC1 (-1639G<A) genotypes in an Egyptian sample and to evaluate the effect of vitamin K epoxide reductase complex subunit 1 (VKORC1) gene polymorphism (-1639G<A) on warfarin dose requirement among patients with venous thromboembolism.
The present study was conducted on two groups:
• Patient group which included 37 patients with venous thromboembolism (VTE) comprising deep vein thrombosis (DVT), pulmonary embolism (PE). They were recruited from the Department of Experimental and Clinical Surgery, Medical Research Institute, Alexandria University, Egypt.
• Control group which included 47 healthy volunteers with no previous history of VTE as a control group.
The patient group was subjected to careful history taking and clinical examination. Both groups were included in the molecular study using PCR/RFLP technique for detection of (VKORC1) gene polymorphism (-1639G>A).
The results of this study revealed the following:
• The mean age in the patients was 47 years old (15-70 years old). Seventeen (45.9 %) were males and twenty (54.1 %) were females. Twenty eight (75.7 %) were non-smokers and nine (24.3 %) were smokers. The mean warfarin maintenance daily dose was 5.4 ± 1.47 mg/day, and ranged from 2.5 - 9.5 mg/day.
• Twelve patients (32.4%) were found with the GG genotype, 19 (51.4%) were found with the AG genotype and only 6 (16.2%) were found with the AA genotype.
• There was a significant variation in warfarin maintenance dose among patients with different genotypes of VKORC1 at position -1639.Hence, VKORC1 polymorphism has an important influence on the warfarin maintenance dose requirements.
• There was no statistically significant difference between patient age, gender, smoking state and daily warfarin maintenance dose.
• It was confirmed that there was a statistically significant difference between VKORC1 (-1639G<A) genotypes and daily warfarin maintenance dose.
• Genotype and allele frequencies of VKORC1 gene polymorphism(-1639G<A) were compared between patients and controls. No significant difference was detected in the gene distribution between the 2 groups.
• The observed genotype frequencies in this study were in Hardy-Weinberg equilibrium