Factor V is a protein of the coagulation cascade, which circulates in the plasma in the form of a single chain molecule. It plays a very important role in the coagulation of blood, by acting as a co-factor to factor Xa, for the conversion of prothrombin to thrombin on the membrane of the cell surface.
Various disorders are associated with mutations in the gene coding for factor V. Deficiency of the protein is associated with a very rare, mild form of hemophilia, called parahemophilia. The mildness of the disease is due to the fact that even a very small level of factor V in the blood (10-20% of normal level) is sufficient for normal clotting. Common symptoms of parahemophilia include nose bleeds, bruising, menorrhagia, excessive bleeding after delivery, surgery or trauma. Supply of fresh frozen plasma to the body is the only treatment for parahemophilia. On the other hand, certain other mutations in the Factor V gene lead to major prothrombotic effects, such as venous thrombosis, pulmonary embolism, arterial clots, miscarriages and stillbirths and/or preeclampsia.
The gene coding for factor V protein is a 72.3 Kb long stretch of DNA, located on chromosome 1 (1q23). Factor Va is composed of a heavy chain and a light chain. The interaction between the two chains is calcium-dependent. Thrombin activates the protein by splicing it into the two constituent heavy (11 KDa) and light (7.3 KDa) chains. Activated factor V is a cofactor of the thrombinase complex. Sulfation of the protein is also necessary for efficient thrombin cleavage. Factor Va is degraded by activated protein C, one of the principal physiological inhibitors of coagulation.
There are several mutations leading to prothrombotic effects. The most common of these is a mutation where an arginine residue is replaced with glutamine at amino acid position 506 (R506Q). This factor V variant is known as factor V Leiden. The other prothrombotic variants include factor V Cambridge, and factor V Hong Kong. All of these variants are resistant to cleavage by activated protein C. They therefore, remain almost constitutively active, and increase the rate of thrombin generation.
Almawi et al. (2005b) studied the prevalence of the Factor V Leiden allele amongst Arab populations. A total of 194 healthy Bahraini subjects were compared to Lebanese, Tunisian, and Saudi Arabian subjects. PCR-RFLP using MnlI was used to genotype the Factor V gene. The FV-Leiden A allele was detected at a prevalence rate of 0.0155 in the Bahraini population. This was comparable to its prevalence in the Saudi Arabian subjects, but significantly lower than in the Lebanese and Tunisian patients. The G/A genotype was seen at a frequency of 3.1% among the Bahrainis, whereas the A/A genotype was not detected at all. The carrier rate of the FV-Leieden allele in Bahrain was found to be comparable to all the other populations, except the Lebanese. The overall average genetic differentiation between the populations was 0.0022 for FV-Leiden [See also: Lebanon, Saudi Arabia, Tunisia > Almawi et al., 2005b]. Later, Almawi et al. (2009) studied 118 patients with risk of stroke and 120 control subjects and found no association of stroke with factor V-Leiden.
Al-Allawi et al. (2004) carried out a study to report the incidence of factor V Leiden in Iraq. One hundred samples were taken from patients who attended the national blood bank in Baghdad as blood donors. All those patients were males with ages ranging from 18 to 52 years (median age of 30.5 years). A second-generation APC resistance test was performed on all included patients and the clotting times were recorded. Reverse hybridization using wild- and mutant-type DNA probe was used to target a single point mutation in the factor V gene (1691G-to-A), followed by enzyme immunoassay for detection. Four cases (4%) were found to be resistant by the second-generation APC resistance test. Three cases (3%) were found to be heterozygous for factor V Leiden by DNA studies and they were also found to be resistant by the second-generation APC resistance test. The remaining case was found to be resistant by the second-generation APC resistance test, but he was found to be a non carrier of factor V Leiden. This result led Al-Allawi et al. (2004) to indicate that an alternative mutation involving the factor V gene may be responsible for APC resistance in this case. This prevalence rate of 3% in Iraqi blood donors is much lower than the prevalence rates reported in Lebanon (14.2%), Syria (13.6%) and Jordan (12.25%). Despite that, it is comparable to the prevalence rate reported in Saudi Arabia (2.5%), leading Al-Allawi et al. (2004) to suggest that the reason for the approximately similar prevalence rates in these two countries may be related to a common origin and closer links between the population of Iraq and that of the Arabian Peninsula throughout history.
Gharaibeh et al. (2014) studied 50 consecutive patients with retinitis pigmentosa and 50 controls matched by age and gender to determine the prevalence of thrombophilic factors. Among patients/controls they found the p.R506Q factor V Leiden heterozygous mutation (12/14). Gharaibeh et al. (2014) concluded that the difference between patients with retinitis pigmentosa and the control group was not statistically significant for the prevalence of this studied factor.
[See also: Iraq > Al-Allawi et al., 2004].
Finan et al. (2002) analyzed the frequencies of factor V G1691A (Factor V-Leiden) and Prothrombin G20210A mutations in 110 Lebanese women with histories of two or more consecutive miscarriages of unexplained etiology. These cases were compared to a control group, comprising of 67 women of similar ethnicity and age group, with uncomplicated pregnancies. Though the aborters and the control group were found to be similar in their acquired risk factors like genital infections, alcohol consumption, use of oral contraceptives etc., the frequency of smokers was higher in the aborters group. Blood samples of the subjects were used for DNA extraction and PCR was followed by RFLP using HindIII for factor V leiden. Finan et al. (2002) reported 40.9% of the aborters to show the FV-Leiden mutation (6% homozygous; allele frequency-0.236), compared to 16.4% of the control group (all heterozygous; allele frequency-0.082). The results demonstrated a clear association between the mutation, and primary recurrent miscarriages. Earlier reports from other authors had failed to demonstrate any such link. Finan et al. (2002) ascribed this failure to the low number of subjects studied, bias in patient selection, and ethnic heterogeneity amongst the subjects. The results of this study necessitated the need for screening for this mutation early in pregnancy.
Almawi et al. (2005a) undertook a case control study to understand the prevalence of the prothrombotic mutations G1691A FV-Leiden, factor II G20210A, and MTHFR C677T mutations. One hundred and ninety eight Lebanese patients (84 males, 114 females), diagnosed with venous thromboembolism (VTE) were compared to 697 healthy age and gender matched controls. Diagnosis of VTE was performed using Doppler ultrasound, duplex scan, D-dimer levels, and phlebogram. Mutation analysis of the subjects was performed by PCR followed by RFLP using restriction enzyme MnlI for factor V. Multiple triple regression model analysis was also performed. The patients showed a significantly higher frequency of the FV-Leiden allele (0.2980) compared to the control (.0789). The G/A and A/A genotypes for the Factor V alleles were significantly higher in the patient group (44.4% and 7.6% resp.) compared to the control (13.8% and 1.0%). Analysis of combined inherited risk factors showed that though the FV-Leiden allele and the G20210A allele by themselves were clearly associated with VTE (odds ratio2.71 and 3.590 respectively), they synergized with the MTHFR 677 T/C allele in increasing the odds of developing the disease. Logistic regression analysis showed that individuals below 45 years of age were 5.5 times more prone to developing VTE. The highest risk for development of the disease was seen to be exerted by the combined presence of FV-Leiden and factor II G20210A mutations. In a second study conducted to compare the prevalence of the Factor V Leiden allele amongst Arab populations, Almawi et al. (2005b) found that the prevalence of the FV-Leiden allele was significantly higher amongst the 698 healthy Lebanese subjects (0.0788), when compared to a Bahraini and Saudi population. The G/A and A/A genotypes were also detected at higher frequencies amongst the Lebanese population (13.8 and 1%). The FV-Leiden carrier rate was highest in the Lebanese population. The overall average genetic differentiation between the populations was 0.0022 for FV-Leiden [See also: Bahrain, Saudi Arabia, Tunisia > Almawi et al., 2005b; Iraq > Al-Allawi et al., 2004].
Tanis et al. (1998) reported a patient with congenital homozygous factor V deficiency and prolonged bleeding after injuries. The 23-year-old male had a large pseudotumour in the right upper leg that was successfully surgically excised under continuous substitution with fresh-frozen plasma.
van Wijk et al. (2001) found a 2491C-T transition in exon 13 of the F5 gene in a 15-year-old girl from Morocco. She was the sister of the patient of Tanis et al. (1998) and daughter of first-cousin parents. The mutation in a gln773-to-ter (Q773X) substitution and resulted in a severe factor V deficiency with F5 activity less than 1%.
Fawaz et al. (2004) carried out a molecular study to assess the prevalence of factor V (FV) Leiden (G1691A/ R506Q) in sickle cell disease (SCD) patients and healthy controls. Study subjects comprised 87 SCD patients (38 males and 49 females; mean age 23.10 ± 14.15 years) and 105 controls (65 males and 40 females; mean age 32.28 ± 15.00 years). All patients were Saudi nationals from Eastern Saudi Arabia. Among the 87 SCD patients, five were found to be heterozygous (G/A) and one was found to be homozygous (A/A) carrier of FV Leiden, giving a prevalence rate of 6.9%. While among the control, two were found to be heterozygous and none was found to be a homozygous carrier (1.90%, P=0.174). This low frequency (1.90%) of FV Leiden was seen among healthy individuals in Eastern Saudi Arabia (Dammam) in this study, in agreement with a study on its prevalence in Western Saudi Arabia (Jeddah), where FV Leiden occurs at a rate of 2.2%. The prevalence of FV Leiden (P=0.174) was not different between patients and controls, thereby giving no support to an association of FV Leiden with SCD. This result led Fawaz et al. (2004) to conclude that the FV Leiden, as inherited hypercoagulability risk factor, has a low impact in the pathogenesis of SCD and/or its complications.
Almawi et al. (2005b) compared the prevalence of the Factor V Leiden allele amongst Arab populations. A total of 149 healthy Saudi Arabian subjects were compared to Lebanese, Tunisian, and Saudi Arabian subjects. The FV-Leiden A allele was detected at a prevalence of 0.0101 in the Bahraini population. This was comparable to prevalence in the Bahrain subjects, but significantly lower than its prevalence in the Lebanese and Tunisian patients. The G/A genotype was seen at a frequency of 2.0% among the Saudis, whereas the A/A genotype was not detected at all. The carrier rate of the FV-Leiden allele in Saudi Arabians was found to be comparable to all the other populations, except the Lebanese. The overall average genetic differentiation between the populations was 0.0022 for FV-Leiden [See also: Bahrain, Lebanon, Tunisia > Almawi et al., 2005b].
[See: Iraq > Al-Allawi et al., 2004]
In a study conducted to compare the prevalence of the Factor V Leiden allele amongst Arab populations, Almawi et al. (2005b) found that the prevalence of the FV-Leiden allele was significantly higher amongst the 313 healthy Tunisian subjects (0.01326), when compared to a Bahraini and Saudi population. The G/A and A/A genotypes were also detected at higher frequencies amongst the Tunisian population (5.8 and 0.6%). The overall average genetic differentiation between the populations was 0.0022 for FV-Leiden [See also: Bahrain, Lebanon, Saudi Arabia > Almawi et al., 2005b; Iraq > Al-Allawi et al., 2004].