Polymorphisms in factor V and antithrombin III gene in recurrent pregnancy loss: a case–control study in Indian population

Abstract

Recurrent pregnancy loss (RPL) can be caused due to diverse factors with thrombophilia being one of them. The association of various thrombophilic risk factors with RPL is inconsistent in different studies and the frequency of these risk factors in Indian population is obscure. Five hundred and eighty patients with either recurrent early miscarriage or a history of at least one late miscarriage were screened for deficiency of protein C (PC), protein S (PS), antithrombin III (AT), APC resistance and prothrombin 20210G > A mutation. APC resistance positive patients were typed for the factor V Leiden, factor V Hong Kong/Cambridge mutations, and HR2 haplotype. PstI and rs2227589 AT mutations were detected by direct sequencing. APC resistance (13.4 %) was detected to be most common in Indian RPL patients followed by PS (10.6 %), PC (9.8 %) and AT deficiency (4.31 %.). FV Leiden was shown to be associated with APC resistance while HR2 haplotype was not associated with APC resistance (p values: 0.0001 and 0.327 respectively) and the increased risk of RPL. PstI and rs2227589 polymorphisms were similar in patients and controls and not associated with AT deficiency in RPL. Our study emphasizes the presence of other contributory factors towards APC resistance rather than FV Leiden alone. This is the first Indian study where HR2 haplotype and rs2227589 are observed to be present in RPL population. Although not significant, occurrence of rs2227589 and FV HR2 in homozygous condition necessitates the study of these polymorphisms in a larger sample size.

Factors contributing to APC-resistance in women with recurrent spontaneous miscarriages: Indian perspective

“…Mutations in the FV gene excluding FV Leiden, particularly at the other cleavage sites of FV, Arg306 and Arg679 have the potential to contribute to the APCR phenotype. These rarer mutations were not found in any of our patients similar to the observations of other Indian studies [5,9]. 14% APCR positive patients had isolated HR2 haplotype abnormality in this study.…”

“…In this study, 6.95% (40/575) of affected women and none of the healthy controls showed the presence of FVL mutation. The prevalence rates were lower than most other western studies due to differences in ethnic distributions of these genetic mutations in Asian populations [5,8,9]. Mutations in the FV gene excluding FV Leiden, particularly at the other cleavage sites of FV, Arg306 and Arg679 have the potential to contribute to the APCR phenotype.…”

“…HR2 haplotype has also been associated with mild APCR when found in association with FVL mutation (5% in this study) but its significance as an independent risk factor still remains controversial. Most studies attribute only a modest or no increase in thrombophilic risk due to this allele in the absence of the FV Leiden mutation [5]. Similarly, a much lower frequency of thrombophilic factors contributing to acquired APCR (7.5%; 43/575) was observed among the affected patients, unlike few other published studies where acquired APCR has been found in 9-38% of women with unexplained recurrent pregnancy versus 0-3% of controls [10,11].…”

“…Total genomic DNA was isolated from peripheral blood leukocytes using commercially available kits (Bioserve). Mutational analysis for FV Leiden, Hong-Kong, Cambridge, and HR2 haplotype was done by polymerase chain reaction-restriction fragment length polymorphism using restriction enzymes Mnll, MvaI, HPaII and RsaI respectively [5]. Factor V Liverpool (Ile359Thr) was identified using allele-specific PCR.…”

Pregnancy complicated with deficiency of antithrombin: Review of current literature

“…AT de iciency is uncommon hereditary thrombophilia with the prevalence in general population of 1/2000-5000 [3,6,7]. AT de iciency is classi ied according to antithrombin plasma activity and antigen levels into Type I (quantitative defect) and Type II (qualitative defect) [8,9]. Thromboembolism in these patients can happen in early age and recurrently and is often life-threatening [10][11][12].…”