Clinical significance of prothrombin G20210A mutation in homozygous patients
Authors: Amit Shemesh, Ron Hoffman, Yona Nadir, Anat Keren‐Politansky, Manuel Monreal, Benjamin Brenner, Inna Tzoran
Journal: American Journal of Hematology (2017)

To the Editor: The prothrombin G20210A mutation (PTM) is known as a risk factor for thrombosis since 1996.1 The prevalence of this mutation is estimated at 1–4%.2 The clinical presentation of PTM has been mainly described in heterozygous individuals. Its carriers have a 3-fold higher risk of venous thromboembolism (VTE),1 are suggested to be predisposed to adverse pregnancy outcome and miscarriages. There is paucity of data addressing the clinical significance of PTM in homozygous individuals.2 The prevalence of homozygous carriers reported in the literature is extremely low, amounting to .014% only.1, 2 The current study aimed to characterize a relatively large group of patients homozygous for PTM, and define clinical significance of this mutation as a risk factor for VTE, obstetric complications, and neuropsychiatric symptoms. The Rambam institutional database was retrospectively searched for patients evaluated for PTM between the years 1996–2015. Four hundred and seventy four patients, who underwent laboratory assessment for thrombophilia due to a previous VTE, obstetric complications or a family history of VTE, were screened. Patients with other clinically significant prothrombotic acquired or genetic conditions, including antiphospholipid antibody (APLA) syndrome, were excluded. Two hundred and thirty nine patients were incorporated in the final analysis and were categorized into three groups according to their prothrombin mutation status: homozygous, heterozygous carriers, or noncarriers. Information on patient age, gender, VTE events, medical history, obstetric history (e.g., spontaneous abortions, recurrent abortions, late pregnancy loss, placental abruption, intrauterine growth restriction [IUGR], pre-eclampsia, and infertility), neuropsychiatric symptoms (e.g., migraine, dementia, demyelinated diseases, epilepsy, or psychiatric diseases, such as anxiety and panic disorders, depression, and psychotic disorders), and VTE risk factors was evaluated. Statistical analysis was conducted using the chi square test (Prison or Fisher, P value, accordingly). Odds ratio (OR) and 95% confidence interval (CI) are reported. Multivariate analysis was conducted using stepwise multinomial logistic regression. P < .05 was considered statistically significant. Data were analyzed using SPSS version 21. The study population comprised 239 subjects: 30 homozygous, 95 heterozygous, and 114 noncarriers of the PTM. The VTE relative risk was 5 (95% CI 2.1–11.92) for homozygous individuals and 1.88 (95% CI 0.9–3.67) for heterozygous carriers compared to noncarriers (Table 1). A superior rate of VTE events was observed in the homozygous male (63%, OR= 5.25, 95% CI, 1.24–22.19) and female (41.2, OR = 4.95, 95% CI, 1.6–15.26) carriers. PTM carriers had a higher rate of VTE recurrence (22% of homozygous; 11% of heterozygous), compared with that found in noncarriers (4%; P < .01) (Table 1). All of the homozygous patients lacking risk factors suffered from VTE, compared to 57.1% in the heterozygous group (OR= 5.67, 95% CI, 1.24–25.88), and only 19% among noncarriers. Homozygous N=30 Heterozygous N=95 Noncarriers N=114 One hundred and forty four women in reproductive age were included in the analysis. Homozygous women displayed a higher incidence of obstetric complications [12 of 18 (66.7%), OR= 7.14 (95% CI, 2.27–22.45)] compared to heterozygous females [14 of 59 (23.7%)] and noncarriers [14 of 64 (21.9%); P = .001] (Table 1). Homozygous PTM carriers had a significantly higher rate of neuropsychiatric symptoms [8 of 30 homozygous (24%), 10 of 95 heterozygous (10.5%), and 12 of 114 noncarriers (8%); P < .05]. Migraine was the most prevalent symptom and was reported in 6 of 8 (75%) homozygous patients, 4 of 12 (33%) heterozygous carriers, and 3 of 12 (25%) noncarriers (P = .06; Table 1). The current study has demonstrated clinical significance of PTM in a relatively large cohort of homozygous carriers. To the best of our knowledge, the precise risk of thromboembolic complications development in this patient population has not been previously reported. This study has shown the key role of homozygous PTM in VTE events, which has been defined as an independent risk factor for VTE in multivariate analysis. Indeed, in the absence of established risk factors, the VTE rate appeared to be higher in homozygous PTM carriers than in noncarriers. In contrast, heterozygous PTM does not have a role in VTE occurrence and recurrence, as previously demonstrated in a large prospective study.3 Only a small number of studies addressed the correlation between PTM and gestational complications; however, most of these studies limited their analysis to women with the heterozygous genotype and were inconclusive.4 The present study has revealed a 7-fold higher prevalence of obstetric complications in women homozygous for this polymorphism. In light of these results one may assume that homozygous PTM has a potential to cause obstetric pathologies and negatively affect placental circulation. Neuropsychiatric symptoms are known to be associated with hypercoagulable states. For instance, the APLA syndrome has a wide variety of neurologic presentations, including headache and migraine, movement disorders, visual disorders, and so forth, as well as psychiatric symptoms, like progressed dementia.5 The present study has demonstrated in a relatively large cohort of individuals, a significantly higher rate of neuropsychiatric manifestations among homozygous PTM carriers than in noncarriers. To the best of our knowledge, this is the first report on the correlation between these two parameters. One of potential underlying mechanisms could be related to impaired brain blood circulation in PTM patients, as suggested in meta-analyses and reviews of the literature, that have found a statistically significant association between PTM, cerebral vein thrombosis, and ischemic stroke.6 Additional mechanisms of this interaction need to be explored. The current study has several limitations. It is retrospective and single-center in nature. Additionally, the study groups are unmatched in terms of age and gender, although this shortcoming has been overcome using multivariate analysis. Patients homozygous for the prothrombin G20210A mutation demonstrate a wide range of clinical manifestations, including an increased risk for obstetric complications, VTE recurrence, and neuropsychiatric manifestations. The optimal management of such patients in these clinical settings requires further research. Nothing to report. Amit Shemesh: performed research, wrote the paper, approved the final version of the paper Ron Hoffman: performed research, approved the final version of the paper Yona Nadir: performed research, approved the final version of the paper Anat Keren-Politansky: performed research, approved the final version of the paper Manuel Monreal: wrote the paper, approved the final version of the paper Benjamin Brenner: wrote the paper, approved the final version of the paper Inna Tzoran: designed and performed research, wrote the paper, approved the final version of the paper