Table 1. Overview of the fundamental studies that show the association between prothrombin gene mutation and ischemic stroke in young patients.

OR-Odds Ratio, CI- Confident Interval, FII- Factor II, FV- Factor V, PT-Prothrombin, PFO- Patent Foramen Ovale

reference Country/Year	Age Group	Study Design	Study Aim	Sample size	Results
Arkel YS et al.    USA/1998 [30]	22years	Case report	To determine that the reported cases of ischemic stroke and protein c deficiency may have had other prothrombotic disorders such as the prothrombin mutation.	Single-subject	To study all patients with premature stroke for prothrombin mutation and the other risk factors for thrombosis.
V De Stefano et al.     Italy/1998     [27]	<50 years of age	Case-control  study	To determine whether the Prothrombin G20210A mutant genotype is a risk factor for ischemic cerebrovascular disease in young patients.	Seventy-two patients (35 male and 37 female) were diagnosed with ischemic stroke, and without any risk factors, 198 thrombosis-free individuals were in the control group.	The mutant factor II allele frequency in the patient group (7.6%, 95% confidence interval [CI], 3.3 to 11.9) was significantly higher than in the controls (1.2%; 95% CI, 0.1 to 2.3; P = .0001). The odds ratio for ischemic stroke associated with the carriership of the mutant factor II allele (both heterozygous and homozygous genotypes) was 5.1 (95% CI, 1.6 to 16.3)
G Young et al.   USA/2003 [8]	<18 years	Consortium study	To determine the clinical manifestations of the prothrombin mutation in children.	38 children	37% (14 out of 38) of children had central nervous system thrombosis
Pezzini A et al.   Italy/2003 [35]	<45 years	Case-control study	To investigate the association between inherited thrombophilic disorders and PFO-related strokes in a series of young adults in the setting of a case-control study.	125 consecutive subjects (age, 34.7±7.3 years) with ischemic stroke and 149 age- and sex-matched control subjects	The PT(G20210A) variant was more frequent in the PFO+ group compared with control subjects and the PFO- group (PFO+ versus control subjects, 11% versus 2%; 95% CI, 0.04 to 0.94; PFO+ versus PFO-, 11% versus 1.1%; 95% CI, 1.09 to 109; P=0.047).
Justo Aznar et al. Spain/2004 [36]	<50 years	Case-control study	To determine the role of Factor V Leiden and prothrombin G20210A mutations in young adults with cryptogenic ischemic stroke.	49 patients with cryptogenic stroke and compared with controls	The odds ratio (OR) for cryptogenic stroke was 3.75 (95% CI, 1.05-13.34) for PT 20210.
Kim RJ et al.   USA/2003 [37]	<55years   Subgroup analysis	Meta-analysis	To determine the association between factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations and events of the arterial circulatory system.	A total of 56 studies and 54,547 persons served as a basis of the final analysis	The association between G20210A mutation and the arterial ischemic event was modest (OR, 1.32; 95% CI, 1.03-1.69)   Subgroup analyses of younger patients revealed a slightly stronger association overall.
Jiang B et al.   USA/2014  [9]	<55 years	Meta-analysis	To determine the association between prothrombin G20210A and ischemic stroke in a white case-control population followed by a metanalysis of the studies.	2305 cases of European ancestry white population	Prothrombin mutation was associated with significantly increased stroke risk in adults ≤55 years (OR=1.4; 95% CI=1.1-1.9; P=0.02), with significance increasing with the addition of the GEOS results (OR=1.5; 95% CI=1.1-2.0; P=0.005)
Sarecka-Hujar B et al.   Poland/2017 [29]	Children, Young adults	Meta-analysis	To address the relation between the FII 20210G>A polymorphism and arterial ischemic stroke.	3586 Cases and 6440 Control Subjects	Carriers of 20210A allele of the prothrombin gene are commonly seen in patients with arterial ischemic stroke, including children and young adults,  as compared to the control group (P = 0.006; odds ratio, 1.83; 95% confidence interval, 1.19 to 2.80 and P = 0.001; odds ratio, 1.69; 95% confidence interval, 1.25 to 2.28, respectively)
Thita Chiasakul et al.     Thailand, USA, Canada/2019 [28]	Adult patients Age>15 years	Meta-analysis	To evaluate the association of inherited thrombophilia and the risk of arterial ischemic stroke in adults.	Sixty-eight eligible studies enrolled 11916 stroke patients and 96057 controls.	As compared to the control group, patients with arterial ischemic stroke were significantly more likely to have the inherited thrombophilias, including prothrombin G20210A mutation (OR, 1.48; 95% CI, 1.22–1.80; I2=0%).
Solomi BSB et al.     India/2019 [16]	Mean age 36.7 years (cases)   mean age 37.6 years (controls)	Case-control study	To determine the prevalence and association of the prothrombin G20210A polymorphism in patients with arterial and venous strokes.	82 patients from north India and 310 patients from south India     278 healthy, age- and sex-matched controls	The heterozygous allele of the polymorphism was detected in both groups with significantly higher prevalence among North Indians (5/154; 3.2%) compared with south Indians (4/516; 0.8%; p = 0.026).Thrombosis as a manifestation of this polymorphism was more among north Indians, with 4/82 (4.9%) of patients with ischemic stroke and cerebral venous thrombosis having this polymorphism compared with South Indian patients 1/72 (1.4%), p = 0.003.