Overcoming Recurrent Miscarriages in a 35-Year-Old Female With Thrombophilia.

Thrombophilias, which include both hereditary and acquired illnesses, are a range of abnormalities that make persons more prone to developing thromboembolism. Thrombophilic conditions carry significant dangers during pregnancy, such as miscarriage in early pregnancy, intrauterine growth restriction, abruptio placenta, and preeclampsia. According to compiled statistics, an average of 15%-20% of pregnancies end in miscarriage. While the risk of miscarriage in a first pregnancy is 11%, this risk increases to between 13% and 17% in subsequent pregnancies, and after the third miscarriage, it reaches 38%. This research article presents a detailed case report that focuses on a patient who has experienced three previous failed pregnancies. The patient's genetic analysis indicates that she has two copies of a mutated version of the methylenetetrahydrofolate reductase (MTHFR) gene (Ala222Val) and a variation in the plasminogen activator inhibitor 1 (PAI-1) gene known as 4G/5G. In addition, an evaluation of immunological characteristics revealed increased amounts of natural killer (NK) cells with enhanced activity, along with the identification of embryotoxins in a blood test that suppress embryotoxicity in a blood test, assisted by DNA isolation and real-time polymerase chain reaction (PCR) DNA analysis.

Plasminogen Activator Inhibitor-1 4G/5G Promoter Polymorphism in Indian Patients with Deep Vein Thrombosis.

A single guanosine deletion/insertion (4G/5G) polymorphism in the promoter region of plasminogen activator inhibitor-1 (PAI-1) gene encoding PAI-1 protein has been investigated in deep vein thrombosis (DVT) patients. The association between PAI-1 4G/5G polymorphism and increased risk of DVT has been reported in some studies, while others have reported a lack of association. The present study aimed to investigate if the PAI-1 4G/5G polymorphism is associated with an increased risk of DVT in the Indian population and to assess its association with thrombophilic risk factors. Fifty-two adult patients with a history of chronic or recurrent DVT and 52 healthy adult controls were genotyped for PAI-1 4G/5G polymorphism. Plasma levels of PAI-1 and other thrombophilic risk factors were also measured. PAI-1 4G/5G polymorphism was not significantly associated with an increased risk of DVT. Protein C deficiency was significantly associated with the 4G/4G genotype. Patients with the 4G/4G genotype had significantly reduced PAI-1 levels as compared to the controls. PAI-1 4G/5G polymorphism did not significantly contribute to an increased risk of DVT in the Indian population. However, in the presence of thrombophilic risk factor abnormalities, the risk of DVT is increased in individuals with the 4G/4G genotype in the Indian cohort. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-023-01660-3.

A Hypertrophic Spinal Pachymeningitis Patient With Factor V Leiden (G1691A), MTHFR C677T, MTHFR A1298C, PAI-1 4G-5G, Glycoprotein IIIa L33P Gene Mutations.

Hypertrophic pachymeningitis (HP) is a rare clinical entity of diverse etiology, characterized by a chronic inflammation that causes dura thickening. Reports of Idiopathic hypertrophic cranial pachymeningitis (IHCP) were related to infections, trauma, tumors, and rheumatologic conditions. It was first described by Charcot and Joffroy regarding spinal meninges in 1869. HP has three stages; progressive radicular symptoms begin first, then muscle weakness and atrophy start. Findings such as paraplegia, loss of bladder and bowel control, and respiratory distress caused by intercostal and diaphragmatic denervation are considered the third stage of the disease. Especially in the cranial form of the disease, nerve ischemia and various cranial neuropathic findings may occur. Factor V Leiden (G1691A), MTHFR C677T, MTHFR A1298C, and PAI-1 4G-5G gene mutation analysis were measured with an ABI Prism. In this case report, the authors present a case of hypertrophic mutations pachymeningitis with Factor V Leiden (G1691A), MTHFR C677T, MTHFR A1298C, PAI-1 4G-5G, Glycoprotein IIIa L33P gene. In conclusion, we report a case of HP with Factor V Leiden (G1691A), MTHFR C677T, MTHFR A1298C, PAI-1 4G-5G, and Glycoprotein IIIa L33P gene mutations. We emphasize that the identification of pachymeningitis can be easily bypassed with the application of limited laboratory techniques. As in this case report, we think that these mutations should be analyzed in patients diagnosed with pachymeningitis.

Genetic Polymorphisms in a Familial Hypercholesterolemia Population from North-Eastern Europe.

(1) Background: Familial hypercholesterolemia (FH) is one of the most prevalent inherited metabolic disorders. The purpose of the study was to investigate the role in cardiovascular disease (CVD) of PAI-1, ACE, ApoB-100, MTHFR A1298C, and C677T. (2) Methods: From a group of 1499 patients, we included 52 patients diagnosed with FH phenotype and 17 patients in a control group. (3) Results: Most of the FH patients had multiple comorbidities compared to the control group, such as atherosclerosis (48.1% vs. 17.6%), atherosclerotic cardiovascular disease (ASCVD 32.7% vs. 11.8%), and metabolic syndrome (MetS, 40.4% vs. 11.8%). In total, 66.7% of the FH patients had PAI-1 4G/5G genotype and MetS. Between 4G/5G and 4G/4G, a statistically significant difference was observed (p = 0.013). FH patients with ApoB R3500Q polymorphism were correlated with ASCVD (p = 0.031). Both MTHFR C677T and A1298C polymorphisms had a significant correlation with gender, alcohol consumption, and smoking status. ACE polymorphism was associated with ATS in FH patients, statistically significant differences being observed between heterozygous and homozygous D genotype (p = 0.036) as well as between heterozygous and homozygous I genotype (p = 0.021). (4) Conclusions: A link between these polymorphisms was demonstrated in the FH group for ATS, ASCVD, and MetS.

Plasminogen Activator Inhibitor-1 4G/5G Promoter Polymorphism in Adults with Splanchnic Vein Thrombosis: A Case-Control Study.

The role of PAI-1 4G/5G polymorphism in venous thrombosis is unclear. PAI-1 4G/4G genotype is associated with elevated levels of PAI-1 resulting in a hypofibrinolytic state and hence increased thrombotic risk. In this study, we assessed the role of PAI-1 4G/5G promoter polymorphism in adult patients with splanchnic vein thrombosis. A total of 40 cases (portal vein thrombosis and Budd-Chiari syndrome) and 40 healthy controls were evaluated for the PAI-1 4G/5G polymorphism by amplification refractory mutation system polymerase chain reaction along with thrombophilia workup. The frequency of PAI-1 4G/4G homozygous, 4G/5G heterozygous and 5G/5G homozygous genotypes were 17.5%, 42.5% and 40%, respectively among cases and 22.5%, 50% and 27.5%, respectively among controls and the difference was not statistically significant (p = 0.61). The  PAI-1 4G/4G genotype was significantly associated with the cases with deranged thrombophilic risk factor (both inherited and acquired) (p = 0.02). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12288-021-01454-5.

Combined Effect of MTHFR C677T and PAI-1 4G/5G Polymorphisms on the Risk of Venous Thromboembolism in Chinese Lung Cancer Patients.

Venous thromboembolism (VTE) is a common and potentially fatal complication in cancer patients. Although several genetic risk factors related to thrombophilia have been identified, their contributions for the occurrence of VTE in cancer patients have conflicting results. The aim of this study was to evaluated the gene polymorphisms of methylenetetrahydrofolate reductase (MTHFR) C677T and plasminogen activator inhibitor-1 (PAI-1) 4G/5G in lung cancer patients, with and without VTE, and the combined effect on the risk of VTE. 92 lung cancer patients diagnosed with VTE (VTE group) and 122 lung cancer patients without VTE (non-VTE group) were enrolled in the study. The gene polymorphisms were analyzed by the method of polymerase chain reaction-restriction fragment length polymorphism. Gene mutation of factor V Leiden was not detected both in non-VTE group and VTE group. The frequency of MTHFR C677T homozygous mutation in VTE group was 25.00%, higher than that in the non-VTE group without statistical difference. It was found that the PAI-1 4G4G genotype is associated with a higher risk of VTE (OR: 2.62, 95%CI: 1.19-5.75). Interestingly, the interaction between MTHFR C677T and PAI-1 4G/5G polymorphisms showed that the coexistence of the 2 homozygous mutation could further increase the risk of VTE. In conclusion, PAI-1 4G/5G polymorphism may be an increased risk factor for VTE among lung cancer patients in Chinese population. The homozygous MTHFR C677T mutation may be not a risk factor for VTE but increases the risk, accompanied with PAI-1 4G5G genotype.

Interaction of thrombophilic SNPs in patients with unexplained infertility-multifactor dimensionality reduction (MDR) model analysis.

PURPOSE: Our aim was to evaluate the frequency and SNP-SNP interactions between factor V Leiden (FVL) G1691A, prothrombin G20210A mutation, and C677T MTHFR and PAI-1 4G/5G gene polymorphisms in female IVF patients with unexplained infertility (UI) by using a multifactor dimensionality reduction (MDR) model analysis. METHODS: A total of 225 subjects were enrolled in the study. There were 105 females in UI group and 120 healthy controls. Designated SNPs were determined by using allele-specific PCR methods. The difference in thrombophilia prevalence was assessed by a chi-square test and logistic regression analysis. Four-locus SNP interaction model was tested using the MDR approach. A ten-fold cross-validation consistency (CVC) and permutation testing were performed. RESULTS: There was a significant difference of MTHFR C677T polymorphism frequency between the groups. Significantly less UI patients had MTHFR CC genotype (p = 0.005), while the risk allele T was more frequent (OR = 1.83, p = 0.0018). Logistic regression determined a significant association only for MTHFR C677T in our patients (TT genotype OR = 2.99). The MDR analysis confirmed the significance of a single-locus model for MTHFR C677T polymorphism (p = 0.015; OR = 2.93). However, the best, significant predictive model was the two-locus model comprising MTHFR C677T and FVL (CVC = 10/10, testing accuracy = 60.95%, p = 0.013; OR = 3.02). CONCLUSION: The MTHFR C677T polymorphism was significantly associated with UI, with minor allele T being more frequent. Additionally, there was a significantly increased presence of MTHFR C677T with FVL mutation in these patients. Therefore, MTHFR and its interaction with FVL should be recognized as contributing factors in the pathogenesis of infertility.

Genetic Background of a Recurrent Unusual Combined Form of Retinal Vein Occlusion: A Case Report.

The authors report a rare case of nonischemic branch retinal vein occlusion and nonischemic hemiretinal vein occlusion in a patient with impaired fibrinolysis. A 61-year-old woman presented to the Department of Ophthalmology, Clinical Hospital Center Split, Croatia, with acute blurring of vision in the right eye (RE) due to branch retinal vein occlusion. Ophthalmologic evaluation revealed a best corrected visual acuity (BCVA) of 0.02 in the RE and of 1.0 in the left eye. Ophthalmoscopy and fluorescein angiography of the RE demonstrated signs of nonischemic branch retinal vein occlusion. She was otherwise healthy and had no other ocular and systemic diseases. She was treated with 3 consecutive intravitreal applications of anti-vascular endothelial growth factor (anti-VEGF; bevacizumab) due to cystoid macular edema with full resolution of the intraretinal fluid and improvement of the BCVA to 0.9. After 8 months, she presented again with acute blurring of vision in the same (right) eye with a BCVA of 0.5. Ophthalmoscopy and fluorescein angiography of the RE indicated nonischemic hemiretinal vein occlusion. She was treated with a single intravitreal application of anti-VEGF (ranibizumab) due to macular edema. Full resolution of the intraretinal fluid and improvement of the BCVA to 0.9 were achieved. A laboratory workup was performed to rule out all known causes of retinal venous occlusive disease, which showed negative results. A molecular analysis showed the gen of thrombophilia - plasminogen activator inhibitor (PAI)-1 4G/5G polymorphism genotype - as the only risk factor for retinal venous occlusive disease in our patient.

Investigation of Plasminogen Activator Inhibitor-1 (PAI-1) 4G/5G promoter polymorphism in Indian venous thrombosis patients: A case-control study.

BACKGROUND: The role of PAI-1 4G/5G polymorphism in venous thrombosis has been contradictory. PAI-1 4G/4G genotype is associated with elevated levels of PAI-1 resulting in a hypofibrinolytic state and a higher thrombotic risk. OBJECTIVE: In this study, the distribution of genotypes and frequency of alleles of the 4G/5G polymorphism of PAI-1 gene in Indian patients with different types of venous thrombosis was investigated for its role in development of thrombosis. METHOD: A total of 87 portal vein thrombosis (PVT), 71 Budd-Chiari syndrome (BCS), 156 cerebral vein thrombosis (CVT), and 163 deep vein thrombosis (DVT) patients were studied alongside 251 healthy controls for the PAI-1 4G/5G polymorphism by allele-specific PCR. RESULTS: Frequency of 4G/4G genotype was higher in all groups in comparison with controls. 4G/4G was associated with PVT risk (OR=2.51, 95% CI=1.29-4.96, P=.0075), BCS risk (OR=5.98, 95% CI=2.68-13.42, P<.0001), and DVT risk (OR=1.75, 95% CI=0.98-3.02, P=.0225). This is the first case-control study from India establishing PAI-1 4G/4G as a strong risk factor for abdominal thrombosis (PVT and BCS). Statistically significant association was not found between 4G/4G genotype and CVT risk. CONCLUSION: PAI-1 4G/4G is a strong risk factor for venous thrombosis in Indian patients and should be included in laboratory testing panel of thrombophilia.

The Association of Plasminogen Activator Inhibitor Type 1 (PAI-1) Level and PAI-1 4G/5G Gene Polymorphism with the Formation and the Grade of Endometrial Cancer.

Plasminogen activator inhibitor type 1 (PAI-1) is a serine protease inhibitor (Serpine 1), and it inhibits both tissue plasminogen activator and urokinase plasminogen activator which are important in fibrinolysis. We aimed to find whether there is a possible association between PAI-1 level, PAI-1 4G/5G polymorphism, and endometrial cancer. PAI-1 levels in peripheral blood were determined in 82 patients with endometrial carcinoma and 76 female healthy controls using an enzyme-linked immunoassay (ELISA). Then, the genomic DNA was extracted and screened by reverse hybridization procedure (Strip assay) to detect PAI 1 4G/5G polymorphism. The levels of PAI-1 in the patients were higher statistically in comparison to controls (P < 0.001). The distribution of PAI-1 4G/5G polymorphism was quite different between patients and controls (P = 0.008), and 4G allelic frequency was significantly higher in the patients of endometrial cancer than in controls (P = 0.026). We found significant difference between Grade 1 and Grade 2+3 patients in terms of the PAI-1 levels (P = 0.047). There was no association between PAI-1 4G/5G polymorphism and the grades of endometrial cancer (P = 0.993). Our data suggest that the level of PAI-1 and PAI-1 4G/5G gene polymorphism are effective in the formation of endometrial cancer. PAI-1 levels are also associated with the grades of endometrial cancer.

A study of the possible association of plasminogen activator inhibitor type 1 4G/5G insertion/deletion polymorphism with susceptibility to schizophrenia and in its subtypes.

WHAT IS KNOWN AND OBJECTIVE: Inhibition of the fibrinolytic system may occur at the level of plasminogen activation, mainly by PAI-1. Mental and physical stress caused to alterations of platelet function, and also decreased to fibrinolytic activity. Furthermore, stress-induced thrombosis regulation was proposed to be by PAI-1 in schizophrenia patients. In this study, the distribution of genotypes and frequency of alleles of the plasminogen activator inhibitor type 1 (PAI-1) gene 4G/5G polymorphism in different Turkish clinical schizophrenia subtypes was investigated for its role in schizophrenia development. METHODS: The clinical schizophrenia subtypes include paranoid, catatonic, disorganized, undifferentiated and residual, as diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition IV (DSM-IV). Samples of genomic DNA (250 total, including 150 schizophrenia patients and 100 healthy subjects) were analysed. PAI-1 4G/5G genotyping was performed by polymerase chain reaction-allele-specific amplification. PCR products were separated by 2% agarose gel electrophoresis and then visualized. RESULTS AND DISCUSSION: The genotype distributions (P = 0·136) and allele frequencies (P = 0·721 for 4G, P = 0. 097 for 5G) were not significantly different between patients with schizophrenia and control subjects for the 4G/5G polymorphism. Similar results were also found for the genotype distributions (P = 0·640) and allele frequencies (P = 0·763 for 4G, P = 0·448 for 5G) in the clinical schizophrenia subtypes compared to the each other. WHAT IS NEW AND CONCLUSION: We conclude that PAI-1 4G/5G polymorphism was not significantly associated with schizophrenia or its subtypes in the Turkish population. However, we recognize that with our sample sizes, we cannot exclude weak associations.

Association Between Plasminogen Activator Inhibitor-1-675 4G/5G Insertion/Deletion Polymorphism and Chronic Obstructive Pulmonary Disease.

Molecular pathology of chronic obstructive pulmonary disease (COPD) is still being investigated to discover relationships with disease pathogenesis. Evidence of plasminogen activator inhibitor-1 (PAI-1) overexpression in the sputum and the blood of COPD patients is growing. We aimed to investigate the potential relation between PAI-1 promoter 4G/5G insertion/deletion polymorphism and COPD development. In a case-control study, we genotyped 117 COPD patients and 160 control subjects for PAI-1 promoter 4G/5G polymorphism by an allele-specific polymerase chain reaction analysis. All subjects were male smokers. In the co-dominant model, there was a significant difference in the distribution of 5G/5G, 4G/5G and 4G/4G genotypes between COPD patients and controls (p = 0.002). In the recessive model, carriers of 4G/4G genotype were significantly higher in COPD patients than controls (p = 0.01). Carriers of 4G/4G genotype were at higher risk to develop COPD than those carrying 5G/5G or 4G/5G genotypes (crude odds ratio (OR) = 2.10, 95% confidence interval (CI) = 1.19-3.73, adjusted OR = 2.5, 95% CI = 1.22-3.99). In conclusion, PAI-1 4G/5G genetic variations are associated with COPD development in males.

Thrombotic events in acute promyelocytic leukemia.

INTRODUCTION: Thrombotic events (TE) appear to be more common in acute promyelocytic leukemia (APL) than in other acute leukemias, with reported prevalence ranging from 2 to 10-15%. MATERIALS AND METHODS: We retrospectively analyzed the data on TE appearance in 63 APL patients. RESULTS: TE occured in 13 (20.6%) cases, four arterial (6.3%) and nine venous (14.3%). TE were more frequently diagnosed after initiation of weekly D-dimer monitoring (7 TE during 20 months vs 6 during 76 months, P=0.032). Patients with and without venous thrombosis were significantly different regarding female/male ratio (P=0.046), PT (P=0.022), aPTT (P=0.044), ISTH DIC score (P=0.001), bcr3 (P=0.02) and FLT3-ITD (P=0.028) mutation. The most significant risk factor for venous TE occurrence in multivariate analysis was FLT3-ITD mutation (P=0.034). PAI-1 4G/4G polymorphism was five times more frequent in patients with venous TE than without it (P=0.05). Regarding risk factors for arterial TE we failed to identify any. CONCLUSIONS: We have demonstrated that APL-related TE rate is higher than previously reported and that weekly D-dimer monitoring might help to identify patients with silent thrombosis. Moreover, our study suggests a possible relationship between venous TE occurrence and several laboratory findings (PT, aPTT, ISTH DIC score, bcr3 isoform, FLT3-ITD mutation and PAI 4G/4G). Prophylactic use of heparin might be considered in patients with ISTH DIC score<5, bcr3 isoform, FLT3-ITD mutation and PAI 4G/4G.

Plasminogen activator inhibitor-1 4G/5G polymorphism and ischemic stroke risk: a meta-analysis in Chinese population.

BACKGROUND: The guanosine insertion/deletion polymorphism (4G/5G) of plasminogen activator inhibitor-1 (PAI-1) gene has been suggested as a risk factor for ischemic stroke (IS), but direct evidence from genetic association studies remains inconclusive even in Chinese population. Therefore, we performed a meta-analysis to evaluate this association. METHODS: All of the relevant studies were identified from PubMed, Embase, Chinese National Knowledge Infrastructure database and Chinese Wanfang database up to September 2013. Statistical analyses were conducted with Revman 5.2 and STATA 12.0 software. Odds ratio (OR) with 95% confidence interval (CI) values were applied to evaluate the strength of the association. Heterogeneity was evaluated by Q-test and the I² statistic. The Begg's test and Egger's test were used to assess the publication bias. RESULTS: A significant association and a borderline association between the PAI-1 4G/5G polymorphism and IS were found under the recessive model (OR = 1.639, 95% CI = 1.136-2.364) and allelic model (OR = 1.256, 95% CI = 1.000-1.578), respectively. However, no significant association was observed under homogeneous comparison model (OR = 1.428, 95% CI = 0.914-2.233), heterogeneous comparison model (OR = 0.856, 95% CI = 0.689-1.063) and dominant model (OR = 1.036, 95% CI = 0.846-1.270). CONCLUSION: This meta-analysis suggested that 4G4G genotype of PAI-1 4G/5G polymorphism might be a risk factor for IS in the Chinese population.

The association between gene polymorphisms and leukocytosis with thrombotic complications in patients with essential thrombocythemia and polycythemia vera.

OBJECTIVE: Vascular events are a common complication in patients with polycythemia vera (PV) and essential thrombocythemia (ET). This study aimed to analyze the association between PAI-1 4G/5G and ACE I/D gene polymorphisms, and leukocytosis with thrombosis in patients with PV and ET. MATERIAL AND METHODS: In total, 64 patients with ET and PV were evaluated. Arterial or venous thrombosis, such as cerebral transient ischemic attack, ischemic stroke, myocardial infarction, peripheral arterial thrombosis, deep venous thrombosis, and pulmonary embolism, were defined as a vascular event. DNA samples were screened for mutations via reverse hybridization strip assay. RESULTS: In terms of PAI-1 gene polymorphism, the frequency of the 4G and 5G allele was 48.5% and 51.5%, respectively. The ACE allele frequency was 51.2% and 48.8% for D and I, respectively. There wasn't an association between occurrence of vascular events and the frequency of any allele. In terms of occurrence of vascular events, there weren't any significance differences between the patients that were carrying the ACE D/D homozygous allele to ACE I/D and those that carried the I/I allele (P = 0.93). There wasn't a significant difference in occurrence of vascular events between the PAI-1 5G/5G homozygote allele carriers, and the 4G/5G and 4G/4G allele carriers (P = 0.97). Vascular events were significantly more common in the patients with leukocytosis (leukocyte count >10 × 109 L-1) than in those without leukocytosis (leukocyte count ≤10 × 109 L-1) (P = 0.00). Age >60 years was also a significant risk factor for occurrence of vascular events(P = 0.008). CONCLUSION: PAI-1 and ACE gene polymorphisms were not considered new risk factors for thrombosis in PV and ET patients. On the other hand, leukocytosis at diagnosis was associated with the occurrence of vascular events in the patients with ET and PV.