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Inherited thrombophilia (IT) has been implicated as a potential causal factor of adverse pregnancy outcomes (APOs), including recurrent miscarriage with and without the presence of antiphospholipid syndrome (APS). The aim of this study was to assess the prevalence and impact of IT on fetal–maternal outcomes and thrombotic risk in women within the spectrum of obstetric APS. Three hundred and twenty-eight women with APS-related obstetric morbidity ever pregnant were included. Of these, 74 met the APS classification criteria, 169 were non-criteria (NC)-APS, and 85 were seronegative (SN)-APS. Patients with other autoimmune diseases were excluded. APOs included early pregnancy loss, fetal death, preeclampsia, abruptio placentae, and preterm birth. Successful pregnancy was defined as the achievement of a live newborn. A literature search was also performed. The mean age of the overall group was 33.9 ± 5.3 years, and the patients were followed up for 35 (11–79) months. During the study period, there were 1332 pregnancies. Nearly 14% of the patients had an associated IT. IT patients more frequently received the standard-of-care (SoC) therapy. The presence of IT was not associated with worse maternal–fetal outcomes in patients treated with SoC treatment. Overall, IT patients had a lower frequency of newborns without treatment, especially those without definite APS. In addition, IT did not increase the risk of thrombosis during pregnancy or the postpartum period. A detailed analysis of the literature review identified only four publications related to our study and did not show conclusive evidence of the impact of IT on patients with obstetric APS. The group of women with APS-related obstetric morbidity and IT who did not receive treatment, especially those without definite APS, had a worse prognosis in terms of a live birth. However, with SoC therapy, the prognosis is similar in those patients without IT. The association of IT with APS does not seem to predispose to the development of thrombosis during pregnancy and/or the postpartum period. [ABSTRACT FROM AUTHOR]

Background: Despite pregnancy's hypercoagulable state, the correlation between inherited thrombophilia and thrombotic adverse pregnancy outcomes remains uncertain. The objective of this study was to determine the prevalence of inherited thrombophilic polymorphisms among asymptomatic pregnant individuals and to examine their potential correlation with adverse perinatal outcomes. Methods: in this single-center prospective study, 105 healthy pregnant women were included. Genotyping was conducted for factor V Leiden (FVL), prothrombin gene mutation, methylenetetrahydrofolate reductase enzyme (MTHFR) C677T, MTHFR A1298C, and plasminogen activator inhibitor-1 (PAI-1), alongside the assessment of protein C (PC), protein S (PS), and antithrombin (AT) levels. The study analyzed the association between inherited thrombophilic polymorphisms and pregnancy complications linked to placental insufficiency, such as gestational hypertension (GH), preeclampsia (PE), intrauterine death (IUD), fetal growth restriction (FGR), and placental abruption. Results: The prevalence of identifiable thrombophilic polymorphism mutations was 61.9% (95% confidence interval—CI 52.4–70.8%), with the most common single mutation being PAI-1 4G/5G (12/105, 11.4%, 95% CI 6.4–18.5). The most frequent combined mutation was heterozygosity for MTHFR C677T and PAI-1 (12/105, 11.4%, 95% CI 6.4–18.5). Notably, no FVL homozygous carriers or single homozygous and heterozygous carriers for prothrombin polymorphisms were found. Additionally, no deficiencies in PC and AT were detected among participants. Except for homozygosity for PAI-1, none of the studied polymorphisms demonstrated a significant association with pregnancy complications linked to placental insufficiency. Conclusions: The asymptomatic carriers of inherited thrombophilic polymorphisms do not have an increased risk of adverse perinatal outcomes. [ABSTRACT FROM AUTHOR]

Inherited defects in the genes of blood coagulation essentially express the severity of the clinical phenotype that is directly correlated to the number of mutated alleles of the candidate leader gene (e.g., heterozygote vs. homozygote) and of possible additional coinherited traits. The F5 gene, which codes for coagulation factor V (FV), plays a two-faced role in the coagulation cascade, exhibiting both procoagulant and anticoagulant functions. Thus, defects in this gene can be predisposed to either bleeding or thrombosis. A Sanger sequence analysis detected a premature stop-codon in exon 13 of the F5 gene (c.3481C>T; p.R1161Ter) in several members of a family characterised by low circulating FV levels and contrasting clinical phenotypes. The propositus, a 29 y.o. male affected by recurrent haemorrhages, was homozygous for the F5 stop-codon and for the F5 c.1691G>A (p.R506Q; FV-Leiden) inherited from the heterozygous parents, which is suggestive of combined cis-segregation. The homozygous condition of the stop-codon completely abolished the F5 gene expression in the propositus (FV:Ag < 1%; FV:C < 1%; assessed by ELISA and PT-based one-stage clotting assay respectively), removing, in turn, any chance for FV-Leiden to act as a prothrombotic molecule. His father (57 y.o.), characterised by severe recurrent venous thromboses, underwent a complete molecular thrombophilic screening, revealing a heterozygous F2 G20210A defect, while his mother (56 y.o.), who was negative for further common coagulation defects, reported fully asymptomatic anamnesis. To dissect these conflicting phenotypes, we performed the ProC®Global (Siemens Helthineers) coagulation test aimed at assessing the global pro- and anticoagulant balance of each family member, investigating the responses to the activated protein C (APC) by means of an APC-sensitivity ratio (APC-sr). The propositus had an unexpectedly poor response to APC (APC-sr: 1.09; n.v. > 2.25), and his father and mother had an APC-sr of 1.5 and 2.0, respectively. Although ProC®Global prevalently detects the anticoagulant side of FV, the exceptionally low APC-sr of the propositus and his discordant severe–moderate haemorrhagic phenotype could suggest a residual expression of mutated FV p.506QQ through a natural readthrough or possible alternative splicing mechanisms. The coagulation pathway may be physiologically rebalanced through natural and induced strategies, and the described insights might be able to track the design of novel treatment approaches and rebalancing molecules. [ABSTRACT FROM AUTHOR]

Background: Kearns-Sayre syndrome (KSS) is classified as one of the mitochondrial DNA (mtDNA) deletion syndromes withmultisystemic involvement. Additionally, the negative prognosis is associated with inherited thrombophilia, which includes the presence of homozygous Factor V G1691A Leiden mutation, MTHFR gene polymorphisms C677T and A1298C, and PAI-1 675 homozygous genotype 5G/5G. Case presentation: This case report presents a 48-year-old man with chronic progressive external ophthalmoplegia, bilateral ptosis, cerebellar ataxia, cardiovascular signs (syncope, dilated cardiomyopathy, and cardiac arrest) with electrocardiographic abnormalities (first-degree atrioventricular block and major right bundle branch block), endocrine dysfunction (short stature, growth hormone insufficiency, primary gonadal insufficiency, hypothyroidism, and secondary hyperparathyroidism), molecular genetic tests (MT-TL2 gene), and abnormal MRI brain images, thus leading to the diagnosis of KSS. The patient came back 4 weeks after the diagnosis to the emergency department with massive bilateral pulmonary embolism with syncope at onset, acute cardiorespiratory failure, deep left femoral-popliteal vein thrombophlebitis, and altered neurological status. In the intensive care unit, he received mechanical ventilation through intubation. Significant improvement was seen after 2 weeks. The patient tested positive for inherited thrombophilia and was discharged in stable conditions on a new treatment with Rivaroxaban 20 mg/day. At 6 months of follow-up, ECG-Holter monitoring and MRI brain images remained unchanged. However, after 3 months, the patient died suddenly while sleeping at home. Conclusion: The genetic tests performed on KSS patients should also include those for inherited thrombophilia. By detecting these mutations, we can prevent major complications such as cerebral venous sinus thrombosis, coronary accidents, or sudden death. [ABSTRACT FROM AUTHOR]

Objectives. Thrombosis is an increasingly recognized complication of childhood malignancy and its treatment. The incidence and etiology of pediatric cancer-related thrombosis is still not well understood. The aim of this study was to evaluate the prevalence of common prothrombotic genetic conditions in children with cancer, the frequency of thrombosis, and the role of inherited thrombophilia in the development of thrombosis in a pediatric oncology population. Patients and Methods. Forty-seven children (36 treated for hematological malignancies and 11 for solid tumors) with a median age of 8.8. years (range 0.4 - 19.3 years) were included in the study. Genetic polymorphisms of Factor V Leiden (G1691A), prothrombin G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T were determined by real-time polymerase chain reaction-based DNA analysis. Results. Four (8.5%) patients were heterozygous for Factor V Leiden, 3 (6.4%) were heterozygous for prothrombin G20210A mutation, and 3 (6.4%) were homozygous for MTHFR C677T mutation. All patients had implanted central venous catheters. Four (8.5%) children had documented thrombosis, three of which were in the upper venous system. Two of the four patients with thrombosis had Factor V Leiden heterozygosity. Conclusions. Thrombosis is an important complication of childhood cancer. The risk of thrombosis may be increased in patients with Factor V Leiden. In the absence of consensus guidelines, our results support the recommendation for thrombophilia screening in children with cancer. [ABSTRACT FROM AUTHOR]

BackgroundKearns-Sayre syndrome (KSS) is classified as one of the mitochondrial DNA (mtDNA) deletion syndromes with multisystemic involvement. Additionally, the negative prognosis is associated with inherited thrombophilia, which includes the presence of homozygous Factor V G1691A Leiden mutation, MTHFR gene polymorphisms C677T and A1298C, and PAI-1 675 homozygous genotype 5G/5G.Case presentationThis case report presents a 48-year-old man with chronic progressive external ophthalmoplegia, bilateral ptosis, cerebellar ataxia, cardiovascular signs (syncope, dilated cardiomyopathy, and cardiac arrest) with electrocardiographic abnormalities (first-degree atrioventricular block and major right bundle branch block), endocrine dysfunction (short stature, growth hormone insufficiency, primary gonadal insufficiency, hypothyroidism, and secondary hyperparathyroidism), molecular genetic tests (MT-TL2 gene), and abnormal MRI brain images, thus leading to the diagnosis of KSS. The patient came back 4 weeks after the diagnosis to the emergency department with massive bilateral pulmonary embolism with syncope at onset, acute cardiorespiratory failure, deep left femoral-popliteal vein thrombophlebitis, and altered neurological status. In the intensive care unit, he received mechanical ventilation through intubation. Significant improvement was seen after 2 weeks. The patient tested positive for inherited thrombophilia and was discharged in stable conditions on a new treatment with Rivaroxaban 20 mg/day. At 6 months of follow-up, ECG-Holter monitoring and MRI brain images remained unchanged. However, after 3 months, the patient died suddenly while sleeping at home.ConclusionThe genetic tests performed on KSS patients should also include those for inherited thrombophilia. By detecting these mutations, we can prevent major complications such as cerebral venous sinus thrombosis, coronary accidents, or sudden death.

Introduction: Recurrent pregnancy loss refers to the occurrence of two or more consecutive abortions before the 20th week of pregnancy, which has a high prevalence and it is necessary to identify the factors affecting it. Therefore, this study was performed with aim to investigate the frequency of various factors affecting pregnancy loss in patients with history of recurrent pregnancy loss. Methods: This cross-sectional study was performed on 280 women with at least two abortions less than 20 weeks who had referred to the only infertility treatment center in Sistan and Balouchestan province in 2017-2018. Data related to abortion was collected based on the patients' file. Data were analyzed using SPSS software (version 20) and Kolmogorov-Smirnov test with lilliefors correction, Student t, Mann-Whitney and Fisher's exact tests. P

Inherited thrombophilia (IT) has been implicated as a potential causal factor of adverse pregnancy outcomes (APOs), including recurrent miscarriage with and without the presence of antiphospholipid syndrome (APS). The aim of this study was to assess the prevalence and impact of IT on fetal–maternal outcomes and thrombotic risk in women within the spectrum of obstetric APS. Three hundred and twenty-eight women with APS-related obstetric morbidity ever pregnant were included. Of these, 74 met the APS classification criteria, 169 were non-criteria (NC)-APS, and 85 were seronegative (SN)-APS. Patients with other autoimmune diseases were excluded. APOs included early pregnancy loss, fetal death, preeclampsia, abruptio placentae, and preterm birth. Successful pregnancy was defined as the achievement of a live newborn. A literature search was also performed. The mean age of the overall group was 33.9 ± 5.3 years, and the patients were followed up for 35 (11–79) months. During the study period, there were 1332 pregnancies. Nearly 14% of the patients had an associated IT. IT patients more frequently received the standard-of-care (SoC) therapy. The presence of IT was not associated with worse maternal–fetal outcomes in patients treated with SoC treatment. Overall, IT patients had a lower frequency of newborns without treatment, especially those without definite APS. In addition, IT did not increase the risk of thrombosis during pregnancy or the postpartum period. A detailed analysis of the literature review identified only four publications related to our study and did not show conclusive evidence of the impact of IT on patients with obstetric APS. The group of women with APS-related obstetric morbidity and IT who did not receive treatment, especially those without definite APS, had a worse prognosis in terms of a live birth. However, with SoC therapy, the prognosis is similar in those patients without IT. The association of IT with APS does not seem to predispose to the development of thrombosis during pregnancy and/or the postpartum period.

Introduction: Chronic thromboembolic pulmonary hypertension (CTEPH) is a phenotype of pulmonary hypertension due to chronic and multiple organized thrombus. The therapeutic strategy for patients with CTEPH and comorbid protein S deficiency remains unknown due to its rarity. Case: We encountered a 49-year-old male patient with CTEPH and concomitant mild protein S deficiency (type III). We could successfully perform balloon pulmonary angioplasty without any major complications, including thromboembolism and bleeding, followed by standard-dose oral anticoagulation therapy instead of warfarin. Conclusion: A currently established standard therapeutic strategy for CTEPH, including pulmonary angioplasty, may be safe and effective even in patients with concomitant inherent coagulation abnormalities. [ABSTRACT FROM AUTHOR]

Thrombosis is an extremely dangerous complication in elderly patients with COVID-19. Since the first months of the pandemic, anticoagulants have been mandatory in treatment protocols for patients with COVID-19, unless there are serious contraindications. We set out to discover if genetic thrombophilia factors continue to play a triggering role in the occurrence of thrombosis in patients with COVID-19 with prophylactic or therapeutic anticoagulants. We considered the following genetic markers as risk factors for thrombophilia: G1691A in the FV gene, C677T and A1298C in the MTHFR gene, G20210A and C494T in the FII gene, and (−675) 4G/5G in the PAI-I gene. In a cohort of 176 patients, we did not obtain a reliable result indicating a higher risk of thrombotic complications when taking therapeutic doses of anticoagulants in carriers of genetic markers for thrombophilia except the C494T mutation in the FII gene. However, there was still a pronounced tendency to a higher incidence of thrombosis in patients with markers of hereditary thrombophilia, such as FV G1691A and FII G20210A mutations. The presence of the C494T (Thr165Met) allele in the FII gene in this group of patients showed a statistically significant effect of the mutation on the risk of thrombotic complications despite anticoagulant therapy. [ABSTRACT FROM AUTHOR]

Abstract Background Although bladder cancer is quite a common cancer, most common encounter being transitional cell carcinomas, paragangliomas with such localization, is a very rare histopathological finding. In addition, hematuria in a patient with a theoretically "hypercoagulable" condition is uncommon; in our case it was the single symptom. Case presentation We report the case of a 44-year-old female referred to our hospital for gross hematuria. The CT scan revealed an intraluminal enhancing bladder mass. Also, the XIII coagulation factor level was 36% and surprisingly genetic mutations suggesting inherited thrombophilia were found: MTHFR C677T negative, A1298C positive and PAI-1 gene polymorphism (675 4G/5G). The hematologist recommended folic acid 5 mgs daily. A TURBT was performed (macroscopically no residual tumor tissue). The immunohistochemical examination revealed tumor cells intensely positive to chromogranin and synaptophysin, negative for cytokeratin AE1/3, p63, 7, 20 or CDX2, and slight (less than 5%) positive for Ki-67. The combined examinations correspond to a bladder paraganglioma. Six months after surgery, the patient had no clinical symptoms and no relapse sonographically and cystoscopically. Conclusions Although a very rare entity, bladder paraganglioma should be suspected in patients with hematuria and unexplained hyperadrenalism symptoms such as hypertension, serious dizziness, headache or palpitation. The immunohistochemical examination is important not only for diagnosis but also for identifying the functionality of the tumors. In such cases the therapeutic management could be different as in transitional cell carcinomas.

Inherited thrombophilia is a coagulation condition that is linked to increased risk of thrombosis. This study investigates the prevalence of FV Leiden (G1691A), FV H1299R (HR2), FV Y1702C, MTHFR C677T, MTHFR A1298C, FII G20210A and PAI-1 mutations among children with thrombotic events. This single-center study included 60 Jordanian children of both sexes (4 days-18 years) admitted to hospital and diagnosed with thrombotic event of any type. The control group consisted of 50 healthy subjects. The presence of thrombophilic mutations was detected using polymerase chain reaction strip assay. The majority of thrombotic events (38.3%) were reported in children at school age (6-12 years) and in adolescents (26.7%) (13-18 years). The most common thrombotic events were deep vein thrombosis (35%) followed by cerebrovascular accidents (18.3%) and cerebral vein sinus thrombosis (16.6%). The most common thrombophilic mutations among children diagnosed with thrombotic events were PAI-1(4G/5G), MTHFR A1298C, MTHFR C677T and FV Leiden (G1691A) constituting 63.3%, 56.7%, 48.3%, and 41.7%, respectively. A statistically significant difference in the occurrence of mutations between the control group and children with thrombotic events was found only in FV Leiden (G1691A), MTHFR A1298C and FV H1299R. This study revealed that neither children with thrombotic events nor subjects in the control group carried the FV Y1702C mutation. In conclusion, the presence of FV Leiden (G1691A), MTHFR A1298C and FV H1299R mutations may be considered as a risk factor for thrombosis in children. Genetic testing of children with family history could play an important role in detecting high-risk subjects. [ABSTRACT FROM AUTHOR]

In January 2020, SARS-COV-2 infection spread worldwide and was declared “pandemic” by WHO. Because of the high contagiousness of the virus and devastating effects of the epidemic on public health, numerous efforts have been made to develop suitable vaccines to prevent the infection. Among the side effects developed by patients who undergone vaccination, there are common symptoms but also more serious reactions such as the thrombosis syndromes. This paper presents two cases of thrombosis temporally associated with live-vectored Covid vaccination similar to vaccine-induced thrombocytopenia (VITT) in patients with inherited thrombophilia (respectively, the deficiency of protein S and a Factor II mutation). The clinical manifestation caused by VITT is characterized by widespread thrombosis especially affecting intracranial venous sinus, which may cause massive bleeding and intracranial hemorrhage. Although this condition is widely described in literature, there is no evident correlation between this side effect and inherited condition of thrombophilia. The authors suggest that the presence of inherited thrombophilia should be better investigated and, if necessary, screened during the anamnestic data collection before the vaccine administration, leading the healthcare professional to choose the appropriate vaccine to the patient.

We retrospectively evaluated the prevalence of non-O blood type – the most frequently inherited prothrombotic factor – and inherited thrombophilia (IT) in a group of women with recurrent spontaneous abortion (RSA). All consecutive women with a history of early unexplained RSA who underwent a screening for IT between December 2008 and December 2021 were considered for enrolment. A group of healthy, age-matched women with ≥1 normal pregnancy and no adverse pregnancy outcomes acted as controls. Two hundred and seventeen women were enrolled. The adjusted odds ratio (aOR) of RSA in non-O vs. O blood type was 1.37 (95% CI, 1.04-2.78), and in women with vs. without IT was 1.26 (95% CI, 1.08-3.61); aOR of RSA in women with non-O blood type and IT was 2.52 (95% CI, 1.12-5.47). We observed a significant association between non-O blood group or IT and RSA. The concomitant presence of non-O blood group and IT further increases RSA risk.

(1) Background: Neonatal cerebral sinovenous thrombosis (CSVT) is a rare disorder, associated with long-term neurological sequelae. The aim of this study was to retrospectively evaluate the most commonly encountered perinatal risk factors for this disease in a cohort of newborns from Romania. (2) Methods: The medical records of neonatal CSVT patients treated between January 2017 and December 2021 were descriptively assessed. (3) Results: The study included nine neonates, five males (55.56%) and four females (44.44%), who were born at term. The most commonly presented clinical manifestations were feeding difficulties, lethargy, respiratory distress, loss of consciousness, and seizures. Maternal-inherited thrombophilia, male sex, complicated delivery, perinatal asphyxia, and mechanical ventilation were frequently identified as potential risk factors for developing CSVT. The lesions were more frequently localized in the superior sagittal sinus (n = 7; 77.78%), followed by the transverse (n = 4; 44.44%), sigmoid (n = 2; 22.22%), and cavernous (n = 1; 11.11%) sinuses. Low-molecular-weight heparin was administered to all patients, and two of them died from thrombotic complications. (4) Conclusions: Recognition of potential risk factors and a prompt diagnosis of neonatal CSVT could lead to better patient management and to a reduction of severe complications. [ABSTRACT FROM AUTHOR]

Introduction: Chronic thromboembolic pulmonary hypertension (CTEPH) is a phenotype of pulmonary hypertension due to chronic and multiple organized thrombus. The therapeutic strategy for patients with CTEPH and comorbid protein S deficiency remains unknown due to its rarity. Case: We encountered a 49-year-old male patient with CTEPH and concomitant mild protein S deficiency (type III). We could successfully perform balloon pulmonary angioplasty without any major complications, including thromboembolism and bleeding, followed by standard-dose oral anticoagulation therapy instead of warfarin. Conclusion: A currently established standard therapeutic strategy for CTEPH, including pulmonary angioplasty, may be safe and effective even in patients with concomitant inherent coagulation abnormalities.

Thrombophilia, blood clotting abnormalities that increase the risk of thrombosis, can be inherited (congenital thrombophilia) or acquired during life. We conducted a study using the questionnaire method, which included 38 questions. The questionnaire was posted on social media groups dedicated to patients with thrombophilia in Romania. 99 patients responded to our request to complete the questionnaire, 91 performed tests for the diagnosis of thrombophilia and 85 were diagnosed with thrombophilia (81 diagnosed with inherited thrombophilia, 1 with acquired thrombophilia and 3 with mixed thrombophilia). It was shown that, in our group, the most common inherited thrombophilias are the factor V mutation (FVL) and the MTHFR gene mutation, in over 95% of cases. The results of the study may be a starting point for larger batch studies on the presence of genetic mutations in patients with inherited thrombophilia, to more effectively prevent pregnancy complications.

Thrombophilias are a group of coagulation disorders associated with a predisposition to thrombotic events. They could be inherited (genetic) or acquired. The most encountered inherited thrombophilias are factor V Leiden (FVL), prothrombin gene mutation (G20210A) (PGM), protein S deficiency, protein C deficiency and antithrombin (AT) deficiency. Based upon the risk of thrombosis, there are two types of inherited thrombophilias, high risk and low risk. The high risk inherited thrombophilia includes antithrombin III deficiency, factor V Leiden homozygotes, prothrombin gene mutation and compound heterozygotes FVL and PGM. The low risk thrombophilia includes factor V Leiden heterozygote, PGM heterozygote, protein C deficiency and protein S deficiency. The incidence of all thromboembolic events is estimated to approximately 1-2 per 1000 pregnancies and about an equal number are identified antepartum and in the puerperium. Screening for thrombophilia in pregnancy is not universally recommended because of the low incidence of the condition and because it is not cost-effective. Some adverse pregnancy outcomes could be associated with some types of thrombophilia, but this association is weak and there is no reason to initiate extensive investigations or therapeutic measures. Both obstetricians and hematologists and women need to be correctly informed and avoid emotional decisions and unnecessary invasive treatments.

Patients with immune thrombocytopenia (ITP) exhibit striking heterogeneity in bleeding manifestations even at similar platelet counts. We report the prevalence and impact of thrombophilia marker expression in chronic ITP patients. For the present study, patients with chronic ITP were clinically assessed at regular intervals using the bleeding assessment tool for ITP, and bleeding was compared among patients with and without thrombophilia marker expression (thrombophilia markers analyzed included clot-based assays for protein C, protein S, Pro C Global®, FVIII levels, and lupus anticoagulant assay). Thirty-six patients (25.5%) tested positive for at least one thrombophilia marker, and the remaining 105 patients (74.5%) were negative for all markers. Patients expressing at least one thrombophilia marker had significantly less bleeding than those without. We conclude that a part of heterogeneity in the clinical presentation of chronic ITP can be explained by the presence of thrombophilia.

Background: Recurrent pregnancy loss (RPL) is a heterogeneous condition affecting up to 5% of women of reproductive age. Inherited thrombophilia have been postulated as one of the causes of RPL. Here we examined the prevalence of nine thrombophilic gene polymorphisms among women with history of recurrent miscarriages and fertile controls. Methods: The study included 70 women with history of at least three early pregnancy losses and 31 fertile controls with no miscarriages. We investigated mutations in genes responsible for clotting and fibrinolysis, including factor V (FV) Leiden, FV H1299R, factor II (FII) G20210A, methylene tetrahydrofolate reductase (MTHFR) C677T and A1298C, factor XIII (FXIII) V34L, plasminogen activator inhibitor-1 (PAI-1) 4G/5G and endothelial protein C receptor (EPCR) H1 and H3 haplotypes using reverse polymerase chain reaction ViennaLab cardiovascular disease StrippAssays. Results: Our results showed no significant increase in prevalence of tested polymorphisms in women with RPL. However, relative risk for PRL among women heterozygous for FXIII V34L was 2.81 times increased (OR 2.81, 95% CI 1.15-6.87, P=0.023). Haplotype analysis showed that combined presence of high-risk genotypes for FXIII and PAI-1 significantly increases risk for RPL (OR 13.98, CI 95% 1.11-17.46, P=0.044). Conclusions: This is the first study in Serbian population that investigated prevalence of FVR2, A1298C, FXIII V34L and EPCR gene variants. Compound heterozygosity for FXIII V34L and PAI-1 4G is significant risk factor for recurrent miscarriage. Our results should be viewed in context of small case-control study, so further large prospective studies are need for confirmation of our findings.

Protein S (PS) deficiency is a risk factor for venous thromboembolism (VTE) and can be caused by variants of the gene encoding PS (PROS1). This study aimed to evaluate the clinical value of molecular analysis of the PROS1 gene in PS-deficient participants. We performed Sanger sequencing of the coding region of the PROS1 gene and multiplex ligation-dependent probe amplification to exclude large structural rearrangements. Free PS was measured by a particle-enhanced immunoassay, while PS activity was assessed by a clotting method. A total of 87 PS-deficient participants and family members were included. In 22 index participants, we identified 13 PROS1 coding variants. Five variants were novel. In 21 index participants, no coding sequence variants or structural rearrangements were identified. The free PS level was lower in index participants carrying a PROS1 variant compared with index participants with no variant (0.51 [0.32–0.61] vs. 0.62 [0.57–0.73] × 103 IU/L; p

Background and objectives: ischemic stroke (IS) is among the most frequent causes of death worldwide; thus, it is of paramount relevance to know predisposing factors that may help to identify and treat the high-risk subjects. Materials and Methods:we tested nine variants in genes involved in thrombotic pathway in 282 patients that experienced IS and 87 that had transient ischemic attacks (TIA) in comparison to 430 subjects from the general population (GP) of the same geographic area (southern Italy). We included cases of young and child IS to evaluate the eventual differences in the role of the analyzed variants. Results: we did not observe significant differences between TIA and the GP for any of the variants, while the allele frequencies of methylene-tetrahydrofolate reductase (MTHFR) C677T, beta-fibrinogen -455G>A and factor (FXIII) V34L were significantly higher in patients with IS than in the subjects from the GP. No significant interaction was observed with sex. Conclusions: the present data argue that some gene variants have a role in IS and this appears to be an interesting possibility to be pursued in large population studies to help design specific strategies for IS prevention. [ABSTRACT FROM AUTHOR]

(1) Background: Neonatal cerebral sinovenous thrombosis (CSVT) is a rare disorder, associated with long-term neurological sequelae. The aim of this study was to retrospectively evaluate the most commonly encountered perinatal risk factors for this disease in a cohort of newborns from Romania. (2) Methods: The medical records of neonatal CSVT patients treated between January 2017 and December 2021 were descriptively assessed. (3) Results: The study included nine neonates, five males (55.56%) and four females (44.44%), who were born at term. The most commonly presented clinical manifestations were feeding difficulties, lethargy, respiratory distress, loss of consciousness, and seizures. Maternal-inherited thrombophilia, male sex, complicated delivery, perinatal asphyxia, and mechanical ventilation were frequently identified as potential risk factors for developing CSVT. The lesions were more frequently localized in the superior sagittal sinus (n = 7; 77.78%), followed by the transverse (n = 4; 44.44%), sigmoid (n = 2; 22.22%), and cavernous (n = 1; 11.11%) sinuses. Low-molecular-weight heparin was administered to all patients, and two of them died from thrombotic complications. (4) Conclusions: Recognition of potential risk factors and a prompt diagnosis of neonatal CSVT could lead to better patient management and to a reduction of severe complications.

Testing for inherited thrombophilia in patients with venous thromboembolism is one of the most common genetic testing options prescribed by clinicians. Despite the large evidence base for the relationship of hereditary hemostasis disorders with the risk of venous thrombosis, most patients should not be tested. Performing tests in the acute phase of thrombosis or during anticoagulant therapy leads to erroneous results. The choice of anticoagulant therapy regimen and its duration are not specified by the presence of hereditary thrombophilia. The test results can be useful for increasing medication adherence of patient, determining the cause of thrombosis, especially at a young age or in atypical localization.

Severe inherited thrombophilia includes rare deficiencies of natural anticoagulants (antithrombin and proteins C and S) and homozygous or combined factor V Leiden and FII G20210A variants. They are associated with a high thrombosis risk and can impact the duration of anticoagulation therapy for patients with a venous thromboembolism (VTE) event. Therefore, it is important to diagnose thrombophilia and to use adapted anticoagulant therapy. The widespread use of direct anticoagulants (DOACs) for VTE has raised new issues concerning inherited thrombophilia. Concerning inherited thrombophilia diagnosis, DOACs are directed toward either FIIa or FXa and can therefore interfere with coagulation assays. This paper reports DOAC interference in several thrombophilia tests, including the assessment of antithrombin, protein S, and protein C activities. Antithrombin activity and clot-based assays used for proteins C and S can be overestimated, with a risk of missing a deficiency. The use of a device to remove DOACs should be considered to minimize the risk of false-negative results. The place of DOACs in the treatment of VTE in thrombophilia patients is also discussed. Available data are encouraging, but given the variability in thrombosis risk within natural anticoagulant deficiencies, evidence in patients with well-characterized thrombophilia would be useful.

Aim. To assess polymorphisms of the hemostatic system genes in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and their influence on the results of thrombendarterectomy from the branches of the pulmonary artery.Material and methods. The study included 70 people with verified CTEPH who underwent thrombendarterectomy from the branches of the pulmonary artery. We studied the prevalence of polymorphisms of the hemostatic system genes (F2: 20210 G>A; F5: 1691 G>A (Arg506Gln); F7: 10976 G>A (Arg353Gln); F13: G>T (Val34Leu); FGB: 455 G>A; ITGA2: 807 C>T (Phe224Phe); ITGB3: 1565 T>C (Leu33Pro); SERPINE1 (PAI-1): 675 5G>4G) and their relationship with the immediate and long-term results of surgical treatment.Results. One or several polymorphisms of the hemostasis system genes were registrated in 98% of cases in the group with CTEPH. The most common polymorphism of the SERPINE1 (PAI-1) gene was 675 5G>4G (in 80% of cases). Mutation of the F2 gene: 20210 G>A was noted in 14% of patients, F5: 1691 G>A (Arg506Gln) - 13%, F7: 10976 G>A (Arg353Gln) - 11%, F13: G> T (Val34Leu) - 34 %, FGB: 455 G> A - 35%, ITGA2: 807 C>T (Phe224Phe) - 48%, ITGB3: 1565 T>C (Leu33Pro) - 24%. The only factor influencing the results of surgical treatment was the polymorphism of the prothrombin gene (20210 G>A), which showed a high predictive value in assessing the risk of respiratory failure in the early postoperative period of thrombendarterectomy from the branches of the pulmonary artery (OR 3,5 (1,7-18,8) p=0,041). Other genetic disorders of the hemostatic system did not show significant associations with the outcome of surgical treatment.Conclusion. We showed the relationship between the presence of prothrombin gene polymorphism (20210 G>A) and the increased risk of respiratory failure in the early postoperative period of thromboendarterectomy from the branches of the pulmonary artery. Other genetic disorders of the hemostatic system and their carriage did not show significant associations with the outcome of surgical treatment.

This article analyzes the frequency of polymorphisms of hemostasis system and folate cycle protein genes associated with increased risk of thrombophilia based on the results of CHGMA (Chita State Medical Academy) genetic laboratory patients with reproductive health disorders. Method of research is allele-specific PCR. It was analyzed 1800 DNA samples. The most frequently mutations occur in the genes of receptors in the platelets and the folate cycle, mostly heterozygous substitution. Leiden mutation (F5) and prothrombin mutation (F2) are the most significant in the thrombophilia development and occur much less frequently. Only in one case revealed a homozygous mutation in the gene F2 and F5.

Thrombophilia, blood clotting abnormalities that increase the risk of thrombosis, can be inherited (congenital thrombophilia) or acquired during life. We conducted a study using the questionnaire method, which included 38 questions. The questionnaire was posted on social media groups dedicated to patients with thrombophilia in Romania. 99 patients responded to our request to complete the questionnaire, 91 performed tests for the diagnosis of thrombophilia and 85 were diagnosed with thrombophilia (81 diagnosed with inherited thrombophilia, 1 with acquired thrombophilia and 3 with mixed thrombophilia). It was shown that, in our group, the most common inherited thrombophilias are the factor V mutation (FVL) and the MTHFR gene mutation, in over 95% of cases. The results of the study may be a starting point for larger batch studies on the presence of genetic mutations in patients with inherited thrombophilia, to more effectively prevent pregnancy complications. [ABSTRACT FROM AUTHOR]

Thrombophilias are a group of coagulation disorders associated with a predisposition to thrombotic events. They could be inherited (genetic) or acquired. The most encountered inherited thrombophilias are factor V Leiden (FVL), prothrombin gene mutation (G20210A) (PGM), protein S deficiency, protein C deficiency and antithrombin (AT) deficiency. Based upon the risk of thrombosis, there are two types of inherited thrombophilias, high risk and low risk. The high risk inherited thrombophilia includes antithrombin III deficiency, factor V Leiden homozygotes, prothrombin gene mutation and compound heterozygotes FVL and PGM. The low risk thrombophilia includes factor V Leiden heterozygote, PGM heterozygote, protein C deficiency and protein S deficiency. The incidence of all thromboembolic events is estimated to approximately 1-2 per 1000 pregnancies and about an equal number are identified antepartum and in the puerperium. Screening for thrombophilia in pregnancy is not universally recommended because of the low incidence of the condition and because it is not cost-effective. Some adverse pregnancy outcomes could be associated with some types of thrombophilia, but this association is weak and there is no reason to initiate extensive investigations or therapeutic measures. Both obstetricians and hematologists and women need to be correctly informed and avoid emotional decisions and unnecessary invasive treatments. [ABSTRACT FROM AUTHOR]

Objective: The ST- elevation myocardial infarction (STEMI), a serious health care problem, is commonly a thrombotic complication of coronary artery disease. We compare the STEMI patients and control group in terms of the possible causes of inherited thrombophilia including FactorV Cambridge G1091C, FactorV Leiden G1691A, MTHFRC677T, MTHFR A1298C, FactorII G20210A, Factor XIII (V34L), PAI-1, FGB, ITGB3, APOB, FVHR2, ACE gene variants. Methods: Fifty-three patients with STEMI and 47 individuals without diagnosis of acute coronary syndrome were included in the study. Percutaneous coronary intervention was performed for patients with STEMI. Echocardiography was performed and inherited thrombophilia genes were evaluated in all subjects. Results: The MTHFR A1298C, Factor XIII (V34L), ITGB, ACE and homozygous or compound heterozygous gene varations of inherited thrombophilia are significantly related with STEMI (p<0.05). Also significantly higher MTHFR A1298C, FactorV Leiden G1691A, PAI and ACE gene variations in MI patients who were smokers; Factor XIII (V34L), PAI and ACE gene variations in MI patients with HT; PAI and ACE gene variation in MI patients with FH and PAI gene variations in MI patients with HL were detected when compared with the control groups with all of the same risk factors (p<0.05). Conclusion: Hereditary thrombophilia factors may show promise in the prevention and management of STEMI when supported studies with larger case series. [ABSTRACT FROM AUTHOR]

Background: In the presence of conflicting advice about the relationship between selenium-type II diabetes-oxidative stress trio, this study aimed to assess the consequences of selenium supplementation on fasting plasma glucose (FPG) level, antioxidant activities of selenodependent and non-selenodependent enzymes, and other markers of oxidative stress studied for the first time during gestational diabetes mellitus (GDM). Methods: This research was carried out among 180 pregnant Algerian women, 60 of whom were in good health, 60 women with GDM did not take supplements, and 60 women with GDM took selenium orally (50 pg/d) for 12 weeks starting from their second trimester of pregnancy. Blood samples were taken in order to assay FPG level and oxidative stress markers. Results: Selenium supplementation during GDM has demonstrated its hypoglycemic power in the significant decline of FPG level, and its antioxidant properties in the significant reinforcement of antioxidant activities of ery-throcyte selenodependent enzymes (glutathione peroxidase and glutathione reductase), the significant increase in erythrocyte catalase and superoxide dismutase activities simultaneously with the highest decrease in erythrocyte and plasma malondialdehyde levels. This decrease was only significant for plasma carbonyl proteins, which was not the case for erythrocyte carbonyl proteins. Conclusions: The recourse to selenium supplementation by seleno-deficient pregnant women with GDM is beneficial for maternal health. This micronutrient exploits its antioxidant and insulin-mimetic properties in the maintenance of blood glucose homeostasis and the fight against oxidative stress, and consequently, its supplementation delays the occurrence of GDM complications. [ABSTRACT FROM AUTHOR]

This clinical case report describes the simultaneous development of an acute myocardial infarction, stroke, and a massive pulmonary thromboembolism in a 44-year-old patient — a carrier of the thrombophilia gene polymorphisms: MTHFR C677T, А1298C, PAI-1 4G/5G, ITGA2 C807T. Multifocal thrombosis was probably due to the initial congenital deficiency of anticoagulants, accompanied by a decrease in antithrombin III and protein C, against the background of their critical consumption in cascade thrombosis, in combination with the carrier of polymorphisms of moderate and low thrombogenic risk. This case is unique in that there is usually a tendency toward clinical thrombosis when the level of antithrombin III is less than 70%. Such patients develop thrombosis at a younger age, and by the age of 35–40 years usually have a verified diagnosis of extremely high-risk hereditary thrombophilia. In this case, multifocal thrombosis was accompanied by critically low values of anticoagulants: antithrombin III — 3.4%, and protein C — 36.8%. The patient had suffered from epilepsy since childhood and took anticonvulsant drugs that increase the deficit of active folic acid and can lead to hyperhomocysteinemia, which in this case, against the background of an innate decrease in the activity of methyltetrahydrofolate reductase, could have aggravated the situation. < Learning objective: To focus on the possibility of the manifestation of multifocal thrombosis in congenital thrombophilia in adulthood against the background of critically low values of anticoagulants — antithrombin III and protein C.> [ABSTRACT FROM AUTHOR]

Thromboembolism (TE) is a complex disease caused by various acquired and inherited factors. The common mutations; factor V Leiden G1691A (FVL G1691A), prothrombin G20210A (PTG20210A), and methylene tetrahydrofolate reductase C677T (MTHFR C677T) are important inherited causes in both venous and arterial thrombosis. The association between ABO blood groups and thrombophilia has been noted by researchers. We aimed to determine the frequency and association of ABO blood groups as a risk factor along with 3 thrombophilia mutations and another 3 thrombophilia markers in a group of patients with unstimulated thrombosis. In a prospective case-control study, we focused on 100 samples, 50 patients with documented thrombosis as well as 50 healthy age-matched controls. Multiplex polymerase chain reaction and reverse hybridization to oligonucleotide particular probes were employed to detect FVL G1691A, PT G20210A, and MTHFR C677T mutations. Analysis of other thrombophilia markers including protein C (PC), protein S (PS), and antithrombin (AT) assays was also performed. ABO blood group typing was done according to standard methods. Non-O blood group was significantly more frequent among cases than controls (76% vs 54%) with high odds of TE (odds ratio [OR] = 2.69). Positivity for at least 1 thrombophilia marker was more in cases (60%) than controls (34%; OR = 2.9). The combined effect of non-O blood group and thrombophilia markers raised the risk of TE (OR = 4.16, P =.001), particularly FVL (OR = 6.76). This study illustrates that harboring the non-O blood group poses an additive effect with other thrombophilia markers in the causation of TE. [ABSTRACT FROM AUTHOR]

In this review the impact of the most common thrombophilias on the risk of ischemic stroke and atherothrombosis is thoroughly analyzed. The functional role of different -fibrinogen genotypes was reviewed and their correlations with ischemic cerebrovascular diseases, brachiocephalic artery atherosclerosis and arterial hypertension are evaluated. In addition, associations of stroke with key genetic factors such as the Leyden mutation (factor V), mutations in the genes of prothrombin, PAI-1 (plasminogen activator inhibitor), glycoprotein IIIa, etc. are assessed. Results of the authors own works on the occurrence of various inherited thrombophilias in a group of 43 patients with ischemic stroke of undefined origin are presented.

Cerebral venous and dural sinus thrombosis (CVT) is an uncommon disease in the general population, although it is a significant stroke type throughout pregnancy and the puerperium. Studies describing this subtype of CVT are limited. Most pregnancy-associated CVT happen in late pregnancy, or more commonly in the first postpartum weeks, being associated with venous thrombosis outside the nervous system. Case presentation: The current study describes a case of multiple CVT in a 38-year-old woman with multiple risk factors (including severe inherited thrombophilia and being in the puerperium period), presenting mixed transcortical aphasia (a rare type of aphasia) associated with right moderate hemiparesis and intracranial hypertension. The clinical diagnosis of CVT was confirmed by laboratory data and neuroimaging data from head computed tomography, magnetic resonance imaging, and magnetic resonance venography. She was successfully treated with low-molecular-weight heparin (anticoagulation) and osmotic diuretics (mannitol) for increased intracranial pressure and cerebral edema. At discharge, after 15 days of evolution, she presented a partial recovery, with anomic plus aphasia and mild right hemiparesis. Clinical and imaging follow-up was performed at 6 months after discharge; our patient presented normal language and mild right central facial paresis, with chronic left thalamic, caudate nucleus, and internal capsule infarcts and a partial recanalization of the dural sinuses.

Background and objectives: ischemic stroke (IS) is among the most frequent causes of death worldwide; thus, it is of paramount relevance to know predisposing factors that may help to identify and treat the high-risk subjects. Materials and Methods:we tested nine variants in genes involved in thrombotic pathway in 282 patients that experienced IS and 87 that had transient ischemic attacks (TIA) in comparison to 430 subjects from the general population (GP) of the same geographic area (southern Italy). We included cases of young and child IS to evaluate the eventual differences in the role of the analyzed variants. Results: we did not observe significant differences between TIA and the GP for any of the variants, while the allele frequencies of methylene-tetrahydrofolate reductase (MTHFR) C677T, beta-fibrinogen -455G>A and factor (FXIII) V34L were significantly higher in patients with IS than in the subjects from the GP. No significant interaction was observed with sex. Conclusions: the present data argue that some gene variants have a role in IS and this appears to be an interesting possibility to be pursued in large population studies to help design specific strategies for IS prevention.

Introduction. Pregravid preparation plays a main role in solving issues with recurrent miscarriage and preterm delivery. Detection of etiologic factors of miscarriage with development of preventive strategies seems reasonable.Study objective was to optimize the assessment and treatment algorithms of threatening miscarriage in the I trimester of pregnancy with subchorionic hematoma formation.Materials and methods. 113 women with subchorionic hematoma were examined in gestational age 4 to 12 weeks. Monitoring of pregnancy till delivery was conducted.Results. The role of the combination of coagulation system genes polymorphisms (II and V coagulation factors, plasminogen activator inhibitor-1, methylenetetrahydrofolatereductase) and altered level of autoantibodies against thyroglobulin in increased probability of miscarriage was shown.Conclusion. Identification of high risk patients for pregnancy loss in the first trimester by the combination of coagulation system genes polymorphisms and antibody marker of thyroiditis together with a personified therapy approach contribute to the prolongation of pregnancy and reduce the frequency of repeated miscarriage.

Hemostatic abnormalities include both bleeding and thrombosis disorders. Adherence to most common guidelines for the diagnosis of thrombophilia is recommended especially in some developing countries. High level of orientation to thrombophilic disorders needs wide spectrum of knowledge about the causes, primary or secondary, investigations to most common risk factors, selecting candidates to investigations, in addition to covering the possibility of multifactorial background of disease. Limited data are available that focus on the thrombophilic disorders with imperfect diagnostic cooperation between clinical and laboratory aspects to reach the full picture of these hemostatic abnormalities. In this short review of literature, we considered the most important publications that assessed the inherited thrombophilia at levels of presentation, diagnosis, and management with focus on the practical side. The aim of this review is to summarize the most important aspects of the thrombophilia presentation, inherited causes, indications for testing, and investigations required for thrombophilic patients.

Although the relationship between venous thromboembolism (VTE) and cancer has been a subject of study, knowledge of the contribution of thrombophilia to thrombosis in patients with cancer is still very limited. The aim of this article is to collect present knowledge on the contribution of inherited thrombophilia to VTE in cancer patients. We performed a search in Google Scholar and PubMed and selected 21 from 76 returned articles. Then we made a narrative review of the selected articles. We describe 11 studies on the contribution of inherited thrombophilia to VTE in cancer patients in general and 10 on that contribution in specific types of cancer: 1 in colorectal cancer, 4 in breast cancer, 1 in gynecologic cancer and 4 in hematopoietic malignancies. All studies investigate the relation of factor V Leiden (FVL) to VTE, 13 that of the prothrombin G20210A mutation (PTG20210A) and 7 studies also investigate other inherited thrombophilias, such methylenetetrahydrofolate reductase gene mutations, although only 2 investigate the contribution of deficiencies of the natural anticoagulants. Studies are very heterogeneous, in design and sample size and conclusions differ considerably. There is no consensus on the contribution of inherited thrombophilia to VTE in cancer patients except for acute lymphoblastic leukemia in children. Probably, that contribution is not the same for all types of cancer and more studies are needed to bring more knowledge on this subject., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Venous thromboembolism (VTE) is a known situation of considerable mortality and morbidity and occurs due to the convergence of multiple acquired and genetic risk factors. In this study, we have comprehensively analyzed the effect of ABO blood groups and inherited thrombophilia factors [Protein C (PC), Protein S (PS), Antithrombin III (AT III), Activated Protein C Resistance (APCR) and Homocysteine (Hcy)] on 150 unprovoked VTE patients, comparing with normal healthy controls. ABO phenotyping was done using gel cards and thrombophilia workup done using standard kits on coagulation autoanalyzer. Non O blood group was significantly more frequent among cases than controls (77.3% vs. 62.7%) and had higher odds of VTE (OR = 2.03, 95%CI: 1.22–3.37). Positivity for at least one marker of thrombophilia was more in cases (40%) than controls (16%), and led to significantly higher odds (OR = 3.5, 95%CI: 2.03–6.04) of VTE. Deficiency of PS was the commonest thrombophilia abnormality. Combination of non O group with positivity for thrombophilia markers was also more among cases (OR = 5.67, 95%CI: 2.76–11.65). Highest odds of VTE in cases were associated with non O group in combination with increased Homocystein (OR = 10.8, 95%CI: 2.27–51.5). The study results show non O blood group and positivity for factors of inherited thrombophilia in cases impart higher odds of VTE individually. Also combination of both non O blood group and positivity for factors of inherited thrombophilia in cases further increases the odds of VTE. This awareness could assist physicians in identifying those at higher risk of VTE and tailor-made the thromboprophylaxis accordingly. [ABSTRACT FROM AUTHOR]

Objective: to study the prevalence of polymorphisms of the coagulation system genes and folate cycle in women with recurrent miscarriage (having two or more reproductive losses. Materials and methods. Carried out of molecular genetic study of 57 women with recurrent miscarriage and 35 patients without reproductive loss and having a history of at least one normally progressing pregnancy, culminating in the birth of a healthy term baby. Results. we have revealed a high incidence of MTHFR C677T, MTRR A66G, FGB G455A, ITGB3 T1565С gene polymorphisms. Conclusion. To prevent repeated reproductive losses in patients with an anamnesis of miscarriage, when other reasons are excluded, it is necessary to conduct a study of gene polymorphisms of coagulation system and folate cycle.