F2c.*C20209T mutation in patients with a history of thrombosis: A case report, retrospective 2 site-results and review of the literature.

INTRODUCTION: G20210A (c.*97G>A) prothrombin gene variant, found in white population has been associated with an increased risk of venous thromboembolism (VTE). Other rare polymorphisms in F2 gene (C20209T) have been reported, more rare and touching black people, but its potential association with VTE remain uncertain. METHODS: About a 69 years-old Caucasian woman presenting an unprovoked deep venous thrombosis of the leg, we analyzed retrospectively 25.000 thrombophilia tests on a 11-year period of time (2007-2018), at Nice and Marseille University Hospitals, and performed extensive review of the literature. RESULTS: Genetic determination included a similar PCR protocol and sequencing. Twenty-one heterozygous cases out of 25.585 determinations (0.08%) was found. The C20209T mutation detected in our Caucasian patient is rare, with a frequency that differed from what was reported in the previous literature, mainly in non-Caucasian patients (Africans, Africans-Americans, and Caribbeans). One hundred and thirteen patients with this mutation have been described in the literature, of which only one homozygous. CONCLUSION: This study is the most important on C20209T mutation performed at present, allowing to precise its frequency and its potential role in venous thromboembolism.

Coronary artery thromboembolism as a cause of myocardial infarction with non-obstructive coronary arteries (MINOCA).

Acute myocardial infarction (AMI) usually represents the clinical manifestation of atherothrombotic coronary artery disease (CAD) resulting from atherosclerotic plaque rupture. However, there are cases in which coronary angiography or coronary computed tomography angiography reveals patients with acute coronary syndrome with non-obstructive CAD. This clinical entity is defined as myocardial infarction with non-obstructive coronary arteries (MINOCA) and often considered as a clinical dynamic working diagnosis that needs further investigations for the establishment of a final etiologic diagnosis. The main causes of a MINOCA working diagnosis include atherosclerotic, non-atherosclerotic (vessel-related and non-vessel-related), and thromboembolic causes This literature review aimed to investigate the major thromboembolic causes in patients presenting with MINOCA regarding their etiology and pathophysiologic mechanisms, as well as diagnostic and treatment methods.

Impact of Inherited Thrombophilia in Women with Obstetric Antiphospholipid Syndrome: A Single-Center Study and Literature Review.

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.

Persistent Peril: Recurrent Deep Vein Thrombosis and Pulmonary Embolism in a Patient With Protein S Deficiency Despite Optimal Anticoagulation Therapies.

The clotting system has evolved as an adaptive mechanism to prevent blood loss during vascular damage. However, the intricate nature of the clotting cascade and the complexities of human life can sometimes lead to the unnatural activation of this delicate cascade. This can result in blood clot formation within the cardiovascular system, contributing to a wide range of pathological conditions. Abnormal intravascular coagulation most commonly occurs in the deep veins of the lower extremities, and can emboli to other organs, hence, it is termed "venous thromboembolism" (VTE). In this report, we introduce a challenging case of VTE that poses a dilemma for current medical management. The patient with possible protein S deficiency underwent various guideline-directed medical treatments, yet experienced recurrent VTE episodes, including deep vein thrombosis (DVT) and pulmonary embolism (PE), leading to hospital readmissions. This case report sheds light on our challenges in effectively treating VTE.

The genetic risk factors for cerebral venous thrombosis: a case-control study in a Chinese national comprehensive hospital.

BACKGROUND: About 13-25% of cerebral venous thrombosis (CVT) cases lack clear etiology, which may be associated with underlying genetic factors. This study aims to investigate genetic factors in CVT patients using whole exome sequencing (WES). METHODS: Thirty-eight CVT patients hospitalized underwent WES. 977 subjects with WES data from a community cohort study --the Shunyi cohort were as the control group. Using bioinformatics analysis, differential genes with rare damaging variants between two groups were filtered (P < 0.05). KEGG enrichment analysis was performed on the screened genes to identify pathways associated with CVT. RESULTS: Through analysis of medical history, routine tests, and imaging examinations, the etiology of 38 patients: 8 cases of antiphospholipid syndrome, 6 cases with hematologic diseases, 3 cases of protein C deficiency, and 2 cases of protein S deficiency. Five cases occurred during pregnancy or puerperium, and 3 cases had a history of oral contraceptive use, and so on. The etiology was unknown in 12 cases (31.6%), and the etiology of 4 patients were further clarified through WES: F9 c.838 + 1_838 + 16del, Hemizygote: F9 EX1-EX7 Dup; CBS c.430G > A, CBS c.949 A > G; F2 c.1787G > A; SERPINC1 c.409-11G > T. Comparing the WES data of two groups, a total of 179 different genes with rare damaging variants were screened (P < 0.05), with 5 genes of interest (JAK2, C3, PROC, PROZ, SERPIND1). Enrichment analysis of the 179 different genes revealed the complement and coagulation pathway and the mitogen activated protein kinases (MAPK) pathway were associated with CVT. CONCLUSION: For CVT patients with unknown etiology, WES could help identify the cause of CVT early, which is of great significance for treatment decisions and prognosis. In addition to the complement and coagulation pathway, MAPK pathway is associated with CVT, potentially related to platelet regulation and inflammatory response.

Recanalization of port-superior mesenteric vein thrombosis with long-term anticoagulant therapy after failed early anticoagulant therapy.

BACKGROUND: Anticoagulant therapy with heparin is the first-line treatment for acute mesenteric vein thrombosis and is effective in improving outcomes. Conversely, patients with failed early anticoagulant therapy occasionally develop bowel infarction requiring surgery. The efficacy of long-term anticoagulant therapy on recanalizing mesenteric vein thrombosis in patients with failed early anticoagulant therapy remains unclear. Herein, we report a patient who achieved recanalization of port-superior mesenteric vein thrombosis treated with anticoagulant therapy for 10 years after failed early anticoagulant therapy, followed by bowel resection. CASE PRESENTATION: A 38-year-old male patient visited an outpatient clinic due to acute exacerbation of abdominal pain that had persisted for a month. He was diagnosed with port-superior mesenteric vein thrombosis on contrast-enhanced computed tomography (CT) scan and was transferred to our institution. Although he presented with abdominal pain, his respiration and circulation were stable upon hospital arrival. Anticoagulant therapy with heparin was started, and the patient was admitted to the intensive care unit. However, the patient's abdominal pain worsened, and he began to develop signs of peritonitis. Repeat CT scan revealed bowel infarction. Thus, the patient underwent bowel resection 6 h after admission. The initial surgery was completed with open abdomen management. Bowel anastomosis was performed on the second-look surgery on the first postoperative day. Finally, the abdomen was closed on the third postoperative day after confirming the absence of bowel ischemia progression. The patient had prolonged impaired bowel function with paralytic ileus, but was discharged on the 60th postoperative day. He was then diagnosed with protein C and S deficiency based on the tests performed. Anticoagulant therapy with warfarin was initiated. He also received anticoagulant therapy in the outpatient setting. The patient's port-superior mesenteric vein thrombosis had improved gradually with warfarin during the follow-up period. At 10 years after surgery, total occlusion of the port-superior mesenteric vein was recanalized with improvement of the portal collateral vessels. In addition, no gastric or esophageal varices were observed. CONCLUSIONS: Long-term anticoagulation therapy could affect the recanalization of extensive thrombus in multiple segments in patients with mesenteric venous thrombosis.

Recurrent Pulmonary Embolism at High Altitude in a Mountaineer with Hereditary Thrombophilia.

Szymczak, Robert K., Magdalena Sawicka, and Malgorzata Jelitto. Recurrent pulmonary embolism at high altitude in a mountaineer with hereditary thrombophilia. High Alt Med Biol. 00:000-000, 2024.-It is speculated that high-altitude travel is an independent risk factor for thrombosis. Mountaineering-specific factors, such as hypoxia, cold, and immobilization, may interact with patient-specific risk factors and contribute to thrombus formation. We present the case of a mountaineer with hereditary thrombophilia who experienced recurrent pulmonary embolism during high-altitude expeditions.

The Roles of NOTCH3 p.R544C and Thrombophilia Genes in Vietnamese Patients With Ischemic Stroke: Study Involving a Hierarchical Cluster Analysis.

BACKGROUND: The etiology of ischemic stroke is multifactorial. Several gene mutations have been identified as leading causes of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary disease that causes stroke and other neurological symptoms. OBJECTIVE: We aimed to identify the variants of NOTCH3 and thrombophilia genes, and their complex interactions with other factors. METHODS: We conducted a hierarchical cluster analysis (HCA) on the data of 100 patients diagnosed with ischemic stroke. The variants of NOTCH3 and thrombophilia genes were identified by polymerase chain reaction with confronting 2-pair primers and real-time polymerase chain reaction. The overall preclinical characteristics, cumulative cutpoint values, and factors associated with these somatic mutations were analyzed in unidimensional and multidimensional scaling models. RESULTS: We identified the following optimal cutpoints: creatinine, 83.67 (SD 9.19) µmol/L; age, 54 (SD 5) years; prothrombin (PT) time, 13.25 (SD 0.17) seconds; and international normalized ratio (INR), 1.02 (SD 0.03). Using the Nagelkerke method, cutpoint 50% values of the Glasgow Coma Scale score; modified Rankin scale score; and National Institutes of Health Stroke Scale scores at admission, after 24 hours, and at discharge were 12.77, 2.86 (SD 1.21), 9.83 (SD 2.85), 7.29 (SD 2.04), and 6.85 (SD 2.90), respectively. CONCLUSIONS: The variants of MTHFR (C677T and A1298C) and NOTCH3 p.R544C may influence the stroke severity under specific conditions of PT, creatinine, INR, and BMI, with risk ratios of 4.8 (95% CI 1.53-15.04) and 3.13 (95% CI 1.60-6.11), respectively (Pfisher<.05). It is interesting that although there are many genes linked to increased atrial fibrillation risk, not all of them are associated with ischemic stroke risk. With the detection of stroke risk loci, more information can be gained on their impacts and interconnections, especially in young patients.

Patent Foramen Ovale Closure in Special Clinical Situations: More Questions Than Answers?

Patent foramen ovale (PFO) is a remnant of the foetal circulation resulting from incomplete occlusion of the septum primum and septum secundum. Although prevalent in about 25% of the population, it mainly remains asymptomatic. However, its clinical significance in situations such as cryptogenic stroke, migraine, and decompression illness (DCI) has been well described. Recent randomised clinical trials (RCTs) have demonstrated the efficacy of percutaneous PFO closure over pharmacological therapy alone for secondary stroke prevention in carefully selected patients. Notably, these trials have excluded older patients or those with concurrent thrombophilia. Furthermore, the role of closure in other clinical conditions associated with PFO, like decompression sickness (DCS) and migraines, remains under investigation. Our review aims to summarise the existing literature regarding epidemiology, pathophysiological mechanisms, optimal management, and closure indications for these special patient groups.

Patent foramen ovale closure in ischemic stroke patients with and without thrombophilia: a systematic review and meta-analyses.

Ischemic stroke patients with thrombophilia and patient foramen ovale (PFO) may have an increased risk of recurrent stroke and transient ischemic attack (TIA), and may benefit from PFO closure. However, screening for thrombophilia is not routinely performed and the impact of thrombophilia on prognosis after PFO closure is uncertain. We aim to compare the risk of recurrent stroke and TIA after PFO closure in patients with thrombophilia versus those without. We performed a systematic review and meta-analyses of the literature, with a comprehensive literature search performed on 12 January 2023. Studies comparing the outcomes of patients with and without thrombophilia after PFO closure were included. The primary outcome evaluated was a recurrence of acute cerebrovascular event (ACE), a composite of recurrent ischemic stroke and recurrent TIA. The secondary outcomes included recurrent ischemic stroke only or TIA only. A total of 8 cohort studies were included, with a total of 3514 patients. There was an increased risk of stroke/TIA in patients with thrombophilia compared to those without thrombophilia after PFO (OR: 1.42, 95% CI: 1.01-1.99, I2 = 50%). The association between risk of TIA only (OR: 1.36, 95% CI: 0.77-2.41, I2 = 0%) and stroke only (OR: 1.09, 95% CI: 0.54-2.21, I2 = 0%) with thrombophilia did not reach statistical significance. There is an increased risk of recurrent cerebral ischemia event in patients with thrombophilia compared to those without thrombophilia after PFO closure. Future large prospective studies are necessary to characterise the risk and benefits of PFO closure, as well as the appropriate medical treatment to reduce the risk of recurrent stroke and TIA in this high-risk population.

Unexplained massive pulmonary embolism in acromegaly patient: A case report.

Key Clinical Message: Our case highlights the importance of recognizing acromegaly as a potential risk factor for venous thromboembolism (VTE). Despite a thorough thrombophilia workup yielding unremarkable results, further research is warranted to elucidate the underlying mechanisms linking acromegaly and thrombophilia. This understanding will aid in improving risk assessment and management strategies for patients with acromegaly. Abstract: Acromegaly, a rare disorder characterized by excessive growth hormone secretion, is associated with various comorbidities including hypertension, diabetes mellitus, and obstructive sleep apnea. While previous studies have identified abnormalities in hemostatic factors in acromegaly patients, the association between acromegaly and venous thromboembolism (VTE) remains poorly understood. We present the case of a 36-year-old male with a history of acromegaly who presented with acute dyspnea, chest pain, and cough. Despite a prior trans-sphenoidal hypophysectomy, his acromegaly symptoms persisted. Upon evaluation, he was found to have bilateral pulmonary embolism. Thorough thrombophilia workup was unremarkable, suggesting acromegaly as a potential risk factor for VTE.

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.

Paternal thrombophilia and recurrent implantation failure: an exploratory case-control study.

OBJECTIVE: Many pieces of literature have reported that inherited and acquired thrombophilia might be a risk factor for recurrent implantation failure (RIF), however, most studies have only focused on RIF patients and not their male partners. We studied the possible association of paternal thrombophilia with RIF risk. METHODS: Forty-two male partners aged 20-45 suffered from RIF compared with 42 males from couples with at least one successful pregnancy. All participants were investigated for thrombophilia markers. RESULTS: The prevalence of coagulation Factor V activity was significantly higher in the case group (42.9%) than in the control group (16.7%) (p=0.008) (OR=3.75; 95% CI, 1.38, 10.12). The prevalence of protein C and protein S deficiencies in RIF patients were 4.8% and 2.4%, respectively, and 0% in the controls. The prevalence of antithrombin III (ATIII) deficiency was significantly higher in the case group (19%) than in the control group (2.4%) (p=0.01). None of MTHFR C677T and MTHFR A1298C were statistically significant between the two groups. Combined thrombophilia was 45.2% in the men of the RIF group when compared with the control, 14.2% (p=0.001) (OR = 4.95; 95% CI, 1.75-13.86). CONCLUSIONS: Paternal thrombophilia may be related to recurrent implantation failure, so evaluation of this factor in RIF patients could be used to identify relevant risk groups and may help in the proper management of these cases to enhance the chance of implantation.

Systematic review and meta-analysis of association between plasminogen activator inhibitor-1 4G/5G polymorphism and recurrent pregnancy loss: an update.

BACKGROUND: We conducted this systematic review and meta-analysis to better understand the association between rs1799762 PAI-1 gene polymorphism and the risk of RPL. METHODS: A systematic search for studies that assessed the association between PAI-1 4G/5G polymorphism and RPL risk published in search sources, PubMed/Medline, ISI Web of Knowledge, Scopus, and Google Scholar till January 2024 was conducted. RESULTS: There were 23 case-control studies in total, with a high degree of statistical heterogeneity among them which indicated the need for subgroup analysis. We found a significant positive association between the risk of RPL and 4G/4G PAI-1 (OR: 2.57; 95% CI: 1.69-3.90), likewise 4G/5G (OR: 2/02 95% CI: 1.39-2.92) and mixed genotype (4G/4G+4G/5G) (OR: 2.31 95% CI: 1.81-2.93). Considering the ethnicity, the 4G/4G polymorphism is significantly associated with Asian descent (OR: 2.10; CI: 1.65-2.69) while the strong association (OR: 6.47; CI: 3.23-12.97) observed in the Greater Middle East descent is not statistically significant (P=0.16). PAI-1 4G/5G polymorphism association with RPL was only significant in Greater Middle East descent (OR: 2.93; CI: 2.41-3.56), and mixed genotype was significantly associated with RPL in Asian (OR: 2.37; CI: 1.55-3.61), Greater Middle East (OR: 3.01; CI: 2.16-4.19), and European populations (OR: 1.38; CI: 0.91-2.10). The association between RPL and PAI-1 4G/4G was significant for RPLs both under 12 weeks (OR: 1.82; 95% CI: 1.34-2.47), and under 24 weeks (OR: 1.46; 95% CI: 1.11-1.92), while considering heterozygote form the association was only significant for RPLs under 24 weeks (OR: 1.91; 95% CI: 1.58-2.31). Regarding the mixed genotype, there is a significant positive association between PAI-1 and RPL for RPLs under 12 weeks (OR: 2.09; 95% CI: 1.49-2.93), and under 24 weeks (OR: 2.10; 95% CI: 1.52-2.92). CONCLUSIONS: Our findings indicate a significant association between the rs1799762 PAI-1 polymorphism and the risk of RPL.

Staphylococcus Scalded Skin Syndrome-Induced Thrombosis Leading to Free Flap Complications: A Case Report and Review.

Staphylococcal scalded skin syndrome (SSSS) is a clinical term used for a spectrum of blistering skin conditions induced by the epidermolytic toxins of the Staphylococcus aureus bacteria. The complications of SSSS include thrombosis; however, the pathophysiology of this is still poorly understood. We present a case of free anterolateral thigh (ALT) flap failure in a patient as a result of widespread flap thrombosis associated with staphylococcal scalded skin syndrome (SSSS). This is the first reported case of free flap failure associated with SSSS. Free flap failure due to acquired prothrombotic conditions, such as infection, is a rare and potentially under-reported phenomenon. This article aims to further explore the role of both thrombophilias and provoked thrombotic events in free flap failure. A review of the literature will also be presented, and cases of free flap failure in patients with infection-induced vascular complications will be summarised.

Enhancing Thrombophilia Risk Prediction Through AI-Based Methodologies.

Thrombophilia, a predisposition to thrombosis, poses significant diagnostic challenges due to its multi-factorial nature, encompassing genetic and acquired factors. Current diagnostic paradigms, primarily relying on a combination of clinical assessment and targeted laboratory tests, often fail to capture the complex interplay of factors contributing to thrombophilia risk. This paper proposes an innovative artificial intelligence (AI)-based methodology aimed to enhance the prediction of thrombophilia risk. The designed multidimensional risk assessment model integrates and elaborates through AI a comprehensive collection of patient data types, including genetic markers, clinical parameters, patient history, and lifestyle factors, in order to obtain advanced and personalized explainable diagnoses.

The Etiology of the Thrombotic Phenomena Involved in the Process of Coronary Artery Disease-What Is the Role of Thrombophilic Genes in the Development of This Pathology?

Cardiovascular diseases, among which includes coronary artery disease, represent one of the most important causes of mortality and morbidity worldwide. Research aimed at determining the risk factors involved recognizes a group of "traditional" risk factors, but also more recent studies identified over 100 "novel" ones which may have a role in the disease. Among the latter is the thrombophilia profile of a patient, a pathology well-established for its involvement in venous thromboembolism, but with less studied implications in arterial thrombosis. This paper reviews the literature, explaining the pathophysiology of the thrombophilia causes associated most with coronary thrombosis events. Results of several studies on the subject, including a meta-analysis with over 60,000 subjects, determined the significant involvement of factor V Leiden, prothrombin G20210A mutation, plasminogen activator inhibitor-1 and antiphospholipid syndrome in the development of coronary artery disease. The mechanisms involved are currently at different stages of research, with some already established and used as therapeutic targets.

The risk profiles of pregnancy-related cerebral venous thrombosis: a retrospective study in a comprehensive hospital.

OBJECTIVES: To investigate the risk factors and underlying causes of pregnancy-related cerebral venous thrombosis (PCVT). METHODS: A retrospective cohort of 16 patients diagnosed with CVT during pregnancy and postpartum (within six weeks after delivery) in a comprehensive hospital in China between 2009 and 2022 were carefully reviewed, focusing on demographic, clinical, and etiological characteristics, especially underlying causes. We matched 16 PCVT patients with 64 pregnant and puerperal women without PCVT to explore risk factors and clinical susceptibility to PCVT. RESULTS: PCVT occurred commonly during the first trimester (43.75%) and the puerperium (37.5%). The frequency of anemia, thrombocytosis and thrombocytopenia during pregnancy, dehydration, and pre-pregnancy anemia was significantly higher in women with PCVT than in those without PCVT (P < 0.05). Among the 16 patients, five were diagnosed with antiphospholipid syndrome and one was diagnosed with systemic lupus erythematosus. Three patients had distinct protein S deficiency and one had protein C deficiency. Whole Exome Sequencing (WES) was performed for five patients and revealed likely pathogenic mutations associated with CVT, including heterozygous PROC c.1218G > A (p. Met406Ile), heterozygous PROS1 c.301C > T (p. Arg101Cys), composite heterozygous mutation in the F8 gene (c.144-1259C > T; c.6724G > A (p. Val2242Met)) and homozygous MTHFR c.677C > T (p. Ala222Val). CONCLUSIONS: The occurrence of anemia, thrombocytopenia and thrombocytosis during pregnancy, dehydration and pre-pregnancy anemia suggested a greater susceptibility to PCVT. For confirmed PCVT patients, autoimmune diseases, hereditary thrombophilia, and hematological disorders were common causes. Screening for potential etiologies should be paid more attention, as it has implications for treatment and long-term management.