Thrombophilic Risk Research Articles

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.

Thrombosis Rates and Genetic Thrombophilia Risk Among Patients With Advanced Germ Cell Tumors Treated With Chemotherapy

IntroductionMen with advanced germ cell tumors (GCT) treated with chemotherapy are at high risk of venous thromboembolism (VTE). Predictors of VTE may identify patients who would benefit from prophylactic anticoagulation. Patients and MethodsMen with advanced GCT (Stage IS, II, III) treated with chemotherapy were identified at 2 centers. High genomic risk was defined from a 5 single nucleotide polymorphism (SNP) germline panel. Logistic regression was used to evaluate the impact of genomic risk on VTE within 6 months of chemotherapy initiation. Orthogonal Projection to Latent Structures Discriminant Analysis (OPLS-DA) was used to build models to predict VTE based on clinical variables and an 86 SNP panel. ResultsThis 123-patient cohort experienced a VTE rate of 26% with an incidence of high genomic risk of 21%. Men with high genomic risk did not have a significantly higher VTE rate (31%, 8/26) than men with low genomic risk (25%, 24/97), unadjusted OR 1.4 (95% CI 0.5-3.5, P = .54). Incorporation of clinical variables (Khorana score, N3 status and elevated LDH) resulted in adjusted OR 2.1 (95% CI 0.7-6.5, P = .18). A combined model using clinical variables and 86 SNPs performed similarly (AUC 0.77) compared to clinical variables alone (AUC 0.72). ConclusionsA previously established 5-SNP panel was not associated with VTE among patients with GCT receiving chemotherapy. However, multivariable models based on clinical variables alone warrant further validation to inform prophylactic anticoagulation strategies.

Inherited thrombophilia gene mutations and risk of venous thromboembolism in patients with cancer: A systematic review and meta-analysis.

In the general population, individuals with an inherited thrombophilia have a higher risk of thrombosis, but the effect of inherited thrombophilia on the risk of cancer-associated venous thromboembolism (VTE) remains controversial. Our objective was to determine the risk of VTE in cancer patients with inherited thrombophilia. We conducted a systematic review and meta-analysis of studies reporting on VTE after a cancer diagnosis in adult patients who were tested for inherited thrombophilia. In September 2022, we searched Medline, EMBASE, and Cochrane Central. Two reviewers screened the abstracts/full texts and assessed study quality using the Quality in Prognostic Studies tool. We used Mantel-Haenszel random-effects models to estimate pooled odds ratios (OR) of VTE and 95% confidence intervals (95%CI). We included 37 and 28 studies in the systematic review and meta-analysis, respectively. Most studies focused on specific cancer types and hematologic malignancies were rare. The risk of VTE was significantly higher in cancer patients with non-O (compared with O) blood types (OR: 1.56 [95% CI: 1.28-1.90]), Factor V Leiden, and Prothrombin Factor II G20210A mutations compared with wild types (OR: 2.28 [95% CI: 1.51-3.48] and 2.14 [95% CI: 1.14-4.03], respectively). Additionally, heterozygous and homozygous methylenetetrahydrofolate reductase C677T had ORs of 1.50 (95% CI: 1.00-2.24) and 1.38 (95% CI: 0.87-2.22), respectively. Among those with Plasminogen-Activator Inhibitor-1 4G/5G, Vascular Endothelial Growth Factor (VEGF) A C634G, and VEGF C2578A mutations, there was no significant association with VTE. In conclusion, this meta-analysis provided evidence that non-O blood types, Factor V Leiden, and Prothrombin Factor II G20210A mutations are important genetic risk factors for VTE in cancer patients.

UTERINE ARTERIES DOPPLER VELOCIMETRY IN A PREGNANT WOMAN WITH GENETIC RISK FOR THROMBOPHILIA

The objective of this study was to follow the velocimetry changes in the uterine arteries and the fetal growth curves in a pregnant woman with a genetic risk for thrombophilia. The patient received aspirin until 25 weeks of gestation, when the hematologist decided on thromboembolism prophylaxis with heparin until 24 hours before delivery. The velocimetry indices in uterine arteries and the umbilical artery were within normal limits until the end of the pregnancy. During the follow-up, the coagulation tests remained within normal parameters for the pregnancy period and fetal growth was within normal limits. The birth was done by cesarean section at 38 weeks of gestation. The fetal weight at birth was 3190 grams and the Apgar score was 8/9.

The risk for venous thromboembolism and cardiometabolic disorders in offspring from thrombosis-prone pedigrees

BackgroundMost family studies on venous thromboembolism (VTE) have focused on first-degree relatives. ObjectivesWe took a pedigree-based approach and examined the risk of VTE and cardiometabolic disorders in offspring from extended pedigrees according to the densities of VTE in pedigrees. MethodsFrom the Swedish population, we identified a total of 482 185 pedigrees containing a mean of 14.2 parents, aunts/uncles, grandparents, and cousins of a core full sibship that we termed the pedigree offspring (n = 751 060). We then derived 8 empirical classes of these pedigrees based on the density of cases of VTE. The risk was determined in offspring for VTE and cardiometabolic disorders as a function of VTE density in their pedigrees. Bonferroni correction for multiple comparisons was performed. ResultsVTE was unevenly distributed in the population; the Gini coefficient was 0.59. Higher VTE density in pedigrees was associated in the offspring with a higher risk of different VTE manifestations (deep venous thrombosis, pulmonary embolism, pregnancy-related VTE, unusual thrombosis, and superficial thrombophlebitis), thrombophilia, and lower age of first VTE event. Moreover, VTE density in pedigrees was significantly associated in the offspring with obesity, diabetes, gout, varicose veins, and arterial embolism and thrombosis (excluding brain and heart). No significant associations were observed for retinal vein occlusion, hypercholesterolemia, hypertension, coronary heart disease, myocardial infarction, ischemic stroke, atrial fibrillation, heart failure, primary pulmonary hypertension, cerebral hemorrhage, aortic aneurysm, peripheral artery disease, and overall mortality. ConclusionOffspring of pedigrees with a high density of VTE are disadvantaged regarding VTE manifestations and certain cardiometabolic disorders.

Evaluation of an Explainable Tree-Based AI Model for Thrombophilia Diagnosis and Thrombosis Risk Stratification

Background: Thrombophilia diagnosis can often be a convoluted process involving collection and analysis of clinical data, specialized laboratory testing, and high-level decision-making. This is inherently subjective due to differences in the clinical practice philosophy of each individual practitioner and can vary depending on institutional guidelines and available resources. Patient care and clinical outcomes may be affected as a result, which in turn provides a potential opportunity for optimization of thrombophilia diagnosis using AI. Methods: This retrospective study evaluated the utility and effectiveness of an AI-powered algorithm (XGBoost) programmed to replicate the process of thrombophilia diagnosis. A total of 256 patients were referred by their clinician for thrombophilia evaluation at our ambulatory coagulation clinic between November 2019 and February 2023 and clinical and laboratory data were collected from the electronic medical record. Thrombophilia diagnosis was established (or ruled out) on the basis of the patients' personal and family history of thrombosis as well as according to the results of thrombophilia testing including established acquired and inherited thrombophilia risk factors. The XGBoost, a gradient boosting algorithm for supervised learning, was used to perform a randomized search over a predefined set of tree parameters and to find a well-performing configuration on the data using cross-validation. The dataset contained 12 clinical data parameters and 26 laboratory data parameters. The target variable was two-dimensional, consisting of the thrombophilia probability score and thrombophilia risk factors. Thrombophilia probability scores were calculated based on clinical data from the following criteria: one point assigned each for a) spontaneous thrombotic event; b) mild risk situation; c) recurrent thrombosis; d) atypical thrombosis localization; e) age <50 years at the time of first thrombosis; f) family history of thrombosis and/or first degree relative with an established thrombophilia diagnosis. A probability score of 0 points corresponded to “unlikely thrombophilia”; 1-2 points “thrombophilia cannot be excluded”; 3 points “likely thrombophilia”; and 4+ points “most likely thrombophilia”. Thrombophilia risk factors were categorized by a scale of 0-3 indicating no risk (0), low risk (1), intermediate risk (2), and high risk (3). Results: Six patients were excluded from analysis due to lack of availability of sufficient clinical data. Clinical and laboratory data from the remaining 250 patients were thus included in the XGBoost analysis. The resulting trees and associated feature importance rankings revealed decisive factors for the detection of thrombophilia and suggested modified thresholds (e.g. age at the first occurrence of thrombosis increased from 50 years to 51.5 years) for an objective and standardized diagnostic procedure. The relative contribution of each clinical and laboratory feature to overall performance of the algorithm is shown in the Figure. The dataset was divided into three subsets: 200 train data, 25 validation data, and 25 test data, ensuring a representative distribution across the evaluation process. The model ultimately showed a sensitivity of 100% and a specificity of 100% for the thrombophilia probability score, and a sensitivity of 75% and specificity of 98% for the thrombophilia risk factors (Table). Conclusion: These results highlight the utility of tree-based AI models to support the objective and complex diagnosis of thrombophilia and thrombosis risk stratification. Furthermore, medical professionals can gain helpful insights from this AI-powered decision-making process due to the explainable nature of the model. We expect that the algorithm will show a higher sensitivity and specificity for the thrombophilia risk factors when we repeat the tests with a larger data set, which is currently ongoing.

Inherited Thrombophilia Gene Mutations and Risk of Venous Thromboembolism in Cancer: A Systematic Review and Meta-Analysis

Inherited thrombophilia and cancer are both recognized risk factors for venous thromboembolism (VTE). In the general population, the risk of thrombosis is increased in patients with inherited thrombophilia, but the role of inherited thrombophilia on the risk of cancer-associated VTE remains controversial. The objective of this study was to summarize and determine whether cancer patients with inherited thrombophilia gene mutations have an increased risk of developing VTE. We conducted a systematic literature search in Medline, EMBASE and Cochrane Central databases, as well as references of included studies from inception until September 26 th 2022. We included observational (cohort or case-control) and interventional studies comprising of human adult cancer patients who were tested for any inherited thrombophilia gene mutation. The outcome was objectively confirmed symptomatic or asymptomatic first VTE (upper or lower limbs deep vein thrombosis, pulmonary embolism, and/or splanchnic or cerebral vein thrombosis) occurring after a cancer diagnosis. Two reviewers independently screened the titles/abstracts and full texts of all potentially eligible articles. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using Mantel-Haenszel random-effects models. We used the Quality in Prognostic Studies (QUIPS) risk of bias tool to assess study risk of bias. A total of 4274 studies were screened for eligibility. Thirty-six studies involving different cancer types and treatments were included in the systematic review, of which 28 studies were included in the meta-analysis (Figure 1). Among studies included in the meta-analysis, 9 studies included various cancer types while the remaining 19 studies were in selected cancer types (3 lung, 3 myeloma, 2 brain, 2 bladder, 2 breast, 2 gynecologic, 1 testicular, 1 lung or gastrointestinal, 1 pancreas, 1 colorectal and 1 breast or gastrointestinal). There were 18 cohort (11 prospective and 7 retrospective) and 10 case-control studies. The following seven inherited thrombophilia gene mutations were meta-analyzed: ABO blood type, Factor V Leiden (FVL), Methylenetrahydrofolate Reductase (MTHFR) C677T, Plasminogen-Activator Inhibitor-1 (PAI-1) 4G/5G, Prothrombin Factor II G20210A, Vascular Endothelial Growth Factor (VEGF) C634G and VEGF C2578A. In cancer patients with non-O blood types, FVL and Prothrombin Factor II G20210A mutations, the risk of VTE was significantly increased with ORs of 1.56 (95% CI: 1.28-1.90), 2.28 (95% CI: 1.51-3.48) and 2.14 (95% CI: 1.14-4.03), respectively, compared to patients with O blood and wild types (Table 1). In addition, heterozygous and homozygous MTHFR C677T were associated with ORs of 1.50 (95% CI: 1.00-2.24) and 1.38 (95% CI: 0.87-2.22), respectively (Table 1). Among those with heterozygous and homozygous PAI-1 4G/5G, VEGF C634G and VEGF C2578A, no significant increase in the odds of VTE and moderate to considerable heterogeneity were observed (Table 1). Few studies had low risk of bias, except for studies of ABO blood group, which predominantly had low risk of bias. In conclusion, this meta-analysis provides evidence that non-O blood type, FVL, Prothrombin Factor II G20210A and heterozygous MTHFR C677T significantly increase the risk of VTE in cancer patients. However, there is moderate to high risk of bias in the currently available data, further well-designed studies are needed.

Ocular venous occlusion in pediatrics: Should thrombophilia investigation and anticoagulant treatment be initiated?

Retinal vein occlusion (RVO) and superior ophthalmic vein thrombosis (SOVT) are rare diseases in the pediatric population; however, the ophthalmic and neurologic morbidity are significant. As published data are scarce for these conditions, we present our experience with pediatric ocular venous thrombosis in four patients, and discuss recommended management for evaluation and treatment. We suggest performing thrombophilia workup for all pediatric patients with RVO or SOVT. In patients with thrombophilia risk factors or patients with additional thrombi, we highly recommend initiating anticoagulation therapy. There is a need for more research in order to determine the optimal management strategy.

Contribution of genotypes in Prothrombin and Factor V Leiden to COVID-19 and disease severity in patients at high risk for hereditary thrombophilia.

Thrombotic and microangiopathic effects have been reported in COVID-19 patients. This study examined the contribution of the hereditary thrombophilia factors Prothrombin (FII) and Factor V Leiden (FVL) genotypes to the severity of COVID-19 disease and the development of thrombosis. This study investigated FII and FVL alleles in a cohort of 9508 patients (2606 male and 6902 female) with thrombophilia. It was observed that 930 of these patients had been infected by SARS-CoV-2 causing COVID-19. The demographic characteristics of the patients and their COVID-19 medical history were recorded. Detailed clinical manifestations were analyzed in a group of cases (n = 4092). This subgroup was age and gender-matched. FII and FVL frequency data of healthy populations without thrombophilia risk were obtained from Bursa Uludag University Medical Genetic Department's Exome Databank.The ratio of males (31.08%; 27.01%) and the mean age (36.85 ± 15.20; 33.89 ± 14.14) were higher among COVID-19 patients compared to non-COVID-19 patients. The prevalence of FVL and computerized tomography (CT) positivity in COVID-19 patients was statistically significant in the thrombotic subgroup (p < 0.05). FVL prevalence, CT positivity rate, history of thrombosis, and pulmonary thromboembolism complication were found to be higher in deceased COVID-19 patients (p < 0.05). Disease severity was mainly affected by FVL and not related to genotypes at the Prothrombin mutations. Overall, disease severity and development of thrombosis in COVID-19 are mainly affected by the variation within the FVL gene. Possible FVL mutation should be investigated in COVID-19 patients and appropriate treatment should be started earlier in FVL-positive patients.

Investigating protein C and S levels in pregnant women with recurrent early pregnancy loss versus normal pregnancy.

Miscarriage in the first and second trimesters of pregnancy is very common, and coagulopathy can be a contributing factor. Protein C and S deficiency are rare, inherited disorders that can increase the risk of thrombophilia. Women with these deficiencies have a higher risk of developing blood clots in the placenta, which can lead to placental insufficiency and, ultimately, to a miscarriage. We aimed to compare the levels of protein C and protein S in pregnant females with recurrent first and second-trimester pregnancy loss and normal pregnant females. We performed a detailed history, examination, and various lab tests on a cohort of 40 females with a history of recurrent first and second-trimester abortions visiting an outpatient clinic at a multi-specialty hospital in Kashmir, India. All the findings were compared with 40 women with normal pregnancies. 10% of the participants had low protein C and S levels (P=0.277), out of whom 75% (p<0.001) had intrauterine growth retardation (IUGR) on ultrasound with 67% (p<0.001) having reduced doppler flow in the umbilical artery. 0.05% of participants had isolated protein S deficiency with no concomitant IUGR seen. Patients with protein C and S deficiencies were treated with heparin and progesterone and followed up for pregnancy outcomes. Screening for protein C and S deficiency is mandatory in all cases of recurrent pregnancy loss. Treatment with low molecular weight heparin and progesterone should be initiated to ensure good fetal outcomes and prevent post-partum/postoperative catastrophic venous thromboembolism events.

Predicting Thrombophilia using Neural Networks and Decision Trees

The occurrence of thrombophilia during pregnancy results from a complex interaction of inherited and acquired factors, followed by an increase in blood coagulation and subsequent placental ischemic conditions. In this paper, a novel method is presented, whose aim is early identification of the risk of developing thrombophilia in pregnancy. The proposed method is based on machine learning algorithms: decision trees and neural networks. The research uses a dataset consisting of demographic, lifestyle, and clinical information from 35 pregnant women (22 healthy and 13 with thrombophilia). The results show the effectiveness of decision trees and neural networks in accurately predicting the risk of developing thrombophilia in pregnancy. The implications of this research are significant for clinical practice and it provides a valuable tool for early identifying women with high risk of thrombophilia in pregnancy that can enable improvement of preventive measures, such as lifestyle modifications and the use of therapeutic prophylaxis. In conclusion, this paper demonstrates the potential of machine learning algorithms for the prediction of thrombophilia in pregnancy. By combining advanced computational techniques with comprehensive datasets, we can enhance our understanding of thrombophilia in pregnancy risk factors and improve patient outcomes through personalized preventive measures.

Validity of CHA2DS2-VASc score in patients with malignancies

Abstract Introduction Anticoagulation for patients with atrial fibrillation/flutter (AF) after risk stratification based on CHA2DS2-VASc score (congestive heart failure, hypertension, age group, Diabetes Mellitus, prior stroke, transient ischemic attack or thromboembolism, prior heart attack, peripheral artery disease or aortic plaque and patient's gender) has been the gold standard practice to prevent cerebrovascular accidents (CVA). Purpose Since patients with malignancies are at increased risk of thrombophilia, we tried to study if cancer patients with atrial fibrillation are at increased risk for CVA beyond what should be expected based on their comorbidities. Methods We used the Nationwide Readmissions Database (NRD) database for the years 2016–2019. First, we extracted all cases with a diagnosis of atrial fibrillation/flutter. Exclusion criteria included patients younger than 18-year-old. We studied the comorbidities and calculated CHA2DS2-VASc score. Then, we compared the risk for admission with an acute CVA in patients with and without any diagnosis of malignancies (solid cancer, leukemia, lymphoma or metastatic disease). Patients with carcinoma in situ were considered non-cancer patients. Corrected logistic regression and Chi-square tests using survey procedures in SAS 8.1 were applied to accommodate for complex sampling (Rao-Scott design). Results We identified 1,748,619 weighted admissions with AF equally distributed across the years. 5% were patients with malignancies. The mean age was 74-year-old for cancer patients and 71-year-old for non-cancer patients with quite equal gender distribution (43–49% were female). Patients with a diagnosis of cancer has high inpatient mortality (13%). Every additional point in CHA2DS2-VASc score was associated with increased odds of admission with CVA. Having a diagnosis of cancer was not associated with increased odds of admission with CVA (odd ratio for 95% confidence interval 1.0 [0.95–1.1]). Patients with history of VTE (assuming they are on anticoagulation) or who are on chronic anticoagulation have lower risk of admission with acute CVA if they have AF. Conclusions Although malignancies is associated with hypercoagulable status including higher risk for stroke, deep venous thrombosis and pulmonary embolism, our cross-sectional study indicates that CHA2DS2-VASc score is still a reliable tool for risk stratification in patients with atrial fibrillation. More longitudinal studies are needed. Funding Acknowledgement Type of funding sources: None.

Upregulation of cytokine signalling in platelets increases risk of thrombophilia in severe COVID-19 patients

Abnormal coagulation dynamics, including disseminated intravascular coagulopathy, pulmonary embolism, venous thromboembolism and risk of thrombosis are often associated with the severity of COVID-19. However, very little is known about the contribution of platelets in above pathogenesis. In order to decipher the pathophysiology of thrombophilia in COVID-19, we recruited severely ill patients from ICU, based on the above symptoms and higher D-dimer levels, and compared these parameters with their asymptomatic counterparts. Elevated levels of platelet-derived microparticles and platelet-leukocyte aggregates suggested the hyperactivation of platelets in ICU patients. Strikingly, platelet transcriptome analysis showed a greater association of IL-6 and TNF signalling pathways in ICU patients along with higher plasma levels of IL-6 and TNFα. In addition, upregulation of pathways like blood coagulation and hemostasis, as well as inflammation coexisted in platelets of these patients. Further, the increment of necrotic pathway and ROS-metabolic processes in platelets was suggestive of its procoagulant phenotype in ICU patients. This study suggests that higher plasma IL-6 and TNFα may trigger platelet activation and coagulation, and in turn aggravate thrombosis and hypercoagulation in severe COVID-19 patients. Therefore, the elevated IL-6 and TNFα, may serve as potential risk factors for platelet activation and thrombophilia in these patients.

Genetic markers for inherited thrombophilia related pregnancy loss and implantation failure in Indian population – implications for diagnosis and clinical management

Aim The biology of recurrent pregnancy loss and recurrent implantation failure (RPL-RIF) is complex with multi-factorial etiology, with defective thrombosis being one of the most important and highly prevalent causes. The role of several thrombophilia related genes and variants associated with RPL-RIF is widely reported, and this study aimed to identify the risk associated with these genes in the Indian population. Methods Next generation sequencing (NGS) was employed for the current study. NGS enables sequencing of multiple genes, identification of new variants, and establishment of genetic correlations with reproductive failure in diverse population groups. The present NGS based study evaluates association of twenty-nine genotypes of ten coagulation pathway genes (F2, F5, F13, MTR, MTRR, MTHFR, ANXA5, PROZ, SERPINE1 and VEGFA) with RPL-RIF in 540 female subjects − 474 patients with early recurrent pregnancy loss, late pregnancy loss, pregnancy complications in late gestation and recurrent implantation failure, with 66 controls. Results The results emphasize inclusion of genotypes of seven thrombophilia genes (MTHFR, MTRR, MTR, ANXA5, PROZ, SERPINE1, VEGFA) for diagnosis of inherited thrombophilia risk for RPL-RIF in Indian population, as against the common practice of testing limited to F2, F5 and MTHFR genes. Conclusion Deriving risk magnitude from Combined Risk Analysis and interpretation of high-risk haplotypes are crucial components for evidence based personalized management such as selection of drugs and dosage, and prenatal or pre-implantation recommendations, for high-risk patients in fertility and obstetric clinics.

Thrombotic Disorders

The three main elements in the pathophysiology of thrombosis are endothelial injury, a decrease in blood flow, and an imbalance between procoagulant and anticoagulant factors. The latter element can be either hereditary (e.g., antithrombin deficiency) or acquired (e.g., antiphospholipid syndrome). This review details the assessment of patients with thrombotic disorders, hereditary and acquired hypercoagulable states, and the management of venous thromboembolism. Figures show how the degradation of thrombin-activated factor V Leiden by activated protein C (APC) is significantly slower than that of normal activated factor V (factor Va), leading to enhanced thrombin generation; how normal factor V serves as a cofactor of APC in the inhibition of factor VIIIa, whereas factor V Leiden has a poor cofactor function; and how IgG antibodies recognize platelet factor 4–heparin complexes in heparin-induced thrombocytopenia. Tables list inherited and acquired hypercoagulable states, questions for assessing thrombosis, screening tests for patients with suspected hypercoagulable states, clinical features that suggest thrombophilia, frequency and relative risk of venous thrombosis in selected hypercoagulable states, proposed clinical and laboratory criteria for antiphospholipid syndrome, the classification of antiphospholipid antibodies, the 4Ts scoring system for heparin-induced thrombocytopenia, and general guidelines for the management of patients with venous thromboembolism. This review contains 2 highly rendered figures, 9 tables, and 168 references.

Thrombotic Disorders

The three main elements in the pathophysiology of thrombosis are endothelial injury, a decrease in blood flow, and an imbalance between procoagulant and anticoagulant factors. The latter element can be either hereditary (e.g., antithrombin deficiency) or acquired (e.g., antiphospholipid syndrome). This review details the assessment of patients with thrombotic disorders, hereditary and acquired hypercoagulable states, and the management of venous thromboembolism. Figures show how the degradation of thrombin-activated factor V Leiden by activated protein C (APC) is significantly slower than that of normal activated factor V (factor Va), leading to enhanced thrombin generation; how normal factor V serves as a cofactor of APC in the inhibition of factor VIIIa, whereas factor V Leiden has a poor cofactor function; and how IgG antibodies recognize platelet factor 4–heparin complexes in heparin-induced thrombocytopenia. Tables list inherited and acquired hypercoagulable states, questions for assessing thrombosis, screening tests for patients with suspected hypercoagulable states, clinical features that suggest thrombophilia, frequency and relative risk of venous thrombosis in selected hypercoagulable states, proposed clinical and laboratory criteria for antiphospholipid syndrome, the classification of antiphospholipid antibodies, the 4Ts scoring system for heparin-induced thrombocytopenia, and general guidelines for the management of patients with venous thromboembolism. This review contains 2 highly rendered figures, 9 tables, and 168 references.

Venous Thromboembolism Post-COVID-19 Among Individuals with Sickle Cell Disease

Background: Individuals with sickle cell disease (SCD) are at risk of severe COVID-19 infection. Those with SCD are also known to be at risk of venous thromboembolism (VTE), with numerous mechanistic pathways likely at interplay. In general, prior studies indicate that COVID-19 infection is associated with a thromboembolic risk. However, it is unknown if COVID-19 infection increases the already high risk of VTE for individuals with SCD. Given the preexisting risk for thrombophilia associated with SCD, we hypothesized that COVID-19 infection would further increase the risk of a venous thromboembolic event. In this study, we leverage electronic health record data to determine, at a population level, whether individuals with SCD hospitalized for COVID-19 have higher VTE rates when compared to hospitalization for any other cause.Method: Using electronic health record data from a multisite research network, TriNetX (years 2010 - 2020) we identified two mutually exclusive cohorts of individuals with SCD between Jan 20, 2020 - Dec 31, 2020: 1) those with hospitalizations related to a diagnosis of COVID-19 and 2) those with hospitalization for other causes. COVID-19 related hospitalizations were defined as admissions occurring within a month of COVID-19 diagnosis. Overall, individuals were considered to have SCD if they had 3 or more instances of ICD coding for SCD during the time frame of years 2010 - May 20, 2021 and did not have any ICD code for sickle cell trait. The outcome of interest was VTE, which included either deep venous thrombosis (DVT), pulmonary embolism (PE) or both. We determined the VTE rates at 1 month, 3 months and 6 months post hospitalization. The VTE rates between the two groups were compared using measures of risk difference and risk ratios, along with the respective 95% confidence intervals. We also matched the groups using propensity scores based on the prevalence of VTE prior to the index event of hospitalization and compared the respective outcomes.Results: Within the TriNetX network, there were 223 (59% females) individuals with SCD hospitalized due to COVID-19, and 3,591 (54% females) hospitalized for causes other than COVID-19. Individuals with SCD hospitalized for COVID-19 were older than individuals with SCD hospitalized for other causes (mean age: 29.4 yrs, sd = 16.4 vs 26.3 yrs, sd = 16.8, p value = 0.006). A significantly higher proportion of individuals hospitalized for COVID-19 had a prior history of portal vein thrombosis (4% vs ~0%, p-value <0.001), phlebitis/thrombophlebitis (4% vs 2%, p-value = 0.026) and other VTE (16% vs 10%, p-value = 0.008). There were no significant differences in sex or proportion of those with prior history of PE between the two groups. Table 1 shows the VTE rates observed in the two groups 1, 3 and 6 months post-hospitalization, respectively. VTE rates were higher among individuals with SCD hospitalized for COVID-19 than among individuals with SCD hospitalized for other causes. After matching for previous history of VTE, individuals with SCD hospitalized for COVID-19 infection did not have significantly higher VTE rates compared to individuals with SCD hospitalized for other causes at any of the time points evaluated.Conclusions: These data suggest that immunothrombosis accompanying SARS-COV-2 infection in individuals with SCD does not exacerbate the underlying known thrombophilia associated with SCD and provide support for current clinical guidelines in this population. Future prospective studies controlled for anticoagulant therapy exposures may provide more direct evidence to guide thromboprophylaxis in this unique population. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

P–358 Characteristics of patients with inherited thrombophilia and anticoagulant treatment in repeated implantation failure (RIF) and recurrent pregnancy loss (RPL)

Abstract Study question Do patients with inherited thrombophilia associated to RIF and RPL benefit from anticoagulant therapy? Summary answer Low molecular weight heparin (LMWH) in patients with medium and high risk of hereditary thrombophilia, associated with RIF could improve the reproductive prognosis. What is known already Thrombophilia is a condition that can be acquired and/or inherited genetically, that is characterized by the predisposition of patients to form venous and arterial thromboembolic events. Inherited thrombophilia has been associated with different complications during pregnancy, such as RPL. Genetic variants linked to hereditary thrombophilia can be classified by the thromboembolic risk: low (F12, F13A1, FGB), medium (MTHFR, PROCR, PROS1, SERPINC1, SERPINC1 PAI–1) and high (F2, F5, GP1BA), according to Martinez - Zamora. RPL rate may reduce with anticoagulant therapy. However, there is no conclusive evidence that prophylactic treatment improves the pregnancy rate in infertile women during IVF. Study design, size, duration We performed a prospective observational study which included patients referred to Ceras Clinic between March 2018 and March 2020, due to RPL (n = 38) and RIF (n = 40). All patients underwent genetic analysis for hereditary thrombophilia(F13, F2, F5, FGB, GP1BA, MTHFR C677T, MTHFR A1298C, PAI1,, PROCR, SERPIN1 CM910058, SERPIN 1 CM920113 ,F12, PROS1) by Sanger sequencing. The characteristics of anticoagulant therapy with clinical pregnancy rate and LBR were analyzed, using chi-squared test with STATA version 16. Participants/materials, setting, methods Patients have been included in the study according to their past medical history (stroke or myocardial infarction, personal or familiar history of deep vein thrombosis or pulmonary embolism, smoking, hormone replacement therapy), and reproductive history. Two groups were formed, the first group (n = 40) corresponds to RIF, and the second (n = 38), RPL. Genetic study of hereditary thrombophilia (11 genes) was performed to examine the genetic risk and assess the administration of anticoagulant therapy. Main results and the role of chance The prevalence of pathological antecedents in patients with RIF and RPL was not statistically significant (p &amp;gt; 0,05), indicating that the factors that contribute to poor reproductive outcomes in these two groups of patients could be similar. Patients with RIF had a medium risk of thrombophilia in 65%, followed by low risk in 32.5% and high risk in 2.5%. RPL group presented 78.95%, 15.79% and 5.26%, respectively. All patients with medium and high risk for trombophilia received anticoagulation. Clinical pregnancy rate (69.7%) and live birth rate (63.64%) were not statistically significant (p &amp;gt; 0.05) in RPL with anticoagulant therapy, compared to RPL group who did not received treatment (clinical pregnancy rate and live birth rate in 60%). Therefore, it is proposed that there may be other factors associated with abortions that require investigation. However, clinical pregnancy rate (77.14%) and live birth rate (74.29%) were statistically significant (p &amp;lt; 0.05) in RIF with anticoagulant therapy, compared to RIF group that did not received treatment (clinical pregnancy rate and live birth rate in 20%). This suggests that there could be a beneficial factor due to anticoagulation. Further studies are needed to assess that anticoagulant treatment could improve obstetric outcomes in patients with RIF and RPL. Limitations, reasons for caution The small number of patients assessed is the main limitation of this work. Larger studies must be designed to accurately determine participation of each mutation associated with recurrent implantation failure and recurrent pregnancy loss. The role of anticoagulant therapy should be evaluated in randomized clinical trials. Wider implications of the findings: Establishing a stronger evidence base implies that future studies should include large population groups. It is primordial to assess whether it is cost-effective to determine the risk of inherited thrombophilia in RIL and RPL, to increase the live birth rate by anticoagulant therapy. The information is controversial to this day. Trial registration number ‘not applicable’

Plasminogen Activator Inhibitor Type 1 (PAI-1) and Thrombophilia: A 10 Year Retrospective Review of Clinical Data at a Large Children's Hospital

Introduction: Plasminogen activator inhibitor type 1 (PAI-1) is the most important regulator of fibrinolysis. Elevated PAI-1 levels are reported to be prothrombotic and have been associated with cardiovascular disease, obesity and cancer. PAI-1 synthesis is regulated by insulin, glucocorticoids and cytokines like tumor necrosis factor-α. The single base pair guanine deletion 4G PAI-1 genetic polymorphism has been linked to elevation of PAI-1 antigen and/or activity levels. Genotype frequencies in Caucasian populations have been estimated at 0.25 (5G/5G), 0.49 (4G/5G) and 0.26 (4G/4G). Increased thrombosis risk has been reported in patients with the combination of PAI-1 4G and factor V Leiden (FVL) genetic polymorphisms. Our pediatric specialty laboratory offers PAI-1 genotyping, PAI-1 antigen and PAI-1 activity assays as part of thrombophilia testing. The laboratory at the children's hospital is also a reference lab for the community. We retrospectively reviewed the results of PAI-1 testing over the last 10 years.We hypothesized that the PAI-1 4G polymorphism would be more prevalent in young patients with thrombosis. We also hypothesized that there would be an additive thrombophilia risk from the combination of PAI-1 4G and FVL in young patients with thrombosis.Methods: After IRB approval, using information from Cerner and EPIC, we created a deidentified thrombophilia database of 11,459 unique patients who had thrombophilia testing between March 8, 2007 and June 6, 2017. We identified 1,896 who had PAI-1 genotyping and 2,573 who had antigen and activity testing. Removing those <3 months of age for whom normal ranges for PAI-1 have not been established, we identified 1,418 subjects who had genotype, antigen and activity levels. We also evaluated a subset of 510 pediatric patients with thrombosis, of whom 338 had all three PAI-1 tests and were 3 months or older, and 292 who had both PAI-1 and FVL genotyping. Local genotype frequency was established by the clinical laboratory on 100 controls and was in agreement with published estimates. All comparisons were made using two-sided Fisher's Exact tests. Significance was assessed at the 0.05 level.Results: Ages for subjects tested for PAI-1 ranged from 0.1 - 89.7 years with a mean of 14.3 years, and 41% were male. Compared to the local genotype frequency, PAI-1 4G was not significantly altered in either the thrombophilia cohort or in the subset with pediatric thrombosis (Table 1). This was true even when we re-evaluated by gender or by selecting for those with thrombophilia testing <22 years of age. Among 53 pediatric thrombosis patients with cancer, genotype frequencies for PAI-1 4G did not differ strongly from control group (p=0.14), but numbers were very small. Of the 1,418 thrombophilia testing subjects who had PAI-1 genotype, antigen and activity, correlation between abnormal antigen (p=0.07) or activity (p=0.28) levels and the 4G polymorphism did not reach statistical significance, though it did for those with both abnormal antigen and activity (p=0.05). Among 292 pediatric thrombosis patients with testing (Table 2), there was a suggestion of an effect from the combination of FVL and PAI-1 4G polymorphisms and thrombosis (p=0.06).Conclusions: Abnormal PAI-1 antigen and activity levels are not solely dependent upon the 4G genotype and are likely influenced by other congenital and acquired factors. Among pediatric patients with thrombosis and particularly those with cancer and thrombosis, a possible effect from the PAI-1 4G polymorphism alone or in combination of FVL should be validated in a larger cohort. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

On the prospects for the use of thiamine, pyridoxine, and cyanocobalamin in the complex therapy and rehabilitation of patients with COVID-19

The new coronavirus infection COVID-19 has highlighted the importance of ongoing support for innate antiviral immunity systems. The aim. Conduct a systematic review of publications on the research of the use of B vitamins to support immunity and rehabilitation of patients with COVID-19. Methods. Intelligent analysis of so-called Big Data and special computational methods for analyzing Big Data of biomedical publications, based on the topological theory of sentiment analysis of medical texts from PubMed/MEDLINE. Results. Low levels of B vitamins contribute to chronic comorbidities and aggravate the clinical course of COVID-19 significantly. Increasing the supply of B vitamins in COVID-19 patients is essential for the maintenance of energy and oxygen metabolism; the direct antiviral effects of vitamins (reduction of SARS-CoV-2 replication); compensation of chronic comorbidities (thromboembolism, impaired liver and kidney functions, diabetes mellitus, polyneuropathy), which aggravate the course of COVID-19; reducing hyperhomocysteinemia and chronic aseptic inflammation; inhibiting carbonic anhydrases to improve oxygen metabolism in the lungs, and increasing the clearance of lactate from the blood and preventing sepsis. Conclusion. By improving myelination of the olfactory sensory neurons, vitamin B 12 can help overcome anosmia, which occurs in 80% of COVID-19 patients. Short courses (up to 2 – 3 weeks) of high-dose parenteral therapy with thiamine, pyridoxine, and cyanocobalamin can be used as a part of a complex of therapeutic measures to improve clinical outcomes in patients with COVID-19, especially in elderly patients with polyhypovitaminosis, diabetes mellitus, hyperhomocysteinemia, thrombophilia, and high risk of sepsis. Oral therapy with thiamine, pyridoxine, and cyanocobalamin is justified as a part of rehabilitation measures after COVID-19 in patients who have faced its consequences in the form of clinical signs of vitamin B vitamin deficiency.