[Early diagnosis of thrombophilia conditions in resuscitation].
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Adolescent↗
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[Assay of antithrombin III and soluble fibrin complexes in the study of blood thrombophilia (author's transl)].
The authors conducted a series of experiments concerning the condition of hypercoagulability of patients with a history of thrombosis, in view of determining whether or not the risk of thrombosis could be assessed by laboratory tests. To that end they assayed antithrombin iii activity and soluble fibrin complexes in their test subjects. Antithrombin activity was assayed by a chromogenic method; soluble fibrin complexes by the hemoagglutination test. The activity of antithrombon III was significantly reduced in patients with venous thrombosis, not so in arterial thrombosis. Testing for soluble fibrin complexes was invariably unrewarding, probably because the thrombosis episodes under investigation were of too long standing.
Adolescent↗
[Recent studies on the use of long-term heparin aerosol in thrombophilia].
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Adult↗
[Primary thrombophilia caused by antithrombin III deficiency].
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Adult↗
Risk of venous thromboembolism after SARS-CoV-2 vaccination-Evidence from genome-wide association study and population-based observational study.
AIM: We aimed to investigate whether genetic variation is associated with venous thromboembolism after immunization with SARS-CoV-2 vaccines. METHODS: We conducted a genome-wide association study (GWAS) on cases of venous thromboembolism within 42 days after SARS-CoV-2 vaccination, recruited from reports of adverse drug reactions sent to the Swedish Medical Products Agency. Two hundred one cases (43% women, 91% Swedish) were compared with 4891 Swedish population controls. Analyses were performed on two candidate variants in coagulation factor II (rs1799963) and coagulation factor V (rs6025), on 14 prespecified candidate genes and across the whole genome. To support the findings, we conducted an observational register study of the Swedish general population with/without a diagnosis of thrombophilia and the risks of venous thromboembolism after SARS-CoV-2 vaccination. RESULTS: In the GWAS, the main findings were that the candidate variants of coagulation factors II rs1799963 and V rs6025 were significantly associated with venous thromboembolism (odds ratio [OR] 2.4 [95% confidence interval (CI) 1.2-4.8], p = .015 and OR 1.8 [95% CI 1.3-2.6], p = .0022). No genetic marker passed the significance threshold in the candidate gene analysis or the full genome-wide analysis. In the register study, people with a thrombophilia diagnosis had a five-fold elevated risk of venous thromboembolism within 42 days after vaccination, adjusted for potential confounders, OR 5.06 [95% CI 3.98-6.44]. CONCLUSION: Well-characterized genetic variants in the genes of coagulation factors II and V were associated with thromboembolism after SARS-CoV-2 immunization. Further research is recommended to elucidate their potential role in vaccine-related thromboembolic events.
Adult↗
A Novel Complete F8 Tandem Duplication Causing Elevated Factor VIII Activity and Associated with Venous Thromboembolism.
Background Coagulation factor VIII (FVIII) is a critical component of the intrinsic coagulation pathway. While elevated FVIII levels are an established risk factor for venous thromboembolism (VTE), genetic variants in the F8 gene directly causing such elevations remain scarce. Here, we report a novel complete F8 tandem duplication identified in a female patient with splanchnic venous thrombosis (SVT). Methods We performed genetic testing using a thrombophilia panel targeting 35 genes involved in thrombosis and haemostasis to detect both point variants and copy number variations (CNVs). Family co-segregation analysis and phenotypic assays for FVIII and von Willebrand factor (VWF) were conducted. The structural basis of the identified F8 copy number gain was elucidated using optical genome mapping (OGM). Full-length F8 mRNA amplification, quantitative PCR, plasma FVIII Western blotting, and X-chromosome inactivation analysis were performed to assess the functional consequences of the duplication. Thrombin generation test (TGT) was employed to assess the hypercoagulable state. Results Genetic testing identified three copies of all 26 exons of the F8 gene in the proband, which was also detected in her mother (CNVs = 3) and son (CNVs = 2). One-stage clotting and chromogenic assays confirmed persistently elevated FVIII activity in the proband and her mother, accompanied by increased FVIII antigen levels. The OGM analysis confirmed a 229 kb tandem duplication including the F8 gene on one of the proband's X chromosomes. The junction regions exhibited high sequence homology and were rich in repetitive sequences, which precluded precise breakpoint mapping. Full-length F8 mRNA amplification revealed no aberrant transcripts, whereas quantitative PCR showed increased F8 mRNA expression in all carriers. Plasma FVIII Western blotting indicated FVIII heavy and light chains of expected molecular weights with increased band intensity in carriers. X-chromosome inactivation analysis in female carriers showed no significant skewing. TGT in two available carriers showed increased thrombin generation compared with a normal control at both low (1 pM) and high (5 pM) tissue factor concentrations. Conclusion We identified a novel complete F8 tandem duplication associated with increased FVIII expression and a hypercoagulable phenotype in a female patient with SVT. These findings support F8 gene dosage gain as a rare gain-of-function mechanism contributing to elevated FVIII levels and thrombophilia, while variation in VWF levels and acquired risk factors may modify thrombotic penetrance.
coagulation factor VIII↗
Prothrombin G20210A and Factor V Leiden Variants Are Not Associated With Thrombotic Events in Congenital Heart Disease: An Observational Trial.
BACKGROUND: Thrombotic events, including acute ischemic stroke, are more common in individuals with congenital heart disease (CHD). Whether common thrombophilia variants contribute to thrombotic risk in this population remains unclear. We evaluated whether prothrombin G20210A (F2 c.97G>A) and factor V Leiden (F5 c.1601G>A; p.Arg534Gln) are associated with thrombotic events in CHD. METHODS: Participants in the Pediatric Cardiac Genomics Consortium with exome sequencing and electronic medical record data were identified. Individuals were stratified by prothrombin G20210A and factor V Leiden genotypes, ventricular physiology, and antithrombotic therapy. The primary outcome was the presence of International Classification of Diseases (ICD) or Phecodes (phenotype codes) for thrombotic events. RESULTS: Among 4008 participants (median age, 11.4 [interquartile range, 5.1-17.9] years; 44.4% boys), thrombotic events occurred in 737 (18%), including 93 (13%) with acute ischemic stroke. Compared with the Genome Aggregation Database, the CHD cohort had a lower prevalence of heterozygous prothrombin G20210A and factor V Leiden variants. Variant prevalence did not differ between participants with and without thrombotic events. Single-ventricle CHD was associated with higher thrombosis frequency than biventricular CHD (35% versus 16%, P≤0.0001), without differences in variant prevalence. CONCLUSIONS: In this multicenter CHD cohort, prothrombin G20210A and factor V Leiden were not significantly associated with thrombotic outcomes, supporting recommendations against routine screening. Given low variant prevalence, the study was powered to exclude only large associations. Reduced variant frequency suggests survivorship bias beginning in fetal life. Larger integrated clinical-genomic studies are needed to refine thrombotic risk stratification in CHD. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03347214.
Humans↗
Association of the PROC rs146922325 variant with venous thrombosis in a Taiwanese population.
BACKGROUND: Hereditary protein C deficiency, caused by pathogenic variants in the PROC gene, is a known risk factor for venous thrombosis. However, data on PROC variants in Asian populations are limited. This study evaluated the clinical relevance of rs146922325 and its association with thrombotic outcomes in Taiwanese patients. METHODS: Using genotyping data from a single-nucleotide polymorphism array as part of the Taiwan Precision Medicine Initiative, we conducted a retrospective case-control study that included 805 carriers of the PROC rs146922325 variant and 8,050 age- and sex-matched non-carriers. The baseline characteristics, coagulation profiles, and thrombotic outcomes were systematically compared. Univariable and multivariable logistic regression analyses were performed to assess the association between rs146922325 and venous thrombosis. Sensitivity analyses were conducted by restricting the cohort to warfarin-naïve participants and incident venous thrombosis events occurring after genotyping. RESULTS: Carriers of the rs146922325 T allele exhibited significantly lower protein C levels than non-carriers (71.28% vs. 114.58%, p < 0.001) and a higher prevalence of venous thrombosis (4.10% vs. 2.48%; p = 0.009). After multivariable adjustment, rs146922325 carrier status remained independently associated with an increased risk of venous thrombosis (adjusted odds ratio [aOR], 1.61; p = 0.015). Allelic analysis further indicated that the T allele was associated with elevated thrombotic risk (aOR, 1.74; p = 0.004). No clear dose-response pattern was observed because of the limited number of homozygous TT individuals. Sex-stratified analyses suggested a similar association across sexes; however, the sex × genotype interaction was not statistically significant. CONCLUSION: The PROC rs146922325 variant was associated with an increased risk of venous thrombosis in the Taiwanese population. These findings expand the current knowledge of PROC-related thrombophilia in East Asians and support the potential value of genetic risk stratification in thrombosis research.
PROC rs146922325↗
[Changes in hemostasis in the postoperative period].
Hemostasis was investigated in the postoperative stage (at 24 hours and at 5 days) in 20 patients that had underwent major surgical interventions. The test applied for study of blood coagulation included : thrombocyte counting, the test of Howell, the activated recalcification time, the activated partial thromboplastin time, the prothrombin time (Quick), the thrombin time, estimation of fibrinogen concentration, the protamine sulphate test. The activity of the fibrinolytic system was investigated by the euglobulin clot lysis test and by the method of fibrin plates, while fibrinolysis inhibitors were assessed by determination of serum antiplasmines. Also the fibrinolytic degratation products were evaluated. The results indicate a biological condition that can be classified as "thrombophilia", characterized by hyperfibrinogenemia, the presence of fibrin monomers, a decrease of the fibrinolytic activators and an increase in the amount of antiplasmins, as well as a high percentage of fibrinolytic degradation products. Although the patients did not show manifest signs of thrombosis in the postoperative period, the results obtained indicate a tendency to intravascular formation and deposition of fibrin and suggest the necessity to apply prophylactic therapy with anticoagulants in the postoperative period.
Anticoagulants↗
[The coagulation picture and plasma clearance capacity in atherosclerotic diabetics].
An attempt is made to set out the complex question of the relations between plasma and wall factors in coagulation, platelets and lipids in atheroscderotic diabetes. The literature data show that this disease is associated the clotting and fibrinolytic systems as a result of the prevalence of thrombogenic factors and/or poor inhibitor activity. A survey is made of fibrinolysis activators and inhibitors, and of the part played by lipids in the aetiopathogenesis of thrombophilia, though the mechanisms responsible have not yet been fully established. Reference is made to De Gaetano's exposition of Walsh's views concerning the rôle of platelets in clotting. An assessment is made of the relations between platelets and lipoproteins, and hence of the importance of platelets in the pathogenesis of atherosclerosis. Reference is made to a series of atherosclerotic diabetics. Hyperaggregability was noted in 60% of 30 cases. The experimental results obtained by Bierman et al. on the relation between insulin and lipoproteinlipase and the interference of insulin with PHLA are presented in an explanation of the clarifying power of plasma in this disease. Lastly, an account is given of lipoproteinlipase values observed in a personal series of 48 cases employing a radioimmunological technique. Baselines were depressed in 24 subjects.
Aged↗
[Gastric tolerance of different preparations of acetylsalicylic acid in postoperative prevention of thrombo-embolism (author's transl)].
The necessity for thrombosis-prophylaxis is indisputable. The evaluation of our patients over a period of 2 years revealed results compatible with other authors. Due to its thrombocyte desaggregating action, acetyl-salicylic acid was found to have a definite effect on the thrombophilia by inhibiting the thrombocyte adhesiveness in a beginning thrombosis. It was shown that acetylsalicylic acid in combination with glycocoll is apparently superior to microencapsulated acetylic acid in terms of gastric tolerance. In a small number of patients the therapeutic efficiency was investigated and according to the platelets agglutination test, verified. Further investigations are planned in a major series of patients where acetylsalicylic acid with glycocoll was administered in respect to the treatment of rheumatic fever.
Aspirin↗
Venous thromboembolism laboratory testing (factor V Leiden and factor II c.∗97G>A), 2025 revision: A technical standard of the American College of Medical Genetics and Genomics (ACMG).
Venous thromboembolism (VTE) occurs when a blood clot forms in a vein. The etiology of VTE is multifactorial, including both environmental and genetic factors. Among the genetic factors, factor V Leiden and factor II c.∗97G>A (formerly referred to as prothrombin 20210G>A) are the 2 most common genetic variants associated with VTE. Testing for these variants is one of the most common referrals in clinical genetics laboratories. Although the methodologies for testing these 2 variants are relatively straightforward, the clinical implementation can be complicated regarding test indications, risk assessment for occurrence, and recurrence of VTE and related genetic counseling. This document provides an overview of VTE, information about the variants and their influence on risk, considerations before initiating genetic testing, and the clinical and analytical sensitivity and specificity of the tests. Key information that should be included in the laboratory report is also provided. This document supersedes the Technical Standards and Guidelines for Venous Thromboembolism Laboratory Testing originally published in 2005 and revised in 2018. It is designed for genetic testing professionals familiar with the disease and the analysis methods.
Humans↗