Prothrombin R541W Mutation Impairs Protein C Activation and Constitutes a New Genetic Risk Factor for Venous Thrombosis

Defective protein C (PC) pathway predisposes patients to venous thromboembolism (VTE)and is mostly, but not exclusively, attributed tohereditary PC or protein S (PS) deficiencies and activated PC resistance caused by factor V Leiden mutation. In a patient with acute mesenteric venous thrombosis and positive family history of VTE associated with the impaired PC pathway function determined by thrombin generation test, we identified a novel heterozygous prothrombin mutation p.Arg541Trp. Two more patients with positive family history of VTE carrying the same mutation were identified in a cohort of another 373 unrelated patients, making an overall prevalence of 0.8%. Family investigation revealed 11 individuals in the three pedigrees harboring the heterozygous prothrombin p.Arg541Trp mutation, and 8 of them (72%) had experienced episodes of VTE. Functional studies indicated the mutation moderately decreased procoagulant activity of prothrombin and had mild impact on the inactivation of thrombin by its inhibitor antithrombin. However, the amino acid residue substitution significantly compromised PC activation by thrombin, both in the absence and presence of soluble thrombomodulin, and thus rendered prothrombin function procoagulant biased. In conclusion, the prothrombin p.Arg541Trp mutation constitutes a new genetic risk factor of VTE by impairing function of PC pathway and tilting thrombin's procoagulant activity over anticoagulant function. Figure Disclosures Ding: Shanghai General Hospital affiliated to Shanghai Jiao Tong University, Shanghai: Patents & Royalties: W.W, Q.D and X.W of the co-authors are named as inventors on a patent application related to this work.. Wang:Ruijin Hospital, Shanghai Jiao Tong University School of Medicine: Patents & Royalties: W.W, Q.D and X.W of the co-authors are named as inventors on a patent application related to this work.. WU:Ruijin Hospital, Shanghai Jiao Tong University School of Medicine: Patents & Royalties: W.W, Q.D and X.W of the co-authors are named as inventors on a patent application related to this work..

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Prothrombin Arg541Trp Mutation Leads to Defective PC (Protein C) Pathway Activation and Constitutes a Novel Genetic Risk Factor for Venous Thrombosis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.119.313373 ◽

2020 ◽

Vol 40 (2) ◽

pp. 483-494 ◽

Cited By ~ 2

Author(s):

Xi Wu ◽

Jing Dai ◽

Xiaoqian Xu ◽

Fang Li ◽

Lei Li ◽

...

Keyword(s):

Risk Factor ◽

Family History ◽

Venous Thrombosis ◽

Genetic Risk ◽

Protein C ◽

Positive Family History ◽

Genetic Risk Factor ◽

Procoagulant Activity ◽

Factor V Leiden Mutation ◽

History Of

Objective: Defective PC (protein C) pathway predisposes patients to venous thromboembolism (VTE) and is mostly, but not exclusively, attributed to hereditary PC or PS (protein S) deficiencies and activated PC resistance caused by factor V Leiden mutation. Approach and Results: In a patient with acute mesenteric venous thrombosis and positive family history of VTE associated with the impaired PC pathway function determined by thrombin generation test, we identified a novel heterozygous prothrombin mutation p.Arg541Trp. Two more patients with positive family history of VTE carrying the same mutation were identified in a cohort of another 373 unrelated patients, making an overall prevalence of 0.8%. Family investigation revealed 11 individuals in the 3 pedigrees harboring the heterozygous prothrombin p.Arg541Trp mutation, and 8 of them (72%) had experienced episodes of VTE. Functional studies indicated the mutation moderately decreased procoagulant activity of prothrombin and had mild impact on the inactivation of thrombin by its inhibitor antithrombin. However, the amino acid residue substitution significantly compromised PC activation by thrombin, both in the absence and presence of soluble thrombomodulin, and thus rendered prothrombin function procoagulant biased. Conclusions: In summary, the prothrombin p.Arg541Trp mutation constitutes a new genetic risk factor of VTE by impairing function of PC pathway and tilting thrombin’s procoagulant activity over anticoagulant function.

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Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives

Blood ◽

10.1182/blood-2008-10-184879 ◽

2009 ◽

Vol 113 (21) ◽

pp. 5314-5322 ◽

Cited By ~ 134

Author(s):

Willem M. Lijfering ◽

Jan-Leendert P. Brouwer ◽

Nic J. G. M. Veeger ◽

Ivan Bank ◽

Michiel Coppens ◽

...

Keyword(s):

Family History ◽

Venous Thrombosis ◽

Protein C ◽

Positive Family History ◽

Protein S ◽

Factor V ◽

Recurrence Rates ◽

Thrombotic Risk ◽

History Of ◽

Fv Leiden

Abstract Thrombophilia screening is controversial. In a retrospective family cohort, where probands had thrombosis and a thrombophilic defect, 2479 relatives were tested for thrombophilia. In antithrombin-, protein C–, and protein S–deficient relatives, annual incidences of venous thrombosis were 1.77% (95% CI, 1.14-2.60), 1.52% (95% CI, 1.06-2.11), and 1.90% (95% CI, 1.32-2.64), respectively, at a median age of 29 years and a positive family history of more than 20% symptomatic relatives. In relatives with factor V (FV) Leiden, prothrombin 20210G>A, or high FVIII levels, these were 0.49% (95% CI, 0.39-0.60), 0.34% (95% CI, 0.22-0.49), and 0.49% (95% CI, 0.41-0.51), respectively. High FIX, FXI, and TAFI, and hyperhomocysteinemia were not independent risk factors. Annual incidence of major bleeding in antithrombin-, protein C–, or protein S–deficient relatives on anticoagulants was 0.29% (95% CI, 0.03-1.04). Cumulative recurrence rates in relatives with antithrombin, protein C, or protein S deficiency were 19% at 2 years, 40% at 5 years, and 55% at 10 years. In relatives with FV Leiden, prothrombin 20210G>A, or high levels FVIII, these were 7%, 11%, and 25%, respectively. Considering its clinical implications, thrombophilia testing should address hereditary deficiencies of antithrombin, protein C, and protein S in patients with first venous thrombosis at young age and/or a strong family history of venous thrombosis.

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Egg Allergy in infancy

Nepal Journal of Dermatology Venereology & Leprology ◽

10.3126/njdvl.v9i1.5766 ◽

1970 ◽

Vol 9 (1) ◽

pp. 28-30

Author(s):

R Shrestha ◽

D Shrestha ◽

R Poudyal ◽

N Mishra

Keyword(s):

Risk Factor ◽

Contact Dermatitis ◽

Family History ◽

Positive Family History ◽

Egg White ◽

Oral Exposure ◽

Allergic Reactions ◽

Egg Allergy ◽

History Of

Egg allergies are one of the most common allergies of childhood and the reactions may vary from mild to severe. A family history of egg allergy or atopy is a risk factor for egg allergy. Most food-induced allergic reactions occur on first known oral exposure, especially in the case of eggs and peanuts. We report a case of nine months old infant who developed egg allery (contact dermatitis) after contact with egg white, with a positive family history of atopy and egg allergy. Keywords Egg allergy; contact dermatitis; infancy. DOI: http://dx.doi.org/10.3126/njdvl.v9i1.5766 NJDVL 2010; 9(1): 28-30

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Positive family history of thyroid disease as a risk factor for differentiated thyroid carcinoma

Polish Archives of Internal Medicine ◽

10.20452/pamw.1111 ◽

2011 ◽

Vol 121 (12) ◽

pp. 441-447 ◽

Cited By ~ 1

Author(s):

Elwira Przybylik-Mazurek ◽

Dorota Pach ◽

Sylwia Kuźniarz-Rymarz ◽

Marta Tracz-Bujnowicz ◽

Krystyna Szafraniec ◽

...

Keyword(s):

Risk Factor ◽

Family History ◽

Thyroid Carcinoma ◽

Thyroid Disease ◽

Positive Family History ◽

Differentiated Thyroid Carcinoma ◽

History Of

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Parkinson’s disease determinants, prediction and gene–environment interactions in the UK Biobank

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2020-323646 ◽

2020 ◽

Vol 91 (10) ◽

pp. 1046-1054 ◽

Cited By ~ 2

Author(s):

Benjamin Meir Jacobs ◽

Daniel Belete ◽

Jonathan Bestwick ◽

Cornelis Blauwendraat ◽

Sara Bandres-Ciga ◽

...

Keyword(s):

Risk Factors ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Family History ◽

Genetic Risk ◽

Positive Family History ◽

Risk Scores ◽

Uk Biobank ◽

Gene Environment ◽

History Of

ObjectiveTo systematically investigate the association of environmental risk factors and prodromal features with incident Parkinson’s disease (PD) diagnosis and the interaction of genetic risk with these factors. To evaluate whether existing risk prediction algorithms are improved by the inclusion of genetic risk scores.MethodsWe identified individuals with an incident diagnosis of PD (n=1276) and controls (n=500 406) in UK Biobank. We determined the association of risk factors with incident PD using adjusted logistic regression models. We constructed polygenic risk scores (PRSs) using external weights and selected the best PRS from a subset of the cohort (30%). The PRS was used in a separate testing set (70%) to examine gene–environment interactions and compare predictive models for PD.ResultsStrong evidence of association (false discovery rate <0.05) was found between PD and a positive family history of PD, a positive family history of dementia, non-smoking, low alcohol consumption, depression, daytime somnolence, epilepsy and earlier menarche. Individuals with the highest 10% of PRSs had increased risk of PD (OR 3.37, 95% CI 2.41 to 4.70) compared with the lowest risk decile. A higher PRS was associated with earlier age at PD diagnosis and inclusion of the PRS in the PREDICT-PD algorithm led to a modest improvement in model performance. We found evidence of an interaction between the PRS and diabetes.InterpretationHere, we used UK Biobank data to reproduce several well-known associations with PD, to demonstrate the validity of a PRS and to demonstrate a novel gene–environment interaction, whereby the effect of diabetes on PD risk appears to depend on background genetic risk for PD.

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Positive family history of glaucoma is a risk factor for increased IOP rather than glaucomatous optic nerve damage (POAG vs OH vs normal control)

Korean Journal of Ophthalmology ◽

10.3341/kjo.1992.6.2.100 ◽

1992 ◽

Vol 6 (2) ◽

pp. 100 ◽

Cited By ~ 3

Author(s):

Ki Bang Uhm ◽

Dong H. Shin

Keyword(s):

Risk Factor ◽

Family History ◽

Optic Nerve ◽

Normal Control ◽

Positive Family History ◽

Nerve Damage ◽

Optic Nerve Damage ◽

History Of

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Application of Thrombomodulin-Thrombin Generation to Diverse Abnormalities of the Protein C System

Blood ◽

10.1182/blood-2020-140385 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 31-32

Author(s):

Marilyn J Manco-Johnson ◽

Linda Jacobson ◽

Dianne Thornhill ◽

Christine Baird ◽

Beth Boulden Warren

Keyword(s):

Family History ◽

Lupus Anticoagulant ◽

Protein C ◽

Thrombin Generation ◽

Conflicts Of Interest ◽

Positive Family History ◽

Factor V Leiden ◽

Healthy Controls ◽

Blood Draw ◽

History Of

Background: Increased thrombin generation is an interesting candidate as a potential indicator of hypercoagulability and thrombosis risk. Increased thrombin generation using the calibrated automated thrombogram (CAT) has been reported in antithrombin deficiency but the CAT does not reflect protein C deficiency without the addition of thrombomodulin (TM). TM activates protein C (PC) in the CAT and reduces thrombin generation. Objective: The objective of this study was to determine the capacity of the TM-augmented CAT to detect defects in various protein C system components; the lupus anticoagulant was also investigated as a cause of decreased protein C activation. Methods: The CAT-TM was performed with reagents and methods per the manufacturer's instructions using 5 pM tissue factor and TM (Stago). Other assays included: PC (chromogenic), free protein S (PS, LIA), activated protein C resistance (aPTT-based clotting assay), factor V Leiden (FVL PCR) and lupus anticoagulant (LA, dRVVT and Staclot LA, Stago). Platelet poor plasma samples were obtained from the biobank of a consented prospective inceptional cohort study of thrombosis and thrombophilia or a positive family history of either (ThromboPICS #05-0339); samples from healthy controls with no personal or family history of thrombosis or thrombophilia were collected on a consented protocol (#09-0816). Samples from participants on therapeutic inhibitors of factor Xa or thrombin were treated with appropriate neutralizers; no sample was tested on warfarin. Clinical data included gender, age (< 18 versus ≥ 18 years), history of thrombosis, timing of sample from most recent thrombosis (acute < 14 days; subacute 14-90 days; or chronic > 90 days) and use of anticoagulants at the time of the blood draw. Tests for violations of normality were negative. Therefore, results of cohorts versus controls were compared with independent sample t-test and subgroup analyses relative to control used One-Way ANOVA. Post-hoc comparisons of each subgroup to the controls were collected for multiple comparisons using the Bonferroni correction. Results: Ninety-nine cases and 45 normal controls were studied. Overall half of the cases had a history of thrombosis and 66% of those with thrombosis were on no anticoagulation at the time of testing. Table 1 displays results of the CAT-TM in the 2 control and 6 study groups. Control adults and children showed a mean 50% thrombin reduction in thrombin generation with CAT-TM; overall, persons with protein C system defects showed approximately 25% reduction, with the least reduction of thrombin generation in the cohort of PC deficiency at 19%. Sensitivity of the CAT-TM was 100% for PC deficiency, 81% for LA positivity, 80% for PS deficiency and 72% for FVL positivity with no difference in degree of thrombin reduction between hetero- and homozygous FVL. In addition, we identified 14 individuals with CAT-TM results similar to protein C system defects but with confirmed normal PC, PS, FVL and LA tests. Although 9 of these unknowns had a personal (7) or family (2) history of thrombosis, five came from the healthy controls. The false positive results in 3 adult and 2 pediatric controls conferred a CAT-TM test specificity of 89%. Furthermore, analyses showed no differences in CAT-TM results related to gender, age group, history of thrombosis, age of clot at blood draw (acute, subacute or chronic) or use of anticoagulation at the time of blood draw. Conclusions: The CAT-TM is a useful screening test for defects in the protein C system, including LA, although this test could not discriminate between heterozygous and homozygous FVL. The etiology of positive CAT-TM in normal individuals or individuals with a personal or family history of thrombosis without identified PC system defects is currently unknown and under ongoing investigation. Disclosures No relevant conflicts of interest to declare.

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Family history of cardiovascular disease as a risk factor for coronary artery disease in adult offspring

Monaldi Archives for Chest Disease ◽

10.4081/monaldi.2008.427 ◽

2016 ◽

Vol 70 (2) ◽

Cited By ~ 1

Author(s):

Kianoosh Hoseini ◽

Saeed Sadeghian ◽

Mehran Mahmoudian ◽

Reza Hamidian ◽

Ali Abbasi

Keyword(s):

Coronary Artery Disease ◽

Risk Factor ◽

Coronary Artery ◽

Family History ◽

Positive Family History ◽

Adult Offspring ◽

Positive History ◽

Coronary Syndrome ◽

History Of ◽

Artery Disease

Background and aims: There is controversy about the role of positive family history as an independent risk factor for coronary artery disease. The aim of this work was to investigate the influence of family history on presentation of coronary artery disease in adult offspring, and on its severity. Methods: In a retrospective cross-sectional study at Tehran Heart Center (University of Tehran Medical Sciences), 6399 patients with established coronary artery disease who underwent coronary angiography for standard indications were assessed. Coronary artery disease was defined as atherosclerotic involvement of more than 50% in at least one major coronary artery. Results: 953 patients (14.9%) had a verified positive family history of coronary artery disease, of whom 193 patients (20.2%) and 215 patients (22.5%) had paternal and maternal positive history, respectively. The mean age of clinical onset of ischemic heart disease in patients with a positive history was significantly lower than patients with no history (p < 0.001). Left main coronary lesion was significantly more frequent in patients with positive history (p = 0.017). Multivariate logistic regression analysis demonstrated that presentation of coronary artery disease in the form of acute coronary syndrome was significantly more prevalent in the background of positive family history (odds ratio, OR = 1.44, 95% confidence interval, CI: 1.14-1.83, p = 0.002), especially above 45 years old. Conclusion: These findings indicate that positive family history is a major risk factor for coronary artery disease which strongly predisposes to the atherosclerotic process at younger ages; therefore, these patients should be evaluated and managed more intensively for other risk factors.

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