Testing for inherited thrombophilia and consequences for antithrombotic prophylaxis in patients with venous thromboembolism and their relatives

SummaryThe clinical penetrance of venous thromboembolism (VTE) susceptibility genes is variable, being lower in heterozygous carriers of factor V Leiden and prothrombin 20210A (mild thrombophilia), and higher in the rare carriers of deficiencies of antithrombin, protein C or S, and those with multiple or homozygous abnormalities (high-risk thrombophilia). The absolute risk of VTE is low, and the utility of laboratory investigation for inherited thrombophilia in patients with VTE and their asymptomatic relatives has been largely debated, leading to the production of several Guidelines from Scientific Societies and Working Groups. The risk for VTE largely depends on the family history of VTE. Therefore, indiscriminate search for carriers is of no utility, and targeted screening is potentially more fruitful. In patients with VTE inherited thrombophilia is not scored as a determinant of recurrence, playing a minor role in the decision of prolonging anticoagulation; indeed, a few guidelines consider testing worthwhile to identify carriers of high-risk thrombophilia, particularly those with a family history of VTE. The identification of the asymptomatic carrier relatives of the probands with VTE and thrombophilia could reduce cases of provoked VTE, offering them primary antithrombotic prophylaxis during risk situations. In most guidelines, this is considered justified only for relatives of probands with a deficiency of natural anticoagulants or multiple abnormalities. Counselling the asymptomatic female relatives of individuals with VTE and/or thrombophilia before pregnancy or the prescription of hormonal treatments should be administered with consideration of the risk driven by the type of thrombophilia and the family history of VTE.

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Venous Thromboembolism: Genetics and Thrombophilias

Seminars in Respiratory and Critical Care Medicine ◽

10.1055/s-0041-1723937 ◽

2021 ◽

Vol 42 (02) ◽

pp. 271-283

Author(s):

Manila Gaddh ◽

Rachel P. Rosovsky

Keyword(s):

Clinical Practice ◽

Venous Thromboembolism ◽

Family History ◽

Morbidity And Mortality ◽

Inherited Thrombophilia ◽

Risks And Benefits ◽

Hereditary Thrombophilia ◽

The World ◽

The Future ◽

History Of

AbstractVenous thromboembolism (VTE) is a major cause of morbidity and mortality throughout the world. Up to one half of patients who present with VTE will have an underlying thrombophilic defect. This knowledge has led to a widespread practice of testing for such defects in patients who develop VTE. However, identifying a hereditary thrombophilia by itself does not necessarily change outcomes or dictate therapy. Furthermore, family history of VTE by itself can increase an asymptomatic person's VTE risk several-fold, independent of detecting a known inherited thrombophilia. In this article, we will describe the current validated hereditary thrombophilias including their history, prevalence, and association with VTE. With a focus on evaluating both risks and benefits of testing, we will also explore the controversies of why, who, and when to test as well as discuss contemporary societal guidelines. Lastly, we will share how these tests have been integrated into clinical practice and how to best utilize them in the future.

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Prostate cancer screening characteristics in men with BRCA1/2 mutations attending a high-risk prevention clinic

Canadian Urological Association Journal ◽

10.5489/cuaj.1970 ◽

2014 ◽

Vol 8 (11-12) ◽

pp. 783 ◽

Cited By ~ 3

Author(s):

Richard Walker ◽

Alyssa Louis ◽

Alejandro Berlin ◽

Sheri Horsburgh ◽

Robert G. Bristow ◽

...

Keyword(s):

Prostate Cancer ◽

Family History ◽

High Risk ◽

Prostate Cancer Screening ◽

Brca2 Mutation ◽

Aggressive Disease ◽

Mutation Carriers ◽

The Family ◽

History Of ◽

Prevention Clinic

Introduction: The prostate-specific antigen (PSA) era and resultant early detection of prostate cancer has presented clinicians with the challenge of distinguishing indolent from aggressive tumours. Mutations in the BRCA1/2 genes have been associated with prostate cancer risk and prognosis. We describe the prostate cancer screening characteristics of BRCA1/2 mutation carriers, who may be classified as genetically-defined high risk, as compared to another high-risk cohort of men with a family history of prostate cancer to evaluate the utility of a targeted screening approach for these men.Methods: We reviewed patient demographics, clinical screening characteristics, pathological features, and treatment outcomes between a group of BRCA1 or BRCA2 mutation carriers and age-matched men with a family history of prostate cancer followed at our institutional Prostate Cancer Prevention Clinic from 1995 to 2012.Results: Screening characteristics were similar between the mutation carriers (n = 53) and the family history group (n = 53). Some cancers would be missed in both groups by using a PSA cut-off of >4 ug/L. While cancer detection was higher in the family history group (21% vs. 15%), the mutation carrier group was more likely to have intermediate- or high-risk disease (88% vs. 36%). BRCA2 mutation carriers were more likely to have aggressive disease, biological recurrence, and distant metastasis.Conclusions: In our cohort, regular screening appears justified for detecting prostate cancer in BRCA1 and BRCA2 carriers and other high-risk populations. Lowering PSA cut-offs and defining monitoring of PSA velocity as part of the screening protocol may be useful. BRCA2 is associated with more aggressive disease, while the outcome for BRCA1 mutation carriers requires further study. Large multinational studies will be important to define screening techniques for this unique high-risk population.

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Risk factors for venous thromboembolism in women under combined oral contraceptive

Thrombosis and Haemostasis ◽

10.1160/th15-01-0045 ◽

2016 ◽

Vol 115 (01) ◽

pp. 135-142 ◽

Cited By ~ 22

Author(s):

Agathe Henneuse ◽

Manal Ibrahim ◽

Dominique Brunet ◽

Marie-Christine Barthet ◽

Marie-Françoise Aillaud ◽

...

Keyword(s):

Risk Factors ◽

Venous Thromboembolism ◽

Family History ◽

Blood Group ◽

Public Health Issue ◽

Abo Blood Group ◽

Inherited Thrombophilia ◽

Thrombophilia Screening ◽

History Of ◽

The Impact

SummaryIdentifying women at risk of venous thromboembolism (VTE) is a major public health issue. The objective of this study was to identify environmental and genetic determinants of VTE risk in a large sample of women under combined oral contraceptives (COC). A total of 968 women who had had one event of VTE during COC use were compared to 874 women under COC but with no personal history of VTE. Clinical data were collected and a systematic thrombophilia screening was performed together with ABO blood group assessment. After adjusting for age, family history, and type and duration of COC use, main environmental determinants of VTE were smoking (odds ratio [OR] =1.65, 95 % confidence interval [1.30–2.10]) and a body mass index higher than 35 kg.m-2 (OR=3.46 [1.81–7.03]). In addition, severe inherited thrombophilia (OR=2.13 [1.32–3.51]) and non-O blood groups (OR=1.98 [1.57–2.49]) were strong genetic risk factors for VTE. Family history poorly predicted thrombophilia as its prevalence was similar in patients with or without first degree family history of VTE (29.3 % vs 23.9 %, p=0.09). In conclusion, this study confirms the influence of smoking and obesity and shows for the first time the impact of ABO blood group on the risk of VTE in women under COC. It also confirms the inaccuracy of the family history of VTE to detect inherited thrombophilia.

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Family History of Venous Thromboembolism and Identifying Factor V Leiden Carriers During Pregnancy

Obstetrics and Gynecology ◽

10.1097/aog.0b013e3181d018a8 ◽

2010 ◽

Vol 115 (3) ◽

pp. 521-525 ◽

Cited By ~ 5

Author(s):

Amanda L. Horton ◽

Valerija Momirova ◽

Donna Dizon-Townson ◽

Katharine Wenstrom ◽

George Wendel ◽

...

Keyword(s):

Venous Thromboembolism ◽

Family History ◽

Factor V Leiden ◽

Factor V ◽

History Of

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Pregnancy-Related Venous Thromboembolism

Journal of Pharmacy Practice ◽

10.1177/0897190014530425 ◽

2014 ◽

Vol 27 (3) ◽

pp. 243-252 ◽

Cited By ~ 5

Author(s):

Emily M. Armstrong ◽

Jessica M. Bellone ◽

Lori B. Hornsby ◽

Sarah Treadway ◽

Haley M. Phillippe

Keyword(s):

Venous Thromboembolism ◽

Family History ◽

Factor V Leiden ◽

Ease Of Use ◽

Factor V ◽

Thromboembolic Risk ◽

Increased Risk ◽

History Of ◽

Prothrombin Gene Mutation ◽

Prothrombin Gene

Pregnancy is associated with an increased risk of venous thromboembolism (VTE), with a reported incidence ranging from 0.49 to 2 events per 1000 deliveries. Risk factors include advanced maternal age, obesity, smoking, and cesarian section. Women with a history of previous VTE are at a 4-fold higher risk of recurrent thromboembolic events during subsequent pregnancies. Additionally, the presence of concomitant thrombophilia, particularly factor V Leiden (homozygosity), prothrombin gene mutation (homozygosity), or antiphospholipid syndrome (APS), increases the risk of pregnancy-related VTE. Low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) are the drugs of choice for anticoagulation during pregnancy. LMWH is preferred due to ease of use and lower rates of adverse events. Women with high thromboembolic risk particularly those with a family history of VTE should receive antepartum thromboprophylaxis. Women with low thromboembolic risk or previous VTE caused by a transient risk factor (ie, provoked), who have no family history of VTE, may undergo antepartum surveillance. Postpartum anticoagulation can be considered in women with both high and low thromboembolic risk.

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Inpatient Thrombophilia Workup in Patients with Acute Venous Thromboembolism

Blood ◽

10.1182/blood.v126.23.4720.4720 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4720-4720

Author(s):

Vivek Rashmikant Mehta ◽

Uzma Khan ◽

Aparna Basu ◽

Asif Jan ◽

Bolanie Gbadamosi ◽

...

Keyword(s):

Venous Thromboembolism ◽

Family History ◽

Gene Mutation ◽

Protein C ◽

Factor V Leiden ◽

Protein S ◽

Factor V ◽

Test Results ◽

History Of ◽

Acute Venous Thromboembolism

Abstract Background Any inherited or acquired condition that increases the risk of developing deep venous thrombosis or pulmonary embolism is considered a thrombophilic disorder. Some examples of inherited causes of thromboembolic disorders are Factor V Leiden mutation (FVL), Prothrombin gene mutation, Protein C deficiency (low or dysfunctional), Protein S deficiency (low or dysfunctional), Anti-thrombin (AT) deficiency (low or dysfunctional). Use of these studies in clinical practice has been questioned. We attempted to identify if there are populations of patients that undergo more inpatient screening for inherited causes of venous thromboembolism (VTE). Methods Retrospective chart review of patients admitted with PE or DVT in a community teaching hospital between May 2012 and December 2014. Only patients who had DVT confirmed with ultrasound or PE confirmed with CT angiogram or had high probability of PE on V/Q scan were included in the study. Individual charts were reviewed to see if thrombophilia workup was ordered. Results A total of 704 patients with acute venous thromboembolism were identified who met our inclusion criteria for the study. Of this 111 patients (15.76%) had one or more thrombophilia screening studies ordered. Risk factors related to venous thromboembolism were evaluated for all of the 704 patients. In our patient population, patients who were smokers (31% vs 20%), had history of sleep apnea (9% vs 3%), a past medical history (PMH) of VTE (37% vs 25%) or who had a family history (FH) of VTE (11% vs 4%) were more likely to have a thrombophilia workup ordered. Table 2 shows the frequency of individual thrombophilia studies ordered among the 111 patients who had testing performed and table 3 shows distribution of positive results. Table. Test Result Abnormal Test Results ANA 1 Decreased AT III 10 Decreased Protein C 10 Decreased Protein S 7 Increased Homocysteine 6 Factor V Leiden 4 PT Gene Mutation 1 APLA 1 Conclusion The largest numbers of positive test results were noted for Protein C, Protein S and Antithrombin III and these are known to be affected by acute thrombosis and therefore could be false positives. Our study shows that those patients with PMH or FH of VTE were more likely to have thrombophilia studies. There is no consensus opinion as to whether to perform thrombophilia screenings in acute care settings. Given this and the fact that personal or family history of VTE do not usually modify future treatment decisions and that there may be significant number of false positives we do not recommend routine screening in these patient populations. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

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Novel SCN5A p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths

International Journal of Molecular Sciences ◽

10.3390/ijms22094700 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4700

Author(s):

Michelle M. Monasky ◽

Emanuele Micaglio ◽

Giuseppe Ciconte ◽

Ilaria Rivolta ◽

Valeria Borrelli ◽

...

Keyword(s):

Genetic Testing ◽

Family History ◽

Risk Stratification ◽

Brugada Syndrome ◽

Electrophysiological Study ◽

Functional Characterization ◽

The Family ◽

Novel Variant ◽

History Of ◽

Scn5a Gene

Genetic testing in Brugada syndrome (BrS) is still not considered to be useful for clinical management of patients in the majority of cases, due to the current lack of understanding about the effect of specific variants. Additionally, family history of sudden death is generally not considered useful for arrhythmic risk stratification. We sought to demonstrate the usefulness of genetic testing and family history in diagnosis and risk stratification. The family history was collected for a proband who presented with a personal history of aborted cardiac arrest and in whom a novel variant in the SCN5A gene was found. Living family members underwent ajmaline testing, electrophysiological study, and genetic testing to determine genotype-phenotype segregation, if any. Patch-clamp experiments on transfected human embryonic kidney 293 cells enabled the functional characterization of the SCN5A novel variant in vitro. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.5000T>A (p.Val1667Asp) in the SCN5A gene, and demonstrate its segregation with a severe form of BrS and multiple sudden deaths. Functional data revealed a loss of function of the protein affected by the variant. These results provide the first disease association with this variant and demonstrate the usefulness of genetic testing for diagnosis and risk stratification in certain patients. This study also demonstrates the usefulness of collecting the family history, which can assist in understanding the severity of the disease in certain situations and confirm the importance of the functional studies to distinguish between pathogenic mutations and harmless genetic variants.

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Cancer Previvors in an Active Duty Service Women Population: An Opportunity for Prevention and Increased Force Readiness

Military Medicine ◽

10.1093/milmed/usaa485 ◽

2020 ◽

Author(s):

Leann A Lovejoy ◽

Clesson E Turner ◽

Craig D Shriver ◽

Rachel E Ellsworth

Keyword(s):

Genetic Testing ◽

Family History ◽

High Risk ◽

Cancer Predisposition ◽

Clinical Genetic ◽

High Risk Women ◽

Clinical Genetic Testing ◽

Pathogenic Mutations ◽

History Of ◽

Risk Reducing

Abstract Background The majority of active duty service women (ADS) are young, have access to healthcare, and meet fitness standards set by the U.S. military, suggesting that ADS represent a healthy population at low risk of cancer. Breast cancer is, however, the most common cancer in ADS and may have a significant effect on troop readiness with lengthy absence during treatment and inability to return to duty after the treatment. The identification of unaffected ADS who carry germline mutations in cancer predisposition genes (“previvors”) would provide the opportunity to prevent or detect cancer at an early stage, thus minimizing effects on troop readiness. In this study, we determined (1) how many high-risk ADS without cancer pursued genetic testing, (2) how many previvors employed risk-reducing strategies, and (3) the number of undiagnosed previvors within an ADS population. Methods The Clinical Breast Care Project (protocol WRNMMC IRB #20704) database of the Murtha Cancer Center/Walter Reed National Military Medical Center was queried to identify all ADS with no current or previous history of cancer. Classification as high genetic risk was calculated using National Comprehensive Cancer Network 2019 guidelines for genetic testing for breast, ovary, colon, and gastric cancer. The history of clinical genetic testing and risk-reducing strategies was extracted from the database. Genomic DNA from ADS with blood specimens available for research purposes were subjected to next-generation sequencing technologies using a cancer predisposition gene panel. Results Of the 336 cancer-free ADS enrolled in the Clinical Breast Care Project, 77 had a family history that met National Comprehensive Cancer Network criteria for genetic testing for BRCA1/2 and 2 had a family history of colon cancer meeting the criteria for genetic testing for Lynch syndrome. Of the 28 (35%) high-risk women who underwent clinical genetic testing, 11 had pathogenic mutations in the breast cancer genes BRCA1 (n = 5), BRCA2 (n = 5), or CHEK2 (n = 1). Five of the six ADS who had a relative with a known pathogenic mutation were carriers of the tested mutation. All of the women who had pathogenic mutations detected through clinical genetic testing underwent prophylactic double mastectomy, and three also had risk-reducing salpingo-oophorectomy. Two (6%) of the 33 high-risk ADS tested only in the research setting had a family history of breast/ovarian cancer and carried pathogenic mutations: one carried a BRCA2 mutation, whereas the other carried a mutation in the colon cancer predisposition gene PMS2. No mutations were detected in the 177 low-risk women tested in the research setting. Discussion Within this unaffected cohort of ADS, 23% were classified as high risk. Although all of the previvors engaged in risk-reduction strategies, only one-third of the high-risk women sought genetic testing. These data suggest that detailed family histories of cancer should be collected in ADS and genetic testing should be encouraged in those at high risk. The identification of previvors and concomitant use of risk-reduction strategies may improve health in the ADS and optimize military readiness by decreasing cancer incidence.

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