Common Risk Factors Add to Inherited Thrombophilia to Predict Venous Thromboembolism Risk in Families

Suchon, Pierre; Resseguier, Noémie; Ibrahim, Manal; Robin, Alexia; Venton, Geoffroy; Barthet, Marie-Christine; Brunet, D.; Alessi, Marie‐Christine; Trégouët, David‐Alexandre; Morange, Pierre‐Emmanuel

doi:10.1055/s-0039-1677807

Cited by 11 publications

(7 citation statements)

References 26 publications

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“…Fetuses with homozygous AT deficiency are also prone to growth restriction if they were born successfully, which is manifested as low birth weight, severe spontaneous thromboembolic events in neonates and children, and even intrautero thromboembolic events (14,(26)(27)(28)(29). Patients with AT deficiency frequently suffered from relapsed VTE, especially after anticoagulant therapy was discontinued or was challenged with other risk factors (30)(31)(32). Thus, long-term anticoagulant therapy is especially important.…”

Section: Discussionmentioning

confidence: 99%

Gene editing of human iPSCs rescues thrombophilia in hereditary antithrombin deficiency in mice

et al. 2022

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Hereditary antithrombin deficiency is caused by SERPINC1 gene mutations and predisposes to recurrent venous thromboembolism that can be life-threatening. Therefore, lifelong anticoagulation is required, which has side effects and may not be effective. In this study, peripheral blood mononuclear cells from a patient with severe antithrombin deficiency were reprogrammed into induced pluripotent stem cells (iPSCs). The mutation was corrected using CRISPR-Cas9 and Cre/LoxP genome editing. iPSCs were differentiated into hepatocytes, which were injected into the spleen of antithrombin knockout mice to restore the activity of antithrombin and reduce the thrombophilic state. Human iPSC-differentiated hepatocytes colonized mice and secreted antithrombin stably, normalizing antithrombin in plasma (activity: from 46.8 ± 5.7% to 88.6 ± 7.6%, P < 0.0001; antigen: from 146.9 ± 19.5 nanograms per milliliter to 390.7 ± 16.1 nanograms per milliliter, P < 0.0001). In venous thrombosis model, the rate of thrombosis in mice treated with edited hepatocytes, parental hepatocytes, and wild-type mice were 60, 90, and 70%, respectively. The thrombus weight was much lighter in mice treated with edited hepatocytes compared with parental hepatocytes (7.25 ± 2.00 milligrams versus 15.32 ± 2.87 milligrams, P = 0.0025) and showed no notable difference compared with that in wild-type mice (10.41 ± 2.91 milligrams). The activity and concentration of antithrombin remained high for 3 weeks after injection. The liver and kidney function markers showed no obvious abnormality during the observation period. This study provides a proof of principle for correction of mutations in patient-derived iPSCs and potential therapeutic applications for hereditary thrombophilia.

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Section: Discussionmentioning

confidence: 99%

Gene editing of human iPSCs rescues thrombophilia in hereditary antithrombin deficiency in mice

et al. 2022

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“… 71 , 72 Congruently, the ABO blood type and VWF levels also modify the risk of VTE in families with hereditary thrombophilias and could add to their overall VTE risk assessment. 73 , 74 …”

Section: Vwf In Venous Thromboembolic Diseasementioning

confidence: 99%

Role of von Willebrand factor in venous thromboembolic disease

Michels

Lillicrap

Yacob

2022

JVS-Vascular Science

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Objective Evolving evidence of the shared risk factors and pathogenic mechanisms in arterial and venous thrombosis questions of the strict vascular dichotomy of arterial vs venous. The connection between arterial and venous thrombosis has been highlighted by common underlying inflammatory processes, a concept known as thromboinflammatory disease. Using this relationship, we can apply knowledge from arterial disease to better understand and potentially mitigate venous disease. A protein that has been extensively studied in atherothrombotic disease and inflammation is von Willebrand factor (VWF). Because many predisposing and provoking factors of venous thromboembolism (VTE) have been shown to directly modulate VWF levels, it is, perhaps, not surprising that VWF has been highlighted by several recent association studies of patients with VTE. Methods In the present narrative review, we investigated more deeply the effects of VWF in venous disease by synthesizing the data from clinical studies of deep vein thrombosis of the limbs, pulmonary embolism, portal and cerebral vein thrombosis, and the complications of thrombosis, including post-thrombotic syndrome, venous insufficiency, and chronic thromboembolic pulmonary hypertension. We have also discussed the findings from preclinical studies to highlight novel VWF biochemistry in thrombosis and therapeutics. Results Across the spectrum of venous thromboembolic disease, we consistently observed that elevated VWF levels conferred an increased risk of VTE and long-term venous complications. We have highlighted important findings from VWF molecular research and have proposed mechanisms by which VWF participates in venous disease. Emerging evidence from preclinical studies might reveal novel targets for thromboinflammatory disease, including specific VWF pathophysiology. Furthermore, we have highlighted the utility of measuring VWF to prognosticate and risk stratify for VTE and its complications. Conclusions As the prevalence of inflammatory processes, such as aging, obesity, and diabetes increases in our population, it is critical to understand the evolving role of VWF in venous disease to guide clinical decisions and therapeutics.

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“…A recent French study that included 2,214 relatives from 651 families with known thrombophilia calculated an annual VTE incidence rate of 0.36% (hazard ratio [HR]: 1.91; 95% CI: 1.30-2.80) in patients with mild thrombophilia and 0.64% (HR: 3.78; 95% CI: 2.50-5.73) in patients with severe thrombophilia. 40 However, there is a remarkable risk increase in women with thrombophilia who use CHCs. The risk increase can be roughly estimated with multiplication of relative risks.…”

Section: Hereditary Thrombophilia and Hormonal Contraceptionmentioning

confidence: 99%

Section: Hereditary Thrombophilia and Hormonal Contraceptionmentioning

confidence: 99%

Venous Thromboembolism Issues in Women

Linnemann

Rott

Zotz³

et al. 2022

Hamostaseologie

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The lifetime risk of venous thromboembolism (VTE) is slightly higher in women than in men. There are several issues related to VTE that are unique to women. Combined hormonal contraceptives and pregnancy increase the risk of VTE in women of childbearing age, whereas hormone replacement therapy increases the VTE risk of postmenopausal women. Hereditary thrombophilia and risk factors such as older age, obesity, or smoking contribute to the risk increase. In women diagnosed with acute hormone-related VTE who are treated with oral anticoagulants, adequate contraception is mandatory to avoid unwanted pregnancies. According to current knowledge, hormonal contraception may be continued during anticoagulant therapy but must be switched to an estrogen-free contraception method at least 6 weeks before the termination of anticoagulation. VTE is also a major cause of maternal morbidity and mortality during pregnancy and the postpartum period. Currently, assisted reproduction technologies such as in vitro fertilization are widely used to treat couples affected by infertility. Complications of fertility treatment comprise VTE cases, especially in women with ovarian hyperstimulation syndrome. With this review, we intended to focus on VTE issues in women and summarize current evidence and guideline recommendations.

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Common Risk Factors Add to Inherited Thrombophilia to Predict Venous Thromboembolism Risk in Families

Cited by 11 publications

References 26 publications

Gene editing of human iPSCs rescues thrombophilia in hereditary antithrombin deficiency in mice

Gene editing of human iPSCs rescues thrombophilia in hereditary antithrombin deficiency in mice

Role of von Willebrand factor in venous thromboembolic disease

Venous Thromboembolism Issues in Women

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