ArticleThe Journal of clinical investigation2020
A coagulation defect arising from heterozygous premature termination of tissue factor.
Article in The Journal of clinical investigation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
What it found
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The trial behind it
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Who cites it
11 citing papers in PubMed, 22 citations in OpenAlex.
- Call to action: identifying an underlying bleeding disorder in adolescents with heavy menstrual bleeding.Research and practice in thrombosis and haemostasis · 2026Review
- Article
- The dysfunction of complement and coagulation in diseases: the implications for the therapeutic interventions.MedComm · 2024Review
- MEK1/2- and ERK1/2-Mediated Lung Endothelial Injury and Altered Hemostasis Promote Diffuse Alveolar Hemorrhage in Murine Lupus.Arthritis & rheumatology (Hoboken, N.J.) · 2024Article
- Human Genetic Variation in F3 and Its Impact on Tissue Factor-Dependent Disease.Seminars in thrombosis and hemostasis · 2024Review
- Review
- Investigating patients for bleeding disorders when most of the "usual" ones have been ruled out.Research and practice in thrombosis and haemostasis · 2023Article
- TMEM16E regulates endothelial cell procoagulant activity and thrombosis.The Journal of clinical investigation · 2023Article
- Genetic duplication of tissue factor reveals subfunctionalization in venous and arterial hemostasis.PLoS genetics · 2022Article
- Article
- Article
Corrections and comments
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Authors and funding
17 authors at 6 institutions in 4 countries.
Funding
Abstract
Tissue factor (TF) is the primary initiator of blood coagulation in vivo and the only blood coagulation factor for which a human genetic defect has not been described. As there are no routine clinical assays that capture the contribution of endogenous TF to coagulation initiation, the extent to which reduced TF activity contributes to unexplained bleeding is unknown. Using whole genome sequencing, we identified a heterozygous frameshift variant (p.Ser117HisfsTer10) in F3, the gene encoding TF, causing premature termination of TF (TFshort) in a woman with unexplained bleeding. Routine hematological laboratory evaluation of the proposita was normal. CRISPR-edited human induced pluripotent stem cells recapitulating the variant were differentiated into vascular smooth muscle and endothelial cells that demonstrated haploinsufficiency of TF. The variant F3 transcript is eliminated by nonsense-mediated decay. Neither overexpression nor addition of exogenous recombinant TFshort inhibited factor Xa or thrombin generation, excluding a dominant-negative mechanism. F3+/- mice provide an animal model of TF haploinsufficiency and exhibited prolonged bleeding times, impaired thrombus formation, and reduced survival following major injury. Heterozygous TF deficiency is present in at least 1 in 25,000 individuals and could limit coagulation initiation in undiagnosed individuals with abnormal bleeding but a normal routine laboratory evaluation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.