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A coagulation defect arising from heterozygous premature termination of tissue factor
- Source :
- J Clin Invest
- Publication Year :
- 2019
-
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.
- Subjects :
- 0301 basic medicine
Male
medicine.medical_specialty
Heterozygote
Vascular smooth muscle
Induced Pluripotent Stem Cells
Haploinsufficiency
Frameshift mutation
Thromboplastin
03 medical and health sciences
Tissue factor
Mice
0302 clinical medicine
Blood Coagulation Disorders, Inherited
Internal medicine
medicine
Animals
Humans
Thrombus
Frameshift Mutation
Gene Editing
Mice, Knockout
Hematology
Base Sequence
business.industry
Abnormal bleeding
General Medicine
Peptide Chain Termination, Translational
medicine.disease
Mice, Inbred C57BL
Disease Models, Animal
030104 developmental biology
Phenotype
Coagulation
Codon, Nonsense
030220 oncology & carcinogenesis
Cancer research
Female
business
Research Article
Subjects
Details
- ISSN :
- 15588238
- Volume :
- 130
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- The Journal of clinical investigation
- Accession number :
- edsair.doi.dedup.....fa836d3c1f116210052b3697b568d3a8