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The trouble with tissue factor

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Science Translational Medicine  23 Sep 2020:
Vol. 12, Issue 562, eabe6021
DOI: 10.1126/scitranslmed.abe6021

Abstract

A bleeding disorder due to genetic deficiency in tissue factor has been identified.

Blood coagulation depends upon ordered interaction and activation of multiple coagulation factor proteins to produce the cascading, amplifying reaction necessary to prevent excessive bleeding. Congenital deficiencies in coagulation factors are known causes of bleeding disorders. However, a bleeding disorder attributable to a genetically encoded deficit in the coagulation protein tissue factor (TF) has not previously been described. Schulman et al. present evidence that a variant of F3, the gene encoding TF, is associated with pathologic bleeding due to decreased production of functional TF.

TF is a membrane protein expressed on subendothelial fibroblasts and smooth muscle cells, which serves an essential role as the primary initiator of coagulation in vivo. In normal physiology, tissue injury results in TF being exposed to the circulation, where it binds coagulation factors VII/VIIa, catalyzing activation of factors IX and X and initiating blood clotting. Here, as part of a study utilizing whole genome sequencing to examine patients in the National Institute for Health Research BioResource Rare Diseases cohort with unexplained bleeding disorders, the authors identified a novel pathogenic variant of F3. A heterozygous frameshift variant (p.Ser117HisfsTer10) resulted in early termination of protein translation, generating a short TF protein (TFshort) lacking the second fibronectin and transmembrane domains. The functional consequences of the TFshort variant were examined using CRISPR/Cas9-edited human induced pluripotent stem cells and mice with heterozygous F3 knockout; introduction of the frameshift variant in F3 resulted in decreased TF production consistent with haploinsufficiency, and haploinsufficiency of TF in mice resulted in pathologically reduced hemostasis.

Beyond the description of this initial patient, Schulman et al. reviewed Genome Aggregation Database (gnomAD) data for other potential pathogenic variants of F3. They identified other unrecognized and potentially pathogenic variants in the F3 gene and estimated that a pathologic deficit in TF could be present in 1 in 25,000 individuals. Given that no clinical assays for TF function currently exist, these deficiencies may not be otherwise discoverable until pathologic bleeding occurs. These data highlight the limitations in current clinical evaluation of coagulopathies and point to new areas for investigation in patients with unexplained bleeding disorders.

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