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| Role of tissue factor testing as a bleeding modifier Sol Schulman. |
Abstract
Tissue factor (TF), encoded by F3 for Factor III, is the primary initiator of blood coagulation. TF allosterically activates factor VIIa to enhance cleavage of its macromolecular substrates factor IX and factor X; TF also supports the autoactivation of factor VII to VIIa. Because routine clinical assays do not capture the direct contribution of endogenous TF to coagulation initiation, the extent to which genetic variation in F3 contributes to blood coagulation, bleeding, and thrombosis in humans remains poorly understood. We previously identified a 2 bp deletion in F3 resulting in premature termination and heterozygous TF deficiency in a young woman with unexplained bleeding. We have since expanded our investigation to evaluate a larger cohort of similar individuals, confirming that heterozygous null variants in F3 lead to reduced TF levels and impaired basal thrombin generation in humans. We have also recently identified selected rare missense variants in F3 that impair the activation of factors VII, IX, and X as well as the basal activation of coagulation in humans. Our data also suggest that selected rare variants, such as p.Gly196Arg, impact the activation of factor VII in vitro and in vivo. The deleterious F3 alleles evaluated so far are too rare to enable definitive association of these variants with bleeding and thrombotic disease in even the largest evaluable populations. Nevertheless, animal models and more common SNPs around the F3 locus associated with D-dimer suggest rare human F3 alleles impacting blood coagulation are likely to modify bleeding and thrombotic phenotypes in humans. We encourage carefully considered F3 sequencing in the research arena to better understand the consequences of F3 variants in humans with unexplained bleeding and thrombotic disease.
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