Ontology highlight
ABSTRACT: Background
The variability in bleeding patterns among individuals with hemophilia A, who have similar factor VIII (FVIII) levels, is significant and the origins are unknown.Objective
To use a previously validated mathematical model of flow-mediated coagulation as a screening tool to identify parameters that are most likely to enhance thrombin generation in the context of FVIII deficiency.Methods
We performed a global sensitivity analysis (GSA) on our mathematical model to identify potential modifiers of thrombin generation. Candidates from the GSA were confirmed by calibrated automated thrombography (CAT) and flow assays on collagen-tissue factor (TF) surfaces at a shear rate of 100 per second.Results
Simulations identified low-normal factor V (FV) (50%) as the strongest modifier, with additional thrombin enhancement when combined with high-normal prothrombin (150%). Low-normal FV levels or partial FV inhibition (60% activity) augmented thrombin generation in FVIII-inhibited or FVIII-deficient plasma in CAT. Partial FV inhibition (60%) boosted fibrin deposition in flow assays performed with whole blood from individuals with mild and moderate FVIII deficiencies. These effects were amplified by high-normal prothrombin levels in both experimental models.Conclusions
These results show that low-normal FV levels can enhance thrombin generation in hemophilia A. Further explorations with the mathematical model suggest a potential mechanism: lowering FV reduces competition between FV and FVIII for factor Xa (FXa) on activated platelet surfaces (APS), which enhances FVIII activation and rescues thrombin generation in FVIII-deficient blood.
SUBMITTER: Link KG
PROVIDER: S-EPMC6994344 | biostudies-literature | 2020 Feb
REPOSITORIES: biostudies-literature
Link Kathryn G KG Stobb Michael T MT Sorrells Matthew G MG Bortot Maria M Ruegg Katherine K Manco-Johnson Marilyn J MJ Di Paola Jorge A JA Sindi Suzanne S SS Fogelson Aaron L AL Leiderman Karin K Neeves Keith B KB
Journal of thrombosis and haemostasis : JTH 20191101 2
<h4>Background</h4>The variability in bleeding patterns among individuals with hemophilia A, who have similar factor VIII (FVIII) levels, is significant and the origins are unknown.<h4>Objective</h4>To use a previously validated mathematical model of flow-mediated coagulation as a screening tool to identify parameters that are most likely to enhance thrombin generation in the context of FVIII deficiency.<h4>Methods</h4>We performed a global sensitivity analysis (GSA) on our mathematical model to ...[more]