Reduced model to predict thrombin and fibrin during thrombosis on collagen/tissue factor under venous flow: Roles of γ'-fibrin and factor XIa

PLoS Computational Biology
Jason Chen, Scott L Diamond

Abstract

During thrombosis, thrombin generates fibrin, however fibrin reversibly binds thrombin with low affinity E-domain sites (KD = 2.8 μM) and high affinity γ'-fibrin sites (KD = 0.1 μM). For blood clotting on collagen/tissue factor (1 TF-molecule/μm2) at 200 s-1 wall shear rate, high μM-levels of intraclot thrombin suggest robust prothrombin penetration into clots. Setting intraclot zymogen concentrations to plasma levels (and neglecting cofactor rate limitations) allowed the linearization of 7 Michaelis-Menton reactions between 6 species to simulate intraclot generation of: Factors FXa (via TF/VIIa or FIXa), FIXa (via TF/FVIIa or FXIa), thrombin, fibrin, and FXIa. This reduced model [7 rates, 2 KD's, enzyme half-lives~1 min] predicted the measured clot elution rate of thrombin-antithrombin (TAT) and fragment F1.2 in the presence and absence of the fibrin inhibitor Gly-Pro-Arg-Pro. To predict intraclot fibrin reaching 30 mg/mL by 15 min, the model required fibrinogen penetration into the clot to be strongly diffusion-limited (actual rate/ideal rate = 0.05). The model required free thrombin in the clot (~100 nM) to have an elution half-life of ~2 sec, consistent with measured albumin elution, with most thrombin (>99%) being fibrin-b...Continue Reading

References

Jan 1, 1992·Methods in Enzymology·M E NesheimK G Mann
Sep 1, 1980·Proceedings of the National Academy of Sciences of the United States of America·C Wolfenstein-Todel, M W Mosesson
Mar 15, 2002·The Journal of Biological Chemistry·Matthew F HockinKenneth G Mann
Jul 11, 2003·Pathophysiology of Haemostasis and Thrombosis·H Coenraad HemkerSuzette Béguin
Sep 17, 2003·Mathematical Medicine and Biology : a Journal of the IMA·Sharene D BungayRodney D Gentry
Oct 16, 2003·Journal of Theoretical Biology·Kalet LeónJorge Carneiro
Jul 13, 2005·The Journal of Experimental Medicine·Thomas RennéBernhard Nieswandt
Jun 29, 2007·Thrombosis and Haemostasis·Michael W Mosesson
Oct 11, 2007·Journal of the Royal Society, Interface·Zhiliang XuMark Alber
May 5, 2010·Mathematical Medicine and Biology : a Journal of the IMA·Karin Leiderman, Aaron L Fogelson
May 6, 2010·Biophysical Journal·Mikhail A PanteleevFazoil I Ataullakhanov
Oct 14, 2010·PLoS Computational Biology·Manash S ChatterjeeScott L Diamond
Jul 16, 2011·Arteriosclerosis, Thrombosis, and Vascular Biology·Rehana S LovelyDavid H Farrell
Apr 21, 2012·Arteriosclerosis, Thrombosis, and Vascular Biology·Thomas V ColaceScott L Diamond
Apr 21, 2012·Blood·Matthew H FlammScott L Diamond
Oct 23, 2012·Arteriosclerosis, Thrombosis, and Vascular Biology·Ryan W Muthard, Scott L Diamond
Apr 25, 2014·Thrombosis Research·Karin Leiderman, Aaron Fogelson
Aug 4, 2015·Annual Review of Fluid Mechanics·Aaron L Fogelson, Keith B Neeves
Feb 6, 2016·Journal of Thrombosis and Haemostasis : JTH·Lawrence F Brass, Scott L Diamond
Apr 30, 2016·Circulation Research·Scott L Diamond
Jun 25, 2016·Integrative Biology : Quantitative Biosciences From Nano to Macro·Shu ZhuScott L Diamond
Dec 22, 2016·Biophysical Journal·Priscilla Elizondo, Aaron L Fogelson
Mar 30, 2017·Mathematical Biosciences·Tatiana GalochkinaVitaly Volpert
Apr 27, 2017·Biophysical Journal·Laura M HaynesKathleen E Brummel-Ziedins

❮ Previous
Next ❯

Citations

Jun 17, 2020·Biophysical Journal·Christian J C BiscombeDalton J E Harvie
May 20, 2021·TH Open : Companion Journal to Thrombosis and Haemostasis·Malebogo N NgoepeWei Hua Ho

❮ Previous
Next ❯

Methods Mentioned

BETA
ELISA

Software Mentioned

Matlab
COMSOL

Related Concepts

Related Feeds

Blood Clotting Disorders

Thrombophilia includes conditions with increased tendency for excessive blood clotting. Blood clotting occurs when the body has insufficient amounts of specialized proteins that make blood clot and stop bleeding. Here is the latest research on blood clotting disorders.