Mitrophanov2013 - Simulation of Hockin Blood Coagulation Model under reduced temperature
Blood coagulation model using an updated Hockin2002 model. New reactions for factor X and V activation by IXa and mIIa respectively (reactions R28 and R29, parameters k43 and k44). Changes to parameters k32 and k38 (appendix not found for cited reference [Danforth 2009] so parameters from Mitrophanov2011 were used). Model introduces formula for adjusting kinetic rates for reduced temperatures.
- Computational analysis of the effects of reduced temperature on thrombin generation: the contributions of hypothermia to coagulopathy.
- Mitrophanov AY, Rosendaal FR, Reifman J
- Anesthesia and analgesia , 9/ 2013 , Volume 117 , Issue 3 , pages: 565-574
- or Jaques Reifman, PhD, DoD Biotechnology High-Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, ATTN: MCMR-TT, 504 Scott St., Fort Detrick, Frederick, MD 21702. firstname.lastname@example.org.
- BACKGROUND: Hypothermia, which can result from tissue hypoperfusion, body exposure, and transfusion of cold resuscitation fluids, is a major factor contributing to coagulopathy of trauma and surgery. Despite considerable efforts, the mechanisms of hypothermia-induced blood coagulation impairment have not been fully understood. We introduce a kinetic modeling approach to investigate the effects of hypothermia on thrombin generation. METHODS: We extended a validated computational model to predict and analyze the impact of low temperatures (with or without concomitant blood dilution) on thrombin generation and its quantitative parameters. The computational model reflects the existing knowledge about the mechanistic details of thrombin generation biochemistry. We performed the analysis for an "average" subject, as well as for 472 subjects in the control group of the Leiden Thrombophilia Study. RESULTS: We computed and analyzed thousands of kinetic curves characterizing the generation of thrombin and the formation of the thrombin-antithrombin complex (TAT). In all simulations, hypothermia in the temperature interval 31°C to 36°C progressively slowed down thrombin generation, as reflected by clotting time, thrombin peak time, and prothrombin time, which increased in all subjects (P < 10(-5)). Maximum slope of the thrombin curve was progressively decreased, and the area under the thrombin curve was increased in hypothermia (P < 10(-5)); thrombin peak height remained practically unaffected. TAT formation was noticeably delayed (P < 10(-5)), but the final TAT levels were not significantly affected. Hypothermia-induced fold changes in the affected thrombin generation parameters were larger for lower temperatures, but were practically independent of the parameter itself and of the subjects' clotting factor composition, despite substantial variability in the subject group. Hypothermia and blood dilution acted additively on the thrombin generation parameters. CONCLUSIONS: We developed a general computational strategy that can be used to simulate the effects of changing temperature on the kinetics of biochemical systems and applied this strategy to analyze the effects of hypothermia on thrombin generation. We found that thrombin generation can be noticeably impaired in subjects with different blood plasma composition even in moderate hypothermia. Our work provides mechanistic support to the notion that thrombin generation impairment may be a key factor in coagulopathy induced by hypothermia and complicated by blood plasma dilution.
|Mitrophanov2013.xml||SBML L2V4 representation of Mitrophanov2013 - Simulation of Hockin Blood Coagulation Model under reduced temperature||219.90 KB||Preview | Download|
|Mitrophanov2013.cps||Model COPASI file. Changes from Hockin2002 include base kinetic rate of k32 and k38. New reactions (R28 and R29) and parameters (k43 and k44).||259.26 KB||Preview | Download|