title: Computational analysis of the effects of reduced temperature on thrombin generation: the contributions of hypothermia to coagulopathy.
abstract: 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.
authors.affiliation: From the DoD Biotechnology High-Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, Fort Detrick, Frederick, Maryland; and Departments of Clinical Epidemiology and Thrombosis and Haemostasis, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Mitrophanov
authors.forename: Frits R
authors.initials: FR
authors.lastname: Rosendaal
authors.forename: Jaques
authors.initials: J
authors.lastname: Reifman
mesh_terms: D000465:Algorithms; D000991:Antithrombins / Q000378:metabolism; D019540:Area Under Curve; D001778:Blood Coagulation Disorders / Q000097:blood* / Q000209:etiology*; D001831:Body Temperature / Q000502:physiology; D006438:Hemodilution; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007035:Hypothermia / Q000097:blood*; D007700:Kinetics; D015233:Models, Statistical; D011517:Prothrombin Time; D013917:Thrombin / Q000378:metabolism*; D014914:Whole Blood Coagulation Time
chemical_list: D000991:Antithrombins; D013917:Thrombin