title: Targeted clinical control of trauma patient coagulation through a thrombin dynamics model.
abstract: We present a methodology for personalizing the clinical treatment of severely injured patients with acute traumatic coagulopathy (ATC), an endogenous biological response of impaired coagulation that occurs early after trauma and shock and that is associated with increased bleeding, morbidity, and mortality. Despite biological characterization of ATC, it is not easily or rapidly diagnosed, not always captured by slow laboratory testing, and not accurately represented by coagulation models. This lack of knowledge, combined with the inherent time pressures of trauma treatment, forces surgeons to treat ATC patients according to empirical resuscitation protocols. These entail transfusing large volumes of poorly characterized, nontargeted blood products that are not tailored to an individual, the injury, or coagulation dynamics. Massive transfusion mortality remains at 40 to 70% in the best of trauma centers. As an alternative to blunt treatments, time-consuming tests, and mechanistic models, we used dynamical systems theory to create a simple, biologically meaningful, and highly accurate model that (i) quickly forecasts a driver of downstream coagulation, thrombin concentration after tissue factor stimulation, using rapidly measurable concentrations of blood protein factors and (ii) determines the amounts of additional coagulation factors needed to rectify the predicted thrombin dynamics and potentially remedy ATC. We successfully demonstrate in vitro thrombin control consistent with the model. Compared to another model, we decreased the mean errors in two key trauma patient parameters: peak thrombin concentration after tissue factor stimulation and the time until this peak occurs. Our methodology helps to advance individualized resuscitation of trauma-induced coagulation deficits.
authors.affiliation: California Institute for Quantitative Biosciences at University of California, Berkeley, 2151 Berkeley Way, Berkeley, CA 94704-5230, USA.|Environmental Genomics and Systems Biology Division at E. O. Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Mailstop 955-512L, Berkeley, CA 94720, USA.
authors.forename: Amor A
authors.initials: AA
authors.lastname: Menezes
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Ryan F
authors.initials: RF
authors.lastname: Vilardi
authors.affiliation: California Institute for Quantitative Biosciences at University of California, Berkeley, 2151 Berkeley Way, Berkeley, CA 94704-5230, USA. aparkin@lbl.gov mitchell.cohen@dhha.org.|Environmental Genomics and Systems Biology Division at E. O. Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Mailstop 955-512L, Berkeley, CA 94720, USA.|Department of Bioengineering, University of California, Berkeley, 2151 Berkeley Way, Berkeley, CA 94704-5230, USA.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Arkin
authors.affiliation: Department of Surgery, Denver Health Medical Center, 777 Bannock Street, Denver, CO 80204-0206, USA. aparkin@lbl.gov mitchell.cohen@dhha.org.|Department of Surgery, University of Colorado, 12631 East 17th Avenue, C-305, Aurora, CO 80045, USA.
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Cohen
mesh_terms: D000328:Adult; D000368:Aged; D001777:Blood Coagulation; D001778:Blood Coagulation Disorders / Q000628:therapy*; D001803:Blood Transfusion; D002138:Calibration; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013917:Thrombin / Q000737:chemistry* / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism; D013927:Thrombosis; D016896:Treatment Outcome; D014947:Wounds and Injuries / Q000628:therapy
chemical_list: D013925:Thromboplastin; D013917:Thrombin