title: Effects of an acidic environment on coagulation dynamics.
abstract: Essentials Acidosis, an outcome of traumatic injury, has been linked to impaired procoagulant efficiency. In vitro model systems were used to assess coagulation dynamics at pH 7.4 and 7.0. Clot formation dynamics are slightly enhanced at pH 7.0 in blood ex vivo. Acidosis induced decreases in antithrombin efficacy offset impairments in procoagulant activity.
  
  
  
  Background Disruption of hydrogen ion homeostasis is a consequence of traumatic injury often associated with clinical coagulopathy. Mechanisms by which acidification of the blood leads to aberrant coagulation require further elucidation. Objective To examine the effects of acidified conditions on coagulation dynamics using in vitro models of increasing complexity. Methods Coagulation dynamics were assessed at pH 7.4 and 7.0 as follows: (i) tissue factor (TF)-initiated coagulation proteome mixtures (±factor [F]XI, ±fibrinogen/FXIII), with reaction progress monitored as thrombin generation or fibrin formation; (ii) enzyme/inhibitor reactions; and (iii) TF-dependent or independent clot dynamics in contact pathway-inhibited blood via viscoelastometry. Results Rate constants for antithrombin inhibition of FXa and thrombin were reduced by ~ 25-30% at pH 7.0. At pH 7.0 (+FXI), TF-initiated thrombin generation showed a 20% increase in maximum thrombin levels and diminished thrombin clearance rates. Viscoelastic analyses showed a 25% increase in clot time and a 25% reduction in maximum clot firmness (MCF). A similar MCF reduction was observed at pH 7.0 when fibrinogen/FXIII were reacted with thrombin. In contrast, in contact pathway-inhibited blood (n = 6) at pH 7.0, MCF values were elevated 6% (95% confidence interval [CI]: 1%-11%) in TF-initiated blood and 15% (95% CI: 1%- 29%) in the absence of TF. Clot times at pH 7.0 decreased 32% (95% CI: 15%-49%) in TF-initiated blood and 51% (95% CI: 35%-68%) in the absence of TF. Conclusions Despite reported decreased procoagulant catalysis at pH 7.0, clot formation dynamics are slightly enhanced in blood ex vivo and suppression of thrombin generation is not observed. A decrease in antithrombin reactivity is one potential mechanism contributing to these outcomes.
authors.affiliation: Department of Biochemistry, University of Vermont, Colchester, VT, USA.
authors.forename: M
authors.initials: M
authors.lastname: Gissel
authors.affiliation: Department of Biochemistry, University of Vermont, Colchester, VT, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Brummel-Ziedins
authors.affiliation: Department of Biochemistry, University of Vermont, Colchester, VT, USA.
authors.forename: S
authors.initials: S
authors.lastname: Butenas
authors.affiliation: US Army Medical Research and Materiel Command, Fort Detrick, MD, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Pusateri
authors.affiliation: Haematologic Technologies, Essex Junction, VT, USA.
authors.forename: K G
authors.initials: KG
authors.lastname: Mann
authors.affiliation: Department of Biochemistry, University of Vermont, Colchester, VT, USA. torfeo@uvm.edu.
authors.forename: T
authors.initials: T
authors.lastname: Orfeo
mesh_terms: D000138:Acidosis / Q000097:blood*; D000990:Antithrombin III / Q000032:analysis; D001777:Blood Coagulation / Q000187:drug effects*; D001778:Blood Coagulation Disorders; D001780:Blood Coagulation Tests / Q000379:methods*; D004548:Elasticity; D005337:Fibrin / Q000032:analysis; D005340:Fibrinogen / Q000494:pharmacology; D064368:Healthy Volunteers; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007477:Ions; D020543:Proteome; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013925:Thromboplastin / Q000494:pharmacology; D013997:Time Factors; D014783:Viscosity
chemical_list: D007477:Ions; D020543:Proteome; D000990:Antithrombin III; D005337:Fibrin; D005340:Fibrinogen; D013925:Thromboplastin; D013917:Thrombin
keywords: acidosis; blood coagulation; blood coagulation factor inhibitors; thromboelastography; trauma