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Abstract: Background: The Abbreviated Injury Scale (AIS) recently underwent a major revision from AIS 98 to AIS 05. AIS injury codes form the basis of widely used injury severity scores such as the injury severity score (ISS). ISS thresholds are often used in trauma case definitions and ISS is widely used in injury research to adjust for injury severity. This study evaluated changes from AIS 98 to AIS 05, the changes’ effect on ISS distributions, and presents an application of the results. Methods: Injury descriptions from medical records of 137 randomly selected patients in the Oklahoma Trauma Registry (OTR) were obtained. A single trained coder used AIS 98 and AIS 05 to code each injury. ISS values were calculated and grouped into 4 categories: 1–8, 9–14, 16–24, >24. Paired ISS was compared using Kappa statistics and tests of symmetry. We identified common injury diagnoses for which AIS severity changed between versions. Estimates of the proportion of patients changing ISS groups were applied to the entire OTR to assess the impact on reporting and on a model for reimbursement. Results: OTR AIS 98 and manual AIS 98-based ISS values had a weighted Kappa of 0.71. OTR AIS 98 and manual AIS 05-based ISS values had a Kappa of 0.58. Manual AIS 98 and manual AIS 05 ISS had the highest Kappa of 0.81, however, though the scores differed by only 1 ISS category, there were 30 discordant pairs. The distribution of these discordant pairs was not symmetrical (Bowker''s S =30; df =6; p <0.0001) with AIS 05-based ISS values consistently shifted to a lower ISS category. Reductions in AIS severity and ISS values using AIS 05 were common for extremity fractures and thorax injuries. The results suggest fewer patients would be reported to the OTR or be eligible for reimbursement. Discussion: Changing from AIS 98 to AIS 05 injury coding resulted in systematic changes in AIS codes and ISS. Specific injuries and body regions were differentially affected. Trauma registries and injury researchers that use AIS based injury coding can use this information to evaluate the potential impact of changes in AIS 2005. [Copyright &y& Elsevier]

Andexanet alfa is a Gla-domainless mutant (S195A) factor Xa (GDXa) approved for acute reversal of oral factor Xa inhibitors. Cardiac surgery patients exposed to andexanet before cardiopulmonary bypass often exhibit severe heparin resistance. There is a paucity of data on the effectiveness and optimal dosage of antithrombin use in this setting. The objective of this study was to evaluate the in vitro effect of increased heparin with antithrombin levels on attenuating heparin resistance induced by GDXa. Heparinised normal pooled plasma and cardiopulmonary bypass plasma were spiked with GDXa 4 μM. Tissue factor-activated thrombin generation was used to assess heparin reversal effects of GDXa and restoration of anticoagulation with additional heparin with and without antithrombin. Serum thrombin–antithrombin complex, antithrombin activity, and tissue factor pathway inhibitor were also measured in tissue factor-activated, recalcified cardiopulmonary bypass plasma spiked with GDXa. In normal pooled plasma, GDXa-induced heparin reversal was mitigated by maintaining a high heparin concentration (12 U ml−1) and supplementing antithrombin (1.5–4.5 μM) based on peak and velocity of thrombin generation. Heparin reversal by GDXa was also demonstrated in cardiopulmonary bypass plasma, but supplementing both heparin (8 U ml−1) and antithrombin (3 μM) attenuated GDXa-induced changes in peak and velocity of thrombin generation by 72.5% and 72.2%, respectively. High heparin and antithrombin levels attenuated thrombin–antithrombin complex formation in tissue factor-activated, GDXa-spiked cardiopulmonary bypass plasma by 85.7%, but tissue factor pathway inhibitor remained depleted compared with control cardiopulmonary bypass plasma. Simultaneous supplementation of heparin and antithrombin mitigate GDXa-induced heparin resistance by compensating for the loss of tissue factor pathway inhibitor. [ABSTRACT FROM AUTHOR]

Andexanet alfa is a Gla-domainless FXa (GDXa) analog used as an antidote to FXa inhibitors. Despite its clinical use, laboratory monitoring for anti-Xa reversal and the effect of andexanet on fibrinolysis has not been explored. We used a GDXa with a serine-to-alanine mutation at position 195 (chymotrypsin numbering) to model the interaction between andexanet and apixaban. Six batches of pooled plasma, and whole blood from healthy volunteers were treated with increasing concentrations of apixaban with/without GDXa. Thrombin generation and plasmin generation (TG and PG) were tested in plasma, and whole blood thrombus formation was tested using thromboelastometry or a flow-chamber system. FXa was also tested in isolation for its ability to support plasmin activation with/without apixaban and GDXa. Apixaban (250–800 nM) concentration-dependently decreased the velocity and peak of TG in plasma. Apixaban prolonged the onset of thrombus formation in thromboelastometry and flow-chamber tests. GDXa normalized apixaban-induced delays in TG and whole blood thrombus formation. However, GDXa minimally affected the low PG velocity and peak caused by apixaban at higher concentrations (500–800 nM). FXa promoted plasmin generation independent of fibrin that was inhibited by apixaban at supratherapeutic concentrations. This study demonstrated the feasibility of assessing coagulation lag time recovery in plasma and whole blood following in vitro apixaban reversal using GDXa, a biosimilar to andexanet. In contrast, GDXa-induced changes in plasmin generation and fibrinolysis were limited in PG and tPA-added ROTEM assays, supporting the endogenous profibrinolytic activity of FXa and its inhibition at elevated apixaban concentrations. Schemata of putative mechanisms of factor Xa modulation of plasmin generation. A trace amount of fibrin initiates the formation of plasmin (Pln), which proteolyzes phospholipid-bound factor Xaα into Xaβ. The latter is further proteolyzed by plasmin into a heterodimer of 33 kDa and 13 kDa fragments (Xa33/13). Both Xaβ and Xa33/13 express carboxy-terminal lysine residues (⊕ in yellow) to which plasminogen (Plg) can be bound and subsequently activated by tissue plasminogen activator (tPA), facilitating the initiation of fibrinolysis. After binding of apixaban to factor Xaα, thrombin (IIa) generation is slowed down (|| in red), and Xa33/13 formation is blocked (× in red), resulting in reduced velocities of plasmin generation. [Display omitted] • Gla-domainless factor Xa S195A (GDXa) is useful in modeling a factor Xa inhibitor reversal with andexanet alpha in vitro • Profibrinolytic activity of factor Xa is inhibited by apixaban. • Despite the recovery of thrombin generation, GDXa had minimal effect on the changes in plasmin generation and fibrinolysis at elevated apixaban concentrations. [ABSTRACT FROM AUTHOR]