Antithrombin supplementation attenuates heparin resistance in plasma spiked with Gla-domainless factor Xa S195A in vitro.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Simultaneous supplementation of heparin and antithrombin mitigate GDXa-induced heparin resistance by compensating for the loss of tissue factor pathway inhibitor.

Viscoelastic coagulation monitoring for tranexamic acid: personalised antifibrinolytic dosing?

Ex vivo viscoelastic testing can be used to assess the concentration responses to tranexamic acid in blood samples obtained from pregnant women across the three trimesters and in non-pregnant controls. Minor variations in fibrinolysis across pregnancy suggest a target tranexamic acid blood concentration of 12.5 mg L-1 for complete inhibition of fibrinolysis. Although the data support the potential utility of viscoelastic testing using the ClotPro® TPA test in maintaining therapeutic tranexamic acid concentrations during postpartum haemorrhage, it might obscure potentially crucial endogenous fibrinolysis inhibitor interactions essential to the microcirculation.

In vitro effects of Gla-domainless factor Xa analog on procoagulant and fibrinolytic pathways in apixaban-treated plasma and whole blood.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Trends and predictions of perioperative transfusion and venous thromboembolism in hepatectomy using a North American Registry.

BACKGROUND: Studies indicate a link between allogeneic blood transfusion and venous thromboembolism (VTE) post-major surgery. Analyzing trends and predictors of these outcomes after hepatectomy can inform risk management. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was used for a retrospective analysis. Primary outcomes were perioperative red blood cell (RBC) transfusion and VTE events within 30 days of hepatectomy. Seven-year trends and predictors were evaluated. RESULTS: Among 29,131 hepatectomy patients, transfusion rates showed no statistically significant decreasing trends (p = .122) from 2014 to 2020 (18.13%-16.71%), while VTE rates showed a downward trend over the 7 years (p = .021); 17.2% received RBC transfusion, with higher rates in surgeries lasting ≥282 min (median: 220 min). Calculated RBC mass [hematocrit (%) × body weight (kg) × 10-5 × 70/ √ (body mass index/22)] at or below 1.5 L substantially increased transfusion odds. VTE was reported postoperatively in 2.6% of cases more frequently in longer cases involving transfusions. The adjusted odds ratio (aOR) of VTE escalated from the shortest operative time to the longest (3.17; 95% confidence interval [CI], 2.37-4.22). The adjusted odds of VTE doubled for transfused patients compared to non-transfused patients (aOR, 2.19; 95% CI, 1.86-2.57). CONCLUSIONS: Rates of RBC transfusion and VTE rates hepatectomy have minimally changed in the recent years. VTE prevention is challenging in extended surgeries at increased risk of bleeding and RBC transfusions. Patient-level data on coagulation and thromboprophylaxis can potentially refine risk assessment for postoperative VTE.