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.

Epidural analgesia in hepatic resection.

BACKGROUND: Randomized trials show equivocal benefit of epidural analgesia (EA) for patients undergoing abdominal operations. Partial hepatectomy is often performed using low central venous pressure anesthesia to reduce intraoperative blood loss. We examined effects of pain management strategy on blood pressure, transfusion, and complications in patients undergoing hepatic resection with either EA or IV analgesia (IVA). STUDY DESIGN: Data on patients undergoing hepatectomy from 2001 to 2004 at Emory University Hospital were analyzed according to route of perioperative pain management. Patient and treatment factors were analyzed for associations with transfusion and morbidity. RESULTS: From 2001 through 2004, 367 patients underwent elective partial hepatectomy at Emory University Hospital. EA patients were more likely to be older, men, and with malignancy. There were no differences between the groups in extent of resection, operative time, blood loss, or starting hematocrit level. The EA group had lower mean arterial pressure in recovery (86.6+/-14.0 mmHg versus 94.5+/-13.2 mmHg, p < 0.001) and were more likely to be transfused with packed red cells during the hospital course (44.5% versus 27.9%, p < 0.001). On multivariate analysis, age greater than 65 years, American Society of Anesthesiologists grade>2, starting hematocrit<38%, operative time>300 minutes, blood loss>1 L, and use of EA were associated with increased numbers of patients receiving packed red blood cells. Complications and length of stay were similar for both groups. CONCLUSIONS: Epidural analgesia was independently associated with increased risk of packed red blood cell transfusion after hepatectomy. EA did not appear to minimize complications or shorten hospital stay. Caution should be exercised when considering EA use in hepatic resection.