Efficacy of pro- and anticoagulant strategies in plasma of patients undergoing hepatobiliary surgery

Abstract

Background: In vitro efficacy of pro- and antihemostatic drugs is profoundly different in patients with compensated cirrhosis and in those who have cirrhosis and are critically ill.

Objectives: Here we assessed the efficacy of pro- and anticoagulant drugs in plasma of patients undergoing hepato-pancreato-biliary (HPB) surgery, which is associated with unique hemostatic changes.

Methods: We performed in vitro analyses on blood samples of 60 patients undergoing HPB surgery and liver transplantation: 20 orthotopic liver transplantations, 20 partial hepatectomies, and 20 pylorus-preserving pancreaticoduodenectomies. We performed thrombin generation experiments before and after in vitro addition of fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), recombinant factor VIIa (rFVIIa), low molecular weight heparin (LMWH), unfractionated heparin, dabigatran, and rivaroxaban.

Results: We showed that patients undergoing HPB surgery are in a hypercoagulable state by thrombin generation testing. FFP and rFVIIa had minimal effects on thrombin generation, whereas PCC had a more pronounced procoagulant effect in patients compared with controls. Dabigatran showed a more pronounced anticoagulant effect in patients compared with controls, whereas rivaroxaban and LMWH had a decreased anticoagulant effect in patients.

Conclusion: We demonstrate profoundly altered in vitro efficacy of commonly used anticoagulants, in patients undergoing HPB surgery compared with healthy controls, which may have implications for anticoagulant dosing in the early postoperative period. In the correction of perioperative bleeding complications, PCCs appear much more potent than FFP or rFVIIa, and PCCs may require conservative dosing and caution in use in patients undergoing HPB surgery.

Keywords: anticoagulants; hepatectomy; liver transplantation; plasma; thrombin.

FIGURE 1

Absolute ETP levels from thrombomodulin modified thrombin generation testing in plasma of controls, and patients during OLT before (−) and after (+) in vitro addition of prohemostatic agents. Start is after induction of anesthesia, anhep is 30 minutes after the start of the anhepatic phase, reperf is 30 minutes after reperfusion, and end is at the end of surgery. Shown are medians with error bars indicating interquartile ranges, and the proportional difference in ETP upon addition of procoagulants. Statistical differences indicated are differences in proportional change in ETP upon addition of procoagulants between controls and patients. *P < .05 vs controls, **P < .01 vs controls, ***P < .001 vs controls. FFP, fresh frozen plasma; PCC, prothrombin complex concentrate; rFVIIa, recombinant factor VIIa

FIGURE 2

Absolute ETP levels from thrombomodulin modified thrombin generation testing in plasma of controls, and patients after OLT before (−) and after (+) in vitro addition of anticoagulants. Start is after induction of anesthesia, POD, postoperative day. Shown are medians with error bars indicating interquartile ranges, and the proportional difference in ETP upon addition of anticoagulants. Statistical differences indicated are differences in proportional change in ETP upon addition of anticoagulants between controls and patients. ***P < .001 vs controls. Dabi, dabigatran; LMWH, low molecular weight heparin; Riva, rivaroxaban; UFH, unfractionated heparin

FIGURE 3

Absolute ETP levels from thrombomodulin modified thrombin generation testing in plasma of controls, and patients during partial hepatectomy before (−) and after (+) in vitro addition of prohemostatic agents. Start is after induction of anesthesia, end is at the end of surgery. Shown are medians with error bars indicating interquartile ranges, and the proportional difference in ETP upon addition of procoagulants. Statistical differences indicated are differences in proportional change in ETP upon addition of procoagulants between controls and patients. ***P < .001 vs controls. FFP, fresh frozen plasma; PCC, prothrombin complex concentrate; rFVIIa, recombinant factor VIIa

FIGURE 4

Absolute ETP levels from thrombomodulin modified thrombin generation testing in plasma of controls, and patients after partial hepatectomy before (−) and after (+) in vitro addition of anticoagulants. Start is after induction of anesthesia, POD, postoperative day. Shown are medians with error bars indicating interquartile ranges, and the proportional difference in ETP upon addition of anticoagulants. Statistical differences indicated are differences in proportional change in ETP upon addition of anticoagulants between controls and patients. *P < .05 vs controls, **P < .01 vs controls, ***P < .001 vs controls. Dabi, dabigatran; LMWH, low molecular weight heparin; Riva, rivaroxaban; UFH, unfractionated heparin

FIGURE 5

Absolute ETP levels from thrombomodulin modified thrombin generation testing in plasma of controls, and patients after PPPD before (−) and after (+) in vitro addition of prohemostatic agents. Start is after induction of anesthesia, end is at the end of surgery. Shown are medians with error bars indicating interquartile ranges, and the proportional difference in ETP upon addition of procoagulants. Statistical differences indicated are differences in proportional change in ETP upon addition of procoagulants between controls and patients. *P < .05 vs controls, **P < .01 vs controls, ***P < .001 vs controls. FFP, fresh frozen plasma; PCC, prothrombin complex concentrate; rFVIIa, recombinant factor VIIa

FIGURE 6

Absolute ETP levels from thrombomodulin modified thrombin generation testing in plasma of controls, and patients after PPPD before (−) and after (+) in vitro addition of anticoagulants. Start is after induction of anesthesia. POD, postoperative day. Shown are medians with error bars indicating interquartile ranges, and the proportional difference in ETP upon addition of anticoagulants. Statistical differences indicated are differences in proportional change in ETP upon addition of anticoagulants between controls and patients. *P < .05 vs controls, **P < .01 vs controls, ***P < .001 vs controls. Dabi, dabigatran; LMWH, low molecular weight heparin; Riva, rivaroxaban; UFH, unfractionated heparin