Tranexamic Acid Failed to Reverse the Anticoagulant Effect and Bleeding by an Oral Direct Factor Xa Inhibitor Edoxaban

Background/Aims: Agents to reverse the anticoagulant effect of edoxaban, an oral direct factor Xa inhibitor, would be desirable in emergency situations. The aim of this study is to determine the effect of tranexamic acid, an antifibrinolytic agent, on the anticoagulant activity and bleeding by edoxaban in rats. Methods: A supratherapeutic dose of edoxaban (3 mg/kg) was intravenously administered to rats. Three minutes after dosing, tranexamic acid (100 mg/kg) was given intravenously. Bleeding was induced by making an incision with a blade on the planta 8 min after edoxaban injection and bleeding time was measured. Prothrombin time (PT) and clot lysis were examined. Results: A supratherapeutic dose of edoxaban significantly prolonged PT and bleeding time. Tranexamic acid did not affect PT or bleeding time prolonged by edoxaban, although tranexamic acid significantly inhibited clot lysis in rat plasma. Conclusion: An antifibrinolytic agent tranexamic acid failed to reverse the anticoagulant effect and bleeding by edoxaban in rats.

Short-term Use of Tranexamic Acid to Reduce Blood Loss in Endoscopic Nasal Surgeries

ABSTRACT Objective To evaluate the effect of tranexamic acid, an antifibrinolytic agent, in reduction of surgical hemorrhage during endoscopic nasal surgery. Design Comparative analysis of the use of tranexamic acid in 200 patients undergoing endoscopic nasal surgery and its demonstrable reduction of hemorrhage and improvement of visibility of operative field. Subjects Around 200 patients with varied indications underwent endoscopic nasal surgery; 100 were given tranexamic acid perioperatively and 100 did not receive tranexamic acid and were used as a control. Selection of patients was done on random basis. We used the following parameters to measure intraoperative blood loss: Visibility of field of surgery, weight of blood swabs postoperatively and amount of blood from suction machine. Result Patient who received tranexamic acid showed reduction of blood loss amounting to 72.48% (p < 0.05). This reduction was compared with results published by other authors using various kinds of anesthesia. Conclusions Tranexamic acid is an antifibrinolytic agent which inhibits the action of plasmin. There is also reduction in blood level of D-dimer. It is seen to significantly reduce intraoperative blood loss during endoscopic nasal surgery. Additionally, there seems to be no alteration of coagulation parameters or untoward systemic effects. The consequent improvement in surgical field visibility is of great benefit which is encouraging and should prompt further trials.

Engineering Kunitz Domain of Human Tissue Factor Pathway Inhibitor-2 to Selectively Inhibit Fibrinolysis: An Antifibrinolytic Agent with Potential to Replace Aprotinin

Tissue factor pathway inhibitor-2 (TFPI-2) inhibits factor XIa, plasma kallikrein and factor VIIa/tissue factor; accordingly, it has been proposed for use as an anticoagulant. Full-length TFPI-2 or its isolated first Kunitz domain (KD1) also inhibits plasmin and therefore it has been proposed for use as an antifibrinolytic agent. However, the anticoagulant properties of TFPI-2 or KD1 would diminish its antifibrinolytic function. In this report, structure based investigations and analysis of the serine proteases profiles revealed that coagulation enzymes prefer a hydrophobic residue at the P2′ (nomenclature of Schechter and Berger, BBRC, 27:157–162, 1967) position in their substrates/inhibitors, whereas plasmin prefers a positively charged arginine residue at the corresponding position in its substrates/inhibitors. Based upon this observation, we changed the P2′ residue Leu17 (bovine pancreatic trypsin inhibitor/aprotinin numbering) in KD1 to Arg (KD1-L17R) and compared its inhibitory properties with the wild-type KD1 (KD1-WT). Both WT and KD1-L17R were expressed in E. Coli, folded and purified to homogeneity. Amino-terminal sequences and mass spectra revealed proper folding of the KD1-WT and KD1-L17R. As compared to KD1-WT, the KD1-L17R neither prolonged the activated partial thromboplastin time of normal plasma nor it inhibited factor XIa, plasma kallikrein or factor VIIa/tissue factor. Further, KD1-L17R inhibited plasmin with ~4-fold increased affinity. In a mouse liver laceration model of bleeding from small vessels, KD1-L17R reduced total blood loss by 84% compared with KD1-WT, which reduced total blood loss by 10%. Moreover, in this bleeding model, KD1-L17R was more effective than aprotinin (70% reduction), which has been used as an antifibrinolytic agent to decrease blood loss during major surgery. In this model, KD1-L17R was also more effective than the lysine analogue tranexamic acid (52% reduction). In additional studies, in a tail transection model of bleeding from a large vessel, KD1-L17R reduced total blood loss by 70% and was more effective than KD1-WT (46% reduction), aprotinin (43% reduction) and tranexamic acid (67% reduction). Notably, as compared to aprotinin, renal toxicity manifesting as multifocal tubular necrosis by histopathology was not observed with KD1-L17R or KD1-WT. In conclusion, KD1-L17R is a specific inhibitor of plasmin without anticoagulant properties and is more effective in reducing blood loss compared with known antifibrinolytic agents in clinical use.