Utility and safety of nafamostat mesilate for anticoagulation in dogs

Abstract

Background: Surgical interventions are recommended for cases of advanced mitral regurgitation, however, limited facilities are available. The most prominent complication in such procedures is heparin-derived bleeding. An alternative anticoagulant to heparin, nafamostat mesilate (NM), can reduce the occurrence of complications associated with heparin such as bleeding or shock.

Objectives: This study aimed to evaluate the utility and safety of using NM during anaesthesia in canines.

Methods: Six healthy adult Beagle dogs were anaesthetised, and NM was administered intravenously as a 10 mg/kg bolus dose over 5 min, followed by a continuous infusion of 10 mg/kg/h over 20 min. Blood tests and blood pressure measurements were performed at 0, 5, 25 and 55 min after NM administration.

Results: Activated thromboplastin times at 0, 25 and 55 min were 13.0 ± 0.7 s, 106.7 ± 13.3 s and 28.2 ± 2.9 s, respectively, with a significant difference between 0 and 25 min (p < 0.01) only. No significant differences were observed in prothrombin time, antithrombin, fibrinogen and fibrin degradation product concentrations between timepoints. Activated clotting times (ACTs) at 0, 5, 25 and 55 min were 119.5 ± 9.6 s, 826.7 ± 78.6 s, 924.8 ± 42.4 s and 165.2 ± 13.5 s, respectively. Significant differences were observed between 0 and 5 min (p < 0.05) and between 0 and 25 min (p < 0.05). Blood pressure changes occurred in four dogs (66.7%). No other serious adverse effects were observed.

Conclusions: ACT results indicated that NM use in anaesthetised healthy dogs was sufficient to obtain procedural anticoagulation with minimal adverse effects. However, these preliminary data require validation in further studies on cardiopulmonary bypass surgery.

Keywords: anticoagulants; cardiac surgery; cardiopulmonary bypass; mitral valve insufficiency.

FIGURE 1

(a) Box and whisker plots for the blood clotting system analysis. Significant differences were observed in APTT (in seconds) between 0 versus 25 min (p < 0.01). There were no significant differences between any of the other time points. There were no significant differences in PT (seconds) and Fib (mg/dl), AT (%), FDP (µg/ml) concentrations between the different time points. Black lines represent the median values, and the error bars represent the range. (b) Box and whisker plots for the blood clotting system analysis. ACT (seconds) was measured at baseline (0 min), after 5 min of bolus administration (5 min), after 20 min of CRI administration (25 min), and after 30 min of a washout period (55 min). Significant differences were observed between 0 versus 5 min (p < 0.05) and 0 versus 25 min (p < 0.05). Black lines represent the median values, and the error bars represent the range. * and ** indicate statistical significance at a p‐value of <0.05 and < 0.01, respectively. ACT, activated clotting time; APTT, activated thromboplastin time; AT, antithrombin; FDP, fibrin degradation products; Fib, fibrinogen; PT, prothrombin time; CRI, continuous rate infusion.

FIGURE 2

Box and whisker plots of the blood clotting system analysis. The white blood cell (WBC; in per µl) counts at 0, 25, and 55 min are displayed. There were significant differences between 0 versus 25 min (p < 0.05); however, there were no significant differences between the other time intervals. There were no significant differences in the haematocrit (%) and platelet (10⁴/µl) counts. The black lines represent the median values and the error bars represent the range. * indicates statistical significance at a p‐value of <0.05.

FIGURE 3

Box and whisker plots of the blood clotting system analysis. Significant differences were observed in the total protein (in g/dl), albumin (g/dl), and chloride (mEq/L) levels between 0 versus 25 min (p < 0.05). There were significant differences in the potassium (mEq/L) concentrations between 0 versus 55 min (p < 0.05). The black lines represent the median values and the error bars represent the range. *Statistical significance at a p‐value of <0.05.

FIGURE 4

Box and whisker plots of the blood clotting system analysis. The systolic blood pressure (SYS; in mmHg), diastolic blood pressure (DIA; mmHg), mean blood pressure (mmHg) and heart rate (HR; beats per minute). All data were collected at baseline (0 min), after 5 min of bolus administration (5 min), after 20 min of continuous rate infusion administration (25 min) and after a 30 min washout period (55 min). There were no significant differences between any of the parameters investigated at any time period. The black lines represent the median values, and the error bars represent the range.