Effect of high or low protamine dosing on postoperative bleeding following heparin anticoagulation in cardiac surgery

Michael I. Meesters; Dennis Veerhoek; Fellery de Lange; Jacob-Willem de Vries; Jan R. de Jong; Johannes W. A. Romijn; Hilde Kelchtermans; Dana Huskens; Robin van der Steeg; Pepijn W. A. Thomas; David T. M. Burtman; Laurentius J. M. van Barneveld; Alexander B. A. Vonk; Christa Boer

doi:10.1160/TH16-02-0117

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 116(02): 251-261
DOI: 10.1160/TH16-02-0117

Coagulation and Fibrinolysis

Schattauer GmbH

Effect of high or low protamine dosing on postoperative bleeding following heparin anticoagulation in cardiac surgery

A randomised clinical trial

Authors

Michael I. Meesters

¹Department of Anaesthesiology, VU University Medical Centre, Amsterdam, the Netherlands
Dennis Veerhoek

²Cardio-thoracic Surgery, VU University Medical Centre, Amsterdam, the Netherlands
Fellery de Lange

³Department of Anaesthesiology, Department of Cardiac Anaesthesiology, Medical Centre Leeuwarden, Leeuwarden, the Netherlands
Jacob-Willem de Vries

³Department of Anaesthesiology, Department of Cardiac Anaesthesiology, Medical Centre Leeuwarden, Leeuwarden, the Netherlands
Jan R. de Jong

¹Department of Anaesthesiology, VU University Medical Centre, Amsterdam, the Netherlands
Johannes W. A. Romijn

¹Department of Anaesthesiology, VU University Medical Centre, Amsterdam, the Netherlands
Hilde Kelchtermans

⁴Synapse B. V., Maastricht, the Netherlands
Dana Huskens

⁴Synapse B. V., Maastricht, the Netherlands
Robin van der Steeg

¹Department of Anaesthesiology, VU University Medical Centre, Amsterdam, the Netherlands
Pepijn W. A. Thomas

¹Department of Anaesthesiology, VU University Medical Centre, Amsterdam, the Netherlands
David T. M. Burtman

¹Department of Anaesthesiology, VU University Medical Centre, Amsterdam, the Netherlands
Laurentius J. M. van Barneveld

²Cardio-thoracic Surgery, VU University Medical Centre, Amsterdam, the Netherlands
Alexander B. A. Vonk

²Cardio-thoracic Surgery, VU University Medical Centre, Amsterdam, the Netherlands
Christa Boer

¹Department of Anaesthesiology, VU University Medical Centre, Amsterdam, the Netherlands

Abstract

Summary

While experimental data state that protamine exerts intrinsic anticoagulation effects, protamine is still frequently overdosed for heparin neutralisation during cardiac surgery with cardiopulmonary bypass (CPB). Since comparative studies are lacking, we assessed the influence of two protamine-to-heparin dosing ratios on perioperative haemostasis and bleeding, and hypothesised that protamine overdosing impairs the coagulation status following cardiac surgery. In this open-label, multicentre, single-blinded, randomised controlled trial, patients undergoing on-pump coronary artery bypass graft surgery were assigned to a low (0.8; n=49) or high (1.3; n=47) protamine-to-heparin dosing group. The primary outcome was 24-hour blood loss. Patient haemostasis was monitored using rotational thromboelastometry and a thrombin generation assay. The low protamine-to-heparin dosing ratio group received less protamine (329 ± 95 vs 539 ± 117 mg; p<0.001), while post-protamine activated clotting times were similar among groups. The high dosing group revealed increased intrinsic clotting times (236 ± 74 vs 196 ± 64 s; p=0.006) and the maximum post-protamine thrombin generation was less suppressed in the low dosing group (38 ± 40% vs 6 ± 9%; p=0.001). Postoperative blood loss was increased in the high dosing ratio group (615 ml; 95% CI 500–830 ml vs 470 ml; 95% CI 420–530 ml; p=0.021) when compared to the low dosing group, respectively. More patients in the high dosing group received fresh frozen plasma (11% vs 0%; p=0.02) and platelet concentrate (21% vs 6%; p=0.04) compared to the low dosing group. Our study confirms in vitro data that abundant protamine dosing is associated with increased postoperative blood loss and higher transfusion rates in cardiac surgery.

Keywords

Heparins - coagulation factors - thrombin - blood products - surgery

Full Text

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