Effect of high or low protamine dosing on postoperative bleeding following heparin anticoagulation in cardiac surgery. A randomised clinical trial

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

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)251-261
Number of pages11
JournalThrombosis and Haemostasis
Volume116
Issue number2
DOIs
Publication statusPublished - 1 Aug 2016

Cite this

Meesters, Michael I ; Veerhoek, Dennis ; de Lange, Fellery ; de Vries, Jacob-Willem ; de Jong, Jan R ; Romijn, Johannes W A ; Kelchtermans, Hilde ; Huskens, Dana ; van der Steeg, Robin ; Thomas, Pepijn W A ; Burtman, David T M ; van Barneveld, Laurentius J M ; Vonk, Alexander B A ; Boer, Christa. / Effect of high or low protamine dosing on postoperative bleeding following heparin anticoagulation in cardiac surgery. A randomised clinical trial. In: Thrombosis and Haemostasis. 2016 ; Vol. 116, No. 2. pp. 251-261.
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title = "Effect of high or low protamine dosing on postoperative bleeding following heparin anticoagulation in cardiac surgery. A randomised clinical trial",
abstract = "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",
author = "Meesters, {Michael I} and Dennis Veerhoek and {de Lange}, Fellery and {de Vries}, Jacob-Willem and {de Jong}, {Jan R} and Romijn, {Johannes W A} and Hilde Kelchtermans and Dana Huskens and {van der Steeg}, Robin and Thomas, {Pepijn W A} and Burtman, {David T M} and {van Barneveld}, {Laurentius J M} and Vonk, {Alexander B A} and Christa Boer",
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Meesters, MI, Veerhoek, D, de Lange, F, de Vries, J-W, de Jong, JR, Romijn, JWA, Kelchtermans, H, Huskens, D, van der Steeg, R, Thomas, PWA, Burtman, DTM, van Barneveld, LJM, Vonk, ABA & Boer, C 2016, 'Effect of high or low protamine dosing on postoperative bleeding following heparin anticoagulation in cardiac surgery. A randomised clinical trial' Thrombosis and Haemostasis, vol. 116, no. 2, pp. 251-261. https://doi.org/10.1160/TH16-02-0117

Effect of high or low protamine dosing on postoperative bleeding following heparin anticoagulation in cardiac surgery. A randomised clinical trial. / Meesters, Michael I; Veerhoek, Dennis; de Lange, Fellery; de Vries, Jacob-Willem; de Jong, Jan R; Romijn, Johannes W A; Kelchtermans, Hilde; Huskens, Dana; van der Steeg, Robin; Thomas, Pepijn W A; Burtman, David T M; van Barneveld, Laurentius J M; Vonk, Alexander B A; Boer, Christa.

In: Thrombosis and Haemostasis, Vol. 116, No. 2, 01.08.2016, p. 251-261.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Effect of high or low protamine dosing on postoperative bleeding following heparin anticoagulation in cardiac surgery. A randomised clinical trial

AU - Meesters, Michael I

AU - Veerhoek, Dennis

AU - de Lange, Fellery

AU - de Vries, Jacob-Willem

AU - de Jong, Jan R

AU - Romijn, Johannes W A

AU - Kelchtermans, Hilde

AU - Huskens, Dana

AU - van der Steeg, Robin

AU - Thomas, Pepijn W A

AU - Burtman, David T M

AU - van Barneveld, Laurentius J M

AU - Vonk, Alexander B A

AU - Boer, Christa

PY - 2016/8/1

Y1 - 2016/8/1

N2 - 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.

AB - 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.

KW - Heparins

KW - coagulation factors

KW - thrombin

KW - blood products

KW - surgery

U2 - 10.1160/TH16-02-0117

DO - 10.1160/TH16-02-0117

M3 - Article

VL - 116

SP - 251

EP - 261

JO - Thrombosis and Haemostasis

JF - Thrombosis and Haemostasis

SN - 0340-6245

IS - 2

ER -