To Örebro University

Introduction: During cardiac surgery, dosing of protamine to reverse heparin after cardiopulmonary bypass is delicate. Overdosing of protamine with negative effects on coagulation1 and platelet function2,3 must be balanced against underdosing with inadequate neutralization of heparin. Modern protamine titration equipments have led to lower doses ofprotamine being used.4 We studied possible remaining or rebound heparin activity after reversal with protamine using a commercial titration system.

Methods: Forty elective CABG patients were included with blood samples collected at arrival to the intensive care unit (ICU) and three hours after arrival to the ICU. The dose of heparin and protamine was calculated by a titration system using a dose response curve. The need for additional protamine was assessed with the titration system at the end of surgery, and additional protamine was given if heparin was detected. Presence of heparin at ICU arrival and at 3 hours was measured by anti-factor Xa (anti-FXa), thrombin time (TT) and aPTT. Coagulation capacity was assessed with endogenous thrombin potential (ETP). Postoperative bleeding was registered after 3 hours and after drain removal. Data are presented as mean ± SD or median and interquartile range (IQR) depending on normality. Association of variables was assessed with Spearman’s rank correlation and linear regression. For categorical variables Fishers exact test was used and for comparison of groups the Wilcoxon test wasused.

Results: The patients received 30 800 ± 6 300 units (U) of heparin. The mean protamine/heparin ratio (P/H ratio) was 0.54 (±0.14) mg/100 U, with a range from 0.25 to 0.84 mg/100 U. At arrival to the ICU (81 (IQR 34) minutes after protamine) 63% of the patients had measurable anti-FXa levels, and median anti-FXa was 0.09 (IQR 0.25) U/mL. Median TT at ICU arrival was 19.7 (IQR 6.4) seconds (s), aPTT was 27.5 (IQR 8.0) s and ETP 603 (IQR 899) U. Anti-FXa correlated significantly to both APTT (r=0.50, p=0.0018) and TT (r=0.66, p<0.001). ETP correlated negatively to anti-FXa (r=-0.57, p<0.001). There was an inverse relation between the P/H ratio and TT (r=-0.48; p=0.004) and aPTT (r=-0.50; p=0.0015) at ICU arrival. There was also an inverse relation between P/H ratio and anti-FXa (r=-0.32; p=0,054) and a positive correlation between P/H ratio and ETP (r=0.41; p=0.012) (Figure 1). Three hours after ICU arrival all but one of the patients had detectable levels of anti-FXa (p<0.001), and over-all anti-FXa had increased slightly to 0.17 (IQR 0.15) U/mL (p=0.11 vs ICU arrival). TT had increased to 22.9 (IQR 8.0) s (p=0.019) and ETP dropped to 215 (IQR 403) U (p<0.001). At this time point however there was no correlation between P/H ratio, heparin or protamine dose on one hand and heparin activity (anti-FXa, TT) or coagulation potential ETP on the other. The total postoperative bleeding was 623 (IQR 290) mL of which 185 (IQR 140) mL was during the first three hours. Bleeding during the first 3 hours did not correlate to P/H ratio or heparin markers and thrombin generation at ICU arrival.

Conclusions: At ICU arrival, 81 minutes after protaminization, most patients showed remaining heparin activity. This activity was directly related to prior dose of protamine. Heparin activity increased during the following 3 hours but did not correlate to protamine dosing or bleeding. The study is consistent with prior data describing reappearance of heparin in the postoperative period independent of the dosing of protamine5. The lack of relation between postoperative heparin activity and postoperative bleeding underlines that other factors than remaining or rebound heparin plays an important role for postoperative bleeding after cardiac surgery.

References:

Protamine sulfate down-regulates thrombin generation by inhibiting factor V activation. 114(8):1658-1665. 2009

Protamine stimulates platelet aggregation in vitro with activation of the fibrinogen receptor and alpha-granule release, but impairs secondary activation via ADP and thrombin receptors. 32(1):90-96. 2021

Platelet Function is Preserved After Moderate Cardiopulmonary Bypass Times But Transiently Impaired After Protamine. 37(7):1110-1120. 2023

Anticoagulation management during multivessel coronary artery bypass grafting: a randomized trial comparing individualized heparin management and conventional hemostasis management. 13(7):1196-1206. 2015

Reappearance of circulating heparin in whole blood heparin concentration-based management does not correlate with postoperative bleeding after cardiac surgery. 28(4): 1003-1007. 2014