Protamine reversal of heparin affects platelet aggregation and activated clotting time after cardiopulmonary bypass.
Bleeding after cardiopulmonary bypass (CPB) is related to multiple factors. Excess protamine weakens clot structure and decreases platelet function; therefore, an increased activated clotting time (ACT) after protamine reversal of heparin may be misinterpreted as residual heparin anticoagulation. We evaluated the effects of protamine, recombinant platelet factor 4 (rPF4), and hexadimethrine on ACT in blood obtained after CPB. In addition, we examined the effect of protamine on in vitro platelet aggregation. Incremental doses of protamine, rPF4, and hexadimethrine were added to heparinized blood from CPB, and ACTs were performed. Incremental concentrations of protamine were added to heparinized platelet-rich plasma, and aggregometry was induced by adenosine diphosphate (ADP) and collagen. The mean heparin concentration at the end of CPB was 3.3 U/mL. Protamine to heparin ratios >1.3:1 produced a significant prolongation of the ACT that was not seen with rPF4 and was observed only with 5:1 hexadimethrine to heparin ratios. ADP-induced platelet aggregation was reduced with protamine administration > or =1.3:1. Excessive protamine reversal of heparin prolongs ACT and alters ADP-induced platelet aggregation in a dose-dependent manner in vitro. Additional protamine administered to treat a prolonged ACT may further increase clotting time, reduce platelet aggregation, and potentially contribute to excess bleeding after CPB.


CONCLUSIONS
We found that excess protamine prolonged the activated clotting time and altered platelet function after cardiopulmonary bypass, whereas heparin antagonists, such as recombinant platelet factor 4 and hexadimethrine, exhibited a wider therapeutic range without adversely affecting the activated clotting time. Approaches to avoid excess protamine or use of alternative heparin antagonists after cardiopulmonary bypass may be beneficial.
Department of Anesthesiology, Emory University School of Medicine, The Emory Clinic, Atlanta, Georgia, USA.
T
T
Mochizuki
P J
PJ
Olson
F
F
Szlam
J G
JG
Ramsay
J H
JH
Levy
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000925:Anticoagulants / Q000494:pharmacology*; D002315:Cardiopulmonary Bypass; D003094:Collagen / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006493:Heparin / Q000494:pharmacology*; D006494:Heparin Antagonists / Q000494:pharmacology*; D006583:Hexadimethrine Bromide / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D010978:Platelet Factor 4 / Q000494:pharmacology; D011479:Protamines / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D014914:Whole Blood Coagulation Time
D000925:Anticoagulants; D006494:Heparin Antagonists; D010975:Platelet Aggregation Inhibitors; D011479:Protamines; D011994:Recombinant Proteins; D010978:Platelet Factor 4; D006583:Hexadimethrine Bromide; D000244:Adenosine Diphosphate; D006493:Heparin; D003094:Collagen