The toxicology of heparin reversal with protamine: past, present and future

References

• Silvain J, Beygui F, Barthelemy O, et al. Efficacy and safety of enoxaparin versus unfractionated heparin during percutaneous coronary intervention: systematic review and meta-analysis. BMJ. 2012;344:e553.
   PubMed Web of Science ®Google Scholar
• Suranyi M, Chow JS. Review: anticoagulation for haemodialysis. Nephrology. 2010;15(4):386–392.
   PubMed Web of Science ®Google Scholar
• Mozzaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2015 update: a report from the American heart association. Circulation. 2015;131(4):e29–e322.
   Google Scholar
• Kaneda H, Suzuki J, Hosokawa G, et al. Impact of heparin neutralization by protamine on restenosis after coronary stent implantation. Int J Cardiol. 2005;105(1):111–112.
   PubMed Web of Science ®Google Scholar
• Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19(4):446–451.
   PubMed Web of Science ®Google Scholar
• Butterworth J, Lin YA, Prielipp R, et al. The pharmacokinetics and cardiovascular effects of a single intravenous dose of protamine in normal volunteers. Anesth Analg. 2002;94(3):514–522.
   PubMed Web of Science ®Google Scholar
• Ng HJ, Lee LH. Recombinant activated clotting factor VII (rFVIIa) in the treatment of surgical and spontaneous bleeding episodes in hemophilic patients. Vasc Health Risk Manag. 2006;2(4):433–434.
   PubMedGoogle Scholar
• Johansson PI. Off-label use of recombinant factor VIIa for treatment of haemorrhage: results from randomized clinical trials. Vox Sang. 2008;95(1):1–7.
   PubMed Web of Science ®Google Scholar
• Ansell J, Bakhru SH, Laulicht SS, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014;371(22):2141–2142.
   PubMed Web of Science ®Google Scholar
• Kalaska B, Sokolowska E, Kaminski K, et al. Cationic derivative of dextran reverses anticoagulant activity of unfractionated heparin in animal models of arterial and venous thrombosis. Eur J Pharmacol. 2012;686(1–3):81–89.
   PubMed Web of Science ®Google Scholar
• Kalaska B, Kaminski K, Sokolowska E, et al. Nonclinical evaluation of novel cationically modified polysaccharide antidotes for unfractionated heparin. PLoS One. 2015;10(3):e0119486.
   Google Scholar
• Sokolowska E, Kalaska B, Kaminski K, et al. The toxicokinetic profile of Dex40-GTMAC3 - a novel polysaccharide candidate for reversal of unfractionated heparin. Front Pharmacol. 2016;7:60.
   PubMed Web of Science ®Google Scholar
• Shenoi RA, Kalathottukaren MT, Travers RJ, et al. Affinity-based design of a synthetic universal reversal agent for heparin anticoagulants. Sci Transl Med. 2014;6(260):260ra150.
   PubMed Web of Science ®Google Scholar
• Lorkowska-Zawicka B, Kamiński K, Ciejka J, et al. Inactivation of heparin by cationically modified chitosan. Mar Drugs. 2014;12(7):3953–3969.
   PubMed Web of Science ®Google Scholar
• Kamiński K, Plonka M, Ciejka J, et al. Cationic derivatives of dextran and hydroxypropylcellulose as novel potential heparin antagonists. J Med Chem. 2011;54(19):6586–6596.
   PubMed Web of Science ®Google Scholar
• He H, Ye J, Liu E, et al. Low molecular weight protamine (LMWP): a nontoxic protamine substitute and an effective cell-penetrating peptide. J Control Release. 2014;10(193):63–73.
   Web of Science ®Google Scholar
• Bromfield SM, Wilde E, Smith DK. Heparin sensing and binding-taking supramolecular chemistry towards clinical applications. Chem Soc Rev. 2013;42(23):9184–9195.
   PubMed Web of Science ®Google Scholar
• Horrow JC. Protamine: a review of its toxicity. Anesth Analg. 1985;64(3):348–361.
   PubMed Web of Science ®Google Scholar
• Balhorn R. The protamine family of sperm nuclear proteins. Genome Biol. 2007;8(9):227.1–227.8.
   PubMed Web of Science ®Google Scholar
• Carr JA, Silverman N. The heparin-protamine interaction: a review. J Cardiovasc Surg. 1999;40(5):659–666.
   PubMed Web of Science ®Google Scholar
• Butterworth J, Lin YA, Prielipp RC, et al. Rapid disappearance of protamine in adults undergoing cardiac operation with cardiopulmonary bypass. Ann Thorac Surg. 2002;74(5):1589–1595.
   PubMed Web of Science ®Google Scholar
• Mochizuki T, Olson PJ, Szlam F, et al. Protamine reversal of heparin affects platelet aggregation and activated clotting time after cardiopulmonary bypass. Anesth Analg. 1998;87(4):781–785.
   PubMed Web of Science ®Google Scholar
• Chu AJ, Wang ZG, Raicu M, et al. Protamine inhibits tissue factor-initiated extrinsic coagulation. Br J Haematol. 2001;115(2):392–399.
   PubMed Web of Science ®Google Scholar
• Ni Ainle F, Preston RJS, Jenkins PV, et al. Protamine sulfate down-regulates thrombin generation by inhibiting factor V activation. Blood. 2009;114(8):1658–1665.
   PubMed Web of Science ®Google Scholar
• Mann KG, Kalafatis M. Factor V: a combination of Dr. Jekyll and Mr. Hyde. Blood. 2003;101(1):20–30.
   PubMed Web of Science ®Google Scholar
• Nielsen VG. Protamine enhances fibrinolysis by decreasing clot strength: role of tissue factor-initiated thrombin generation. Ann Thorac Surg. 2006;81(5):1720–1727.
   PubMed Web of Science ®Google Scholar
• Griffin MJ, Rinder HM, Smith BR, et al. The effects of heparin, protamine, and heparin/protamine reversal on platelet function under conditions of arterial shear stress. Anesth Analg. 2001;93(1):20–27.
   PubMed Web of Science ®Google Scholar
• Woltz M, Weltermann A, Nieszpaur-Los M, et al. Studies on the neutralizing effect of protamine on unfractionated and low molecular weight heparin (Fragmin) at the site of activation of the coagulation system in man. Thromb Haemost. 1995;73(3):439–443.
   PubMed Web of Science ®Google Scholar
• Crowther MA, Berry LR, Monagle PT, et al. Mechanisms responsible for the failure of protamine to inactivate low-molecular-weight heparin. Br J Haematol. 2002;116(1):178–186.
   PubMed Web of Science ®Google Scholar
• Zhao D, Sang Q, Cui H. Preparation and evaluation a new generation of low molecular weight heparin. Biomed Pharmacother. 2016;79:194–200.
   PubMed Web of Science ®Google Scholar
• DeLucia A 3rd, Wakefield TW, Kadell AM, et al. Tissue distribution, circulating half-life, and excretion of intravenously administered protamine sulfate. Asaio. 1993;39(3):M715–M18.
   Google Scholar
• Dougherty KG, Gaos CM, Bush HS, et al. Activated clotting times and activated partial thromboplastin times in patients undergoing coronary angioplasty who receive bolus doses of heparin. Cathet Cardiovasc Diagn. 1992;26(4):260–263.
   PubMedGoogle Scholar
• Whitman G, Martel D, Weiss M, et al. Reversal of protamine-induced catastrophic pulmonary vasoconstriction by prostaglandin E1. Ann Thorac Surg. 1990;50(2):303–305.
   PubMed Web of Science ®Google Scholar
• Chu YQ, Cai LJ, Jiang DC, et al. Allergic shock and death associated with protamine administration in a diabetic patient. Clin Ther. 2010;32(10):1729–1732.
   PubMed Web of Science ®Google Scholar
• Kimmel SE, Sekeres MA, Berlin JA, et al. Risk factor for clinically important adverse events after protamine administration following cardiopulmonary bypass. Am J Coll Cardiol. 1998;32(7):1916–1922.
   PubMed Web of Science ®Google Scholar
• Weitz JI, Hirsh J, Samama MM. American collage of chest physicans. New antithrombotic drugs: American collage of chest physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(6Suppl):234S–256S.
   Google Scholar
• Lakin JD, Blocker TJ, Strong DM, et al. Anaphylaxis to protamine sulfate mediated by a complement-dependent IgG antibody. J Allergy Clin Immunol. 1978;61(2):102–107.
   PubMed Web of Science ®Google Scholar
• Horiguchi T, Enzan K, Matsumoto J, et al. Marked systemic hypotension accopanied by pulmonary hypertension following protamine reversal of heparin: case report. J Anesth. 1994;8(4):503–505.
   Google Scholar
• Marin-Neto JA, Sykes MK, Marin JL, et al. Effect of heparin and protamine on left ventricular performance in the dog. Cardiovasc Res. 1979;13(5):254–259.
   PubMed Web of Science ®Google Scholar
• Wakefield TW, Hinshaw DB, Burger JM, et al. Protamine-induced reduction of endothelial cell ATP. Surgery. 1989;106(2):378–385.
   PubMed Web of Science ®Google Scholar
• Knape JT, Schuller JL, De Haan P, et al. An anaphylactic reaction to protamine in a patient allergic to fish. Aneasthesiology. 1981;55(3):324–325.
   PubMed Web of Science ®Google Scholar
• Stewart WJ, McSweeney SM, Kellett MA, et al. Increased risk of severe protamine reactions in NPH insulin-dependent diabetics undergoing cardiac catheterization. Circulation. 1984;70(5):788–792.
   PubMed Web of Science ®Google Scholar
• Adourian U, Shampaine EL, Hirshman CA, et al. High-titer protamine-specific IgG antibody associated with anaphylaxis: report of a case and quantitative analysis of antibody in vasectomized men. Anesthesiology. 1993;78(2):368–372.
   PubMed Web of Science ®Google Scholar
• Levy JH, Schweiger IM, Zaidan JR, et al. Evaluation of patients at risk for protamine reactions. J Throac Cardiovasc Surg. 1989;98(2):200–204.
   PubMed Web of Science ®Google Scholar
• Brooks JC. Noncardiogenic pulmonary edema immediately following rapid protamine administration. Ann Pharmacother. 1999;33(9):927–930.
   PubMed Web of Science ®Google Scholar
• Lowenstein E, Johnston WE, Lappas DG, et al. Catastrophic pulmonary vasoconstriction associated with protamine reversal of heparin. Anesthesiology. 1983;59(5):470–473.
   PubMed Web of Science ®Google Scholar
• Wakefield TW, Lindblad B, Stanley TJ, et al. Heparin and protamine use in peripheral vascular surgery: a comparison between surgeons of the society for vascular surgery and the European society for vascular surgery. Eur J Vasc Surg. 1994;8(2):193–198.
   PubMedGoogle Scholar
• Seifert HA, Jobes DR, Ten HT, et al. Adverse events after protamine administration following cardiopulmonary bypass in infants and children. Anesth Analg. 2003;97(2):383–389.
   PubMed Web of Science ®Google Scholar
• Welsby IJ, Newman MF, Phillips-Bute B, et al. Hemodynamic changes after protamine administration: association with mortality after coronary artery bypass surgery. Anesthesiology. 2005;102(2):308–314.
   PubMed Web of Science ®Google Scholar
• Weiler JM, Gellhaus MA, Carter JG, et al. A prospective study of the risk of an immediate adverse reaction to protamine sulfate during cardiopulmonary bypass surgery. J Allergy Clin Immunol. 1990;85(4):713–719.
   PubMed Web of Science ®Google Scholar
• Nybo M, Madsen JS. Serious anaphylactic reactions due to protamine sulfate: a systematic literature review. Basic Clin Pharmacol Toxicol. 2008;103(2):192–196.
   PubMed Web of Science ®Google Scholar
• Levy J, Zaidan JR, Faraj B. Prospective evaluation of risk of protamine reactions in patients with NPH insulin-dependent diabetes. Anesth Analg. 1986;65(7):739–742.
   PubMed Web of Science ®Google Scholar
• Fowler A, Baird M, Eberle D, et al. Attack rates and mortality of the adult respiratory distress syndrome in patients with known predispositions. Am Rev Respir Dis. 1983;125(4):77.
   Web of Science ®Google Scholar
• Hashim S, Kay H, Hammond G, et al. Noncardiogenic pulmonary edema after cardiopulmonary bypass: an anaphylactic reaction to fresh frozen plasma. Am J Surg. 1984;147(4):560–564.
   PubMed Web of Science ®Google Scholar
• Shapira N, Schaff HV, Piehler JM, et al. Cardiovascular effects of protamine sulfate in man. J Thorac Cardiovasc Surg. 1982;84(4):505–514.
   PubMed Web of Science ®Google Scholar
• Fadali MA, Ledbetter M, Papacostas CA, et al. Mechanism responsible for the cardiovascular depressant effect of protamine sulfate. Ann Surg. 1974;180(2):232–235.
   PubMed Web of Science ®Google Scholar
• Katz NM, Kim YD, Siegelman R, et al. Hemodynamics of protamine administration. Comparison of right atrial, left atrial, and aortic injections. J Thorac Cardiovasc Surg. 1987;94(6):881–886.
   PubMed Web of Science ®Google Scholar
• Pevni D, Gurevich J, Frolkis I, et al. Protamine induces vasorelaxation of human internal thoracic artery by endothelial NO-synthase pathway. Ann Thorac Surg. 2000;70(6):2050–2053.
   PubMed Web of Science ®Google Scholar
• Hines RL, Barash PG. Protamine does it alter right ventricular function? Anesth Analg. 1986;65(12):1271–1274.
   PubMed Web of Science ®Google Scholar
• Wakefield TW, Ucios I, Kresowik TF, et al. Decreased oxygen consumption as a toxic manifestation of protamine sulfate reversal of heparin anticoagulation. J Vasc Surg. 1989;9(6):772–777.
   PubMed Web of Science ®Google Scholar
• Pearson PJ, Evora PR, Ayrancioglu K, et al. Protamine releases endothelium-derived relaxing factor from systemic arteries. A possible mechanism of hypotension during heparin neutralization. Circulation. 1992;86(1):289–294.
   PubMed Web of Science ®Google Scholar
• Uruno T, Matsumoto R, Okushita K, et al. Possible mechanisms of inhibitory actions of protamine on contractile activity of rat aorta. J Pharm Pharmacol. 1985;37(7):476)–480.
   PubMed Web of Science ®Google Scholar
• Ignarro LJ, Gold ME, Buga GM, et al. Basic polyamino acids rich in arginine, lysine, or ornithine cause both enhancement of and refractoriness to formation of endothelium-derived nitric oxide in pulmonary artery and vein. Circ Res. 1989;64(2):315–329.
   PubMed Web of Science ®Google Scholar
• Horrow JC. Protamine allergy. J Cardiothorac Anesth. 1988;2(2):225–242.
   PubMedGoogle Scholar
• Friedman M, Johnson RG, Wang SY, et al. Pulmonary microvascular responses to protamine and histamine. Effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg. 1994;108(6):1092–1099.
   PubMed Web of Science ®Google Scholar
• Baraka A, Choueiry P, Taha S, et al. Hydrocortisone pretreatment for attenuation of protamine induced adverse hemodynamic reactions. J Cardiothorac Vasc Anesth. 1995;9(4):481–482.
   PubMed Web of Science ®Google Scholar
• Behne M, Bremerich D, Schiesser S, et al. Efficiency of hypotension prophylaxis with H1/H2 receptor antagonists before protamine administration. Infus Ther Transfusionsmed. 1994;21(2):81–85.
   PubMedGoogle Scholar
• Pretorius M, Scholl FG, McFarlane JA, et al. A pilot study indicating that bradykinin B2 receptor antagonism attenuates protamine-related hypotension after cardiopulmonary bypass. Clin Pharmacol Ther. 2005;78(5):477–485.
   PubMed Web of Science ®Google Scholar
• Buczko W, Kramkowski K, Mogielnicki A. Are the endothelial mechanisms of ACE-Is already established? Pharmacol Rep. 2006;58Suppl:126–131.
   Google Scholar
• Palmer RM, Rees DD, Ashton DS, et al. L-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. Biochem Biophys Res Commun. 1988;153(3):1251–1256.
   PubMed Web of Science ®Google Scholar
• Moncada S, Higgs AE. Endogenous nitric oxide: physiology, pathology and clinical relevance. Eur J Clin Invest. 1991;21(4):361–374.
   PubMed Web of Science ®Google Scholar
• Cylwik D, Mogielnicki A, Buczko W. L-arginine and cardiovascular system. Pharmacol Rep. 2005;57(1):14–22.
   PubMed Web of Science ®Google Scholar
• Cylwik D, Mogielnicki A, Kramkowski K, et al. Antithrombotic effect of L-arginine in hypertensive rats. J Physiol Pharmacol. 2004;55(3):563–574.
   PubMed Web of Science ®Google Scholar
• Nakaki T, Hishikawa K, Suzuki H, et al. L-arginine induced hypotension. Lancet. 1990;336(8716):696.
   PubMed Web of Science ®Google Scholar
• Evora PRB, Pearson PJ, Schaff HV. Protamine induces endothelium dependent vasodilatation of the pulmonary artery. Ann Thorac Surg. 1995;60(2):405–410.
   PubMed Web of Science ®Google Scholar
• Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases: structure, function and inhibition. Biochem J. 2001;357(Pt 3):593–615.
   PubMed Web of Science ®Google Scholar
• Hayashi Y, Sawa Y, Fukuyama N, et al. Inducible nitric oxide production is an adaptation to cardiopulmonary bypass-induced inflammatory response. Ann Thorac Surg. 2001;72(1):149–155.
   PubMed Web of Science ®Google Scholar
• Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991;43(2):109–142.
   PubMed Web of Science ®Google Scholar
• Ruvolo G, Greco E, Speziale G, et al. Nitric oxide formation during cardiopulmonary bypass. Ann Thorac Surg. 1994;57(4):1055–1057.
   PubMed Web of Science ®Google Scholar
• Wan S, DeSmet JM, Barvais L, et al. Myocardium is major source of proinflammatory cytokines in patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg. 1996;112(3):806–811.
   PubMed Web of Science ®Google Scholar
• Takakura K, Mizogami M, Fukuda S. Protamine sulfate causes endothelium-independent vasorelaxation via inducible nitric oxide synthase pathway. Can J Anesth. 2006;53(2):162–167.
   PubMed Web of Science ®Google Scholar
• Akata T, Kodama K, Yoshite J, et al. Heparin prevents the vasodilatating action of protamine on human small mesenteric arteries. Anesth Analg. 1993;76(6):1213–1221.
   PubMed Web of Science ®Google Scholar
• Orescanin-Dusic Z, Milovanovic S, Spasic MB, et al. Effect of protamine sulfate on the isolated mesenteric arteries of normotensive and a spontaneously hypertensive rats. Arch Biol Sci. 2008;60(2):163–168.
   Google Scholar
• Murase K, Naruse K, Kimura A, et al. Protamine augments stretch induced calcium increase in vascular endothelium. Br J Pharmacol. 2001;134(7):1403–1410.
   PubMed Web of Science ®Google Scholar
• Orescanin-Dusic Z, Milovanovic S, Radojicic R, et al. Effects of protamine sulphate on spontaneous and calcium-induced contractile activity in the rat uterus are potassium channels-mediated. Gen Physiol Biophys. 2009;28(SpecNo):143–148.
   PubMed Web of Science ®Google Scholar
• Golbasi I, Nacitarhan C, Ozdem S, et al. The inhibitory action of protamine on human internal thoracic artery contractions: the effect of free hemoglobin. Eur J Cardiothorac Surg. 2003;23(6):962–968.
   PubMed Web of Science ®Google Scholar
• Appiah J, Milovanovic S, Radojicic R, et al. Hydrogen peroxide affects contractile activity and antioxidant enzymes in rat uterus. Br J Pharmacol. 2009;158(8):1932–1941.
   PubMed Web of Science ®Google Scholar
• David JS, Vivien B, Lecarpentier Y, et al. Interaction of protamine with alpha- and beta-adrenoceptor stimulations in rat myocardium. Anesthesiology. 2001;95(5):1226–1233.
   PubMed Web of Science ®Google Scholar
• Hird RB, Crawford FA, Mukherjee R, et al. Effect of protamine on myocyte contractile function and β adrenergic responsiveness. Ann Thorac Surg. 1994;57(5):1066–1075.
   PubMed Web of Science ®Google Scholar
• Pugsley MK, Kalra V, Froebel-Wilson S. Protamine is a low molecular weight polycationic amine that produces actions on cardiac muscle. Life Sci. 2002;72(3):293–305.
   PubMed Web of Science ®Google Scholar
• Chudasama SL, Espinasse B, Hwang F, et al. Heparin modifies the immunogenicity of positively charged proteins. Blood. 2010;116(26):6046–6053.
   PubMed Web of Science ®Google Scholar
• Gurses KM, Kocyigit D, Yalcin MU, et al. Safety and efficacy outcomes of protamine administration for heparin reversal following cryoballoon-based pulmonary vein isolation. J Interv Card Electrophysiol. 2015;43(2):161–167.
   PubMed Web of Science ®Google Scholar
• Chilukuri K, Henrikson CA, Dalal D, et al. Incidence and outcomes of protamine reactions in patients undergoing catheter ablation of atrial fibrillation. J Interv Card Electrophysiol. 2009;25(3):175–181.
   PubMed Web of Science ®Google Scholar
• Bakchoul T, Zöllner H, Amiral J, et al. Anti-protamine-heparin antibodies: incidence, clinical relevance, and pathogenesis. Blood. 2013;121(15):2821–2827.
   PubMed Web of Science ®Google Scholar
• Lee GM, Welsby IJ, Phillips-Bute B, et al. High incidence of antibodies to protamine and protamine/heparin complexes in patients undergoing cardiopulmonary bypass. Blood. 2013;121(15):2828–2835.
   PubMed Web of Science ®Google Scholar
• Grieshaber P, Bakchoul T, Wilhelm J, et al. Platelet-activating protamine-heparin-antibodies lead to higher protamine demand in patients undergoing cardiac surgery. J Thorac Cardiovasc Surg. 2015;150(4):967–973.
   PubMed Web of Science ®Google Scholar
• Panzer S, Schiferer A, Steinlechner B, et al. Serological features of antibodies to protamine inducing thrombocytopenia and thrombosis. Clin Chem Lab Med. 2015;53(2):249–255.
   PubMed Web of Science ®Google Scholar
• Morel DR, Zapol WM, Thomas SJ, et al. C5a and thromboxane generation associated with pulmonary vaso- and broncho-constriction during protamine reversal of heparin. Anesthesiology. 1987;66(5):597–604.
   PubMed Web of Science ®Google Scholar
• Ocal A, Kiris I, Erdinc M, et al. Efficiency of prostacyclin in the treatment of protamine-mediated right ventricular failure and acute pulmonary hypertension. Tohoku J Exp Med. 2005;207(1):51–58.
   PubMed Web of Science ®Google Scholar
• Jastrzebski J, Sykes MK, Woods DG. Cardiorespiratory effects of protamine sulfate in man. Thorax. 1974;29(5):534–538.
   PubMed Web of Science ®Google Scholar
• Laubser PG. Effect of methylprednisolone on complement activation during heparin neutralization. J Cardiovasc Pharmacol. 1997;29(1):23–27.
   PubMed Web of Science ®Google Scholar
• Fairman RP, Sessler CN, Bierman M, et al. Protamine sulfate causes pulmonary hypertension and edema in isolated rat lungs. J Appl Physiol. 1987;62(4):1363–1367.
   PubMed Web of Science ®Google Scholar
• Morel DR, Lowenstein D, Nguyenduy T, et al. Acute pulmonary vasoconstriction and thromboxane release during protamine reversal of heparin anticoagulation in awake sheep: evidence for the role of reactive oxygen metabolites following nonimmunological complement activation. Circ Res. 1988;62(5):905–915.
   PubMed Web of Science ®Google Scholar
• Conzen PF, Habazettl H, Gutmann R, et al. Thromboxane mediation of pulmonary hemodynamic responses after neutralization of heparin by protamine in pigs. Anesth Analg. 1989;68(1):25–31.
   PubMed Web of Science ®Google Scholar
• Deggers RD, Foster ME, Dang AQ, et al. Pulmonary hypertensive effect of heparin and protamine interaction: evidence for thromboxane B2 release from the lung. Am J Surg. 1987;154(6):696–699.
   PubMed Web of Science ®Google Scholar
• Pearson PJ, Schaff HV, Vanhoutte PM. Long-term impairment of endothelium-dependent relaxations to aggregating platelets after reperfusion injury in canine coronary arteries. Circulation. 1990;81(6):1921–1927.
   PubMed Web of Science ®Google Scholar
• Berger GMB, Abraham PR. Selective protamine sulphate inactivation of lipoprotein lipase and hepatic lipase in human postheparin plasma: specific lipase levels in normals and in type I hyperlipoproteinaemia. Clin Chim Acta. 1977;81(3):219–228.
   PubMed Web of Science ®Google Scholar
• Harwood JL, Riley SE, Robinso DS. The action of protamine on clearing factor lipase and plasma triglyceride metabolism. Biochem Biophys Acta- Lipids and Lipid Metabolism. 1974;337(2):225–238.
   PubMed Web of Science ®Google Scholar
• Saito T, Sumithran E, Glasgow EF, et al. The enhancement of aminonucleoside nephrosis by co-administration of protamine. Kidney Int. 1987;32(5):691–699.
   PubMed Web of Science ®Google Scholar
• Vehaskari VM, Root ER, Germuth FG Jr, et al. Glomerular charge and urinary protein excretion: effects of systemic and intrarenal polycation infusion in the rat. Kidney Int. 1982;22(2):127–135.
   PubMed Web of Science ®Google Scholar
• Messina A, Davies DJ, Ryan GB. Protamine sulphate-induced proteinuria: the roles of glomerular injury and depletion of polyanion. J Pathol. 1989;158(2):147–156.
   PubMed Web of Science ®Google Scholar
• Adler SG, Wang H, Ward HJ, et al. Electrical charge. Its role in the pathogenesis and prevention of experimental membranous nephropathy in the rabbit. J Clin Invest. 1983;71(3):487–499.
   PubMed Web of Science ®Google Scholar
• Koslow AR, DeFouw DO, Farad MD, et al. Protamine-induced pulmonary edema in rats. Curr Surg. 1987;44(3):219–224.
   PubMedGoogle Scholar
• Cook JJ, Niewiarowski S, Yan Z, et al. Platelet factor 4 efficiently reverses heparin anticoagulation in the rat without adverse effects of heparin-protamine complexes. Circulation. 1992;85(3):1102–1109.
   PubMed Web of Science ®Google Scholar
• Chang SW, Voelkel NF. Charge-related lung microvascular injury. Am Rev Respir Dis. 1989;139(2):534–545.
   PubMed Web of Science ®Google Scholar
• Jenkins CSP, Packham MA, Kinlough-Rathbone RL, et al. Interactions of polylysine with platelets. Blood. 1971;37(4):395–412.
   PubMed Web of Science ®Google Scholar
• Eika C. On the mechanism of platelet aggregation induced by heparin, protamine and polybrene. Scand J Haematol. 1972;9(3):248–257.
   PubMedGoogle Scholar
• Olsson A, Alfredsson J, Hakansson E, et al. Protamine reduces whole blood platelet aggregation after cardiopulmonary bypass. Scand Cardiovasc J. 2016;50(1):58–63.
   PubMed Web of Science ®Google Scholar
• Schulman JH, Pethica BA, Few AV, et al. The physical chemistry of haemolysis and bacteriolysis by surface active agents and antibiotics. Progr Biophys. 1955;5:41–71.
   Web of Science ®Google Scholar
• Becker FF. Studies on the hemolytic properties of protamine. J Gen Physiol. 1961;44:433–442.
   PubMed Web of Science ®Google Scholar
• Ransdell HT, Haller JA Jr, Stowens D, et al. Renal toxicity of polybrene (hexadimethrine bromide). J Surg Res. 1965;5:195–199.
   PubMed Web of Science ®Google Scholar
• Jacobsen F, Hirsch T, Mittler D, et al. Polybrene improves transfection efficacy of recombinant replication-deficient adenovirus in cutaneous cells and burned skin. J Gene Med. 2006;8(2):138–146.
   PubMed Web of Science ®Google Scholar
• Kim BJ, Kim KJ, Kim YH, et al. Efficient enhancement of lentiviral transduction efficiency in murine spermatogonial stem cells. Mol Cells. 2012;33(5):449–455.
   PubMed Web of Science ®Google Scholar
• Zhao C, Wu N, Deng F, et al. Adenovirus-mediated gene transfer in mesenchymal stem cells can be significantly enhanced by the cationic polymer polybrene. PLoS One. 2014;9(3):e92908.
   PubMed Web of Science ®Google Scholar
• Kelton JG, Smith JW, Warkentin TE, et al. Immunoglobulin G from patients with heparin-induced thrombocytopenia binds to a complex of heparin and platelet factor 4. Blood. 1994;83(11):3232–3239.
   PubMed Web of Science ®Google Scholar
• Levy JH, Cormack JG, Morales A. Heparin neutralization by recombinant platelet factor 4 and protamine. Anesth Analg. 1995;81(1):35–37.
   PubMed Web of Science ®Google Scholar
• Demma L, Levy JH. A case series of recombinant platelet factor 4 for heparin reversal after cardiopulmonary bypass. Anesth Analg. 2012;115(6):1273–1278.
   PubMed Web of Science ®Google Scholar
• Rosenfeld SB, Watkinson KK, Thompson BH, et al. Pulmonary embolism after sequential use of recombinant factor VIIa and activated prothrombin complex concentrate in a factor VIII inhibitor patient. Thromb Haemost. 2002;87(5):925–926.
   PubMed Web of Science ®Google Scholar
• d’Oiron R, Menart C, Trzeciak MC, et al. Use of recombinant factor VIIa in 3 patients with inherited type I Glanzmann’s thrombasthenia undergoing invasive procedures. Thromb Haemost. 2000;83(5):644–647.
   PubMed Web of Science ®Google Scholar
• Peerlinck K, Vermylen J. Acute myocardial infarction following administration of recombinant activated factor VII (Novo Seven) in a patient with haemophilia A and inhibitor. Thromb Haemost. 1999;82(6):1775–1776.
   PubMed Web of Science ®Google Scholar
• Levi M, Levy JH, Andersen HF, et al. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010;363(19):1791–1800.
   PubMed Web of Science ®Google Scholar
• Mahan CE. A 1-year drug utilization evaluation of protamine in hospitalized patients to identify possible future roles of heparin and low molecular weight heparin reversal agents. J Thromb Thrombolysis. 2014;37(3):271–278.
   PubMed Web of Science ®Google Scholar
• Cushing DJ, Cooper WD, Cohen ML, et al. Reversal of heparin-induced increases in aPTT in the rat by PM102, a novel heparin antagonist. Eur J Pharmacol. 2010;635(1–3):165–170.
   PubMed Web of Science ®Google Scholar
• Gale AJ, Elias DJ, Averell PM, et al. Engineered virus-like nanoparticles reverse heparin anticoagulation more consistently than protamine in plasma from heparin-treated patients. Thromb Res. 2011;128(4):e9–e13.
   Google Scholar
• Lincoff AM, Mehran R, Povsic TJ, et al. Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): a randomised clinical trial. Lancet. 2016;387(10016):349–356.
   PubMed Web of Science ®Google Scholar
• Pollack CV, Reilly PA, Eikelboom J, et al. Idarucizumab for dabigatran reversal. N Engl J Med. 2015;373(6):511–520.
   PubMed Web of Science ®Google Scholar
• Kalaska B, Kaminski K, Sokolowska E, et al. Novel synthetic copolymers able to bind unfractionated and low molecular weight heparins. ISTH 2015 Congress; 2015 Jun 20–25; Toronto. 13(Suppl 2): 371(abstract).
   Google Scholar
• Crowther M, Kitt M, Lorenz T, et al. A phase 2 randomized, double blind placebo controlled trial of PRT064445, a novel, universal antidote for direct and indirect factor Xa inhibitors. J Thromb Haemost. 2013;11(Suppl2): AS20.1. Abstract no. 3636.
   Google Scholar
• Davidsson FÖ, Johagen D, Appelblad M, et al. Reversal of heparin after cardiac surgery: protamine titration using a statistical model. J Cardiothorac Vasc Anesth. 2015;29(3):710–714.
   PubMed Web of Science ®Google Scholar
• Bouraghda A, Gillois P, Albaladejo P. Alternatives to heparin and protamine anticoagulation for cardiopulmonary bypass in cardiac surgery. Can J Anaesth. 2015;62(5):518–528.
   PubMed Web of Science ®Google Scholar