A new mechanism of the protamine-dependent hypotension after cardiopulmonary bypass and the role of calcium

Suna Aydin; Suleyman Aydin

doi:10.14715/cmb/2019.65.6.6

Issue

Vol. 65 No. 6: Issue 6

Issue Published : August 5, 2019

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A new mechanism of the protamine-dependent hypotension after cardiopulmonary bypass and the role of calcium

https://doi.org/10.14715/cmb/2019.65.6.6

Suna Aydin

Cardiovascular Surgery Department, Elazig Research and Education Hospital, Health Science University, 23119 Elazig. Turkey

Suleyman Aydin

Department of Medical Biochemistry and Clinical Biochemistry (Firat Hormones Research group); Firat University Hospital, Elazig 23119, Turkey

Corresponding Author(s) : Suna Aydin

saydin1@hotmail.com

Cellular and Molecular Biology, Vol. 65 No. 6: Issue 6
Article Published : July 31, 2019

Abstract

Heparin and protamine are two indispensable agents of cardiopulmonary bypass surgery with effects on the cardiovascular and hematological system. Heparin is used as an anticoagulant in open heart surgery; whereas protamine is used to neutralize heparin effects when surgery is terminated. Protamine is given in order to neutralize heparin effects after cardiopulmonary bypass surgery and it causes hypotension in patients. However, the mechanism of this side effect is not clearly known. Current mechanism is that hypotension occurs after the administration of protamine due to the conformational change in the calcium channels or anaphylactoid thromboxane release or serum ionized calcium levels. The present study was to explain how protamine causes hypotension in evidence-based medicine indexed in PubMed and Web of Science. In addition to above mechanisms, possibly the infused protamine binds heparin and causes the coagulation cascade to activate heparin-AT complex on thrombin beside activating FXIa, FXa and FIXa and causing the re-use of Ca2+. The re-use of Ca2+ at the coagulation cascade initiates an anion gap and it is assumed that hypotension develops because of the Ca2+ deficiency. Ca2+ ions are trapped in the thrombus by the resumption of thrombus formation. Ca2+ ions trapped in the thrombus cannot be used, so that Ca2+ ion deficit will develop in circulation and hypotension occurs due to the insufficiency of Ca2+ ions. The administration of Ca2+ ions together with the protamine might help to eliminate the side effect of the protamine (hypotension) while neutralizing heparin after open heart surgery in light of the information provided in the literature.

Keywords

Calcium Cardiopulmonary bypass Heparin Hypotension Protamine.

Aydin, S., & Aydin, S. (2019). A new mechanism of the protamine-dependent hypotension after cardiopulmonary bypass and the role of calcium. Cellular and Molecular Biology, 65(6), 28–32. https://doi.org/10.14715/cmb/2019.65.6.6

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References

Hurt R. The History of Cardiothoracic Surgery. The Parthenon Publishing Group. London. 1996.
Aylin O, Oztekin O. Dünden Bugüne Kalp Cerrahisi. GKDC Dergisi 1999; 7:1-6.
Aydin S, Aydin S, Nesimi Eren M, Sahin I, Yilmaz M, Kalayci M, et al. The cardiovascular system and the biochemistry of grafts used in heart surgery. Springerplus 2013; 2:612.
Nakayama DK. The Development of Extracorporeal Membrane Oxygenation. Am Surg 2018; 84:587-92.
Erik J, Sixten K, Harry B. Protamine for Intravenous Use in Man and in Animal Experiments. Acta Med Scand 1949; CXXXIV:444-7.
Rezaie AR. Prothrombin protects factor Xa in the prothrombinase complex from inhibition by the heparin-antithrombin complex. Blood 2001; 97:2308-13.
Reichert HA. Rath TE. Cardiac Surgery in Developing Countries. J Extra Corpor Technol 2017; 49:98-106.
Kellett DN. On the mechanism of the anti-inflammatory activity of hexadimethrine bromide. Br J Pharmacol Chemother. 1966; 26:351-7.
Bahandari M, Hirsh J, Weitz JI, Young E, Venner TJ, Shaughnessy SG. The effects of standard and low molecular weight heparin on bone module formation in vitro. Thromb Haemost 1998; 80:413-7.
Teoh KH, Young E, Blackall MH, Roberts RS, Hirsh J. Can extra protamine eliminate heparin rebound following cardiopulmonary bypass surgery? J Thorac Cardiovasc Surg 2004; 128:211-9.
Töbü S. [Antikoagülan Tedavi]. Türk Hematoloji Derneği - Temel Hemostaz Tromboz Kursu. 2007; 08-09. Eylül. http://www.thd.org.tr/thdData/userfiles/file/2007thtk_15.pdf
Hurwitz L, Von Hagen S, Joiner PD. Acetylcholine and calcium on membrane permeability and contraction of intestinal smooth muscle. J Gen Physiol 1967; 50:1157-72.
Cox MH, O SJ, Clair MJ, Mukherjee R, Wakefield TW, Andrews PC, et al. Differential effects of novel protamine variants on myocyte contractile function with left ventricular failure. Surgery 1997; 121:304-13.
Kisilevsky AE, Zamponi GW. Presynaptic calcium channels: structure, regulators, and blockers. Handb Exp Pharmacol 2008; 184:45-75.
Marshall CB, Nishikawa T, Osawa M, Stathopulos PB, Ikura M. Calmodulin and STIM proteins: Two major calcium sensors in the cytoplasm and endoplasmic reticulum. Biochem Biophys Res Commun 2015; 460:5-21.
Wortsman J, Traycoff RB. Biological activity of protein-bound calcium in serum. Am J Physiol 1980; 238:E104-7.
Wang S, McDonnell EH, Sedor FA, Toffaletti JG. pH effects on measurements of ionized calcium and ionized magnesium in blood. Arch Pathol Lab Med 2002; 126:947-50.
Power ML, Heaney RP, Kalkwarf HJ, Pitkin RM, Repke JT, Tsang RC, et al. The role of calcium in health and disease. Am J Obstet Gynecol 1999; 181:1560-9.
Tertti R, Harmoinen A, Leskinen Y, Metsärinne KP, Saha H. Comparison of calcium phosphate product values using measurement of plasma total calcium and serum ionized calcium. Hemodial Int 2007; 11:411-6.
Triplett DA. Coagulation and bleeding disorders: review and update. Clin Chem 2000; 46:1260-9.
Palta S, Saroa R, Palta A. Overview of the coagulation system. Indian J Anaesth 2014; 58:515-23.
Smith SA, Travers RJ, Morrissey JH. How it all starts: Initiation of the clotting cascade. Crit Rev Biochem Mol Biol 2015; 50:326-36.
Stenflo J, Fernlund P, Egan W, Roepstorff P. Vitamin K dependent modifications of glutamic acid residues in prothrombin. Proc Natl Acad Sci U S A 1974; 71:2730-3.
Petrou T, Olsen HL, Thrasivoulou C, Masters JR, Ashmore JF, Ahmed A. Intracellular Calcium Mobilization in Response to Ion Channel Regulators via a Calcium-Induced Calcium Release Mechanism. J Pharmacol Exp Ther 2017; 360:378-87.
Lee GM, Welsby IJ, Phillips-Bute B, Ortel TL, Arepally GM. High incidence of antibodies to protamine and protamine/heparin complexes in patients undergoing cardiopulmonary bypass. Blood 2013; 121:2828-35.
Biala G, Kruk-Slomka M, Jozwiak K. Influence of acute or chronic calcium channel antagonists on the acquisition and consolidation of memory and nicotine-induced cognitive effects in mice. Naunyn Schmiedebergs Arch Pharmacol 2013; 386:651-64.
Schwartz JB. Calcium antagonists in the elderly. A risk-benefit analysis. Drug Aging 1996; 9:24-36.
Massry SG, Iseki K, Campese VM. Serum calcium, parathyroid hormone, and blood pressure. Am J Nephrol 1986; 6:19-28.
Massry SG, Smogorzewski M. The effects of serum calcium and parathyroid hormone and the interaction between them on blood pressure in normal subjects and in patients with chronic kidney failure. J Ren Nutr 2005; 15:173-7.
Goto H, Kushihashi T, Benson KT, Kato H, Fox DK, Arakawa K. Heparin, protamine, and ionized calcium in vitro and in vivo. Anesth Analg 1985; 64:1081-4.
Catinella FP, Cunningham JN Jr, Strauss ED, Adams PX, Laschinger JC, Spencer FC. Variations in total and ionized calcium during cardiac surgery. J Cardiovasc Surg (Torino) 1983; 24:593-602.
Lee JA, Allen DG. Calcium sensitisers: mechanisms of action and potential usefulness as inotropes. Cardiovasc Res 1997; 36:10-20.
Kwaan HC, Samama MM. Anticoagulant drugs: an update. Expert Rev Cardiovasc Ther 2004; 2:511-22.
Hambleton J, Leung LL, Levi M. Coagulation: consultative hemostasis. Hematology Am Soc Hematol Educ Program 2002; 2002:335-52.

References

Hurt R. The History of Cardiothoracic Surgery. The Parthenon Publishing Group. London. 1996.

Aylin O, Oztekin O. Dünden Bugüne Kalp Cerrahisi. GKDC Dergisi 1999; 7:1-6.

Aydin S, Aydin S, Nesimi Eren M, Sahin I, Yilmaz M, Kalayci M, et al. The cardiovascular system and the biochemistry of grafts used in heart surgery. Springerplus 2013; 2:612.

Nakayama DK. The Development of Extracorporeal Membrane Oxygenation. Am Surg 2018; 84:587-92.

Erik J, Sixten K, Harry B. Protamine for Intravenous Use in Man and in Animal Experiments. Acta Med Scand 1949; CXXXIV:444-7.

Rezaie AR. Prothrombin protects factor Xa in the prothrombinase complex from inhibition by the heparin-antithrombin complex. Blood 2001; 97:2308-13.

Reichert HA. Rath TE. Cardiac Surgery in Developing Countries. J Extra Corpor Technol 2017; 49:98-106.

Kellett DN. On the mechanism of the anti-inflammatory activity of hexadimethrine bromide. Br J Pharmacol Chemother. 1966; 26:351-7.

Bahandari M, Hirsh J, Weitz JI, Young E, Venner TJ, Shaughnessy SG. The effects of standard and low molecular weight heparin on bone module formation in vitro. Thromb Haemost 1998; 80:413-7.

Teoh KH, Young E, Blackall MH, Roberts RS, Hirsh J. Can extra protamine eliminate heparin rebound following cardiopulmonary bypass surgery? J Thorac Cardiovasc Surg 2004; 128:211-9.

Töbü S. [Antikoagülan Tedavi]. Türk Hematoloji Derneği - Temel Hemostaz Tromboz Kursu. 2007; 08-09. Eylül. http://www.thd.org.tr/thdData/userfiles/file/2007thtk_15.pdf

Hurwitz L, Von Hagen S, Joiner PD. Acetylcholine and calcium on membrane permeability and contraction of intestinal smooth muscle. J Gen Physiol 1967; 50:1157-72.

Cox MH, O SJ, Clair MJ, Mukherjee R, Wakefield TW, Andrews PC, et al. Differential effects of novel protamine variants on myocyte contractile function with left ventricular failure. Surgery 1997; 121:304-13.

Kisilevsky AE, Zamponi GW. Presynaptic calcium channels: structure, regulators, and blockers. Handb Exp Pharmacol 2008; 184:45-75.

Marshall CB, Nishikawa T, Osawa M, Stathopulos PB, Ikura M. Calmodulin and STIM proteins: Two major calcium sensors in the cytoplasm and endoplasmic reticulum. Biochem Biophys Res Commun 2015; 460:5-21.

Wortsman J, Traycoff RB. Biological activity of protein-bound calcium in serum. Am J Physiol 1980; 238:E104-7.

Wang S, McDonnell EH, Sedor FA, Toffaletti JG. pH effects on measurements of ionized calcium and ionized magnesium in blood. Arch Pathol Lab Med 2002; 126:947-50.

Power ML, Heaney RP, Kalkwarf HJ, Pitkin RM, Repke JT, Tsang RC, et al. The role of calcium in health and disease. Am J Obstet Gynecol 1999; 181:1560-9.

Tertti R, Harmoinen A, Leskinen Y, Metsärinne KP, Saha H. Comparison of calcium phosphate product values using measurement of plasma total calcium and serum ionized calcium. Hemodial Int 2007; 11:411-6.

Triplett DA. Coagulation and bleeding disorders: review and update. Clin Chem 2000; 46:1260-9.

Palta S, Saroa R, Palta A. Overview of the coagulation system. Indian J Anaesth 2014; 58:515-23.

Smith SA, Travers RJ, Morrissey JH. How it all starts: Initiation of the clotting cascade. Crit Rev Biochem Mol Biol 2015; 50:326-36.

Stenflo J, Fernlund P, Egan W, Roepstorff P. Vitamin K dependent modifications of glutamic acid residues in prothrombin. Proc Natl Acad Sci U S A 1974; 71:2730-3.

Petrou T, Olsen HL, Thrasivoulou C, Masters JR, Ashmore JF, Ahmed A. Intracellular Calcium Mobilization in Response to Ion Channel Regulators via a Calcium-Induced Calcium Release Mechanism. J Pharmacol Exp Ther 2017; 360:378-87.

Lee GM, Welsby IJ, Phillips-Bute B, Ortel TL, Arepally GM. High incidence of antibodies to protamine and protamine/heparin complexes in patients undergoing cardiopulmonary bypass. Blood 2013; 121:2828-35.

Biala G, Kruk-Slomka M, Jozwiak K. Influence of acute or chronic calcium channel antagonists on the acquisition and consolidation of memory and nicotine-induced cognitive effects in mice. Naunyn Schmiedebergs Arch Pharmacol 2013; 386:651-64.

Schwartz JB. Calcium antagonists in the elderly. A risk-benefit analysis. Drug Aging 1996; 9:24-36.

Massry SG, Iseki K, Campese VM. Serum calcium, parathyroid hormone, and blood pressure. Am J Nephrol 1986; 6:19-28.

Massry SG, Smogorzewski M. The effects of serum calcium and parathyroid hormone and the interaction between them on blood pressure in normal subjects and in patients with chronic kidney failure. J Ren Nutr 2005; 15:173-7.

Goto H, Kushihashi T, Benson KT, Kato H, Fox DK, Arakawa K. Heparin, protamine, and ionized calcium in vitro and in vivo. Anesth Analg 1985; 64:1081-4.

Catinella FP, Cunningham JN Jr, Strauss ED, Adams PX, Laschinger JC, Spencer FC. Variations in total and ionized calcium during cardiac surgery. J Cardiovasc Surg (Torino) 1983; 24:593-602.

Lee JA, Allen DG. Calcium sensitisers: mechanisms of action and potential usefulness as inotropes. Cardiovasc Res 1997; 36:10-20.

Kwaan HC, Samama MM. Anticoagulant drugs: an update. Expert Rev Cardiovasc Ther 2004; 2:511-22.

Hambleton J, Leung LL, Levi M. Coagulation: consultative hemostasis. Hematology Am Soc Hematol Educ Program 2002; 2002:335-52.

Author biographies is not available.