open access

Vol 12, No 4 (2017)
Review Papers
Published online: 2017-09-19
Get Citation

Protamine-induced thrombocytopenia: a new clinical complication or other type of heparin-induced thrombocytopenia?

Joanna Mikłosz, Bartłomiej Kałaska, Emilia Sokołowska, Andrzej Mogielnicki
DOI: 10.5603/FC.2017.0068
·
Folia Cardiologica 2017;12(4):355-361.

open access

Vol 12, No 4 (2017)
Review Papers
Published online: 2017-09-19

Abstract

Protamine is widely used to neutralize the anticoagulant effects of unfractionated heparin, particularly after cardiac surgery. Recent reports suggest that some patients undergoing cardiopulmonary bypass exposed to heparin and protamine may develop thrombocytopenia. Multimolecular protamine-heparin complexes lead to immunization and production of immunoglobulin G class antibodies that may activate platelets through FcγIIa receptors. Some patients injected with protamine during cardiopulmonary bypass have increased the risk of early thromboembolic events due to the presence of these antibodies in the blood. In the present review, we will focus on studies investigating the mechanism of platelet activation by anti-protamine-heparin antibodies. We will compare antibodies that are associated with immune heparin-induced thrombocytopenia. In addition, we will describe the clinical consequences of protamine-induced thrombocytopenia, risk factors and general guidelines for management of thromboembolic complications in the post-cardiac surgery patients.

Abstract

Protamine is widely used to neutralize the anticoagulant effects of unfractionated heparin, particularly after cardiac surgery. Recent reports suggest that some patients undergoing cardiopulmonary bypass exposed to heparin and protamine may develop thrombocytopenia. Multimolecular protamine-heparin complexes lead to immunization and production of immunoglobulin G class antibodies that may activate platelets through FcγIIa receptors. Some patients injected with protamine during cardiopulmonary bypass have increased the risk of early thromboembolic events due to the presence of these antibodies in the blood. In the present review, we will focus on studies investigating the mechanism of platelet activation by anti-protamine-heparin antibodies. We will compare antibodies that are associated with immune heparin-induced thrombocytopenia. In addition, we will describe the clinical consequences of protamine-induced thrombocytopenia, risk factors and general guidelines for management of thromboembolic complications in the post-cardiac surgery patients.

Get Citation

Keywords

protamine, heparin, thrombocytopenia

About this article
Title

Protamine-induced thrombocytopenia: a new clinical complication or other type of heparin-induced thrombocytopenia?

Journal

Folia Cardiologica

Issue

Vol 12, No 4 (2017)

Pages

355-361

Published online

2017-09-19

DOI

10.5603/FC.2017.0068

Bibliographic record

Folia Cardiologica 2017;12(4):355-361.

Keywords

protamine
heparin
thrombocytopenia

Authors

Joanna Mikłosz
Bartłomiej Kałaska
Emilia Sokołowska
Andrzej Mogielnicki

References (47)
  1. Baehner T, Boehm O, Probst C, et al. [Cardiopulmonary bypass in cardiac surgery]. Anaesthesist. 2012; 61(10): 846–856.
  2. Yavari M, Becker RC. Anticoagulant therapy during cardiopulmonary bypass. J Thromb Thrombolysis. 2008; 26(3): 218–228.
  3. Sokolowska E, Kalaska B, Miklosz J, et al. The toxicology of heparin reversal with protamine: past, present and future. Expert Opin Drug Metab Toxicol. 2016; 12(8): 897–909.
  4. 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.
  5. Bakchoul T, Zöllner H, Amiral J, et al. Anti-protamine-heparin antibodies: incidence, clinical relevance, and pathogenesis. Blood. 2013; 121(15): 2821–2827.
  6. Al-Mondhiry H, Pierce WS, Basarab RM. Protamine-induced thrombocytopenia and leukopenia. Thromb Haemost. 1985; 53(1): 60–64.
  7. Schnitzler S, Renner H, Pfüller U. Histamine release from rat mast cells induced by protamine sulfate and polyethylene imine. Agents Actions. 1981; 11(1-2): 73–74.
  8. Shastri KA, Logue GL, Stern MP, et al. Complement activation by heparin-protamine complexes during cardiopulmonary bypass: effect of C4A null allele. J Thorac Cardiovasc Surg. 1997; 114(3): 482–488.
  9. 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.
  10. 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.
  11. Collins C, O'Donnell A. Does an allergy to fish pre-empt an adverse protamine reaction? A case report and a literature review. Perfusion. 2008; 23(6): 369–372.
  12. Chudasama SL, Espinasse B, Hwang F, et al. Heparin modifies the immunogenicity of positively charged proteins. Blood. 2010; 116(26): 6046–6053.
  13. Bakchoul T, Giptner A, Krautwurst A, et al. In vivo animal model of drug-induced thrombocytopenia: the clinical relevance of anti-protamine sulfate antibodies. J Thromb Haemost. 2011; 9(S2).
  14. Arepally G, Cines DB. Pathogenesis of heparin-induced thrombocytopenia and thrombosis. Autoimmun Rev. 2002; 1(3): 125–132.
  15. Rauova L, Zhai Li, Kowalska MA, et al. Role of platelet surface PF4 antigenic complexes in heparin-induced thrombocytopenia pathogenesis: diagnostic and therapeutic implications. Blood. 2006; 107(6): 2346–2353.
  16. Rauova L, Hirsch JD, Greene TK, et al. Monocyte-bound PF4 in the pathogenesis of heparin-induced thrombocytopenia. Blood. 2010; 116(23): 5021–5031.
  17. Cines DB, Tomaski A, Tannenbaum S. Immune endothelial-cell injury in heparin-associated thrombocytopenia. N Engl J Med. 1987; 316(10): 581–589.
  18. Kowalska MA, Krishnaswamy S, Rauova L, et al. Antibodies associated with heparin-induced thrombocytopenia (HIT) inhibit activated protein C generation: new insights into the prothrombotic nature of HIT. Blood. 2011; 118(10): 2882–2888.
  19. 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.
  20. Singla A, Sullivan MJ, Lee G, et al. Protamine-induced immune thrombocytopenia. Transfusion. 2013; 53(10): 2158–2163.
  21. 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; table of contents.
  22. Warkentin TE, Warkentin TE, Greinacher A, et al. Delayed-onset heparin-induced thrombocytopenia and thrombosis. Ann Intern Med. 2001; 135(7): 502–506.
  23. Teoh KH, Young E, Bradley CA, et al. Heparin binding proteins. Contribution to heparin rebound after cardiopulmonary bypass. Circulation. 1993; 88(5 Pt 2): II420–II425.
  24. Nurden P, Poujol C, Durrieu-Jais C, et al. Labeling of the internal pool of GP IIb-IIIa in platelets by c7E3 Fab fragments (abciximab): flow and endocytic mechanisms contribute to the transport. Blood. 1999; 93(5): 1622–1633.
  25. Heyns AD, Lötter MG, Badenhorst PN, et al. Kinetics and in vivo redistribution of (111)Indium-labelled human platelets after intravenous protamine sulphate. Thromb Haemost. 1980; 44(2): 65–68.
  26. Greinacher A, Fuerll B, Zinke H, et al. Megakaryocyte impairment by eptifibatide-induced antibodies causes prolonged thrombocytopenia. Blood. 2009; 114(6): 1250–1253.
  27. Pouplard C, Leroux D, Rollin J, et al. Incidence of antibodies to protamine sulfate/heparin complexes incardiac surgery patients and impact on platelet activation and clinical outcome. Thromb Haemost. 2013; 109(6): 1141–1147.
  28. Zöllner H, Jouni R, Panzer S, et al. Platelet activation in the presence of neutral protamine Hagedorn insulin: a new feature of antibodies against protamine/heparin complexes. Journal of Thrombosis and Haemostasis. 2016; 15(1): 176–184.
  29. Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med. 1996; 101(5): 502–507.
  30. Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2 Suppl): e495S–e530S.
  31. Watson H, Davidson S, Keeling D, et al. Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. Guidelines on the diagnosis and management of heparin-induced thrombocytopenia: second edition. Br J Haematol. 2012; 159(5): 528–540.
  32. Lewis BE, Wallis DE, Hursting MJ, et al. Effects of argatroban therapy, demographic variables, and platelet count on thrombotic risks in heparin-induced thrombocytopenia. Chest. 2006; 129(6): 1407–1416.
  33. Magnani HN, Gallus A. Heparin-induced thrombocytopenia (HIT). A report of 1,478 clinical outcomes of patients treated with danaparoid (Orgaran) from 1982 to mid-2004. Thromb Haemost. 2006; 95(6): 967–981.
  34. Warkentin TE, Maurer BT, Aster RH. Heparin-induced thrombocytopenia associated with fondaparinux. N Engl J Med. 2007; 356(25): 2653–2655; discussion 2653.
  35. Greinacher A. Heparin-Induced Thrombocytopenia. New England Journal of Medicine. 2015; 373(3): 252–261.
  36. Linkins LA, Warkentin TE, Pai M, et al. Design of the rivaroxaban for heparin-induced thrombocytopenia study. J Thromb Thrombolysis. 2014; 38(4): 485–492.
  37. Abo-Salem E, Becker RC. Reversal of novel oral anticoagulants. Curr Opin Pharmacol. 2016; 27: 86–91.
  38. Reilly MP, Sinha U, André P, et al. PRT-060318, a novel Syk inhibitor, prevents heparin-induced thrombocytopenia and thrombosis in a transgenic mouse model. Blood. 2011; 117(7): 2241–2246.
  39. Stolla M, Stefanini L, André P, et al. CalDAG-GEFI deficiency protects mice in a novel model of Fcγ RIIA-mediated thrombosis and thrombocytopenia. Blood. 2011; 118(4): 1113–1120.
  40. 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.
  41. 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.
  42. 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.
  43. 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.
  44. Kamiński K, Płonka M, Ciejka J, et al. Cationic derivatives of dextran and hydroxypropylcellulose as novel potential heparin antagonists. J Med Chem. 2011; 54(19): 6586–6596.
  45. Kalaska B, Kaminski K, Miklosz J, et al. Heparin-binding copolymer reverses effects of unfractionated heparin, enoxaparin, and fondaparinux in rats and mice. Transl Res. 2016; 177: 98–112.e10.
  46. Joglekar MV, Quintana Diez PM, Marcus S, et al. Disruption of PF4/H multimolecular complex formation with a minimally anticoagulant heparin (ODSH). Thromb Haemost. 2012; 107(4): 717–725.
  47. Jouni R, Zöllner H, Khadour A, et al. Partially desulfated heparin modulates the interaction between anti-protamine/heparin antibodies and platelets. Thromb Haemost. 2016; 115(2): 324–332.

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

 

Wydawcą serwisu jest  "Via Medica sp. z o.o." sp.k., ul. Świętokrzyska 73, 80–180 Gdańsk

tel.:+48 58 320 94 94, faks:+48 58 320 94 60, e-mail:  viamedica@viamedica.pl