Successful Management of IgE-Mediated Protamine Allergy in Cardiac Surgery: A Two-Case Series

Successful Management of IgE-Mediated Protamine Allergy in Cardiac Surgery: A Two-Case Series | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Successful Management of IgE-Mediated Protamine Allergy in Cardiac Surgery: A Two-Case Series Philippe Portran, Martin Charvin, Matthias Jacquet-Lagrèze, Léa Didier, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7343795/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Feb, 2026 Read the published version in BMC Anesthesiology → Version 1 posted 10 You are reading this latest preprint version Abstract Since the use of heparin reversed by protamine is the gold standard for anticoagulation during cardiopulmonary bypass (CPB), a documented allergy to protamine represents a serious challenge for cardiac anaesthesiologists. We report two cases of patients with documented IgE-mediated allergy to protamine requiring redo cardiac surgery. Given the high hemorrhagic risk, a perioperative desensitization strategy was implemented to enable the use of protamine at CPB termination. The protocol was initially tested in outpatient care and demonstrated excellent tolerance. During surgery, standard heparin anticoagulation was used, followed by intraoperative desensitization to allow full heparin reversal. Protamine was hemodynamically well tolerated in both cases, and postoperative recovery was uneventful. To the best of our knowledge, this is the first description of a perioperative strategy designed to induce protamine tolerance in IgE-mediated protamine allergy during cardiac surgery with CPB. This management strategy appears particularly promising, as it offers a strategy that effectively minimises the risk of haemorrhagic complications. anaphylactic shock cardiac surgery cardiopulmonary bypass protamine heart transplantation IgE-mediated hypersensitivity immunologic desensitization Figures Figure 1 Introduction In conventional cardiac surgery, cardiopulmonary bypass (CPB) stands as a pivotal procedure. Since the use of heparin reversed by protamine is the gold standard for anticoagulation during CPB, a documented allergy to protamine represents a serious challenge for cardiac anaesthesiologists.( 1 ) Although anaphylactic reactions to protamine are rare, they are associated with a significant increase in organ failure and mortality. ( 2 , 3 ) Considering the risk of perioperative thrombosis and bleeding, no alternative provides a similar degree of both efficacy and safety.( 1 ) In cases of IgE-mediated hypersensitivity reactions to an essential and non-substitutable medication, desensitisation emerges as a compelling strategy, particularly well-documented for chemotherapies, humanised monoclonal antibodies, and aspirin. ( 4 ) In the context of confirmed IgE-mediated allergy to protamine, a desensitisation protocol could thus enable the use of protamine during the perioperative period and reduce the haemorrhagic risk. This case series presents two patients with confirmed IgE-mediated protamine hypersensitivity who underwent complex cardiac surgeries involving CPB. Both were successfully managed using perioperative desensitization protocols designed to allow safe administration of protamine. Case Presentations Case 1 A 30-year-old woman with a complex medical history, including chronic obstructive pulmonary disease due to bronchiectasis, multiple drug allergies (including low-molecular-weight heparin and daptomycin), and previous cardiac surgeries, presented with recurrent endocarditis requiring orthotopic heart transplantation. During a previous surgery, she experienced a severe anaphylactic reaction to protamine characterized by vasoplegia, requiring high doses of vasopressors and temporary extracorporeal support. A tryptase level increased from 3.5 to 8.5 µg/L during the reaction, consistent with IgE-mediated hypersensitivity. Subsequent testing showed a weakly positive basophil activation test (negative control at 2%, positive control at 97%, and protamine at 6%), thus confirming the diagnosis of grade 3 IgE-mediated allergy to protamine. Due to the high hemorrhagic risk associated with cardiac transplantation and reoperation, alternatives to protamine, including bivalirudin and unopposed heparin, were deemed too risky. A desensitization protocol was developed and trialed in outpatient care. Premedication included desloratadine 10 mg the evening before and the morning of the challenge. Protamine was administered incrementally, beginning at 0.012mg and doubling every 15 minutes up to 18mg over 180 minutes. No adverse reactions occurred. Six weeks later, the patient underwent heart transplantation. CPB was initiated with 5,000 IU of heparin during priming and an additional 300 IU/kg. The desensitisation protocol began 15min after the start of CPB. ACT was measured after each protamine injection into the CPB reservoir (slow injection of 1 IU/ml). Two re-administrations of 2,500 IU of heparin were required during CPB (Fig. 1 ). Rotational thromboelastometry (ROTEM) after the fourth and eighth protamine doses confirmed adequate anticoagulation. Norepinephrine requirement remained unchanged (< 0.5mg/h) and no cutaneous reaction occurred throughout CPB. Before the final dose of protamine, tryptase was 3.5µg/L and histamine was below 1nmol/L. No clot was observed in the oxygenator and pressures remained unchanged. After 150min, the termination of CPB was achieved easily and a final protamine dose of 23mg was given. ROTEM analysis indicated comparable clotting times between heparin-sensitive INTEM and heparinase-containing HEPTEM tests, excluding residual heparin. Satisfactory surgical haemostasis allowed rapid sternal closure and the patient was transferred to the intensive care unit (ICU). Postoperative bleeding was minimal (240 mL/24h), and no transfusion was needed. The patient was extubated four hours after ICU admission and discharged from ICU on day 6. Case 2 A 75-year-old man with diabetes, chronic renal failure, COPD, severe pulmonary hypertension, atrial fibrillation, hepatic steatosis, and previous protamine-related cardiac arrest required redo aortic valve replacement due to prosthetic degeneration. He had a risk factor for a protamine allergy: he received human neuter protamine Hagedorn (NPH) insulin in 2011 during a diabetic decompensation. During his initial surgery in 2018, protamine administration led to sudden cardiac arrest. A tryptase level increased from 4.9 to 8.9 µg/L. Although specific IgE was negative, BAT confirmed strong basophil activation starting at 1 UAH/mL and remaining positive at higher concentrations (10 and 100 UAH/mL), surpassing the positive threshold of 5% and confirming the diagnosis of grade 4 IgE-mediated allergy to protamine. Given his history and comorbidities, a desensitization approach was selected. Skin prick tests could not be performed due to the risk of severe anaphylaxis and the lack of a standardized protocol in the literature. Premedication included cetirizine 10 mg, montelukast 10 mg, and aspirin 325 mg daily for three days. Anesthesia induction was uncomplicated. CPB was initiated with 250 IU/kg of heparin (14,000 units). Protamine was administered every 10 minutes in increasing doses from 0.012 to 0.8mg. The total CPB duration was 79 minutes. ACT values were within target range throughout, and no additional heparin was needed. Final protamine infusion totaled 4mg delivered over 30 minutes. ROTEM revealed residual anticoagulation, corrected with an additional 2mg of protamine. No intraoperative anaphylaxis occurred. The patient was extubated 3 hours after ICU admission, with no abnormal post operative bleeding. On post operative day 3 he developed acute right heart failure related to severe pulmonary hypertension during milrinone weaning, requiring reintubation. He recovered and was discharged home on day 14. Discussion These cases underscore the clinical complexity and risks associated with managing patients with IgE-mediated protamine allergy undergoing cardiac surgery. In such scenarios, perioperative desensitization to protamine may offer a valuable and feasible management strategy. There are currently no established recommendations for managing CPB in patients with protamine allergy. ( 1 ) Protamine is the single FDA-recommended antidote to heparin leaving only two options for managing patients with IgE-mediated protamine allergy undergoing cardiac surgery: using heparin without antagonisation or an alternative anticoagulation treatment.( 1 ) However, managing without reversal is rarely reported and has been associated with severe bleeding, as noted in a recent case.( 5 ) Given the high bleeding risk of reoperative surgery, this approach was deemed unsafe. Alternatives anticoagulation treatment, such as bivalirudin and argatroban, present significant limitations. Bivalirudin has the broadest experience among patients undergoing cardiac surgery but managing CPB anticoagulation with bivalirudin is more complex and requires specialised expertise.( 6 ) Bivalirudin has no antidote and may cause thrombus formation in CPB circuits, especially with stagnation.( 7 ) Also, anticoagulation monitoring should be performed using ecarin clotting time (ECT), but this test is not commonly available. Alternatively, ACT can be used, albeit with lesser accuracy. ( 8 ) Argatroban, a direct thrombin inhibitor, is considered an alternative anticoagulant during cardiopulmonary bypass in patients with severe renal impairment; however, its unpredictable pharmacokinetics and association with significant bleeding risk limit its clinical applicability. ( 9 ) To the best of our knowledge, this is the first descriptions of perioperative strategies designed to induce protamine tolerance for CPB. Both cases utilized structured protocols involving premedication and graded protamine administration. Key elements contributing to safety included the use of BAT to confirm diagnosis, premedication to blunt mediator release, intraoperative desensitization with hemodynamic monitoring, and coagulation assessment using ROTEM and ACT. Tolerance induction thus allowed these two hypersensitive patients to tolerate an indispensable and non-substitutable medication by gradually administering increasing doses until the full therapeutic dose was reached. Tolerance induction produces cellular and molecular modifications resulting in increased mast cell activation thresholds and the activation of regulatory/suppressor lymphocytes. ( 4 ) Tolerance induction is limited in time: tolerance is broken if the medication intake is interrupted, and the protocol must be restarted from the beginning. ( 4 ) In the current case report, desensitisation had to be performed during CPB. Protamine injection is usually contraindicated during CPB but given the low doses of protamine during desensitisation, the risk of clot formation appeared moderate, pending a tight monitoring of CPB pressures, and oxygenator visual control. It is also essential to ensure complete heparin reversal and to avoid heparin rebound, particularly sincea 2-hour desensitisation period is required before administering a new therapeutic dose of protamine. To limit the risk of heparin rebound, we monitored for residual heparin using ROTEM.( 1 ) In Case 2, ROTEM analysis revealed residual anticoagulation, which was corrected with an additional 2,000 IU of protamine. Conclusion Perioperative desensitization to protamine can allow safe administration in patients with confirmed IgE-mediated allergy undergoing high-risk cardiac surgery. These cases demonstrate the feasibility of this approach with appropriate multidisciplinary coordination, premedication, and intraoperative vigilance. In the absence of alternative reversal agents, desensitization provides a vital option for safe anticoagulation management. Abbreviations ACT = Activated clotting time ; CPB = Cardiopulmonary bypass ; PRBC : Packed red blood cells ; ROTEM = Rotational thromboelastometry. Declarations Ethics approval and consent to participate According to the policy of Hospices civils de Lyon, ethical approval was not required for a case report. In France, the allocation and distribution of organs for transplantation are centrally managed by the French Biomedicine Agency under national legislation. In accordance with French law, the originating hospital of the donor organ cannot be disclosed. Organ donation in France is based on presumed consent: the national register of refusals is consulted and, if the individual is not listed, consent for organ donation is presumed. No organs or tissues were procured from prisoners or individuals under detention. All recipients provided informed consent for transplantation, and the procurement process complied with the Declaration of Helsinki and relevant national regulations. Consent for publication Written informed consent was obtained from both patients for publication of these case reports and accompanying clinical details. Availability of data and materials All data generated or analysed during this study are included in this published article. Competing Interests The authors declare no conflicts of interest related to the content of the following case report: Successful Management of IgE-Mediated Protamine Allergy in Cardiac Surgery: A Two-Case Series. Funding The authors have no financial, personal, or professional relationships that could be construed to have influenced the content or conclusions of this manuscript. Authors' contributions P.P. and M.C. wrote the main manuscript. B.B. drafted the desensitization protocol and reviewed the manuscript. M. J-L., M.P., J-L.F., L.S. and L.D. reviewed the manuscript and contributed to its improvement. Acknowledgements We sincerely thank Dr. Ruste for his insightful suggestions that enhanced the quality and publication prospects of this case report. References Shore-Lesserson L, Baker RA, Ferraris V, Greilich PE, Fitzgerald D, Roman P, et al. STS/SCA/AmSECT Clinical Practice Guidelines: Anticoagulation during Cardiopulmonary Bypass. J Extra Corpor Technol. mars 2018;50(1):5‑18. Nybo M, Madsen JS. Serious anaphylactic reactions due to protamine sulfate: a systematic literature review. Basic Clin Pharmacol Toxicol. août 2008;103(2):192‑6. Kimmel SE, Sekeres M, Berlin JA, Ellison N. Mortality and adverse events after protamine administration in patients undergoing cardiopulmonary bypass. Anesth Analg. juin 2002;94(6):1402‑8, table of contents. Liu A, Fanning L, Chong H, Fernandez J, Sloane D, Sancho-Serra M, et al. Desensitization regimens for drug allergy: state of the art in the 21st century. Clin Exp Allergy J Br Soc Allergy Clin Immunol. déc 2011;41(12):1679‑89. He YY, Huang YP, Wang L, Song B. A case with no administration of protamine to neutralize heparin in aortic valve replacement with cardiopulmonary bypass. Transpl Immunol. août 2022;73:101601. Warkentin TE, Koster A. Bivalirudin: a review. Expert Opin Pharmacother. juill 2005;6(8):1349‑71. Wong JK, Tian Y, Shuttleworth P, Caffarelli AD, Reitz BA, Mora-Mangano CT. Case report: a thrombus in the venous reservoir while using bivalirudin in a patient with heparin-induced thrombocytopenia undergoing heart transplantation. Anesth Analg. sept 2010;111(3):609‑12. Casserly IP, Kereiakes DJ, Gray WA, Gibson PH, Lauer MA, Reginelli JP, et al. Point-of-care ecarin clotting time versus activated clotting time in correlation with bivalirudin concentration. Thromb Res. 2004;113(2):115‑21. Agarwal S, Ullom B, Al-Baghdadi Y, Okumura M. Challenges encountered with argatroban anticoagulation during cardiopulmonary bypass. J Anaesthesiol Clin Pharmacol. janv 2012;28(1):106‑10. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 07 Feb, 2026 Read the published version in BMC Anesthesiology → Version 1 posted Editorial decision: Revision requested 31 Oct, 2025 Reviews received at journal 31 Oct, 2025 Reviewers agreed at journal 10 Oct, 2025 Reviews received at journal 06 Oct, 2025 Reviewers agreed at journal 06 Oct, 2025 Reviewers invited by journal 02 Oct, 2025 Editor assigned by journal 29 Sep, 2025 Editor invited by journal 29 Sep, 2025 Submission checks completed at journal 25 Sep, 2025 First submitted to journal 25 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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1","display":"","copyAsset":false,"role":"figure","size":120708,"visible":true,"origin":"","legend":"\u003cp\u003eAdministration of protamine, activated clotting time, and transfusion during the whole procedure in case 1.\u003c/p\u003e\n\u003cp\u003eProtamine was slowly injected over 1min except for the final dose. Norepinephrine requirement remained below 0.5 mg.h\u003csup\u003e-1\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eACT: activated clotting time; CPB: cardiopulmonary bypass; PRBC: packed red blood cells; ROTEM: rotational thromboelastometry.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7343795/v1/5e4ecef7e529d45b9a3ea5e4.png"},{"id":102235695,"identity":"218cd94a-09da-426c-bc93-a7b71bd25ea8","added_by":"auto","created_at":"2026-02-09 16:17:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":463840,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7343795/v1/6059abfd-1ea5-490f-9dcf-aaa49b9596a0.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Successful Management of IgE-Mediated Protamine Allergy in Cardiac Surgery: A Two-Case Series","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn conventional cardiac surgery, cardiopulmonary bypass (CPB) stands as a pivotal procedure. Since the use of heparin reversed by protamine is the gold standard for anticoagulation during CPB, a documented allergy to protamine represents a serious challenge for cardiac anaesthesiologists.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Although anaphylactic reactions to protamine are rare, they are associated with a significant increase in organ failure and mortality. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) Considering the risk of perioperative thrombosis and bleeding, no alternative provides a similar degree of both efficacy and safety.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) In cases of IgE-mediated hypersensitivity reactions to an essential and non-substitutable medication, desensitisation emerges as a compelling strategy, particularly well-documented for chemotherapies, humanised monoclonal antibodies, and aspirin. (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) In the context of confirmed IgE-mediated allergy to protamine, a desensitisation protocol could thus enable the use of protamine during the perioperative period and reduce the haemorrhagic risk.\u003c/p\u003e\u003cp\u003eThis case series presents two patients with confirmed IgE-mediated protamine hypersensitivity who underwent complex cardiac surgeries involving CPB. Both were successfully managed using perioperative desensitization protocols designed to allow safe administration of protamine.\u003c/p\u003e"},{"header":"Case Presentations","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eCase 1\u003c/h2\u003e\u003cp\u003eA 30-year-old woman with a complex medical history, including chronic obstructive pulmonary disease due to bronchiectasis, multiple drug allergies (including low-molecular-weight heparin and daptomycin), and previous cardiac surgeries, presented with recurrent endocarditis requiring orthotopic heart transplantation. During a previous surgery, she experienced a severe anaphylactic reaction to protamine characterized by vasoplegia, requiring high doses of vasopressors and temporary extracorporeal support. A tryptase level increased from 3.5 to 8.5 \u0026micro;g/L during the reaction, consistent with IgE-mediated hypersensitivity. Subsequent testing showed a weakly positive basophil activation test (negative control at 2%, positive control at 97%, and protamine at 6%), thus confirming the diagnosis of grade 3 IgE-mediated allergy to protamine.\u003c/p\u003e\u003cp\u003eDue to the high hemorrhagic risk associated with cardiac transplantation and reoperation, alternatives to protamine, including bivalirudin and unopposed heparin, were deemed too risky. A desensitization protocol was developed and trialed in outpatient care. Premedication included desloratadine 10 mg the evening before and the morning of the challenge. Protamine was administered incrementally, beginning at 0.012mg and doubling every 15 minutes up to 18mg over 180 minutes. No adverse reactions occurred.\u003c/p\u003e\u003cp\u003eSix weeks later, the patient underwent heart transplantation. CPB was initiated with 5,000 IU of heparin during priming and an additional 300 IU/kg. The desensitisation protocol began 15min after the start of CPB. ACT was measured after each protamine injection into the CPB reservoir (slow injection of 1 IU/ml). Two re-administrations of 2,500 IU of heparin were required during CPB (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Rotational thromboelastometry (ROTEM) after the fourth and eighth protamine doses confirmed adequate anticoagulation. Norepinephrine requirement remained unchanged (\u0026lt;\u0026thinsp;0.5mg/h) and no cutaneous reaction occurred throughout CPB. Before the final dose of protamine, tryptase was 3.5\u0026micro;g/L and histamine was below 1nmol/L. No clot was observed in the oxygenator and pressures remained unchanged. After 150min, the termination of CPB was achieved easily and a final protamine dose of 23mg was given. ROTEM analysis indicated comparable clotting times between heparin-sensitive INTEM and heparinase-containing HEPTEM tests, excluding residual heparin. Satisfactory surgical haemostasis allowed rapid sternal closure and the patient was transferred to the intensive care unit (ICU). Postoperative bleeding was minimal (240 mL/24h), and no transfusion was needed. The patient was extubated four hours after ICU admission and discharged from ICU on day 6.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eCase 2\u003c/h3\u003e\n\u003cp\u003eA 75-year-old man with diabetes, chronic renal failure, COPD, severe pulmonary hypertension, atrial fibrillation, hepatic steatosis, and previous protamine-related cardiac arrest required redo aortic valve replacement due to prosthetic degeneration. He had a risk factor for a protamine allergy: he received human neuter protamine Hagedorn (NPH) insulin in 2011 during a diabetic decompensation. During his initial surgery in 2018, protamine administration led to sudden cardiac arrest. A tryptase level increased from 4.9 to 8.9 \u0026micro;g/L. Although specific IgE was negative, BAT confirmed strong basophil activation starting at 1 UAH/mL and remaining positive at higher concentrations (10 and 100 UAH/mL), surpassing the positive threshold of 5% and confirming the diagnosis of grade 4 IgE-mediated allergy to protamine.\u003c/p\u003e\u003cp\u003eGiven his history and comorbidities, a desensitization approach was selected. Skin prick tests could not be performed due to the risk of severe anaphylaxis and the lack of a standardized protocol in the literature. Premedication included cetirizine 10 mg, montelukast 10 mg, and aspirin 325 mg daily for three days. Anesthesia induction was uncomplicated. CPB was initiated with 250 IU/kg of heparin (14,000 units). Protamine was administered every 10 minutes in increasing doses from 0.012 to 0.8mg. The total CPB duration was 79 minutes. ACT values were within target range throughout, and no additional heparin was needed.\u003c/p\u003e\u003cp\u003eFinal protamine infusion totaled 4mg delivered over 30 minutes. ROTEM revealed residual anticoagulation, corrected with an additional 2mg of protamine. No intraoperative anaphylaxis occurred. The patient was extubated 3 hours after ICU admission, with no abnormal post operative bleeding. On post operative day 3 he developed acute right heart failure related to severe pulmonary hypertension during milrinone weaning, requiring reintubation. He recovered and was discharged home on day 14.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThese cases underscore the clinical complexity and risks associated with managing patients with IgE-mediated protamine allergy undergoing cardiac surgery. In such scenarios, perioperative desensitization to protamine may offer a valuable and feasible management strategy.\u003c/p\u003e\u003cp\u003eThere are currently no established recommendations for managing CPB in patients with protamine allergy. (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) Protamine is the single FDA-recommended antidote to heparin leaving only two options for managing patients with IgE-mediated protamine allergy undergoing cardiac surgery: using heparin without antagonisation or an alternative anticoagulation treatment.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) However, managing without reversal is rarely reported and has been associated with severe bleeding, as noted in a recent case.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) Given the high bleeding risk of reoperative surgery, this approach was deemed unsafe. Alternatives anticoagulation treatment, such as bivalirudin and argatroban, present significant limitations. Bivalirudin has the broadest experience among patients undergoing cardiac surgery but managing CPB anticoagulation with bivalirudin is more complex and requires specialised expertise.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) Bivalirudin has no antidote and may cause thrombus formation in CPB circuits, especially with stagnation.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) Also, anticoagulation monitoring should be performed using ecarin clotting time (ECT), but this test is not commonly available. Alternatively, ACT can be used, albeit with lesser accuracy. (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) Argatroban, a direct thrombin inhibitor, is considered an alternative anticoagulant during cardiopulmonary bypass in patients with severe renal impairment; however, its unpredictable pharmacokinetics and association with significant bleeding risk limit its clinical applicability. (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eTo the best of our knowledge, this is the first descriptions of perioperative strategies designed to induce protamine tolerance for CPB. Both cases utilized structured protocols involving premedication and graded protamine administration. Key elements contributing to safety included the use of BAT to confirm diagnosis, premedication to blunt mediator release, intraoperative desensitization with hemodynamic monitoring, and coagulation assessment using ROTEM and ACT. Tolerance induction thus allowed these two hypersensitive patients to tolerate an indispensable and non-substitutable medication by gradually administering increasing doses until the full therapeutic dose was reached. Tolerance induction produces cellular and molecular modifications resulting in increased mast cell activation thresholds and the activation of regulatory/suppressor lymphocytes. (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) Tolerance induction is limited in time: tolerance is broken if the medication intake is interrupted, and the protocol must be restarted from the beginning. (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) In the current case report, desensitisation had to be performed during CPB. Protamine injection is usually contraindicated during CPB but given the low doses of protamine during desensitisation, the risk of clot formation appeared moderate, pending a tight monitoring of CPB pressures, and oxygenator visual control. It is also essential to ensure complete heparin reversal and to avoid heparin rebound, particularly sincea 2-hour desensitisation period is required before administering a new therapeutic dose of protamine. To limit the risk of heparin rebound, we monitored for residual heparin using ROTEM.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) In Case 2, ROTEM analysis revealed residual anticoagulation, which was corrected with an additional 2,000 IU of protamine.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePerioperative desensitization to protamine can allow safe administration in patients with confirmed IgE-mediated allergy undergoing high-risk cardiac surgery. These cases demonstrate the feasibility of this approach with appropriate multidisciplinary coordination, premedication, and intraoperative vigilance. In the absence of alternative reversal agents, desensitization provides a vital option for safe anticoagulation management.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eACT = Activated clotting time ; CPB = Cardiopulmonary bypass ; PRBC : Packed red blood cells ; \u0026nbsp;ROTEM = Rotational thromboelastometry.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAccording to the policy of Hospices civils de Lyon, ethical approval was not required for a case report. In France, the allocation and distribution of organs for transplantation are centrally managed by the French Biomedicine Agency under national legislation. In accordance with French law, the originating hospital of the donor organ cannot be disclosed. Organ donation in France is based on presumed consent: the national register of refusals is consulted and, if the individual is not listed, consent for organ donation is presumed. No organs or tissues were procured from prisoners or individuals under detention. All recipients provided informed consent for transplantation, and the procurement process complied with the Declaration of Helsinki and relevant national regulations.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from both patients for publication of these case reports and accompanying clinical details.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare \u003cstrong\u003eno conflicts of interest\u003c/strong\u003e related to the content of the following case report:\u003c/p\u003e\n\u003cp\u003eSuccessful Management of IgE-Mediated Protamine Allergy in Cardiac Surgery: A Two-Case Series.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no financial, personal, or professional relationships that could be construed to have influenced the content or conclusions of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eP.P. and M.C. wrote the main manuscript. B.B. drafted the desensitization protocol and reviewed the manuscript. M. J-L., M.P., J-L.F., L.S. and L.D. reviewed the manuscript and contributed to its improvement.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe sincerely thank Dr. Ruste for his insightful suggestions that enhanced the quality and publication prospects of this case report.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eShore-Lesserson L, Baker RA, Ferraris V, Greilich PE, Fitzgerald D, Roman P, et al. STS/SCA/AmSECT Clinical Practice Guidelines: Anticoagulation during Cardiopulmonary Bypass. J Extra Corpor Technol. mars 2018;50(1):5‑18. \u003c/li\u003e\n\u003cli\u003eNybo M, Madsen JS. Serious anaphylactic reactions due to protamine sulfate: a systematic literature review. Basic Clin Pharmacol Toxicol. ao\u0026ucirc;t 2008;103(2):192‑6. \u003c/li\u003e\n\u003cli\u003eKimmel SE, Sekeres M, Berlin JA, Ellison N. Mortality and adverse events after protamine administration in patients undergoing cardiopulmonary bypass. Anesth Analg. juin 2002;94(6):1402‑8, table of contents. \u003c/li\u003e\n\u003cli\u003eLiu A, Fanning L, Chong H, Fernandez J, Sloane D, Sancho-Serra M, et al. Desensitization regimens for drug allergy: state of the art in the 21st century. Clin Exp Allergy J Br Soc Allergy Clin Immunol. d\u0026eacute;c 2011;41(12):1679‑89. \u003c/li\u003e\n\u003cli\u003eHe YY, Huang YP, Wang L, Song B. A case with no administration of protamine to neutralize heparin in aortic valve replacement with cardiopulmonary bypass. Transpl Immunol. ao\u0026ucirc;t 2022;73:101601. \u003c/li\u003e\n\u003cli\u003eWarkentin TE, Koster A. Bivalirudin: a review. Expert Opin Pharmacother. juill 2005;6(8):1349‑71. \u003c/li\u003e\n\u003cli\u003eWong JK, Tian Y, Shuttleworth P, Caffarelli AD, Reitz BA, Mora-Mangano CT. Case report: a thrombus in the venous reservoir while using bivalirudin in a patient with heparin-induced thrombocytopenia undergoing heart transplantation. Anesth Analg. sept 2010;111(3):609‑12. \u003c/li\u003e\n\u003cli\u003eCasserly IP, Kereiakes DJ, Gray WA, Gibson PH, Lauer MA, Reginelli JP, et al. Point-of-care ecarin clotting time versus activated clotting time in correlation with bivalirudin concentration. Thromb Res. 2004;113(2):115‑21. \u003c/li\u003e\n\u003cli\u003eAgarwal S, Ullom B, Al-Baghdadi Y, Okumura M. Challenges encountered with argatroban anticoagulation during cardiopulmonary bypass. J Anaesthesiol Clin Pharmacol. janv 2012;28(1):106‑10. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-anesthesiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bane","sideBox":"Learn more about [BMC Anesthesiology](http://bmcanesthesiol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bane","title":"BMC Anesthesiology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"anaphylactic shock, cardiac surgery, cardiopulmonary bypass, protamine, heart transplantation, IgE-mediated hypersensitivity, immunologic desensitization","lastPublishedDoi":"10.21203/rs.3.rs-7343795/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7343795/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSince the use of heparin reversed by protamine is the gold standard for anticoagulation during cardiopulmonary bypass (CPB), a documented allergy to protamine represents a serious challenge for cardiac anaesthesiologists. We report two cases of patients with documented IgE-mediated allergy to protamine requiring redo cardiac surgery. Given the high hemorrhagic risk, a perioperative desensitization strategy was implemented to enable the use of protamine at CPB termination. The protocol was initially tested in outpatient care and demonstrated excellent tolerance. During surgery, standard heparin anticoagulation was used, followed by intraoperative desensitization to allow full heparin reversal. Protamine was hemodynamically well tolerated in both cases, and postoperative recovery was uneventful. To the best of our knowledge, this is the first description of a perioperative strategy designed to induce protamine tolerance in IgE-mediated protamine allergy during cardiac surgery with CPB. This management strategy appears particularly promising, as it offers a strategy that effectively minimises the risk of haemorrhagic complications.\u003c/p\u003e","manuscriptTitle":"Successful Management of IgE-Mediated Protamine Allergy in Cardiac Surgery: A Two-Case Series","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-15 16:14:25","doi":"10.21203/rs.3.rs-7343795/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-31T12:04:51+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-31T07:33:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"285881082201088889760313446825896551265","date":"2025-10-10T12:58:51+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-06T11:55:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"296702988968517072690054343516902425714","date":"2025-10-06T10:25:35+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-02T12:22:58+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-29T10:35:27+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-29T09:53:33+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-25T09:53:18+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Anesthesiology","date":"2025-09-25T09:50:48+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-anesthesiology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bane","sideBox":"Learn more about [BMC Anesthesiology](http://bmcanesthesiol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bane","title":"BMC Anesthesiology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"67b5bc35-9390-4985-a8d9-d6c051d9e31a","owner":[],"postedDate":"October 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-09T16:15:51+00:00","versionOfRecord":{"articleIdentity":"rs-7343795","link":"https://doi.org/10.1186/s12871-025-03549-2","journal":{"identity":"bmc-anesthesiology","isVorOnly":false,"title":"BMC Anesthesiology"},"publishedOn":"2026-02-07 15:58:32","publishedOnDateReadable":"February 7th, 2026"},"versionCreatedAt":"2025-10-15 16:14:25","video":"","vorDoi":"10.1186/s12871-025-03549-2","vorDoiUrl":"https://doi.org/10.1186/s12871-025-03549-2","workflowStages":[]},"version":"v1","identity":"rs-7343795","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7343795","identity":"rs-7343795","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}