Acute pulmonary hypertension induced by Heparin–protamine complex during thoracoabdominal aortic grafting

Acute pulmonary hypertension induced by Heparin–protamine complex during thoracoabdominal aortic grafting | 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 Acute pulmonary hypertension induced by Heparin–protamine complex during thoracoabdominal aortic grafting Koki Yokawa, Masakazu Kawakami, Yosuke Tanaka, Tomonori Higuma, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7069855/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Jan, 2026 Read the published version in Journal of Cardiothoracic Surgery → Version 1 posted 20 You are reading this latest preprint version Abstract Background Protamine has a more difficult side-effect profile. Circulatory collapse has been reported as a result of acute pulmonary artery spasm caused by complement cascade activation by large heparin–protamine complexes. Case presentation A 79-year-old male underwent endovascular aneurysm repair 11 years ago for a ruptured abdominal aortic aneurysm. A saccular aneurysm (maximum diameter: 57 mm) appeared at the proximal end of the stent graft. Thoracoabdominal aortic replacement was performed under partial cardiopulmonary bypass. The cardiopulmonary bypass was removed, and 15 min after protamine initiation, circulatory collapse emerged with pulmonary hypertension. Extracorporeal membrane oxygenation was then initiated. Unfortunately, the patient developed coagulopathy, followed by severe pulmonary hemorrhage occurred, leading to death. Conclusion Pulmonary artery spasm should always be considered as a differential diagnosis for hypotension after protamine administration, and prompt intervention is crucial. Protamine Protamine shock pulmonary artery spasm Figures Figure 1 Figure 2 Background Aortic surgery with cardiopulmonary bypass (CPB) has become a routine for various aortic aneurysms, including thoracoabdominal aortic aneurysms. CPB requires reliable anticoagulation, which is mostly achieved with heparin. Its antidote, protamine, has a more difficult side-effect profile. The in-hospital mortality rate is reportedly high in cardiac surgery cases where severe side effects from protamine are experienced 1 . Protamine is a large molecule that produces allergic reactions such as erythema, angioedema, and, in rare cases, life-threatening anaphylaxis 2 , 3 . Among these reactions, circulatory collapse occurs in some patients as a result of acute pulmonary artery spasm caused by complement cascade activation by large heparin–protamine complexes 3 . Herein, we report a patient who experienced circulatory collapse during thoracoabdominal aortic replacement, possibly caused by pulmonary artery spasm due to complement cascade activation by large heparin–protamine complexes. Case Presentation A 79-year-old male patient underwent endovascular aortic repair (EVAR) 11 years earlier for a ruptured abdominal aortic aneurysm. Subsequently, he underwent three endovascular treatments for arteriosclerosis obliterans. Four years ago, he developed nonocclusive mesenteric ischemia, and a stoma was created. Although endoleak did not occur after EVAR, a saccular aneurysm developed, gradually expanding at the proximal end of EVAR; meanwhile, a 50 mm aneurysm was identified in the descending aorta. As the saccular aneurysm at the proximal end reached 57 mm, thoracoabdominal aortic replacement surgery was planned. For the descending aortic aneurysm, we planned a second-stage thoracic endovascular aortic repair (TEVAR). Contrast-enhanced computed tomography (CT) revealed that the anterior spinal artery originated from the right 7th intercostal artery (Fig. 1 ). Hence, the surgery was performed via a right 7th intercostal thoracotomy and a retroperitoneal approach through a paramedian abdominal incision. After 85,000 units of heparin was administered, systemic heparinization was achieved. CPB was established using the right femoral artery for perfusion and the right femoral vein for venous drainage; then, partial extracorporeal circulation was initiated. The rectal temperature was lowered to 30°C. The descending aorta was clamped distal to the aneurysm. To achieve circulatory arrest in the lower body, we temporarily halted the perfusion from the CPB. We subsequently incised the thoracoabdominal aorta and initiated selective visceral branch perfusion for the celiac artery, superior mesenteric artery, and bilateral renal arteries. Next, we opened the abdominal aorta, removed the thrombus within the aneurysm, excised a portion of the stent graft, and clamped both limbs of the stent graft. Perfusion from the CPB was then resumed, terminating the circulatory arrest in the lower body. The reconstructions were completed in the following order: the descending aorta, right renal artery, superior mesenteric artery, celiac artery, left renal artery, right limb of the stent graft, and left limb of the stent graft. The CBP was successfully terminated, with the total CPB time of 215 min. To neutralize heparin effects, we administered 85 mg of protamine. After 15 min of administration, the pulmonary artery pressure suddenly and rapidly rose to 52/36 mmHg, while the systemic blood pressure dropped to 57/42 mmHg. Initially, this change was assessed as protamine-induced vasodilation. Vasoconstrictors were then administered. Unfortunately, the blood pressure did not increase at all; hence, direct heart massage was initiated. However, while the pulmonary artery pressure waveform remained visible, the systemic blood pressure waveform did not appear, and the systemic blood pressure remained low. A total of 4 mg of adrenaline was administered, but no blood pressure elevation was observed. We initiated nitric oxide inhalation at 20 ppm for severe pulmonary hypertension. Once extracorporeal membrane oxygenation (ECMO) was initiated, the hemodynamics improved significantly (Fig. 2 ). The time from the blood pressure drop to ECMO initiation was 25 min. Additionally, severe hypocalcemia was observed during the blood pressure drop; thus, a total of 41.4 mEq of calcium chloride was administered for correction. Although the circulatory dynamics improved through ECMO, the patient developed a marked bleeding tendency caused by coagulation abnormalities, leading to severe pulmonary hemorrhage. The bleeding became uncontrollable, and after surgical wound closure, death was confirmed in the intensive care unit with the family present. A pathological autopsy was planned, but the family declined. Therefore, a postmortem CT scan was conducted for diagnostic purposes. However, no findings directly indicated the cause of death. Informed consent was obtained from the patient for this report. Discussion and Conclusions In cardiovascular surgeries requiring CPB, systemic heparinization is typically performed, followed by neutralization with protamine. In rare cases, the systemic blood pressure drops as a reaction to protamine. The mechanism often attributed to this outcome includes peripheral vasodilation caused by protamine or anaphylactic shock resulting from an allergic reaction. A less frequently reported mechanism involves severe pulmonary vasoconstriction leading to pulmonary hypertension. Thus, acute pulmonary hypertension, right heart failure, and extreme hypotension might occur shortly after protamine administration. Although rare, this mechanism could be triggered by substances produced by the protamine–heparin complex. Among these substances is thromboxane. As a treatment, protamine infusion should be immediately discontinued, while efforts should be made to stabilize the hemodynamics. Circulatory support, such as mechanical assistance, was used successfully to save patients in the same situation. Adrenaline is commonly administered for shock, but vasodilators specific to the pulmonary vasculature (e.g., nitroglycerin, isoproterenol, and phosphodiesterase III inhibitors) may also be employed. If these treatments are ineffective, reheparinization and transitioning to mechanical circulatory support might be necessary 4 . Reheparinization can potentially reduce the protamine–heparin complex size, potentially improving the situation. Protamine should not be readministered; rather, the natural degradation of heparin activity should be allowed without further protamine use. In this case, the sudden rise in pulmonary artery pressure following protamine administration led to a circulatory collapse, which was attributed to an acute pulmonary artery spasm resulting from the protamine–heparin complex. After the circulatory failure, the bleeding became uncontrollable, leading to the patient’s death. However, the patient could have possibly been saved if the appropriate interventions, as outlined above, had been rapidly implemented. Nonetheless, this phenomenon is extremely rare. Without considering it as part of the differential diagnosis for shock after protamine administration, timely and effective intervention becomes challenging. In conclusion, circulatory collapse resulting from severe pulmonary artery spasm can possibly occur after protamine administration. Thus, pulmonary spasm should always be considered as a differential diagnosis for hypotension after protamine administration, and prompt intervention is crucial. Abbreviations cardiopulmonary bypass CPB endovascular aortic repair EVAR thoracic endovascular aortic repair TEVAR computed tomography CT extracorporeal membrane oxygenation ECMO Declarations COI statement: Nothing to disclose Consent for publication: Informed consent was obtained from the patient for this report. Availability of data and materials All data generated or analysed during this study are included in this published article. Competing interests: The authors declare that they have no competing interests Funding: Nothing Authors' contributions: KY and MK analyzed and interpreted patient data regarding the intraoperative hemodynamics. KY was a major contributor in writing the manuscript. TH, YT, KY, HO, YK and HW supervised this manuscript. All authors read and approved of the final manuscript. References Stephen E, Kimmel M, Sekeres JA, Berlin N, Ellison. Mortality and adverse events after protamine administration in patients undergoing cardiopulmonary bypass. Anesth Analg. 2002;94(6):1402–8. Kamen Valchanov F, Falter S. Three cases of anaphylaxis to protamine:management of anticoagulation reversal. J Cardiothorac Vasc Anesth. 2019;33(2):482–6. Weiss ME, Nyhan D. Association of protamine IgE and IgG antibodies with life-threatening reactions to intravenous protamine. N Engl J Med. 1989;320(14):886–92. Kyle R, Geurink CB, Granger L, Liao, et al. A reversal of fortune: a case of cardiovascular collapse following protamine sulfate infusion. Heart Rhythm Case Rep. 2020;6(6):322–4. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 24 Jan, 2026 Read the published version in Journal of Cardiothoracic Surgery → Version 1 posted Editorial decision: Revision requested 08 Oct, 2025 Reviews received at journal 20 Aug, 2025 Reviewers agreed at journal 20 Aug, 2025 Reviews received at journal 20 Aug, 2025 Reviewers agreed at journal 20 Aug, 2025 Reviewers agreed at journal 18 Aug, 2025 Reviewers agreed at journal 17 Aug, 2025 Reviewers agreed at journal 16 Aug, 2025 Reviews received at journal 15 Aug, 2025 Reviews received at journal 15 Aug, 2025 Reviewers agreed at journal 15 Aug, 2025 Reviewers agreed at journal 14 Aug, 2025 Reviews received at journal 14 Aug, 2025 Reviewers agreed at journal 14 Aug, 2025 Reviewers agreed at journal 14 Aug, 2025 Reviewers agreed at journal 14 Aug, 2025 Reviewers invited by journal 14 Aug, 2025 Editor assigned by journal 10 Jul, 2025 Submission checks completed at journal 10 Jul, 2025 First submitted to journal 07 Jul, 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7069855","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":503855576,"identity":"78941714-b0cc-42e3-a133-9f3ae0f40334","order_by":0,"name":"Koki Yokawa","email":"","orcid":"","institution":"Kakogawa Central City Hospital","correspondingAuthor":false,"prefix":"","firstName":"Koki","middleName":"","lastName":"Yokawa","suffix":""},{"id":503855577,"identity":"ca81d837-5ffb-4855-840b-c21ef97182c3","order_by":1,"name":"Masakazu Kawakami","email":"","orcid":"","institution":"Kakogawa Central City 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yoriko","middleName":"","lastName":"Kujime","suffix":""},{"id":503855585,"identity":"ee6cf5c8-cbcf-4d61-a179-60337dc3ec91","order_by":8,"name":"Hidetaka Wakiyama","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA50lEQVRIiWNgGAWjYBACAyBmbACRDMyHGRgOMCQAWQnEamFLJkULmMljDNOCH5gz8Bh+nFFwWF63/cxngx9nbPLMGRiePcCnxbKBx1hyg8Fhw21ncjcn9txIK7ZsYEg3wOuw+283SD4wOMy47UDu5gM8Hw4nbjjAkCaBV8sB3s0/gVrst51/8/jgHyK1bAM5LHHbjRzmZJ4bRGnh/2Y5wyA9eduNZ8bGMmfSEnc2E/LLAbbkmz1/rG23nU9+LPnmmE3idvaetAf4tEBBM5IhzDxpROhgqEPSwsB+jBgto2AUjIJRMHIAAOz0WHk9UEBpAAAAAElFTkSuQmCC","orcid":"","institution":"Kakogawa Central City Hospital","correspondingAuthor":true,"prefix":"","firstName":"Hidetaka","middleName":"","lastName":"Wakiyama","suffix":""}],"badges":[],"createdAt":"2025-07-08 02:53:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7069855/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7069855/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13019-025-03807-x","type":"published","date":"2026-01-24T15:59:23+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":89672315,"identity":"668a6d37-ba5a-4acc-8af0-78331ad57067","added_by":"auto","created_at":"2025-08-22 13:08:59","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":599979,"visible":true,"origin":"","legend":"\u003cp\u003ePreoperative CT images\u003c/p\u003e\n\u003cp\u003ea. axial image, b. 3D image\u003c/p\u003e\n\u003cp\u003eThe yellow arrowhead shows the saccular aneurysm.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7069855/v1/d2b3b84800b99f1f21a9b62e.jpeg"},{"id":89672332,"identity":"d6f98da1-a39c-46bd-88d5-94264d84d8e3","added_by":"auto","created_at":"2025-08-22 13:09:02","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":335293,"visible":true,"origin":"","legend":"\u003cp\u003eIntraoperative changes in systemic blood pressure and pulmonary artery pressure before and after protamine administration.\u003c/p\u003e\n\u003cp\u003eThe area enclosed by the red line indicates a rapid increase in pulmonary artery pressure accompanied with a significant decrease in systemic blood pressure, while the area pointed by the blue arrow shows a sustained elevation in pulmonary artery pressure with persistently low systemic blood pressure.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7069855/v1/2db53a3139300aff3ad48732.png"},{"id":101153376,"identity":"0646ca82-eaaf-462d-9048-fde2b0cb49b7","added_by":"auto","created_at":"2026-01-26 16:15:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1274710,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7069855/v1/05152939-7f19-4ac0-b5f9-10fc942cb17e.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Acute pulmonary hypertension induced by Heparin–protamine complex during thoracoabdominal aortic grafting","fulltext":[{"header":"Background","content":"\u003cp\u003eAortic surgery with cardiopulmonary bypass (CPB) has become a routine for various aortic aneurysms, including thoracoabdominal aortic aneurysms. CPB requires reliable anticoagulation, which is mostly achieved with heparin. Its antidote, protamine, has a more difficult side-effect profile. The in-hospital mortality rate is reportedly high in cardiac surgery cases where severe side effects from protamine are experienced\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Protamine is a large molecule that produces allergic reactions such as erythema, angioedema, and, in rare cases, life-threatening anaphylaxis\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Among these reactions, circulatory collapse occurs in some patients as a result of acute pulmonary artery spasm caused by complement cascade activation by large heparin\u0026ndash;protamine complexes\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Herein, we report a patient who experienced circulatory collapse during thoracoabdominal aortic replacement, possibly caused by pulmonary artery spasm due to complement cascade activation by large heparin\u0026ndash;protamine complexes.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 79-year-old male patient underwent endovascular aortic repair (EVAR) 11 years earlier for a ruptured abdominal aortic aneurysm. Subsequently, he underwent three endovascular treatments for arteriosclerosis obliterans. Four years ago, he developed nonocclusive mesenteric ischemia, and a stoma was created. Although endoleak did not occur after EVAR, a saccular aneurysm developed, gradually expanding at the proximal end of EVAR; meanwhile, a 50 mm aneurysm was identified in the descending aorta. As the saccular aneurysm at the proximal end reached 57 mm, thoracoabdominal aortic replacement surgery was planned. For the descending aortic aneurysm, we planned a second-stage thoracic endovascular aortic repair (TEVAR). Contrast-enhanced computed tomography (CT) revealed that the anterior spinal artery originated from the right 7th intercostal artery (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eHence, the surgery was performed via a right 7th intercostal thoracotomy and a retroperitoneal approach through a paramedian abdominal incision. After 85,000 units of heparin was administered, systemic heparinization was achieved. CPB was established using the right femoral artery for perfusion and the right femoral vein for venous drainage; then, partial extracorporeal circulation was initiated. The rectal temperature was lowered to 30\u0026deg;C. The descending aorta was clamped distal to the aneurysm. To achieve circulatory arrest in the lower body, we temporarily halted the perfusion from the CPB.\u003c/p\u003e\u003cp\u003eWe subsequently incised the thoracoabdominal aorta and initiated selective visceral branch perfusion for the celiac artery, superior mesenteric artery, and bilateral renal arteries. Next, we opened the abdominal aorta, removed the thrombus within the aneurysm, excised a portion of the stent graft, and clamped both limbs of the stent graft. Perfusion from the CPB was then resumed, terminating the circulatory arrest in the lower body. The reconstructions were completed in the following order: the descending aorta, right renal artery, superior mesenteric artery, celiac artery, left renal artery, right limb of the stent graft, and left limb of the stent graft. The CBP was successfully terminated, with the total CPB time of 215 min.\u003c/p\u003e\u003cp\u003eTo neutralize heparin effects, we administered 85 mg of protamine. After 15 min of administration, the pulmonary artery pressure suddenly and rapidly rose to 52/36 mmHg, while the systemic blood pressure dropped to 57/42 mmHg. Initially, this change was assessed as protamine-induced vasodilation. Vasoconstrictors were then administered. Unfortunately, the blood pressure did not increase at all; hence, direct heart massage was initiated. However, while the pulmonary artery pressure waveform remained visible, the systemic blood pressure waveform did not appear, and the systemic blood pressure remained low. A total of 4 mg of adrenaline was administered, but no blood pressure elevation was observed. We initiated nitric oxide inhalation at 20 ppm for severe pulmonary hypertension. Once extracorporeal membrane oxygenation (ECMO) was initiated, the hemodynamics improved significantly (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The time from the blood pressure drop to ECMO initiation was 25 min. Additionally, severe hypocalcemia was observed during the blood pressure drop; thus, a total of 41.4 mEq of calcium chloride was administered for correction.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eAlthough the circulatory dynamics improved through ECMO, the patient developed a marked bleeding tendency caused by coagulation abnormalities, leading to severe pulmonary hemorrhage. The bleeding became uncontrollable, and after surgical wound closure, death was confirmed in the intensive care unit with the family present. A pathological autopsy was planned, but the family declined. Therefore, a postmortem CT scan was conducted for diagnostic purposes. However, no findings directly indicated the cause of death. Informed consent was obtained from the patient for this report.\u003c/p\u003e"},{"header":"Discussion and Conclusions","content":"\u003cp\u003eIn cardiovascular surgeries requiring CPB, systemic heparinization is typically performed, followed by neutralization with protamine. In rare cases, the systemic blood pressure drops as a reaction to protamine. The mechanism often attributed to this outcome includes peripheral vasodilation caused by protamine or anaphylactic shock resulting from an allergic reaction. A less frequently reported mechanism involves severe pulmonary vasoconstriction leading to pulmonary hypertension. Thus, acute pulmonary hypertension, right heart failure, and extreme hypotension might occur shortly after protamine administration. Although rare, this mechanism could be triggered by substances produced by the protamine\u0026ndash;heparin complex. Among these substances is thromboxane.\u003c/p\u003e\u003cp\u003eAs a treatment, protamine infusion should be immediately discontinued, while efforts should be made to stabilize the hemodynamics. Circulatory support, such as mechanical assistance, was used successfully to save patients in the same situation. Adrenaline is commonly administered for shock, but vasodilators specific to the pulmonary vasculature (e.g., nitroglycerin, isoproterenol, and phosphodiesterase III inhibitors) may also be employed. If these treatments are ineffective, reheparinization and transitioning to mechanical circulatory support might be necessary\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Reheparinization can potentially reduce the protamine\u0026ndash;heparin complex size, potentially improving the situation. Protamine should not be readministered; rather, the natural degradation of heparin activity should be allowed without further protamine use.\u003c/p\u003e\u003cp\u003eIn this case, the sudden rise in pulmonary artery pressure following protamine administration led to a circulatory collapse, which was attributed to an acute pulmonary artery spasm resulting from the protamine\u0026ndash;heparin complex. After the circulatory failure, the bleeding became uncontrollable, leading to the patient\u0026rsquo;s death. However, the patient could have possibly been saved if the appropriate interventions, as outlined above, had been rapidly implemented. Nonetheless, this phenomenon is extremely rare. Without considering it as part of the differential diagnosis for shock after protamine administration, timely and effective intervention becomes challenging.\u003c/p\u003e\u003cp\u003eIn conclusion, circulatory collapse resulting from severe pulmonary artery spasm can possibly occur after protamine administration. Thus, pulmonary spasm should always be considered as a differential diagnosis for hypotension after protamine administration, and prompt intervention is crucial.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ecardiopulmonary bypass\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCPB\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eendovascular aortic repair\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eEVAR\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ethoracic endovascular aortic repair\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eTEVAR\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ecomputed tomography\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eCT\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eextracorporeal membrane oxygenation\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eECMO\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCOI statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNothing to disclose\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from the patient for this report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\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 that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eNothing\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKY and MK analyzed and interpreted patient data regarding the intraoperative hemodynamics. KY was a major contributor in writing the manuscript. TH, YT, KY, HO, YK and HW supervised this manuscript. All authors read and approved of the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eStephen E, Kimmel M, Sekeres JA, Berlin N, Ellison. Mortality and adverse events after protamine administration in patients undergoing cardiopulmonary bypass. Anesth Analg. 2002;94(6):1402\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKamen Valchanov F, Falter S. Three cases of anaphylaxis to protamine:management of anticoagulation reversal. J Cardiothorac Vasc Anesth. 2019;33(2):482\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWeiss ME, Nyhan D. Association of protamine IgE and IgG antibodies with life-threatening reactions to intravenous protamine. N Engl J Med. 1989;320(14):886\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKyle R, Geurink CB, Granger L, Liao, et al. A reversal of fortune: a case of cardiovascular collapse following protamine sulfate infusion. Heart Rhythm Case Rep. 2020;6(6):322\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e\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":"journal-of-cardiothoracic-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jcts","sideBox":"Learn more about [Journal of Cardiothoracic Surgery](http://cardiothoracicsurgery.biomedcentral.com)","snPcode":"13019","submissionUrl":"https://submission.nature.com/new-submission/13019/3","title":"Journal of Cardiothoracic Surgery","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Protamine, Protamine shock, pulmonary artery spasm","lastPublishedDoi":"10.21203/rs.3.rs-7069855/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7069855/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eProtamine has a more difficult side-effect profile. Circulatory collapse has been reported as a result of acute pulmonary artery spasm caused by complement cascade activation by large heparin\u0026ndash;protamine complexes.\u003c/p\u003e\u003ch2\u003eCase presentation\u003c/h2\u003e\u003cp\u003eA 79-year-old male underwent endovascular aneurysm repair 11 years ago for a ruptured abdominal aortic aneurysm. A saccular aneurysm (maximum diameter: 57 mm) appeared at the proximal end of the stent graft. Thoracoabdominal aortic replacement was performed under partial cardiopulmonary bypass. The cardiopulmonary bypass was removed, and 15 min after protamine initiation, circulatory collapse emerged with pulmonary hypertension. Extracorporeal membrane oxygenation was then initiated. Unfortunately, the patient developed coagulopathy, followed by severe pulmonary hemorrhage occurred, leading to death.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003ePulmonary artery spasm should always be considered as a differential diagnosis for hypotension after protamine administration, and prompt intervention is crucial.\u003c/p\u003e","manuscriptTitle":"Acute pulmonary hypertension induced by Heparin–protamine complex during thoracoabdominal aortic grafting","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-22 13:08:43","doi":"10.21203/rs.3.rs-7069855/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-08T11:19:21+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-20T13:26:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"138410069248271614528743134743805447565","date":"2025-08-20T12:26:07+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-20T09:22:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"134598867057316779360115257098483436240","date":"2025-08-20T07:57:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"101646265710590800987027375411840374118","date":"2025-08-18T12:29:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"315845385982059202995732215579759740183","date":"2025-08-17T07:35:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"160525685017573674227131307535875928642","date":"2025-08-16T14:57:08+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-16T01:19:07+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-15T12:29:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"94621547265966147320384112291253105860","date":"2025-08-15T04:11:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"267480582741610133947438245551969890506","date":"2025-08-15T00:19:54+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-14T12:41:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"138990949105972405038642017270039370176","date":"2025-08-14T12:21:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"14847128174532325906589006884729322391","date":"2025-08-14T12:16:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"339372094022686357661504260429668727926","date":"2025-08-14T10:36:14+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-14T10:30:36+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-10T13:46:31+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-10T13:44:12+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Cardiothoracic Surgery","date":"2025-07-08T02:46:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-cardiothoracic-surgery","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jcts","sideBox":"Learn more about [Journal of Cardiothoracic Surgery](http://cardiothoracicsurgery.biomedcentral.com)","snPcode":"13019","submissionUrl":"https://submission.nature.com/new-submission/13019/3","title":"Journal of Cardiothoracic Surgery","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"abbed355-a542-4ec3-8432-8d1e6030e872","owner":[],"postedDate":"August 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-26T16:13:45+00:00","versionOfRecord":{"articleIdentity":"rs-7069855","link":"https://doi.org/10.1186/s13019-025-03807-x","journal":{"identity":"journal-of-cardiothoracic-surgery","isVorOnly":false,"title":"Journal of Cardiothoracic Surgery"},"publishedOn":"2026-01-24 15:59:23","publishedOnDateReadable":"January 24th, 2026"},"versionCreatedAt":"2025-08-22 13:08:43","video":"","vorDoi":"10.1186/s13019-025-03807-x","vorDoiUrl":"https://doi.org/10.1186/s13019-025-03807-x","workflowStages":[]},"version":"v1","identity":"rs-7069855","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7069855","identity":"rs-7069855","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}