Prophylaxis and Management of Thromboembolism in Pnh Patients: An Italian Survey

Prophylaxis and Management of Thromboembolism in Pnh Patients: An Italian Survey | 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 Research Article Prophylaxis and Management of Thromboembolism in Pnh Patients: An Italian Survey Anna Paola Iori, Rosario Notaro, Martina Salvatori, Camilla Frieri, and 22 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8777240/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disorder characterized by uncontrolled complement-mediated intravascular hemolysis and a disproportionately high thromboembolic risk. Although terminal complement inhibition (CIT) has substantially modified the disease course, reducing thromboembolic events (TE), the residual risk remains elevated, and evidence-based anticoagulation guidelines are lacking. To characterize real-world practice, we conducted a nationwide, cross-sectional survey involving 24 Italian Centers caring for 291 patients, evaluating strategies for primary antithrombotic prophylaxis (PAP), secondary prophylaxis (SAP), and management of breakthrough hemolysis (BTH). Marked heterogeneity emerged. PAP prior to CIT was routinely employed in only one-third of Centers, whereas an equal proportion did not use it; the remainder adopted risk-based approaches integrating thrombophilia traits or clone size. SAP was universally administered after TE, with 75%of Centers maintaining indefinite anticoagulation regardless of CIT response. Anticoagulation during BTH was likewise variable, with LMWH as the preferred agent and duration largely dictated by biochemical resolution. These findings demonstrate substantial inter-center variability, underscoring the lack of harmonized national frameworks. The results highlight the need for structured expert consensus and standardized clinical algorithms to optimize thrombosis prevention and management in PNH in the era of complement inhibition. Paroxysmal Nocturnal Hemoglobinuria Venous Thromboembolism Complement Inhibition Antithrombotic Prophylaxis Figures Figure 1 Figure 2 Introduction Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, clonal, non-neoplastic hematopoietic stem cell disorder characterized by complement-mediated intravascular hemolysis, bone marrow failure, and increased risk of thromboembolic events (TE)( 1 – 3 ). Among its clinical manifestations, thrombosis represents the leading cause of morbidity and mortality in affected patients ( 4 ), prompting PNH to be defined as "the most vicious acquired thrombophilic state known in medicine”( 5 ). The pathogenesis of thrombosis in PNH is multifactorial, involving several not mutually exclusive mechanisms, including complement-mediated activation, release of prothrombotic factors secondary to hemolysis, impaired fibrinolytic activity, and endothelial dysfunction ( 6 ). Indeed, in the pre-complement inhibition therapy (CIT) era, the lifetime risk of thrombosis in individuals with PNH was estimated to range between 40% and 50%. Thrombotic events accounted for up to 67% of PNH-related deaths and patients presenting with thrombosis at diagnosis had a 4-year overall survival rate of only 40%. Furthermore, thrombotic episodes in PNH were often unpredictable, sometimes presenting as catastrophic events (e.g., those involving abdominal and cerebral veins at onset) ( 6 – 13 ), and could even arise in patients receiving adequate anticoagulation therapy. ( 14 ) The advent of CIT has significantly transformed the natural history of PNH by effectively controlling hemolysis and reducing the risk of TE from 7.37 events/100 patient-years prior to eculizumab treatment to 1.07 events/100 patient-years with CIT (P < .001). ( 15 – 19 ) However, considering that the risk of thromboembolic events in the general population is estimated at only 1 to 2 per 1,000 person-years in Western countries the residual risk in PNH patients remains significantly elevated even during CIT. Thus, managing thrombosis remains a major clinical challenge, largely due to the lack of standardized guidelines ( 19 – 24 ). Although direct oral anticoagulants (DOACs) have emerged as a potential alternative to vitamin K antagonists (VKAs) in several thromboembolic conditions, data on their safety and efficacy in PNH remain limited, leaving a significant gap in evidence-based clinical decision-making ( 8 , 25 – 27 ). Therefore, despite the evolving therapeutic landscapes—marked by the integration of complement inhibitors and novel anticoagulant agents—significant unmet clinical needs persist regarding the optimal management of thrombotic risk in PNH. This study aimed to evaluate current practices and institutional policies concerning the prophylaxis and management of thrombotic complications in patients with PNH across Italian Centers. By mapping the national approach to thrombosis in PNH, the study seeks to identify shared practices and existing disparities, thereby providing a foundation for the development of standardized and harmonized clinical strategies. Methods A cross-sectional survey was conducted between September 2024 and January 2025 to assess thrombosis management practices among Italian Centers that following and treating PNH patients, provided that at least one patient per center was treated with a complement inhibitor. The structured questionnaire comprised the following domains (Table 1 ): Table 1 Survey questionnaire. BTH: breakthrough hemolysis Item 1: Primary Phophylaxis • Do you perform thrombophilia screening at diagnosis of PNH? • Is anticoagulant prophylaxis administered to PNH patients who are not receiving complement inhibitors or are awaiting treatment initiation, in the absence of a history of thrombosis? • If yes, in which patients? • If yes, which drugs do you use? • Does your center discontinue primary anticoagulant therapy in PNH patients undergoing complement inhibitor treatment? • If yes, in which cases? ITEM 2. Secondary Prophylaxis • Which anticoagulant drugs are used for secondary prophylaxis? • Does your Center discontinue secondary anticoagulant prophylaxis • If yes in which patients ITEM 3. Anticoagulation and BTH • Do you administer anticoagulant therapy for prophylaxis in patients with BTH? • If yes, in which cases? • If yes, which anticoagulant drugs are used? • If yes, for how long? Indication of primary anti-thrombotic prophylaxis (PAP) in patients awaiting initiation of CIT Indication of secondary anti-thrombotic prophylaxis (SAP) and discontinuation of SAP therapy during CIT in patients who experienced thrombotic events before CIT. Indication of PAP in patients on CIT, choice of anticoagulants class and duration of PAP. Indication of PAP in the event of breakthrough hemolysis (BTH), choice of anticoagulants class and duration of PAP post-BTH Operational Definitions: Primary anti-thrombotic prophylaxis (PAP) is defined as the preventive use of medications to reduce the risk of blood clot formation in patients who have not yet experienced a thrombotic event but who are considered at increased risk due to hematologic features of PNH or coexisting thrombotic risks. Secondary anti-thrombotic prophylaxis (SAP) refers to the ongoing use of medications or interventions to prevent the recurrence of thrombotic events in PNH patients who have already experienced a thrombotic episode. Breakthrough hemolysis (BTH) is defined as the occurrence of any level of intravascular hemolysis, despite ongoing treatment with CIT. Clinically significant BTH is the occurrence of intravascular hemolysis associated with significantly increased lactate dehydrogenase (LDH) levels (≥ 2 ×basal value) and falling hemoglobin levels (> 2 gr/dl). ( 26 ) Results Overall, 24 Centers participated in the survey, collectively managing 291 PNH patients. The median number of patients per center was 6 (range, 1–40) (Fig. 1 ). Antithrombotic prophylaxis in patients before CIT Regarding the use of Primary Anti-thrombotic Prophylaxis (PAP), practices were divided among the surveyed centers (Fig. 2 A): Eight Centers (33%) reported never using PAP. Eight Centers (33%) reported systematic use of PAP regardless of additional thrombotic risk factors; 6 Centers (25%) reported prescribing PAP only in patients with additional thrombotic risk factors, based on thrombophilia screening results; 2 Centers (9%) utilized PAP based on PNH neutrophils population size (e.g., PNH neutrophils > 50% or PNH neutrophils > 10% associated with positive thrombophilia tests). Among the 16 Centers that reported using PAP, VKA was the preferred choice in 9 Centers, and LMWH was preferred in 7 Centers. PAP was always discontinued after the initiation of CIT in 15 Centers (93%). One center (7%) reported continuing PAP indefinitely in patients with underlying thrombophilia. All 25 Centers reported using SAP in patients with a prior history of TE. The preferred anticoagulants for SAP included VKAs (15 Centers), LMWH (5 Centers), and DOACs (2 Centers). Three Centers reported using VKAs and LMWH interchangeably. Antithrombotic prophylaxis in patients receiving CIT All Centers reported that PAP was not used after starting CIT in the absence of a history of TE or of additional thrombotic risk factors identified by thrombophilia screening. All Centers reported using SAP in patients with breakthrough TE documented during CIT. The majority of Centers, 18 (75%), declared to continue SAP indefinitely, while 6 Centers (25%) reported discontinuing anticoagulation based on distinct criteria: (i) patients with imaging (ultrasound, CT, or MRI) proved resolution of TE and ≥ 2 years of event-free follow-up (2 Centers); (ii) patients with only superficial vein thrombosis (2 Centers); (iii) patients who achieved a well-controlled hemolysis and absence of atypical thrombotic events (2 Centers) (Fig. 2 B). Antithrombotic prophylaxis in the setting of breakthrough hemolysis (BTH) 7 Centers (29%) reported never using PAP during episodes of BTH. 6 Centers (25%) reported the use of PAP in all BTH episodes and 7 Centers (29%) reported using PAP only in clinically significant BTH episodes. The remaining 4 Centers (17%) utilized PAP only in BTH episodes associated with additional thrombotic risks (i.e., infections or prolonged bed rest). LMWH was the sole anticoagulant reported for PAP during BTH, with dosing consistently adjusted based on the patient’s platelet count. Among the 17 Centers that reported the use of PAP during BTH, anticoagulation was discontinued once hemolytic parameters returned to baseline in 15 Centers (88%), while 2 Centers (12%) continued anticoagulation for 3 months following the resolution of BTH (Fig. 2 C). Discussion Despite the evolving therapeutic armamentarium of PNH-directed treatments, a scarcity of data exists regarding the selection, duration, and general necessity of anticoagulation therapy in patients receiving CIT. Indeed, the use of the newer class of DOACs has never been formally investigated, and the choice between various classes of anticoagulants is anecdotal, deriving from the unstandardized practices of individual Centers that are not based on strong scientific evidence. This nationwide survey provides the first comprehensive overview of thrombosis management strategies in PNH across Italian Centers, encompassing more than half of the known national PNH population. A recently published study on a large real-world cohort of PNH patients from 4 US Centers explored the features, predictors of TE, and anticoagulation strategies among 267 patients followed for a total of 2043 patient-years ( 26 ) Overall, 21% of patients developed TEs, which occurred at disease onset in 43% of cases. The rate of TEs was halved in patients receiving CIT compared to untreated patients (20 vs 40 TEs per 1000 patient-years, respectively). This study described in detail the management of TEs, and the anticoagulation strategy consisting of warfarin (45%), DOACs (41%), and LMWH (14%), with a median treatment duration of 46 months. However, no information was specifically reported on the PAP and SAP strategies employed in the 4 US Centers, particularly in patients awaiting or on CIT. The results of our survey reveal substantial variability in clinical practices, reflecting the absence of unified guidelines and confirming that PAP remains a controversial area. Only one-third of centers systematically prescribe prophylaxis in untreated patients or those awaiting complement inhibitors, while the majority adopt a risk-based approach. This mirrors the uncertainty in the field, as emphasized by Fattizzo et al ( 20 ) who highlighted the paucity of robust evidence supporting universal primary prophylaxis in PNH and underscored the importance of individualized risk assessment strategies, including clone size and concomitant thrombophilia traits ( 5 , 17 , 21 ). Gurnari et al. have proposed that an extended coagulation workup at diagnosis may help identify a subset of patients who could benefit from early intervention ( 26 ). Uncertainty regarding this approach also emerged in our survey, as only 11 out of 25 Centers perform thrombophilia screening at diagnosis as a potential tool to guide decisions on PAP treatment. The discontinuation of PAP represents another controversial issue, even though the initiation of CIT, good disease control (using LDH value < 1.5 the upper limit as a valid marker of control of intravascular hemolysis), and the absence of signs of thrombosis may be considered reasonable criteria for safe suspension of antithrombotic therapy ( 24 ). In terms of SAP , our results show that most centers maintain anticoagulation indefinitely after a thrombotic event, regardless of CIT. This aligns with data from Brodsky and colleagues, who have long advocated for a cautious approach to stopping anticoagulation due to the unpredictable nature of thrombosis in PNH, even in the setting of CIT ( 28 ). However, some centers in our survey reported considering anticoagulation discontinuation following prolonged remission, resolution of imaging findings (e.g., CT scan, MR angiography, or Doppler ultrasound), and sustained control of hemolysis. These observations raise important questions regarding the optimal duration of anticoagulant therapy in the context of effective complement inhibition. Management of breakthrough hemolysis (BTH) also showed variation in centers’ policy. LMWH initiation during BTH was influenced by the presence of precipitating factors (e.g., infections or immobilization) and the severity of hemolysis, highlighting a reactive approach rather than standardized protocols. Fattizzo et al. have emphasized that not all BTH events carry the same thrombotic risk, and that clinical context—including markers such as LDH surge and D-dimer elevation—should guide anticoagulant decisions ( 20 , 27 , 29 ) Notably, DOACs were used by only a minority of centers, suggesting continued caution in adopting newer anticoagulants in this setting, despite their expanding use in other high-risk thrombophilic states. Preliminary case series and pharmacologic analyses suggest that DOACs may be safe and effective in selected PNH patients, but controlled prospective data remain lacking ( 25 , 27 , 29 , 30 ). This study has several limitations, including its reliance on self-reported institutional policies and incomplete data on individual patient characteristics. However, the high response rate and broad national coverage strengthen the representativeness of the findings that clearly suggest the urgent need to produce shared guidelines with the aim of harmonizing patient management in clinical practice. In conclusion, the therapeutic landscape has evolved dramatically with complement inhibitors, but clinical practice has not yet standardized. Our study underscores the need for c ollaborative prospective studies, registry-based analyses and evidence-based recommendations for thrombosis management in PNH to harmonize anticoagulation strategies, both in PAP and in long-term SAP. However, due to the rarity of the disease and the great variability of risks and manifestations of TEs, conducting appropriate clinical trials will likely remain challenging. Therefore, guidelines derived from formal and structured expert consensus studies may represent a valid tool for the harmonization of antithrombotic strategies in patients with PNH. Declarations Ethical Approval and Consent to Participate The study was conducted in accordance with the Declaration of Helsinki. Since this research consisted of a survey addressed to healthcare professionals (referents of Italian PNH hub centers) regarding clinical management protocols and did not involve patients, clinical interventions, or the use of identifiable human biological material, formal approval by an Ethics Committee was not required according to national and institutional guidelines. Consent to Participate Formal informed consent was not applicable as no human participants (patients) were involved. Completion and submission of the survey by the healthcare professionals were considered as implied consent to participate in the study. Funding The authors declare that no funds or grants were received during the preparation of this manuscript. Data Availability The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request. References Parker C (2003) Paroxysmal nocturnal hemoglobinuria. NORD Guide to Rare Disorders. Lippincott Williams & WIlkins, pp 389–390 Schrezenmeier H, Röth A, Araten DJ et al (2020) Baseline clinical characteristics and disease burden in patients with paroxysmal nocturnal hemoglobinuria (PNH): updated analysis from the International PNH Registry. Ann Hematol 99(7):1505–1514 Schrezenmeier H, Muus P, Socié G et al (2014) Baseline characteristics and disease burden in patients in the International Paroxysmal Nocturnal Hemoglobinuria Registry. 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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-8777240","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":596426577,"identity":"b5e74410-5439-4c95-b993-2ee38ddc68cd","order_by":0,"name":"Anna Paola Iori","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0ElEQVRIiWNgGAWjYBACNiA+8LEBwjkAEWFsIKjl4ExkLXwMjI349QABMy+yEjkGAtbwsfc+PGy7w06OQSL34OGKim3ybAzM7Q/wOoznuMHh3DPJxgwSeQkHz5y5bdhGyGFsEmkMh3PbDiQ2SOQYHGxsu81InBbLtgP1MC32xGlhbDuQwADVkkhYC88xhoO9Z5IN23jeGBxsOHM7uY2ZsXEGPi3y7W3MH37usJPnZ88x/thQcdt2fnv7gw/4tCCsg7OYiVI/CkbBKBgFowAfAAAZGkn4YN5DLgAAAABJRU5ErkJggg==","orcid":"","institution":"UOC Ematologia, Sapienza University of Rome","correspondingAuthor":true,"prefix":"","firstName":"Anna","middleName":"Paola","lastName":"Iori","suffix":""},{"id":596426578,"identity":"145676a7-2515-4814-ac0b-6f714976bfcb","order_by":1,"name":"Rosario Notaro","email":"","orcid":"","institution":"Istituto per lo Studio, la Prevenzione e la Rete Oncologica -ISPRO – PNH","correspondingAuthor":false,"prefix":"","firstName":"Rosario","middleName":"","lastName":"Notaro","suffix":""},{"id":596426579,"identity":"b4b5ba32-8aa8-4190-a6b5-c975b852aab5","order_by":2,"name":"Martina Salvatori","email":"","orcid":"","institution":"Department of Translational and Precision Medicine, Hematology, Sapienza University of Rome","correspondingAuthor":false,"prefix":"","firstName":"Martina","middleName":"","lastName":"Salvatori","suffix":""},{"id":596426580,"identity":"dd3c97fe-af24-439a-9c59-45247bb3dcbf","order_by":3,"name":"Camilla Frieri","email":"","orcid":"","institution":"AORN San Giuseppe Moscati","correspondingAuthor":false,"prefix":"","firstName":"Camilla","middleName":"","lastName":"Frieri","suffix":""},{"id":596426581,"identity":"1807e08b-ada8-4458-839f-fe37787d4b69","order_by":4,"name":"Eros Di Bona","email":"","orcid":"","institution":"AULSS7 Pedemontana, UOC Oncoematologia","correspondingAuthor":false,"prefix":"","firstName":"Eros","middleName":"Di","lastName":"Bona","suffix":""},{"id":596426582,"identity":"3eea12c9-a600-436a-a195-7f99fcfde1cf","order_by":5,"name":"Antonio De Vivo","email":"","orcid":"","institution":"Hematology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), S. 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Spirito Santo","correspondingAuthor":false,"prefix":"","firstName":"Antonella","middleName":"","lastName":"Sau","suffix":""},{"id":596426589,"identity":"2bbc924b-e131-49fc-a3ca-7854fa014d67","order_by":12,"name":"Eloise Beggiato","email":"","orcid":"","institution":"University Hospital City of Health and Science of Turin - Hospital Molinette, Oncology and Hematology","correspondingAuthor":false,"prefix":"","firstName":"Eloise","middleName":"","lastName":"Beggiato","suffix":""},{"id":596426590,"identity":"562d7907-6e08-4140-9c3f-6432dcb626b4","order_by":13,"name":"Simona Raso","email":"","orcid":"","institution":"Department of Hematology and Rare Diseases, Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello","correspondingAuthor":false,"prefix":"","firstName":"Simona","middleName":"","lastName":"Raso","suffix":""},{"id":596426591,"identity":"a01b86fb-9695-4a5a-8731-dd610c647563","order_by":14,"name":"Alessandro Costa","email":"","orcid":"","institution":"Businco Hospital, University of Cagliari","correspondingAuthor":false,"prefix":"","firstName":"Alessandro","middleName":"","lastName":"Costa","suffix":""},{"id":596426592,"identity":"de2e50be-8bea-4cbb-981d-bace084fda46","order_by":15,"name":"Amalia Figuera","email":"","orcid":"","institution":"Division of Hematology AOU. Policlinico \"G. Rodolico-S. Marco\",","correspondingAuthor":false,"prefix":"","firstName":"Amalia","middleName":"","lastName":"Figuera","suffix":""},{"id":596426593,"identity":"7a051a83-adbc-437a-bc67-003ef6d5f9a5","order_by":16,"name":"Maria Bruna Greve","email":"","orcid":"","institution":"Clinical of Haematology Grande Ospedale Metropolitano di Reggio Calabria","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Bruna","lastName":"Greve","suffix":""},{"id":596426594,"identity":"4d0992bb-07ad-444a-970c-7286acf4f5d8","order_by":17,"name":"Filippo Achille Brioschi","email":"","orcid":"","institution":"Fondazione IRCCS San Gerardo dei Tintori","correspondingAuthor":false,"prefix":"","firstName":"Filippo","middleName":"Achille","lastName":"Brioschi","suffix":""},{"id":596426595,"identity":"8e787df9-1880-467c-8650-a3a6ad26bd0a","order_by":18,"name":"Marica Laurino","email":"","orcid":"","institution":"Hematology and Cellular Therapy Unit, IRCCS Ospedale Policlinico San Martino","correspondingAuthor":false,"prefix":"","firstName":"Marica","middleName":"","lastName":"Laurino","suffix":""},{"id":596426596,"identity":"b6f0b4ea-055a-4173-85ae-5d5654732b26","order_by":19,"name":"Giulio Giordano","email":"","orcid":"","institution":"Unità Operativa Complessa, Medicina Servizio e Ambulatorio di Ematologia Ospedale di Riferimento Regionale Antonio Cardarelli","correspondingAuthor":false,"prefix":"","firstName":"Giulio","middleName":"","lastName":"Giordano","suffix":""},{"id":596426597,"identity":"4a015d35-9e20-4188-a1be-e77966aa93ab","order_by":20,"name":"Elisabetta Metafuni","email":"","orcid":"","institution":"Istituto di Ematologia, Fondazione Policlinico Universitario A Gemelli IRCCS","correspondingAuthor":false,"prefix":"","firstName":"Elisabetta","middleName":"","lastName":"Metafuni","suffix":""},{"id":596426598,"identity":"bb86536f-d106-4567-b8d9-cbec8dc88136","order_by":21,"name":"Francesca D'adamo","email":"","orcid":"","institution":"Hematology and Hematopoietic Stem Cell Transplant Center, San Salvatore Hospital","correspondingAuthor":false,"prefix":"","firstName":"Francesca","middleName":"","lastName":"D'adamo","suffix":""},{"id":596426599,"identity":"45c24116-79ac-4188-86fb-6c3b088d035d","order_by":22,"name":"Tania Maria Santeramo","email":"","orcid":"","institution":"Division of Hematology, \"Monsignor Raffaele Dimiccoli\" Hospital Barletta","correspondingAuthor":false,"prefix":"","firstName":"Tania","middleName":"Maria","lastName":"Santeramo","suffix":""},{"id":596426600,"identity":"afd23052-6bb6-461e-8bd9-4f4992d4e395","order_by":23,"name":"Angela Amendola","email":"","orcid":"","institution":"UOC Ematologia con Centro trapianto di Midollo, Cellule staminali e terapie cellulari AOR SAN CARLO","correspondingAuthor":false,"prefix":"","firstName":"Angela","middleName":"","lastName":"Amendola","suffix":""},{"id":596426601,"identity":"d34d30f6-b2db-41a9-85fb-f9335d2a7e22","order_by":24,"name":"Giorgia Mancini","email":"","orcid":"","institution":"Clinic of Hematology Azienda Ospedaliero Universitaria delle Marche","correspondingAuthor":false,"prefix":"","firstName":"Giorgia","middleName":"","lastName":"Mancini","suffix":""},{"id":596426602,"identity":"2e8deea9-44ff-4051-a835-42e6cf100bbc","order_by":25,"name":"Bruno Fattizzo","email":"","orcid":"","institution":"Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico","correspondingAuthor":false,"prefix":"","firstName":"Bruno","middleName":"","lastName":"Fattizzo","suffix":""}],"badges":[],"createdAt":"2026-02-03 14:39:57","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8777240/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8777240/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103590519,"identity":"95508b2f-cf5a-489a-9094-c96232150982","added_by":"auto","created_at":"2026-02-27 12:05:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":367162,"visible":true,"origin":"","legend":"\u003cp\u003eItalian PNH Centers and number of patients for each Center\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8777240/v1/a93200f0c36734b35d4abd92.png"},{"id":103590518,"identity":"ff294200-16a4-4997-8469-a31e7831c58c","added_by":"auto","created_at":"2026-02-27 12:05:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":75118,"visible":true,"origin":"","legend":"\u003cp\u003eSurvey answers. A: Item 1. B: Item 2. C: Item 3. PAP: primary anti-coagulant prophylaxis; LMWH: low molecular weight heparin; DOACs: direct oral anti-coagulants; VKA: vitamin k antagonists; CI: complement inhibitors; SAP: secondary anticoagulant prophylaxis; BTH: breakthrough hemolysis; MBTH: major breakthrough hemolysis\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8777240/v1/14f87eb8ef81eb9f12e4ea62.png"},{"id":103590583,"identity":"4b84ce46-a9a2-411a-8ef3-fb598b23db23","added_by":"auto","created_at":"2026-02-27 12:05:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1005596,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8777240/v1/c720f2e1-2f19-477c-8de2-df872bcb0fba.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eProphylaxis and Management of Thromboembolism in Pnh Patients: An Italian Survey\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eParoxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, clonal, non-neoplastic hematopoietic stem cell disorder characterized by complement-mediated intravascular hemolysis, bone marrow failure, and increased risk of thromboembolic events (TE)(\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Among its clinical manifestations, thrombosis represents the leading cause of morbidity and mortality in affected patients (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e), prompting PNH to be defined as \"the most vicious acquired thrombophilic state known in medicine\u0026rdquo;(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). The pathogenesis of thrombosis in PNH is multifactorial, involving several not mutually exclusive mechanisms, including complement-mediated activation, release of prothrombotic factors secondary to hemolysis, impaired fibrinolytic activity, and endothelial dysfunction (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIndeed, in the pre-complement inhibition therapy (CIT) era, the lifetime risk of thrombosis in individuals with PNH was estimated to range between 40% and 50%. Thrombotic events accounted for up to 67% of PNH-related deaths and patients presenting with thrombosis at diagnosis had a 4-year overall survival rate of only 40%. Furthermore, thrombotic episodes in PNH were often unpredictable, sometimes presenting as catastrophic events (e.g., those involving abdominal and cerebral veins at onset) (\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10 CR11 CR12\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), and could even arise in patients receiving adequate anticoagulation therapy. (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eThe advent of CIT has significantly transformed the natural history of PNH by effectively controlling hemolysis and reducing the risk of TE from 7.37 events/100 patient-years prior to eculizumab treatment to 1.07 events/100 patient-years with CIT (P \u0026lt; .001). (\u003cspan additionalcitationids=\"CR16 CR17 CR18\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) However, considering that the risk of thromboembolic events in the general population is estimated at only 1 to 2 per 1,000 person-years in Western countries the residual risk in PNH patients remains significantly elevated even during CIT. Thus, managing thrombosis remains a major clinical challenge, largely due to the lack of standardized guidelines (\u003cspan additionalcitationids=\"CR20 CR21 CR22 CR23\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Although direct oral anticoagulants (DOACs) have emerged as a potential alternative to vitamin K antagonists (VKAs) in several thromboembolic conditions, data on their safety and efficacy in PNH remain limited, leaving a significant gap in evidence-based clinical decision-making (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTherefore, despite the evolving therapeutic landscapes\u0026mdash;marked by the integration of complement inhibitors and novel anticoagulant agents\u0026mdash;significant unmet clinical needs persist regarding the optimal management of thrombotic risk in PNH.\u003c/p\u003e \u003cp\u003eThis study aimed to evaluate current practices and institutional policies concerning the prophylaxis and management of thrombotic complications in patients with PNH across Italian Centers. By mapping the national approach to thrombosis in PNH, the study seeks to identify shared practices and existing disparities, thereby providing a foundation for the development of standardized and harmonized clinical strategies.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e A cross-sectional survey was conducted between September 2024 and January 2025 to assess thrombosis management practices among Italian Centers that following and treating PNH patients, provided that at least one patient per center was treated with a complement inhibitor.\u003c/p\u003e \u003cp\u003eThe structured questionnaire comprised the following domains (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e):\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSurvey questionnaire. BTH: breakthrough hemolysis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eItem 1: Primary Phophylaxis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Do you perform thrombophilia screening at diagnosis of PNH?\u003c/p\u003e \u003cp\u003e\u0026bull; Is anticoagulant prophylaxis administered to PNH patients who are not receiving complement inhibitors or are awaiting treatment initiation, in the absence of a history of thrombosis?\u003c/p\u003e \u003cp\u003e\u0026bull; If yes, in which patients?\u003c/p\u003e \u003cp\u003e\u0026bull; If yes, which drugs do you use?\u003c/p\u003e \u003cp\u003e\u0026bull; Does your center discontinue primary anticoagulant therapy in PNH patients undergoing complement inhibitor treatment?\u003c/p\u003e \u003cp\u003e\u0026bull; If yes, in which cases?\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eITEM 2. Secondary Prophylaxis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Which anticoagulant drugs are used for secondary prophylaxis?\u003c/p\u003e \u003cp\u003e\u0026bull; Does your Center discontinue secondary anticoagulant prophylaxis\u003c/p\u003e \u003cp\u003e\u0026bull; If yes in which patients\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eITEM 3. Anticoagulation and BTH\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Do you administer anticoagulant therapy for prophylaxis in patients with BTH?\u003c/p\u003e \u003cp\u003e\u0026bull; If yes, in which cases?\u003c/p\u003e \u003cp\u003e\u0026bull; If yes, which anticoagulant drugs are used?\u003c/p\u003e \u003cp\u003e\u0026bull; If yes, for how long?\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eIndication of primary anti-thrombotic prophylaxis (PAP) in patients awaiting initiation of CIT\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIndication of secondary anti-thrombotic prophylaxis (SAP) and discontinuation of SAP therapy during CIT in patients who experienced thrombotic events before CIT.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIndication of PAP in patients on CIT, choice of anticoagulants class and duration of PAP.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eIndication of PAP in the event of breakthrough hemolysis (BTH), choice of anticoagulants class and duration of PAP post-BTH\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eOperational Definitions:\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003ePrimary anti-thrombotic prophylaxis (PAP) is defined \u003cb\u003eas\u003c/b\u003e the preventive use of medications to reduce the risk of blood clot formation in patients who have not yet experienced a thrombotic event but who are considered at increased risk due to hematologic features of PNH or coexisting thrombotic risks.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eSecondary anti-thrombotic prophylaxis (SAP) refers to the ongoing use of medications or interventions to prevent the recurrence of thrombotic events in PNH patients who have already experienced a thrombotic episode.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eBreakthrough hemolysis (BTH) is defined as the occurrence of any level of intravascular hemolysis, despite ongoing treatment with CIT. Clinically significant BTH is the occurrence of intravascular hemolysis associated with significantly increased lactate dehydrogenase (LDH) levels (\u0026ge;\u0026thinsp;2 \u0026times;basal value) and falling hemoglobin levels (\u0026gt;\u0026thinsp;2 gr/dl). (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eOverall, 24 Centers participated in the survey, collectively managing 291 PNH patients. The median number of patients per center was 6 (range, 1\u0026ndash;40) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eAntithrombotic prophylaxis in patients before CIT\u003c/h3\u003e\n\u003cp\u003eRegarding the use of Primary Anti-thrombotic Prophylaxis (PAP), practices were divided among the surveyed centers (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA):\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eEight Centers (33%) reported never using PAP. Eight Centers (33%) reported systematic use of PAP regardless of additional thrombotic risk factors; 6 Centers (25%) reported prescribing PAP only in patients with additional thrombotic risk factors, based on thrombophilia screening results; 2 Centers (9%) utilized PAP based on PNH neutrophils population size (e.g., PNH neutrophils\u0026thinsp;\u0026gt;\u0026thinsp;50% or PNH neutrophils\u0026thinsp;\u0026gt;\u0026thinsp;10% associated with positive thrombophilia tests).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAmong the 16 Centers that reported using PAP, VKA was the preferred choice in 9 Centers, and LMWH was preferred in 7 Centers.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePAP was always discontinued after the initiation of CIT in 15 Centers (93%). One center (7%) reported continuing PAP indefinitely in patients with underlying thrombophilia.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAll 25 Centers reported using SAP in patients with a prior history of TE. The preferred anticoagulants for SAP included VKAs (15 Centers), LMWH (5 Centers), and DOACs (2 Centers). Three Centers reported using VKAs and LMWH interchangeably.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e\n\u003ch3\u003eAntithrombotic prophylaxis in patients receiving CIT\u003c/h3\u003e\n\u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eAll Centers reported that PAP was not used after starting CIT in the absence of a history of TE or of additional thrombotic risk factors identified by thrombophilia screening.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAll Centers reported using SAP in patients with breakthrough TE documented during CIT. The majority of Centers, 18 (75%), declared to continue SAP indefinitely, while 6 Centers (25%) reported discontinuing anticoagulation based on distinct criteria: (i) patients with imaging (ultrasound, CT, or MRI) proved resolution of TE and \u0026ge;\u0026thinsp;2 years of event-free follow-up (2 Centers); (ii) patients with only superficial vein thrombosis (2 Centers); (iii) patients who achieved a well-controlled hemolysis and absence of atypical thrombotic events (2 Centers) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e\n\u003ch3\u003eAntithrombotic prophylaxis in the setting of breakthrough hemolysis (BTH)\u003c/h3\u003e\n\u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e7 Centers (29%) reported never using PAP during episodes of BTH. 6 Centers (25%) reported the use of PAP in all BTH episodes and 7 Centers (29%) reported using PAP only in clinically significant BTH episodes. The remaining 4 Centers (17%) utilized PAP only in BTH episodes associated with additional thrombotic risks (i.e., infections or prolonged bed rest).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eLMWH was the sole anticoagulant reported for PAP during BTH, with dosing consistently adjusted based on the patient\u0026rsquo;s platelet count. Among the 17 Centers that reported the use of PAP during BTH, anticoagulation was discontinued once hemolytic parameters returned to baseline in 15 Centers (88%), while 2 Centers (12%) continued anticoagulation for 3 months following the resolution of BTH (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC).\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eDespite the evolving therapeutic armamentarium of PNH-directed treatments, a scarcity of data exists regarding the selection, duration, and general necessity of anticoagulation therapy in patients receiving CIT. Indeed, the use of the newer class of DOACs has never been formally investigated, and the choice between various classes of anticoagulants is anecdotal, deriving from the unstandardized practices of individual Centers that are not based on strong scientific evidence.\u003c/p\u003e \u003cp\u003eThis nationwide survey provides the first comprehensive overview of thrombosis management strategies in PNH across Italian Centers, encompassing more than half of the known national PNH population.\u003c/p\u003e \u003cp\u003eA recently published study on a large real-world cohort of PNH patients from 4 US Centers explored the features, predictors of TE, and anticoagulation strategies among 267 patients followed for a total of 2043 patient-years (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) Overall, 21% of patients developed TEs, which occurred at disease onset in 43% of cases. The rate of TEs was halved in patients receiving CIT compared to untreated patients (20 vs 40 TEs per 1000 patient-years, respectively). This study described in detail the management of TEs, and the anticoagulation strategy consisting of warfarin (45%), DOACs (41%), and LMWH (14%), with a median treatment duration of 46 months. However, no information was specifically reported on the PAP and SAP strategies employed in the 4 US Centers, particularly in patients awaiting or on CIT.\u003c/p\u003e \u003cp\u003e The results of our survey reveal substantial variability in clinical practices, reflecting the absence of unified guidelines and confirming that PAP remains a controversial area. Only one-third of centers systematically prescribe prophylaxis in untreated patients or those awaiting complement inhibitors, while the majority adopt a risk-based approach. This mirrors the uncertainty in the field, as emphasized by Fattizzo et al (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) who highlighted the paucity of robust evidence supporting universal primary prophylaxis in PNH and underscored the importance of individualized risk assessment strategies, including clone size and concomitant thrombophilia traits (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Gurnari et al. have proposed that an extended coagulation workup at diagnosis may help identify a subset of patients who could benefit from early intervention (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Uncertainty regarding this approach also emerged in our survey, as only 11 out of 25 Centers perform thrombophilia screening at diagnosis as a potential tool to guide decisions on PAP treatment. The discontinuation of PAP represents another controversial issue, even though the initiation of CIT, good disease control (using LDH value\u0026thinsp;\u0026lt;\u0026thinsp;1.5 the upper limit as a valid marker of control of intravascular hemolysis), and the absence of signs of thrombosis may be considered reasonable criteria for safe suspension of antithrombotic therapy (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn terms of \u003cb\u003eSAP\u003c/b\u003e, our results show that most centers maintain anticoagulation indefinitely after a thrombotic event, regardless of CIT. This aligns with data from Brodsky and colleagues, who have long advocated for a cautious approach to stopping anticoagulation due to the unpredictable nature of thrombosis in PNH, even in the setting of CIT (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). However, some centers in our survey reported considering anticoagulation discontinuation following prolonged remission, resolution of imaging findings (e.g., CT scan, MR angiography, or Doppler ultrasound), and sustained control of hemolysis. These observations raise important questions regarding the optimal duration of anticoagulant therapy in the context of effective complement inhibition.\u003c/p\u003e \u003cp\u003eManagement of breakthrough hemolysis (BTH) also showed variation in centers\u0026rsquo; policy. LMWH initiation during BTH was influenced by the presence of precipitating factors (e.g., infections or immobilization) and the severity of hemolysis, highlighting a reactive approach rather than standardized protocols. Fattizzo et al. have emphasized that not all BTH events carry the same thrombotic risk, and that clinical context\u0026mdash;including markers such as LDH surge and D-dimer elevation\u0026mdash;should guide anticoagulant decisions (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eNotably, DOACs were used by only a minority of centers, suggesting continued caution in adopting newer anticoagulants in this setting, despite their expanding use in other high-risk thrombophilic states. Preliminary case series and pharmacologic analyses suggest that DOACs may be safe and effective in selected PNH patients, but controlled prospective data remain lacking (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis study has several limitations, including its reliance on self-reported institutional policies and incomplete data on individual patient characteristics. However, the high response rate and broad national coverage strengthen the representativeness of the findings that clearly suggest the urgent need to produce shared guidelines with the aim of harmonizing patient management in clinical practice.\u003c/p\u003e \u003cp\u003eIn conclusion, the therapeutic landscape has evolved dramatically with complement inhibitors, but clinical practice has not yet standardized. Our study underscores the need for \u003cb\u003ec\u003c/b\u003eollaborative prospective studies, registry-based analyses and evidence-based recommendations for thrombosis management in PNH to harmonize anticoagulation strategies, both in PAP and in long-term SAP. However, due to the rarity of the disease and the great variability of risks and manifestations of TEs, conducting appropriate clinical trials will likely remain challenging. Therefore, guidelines derived from formal and structured expert consensus studies may represent a valid tool for the harmonization of antithrombotic strategies in patients with PNH.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval and Consent to Participate\u003c/strong\u003e The study was conducted in accordance with the Declaration of Helsinki. Since this research consisted of a survey addressed to healthcare professionals (referents of Italian PNH hub centers) regarding clinical management protocols and did not involve patients, clinical interventions, or the use of identifiable human biological material, formal approval by an Ethics Committee was not required according to national and institutional guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate\u003c/strong\u003e Formal informed consent was not applicable as no human participants (patients) were involved. Completion and submission of the survey by the healthcare professionals were considered as implied consent to participate in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e The authors declare that no funds or grants were received during the preparation of this manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eParker C (2003) Paroxysmal nocturnal hemoglobinuria. NORD Guide to Rare Disorders. Lippincott Williams \u0026amp; WIlkins, pp 389\u0026ndash;390\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchrezenmeier H, R\u0026ouml;th A, Araten DJ et al (2020) Baseline clinical characteristics and disease burden in patients with paroxysmal nocturnal hemoglobinuria (PNH): updated analysis from the International PNH Registry. Ann Hematol 99(7):1505\u0026ndash;1514\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchrezenmeier H, Muus P, Soci\u0026eacute; G et al (2014) Baseline characteristics and disease burden in patients in the International Paroxysmal Nocturnal Hemoglobinuria Registry. Haematologica 99(5):922\u0026ndash;929\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede Latour RP, Mary JY, Salanoubat C et al (2008) Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood 112(8):3099\u0026ndash;3106\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuzzatto L, Gianfaldoni G, Notaro R (2011 June) Management of paroxysmal nocturnal haemoglobinuria: a personal view. Br J Haematol 153(6):709\u0026ndash;720\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHill A, Kelly RJ, Hillmen P Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood 2013 June 20;121(25):4985\u0026ndash;4996\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede Latour RP, Mary JY, Salanoubat C, Terriou L et al (2008) Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories. Blood 112(8):3099\u0026ndash;3106\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHall C, Richards S, Hillmen P (2003) Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH). Blood 102(10):3587\u0026ndash;3591\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZiakas PD, Poulou LS, Rokas GI et al (2007) Thrombosis in paroxysmal nocturnal hemoglobinuria: sites, risks, outcome. An overview. J Thromb Haemost 5(3):642\u0026ndash;645\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGriffin M, Hillmen P, Munir T, Richards S et al (2019) Significant hemolysis is not required for thrombosis in paroxysmal nocturnal hemoglobinuria. Haematologica 104(3):e94\u0026ndash;e96\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoyo VM, Mukhina GL, Garrett ES, Brodsky RA (2004) Natural history of paroxysmal nocturnal haemoglobinuria using modern diagnostic assays. Br J Haematol 126(1):133\u0026ndash;138\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNishimura JI, Kanakura Y, Ware RE et al (2004) Clinical Course and Flow Cytometric Analysis of Paroxysmal Nocturnal Hemoglobinuria in the United States and Japan. 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Blood 2011 June 23;117(25):6786\u0026ndash;6792\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSoci\u0026eacute; G, Schrezenmeier H, Muus P et al (2016 Sept) Changing prognosis in paroxysmal nocturnal haemoglobinuria disease subcategories: an analysis of the International PNH Registry. Intern Med J 46(9):1044\u0026ndash;1053\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHillmen P, Muus P, D\u0026uuml;hrsen U, Risitano AM et al (2007) Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood 110(12):4123\u0026ndash;4128\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKelly RJ, Holt M, Vidler J, Arnold LM et al (2024) Treatment outcomes of complement protein C5 inhibition in 509 UK patients with paroxysmal nocturnal hemoglobinuria. Blood 143(12):1157\u0026ndash;1166\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchubert J, Hillmen P, R\u0026ouml;th A, Young NS et al (2008 June) Eculizumab, a terminal complement inhibitor, improves anaemia in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 142(2):263\u0026ndash;272\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFattizzo B, Cavallaro F, Oliva EN, Barcellini W (2022) Managing Fatigue in Patients with Paroxysmal Nocturnal Hemoglobinuria: A Patient-Focused Perspective. J Blood Med 13:327\u0026ndash;335\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDingli D, De Castro Iii C, Koprivnikar J et al (2024) Expert consensus on the management of pharmacodynamic breakthrough-hemolysis in treated paroxysmal nocturnal hemoglobinuria. 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June 9\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrodsky RA (2021) How I treat paroxysmal nocturnal hemoglobinuria. Blood 137(10):1304\u0026ndash;1309\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUeda Y, Chou WC, Goh YT et al (2025) Prevention and Management of Thromboembolism in Patients with Paroxysmal Nocturnal Hemoglobinuria in Asia: A Narrative Review. Int J Mol Sci 26(6):2504\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVersino F, Fattizzo B (2024) Complement inhibition in paroxysmal nocturnal hemoglobinuria: From biology to therapy. Int J Lab Hematol 46(Suppl 1):43\u0026ndash;54\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":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Paroxysmal Nocturnal Hemoglobinuria, Venous Thromboembolism, Complement Inhibition, Antithrombotic Prophylaxis","lastPublishedDoi":"10.21203/rs.3.rs-8777240/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8777240/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disorder characterized by uncontrolled complement-mediated intravascular hemolysis and a disproportionately high thromboembolic risk. Although terminal complement inhibition (CIT) has substantially modified the disease course, reducing thromboembolic events (TE), the residual risk remains elevated, and evidence-based anticoagulation guidelines are lacking. To characterize real-world practice, we conducted a nationwide, cross-sectional survey involving 24 Italian Centers caring for 291 patients, evaluating strategies for primary antithrombotic prophylaxis (PAP), secondary prophylaxis (SAP), and management of breakthrough hemolysis (BTH). Marked heterogeneity emerged. PAP prior to CIT was routinely employed in only one-third of Centers, whereas an equal proportion did not use it; the remainder adopted risk-based approaches integrating thrombophilia traits or clone size. SAP was universally administered after TE, with 75%of Centers maintaining indefinite anticoagulation regardless of CIT response. Anticoagulation during BTH was likewise variable, with LMWH as the preferred agent and duration largely dictated by biochemical resolution. These findings demonstrate substantial inter-center variability, underscoring the lack of harmonized national frameworks. The results highlight the need for structured expert consensus and standardized clinical algorithms to optimize thrombosis prevention and management in PNH in the era of complement inhibition.","manuscriptTitle":"Prophylaxis and Management of Thromboembolism in Pnh Patients: An Italian Survey","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-27 12:05:35","doi":"10.21203/rs.3.rs-8777240/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-14T07:00:26+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-13T22:17:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"34597955742674266354883860963203531712","date":"2026-03-02T00:50:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"242630465402068540813204272907366240386","date":"2026-02-24T15:58:53+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-24T13:40:13+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-24T13:32:28+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-24T13:30:58+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Hematology","date":"2026-02-03T14:06:58+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"5c8eeeed-e357-4788-8f70-e575927482a1","owner":[],"postedDate":"February 27th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-27T14:38:48+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-27 12:05:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8777240","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8777240","identity":"rs-8777240","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}