TYPE Review PUBLISHED 15 September 2022 DOI 10.3389/fmed.2022.903739 Indications and hemoglobin OPEN ACCESS thresholds for red blood cell EDITED BY Alicia Mohr, University of Florida, United States transfusion and iron REVIEWED BY Bálint Mihály Eross, replacement in adults with University of Pécs, Hungary Sinem Civriz Bozdağ, Ankara University, Turkey gastrointestinal bleeding: An *CORRESPONDENCE Miguel Montoro algorithm proposed by maimontoro@gmail.com † These authors have contributed equally to this work gastroenterologists and patient SPECIALTY SECTION This article was submitted to blood management experts Gastroenterology, a section of the journal Miguel Montoro1,2,3,4*† , Mercedes Cucala5 , Ángel Lanas2,4,6,7 , Frontiers in Medicine Cándido Villanueva7,8 , Antonio José Hervás9 , RECEIVED 24 March 2022 ACCEPTED 11 August 2022 Javier Alcedo2,10 , Javier P. Gisbert7,11,12 , Ángeles P. Aisa13 , PUBLISHED 15 September 2022 Luis Bujanda7,14,15 , Xavier Calvet7,16,17 , Fermín Mearin18 , CITATION Montoro M, Cucala M, Lanas Á, Óscar Murcia19 , Pilar Canelles20 , Santiago García López2,10 , Villanueva C, Hervás AJ, Alcedo J, Carlos Martín de Argila21 , Montserrat Planella22,23 , Gisbert JP, Aisa ÁP, Bujanda L, Calvet X, Mearin F, Murcia Ó, Canelles P, Manuel Quintana24,25 , Carlos Jericó26,27 , García López S, Martín de Argila C, Planella M, Quintana M, Jericó C and and José Antonio García Erce25,27,28,29† on behalf of the García Erce JA (2022) Indications Spanish Association of Gastroenterology (AEG) and hemoglobin thresholds for red blood cell transfusion and iron 1 Unidad de Gastroenterología, Hepatología y Nutrición, Hospital Universitario San Jorge, Huesca, replacement in adults with Spain, 2 Departamento de Medicina, Universidad de Zaragoza, Zaragoza, Spain, 3 Instituto Aragonés gastrointestinal bleeding: An algorithm de Ciencias de la Salud (IACS), Zaragoza, Spain, 4 Instituto de Investigación Sanitaria Aragón (IIS), proposed by gastroenterologists Zaragoza, Spain, 5 Vifor Pharma, Barcelona, Spain, 6 Servicio de Aparato Digestivo, Hospital Clínico and patient blood management Universitario “Lozano Blesa”, Zaragoza, Spain, 7 Centro de Investigación Biomédica en Red experts. de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain, 8 Servei de Digestiu, Hospital Front. Med. 9:903739. de la Santa Creu y Sant Pau, Universidad Autónoma de Barcelona, Barcelona, Spain, 9 Unidad doi: 10.3389/fmed.2022.903739 de Gestión Clínica de Aparato Digestivo, Hospital Universitario Reina Sofía de Córdoba, Córdoba, Spain, 10 Servicio de Aparato Digestivo, Hospital Universitario Miguel Servet, Zaragoza, Spain, COPYRIGHT 11 Servicio de Aparato Digestivo, Hospital Universitario de La Princesa, Madrid, Spain, 12 Instituto © 2022 Montoro, Cucala, Lanas, de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), Madrid, Spain, Villanueva, Hervás, Alcedo, Gisbert, 13 Servicio de Aparato Digestivo, Hospital Universitario Costa del Sol, Marbella, Spain, 14 Servicio Aisa, Bujanda, Calvet, Mearin, Murcia, de Aparato Digestivo, Hospital Universitario Donostia, Donostia, Spain, 15 Instituto de Investigación Canelles, García López, Martín de Sanitaria Biodonostia, Universidad del País Vasco (UPV/EHU), Donostia, Spain, 16 Servei de Digestiu, Argila, Planella, Quintana, Jericó and Corporació Sanitaria Park Taulí, Sabadell, Spain, 17 Department of Medicine, Universidad Autónoma García Erce. This is an open-access de Barcelona, Barcelona, Spain, 18 Servicio de Aparato Digestivo, Centro Médico Teknon, Barcelona, article distributed under the terms of Spain, 19 Servicio de Aparato Digestivo, Hospital General Universitario de Alicante, Alicante, Spain, the Creative Commons Attribution 20 Servicio de Aparato Digestivo, Hospital General Universitario de Valencia, Valencia, Spain, License (CC BY). The use, distribution 21 Servicio de Aparato Digestivo, Hospital Universitario Ramón y Cajal, Madrid, Spain, 22 Servei or reproduction in other forums is de Digestiu, Hospital Universitario Arnau de Vilanova, Lleida, Spain, 23 Department of Medicine, permitted, provided the original Universidad de Lleida, Lleida, Spain, 24 Servicio a Medicina Intensiva, Hospital Universitario La Paz author(s) and the copyright owner(s) (IdiPAZ), Madrid, Spain, 25 PBM Group, Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, are credited and that the original Spain, 26 Servicio de Medicina Interna, Complex Hospitalari Moisès Broggi, Sant Joan Despí, publication in this journal is cited, in Barcelona, Spain, 27 Grupo Español de Rehabilitación Multimodal (GERM), Zaragoza, Spain, 28 Banco accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Frontiers in Medicine 01 frontiersin.org Montoro et al. 10.3389/fmed.2022.903739 de Sangre y Tejidos de Navarra, Servicio Navarro de Salud, Osasunbidea, Pamplona, Spain, 29 Instituto Aragonés de Ciencias de la Salud, Universidad de Zaragoza, Zaragoza, Spain Gastrointestinal (GI) bleeding is associated with considerable morbidity and mortality. Red blood cell (RBC) transfusion has long been the cornerstone of treatment for anemia due to GI bleeding. However, blood is not devoid of potential adverse effects, and it is also a precious resource, with limited supplies in blood banks. Nowadays, all patients should benefit from a patient blood management (PBM) program that aims to minimize blood loss, optimize hematopoiesis (mainly by using iron replacement therapy), maximize tolerance of anemia, and avoid unnecessary transfusions. Integration of PBM into healthcare management reduces patient mortality and morbidity and supports a restrictive RBC transfusion approach by reducing transfusion rates. The European Commission has outlined strategies to support hospitals with the implementation of PBM, but it is vital that these initiatives are translated into clinical practice. To help optimize management of anemia and iron deficiency in adults with acute or chronic GI bleeding, we developed a protocol under the auspices of the Spanish Association of Gastroenterology, in collaboration with healthcare professionals from 16 hospitals across Spain, including expert advice from different specialties involved in PBM strategies, such as internal medicine physicians, intensive care specialists, and hematologists. Recommendations include how to identify patients who have anemia (or iron deficiency) requiring oral/intravenous iron replacement therapy and/or RBC transfusion (using a restrictive approach to transfusion), and transfusing RBC units 1 unit at a time, with assessment of patients after each given unit (i.e., “don’t give two without review”). The advantages and limitations of oral versus intravenous iron and guidance on the safe and effective use of intravenous iron are also described. Implementation of a PBM strategy and clinical decision-making support, including early treatment of anemia with iron supplementation in patients with GI bleeding, may improve patient outcomes and lower hospital costs. KEYWORDS anemia, ferric carboxymaltose (FCM), gastrointestinal bleeding, iron supplementation, patient blood management, transfusion Introduction although the rate of transfusions vary, with 6% of RBC transfusions in Northern Spain (10) and 11–14% of RBC Acute or chronic gastrointestinal (GI) bleeding affects 47 in transfusions in England (11, 12) being given due to GI 100,000 people worldwide (1) and is one of the most significant bleeding. However, evidence is accumulating of a dose- clinical problems observed by gastroenterologists, hepatologists, response relationship between transfusion and increased internal medicine physicians, and surgeons (2–5). Upper GI patient morbidity, mortality, and length of hospital stay (13– bleeding is associated with mortality rates of 3–14% (3), while a 17). Therefore, there has recently been a shift toward a mortality rate of approximately 3% has been reported in patients more restrictive use of RBC transfusion on the basis that with lower GI bleeding (6). However, rapid correction of anemia outcomes are similar or better than when a more liberal and hypotension may reduce bleeding-associated mortality by strategy is used (18–28). Reduced rates of rebleeding (20, preventing cardiovascular decompensation (7–9). 21), reduced transfusion-associated risks (29, 30), lower all- Red blood cell (RBC) transfusion has long been the cause mortality (20), and shorter hospital stays (21) have cornerstone of treatment for anemia due to GI bleeding all been reported when a restrictive rather than liberal Frontiers in Medicine 02 frontiersin.org Montoro et al. 10.3389/fmed.2022.903739 transfusion strategy had been implemented. Furthermore, no over-transfusion, thereby preventing many transfusions that differences in the risk of ischemic events (20) or major adverse would otherwise have been deemed appropriate. cardiovascular events (24) have been noted between liberal We therefore developed the current protocol, based on and restrictive strategies. A restrictive transfusion strategy can the three pillars of PBM, with the aim of optimizing the also reduce healthcare resource utilization and costs (31– management of patients with anemia and iron deficiency due to 33). For example, the United Kingdom’s National Health GI bleeding in clinical practice. For this purpose, it was deemed Service (NHS) saved £3.3 million in the year following the very important to include the expert opinion of PBM experts, introduction of a restrictive transfusion policy for lower GI because of their high awareness of the need to save blood and bleeding (33). Cochrane meta-analyses support the use of minimize healthcare costs. restrictive RBC transfusion strategies across a broad range of clinical indications, including in hemodynamically stable patients with GI bleeding (34). A restrictive approach is Aims of the protocol now commonly used, resulting in a global reduction in RBC transfusions (35) and transfusion-associated risks. Importantly, This protocol was commissioned and approved by the reduced demand for blood supplies helps to ensure that Spanish Association of Gastroenterology (Asociación Española blood is available for those who need it most, which is de Gastroenterología [AEG]), after an expert review was important given that currently approximately 25 million units performed by professionals from 16 Spanish hospitals, who of blood are transfused to more than 5 million patients were also part of the Working Group on “Esophagus, Stomach, each year in Europe (36). With an aging population and and Duodenum” for the AEG. The review was conducted a decreasing number of blood donors, it is expected that in collaboration with internal medicine physicians, intensive more and more countries will experience challenges in care specialists, and hematologists with advanced knowledge ensuring that blood supplies are adequate (37). Indeed, blood of PBM programs. This was not a formal systematic literature shortages have been reported in several European countries review but was based on a review of the literature to during health emergencies in recent years (38). Despite the provide best practice advice statements. No formal rating continued efforts of the European Commission to ensure the of the quality of evidence or strength of recommendation optimum use of blood components (39), data from the NHS was performed. suggest that approximately 15–20% of RBC transfusions are All the authors were invited for their experience, used inappropriately (40). Moreover, the persistent variation prestige, academic recognition, and representation in blood utilization across European Union member states in their respective societies. Most of the authors indicates that the inappropriate use of blood supplies is worked on the initial reference document, which was widespread (41). Despite the benefits of a restrictive approach to presented at a Congress of the AEG. Subsequently, it transfusion, consensus recommendations are lacking, and major was disseminated among the members of the AEG and shortcomings have been identified in many clinical practice underwent internal and external peer-review through guidelines for transfusion practice (42). Applying consistent the standard procedures of Clinical Gastroenterology criteria to clinical decision-making regarding the eligibility and Hepatology. Several years later, the document was and timing of transfusion in patients with GI bleeding is updated with the comments and criticism received and crucial (29). presented for additional rounds of review and discussion; Patient blood management (PBM) is an evidence-based it was unanimously approved 6 months later. A shorter bundle of care that aims to optimize outcomes for all patients online version of the protocol is also available on the with bleeding potential by managing and preserving blood. AEG website: https://www.aegastro.es/documents/prodiggest/ The concept of PBM is built on 3 pillars: (1) optimization Prodiggest-Management-of-anaemia-and-iron-deficiency-in- of RBC mass, including the use of iron replacement therapy gastrointestinal-bleeding.pdf. and/or erythropoiesis-stimulating agents where needed; (2) The primary goal of the project was to develop a healthcare minimization of blood loss/bleeding; and (3) optimization of protocol for the management of anemia and iron deficiency the patient’s tolerance of anemia (35, 43, 44). PBM can reduce associated with GI bleeding. Therefore, current indications patient mortality and morbidity (45) and its incorporation into for RBC transfusion were reviewed in the context of patients healthcare management has the potential to bring benefits to with GI bleeding. The protocol aimed to provide guidance on many patients and healthcare institutions (46–49). It is also achieving an adequate balance between the use and overuse of crucial to raise awareness about the importance of preserving RBC transfusion according to a restrictive model, promoting and managing the patient’s own blood and maintaining well- the use of restrictive rather than liberal criteria and a 1 blood functioning bone marrow erythropoiesis, rather than routinely unit policy (i.e., “don’t give two without review”). Other aims of resorting to the use of donor blood. This approach should the protocol were to provide information on the advantages and improve patient outcomes as well as reduce the rate of limitations of oral versus intravenous iron in patients with GI Frontiers in Medicine 03 frontiersin.org Montoro et al. 10.3389/fmed.2022.903739 bleeding and to provide guidance on the safe and effective use do not respond to fluid therapy. Adaptation of transfusion of intravenous iron for the treatment of blood loss associated criteria to align with clinical practice guidelines and expert with GI bleeding. reviews (25, 28, 56, 61–64) is therefore required to help optimize This protocol focuses on the management of acute anemia the use of transfusion resources and improve patient outcomes or iron deficiency in patients with acute GI bleeding (with and clinical results. or without portal hypertension) and on the management of Before determining what, when, and how to transfuse, chronic anemia or iron deficiency due to fecal occult blood certain considerations must be highlighted. First, it should be loss. The protocol is not intended for use in pediatric patients noted that hemoglobin levels are not always indicative of the full or for patients with anemia or iron deficiency due to causes extent of blood loss in patients with GI bleeding. For example, other than GI bleeding such as inflammatory bowel disease. decreased hemoglobin levels can be caused by fluid movement The management of other aspects of GI bleeding are also out from the interstitial space to the vascular compartment, and of the scope of the protocol (e.g., evaluating the extent of infusion of intravenous fluids or overhydration may also blood loss, resuscitation measures, identifying and treating the lead to false low-concentration readings. A “normal” initial sources of bleeding). hemoglobin level, therefore, does not exclude the possibility This protocol is relevant to clinicians and nurses who of severe bleeding. Hemodynamic parameters may provide a treat adults with acute or chronic GI bleeding, and it is better overview of the extent of blood loss together with regular intended for use in general clinical practice in both the monitoring of hemoglobin levels in the event of potentially primary and secondary care settings. Management of severely bleeding lesions. acute GI bleeding currently requires an interdisciplinary Second, excessive blood volume replacement can lead to an approach, which may involve general practitioners, emergency increased risk of rebleeding. This is because vasodilation and the and internal medicine physicians, gastroenterologists, subsequent increase in blood pressure can result in erosion of hepatologists, endoscopists, surgeons, critical care practitioners, newly formed hemostatic plugs and dilution of clotting factors. hematologists, biopathologists, intensive care specialists, nurses, Furthermore, the impact of hypothermia on in vivo coagulation and interventional radiologists, depending on local practice. must be considered. Overexpansion of plasma volume in patients bleeding because of portal hypertension may also induce an increase in portal pressure that may favor recurrent Treatment of anemia bleeding. A restrictive transfusion model that precludes the use of blood to increase blood volume is therefore recommended Preliminary considerations (28, 56), and RBC units should be transfused 1 unit at a time (65, 66), except in severe cases or in the case of uncontrolled Acute GI bleeding results in blood loss, which, in active bleeding. extreme cases, can lead to hypovolemic shock and death. Third, the source of bleeding should be identified and Although several international consensus/guidelines were the management of clotting disorders in patients with GI published between 2012 and 2021 by the American bleeding should also be considered. Thrombocytopenia is Society for Gastrointestinal Endoscopy, the European uncommon and is observed in only 5% of patients with Society of Gastrointestinal Endoscopy, and the American upper GI bleeding and 1% of those with lower GI bleeding College of Gastroenterology (26, 50–54), the importance (67, 68). International normalized ratio (INR) levels > 1.5 of correcting anemia and iron deficiency often remains are detected in 15% and 11% of patients with upper and undervalued or underestimated within the complexities of lower GI bleeding, respectively, due primarily to the presence managing GI bleeding. of liver failure or the use of oral anticoagulants such as Until recently, RBC transfusion was considered a key warfarin or acenocoumarol (6, 67). Platelet transfusions are treatment for acute blood loss anemia for many patients. recommended for patients who have significant bleeding and a However, its use in this setting is subject to substantial platelet count < 30 × 109 /L (65), particularly in cases of acute variability, with observational studies suggesting that RBC bleeding related to portal hypertension. It is not recommended transfusion is used in 25–43% of cases of GI bleeding overall to correct slight coagulation abnormalities with fresh frozen and that over 40% and 60% of transfusions in patients with plasma transfusions in patients who have been receiving vitamin upper and lower GI bleeding, respectively, are given in the K antagonist treatment (65). The use of prothrombin complex absence of clinically significant anemia (hemoglobin ≥ 8 g/dL) concentrates and vitamin K to reverse the effects of oral (4, 55–57). More recently, goal-directed fluid therapy with anticoagulants is usually preferred. restrictive volume restitution (58–60) has started to be used Finally, consideration should be given to the adverse to correct hemodynamic instability, achieve hemodynamic consequences that can accompany transfusion (Table 1) and the control, and avoid hypovolemic shock, with RBC transfusions associated costs [e.g., in one European analysis, the estimated only recommended for patients with symptomatic anemia who cost of a 2-unit RBC transfusion was €878 (69)]. Frontiers in Medicine 04 frontiersin.org Montoro et al. 10.3389/fmed.2022.903739 TABLE 1 Acute and delayed adverse reactions associated with blood on hemodynamic stability, the source and activity of the transfusion (63, 80). bleeding, the likelihood of rebleeding, and the presence of Reaction type Acute transfusion Delayed transfusion comorbidities (70) that may affect bleeding control or increase reactions (incidence) reactions (incidence) the risk of tissue hypoxia (Figure 1). Blood transfusion is an early example of “personalized medicine” as treatment Immunologic Acute hemolytic transfusion Delayed hemolytic reaction (1/6,000) transfusion reaction decisions should be individualized and guidelines should not Febrile non-hemolytic Alloimmunization against supersede the clinical judgment of the treating physician when transfusion reaction (1/300) cell antigens (also against deciding which patients should undergo transfusion. Adequate platelets and leukocytes) replenishment of blood volume is essential to maintain and (1/5–100) optimize organ perfusion. However, this should generally Cutaneous allergic Graft-versus-host disease involve crystalloid- and colloid-based fluid therapy rather transfusion reaction and urticaria (1/50–100) than blood transfusion. The following section includes some Anaphylactic reaction Transfusion-related important considerations in the management of patients with (1/20,000–50,000) immunomodulation anemia due to acute blood loss. Acute non-cardiogenic Post-transfusion purpura pulmonary edema: 1. Patients receiving anticoagulant treatment are at increased transfusion-related acute risk of severe or persistent bleeding; therefore, this should lung injury (1/1,000–5,000) firstly be reversed. In contrast, antiplatelet drugs should Fatal hemolysis (1/1,000,000) only be discontinued if absolutely necessary (5, 61). Transfusion-associated immunomodulation 2. Dyspnea, chest pain, tachycardia, hypotension that Non-immunologic Bacterial contamination Transfusion-transmitted is refractory to initial blood volume replacement, (1/5,000,000) infections*: virus (e.g., obnubilation, and oliguria are warning signs or symptoms HAV/HBV/HCV/HEV, HIV of acute blood loss (26). 1-2, West Nile, HTLV I-II, 3. Active bleeding or identification of a visible vessel during cytomegalovirus, Herpesviridae, TTV, SEN-1, endoscopy indicates an increased risk of rebleeding (26). SARS), protozoa (e.g., 4. The presence of gastroesophageal varices also increases the malaria, babesiosis, Chagas risk of rebleeding if the plasma volume is overexpanded disease), prion (new variant following transfusion (18, 20, 28). of Creutzfeldt-Jakob disease) 5. Factors that increase the risk of a vascular event (e.g., Transfusion-associated Transfusional hemosiderosis circulatory overload (iron overload) history of coronary artery disease, arrhythmias, and/or (1/100–500) heart failure – see section below) add to the complexity of Transfusion-related acute the decision-making process (54). lung injury (1/1,000–5,000) Hypotension Non-immunologic hemolysis Others: hypocalcemia, Clinical evaluations used within the hyperkalemia (cardiac arrest), hypothermia, patient blood management protocol hyperglycemia, etc. It is necessary to consider and record any variables that may HAV/HBV/HCV/HEV, hepatitis A/B/C/E virus; HIV, human immunodeficiency virus; HTLV, human T-lymphotropic virus; SARS, severe acute respiratory syndrome; influence the decision whether to administer a RBC transfusion, TTV, Torque teno virus. as well as variables that have an impact on the rate of transfusion *Malaria 1/4,000,000; HIV < 1/2,000,000; HCV < 1/1,000,000; HTLV: 1/641,000; HBV: 1/100,000. or route of administration of iron replacement therapy (oral vs. intravenous) (65). This includes: Management of anemia due to acute • The patient’s medical history, especially any recent history gastrointestinal blood loss of ischemic or thrombotic events, cardiopulmonary disease, chronic kidney disease, imminent surgery The GI bleeding protocol presented here should be (within < 30 days), severity of bleeding and associated integrated into a hospital’s wider PBM program. Many factors anemia, or any clinical condition that may interfere with should be considered when deciding whether to give an oral iron availability or absorption (e.g., iron tolerance RBC transfusion to patients with anemia. The criteria used or refractivity). in PBM to decide what, who, and when to transfuse are • As a minimum, the following laboratory tests that could broadly based on the severity of the bleeding, the impact indicate the presence or absence of iron deficiency Frontiers in Medicine 05 frontiersin.org Montoro et al. 10.3389/fmed.2022.903739 FIGURE 1 Factors influencing the decision to give transfusions. COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident. FIGURE 2 The management of anemia and iron deficiency in patients with acute gastrointestinal bleeding (63, 80). AABB, American Association of Blood Banks; ABIM, American Board of Internal Medicine; AEG, Asociación Española de Gastroenterología; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; Hb, hemoglobin; i.v., intravenous; OD, organ dysfunction; RF, risk factors. * < 10 g/dL if severe bleeding. should also be performed: hemoglobin level; numbers • Additional complementary tests may be performed of RBC and reticulocytes; RBC distribution width; depending on the clinical scenario, such as more extensive mean corpuscular hemoglobin; mean corpuscular volume; laboratory tests including the measurement of serum serum ferritin and transferrin saturation (TSAT) levels; vitamin B12 , folate, haptoglobin, soluble transferrin and measurement of C-reactive protein, creatinine, and receptor, or lactate dehydrogenase levels, and reticulocyte urea levels. hemoglobin content. Frontiers in Medicine 06 frontiersin.org Montoro et al. 10.3389/fmed.2022.903739 • A GI endoscopy or computed tomography angiogram may scenarios. An algorithm to determine if transfusion also be performed to identify the cause and extent of the is indicated in patients with cardiovascular risk can bleeding as well as the presence of endoscopic warning be found in Figure 3 (80). For most patients in signs of rebleeding (according to the Forrest Classification this category, the recommendation is to transfuse to System), which could reduce the risk of rebleeding and maintain hemoglobin levels > 8 g/dL but no more than transfusion. Both endoscopy and angiography can offer 9 g/dL. Therefore, following the recommendations of the additional and effective therapeutic resources in the control American Association of Blood Banks (63) and based and cessation of bleeding. on the clinical trial results available to date, restrictive RBC transfusion should be considered for patients with a hemoglobin level of < 8 g/dL in the following cases (24, 74–80): Restrictive red blood cell transfusion within patient blood management • Patients with an acute coronary syndrome (e.g., acute myocardial infarction or with known coronary Various measures for avoiding transfusion are proposed artery disease and unstable angina) and who have by the PBM strategy. These include testing for and evaluating ongoing ischemia despite anti-ischemic therapy, such any anemia (and its origin) or coagulopathy issues, and as medical therapy or angioplasty. Lower target providing specific treatment (e.g., intravenous iron replacement hemoglobin levels are often used for patients whose therapy in the case of iron deficiency anemia, reversal signs and/or symptoms of ischemia resolve with anti- of anticoagulant/antiplatelet therapy, prohemostatic drugs). ischemic therapy. Strategies to reduce the risk of bleeding associated with invasive • Patients with other findings suggestive of procedures should also be employed. Iatrogenic blood loss active ischemia, including anginal chest pain, due to the taking of excessive analytical samples should be electrocardiographic changes suggestive of ischemia, avoided by using pediatric tubes and non-invasive point-of-care orthostatic hypotension or tachycardia that does not monitoring for hemoglobin levels, INR, hypoxia, etc. Moreover, respond to fluid resuscitation, or severe dyspnea or the minimum clinically effective transfusion volume should be tachypnea at rest. Clinical judgment is required to used (where feasible) (71). determine if a patient’s symptoms signify active ongoing ischemia (i.e., transfusion is indicated) or merely reduced oxygen carrying capacity (which may be Transfusion thresholds treated without transfusion). Signs or symptoms that do not necessarily warrant transfusion include irritability, An algorithm depicting the indications for RBC transfusion weakness, tiredness, or exertional dyspnea. Conversely, in patients with acute GI bleeding is shown in Figure 2. The these signs/symptoms may not always be present in protocol establishes the following guidelines: a patient with ischemia (e.g., a patient receiving a beta-blocker may not have tachycardia). 1. In the absence of risk factors and warning signs or organ • Patients with chronic obstructive pulmonary dysfunction, a hemoglobin level of < 7 g/dL is often used disease (COPD). as the cutoff for transfusion when a restrictive approach • The presence of vascular risk factors for arteriosclerosis is being used (15, 16, 19, 72, 73). This threshold is not (e.g., diabetes, hypertension, dyslipidemia, smoking) mandatory and the final decision whether to transfuse alone are not sufficient to warrant transfusion, unless should be made on an individual basis. Close monitoring the patient has signs of active bleeding and/or alone without transfusion is an option for patients with hemodynamic instability that is not corrected with hemoglobin levels below this threshold who have no fluid replacement. comorbidities or symptoms, are hemodynamically stable, • The threshold for patients with a history of heart failure have inactive bleeding, and have a low risk of rebleeding. is less clear, but a hemoglobin threshold of between 2. The question of when to transfuse the patient who 7 and 8 g/dL (70–80 g/L) is likely to be appropriate has ischemic heart disease and/or heart failure remains for most patients. Hospitalized patients with heart controversial. In fact, taken together, the short- and failure are especially challenging to manage, and the long-term findings from available clinical trials indicate improvement in oxygenation from transfusion must be that the question of non-inferiority and/or superiority balanced against the risks of worsening heart failure of the two transfusion approaches (restrictive vs. liberal) due to the volume of transfused blood. When RBC in these patients remains unanswered (24, 74–80). The transfusion is required in a patient with heart failure, greatest difficulty lies in the large number of possible careful attention to volume status is recommended, Frontiers in Medicine 07 frontiersin.org Montoro et al. 10.3389/fmed.2022.903739 FIGURE 3 Indications for red blood cell transfusion in the presence of cardiovascular risk factors (63, 76–80). In cases of both acute hemorrhage and chronic blood loss, the decision to transfuse red blood cell concentrates does not exempt the indication to replenish iron stores, because 1 red blood cell unit only provides 200 mg of iron. This consideration is especially important in patients with CAD and/or heart failure. CAD, coronary artery disease; ECG, electrocardiographic; Hb, hemoglobin. *Consider transfusion if Hb < 7.5 g/dL. including adjustment of transfusion rate and use of differ from those used in the setting of acute bleeding supplemental diuretics as needed to avoid volume (Figure 2) (72, 73, 81). RBC transfusion should be considered overload. for patients with hemoglobin levels < 5 g/dL and for those with hemoglobin levels < 6 g/dL in the presence of risk 3. RBC transfusion should only be considered for patients factors such as cardiopulmonary failure, ischemic heart disease, with hemoglobin levels > 8 g/dL but < 9 g/dL in the cardiac arrhythmia, and COPD. These hemoglobin thresholds presence of organ (heart, brain, lung, or liver) dysfunction. are supported by studies showing how in patients with In this situation, clinicians should consider the advantages severe chronic anemia (hemoglobin < 6 g/dL), and even and disadvantages of use/overuse of transfusion, regardless extreme anemia (hemoglobin ≤ 5 g/dL) due to digestive or of any laboratory test results. The volume of blood gynecological blood loss, third-generation intravenous iron is transfused should not exceed the amount required to effective and safe for the rapid correction of anemia (28, 72). relieve symptoms of anemia or to achieve a hemoglobin This policy helps to avoid unnecessary blood transfusions. level of 7–8 g/dL (which is also considered safe for stable, Transfusion should also be considered for patients with non-cardiac patients). An important point to consider hemoglobin levels < 7 g/dL with associated warning signs and is that RBC transfusion does not exempt the need for symptoms of organ dysfunction, such as dyspnea, precordial intravenous iron replacement therapy, since 1 RBC unit pain, tachycardia, hypoxia, or orthostatic hypotension. Patients provides no more than 200 mg of iron. with hemoglobin levels > 7 g/dL and no symptoms of organ dysfunction should undergo observation and correction of any iron deficiency. As mentioned previously, if a patient Management of chronic anemia due to receives a transfusion, this does not exempt the need occult blood loss for intravenous iron replacement therapy, and vice versa. RBC transfusions should not be administered to patients Hemoglobin thresholds for transfusion in the case of who only have iron deficiency, except in those who are chronic anemia associated with occult GI bleeding (Figure 4) hemodynamically unstable. Frontiers in Medicine 08 frontiersin.org Montoro et al. 10.3389/fmed.2022.903739 FIGURE 4 Algorithm for the management of chronic anemia associated with gastrointestinal blood loss. CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; EPO, erythropoietin; Hb, hemoglobin; i.v., intravenous; OD, organ dysfunction; RBC, red blood cell; RF, risk factors; WS, warning signs. *RBC transfusion is not enough to replenish iron stores; 1 RBC unit supplies 200 mg of iron; **Warning signs in patients with Hb levels < 7 g/dL could be triggered by events such as atrial fibrillation, sepsis with a systemic inflammatory response, or an “acute on chronic” bleeding episode. Treatment of iron deficiency factors for the development of iron deficiency anemia were age > 75 years, initial ferritinemia < 65 µg/L, initial hemoglobin Preliminary considerations levels < 10 g/dL, and TSAT < 10% at day 5. After an episode Iron is crucial for erythropoiesis and oxygen transport, of upper GI bleeding, blood urea levels temporarily rise due to and it also serves important roles in cell energy production, the absorption of extravasated urea nitrogen in the intestinal maturation of the immune system, and efficient organ function (82–85). Although iron deficiency anemia is the most prevalent TABLE 2 Criteria and other indicators for diagnosing iron deficiency. cause of anemia worldwide, not all anemias are due to an iron deficit. Furthermore, many patients have been found to have Criteria for diagnosing iron deficiency: iron deficiency who do not have anemia. The criteria used to • Ferritin (acute-phase reactant) < 30–100 µg/L* diagnose iron deficiency are summarized in Table 2. It should be • Transferrin > 300–350 mg/dL† noted that the terms iron deficiency and iron deficiency anemia • Transferrin saturation < 20%‡ are often confused in publications and these terms are not Markers of iron deficiency in circulating red blood cells: • Mean corpuscular volume < 81 fL necessarily synonymous (86–88). GI-related issues that may lead • Mean corpuscular hemoglobin < 28 pg/cell to the onset of iron deficiency and iron deficiency anemia are • Red blood cell distribution width > 15% shown in Table 3. • Hypochromic red blood cells > 5% Acute GI bleeding leads to a reduction in RBC volume Other indicators of iron deficiency: resulting in a need for RBC regeneration, which subsequently • sTfR > 2.0 mg/L • sTfR/log ferritin index > 2.0 can lead to iron deficiency and iron deficiency anemia; hence, • Mean reticulocyte hemoglobin content < 27.2 pg/cell it is important to consider the use of iron replacement therapy • Low hemoglobin density > 5–10% in these patients. Although the anemia in acute GI bleeding sTfR, soluble transferrin receptor. is initially due to blood loss, if iron stores are reduced or *Since ferritin is an acute-phase reactant, levels < 100 µg/L may be indicative of iron iron absorption is disrupted, the iron deficit will continue deficiency in the presence of inflammation. to be observed over time. For example, > 60% of patients † In iron deficiency due to acute gastrointestinal bleeding, transferrin levels are often relatively low (200–250 mg/dL) because of associated protein loss. enrolled in a Spanish study developed iron deficiency anemia ‡ In iron deficiency due to acute gastrointestinal bleeding, transferrin saturation is often within 1 month of non-variceal upper GI bleeding (89). Risk relatively high (≥ 45%) because of associated low transferrin levels. Frontiers in Medicine 09 frontiersin.org Montoro et al. 10.3389/fmed.2022.903739 TABLE 3 Gastrointestinal causes of iron deficiency and iron and the lack of clarity regarding total costs, which may be deficiency anemia. higher than initially expected when absenteeism/presenteeism considerations are also taken into consideration. Newer Factors associated with gastrointestinal bleeding (macro or microscopic): intravenous iron compounds are considered safer than blood • Gastroduodenal peptic ulcer/Heliobacter pylori infection • Hemorrhage due to esophagogastric varices transfusion, have fewer GI side effects than oral iron (99, 100), • Portal hypertension gastropathy and are also associated with improved/guaranteed adherence • Gastric antral vascular ectasia (66, 90, 93, 100, 101). These compounds also provide the total • Angiodysplasia iron dose required (often in a single infusion), quickly increase • Inflammatory bowel disease • Use of acetylsalicylic acid or other non-steroidal anti-inflammatory drugs hemoglobin levels, and promote more effective replenishment • Gastrointestinal malignancies of iron stores in comparison with oral iron (66, 90, 93, 100– • Diverticular bleeding 103). Much of the data supporting the efficacy and safety • Hemorrhoid bleeding of intravenous iron in patients with GI bleeding come from • Postoperative bleeding • Large hiatus hernias (Cameron lesions) studies of ferric carboxymaltose (FCM) (32, 90, 100, 101). • Parasitic infections A prospective study showed that 1,500/2,000 mg of intravenous Factors associated with impaired absorption due to limited availability of or damage FCM (given over 2 infusions) increased hemoglobin and iron to enterocytes: levels faster and more effectively when compared with 6 weeks • Low-iron diets of oral ferrous sulfate treatment in patients with anemia due • Chronic autoimmune atrophic gastritis • Celiac disease/non-celiac gluten sensitivity to acute GI bleeding (101). FCM was also better tolerated than • Inflammatory bowel disease oral iron and associated with significantly improved quality of • Intestinal lymphoma life (101). Furthermore, a retrospective study showed that a • Bariatric surgery/gastric bypass surgery single 1,000-mg FCM infusion effectively increased hemoglobin • Short bowel syndrome • Gastrectomy or gastrojejunostomy levels in elderly patients who had comorbidities and acute GI • Bacterial overgrowth bleeding (including some who were hemodynamically unstable), thereby supporting the use of a restrictive transfusion policy (32). Hemoglobin levels were also increased, and transfusion lumen, and urea levels may therefore be higher than creatinine rates significantly reduced in a retrospective study of FCM in levels. Consequently, blood urea levels > 80 mg/dL at admission patients with chronic GI bleeding who had previously been may indicate significant bleeding and an increased risk of receiving chronic transfusion support (90). Similar effects on anemia. The use of iron replacement therapy in patients with iron parameters have been reported for other intravenous iron chronic iron deficiency anemia can lead to a reduction in RBC formulations (104–106). transfusions (90) and a consequent reduction in the associated There are, however, limitations to the use of intravenous risks. Iron replacement therapy should be started as soon as iron. These include the requirement for monitoring during iron deficiency is detected, to replenish iron stores and restore infusion, the risk of infusion-related reactions (although these normal erythropoiesis as soon as possible (91, 92). are extremely uncommon), the requirement for equipment and staff training, and the potential for increased costs (66, 90, Advantages and limitations of oral and 93, 100, 101). Furthermore, although increases in hemoglobin intravenous iron administration levels occur more quickly than with oral iron, it may still take The choice between oral and intravenous iron replacement 3–5 days for levels to improve following infusion. Therefore, therapy depends on various factors, such as the severity and blood transfusion is a necessary therapeutic option to maintain speed of the onset of anemia, cost, the availability of existing the transport of oxygen to the tissues in cases of severe anemia formulations, patient tolerance to oral iron, patient preferences, where alternative treatments are not available or where it is not and the existence of other limiting factors (e.g., malabsorption possible to wait for these to take effect. Nonetheless, intravenous of oral iron, inflammation, or allergies to intravenous iron) iron can be complementary to blood transfusion to treat any (85, 93–95). Under suitable conditions, oral iron is effective, underlying iron deficiency (i.e., blood transfusion does not readily available, inexpensive, and well tolerated (96–98). For contraindicate intravenous iron treatment or vice versa). The example, many patients who have mild iron deficiency anemia decision about when intravenous iron should be administered associated with chronic fecal occult blood loss may be effectively (before, during, or after blood transfusion) is related to the managed with oral iron. However, treatment with oral iron patient’s hemodynamic status. In patients with hemodynamic (especially iron sulfate) is associated with GI side effects in instability, alarm signs, or organ dysfunction, transfusion should many patients (99). Other limitations to oral iron therapy be prioritized, and transfusion should not coincide with the are low levels of adherence, lack of suitability for patients intravenous iron infusion, i.e, it should not be administered with severe bleeding or continuous occult blood loss, the in the same line nor at the same time. Intravenous iron excessive time (months) required to replenish iron stores, should be administered once the transfusion of the first unit Frontiers in Medicine 10 frontiersin.org Montoro et al. 10.3389/fmed.2022.903739 has been completed, after clinical and analytical evaluation, Contraindications to intravenous iron include persistent and in the absence of any adverse reactions. However, in the bacteremia, serious known allergy, hypersensitivity to event of hemodynamic stability, with stabilized and controlled other parenteral iron-containing products, TSAT > 45% bleeding, and in the absence of clinical signs or symptoms (or ferritin levels > 500 µg/L with TSAT > 25% suggesting that an urgent transfusion is required, intravenous in patients with inflammatory conditions), or iron can be administered (over 15–30 min), while the pre- hemochromatosis/hemosiderosis/porphyria cutanea tarda. transfusion compatibility tests are being performed by the A history of bronchial asthma or severe eczema also increases transfusion service and the red blood cell concentrates are the risk of a hypersensitivity reaction after administration of awaited. In general, we must aim to transfuse the minimum intravenous iron, and this aspect should be considered before number of blood units possible to achieve the required clinical establishing the need for intravenous iron treatment in such effect alongside treatment specific to the cause of the anemia. Adverse effects associated with intravenous iron infusion can include nausea, headache, dizziness, hypertension, skin rash, injection-site reactions, hypophosphatemia, increased alanine TABLE 4 Indications for the use of intravenous iron in patients with aminotransferase levels, and (extremely rarely) hypersensitivity gastrointestinal bleeding. reactions. In general, the third-generation compounds have While in hospital After hospital discharge the safest profiles. These agents are better tolerated and are associated with a lower risk of infusion-related/anaphylactoid Where there is a need for rapid Where there is a need for rapid reactions, and a reduced generation of non-transferrin bound correction of moderate/severe iron correction of moderate/severe iron deficiency anemia deficiency anemia free iron when compared with earlier compounds (107, 108). • Where there is iron deficiency • When iron deposits are very low However, each intravenous iron product is unique and thus and concomitant inflammatory status and there is a need for rapid repletion it is not possible to extrapolate data from one product to (CRP > 5 mg/dL) causing reduced to initiate erythropoiesis compare with that of another (109). The use of FCM also absorption of oral iron due to the • In the event of oral iron therapy effects of hepcidin on ferroportin failure due to: permits a higher iron dose to be given over fewer, shorter • In patients with gastrointestinal ◦ Intolerance of side effects that infusions (only 1 or 2 doses of 1,000 mg, each given over a bleeding who also meet any of the do not respond to recommended 15-min infusion, are usually required in comparison with, for following criteria: measures for improving tolerability example, multiple, longer infusions for iron sucrose) (102, 108, ◦ Need for imminent surgery ◦ Poor adherence (<30 days) with estimated ◦ Monthly increments 110, 111). perioperative blood loss > 1–1.5 L* of < 1 g/dL of hemoglobin (iron ◦ Need for invasive surgery with deficiency anemia that does not a risk of significant bleeding respond to oral iron)‡,§ ◦ Need for • Where there is a Indications for the use of intravenous iron erythropoiesis-stimulating agent contraindication to oral iron The indications for the use of intravenous iron in patients treatment (preemptive intravenous preparations or another reason why with GI bleeding are shown in Table 4. In patients with acute iron is given to prevent non-response oral iron cannot be used GI bleeding and uncontrolled hypertension or hemodynamic to EPO – the primary cause of which is functional iron deficiency† ) instability (as indicated by a systolic blood pressure < 90 mmHg • Need for artificial feeding or heart rate > 100 bpm), blood volume should initially be (parenteral or enteral) replenished with fluids and transfusion is not needed. However, • As an alternative to blood in the case of acute anemia due to severe GI bleeding, RBC transfusion (e.g., in patients who reject blood transfusion based on transfusion is recommended. religious grounds or personal beliefs) None of the scenarios that support the use of RBC transfusion preclude the use of intravenous iron for the CRP, C-reactive protein; EPO, erythropoietin. *For example, when bleeding is due to a resectable malignancy or the patient is admitted treatment of any associated iron deficiency. It should while awaiting orthopedic hip surgery. † A situation in which iron requirements exceed available iron stores. This term be remembered that 1 unit of RBC concentrate provides implies iron status with ferritin < 100 µg/dL and a transferrin saturation < 20% (or approximately 200 mg of iron and, therefore, is not enough to ferritin < 500 µg/L and a transferrin saturation < 30% in the presence of chronic replenish iron stores (estimated at up to 2 g in patients with kidney failure). ‡ Intravenous iron replacement therapy should be considered prior to discharge when hemoglobin levels < 10 g/dL post-bleeding and a body weight factors that limit absorption have been identified during hospitalization. of 75 kg; Table 5) (110, 112). § Reasons that may explain refractoriness to oral iron include: interference with In patients with iron deficiency/iron deficiency anemia due absorption (hypoacidity secondary to chronic autoimmune atrophic gastritis or the use of proton pump inhibitors, lymphocytic duodenosis due to Helicobacter pylori to chronic GI bleeding, treatment with intravenous iron can be infection); reduced surface area available for absorption (gastrectomy, bariatric surgery); a very good alternative to RBC transfusion, thereby reducing or gluten-sensitive enteropathy or other clinical conditions that cause malabsorption, avoiding the need for transfusions (72). However, transfusion including edematous bowel loops due to heart or chronic kidney disease or severe hypoalbuminemia; or active inflammatory bowel disease. Other inflammatory should be used in these patients when pharmacologic treatment conditions, such as systolic heart failure and left ventricular ejection fraction < 45%, of anemia has failed or in cases of severe anemia. should also be considered. Frontiers in Medicine 11 frontiersin.org Montoro et al. 10.3389/fmed.2022.903739 TABLE 5 A simplified formula for calculating the required dose of clinical tolerance of anemia. Several studies support the use of ferric carboxymaltose, based on patient body weight and hemoglobin levels* (109, 111). clinical decision-making tools to promote PBM and restrictive transfusion practices, and to improve RBC utilization, even in Ferric carboxymaltose dose (mg) high-risk patients (32, 49, 73, 90, 115–117). In some patient groups, a restrictive strategy can reduce unnecessary use of Weight 35 to < 70 kg Weight ≥ 70 kg allogeneic transfusions and is associated with equivalent or Hemoglobin level, g/dL better outcomes than a liberal strategy. <10 1,500 2,000 The decision to administer oral or intravenous iron to a 10 to < 14 1,000 1,500 patient with bleeding depends on multiple factors, including ≥14 500 500 the severity of anemia, the presence of inflammation, whether a rapid increase in hemoglobin levels and replenishment of iron *The maximum recommended cumulative dose of ferric carboxymaltose is 1,000 mg/week. stores are needed to benefit patient symptoms and quality of life, costs, and patient adherence to treatment with oral iron (93, 96, 102, 118, 119). The protocol presented here is the patients. Intravenous iron should also generally not be used result of a thorough review performed by gastroenterologists, during the first trimester of pregnancy. hepatologists, hematologists, and PBM experts with solid Until recently, intravenous doses of iron were often training in the implementation of PBM-based policies. It calculated using the Ganzoni formula (113). This formula is also reflects current clinical practice in Spain regarding the based on body weight, actual compared with target hemoglobin management of anemia and iron deficiency in patients with levels, and iron stores. A limitation of this formula is that acute or chronic GI bleeding. The protocol has been designed to it underestimates the dose of iron required in patients with maintain a balance between the use and overuse of transfusion acute bleeding and is only reliable in patients with pure iron and advises on the safe use of oral versus intravenous iron deficiency. In patients with mixed anemia (where anemia is in these settings. This has permitted the introduction of a partly due to other causes), use of the Ganzoni formula may lead prospective database – AEG-REDCap (Research Electronic Data to excessive iron replenishment and subsequent iron overload. Capture Service of the AEG) – in many Spanish hospitals, in A simple and efficient method for calculating the dose of which the clinical characteristics of patients who are admitted intravenous iron based on body weight and hemoglobin levels because of GI bleeding can be recorded. Having a prospective has been developed based on information included in the registry of cases should help avoid the confounding bias that summary of product characteristics for FCM (Table 5) (110, may result from inadequate variability in clinical practice. 112). This is commonly used in hospital settings in the context of In summary, collaboration between physicians in direct GI bleeding, especially in severe cases. In a randomized, placebo- contact with patients who have GI bleeding and hematologists controlled clinical trial of oral vs. intravenous iron in patients and other specialists involved in PBM is important and who had experienced an upper gastrointestinal hemorrhage, should contribute to the improved future management and the authors suggested that treatment with intravenous FCM, correction of iron deficiency anemia. While blood is a costly even when given at lower than standard doses, was significantly resource, which is dependent on the participation of donors, beneficial compared with oral ferrous sulphate in patients with replenishment of iron stores in patients contributes to an lower body weight (114), although this finding needs to be improvement in health-related quality of life and an overall validated in studies involving a larger number of patients. reduction in healthcare costs. Summary Author contributions GI bleeding is common in hospital settings and requires MM and JAGE developed the concept for the manuscript management by an interdisciplinary team (2). Blood volume and wrote the main body of the article. All authors depletion, loss of RBC mass, and associated clotting disorders contributed to manuscript revision, read, and approved the require support and replacement strategies. Although submitted version. transfusions undoubtedly save lives and are a fundamental pillar of the management of severe GI bleeding, they remain one of the most overused medical procedures and are associated with many “Do Not Do Recommendations” (65). The decision Funding to give an RBC transfusion is challenging and should take into account individual patient characteristics, together with This study received funding from an unrestricted grant from the source, activity, and extent of bleeding and the patient’s Vifor Pharma. The funder was not involved in the study design, Frontiers in Medicine 12 frontiersin.org Montoro et al. 10.3389/fmed.2022.903739 collection, analysis, and interpretation of data or the decision to and Vifor Pharma. XC has served as a speaker, consultant, and submit for publication. advisory board member for, or has received research funding from: AbbVie, Allergan, Ferring, Janssen, Kern Pharma, MSD, Pfizer, Sandoz, Takeda, and Vifor Pharma. SGL has served Acknowledgments as a speaker, consultant, and advisory member for, or has received research funding from: AbbVie, Dr Falk Pharma, Faes Medical writing support (including development of a Farma, Ferring, Janssen, MSD, Pfizer, Shire Pharmaceuticals, draft outline and subsequent drafts in consultation with Takeda, Tillotts Pharma, and Vifor Pharma. CMdA has served the authors, assembling tables and figures, collating author as a speaker, consultant, and advisory board member for, comments, copyediting, fact checking, and referencing) was or has received research funding from: Allergan, BioGaia, provided by Dawn Batty, PhD, of Aspire Scientific (Bollington, Casen Recordati, Norgine, Vifor Pharma, and Zambon. MP United Kingdom) and was funded by an unrestricted grant from has served as a speaker for Vifor Pharma. CJ has served Vifor Pharma. The authors thank Eloísa Urrechaga, Biocruces as a speaker, consultant, and advisory member for, or has Bizkaia Research Institute, Bilbao, Spain, for reviewing the received support for attending meetings and/or travel, or sections on laboratory tests. organized courses with scholarships or funding from: Amgen, Bial, Sanofi, Vifor Pharma, and Zambon. JAGE has previously managed grants, given talks, participated in consultancies, Conflict of interest moderated tables at congresses and conferences, or organized courses with scholarships or funding for/from: Alexion, Amgen, MM has served as a speaker, consultant, and advisory Braun, Celgene, CSL Behring, Ferrer, GSK, Inmucor, Jansen, member for, or has organized courses with scholarships Novartis, Novo Nordisk, Octapharma, Roche, Sandoz, Sanofi, or funding from: AbbVie, Almirall, Casen Fleet, Chiesi, Terumo, UCB Pharm, Uriach, Vifor, Wellspect HealthCare, and Falk Pharma, Faes Farma, Ferring, Janssen, MSD, Otsuka Zambon. Pharmaceutical, Pfizer, Roche, Shire Pharmaceuticals, Takeda, The remaining authors declare that the research was Tillotts Pharma, and Vifor Pharma. MC was previously an conducted in the absence of any commercial or financial employee of Vifor Pharma. ÁL has been an advisor to Vifor relationships that could be construed as a potential conflict of Pharma. CV has organized courses with scholarships or funding interest. from: AbbVie, Bayer, Boston Scientific, Faes Farma, Ferrer, Ferring, Fujifilm, Gilead, Intercept, MSD, Mylan, Norgine, Salvat, Takeda, and Vifor Pharma. AJH has served as a speaker, consultant, and advisory board member for, or has received Publisher’s note research funding from Vifor Pharma. JPG has served as a speaker, consultant, and advisory board member for, or has All claims expressed in this article are solely those of the received research funding from: AbbVie, Allergan, Biogen, authors and do not necessarily represent those of their affiliated Casen Fleet, Celgene, Chiesi, Diasorin, Falk Pharma, Faes organizations, or those of the publisher, the editors and the Farma, Ferring, Gebro Pharma, Gilead, Janssen, Kern Pharma, reviewers. Any product that may be evaluated in this article, or Mayoly, MSD, Mylan, Otsuka Pharmaceutical, Pfizer, Phathom, claim that may be made by its manufacturer, is not guaranteed Roche, Sandoz, Shire Pharmaceuticals, Takeda, Tillotts Pharma, or endorsed by the publisher. References 1. Oakland K. Changing epidemiology and etiology of upper and lower 4. Oakland K, Chadwick G, East JE, Guy R, Humphries A, Jairath V, et al. gastrointestinal bleeding. Best Pract Res Clin Gastroenterol. (2019) 42–43:101610. Diagnosis and management of acute lower gastrointestinal bleeding: Guidelines doi: 10.1016/j.bpg.2019.04.003 from the British Society of Gastroenterology. Gut. (2019) 68:776–89. doi: 10.1136/ gutjnl-2018-317807 2. Mearin F, Lanas A, Bujanda L, Canelles P, Cotter J, Hervas A, et al. Open questions and misconceptions in the diagnosis and 5. Lanas-Gimeno A, Lanas A. Risk of gastrointestinal bleeding during management of anemia in patients with gastrointestinal bleeding. anticoagulant treatment. Expert Opin Drug Saf. (2017) 16:673–85. doi: 10.1080/ Gastroenterol Hepatol. (2018) 41:63–76. doi: 10.1016/j.gastrohep.2017. 14740338.2017.1325870 08.012 6. Oakland K, Guy R, Uberoi R, Hogg R, Mortensen N, Murphy MF, et al. Acute 3. Miilunpohja S, Jyrkka J, Karkkainen JM, Kastarinen H, Heikkinen M, Paajanen lower GI bleeding in the UK: Patient characteristics, interventions and outcomes H, et al. Long-term mortality and causes of death in endoscopically verified in the first nationwide audit. Gut. (2018) 67:654–62. doi: 10.1136/gutjnl-2016- upper gastrointestinal bleeding: Comparison of bleeding patients and population 313428 controls. Scand J Gastroenterol. (2017) 52:1211–8. doi: 10.1080/00365521.2017. 7. Ng KS, Nassar N, Soares D, Stewart P, Gladman MA. Acute lower 1347811 gastrointestinal haemorrhage: Outcomes and risk factors for intervention in 949 Frontiers in Medicine 13 frontiersin.org Montoro et al. 10.3389/fmed.2022.903739 emergency cases. Int J Colorectal Dis. (2017) 32:1327–35. doi: 10.1007/s00384- bleeding (TRIGGER): A pragmatic, open-label, cluster randomised feasibility trial. 017-2844-2 Lancet. (2015) 386:137–44. doi: 10.1016/s0140-6736(14)61999-1 8. Hearnshaw S, Travis S, Murphy M. The role of blood transfusion in the 28. Villanueva C, Colomo A, Bosch A, Concepción M, Hernandez-Gea V, Aracil management of upper and lower intestinal tract bleeding. Best Pract Res Clin C, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Gastroenterol. (2008) 22:355–71. doi: 10.1016/j.bpg.2007.10.012 Med. (2013) 368:11–21. doi: 10.1056/NEJMoa1211801 9. Baradarian R, Ramdhaney S, Chapalamadugu R, Skoczylas L, Wang K, Rivilis 29. Goodnough LT, Murphy MF. Do liberal blood transfusions cause more harm S, et al. Early intensive resuscitation of patients with upper gastrointestinal than good? BMJ. (2014) 349:g6897. doi: 10.1136/bmj.g6897 bleeding decreases mortality. Am J Gastroenterol. (2004) 99:619–22. doi: 10.1111/ j.1572-0241.2004.04073.x 30. Goodnough LT, Panigrahi AK. Blood transfusion therapy. Med Clin North Am. (2017) 101:431–47. doi: 10.1016/j.mcna.2016.09.012 10. Bosch MA, Contreras E, Madoz P, Ortiz P, Pereira A, Pujol MM. The epidemiology of blood component transfusion in Catalonia, Northeastern Spain. 31. Leahy MF, Hofmann A, Towler S, Trentino KM, Burrows SA, Swain SG, Transfusion. (2011) 51:105–16. doi: 10.1111/j.1537-2995.2010.02785.x et al. Improved outcomes and reduced costs associated with a health-system- wide patient blood management program: A retrospective observational study 11. Tinegate H, Chattree S, Iqbal A, Plews D, Whitehead J, Wallis JP. Ten- in four major adult tertiary-care hospitals. Transfusion. (2017) 57:1347–58. doi: year pattern of red blood cell use in the North of England. Transfusion. (2013) 10.1111/trf.14006 53:483–9. doi: 10.1111/j.1537-2995.2012.03782.x 32. Ballester-Clau R, Torres Vicente G, Voltà-Pardo T, López-Barroso L, Cucala- 12. Wallis JP, Wells AW, Chapman CE. Changing indications for red cell Ramos M, Reñé-Espinet JM, et al. Clinical experience with ferric carboxymaltose transfusion from 2000 to 2004 in the North of England. Transfus Med. (2006) in the management of anemia in acute gastrointestinal bleeding. Eur J 16:411–7. doi: 10.1111/j.1365-3148.2006.00702.x Gastroenterol Hepatol. (2019) 31:116–22. doi: 10.1097/meg.0000000000001282 13. Ferraris VA, Davenport DL, Saha SP, Bernard A, Austin PC, Zwischenberger JB. Intraoperative transfusion of small amounts of blood heralds worse 33. Jairath V, Kahan BC, Gray A, Doré CJ, Mora A, Dyer C, et al. Restrictive postoperative outcome in patients having noncardiac thoracic operations. Ann vs liberal blood transfusion for acute upper gastrointestinal bleeding: Rationale Thorac Surg. (2011) 91:1674–80. doi: 10.1016/j.athoracsur.2011.01.025 and protocol for a cluster randomized feasibility trial. Transfus Med Rev. (2013) 27:146–53. doi: 10.1016/j.tmrv.2013.04.001 14. Goel R, Patel EU, Cushing MM, Frank SM, Ness PM, Takemoto CM, et al. Association of perioperative red blood cell transfusions with venous 34. Carson JL, Stanworth SJ, Roubinian N, Fergusson DA, Triulzi D, Doree C, thromboembolism in a North American registry. JAMA Surg. (2018) 153:826–33. et al. Transfusion thresholds and other strategies for guiding allogeneic red blood doi: 10.1001/jamasurg.2018.1565 cell transfusion. Cochrane Database Syst Rev. (2016) 10:CD002042. doi: 10.1002/ 14651858.CD002042.pub4 15. Rohde JM, Dimcheff DE, Blumberg N, Saint S, Langa KM, Kuhn L, et al. Health care-associated infection after red blood cell transfusion: A systematic 35. Murphy MF, Palmer A. Patient blood management as the standard of care. review and meta-analysis. JAMA. (2014) 311:1317–26. doi: 10.1001/jama.2014. Hematology Am Soc Hematol Educ Program. (2019) 2019:583–9. doi: 10.1182/ 2726 hematology.2019000063 16. Salpeter SR, Buckley JS, Chatterjee S. Impact of more restrictive blood 36. European Commission [EC]. Infographic on organs, blood, tissues and cells transfusion strategies on clinical outcomes: A meta-analysis and systematic in the EU. (2021). Available online at: https://ec.europa.eu/health/publications/ review. Am J Med. (2014) 127:124–31.e3. doi: 10.1016/j.amjmed.2013.09.017 infographic-organs-blood-tissues-and-cells-eu_en (accessed February 1 2022). 17. Yang TO, Cairns BJ, Reeves GK, Green J, Beral V. Cancer risk among 21st 37. International Foundation for Patient Blood Management [IFPBM]. Manifesto century blood transfusion recipients. Ann Oncol. (2017) 28:393–9. doi: 10.1093/ for European action on patient blood management (PBM). (2020). Available online annonc/mdw555 at: https://www.ifpbm.org/images/EU%20PBM%20Manifesto%20February% 18. Kherad O, Restellini S, Martel M, Sey M, Murphy MF, Oakland K, et al. 202020%2024.pdf (accessed January 25, 2022). Outcomes following restrictive or liberal red blood cell transfusion in patients with lower gastrointestinal bleeding. Aliment Pharmacol Ther. (2019) 49:919–25. 38. European Commission [EC]. Commission staff working document: Evaluation doi: 10.1111/apt.15158 of the Union legislation on blood, tissues and cells. (2019). Available online at: https://ec.europa.eu/health/sites/health/files/blood_tissues_organs/docs/swd_ 19. Kola G, Sureshkumar S, Mohsina S, Sreenath GS, Kate V. Restrictive versus 2019_376_en.pdf (accessed January 25, 2022). liberal transfusion strategy in upper gastrointestinal bleeding: A randomized controlled trial. Saudi J Gastroenterol. (2021) 27:13–9. doi: 10.4103/sjg.SJG_ 39. European Commission [EC]. Building national programmes of patient blood 152_20 management (PBM) in the EU – A guide for health authorities. (2017). Available oline at: https://op.europa.eu/en/publication-detail/-/publication/5ec54745- 20. Odutayo A, Desborough MJ, Trivella M, Stanley AJ, Dorée C, Collins GS, 1a8c-11e7-808e-01aa75ed71a1/language-en (accessed January 25, 2022). et al. Restrictive versus liberal blood transfusion for gastrointestinal bleeding: A systematic review and meta-analysis of randomised controlled trials. Lancet 40. Joint United Kingdom (UK) Blood Transfusion and Tissue Transplantation Gastroenterol Hepatol. (2017) 2:354–60. doi: 10.1016/s2468-1253(17)30054-7 Services Professional Advisory Committee. Patient blood management – An evidence-based approach to patient care. (2014). Available online at: 21. Wang J, Bao YX, Bai M, Zhang YG, Xu WD, Qi XS. Restrictive vs liberal https://www.transfusionguidelines.org/document-library/documents/national- transfusion for upper gastrointestinal bleeding: A meta-analysis of randomized pbm-recommendationsfinaljune2014-pdf/ (accessed January 25, 2022). controlled trials. World J Gastroenterol. (2013) 19:6919–27. doi: 10.3748/wjg.v19. i40.6919 41. Quintana-Díaz M, Andrés-Esteban EM, Sánchez-Serrano J, Martínez-Virto 22. García-Erce JA, Gomollón F, Muñoz M. Blood transfusion for the treatment A, Juárez-Vela R, García-Erce JA. Transfusions in the emergency department: of acute anaemia in inflammatory bowel disease and other digestive diseases. More than a blood transfusion. Rev Clin Esp. (2020) 220:393–9. doi: 10.1016/j. World J Gastroenterol. (2009) 15:4686–94. doi: 10.3748/wjg.15.4686 rce.2019.10.002 23. Ripollés-Melchor J, Jericó-Alba C, Quintana-Díaz M, García-Erce JA. From 42. Simancas-Racines D, Montero-Oleas N, Vernooij RWM, Arevalo-Rodriguez blood saving programs to patient blood management and beyond. Med Clin I, Fuentes P, Gich I, et al. Quality of clinical practice guidelines about red blood (Barc). (2018) 151:368–73. doi: 10.1016/j.medcli.2018.02.027 cell transfusion. J Evid Based Med. (2019) 12:113–24. doi: 10.1111/jebm.12330 24. Ducrocq G, Gonzalez-Juanatey JR, Puymirat E, Lemesle G, Cachanado M, 43. Gombotz H. Patient blood management: A patient-orientated approach to Durand-Zaleski I, et al. Effect of a restrictive vs liberal blood transfusion strategy blood replacement with the goal of reducing anemia, blood loss and the need for on major cardiovascular events among patients with acute myocardial infarction blood transfusion in elective surgery. Transfus Med Hemother. (2012) 39:67–72. and anemia: The REALITY randomized clinical trial. JAMA. (2021) 325:552–60. doi: 10.1159/000337183 doi: 10.1001/jama.2021.0135 44. Jericó C, Osorio J, García-Erce JA, Pera M. Patient blood management 25. Jairath V, Hearnshaw S, Brunskill SJ, Doree C, Hopewell S, Hyde C, strategies for iron deficiency anemia management in gastric cancer. Eur et al. Red cell transfusion for the management of upper gastrointestinal J Gastroenterol Hepatol. (2019) 31:547–8. doi: 10.1097/meg.000000000000 haemorrhage. Cochrane Database Syst Rev. (2010) 9:CD006613. doi: 10.1002/ 1383 14651858.CD006613.pub3 45. Althoff FC, Neb H, Herrmann E, Trentino KM, Vernich L, Fullenbach C, 26. Gralnek IM, Stanley AJ, Morris AJ, Camus M, Lau J, Lanas A, et al. et al. Multimodal patient blood management program based on a three-pillar Endoscopic diagnosis and management of nonvariceal upper gastrointestinal strategy: A systematic review and meta-analysis. Ann Surg. (2019) 269:794–804. hemorrhage (NVUGIH): European Society of Gastrointestinal Endoscopy (ESGE) doi: 10.1097/SLA.0000000000003095 Guideline – Update 2021. Endoscopy. (2021) 53:300–32. doi: 10.1055/a-1369-5274 27. Jairath V, Kahan BC, Gray A, Doré CJ, Mora A, James MW, et al. 46. Klein HG, Hrouda JC, Epstein JS. Crisis in the sustainability of the U.S. blood Restrictive versus liberal blood transfusion for acute upper gastrointestinal system. N Engl J Med. (2018) 378:305–6. doi: 10.1056/NEJMc1714807 Frontiers in Medicine 14 frontiersin.org Montoro et al. 10.3389/fmed.2022.903739 47. Fredrick J, Berger JJ, Menitove JE. Strategic issues currently facing the US 67. Hearnshaw SA, Logan RF, Lowe D, Travis SP, Murphy MF, Palmer KR. Acute blood system. Transfusion. (2020) 60:1093–6. doi: 10.1111/trf.15769 upper gastrointestinal bleeding in the UK: Patient characteristics, diagnoses and outcomes in the 2007 UK audit. Gut. (2011) 60:1327–35. doi: 10.1136/gut.2010. 48. Roman MA, Abbasciano RG, Pathak S, Oo S, Yusoff S, Wozniak M, et al. 228437 Patient blood management interventions do not lead to important clinical benefits or cost-effectiveness for major surgery: A network meta-analysis. Br J Anaesth. 68. Oakland K, Guy R, Uberoi R, Seeney F, Collins G, Grant-Casey J, et al. (2021) 126:149–56. doi: 10.1016/j.bja.2020.04.087 Study protocol: First nationwide comparative audit of acute lower gastrointestinal bleeding in the UK. BMJ Open. (2016) 6:e011752. doi: 10.1136/bmjopen-2016- 49. Warner MA, Schulte PJ, Hanson AC, Madde NR, Burt JM, Higgins AA, 011752 et al. Implementation of a comprehensive patient blood management program for hospitalized patients at a large United States medical center. Mayo Clin Proc. 69. Abraham I, Sun D. The cost of blood transfusion in Western Europe as (2021) 96:2980–90. doi: 10.1016/j.mayocp.2021.07.017 estimated from six studies. Transfusion. (2012) 52:1983–8. doi: 10.1111/j.1537- 2995.2011.03532.x 50. Hwang JH, Fisher DA, Ben-Menachem T, Chandrasekhara V, Chathadi K, Decker GA, et al. The role of endoscopy in the management of acute non-variceal 70. Lanas A, Perez-Aisa MA, Feu F, Ponce J, Saperas E, Santolaria S, et al. A upper GI bleeding. Gastrointest Endosc. (2012) 75:1132–8. doi: 10.1016/j.gie.2012. nationwide study of mortality associated with hospital admission due to severe 02.033 gastrointestinal events and those associated with nonsteroidal antiinflammatory drug use. Am J Gastroenterol. (2005) 100:1685–93. doi: 10.1111/j.1572-0241.2005. 51. Gralnek IM, Dumonceau JM, Kuipers EJ, Lanas A, Sanders DS, Kurien 41833.x M, et al. Diagnosis and management of nonvariceal upper gastrointestinal hemorrhage: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. 71. Muñoz Gómez M, Bisbe Vives E, Basora Macaya M, García Erce JA, Gómez Endoscopy. (2015) 47:a1–46. doi: 10.1055/s-0034-1393172 Luque A, Leal-Noval SR, et al. Forum for debate: Safety of allogeneic blood transfusion alternatives in the surgical/critically ill patient. Med Intensiva. (2015) 52. Barkun AN, Almadi M, Kuipers EJ, Laine L, Sung J, Tse F, et al. Management 39:552–62. doi: 10.1016/j.medin.2015.05.006 of nonvariceal upper gastrointestinal bleeding: Guideline recommendations from 72. Jericó C, Beverina I, Quintana-Diaz M, Salvadori U, Melli C, Rondinelli MB, the International Consensus Group. Ann Intern Med. (2019) 171:805–22. doi: et al. Efficacy and safety of high-dose intravenous iron as the first-choice therapy 10.7326/m19-1795 in outpatients with severe iron deficiency anemia. Transfusion. (2020) 60:1443–9. 53. Laine L, Barkun AN, Saltzman JR, Martel M, Leontiadis GI. ACG Clinical doi: 10.1111/trf.15870 Guideline: Upper gastrointestinal and ulcer bleeding. Am J Gastroenterol. (2021) 73. Gani F, Cerullo M, Ejaz A, Gupta PB, Demario VM, Johnston FM, et al. 116:899–917. doi: 10.14309/ajg.0000000000001245 Implementation of a blood management program at a tertiary care hospital: 54. Snook J, Bhala N, Beales ILP, Cannings D, Kightley C, Logan RP, et al. British Effect on transfusion practices and clinical outcomes among patients undergoing Society of Gastroenterology guidelines for the management of iron deficiency surgery. Ann Surg. (2019) 269:1073–9. doi: 10.1097/SLA.0000000000002585 anaemia in adults. Gut. (2021) 70:2030–51. doi: 10.1136/gutjnl-2021-325210 74. Carson JL, Terrin ML, Noveck H, Sanders DW, Chaitman BR, Rhoads GG, 55. NHS Blood and Transplant. National comparative audit of lower et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N gastrointestinal bleeding and the use of blood. Resulst from a National audit. (2016). Engl J Med. (2011) 365:2453–62. doi: 10.1056/NEJMoa1012452 Available online at: https://hospital.blood.co.uk/audits/national-comparative- 75. Cooper HA, Rao SV, Greenberg MD, Rumsey MP, McKenzie M, Alcorn audit/surgical-audits/lower-gastrointestinal-bleeding-audit/ (accessed February KW, et al. Conservative versus liberal red cell transfusion in acute myocardial 9, 2022). infarction (the CRIT Randomized Pilot Study). Am J Cardiol. (2011) 108:1108–11. doi: 10.1016/j.amjcard.2011.06.014 56. Oakland K, Jairath V, Murphy MF. Advances in transfusion medicine: Gastrointestinal bleeding. Transfus Med. (2018) 28:132–9. doi: 10.1111/tme.12446 76. Carson JL, Brooks MM, Abbott JD, Chaitman B, Kelsey SF, Triulzi DJ, et al. Liberal versus restrictive transfusion thresholds for patients with symptomatic 57. Donovan K, Stanworth S, Jairath V. The optimal use of blood components coronary artery disease. Am Heart J. (2013) 165:964–71.e1. doi: 10.1016/j.ahj.2013. in the management of gastrointestinal bleeding. Best Pract Res Clin Gastroenterol. 03.001 (2019) 4:101600. doi: 10.1016/j.bpg.2019.02.002 77. Kansagara D, Dyer E, Englander H, Fu R, Freeman M, Kagen D. Treatment 58. Joosten A, Alexander B, Delaporte A, Lilot M, Rinehart J, Cannesson of anemia in patients with heart disease: A systematic review. Ann Intern Med. M. Perioperative goal directed therapy using automated closed-loop fluid (2013) 159:746–57. doi: 10.7326/0003-4819-159-11-201312030-00007 management: The future? Anaesthesiol Intensive Ther. (2015) 47:517–23. doi: 10.5603/AIT.a2015.0069 78. Sherwood MW, Wang Y, Curtis JP, Peterson ED, Rao SV. Patterns and outcomes of red blood cell transfusion in patients undergoing percutaneous 59. Kendrick JB, Kaye AD, Tong Y, Belani K, Urman RD, Hoffman C, et al. Goal- coronary intervention. JAMA. (2014) 311:836–43. doi: 10.1001/jama.2014.980 directed fluid therapy in the perioperative setting. J Anaesthesiol Clin Pharmacol. 79. Docherty AB, O’Donnell R, Brunskill S, Trivella M, Doree C, Holst L, et al. (2019) 35:S29–34. doi: 10.4103/joacp.JOACP_26_18 Effect of restrictive versus liberal transfusion strategies on outcomes in patients 60. Tomescu DR, Scarlatescu E, Bubenek-Turconi SI. Can goal-directed fluid with cardiovascular disease in a non-cardiac surgery setting: Systematic review therapy decrease the use of blood and hemoderivates in surgical patients? Minerva and meta-analysis. BMJ. (2016) 352:i1351. doi: 10.1136/bmj.i1351 Anestesiol. (2020) 86:1346–52. doi: 10.23736/s0375-9393.20.14154-3 80. Carson JL, Stanworth SJ, Alexander JH, Roubinian N, Fergusson DA, 61. García-Erce JA, Quintana Díaz M, Muñoz Gómez M. Transfusion and Triulzi DJ, et al. Clinical trials evaluating red blood cell transfusion thresholds: anticoagulation in the management of nonvariceal upper gastrointestinal bleeding An updated systematic review and with additional focus on patients with in Spain [article in Spanish]. Gastroenterol Hepatol. (2013) 36:115–6. doi: 10.1016/ cardiovascular disease. Am Heart J. (2018) 200:96–101. doi: 10.1016/j.ahj.2018.04. j.gastrohep.2012.09.004 007 81. Ortiz P, Mingo A, Lozano M, Vesga MA, Grifols JR, Castrillo A, et al. Guide 62. Lanas A, Calvet X, Feu F, Ponce J, Gisbert JP, Barkun A, et al. First Spanish for transfusion of blood components [article in Spanish]. Med Clin (Barc). (2005) consensus on peptic ulcer bleeding management. Consenso sobre Hemorragia 125:389–96. doi: 10.1157/13079172 Digestiva por Ulcera Peptica [article in Spanish]. Med Clin (Barc). (2010) 135:608– 16. doi: 10.1016/j.medcli.2010.07.002 82. Ghosh K. Non haematological effects of iron deficiency – a perspective. Indian J Med Sci. (2006) 60:30–7. doi: 10.4103/0019-5359.19676 63. Carson JL, Guyatt G, Heddle NM, Grossman BJ, Cohn CS, Fung MK, et al. Clinical practice guidelines from the AABB: Red blood cell transfusion thresholds 83. Wang J, Pantopoulos K. Regulation of cellular iron metabolism. Biochem J. and storage. JAMA. (2016) 316:2025–35. doi: 10.1001/jama.2016.9185 (2011) 434:365–81. doi: 10.1042/bj20101825 64. Jairath V, Desborough MJ. Modern-day management of upper 84. Wessling-Resnick M. Iron homeostasis and the inflammatory response. Annu gastrointestinal haemorrhage. Transfus Med. (2015) 25:351–7. doi: Rev Nutr. (2010) 30:105–22. doi: 10.1146/annurev.nutr.012809.104804 10.1111/tme.12266 85. Pasricha SR, Tye-Din J, Muckenthaler MU, Swinkels DW. Iron deficiency. 65. National Institute for Health and Care Excellence [NICE]. Blood transfusion Lancet. (2021) 397:233–48. doi: 10.1016/S0140-6736(20)32594-0 [NICE guideline NG24]. (2015). Available online at: https://www.nice.org.uk/ 86. World Health Organization [WHO]. Iron deficiency anaemia – Assessment, guidance/ng24 (accessed January 25, 2022). prevention, and control. A guide for programme managers. (2001). Available online at: https://apps.who.int/nutrition/publications/micronutrients/anaemia_ 66. Leal-Noval SR, Muñoz M, Asuero M, Contreras E, García-Erce JA, Llau JV, iron_deficiency/WHO_NHD_01.3/en/index.html (accessed January 25, 2022). et al. Spanish Consensus Statement on alternatives to allogeneic blood transfusion: The 2013 update of the “Seville Document”. Blood Transfus. (2013) 11:585–610. 87. Camaschella C. Iron deficiency. Blood. (2019) 133:30–9. doi: 10.1182/blood- doi: 10.2450/2013.0029-13 2018-05-815944 Frontiers in Medicine 15 frontiersin.org Montoro et al. 10.3389/fmed.2022.903739 88. Muñoz M, Gómez-Ramírez S, Besser M, Pavía J, Gomollón F, Liumbruno 104. Auerbach M, Pappadakis JA, Bahrain H, Auerbach SA, Ballard H, Dahl NV. GM, et al. Current misconceptions in diagnosis and management of iron Safety and efficacy of rapidly administered (one hour) one gram of low molecular deficiency. Blood Transfus. (2017) 15:422–37. doi: 10.2450/2017.0113-17 weight iron dextran (INFeD) for the treatment of iron deficient anemia. Am J Hematol. (2011) 86:860–2. doi: 10.1002/ajh.22153 89. Planella de Rubinat M, Teixido Amoros M, Ballester Clau R, Trujillano Cabello J, Ibarz Escuer M, Rene Espinet JM. Incidence and predictive factors of 105. Auerbach M, Strauss W, Auerbach S, Rineer S, Bahrain H. Safety and efficacy iron deficiency anemia after acute non-variceal upper gastrointestinal bleeding of total dose infusion of 1,020 mg of ferumoxytol administered over 15 min. Am J without portal hypertension [article in Spanish]. Gastroenterol Hepatol. (2015) Hematol. (2013) 88:944–7. doi: 10.1002/ajh.23534 38:525–33. doi: 10.1016/j.gastrohep.2015.02.012 106. Reinisch W, Staun M, Tandon RK, Altorjay I, Thillainayagam AV, Gratzer 90. Salvadori U, Sandri M, Melli C, Polese F, Simeoni M, Capelli S, et al. Ferric C, et al. A randomized, open-label, non-inferiority study of intravenous iron carboxymaltose reduces the number of red blood cell units transfused and allows isomaltoside 1,000 (Monofer) compared with oral iron for treatment of anemia transfusion independence to be obtained in patients with iron deficiency anemia in IBD (PROCEED). Am J Gastroenterol. (2013) 108:1877–88. doi: 10.1038/ajg. secondary to gastrointestinal chronic blood loss. Transfusion. (2016) 56:2720–6. 2013.335 doi: 10.1111/trf.13794 107. Bhandari S, Pereira DIA, Chappell HF, Drakesmith H. Intravenous irons: 91. Muñoz M, García-Erce JA, Remacha AF. Disorders of iron metabolism. Part From basic science to clinical practice. Pharmaceuticals (Basel). (2018) 11:82. II: Iron deficiency and iron overload. J Clin Pathol. (2011) 64:287–96. doi: 10.1136/ doi: 10.3390/ph11030082 jcp.2010.086991 108. Lichtenstein GR, Onken JE. Improved hemoglobin response with ferric 92. Muñoz M, Villar I, García-Erce JA. An update on iron physiology. World J carboxymaltose in patients with gastrointestinal-telated iron-deficiency anemia Gastroenterol. (2009) 15:4617–26. doi: 10.3748/wjg.15.4617 versus oral iron. Dig Dis Sci. (2018) 63:3009–19. doi: 10.1007/s10620-018-5204-3 93. García Erce JA, Altés A, López Rubio M, Remacha AF. Management of 109. Martin-Malo A, Borchard G, Flühmann B, Mori C, Silverberg D, Jankowska iron deficiency in various clinical conditions and the role of intravenous iron: EA. Differences between intravenous iron products: Focus on treatment of iron Recommendations of the Spanish Erythropathology Group of the Spanish Society deficiency in chronic heart failure patients. ESC Heart Fail. (2019) 6:241–53. of Haematology and Haemotherapy. Rev Clin Esp. (2020) 220:31–42. doi: 10.1016/ doi: 10.1002/ehf2.12400 j.rce.2019.09.004 110. Vifor Pharma UK Limited. Ferinject (ferric carboxymaltose) [summary of 94. Gargallo-Puyuelo CJ, Alfambra E, García-Erce JA, Gomollon F. Iron product characteristics]. (2020). Available online at: https://www.medicines.org. treatment may be difficult in inflammatory diseases:Inflammatory bowel disease uk/emc/product/5910/smpc#gref (accessed January 25, 2022). as a paradigm. Nutrients. (2018) 10:1959. doi: 10.3390/nu10121959 111. Vifor Pharma UK Limited. Venofer (iron sucrose) 20 mg iron/ml, solution 95. Ko CW, Siddique SM, Patel A, Harris A, Sultan S, Altayar O, et al. AGA for injection or concentrate for solution for infusion [summary of product clinical practice guidelines on the gastrointestinal evaluation of iron deficiency characteristics]. (2020). Available online at: https://www.medicines.org.uk/emc/ anemia. Gastroenterology. (2020) 159:1085–94. doi: 10.1053/j.gastro.2020.06.046 product/5911 (accessed January 25, 2022). 96. Auerbach M, Adamson JW. How we diagnose and treat iron deficiency 112. Evstatiev R, Marteau P, Iqbal T, Khalif IL, Stein J, Bokemeyer B, et al. anemia. Am J Hematol. (2016) 91:31–8. doi: 10.1002/ajh.24201 FERGIcor, a randomized controlled trial on ferric carboxymaltose for iron deficiency anemia in inflammatory bowel disease. Gastroenterology. (2011) 97. Rimon E, Kagansky N, Kagansky M, Mechnick L, Mashiah T, Namir M, et al. 141:846–53.e1–2. doi: 10.1053/j.gastro.2011.06.005 Are we giving too much iron? Low-dose iron therapy is effective in octogenarians. Am J Med. (2005) 118:1142–7. doi: 10.1016/j.amjmed.2005.01.065 113. Ganzoni AM. [Intravenous iron-dextran: Therapeutic and experimental possibilities]. Schweiz Med Wochenschr. (1970) 100:301–3. 98. Schrier SL. So you know how to treat iron deficiency anemia. Blood. (2015) 126:1971. doi: 10.1182/blood-2015-09-666511 114. Bager P, Dahlerup JF. Randomised clinical trial: Oral vs. intravenous iron after upper gastrointestinal haemorrhage – a placebo-controlled study. Aliment 99. Tolkien Z, Stecher L, Mander AP, Pereira DI, Powell JJ. Ferrous sulfate Pharmacol Ther. (2014) 39:176–87. doi: 10.1111/apt.12556 supplementation causes significant gastrointestinal side-effects in adults: A systematic review and meta-analysis. PLoS One. (2015) 10:e0117383. doi: 10.1371/ 115. Goodnough LT, Hollenhorst MA. Clinical decision support and improved journal.pone.0117383 blood use in patient blood management. Hematology Am Soc Hematol Educ Program. (2019) 2019:577–82. doi: 10.1182/hematology.2019000062 100. Koduru P, Abraham BP. The role of ferric carboxymaltose in the treatment of iron deficiency anemia in patients with gastrointestinal disease. Therap Adv 116. Di Bartolomeo E, Merolle L, Marraccini C, Canovi L, Berni P, Guberti Gastroenterol. (2016) 9:76–85. doi: 10.1177/1756283X15616577 M, et al. Patient blood management: Transfusion appropriateness in the post- operative period. Blood Transfus. (2019) 17:459–64. doi: 10.2450/2019.0035-19 101. Ferrer-Barcelo L, Sanchis Artero L, Sempere Garcia-Arguelles J, Canelles Gamir P, Gisbert JP, Ferrer-Arranz LM, et al. Randomised clinical trial: 117. Beal EW, Bagante F, Paredes A, Akgul O, Merath K, Cua S, et al. Intravenous vs oral iron for the treatment of anaemia after acute gastrointestinal Perioperative use of blood products is associated with risk of morbidity and bleeding. Aliment Pharmacol Ther. (2019) 50:258–68. doi: 10.1111/apt.15327 mortality after surgery. Am J Surg. (2019) 218:62–70. doi: 10.1016/j.amjsurg.2018. 11.015 102. Cotter J, Baldaia C, Ferreira M, Macedo G, Pedroto I. Diagnosis and treatment of iron-deficiency anemia in gastrointestinal bleeding: A systematic 118. Gomollón F, Gisbert JP. Current management of iron deficiency anemia review. World J Gastroenterol. (2020) 26:7242–57. doi: 10.3748/wjg.v26.i45.7242 in inflammatory bowel diseases: A practical guide. Drugs. (2013) 73:1761–70. doi: 10.1007/s40265-013-0131-2 103. Dignass AU, Gasche C, Bettenworth D, Birgegård G, Danese S, Gisbert JP, et al. European consensus on the diagnosis and management of iron deficiency 119. Gomollón F, Gisbert JP. Intravenous iron in inflammatory bowel diseases. and anaemia in inflammatory bowel diseases. J Crohns Colitis. (2015) 9:211–22. Curr Opin Gastroenterol. (2013) 29:201–7. doi: 10.1097/MOG.0b013e32835 doi: 10.1093/ecco-jcc/jju009 bdc2e Frontiers in Medicine 16 frontiersin.org