Position Statement on Patient Blood Management

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Summary

The National Advisory Committee on Blood and Blood products would like to acknowledge the authors of the original version, listed in Appendix C, as well as the contributions made to this updated version by Drs. Joshua Nicholas, Davinder Sidhu, Michael Vargo, Austin Ho, Susan Nahirniak, Matthew Kokotilo, and Lorraine Chow.

Credits
Author
Ryan Lett, MD
NAC Chair
Andrew Shih, MD
Provincial Ministry Representative
Madeleine McKay (NS)
NAC Coordinator
Kendra Stuart
Date of Original Release
Date of Last Revision:
Publication Date

List of abbreviations

ESA

Erythropoietin Stimulating Agent

ONTraC

Ontario Nurse Transfusion Coordinators

PBM

Patient Blood Management

IV Iron

Intravenous Iron

Hb

Hemoglobin

NAC

National Advisory Committee on Blood and Blood Products

RBC

Red Blood Cell

Summary of Revisions

Revision Date

Details

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2026-06-23 Summary of Revisions - June 2026
Definitions

Patient Blood Management – a patient-centered, systematic, evidence-based approach to improve patient outcomes by managing and preserving a patient’s own blood, while promoting patient safety and empowerment.

1.0 Introduction

Patient Blood Management (PBM) is a patient-centered, systematic, evidence-based approach to improve patient outcomes by managing and preserving a patient's own blood, while promoting patient safety and empowerment.1 Frameworks for PBM programs may vary whether in a surgical setting (pre-operative, intra-operative, and post-operative)2 or by goal (to stop/minimize blood loss and diagnostic phlebotomy, diagnose and treat coagulopathy, manage anemia, and improve tolerance of anemia).3 The aim, regardless of framework, is to improve patient outcomes and make patients the center of care.

PBM programs consistently demonstrate reduced transfusion utilization and cost avoidance,4 frequently demonstrate reductions to hospital length of stay, morbidity, and mortality, and show overall improved patient outcomes.5 These benefits are in contrast to the increased recognition that ignoring anemia or utilizing transfusion to treat anemia may increase complications including infection,6 thrombosis,7 stroke/myocardial infarction,8 transfusion related immunomodulation (which may increase cancer progression and/or recurrence),9,10 and transfusion reactions such as transfusion associated circulatory overload and transfusion associated lung injury.11

In many institutions, PBM is the standard of care.12 The World Health Organization issued a resolution in 2010 to improve patient safety by implementing PBM programs,13 and in 2021 issued an updated policy brief calling for an urgent need to implement PBM.14 Specifically, they state, “All Member States should act quickly through their ministry or department of health to adopt their national PBM policy, install the necessary governance, and reallocate resources to improve the population health status and individual patient outcomes while reducing overall health care expenditures.” In 2024, the World Health Organization published a multidisciplinary guidance document for systematic implementation of PBM.15

World-wide, there has been country-wide implementation in Austria, the Netherlands,16 and Western Australia.17 While there are some references to PBM by Canadian Blood Services,18 and principles may be found in the National Advisory Committee on Blood and Blood Products (NAC) blood shortages document,19 more wide-spread application across the healthcare spectrum is necessary to improve health care provision and blood utilization in Canada. Many processes need to be aligned, and it is short sighted to attempt to perfect anemia management once a blood shortage occurs. PBM is interdisciplinary and goes beyond transfusion; cooperation and education amongst nursing, physician, administration, pharmacy, laboratory, and perfusion staff is necessary. PBM should also reflect the patient’s medical history, preferences, and values.

2.0 Components of a Patient Blood Management Program

Successful Patient Blood Management Programs include the following:20

Education - Many medical practitioners are accustomed to certain practice behaviours that become out-dated over time.21 An example of this is the transfusion of two units of red blood cells (RBCs) in response to anemia. This has become a focus for Choosing Wisely’s “Why Use Two When One Will Do” campaign.22 Likewise, many transfusion thresholds have steadily decreased over time in response to higher quality evidence advocating for more restrictive thresholds. Unfortunately, implementation of this evidence has been slow and heterogeneous. This not only affects transfusion, but also lab reference values and clinical indications for medication administration such as intravenous iron (IV iron). While the evidence has supported the use of IV iron and erythropoietin stimulating agents (ESA) to reduce transfusion needs,23 their implementation is poor.24 Lack of medical practitioner education, appropriate laboratory reference alerts, and pharmacy availability on these transfusion alternatives represents a significant barrier to their adoption.

Physician resources - Many programs have a physician director for managing referrals and intervention of complex forms of anemia. A lack of physician education and assigned responsibility for managing anemia results in patients missing opportunities for optimization and better outcomes prior to and during their hospital admission.

Nursing resources - Nursing care often forms the backbone of PBM programs in terms of direct patient care. A dedicated nursing position ensures continuity of care. Currently in Canada, the Ontario Nurse Transfusion Coordinator (ONTraC) program exemplifies the important role of nursing in PBM.25 Not all sites in Ontario have this program, and most sites outside of Ontario have no formal program. The ONTraC program has one of the best toolkits available for hospital implementation.26

Administrative resources - Scheduling patient consultations, interventions, and follow-up is also necessary to maintain patient flow in their care journey. A key component is coordinating the timing of surgery with the timing of patient optimization. The patient and their PBM care team should receive early notification (at least six weeks) prior to surgery to coordinate their optimization strategy.

Physical resources - Some aspects of PBM include administration of intravenous and subcutaneous injections, which require patient assessment and monitoring. The best example of this is IV iron. Depending on the IV iron formulation chosen, total chair time to restore iron stores may be as short as 15 minutes or as long as 10 hours.27 This requires monitored space to accommodate patients undergoing treatment, as well as nursing and physician resources to staff and supervise administration.

Timing to critical events - A robust system identifies patients well in advance of their surgical or obstetrical delivery date. To utilize low-cost oral iron requires nearly three months on average to restore iron in deficient patients. Most surgical systems do not notify patients or practitioners of upcoming dates with enough time to utilize oral supplements. Peak effect for IV iron and ESA still requires several weeks of planning to optimize anemia and limit transfusion, although there is some evidence that even a single day results in some improvement.28,29

Pharmacy resources - Pharmacy needs to be actively engaged as most budgets are isolated from one another. Labile blood components are funded by a transfusion budget, but adjunctive therapy, including IV iron and ESAs, are funded by a pharmacy budget through exceptional drug status, private insurance, or a patients’ own funds. Savings in PBM are a result of reduced transfusion costs, activity costs (compatibility testing, inventory management), and reduced hospital costs when the hospital stay is reduced. Conversely, treating anemia without transfusion often increases the pharmaceutical cost. As a net equation, PBM reduces overall system costs. Therefore, pharmacists need to be actively engaged in ensuring appropriate resource management and reimbursement, and to consider the risks and benefits of labile blood components as compared to the risks and benefits of a medication.

Medication funding - Medications specifically shown to reduce transfusion or treat anemia should be funded in PBM programs. Specifically, antifibrinolytics (tranexamic acid),30 IV iron (ferric gluconate, iron sucrose, ferric derisomaltose, ferric carboxymaltose),31 and ESAs (Darbopoetin, Epoetin alfa)32 have a significant transfusion-sparing effect and should be publicly funded. Access to these medications is inequitable across jurisdictions in Canada, putting patients at increased risk of transfusion and associated complications (see Section 1.0). It is untenable that a patient with a treatable underlying cause of anemia such as iron deficiency should be provided with an inferior treatment such as a blood transfusion when hemodynamically stable. On a gram per litre increase in hemoglobin (Hb) basis, the use of IV iron surpasses that of a unit of RBCs by a factor of three for the same cost (see Table 1: Cost comparisons of anemia strategies). Moreover, IV iron has a superior safety profile with fewer side effects and lower morbidity and mortality compared to RBC transfusion. Whereas transfusion suppresses erythropoiesis and prolongs the duration of endogenous Hb recovery, the use of IV iron (and ESAs) supports the recovery of a patient’s own RBCs.

Laboratory resources - Laboratory clinicians can often improve diagnostic accuracy and timeliness to assess patient response to therapy. An example would be measuring reticulocyte markers (early RBC production) in response to oral iron to assess the need to progress to IV iron or add an ESA. Many laboratories also oversee point of care testing which may reduce the volume of blood lost by patients during diagnosis. Similarly, laboratories can strive to reduce unnecessary diagnostic phlebotomy,33,34 duplicate or mislabeled specimens by use of positive patient identification, and use of smaller tubes35 or those with less vacuum to collect blood samples. One universal barrier to optimal PBM therapy that the laboratory can eliminate is the introduction of clinically relevant Hb and ferritin thresholds rather than population or analyzer-based thresholds. For example, females have higher transfusion rates and associated morbidity and mortality following surgery due to normalized lower Hb levels.31,36,37 Laboratories should flag all Hb levels in adults less than 130g/L as abnormal.38,39 Likewise ferritin thresholds are reported as diagnostically accurate with very low levels (less than 15ucg/L) but the clinical reference range for improving patient function and outcomes is at least 30ucg/L and probably 50ucg/L in most adult patients.39-44 In children this value should be at least 20ucg/L.43

Information technology support - Data drives decisions and informs future management. A robust system to capture standardized pre and post implementation data allows evaluation of value-added PBM and helps drive future clinical decisions.45 Implementing clinical decision support for physician order entry has been shown to reduce unnecessary transfusions.46

Perfusion resources - Not every hospital will have perfusion personnel, but where present and in appropriate situations, perfusionists provide cell saver support in massive hemorrhage and high-risk operations. They are an integral part of providing safe cardiovascular surgical care and introducing measures to reduce the risk of transfusion in cardiac surgery.

3.0 Recommendations
3.1 Systematic Recommendations

a) All hospitals should work with their provincial/territorial Ministry of Health and health sector partners to implement PBM as a best practice that improves patient outcomes and system efficacy. A multimodal, peri-operative PBM program should be instituted in all surgical programs to address pre-operative, intra-operative, and post-operative anemia. The resources outlined in Section 2.0, which are required for successful implementation of PBM, should be provided on a site-by-site basis with consideration of clinical need and system resources.15

b) Provinces/territories should encourage hospitals to participate in initiatives including Choosing Wisely, Using Blood Wisely, and Using Labs Wisely which align with PBM principles. Providing order sets, and screening for single unit transfusions and appropriate transfusion thresholds reduces blood utilization without adding cost. Current appropriate thresholds are defined as less than 70g/L in most patients (it may be even lower in asymptomatic and chronic anemia);47-49 less than 80g/L in those at risk of ischemia, and less than 90g/L in myocardial infarction50 and traumatic brain injury.51

c) Educational resources should foster the development of local PBM leaders and champions. All health care practitioners should be aware that anemia (Hb less than 130g/L in all adults) increases morbidity and mortality. The risk to women is disproportionately higher than men at lower Hb levels, therefore Hb thresholds should not discriminate.38,39,44 This is true of pre-existing anemia and hospital acquired anemia. Hospitals should recognize that routine or avoidable diagnostic blood draws can result in hospital acquired anemia and prolong patient recovery.33-35 Stopping and minimizing blood loss requires interdisciplinary efforts and should be a primary pillar for PBM programs.

 

3.2 Clinical Recommendations

d) All patients undergoing surgery or delivery should be screened for anemia (Hb less than 130g/L in all adults) at least six weeks prior to their anticipated surgical or delivery date. When present, subsequent investigations should be directed at elucidating the mechanism (i.e. iron deficiency) and source (i.e. gastrointestinal losses). Using the mean corpuscular volume from a complete blood count is inadequate to screen for iron deficiency.52 Ferritin is preferred in an otherwise healthy population, but serum iron or transferrin saturation is preferred in the setting of myocardial infarction,53 congestive heart failure,54 renal failure,55 cancer, systemic infection, or other inflammatory conditions. Reference ranges for ferritin from most laboratories use diagnostic values below the clinically important values of 30 50ucg/L41 and relying on flagged values of 8-15ucg/L will miss relevant cases of iron deficiency.42

e) Appropriate referral to a specialist for investigation and management of underlying conditions is recommended and may include gastroenterology, gynecology, hematology, nephrology, or others according to the underlying etiology.

f) In anemic patients (Hb less than 130g/L in all adults) with ferritin less than 30-50ucg/L and more than six weeks to an operative or delivery date, oral iron therapy should be instituted. While ferritin less than 30ucg/L is highly sensitive and specific, patients who exhibit symptoms of iron deficiency may benefit from iron replacement targeting a ferritin of 50-100ucg/L.41

g) In anemic patients (Hb less than 130g/L in all adults) with ferritin less than 30-50ucg/L and less than six weeks to an operative or delivery date, IV iron therapy should be instituted.

h) In patients at risk of anemia (Hb greater than 130g/L but at risk of bleeding) and ferritin less than 30-50ucg/L, oral iron therapy should be instituted.

i) In patients with anemia (Hb less than 130g/L in all adults) and iron restricted erythropoiesis, inflammation, or tissue damage, ferritin is unreliable40,53 and serum iron and total iron binding capacity should be measured and used to guide therapy instead. For this population, IV iron therapy should be instituted for transferrin saturation less than 20% in most patients, although 24% is suggested in heart failure,54 and 30% in kidney failure.55

j) In patients with inadequate response to IV iron or when iron sequestration or inflammation limits the bioavailability of iron, an ESA should be considered on a case-by-case basis.

k) In patients with anemia and evidence of inflammation or renal failure where an ESA is indicated, it should be combined with IV iron.

l) When an ESA is used, concomitant use of thromboembolic prophylaxis should be considered on a case-by-case basis.56

m) Although iron deficiency is the most common nutritional deficiency in Canada and worldwide, other deficiencies should be considered on a case-by-case basis.

n) Folate deficiency is rare in the general population when white fortified flour is consumed,57 but whole wheat and alternative flours are not fortified with folate.58 When non-fortified flour is consumed, folate deficiency may be present in up to 14% of the population.59 Serum folate testing has a low positive predictive value and testing is not routinely recommended, but oral replacement is cheap and effective in those considered at risk.60

o) Vitamin B12 deficiency affects about 5% of the younger Canadian population but is higher in vegans, vegetarians, and the elderly.61 Testing is readily available and diagnostic when levels are less than 148pmol/L. Marginal deficiency at levels less than 221pmol/L are unlikely to result in anemia, but may be associated with complications in surgery and anesthesia.62 Treatment can be either intramuscular or oral depending on severity and response to treatment.

p) A protein deficient diet (prolonged periods less than 0.7g/kg/day) produces anemia. This is more common in the elderly and institutionalized and should be considered in patients with frailty. Increased protein intake is recommended in the peri-operative period and patients should consider consuming between 2-2.5g/kg/day while recovering.63

q) Other micronutrient deficiencies such as copper may contribute to anemia,64 but diagnostic testing can be challenging. Copper in particular appears to be important for utilization of iron and avoidance of free radical formation. Vitamins C, K, D, and thiamine deficiency are associated with poor wound healing, bleeding, delirium and neurological complications.65

r) Anemia should be corrected prior to all elective surgery. Institutions should have guidelines on postponing surgery until anemia is corrected.66

s) In patients who develop post-operative or post-hemorrhage related anemia, IV iron is recommended.67,68

t) The risk of surgical bleeding, urgency of surgery, and type of anticoagulation should be addressed to reduce blood loss. For specific recommendations for individual agents, resources such as Thrombosis Canada or a local peri-operative thrombosis expert should be consulted. In some circumstances (such as proximal femur fractures), early surgical fixation even in the presence of anticoagulation results in the same or less blood loss while reducing hospital length of stay and peri-operative complications.69-71

u) During hemorrhage, permissive hypotension or deliberately induced hypotension should be considered while balancing the risk of blood loss and preservation of vital organ perfusion.

v) When substantial blood loss is anticipated, acute normovolemic hemodilution should be considered.72,73 In some populations where the patient may be hypervolemic (i.e. liver failure), hypovolemic phlebotomy and return of whole blood post-procedure also reduces the risk of receiving a blood transfusion.74

w) When substantial blood loss is anticipated or encountered, intra-operative cell salvage should be considered.75

x) When substantial blood loss is anticipated or encountered, or the patient is involved in trauma or post-partum hemorrhage, antifibrinolytics (tranexamic acid) should be administered.76

y) When patients are recovering from anemia, other physiologic parameters should be addressed to reduce oxygen requirements. Hypothermia should be avoided with active warming. Processes that contribute to hospital acquired infections should be minimized, including nasogastric tubes and foley catheters.

z) Coagulopathy encountered in the hemorrhaging patient should treat the underlying coagulopathy. Low calcium (ionized less than 1.15mmol/L or uncorrected calcium less than 2.14mmol/L) should be treated with intravenous calcium and retested. Fibrinogen should be replaced in accordance with current guidelines available from NAC.77 The decision to use plasma or prothrombin concentrates should be made based on guidelines from NAC.78 When a known isolated defect is present (such as antithrombin in cardiac surgery) replacement using the corresponding factor concentrate is preferable to plasma.

Patients must be placed at the center of care. Improving long term outcomes and reducing morbidity and mortality is necessary to improve the quality of care delivered to Canadians. Implementing multidisciplinary strategies as part of a PBM program has the potential to improve outcomes and simultaneously reduce system costs. In the interest of improving care to its citizens, every province and territory should develop a PBM program.

Current clinical recommendations already exist, and examples are offered from ONTraC,26 the American Society of Hematology,79 and the Mayo Clinic.2 For visualization purposes, see ONTraC’s algorithm below (Figure 1).

A cost comparison using a single unit of RBCs in managing anemia is provided in Table 1 below. While transfusion of a single RBC unit may raise Hb levels temporarily, the transfused cells are generally destroyed more rapidly than endogenous cells and contribute to inhibiting production of endogenous cells. Transfused blood is not equivalent to endogenous production of blood.

Image
2026-06-23 Figure 1 - ONTraC Revised PBM algorithm 2021
Figure 1: ONTraC's Peri-operative Hemoglobin Optimization and Anemia Management Algorithm.80
4.0 Cost Comparisons

Table 1: Cost comparisons of anemia strategies.
See Appendix A: Table 1 & 2 Notes and Assumptions for additional information.

Image
2026-06-23 Table 1 - Cost Comparisons of Anemia Strategies

Table 2: Inflation cost of eopoetin alfa.
See Appendix A: Table 1 & 2 Notes and Assumptions for additional information.

Image
2026-06-23 Table 2 - Inflation Cost of Epoetin Alfa

References

  1. Shander A, Hardy JF, Ozawa S, Farmer SL, Hofmann A, Frank SM, Kor DJ, Faraoni D, Freedman J; Collaborators. A Global Definition of Patient Blood Management. Anesth Analg. 2022 Sep 1;135(3):476-488. doi: 10.1213/ANE.0000000000005873.
  2. Warner MA, Shore-Lesserson L, Shander A, Patel SY, Perelman SI, Guinn NR. Perioperative Anemia: Prevention, Diagnosis, and Management Throughout the Spectrum of Perioperative Care. Anesth Analg. 2020 May;130(5):1364-80. doi: 10.1213/ANE.0000000000004727.
  3. Althoff FC, Neb H, Herrmann E, Trentino KM, Vernich L, Füllenbach C, Freedman J, Waters JH, Farmer S, Leahy MF, Zacharowski K, Meybohm P, Choorapoikayil S. Multimodal Patient Blood Management Program Based on a Three-pillar Strategy: A Systematic Review and Meta-analysis. Ann Surg. 2019 May;269(5):794–804. doi: 10.1097/SLA.0000000000003095.
  4. Mueller MM, Van Remoortel H, Meybohm P, Aranko K, Aubron C, Burger R, Carson JL, Cichutek K, De Buck E, Devine D, Fergusson D, Folléa G, French C, Frey KP, Gammon R, Levy JH, Murphy MF, Ozier Y, Pavenski K, So-Osman C, Tiberghien P, Volmink J, Waters JH, Wood EM, Seifried E; ICC PBM Frankfurt 2018 Group. Patient Blood Management: Recommendations From the 2018 Frankfurt Consensus Conference. JAMA. 2019 Mar 12;321(10):983-997. doi: 10.1001/jama.2019.0554.
  5. Farmer SL, Trentino K, Hofmann A, Semmens JB, Mukhtar A, Prosser G, Hamdorf JM, Rao S, Leahy MF. A Programmatic Approach to Patient Blood Management - Reducing Transfusions and Improving Patient Outcomes. Open Anesth J. 2015;9:6-16. doi: 10.2174/1874321801509010006.
  6. Rohde JM, Dimcheff DE, Blumberg N, Saint S, Langa KM, Kuhn L, Hickner A, Rogers MA. Health care-associated infection after red blood cell transfusion: a systematic review and meta-analysis. JAMA. 2014 Apr 2;311(13):1317-26. doi: 10.1001/jama.2014.2726.
  7. Goel R, Patel EU, Cushing MM, Frank SM, Ness PM, Takemoto CM, Vasovic LV, Sheth S, Nellis ME, Shaz B, Tobian AAR. Association of Perioperative Red Blood Cell Transfusions With Venous Thromboembolism in a North American Registry. JAMA Surg. 2018 Sep 1;153(9):826-833. doi: 10.1001/jamasurg.2018.1565.
  8. Whitlock EL, Kim H, Auerbach AD. Harms associated with single unit perioperative transfusion: retrospective population based analysis. BMJ. 2015 Jun 12;350:h3037. doi: 10.1136/bmj.h3037.
  9. Pang QY, An R, Liu HL. Perioperative transfusion and the prognosis of colorectal cancer surgery: a systematic review and meta-analysis. World J Surg Oncol. 2019 Jan 5;17(1):7. doi: 10.1186/s12957-018-1551-y.
  10. Agudelo-Jimenez RD, Heatter JA, Cata JP. Transfusion Therapy: Is There a Link with Cancer Recurrence? Curr Anesth Rep. 2018 Oct 13;8:426–38. doi: 10.1007/s40140-018-0292-3.
  11. Semple JW, Rebetz J, Kapur R. Transfusion-associated circulatory overload and transfusion-related acute lung injury. Blood. 2019 Apr 25;133(17):1840-1853. doi: 10.1182/blood-2018-10-860809.
  12. Shander A, Bracey AW Jr, Goodnough LT, Gross I, Hassan NE, Ozawa S, Marques MB. Patient Blood Management as Standard of Care. Anesth Analg. 2016 Oct;123(4):1051-3. doi: 10.1213/ANE.0000000000001496. 
  13. World Health Organization. Global Forum for Blood Safety: Patient Blood Management Concept Paper [Internet]. Dubai: Government of the United Arab Emirates; 2011 Mar. [cited 11 Jan 2021]. Available from: https://www.who.int/bloodsafety/events/gfbs_01_pbm_concept_paper.pdf 
  14. World Health Organization. The urgent need to implement patient blood management: policy brief [Internet]. World Health Organization; 2021 Oct 19. [cited 2026 Feb 24]. Available from: https://www.who.int/publications/i/item/9789240035744 
  15. World Health Organization. Guidance on implementing patient blood management to improve global blood health status [Internet]. Geneva: World Health Organization; 2025 Apr 23. [cited 2026 Feb 24]. Available from: https://www.who.int/publications/i/item/9789240104662 
  16. Shander A, Van Aken H, Colomina MJ, Gombotz H, Hofmann A, Krauspe R, Lasocki S, Richards T, Slappendel R, Spahn DR. Patient blood management in Europe. Br J Anaesth. 2012 Jul;109(1):55-68. doi: 10.1093/bja/aes139.
  17. National Blood Authority. Patient Blood Management Guidelines [Internet]. Australia National Blood Authority; 2024 Jul 8. [cited 2021 Jan 11]. Available from: https://www.blood.gov.au/patient-blood-management-guidelines#pbm-guidelines 
  18. O’Reilly C. Professional Education Chapter 9: Blood Administration [Internet]. Canadian Blood Services; 2020 Oct 6 [cited 2021 Jan 11] Available from: https://professionaleducation.blood.ca/en/transfusion/clinical-guide/blood-administration 
  19. Nahirniak S, Prokopchuk-Gauk O, Shih A, Musuka C, Tinmouth A, Pavenski Km Quinn J, Petraszko T, Pour P, Hook J, Han J, Ronderos-Morgan S, LeFrense J, Traer MacKinnon S, Moore A, Romans R, Fawcett J, McIntyre L, Teklehaimanot S, Mahadevan B. The National Plan for Management of Shortages of Labile Blood Components [Internet]. Ottawa: National Advisory Committee on Blood and Blood Products; July 27, 2009 [updated 2025 11 07; cited 2026 Feb 24]. Available from: https://nacblood.ca/en/blood-shortage 
  20. Meybohm P, Froessler B, Goodnough LT, Klein AA, Muñoz M, Murphy MF, Richards T, Shander A, Spahn DR, Zacharowski K. "Simplified International Recommendations for the Implementation of Patient Blood Management" (SIR4PBM). Perioper Med (Lond). 2017 Mar 17;6:5. doi: 10.1186/s13741-017-0061-8.
  21. Manzini PM, Dall'Omo AM, D'Antico S, Valfrè A, Pendry K, Wikman A, Fischer D, Borg-Aquilina D, Laspina S, van Pampus ECM, van Kraaij M, Bruun MT, Georgsen J, Grant-Casey J, Babra PS, Murphy MF, Folléa G, Aranko K. Patient blood management knowledge and practice among clinicians from seven European university hospitals: a multicentre survey. Vox Sang. 2018 Jan;113(1):60-71. doi: 10.1111/vox.12599. 
  22. Lin Y, Thompson T. Why Give Two When One Will Do? A toolkit for reducing unnecessary red blood cell transfusions in hospitals [Internet]. Choosing Wisely Canada; 2019 May. [cited 2026 Feb 24]. Available from: https://choosingwiselycanada.org/wp-content/uploads/2017/07/CWC_Transfusion_Toolkit_v1.2_2017-07-12.pdf 
  23. Kei T, Mistry N, Curley G, Pavenski K, Shehata N, Tanzini RM, Gauthier MF, Thorpe K, Schweizer TA, Ward S, Mazer CD, Hare GMT. Efficacy and safety of erythropoietin and iron therapy to reduce red blood cell transfusion in surgical patients: a systematic review and meta-analysis. Can J Anaesth. 2019 Jun;66(6):716-731. doi: 10.1007/s12630-019-01351-6.
  24. Gabarin N, Liu Y, Coll-Black M, Luketic L, Pai M, St John M, Shirinzadeh M, Sirotich E, Arnold DM, Zeller MP. Perioperative Anemia Management in Patients Undergoing Gynaecologic Procedures: A 12-Year Multisite Study. J Obstet Gynaecol Can. 2025 Jul;47(7):102923. doi: 10.1016/j.jogc.2025.102923.
  25. Ontario Nurse Transfusion Coordinators (ONTraC) A Provincial Patient Blood Management Program [Internet]. Ontario: Ontario Transfusion Coordinators; 2023 [cited 2021 Jan 11]. Available from: https://www.ontracprogram.com/Public.aspx 
  26. Freedman J. Patient Blood Management: An ONTraC Toolkit Guide for Hospitals [Internet]. Ontario: Ontario Transfusion Coordinators. 2016 [updated 2020; cited 2021 Jan 11]. Available from: https://www.ontracprogram.com/ckupload/files/103/Final%20toolkit%20Aug%2020%202020(1).pdf 
  27. Pollock RF, Muduma G. A budget impact analysis of parenteral iron treatments for iron deficiency anemia in the UK: reduced resource utilization with iron isomaltoside 1000. Clinicoecon Outcomes Res. 2017 Aug 10;9:475-483. doi: 10.2147/CEOR.S139525.
  28. Spahn D R, Schoenrath F, Spahn GH, Seifert B, Stein P, Theusinger OM, Kaserer A, Hegemann I, Hofmann A, Maisano F, Falk V. Effect of ultra-short-term treatment of patients with iron deficiency or anaemia undergoing cardiac surgery: a prospective randomised trial. Lancet. 2019 Jun 1;393(10187):2201-2212. doi: 10.1016/S0140-6736(18)32555-8.
  29. Froessler B, Dekker G, McAuliffe G. To the rescue: the role of intravenous iron in the management of severe anaemia in the peri-partum setting. Blood Transfus. 2015 Jan;13(1):150-2. doi: 10.2450/2014.0220-14.
  30. Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. BMJ. 2012 May 17;344:e3054. doi: 10.1136/bmj.e3054.
  31. Muñoz M, Acheson AG, Auerbach M, Besser M, Habler O, Kehlet H, Liumbruno GM, Lasocki S, Meybohm P, Rao Baikady R, Richards T, Shander A, So-Osman C, Spahn DR, Klein AA. International consensus statement on the peri-operative management of anaemia and iron deficiency. Anaesthesia. 2017 Feb;72(2):233-247. doi: 10.1111/anae.13773.
  32. Cho BC, Serini J, Zorrilla-Vaca A, Scott MJ, Gehrie EA, Frank SM, Grant MC. Impact of Preoperative Erythropoietin on Allogeneic Blood Transfusions in Surgical Patients: Results from a Systematic Review and Meta-analysis. Anesth Analg. 2019 May;128(5):981-992. doi: 10.1213/ANE.0000000000004005.
  33. Hicks L, O’Brien P, Longmore A. Pause the Draws: A toolkit for reducing repetitive routine blood draws in hospitals [Internet]. Choosing Wisely Canada; 2019 May. [cited 2025 Oct 14]. Available from: https://choosingwiselycanada.org/toolkit/pause-the-draws/ 
  34. Using Labs Wisely [Internet]. Ontario: Choosing Wisely Canada. [cited 2025 Oct 14]. Available from: https://choosingwiselycanada.org/hospitals/using-labs-wisely/ 
  35. Siegal DM, Belley-Côté EP, Lee SF, Hill S, D'Aragon F, Zarychanski R, Rochwerg B, Chassé M, Binnie A, Honarmand K, Lauzier F, Ball I, Al-Hazzani W, Archambault P, Duan E, Khwaja K, Lellouche F, Lysecki P, Marquis F, Naud JF, Shahin J, Shea J, Tsang JLY, Wang HT, Crowther M, Arnold DM, Di Sante E, Marfo G, Kovalova T, Fonguh S, Vincent J, Connolly SJ. Small-Volume Blood Collection Tubes to Reduce Transfusions in Intensive Care: The STRATUS Randomized Clinical Trial. JAMA. 2023 Nov 21;330(19):1872-1881. doi: 10.1001/jama.2023.20820.
  36. Arya S, Howell A, Vernich L, Lin Y, Pavenski K, Freedman J. Re-evaluating treatment thresholds in patient blood management: Female patients experience more perioperative anaemia and higher transfusion rates in major elective surgery. Vox Sang. 2024 Oct;119(10):1090-1095. doi: 10.1111/vox.13717.
  37. Blaudszun G, Munting KE, Butchart A, Gerrard C, Klein AA. The association between borderline pre-operative anaemia in women and outcomes after cardiac surgery: a cohort study. Anaesthesia. 2018 May;73(5):572-578. doi: 10.1111/anae.14185.
  38. Muñoz M, Gómez-Ramírez S, Kozek-Langenecker S, Shander A, Richards T, Pavía J, Kehlet H, Acheson AG, Evans C, Raobaikady R, Javidroozi M, Auerbach M. ‘Fit to fly’: overcoming barriers to preoperative haemoglobin optimization in surgical patients. Br J Anaesth. 2015 Jul;115(1):15–24. doi: 10.1093/bja/aev165.
  39. Merz LE, Siad FM, Creary M, Sholzberg M, Weyand AC. Laboratory-based inequity in thrombosis and hemostasis: review of the evidence. Res Pract Thromb Haemost. 2023 Mar 15;7(2):100117. doi: 10.1016/j.rpth.2023.100117.
  40. Rohr M, Brandenburg V, Brunner-La Rocca HP. How to diagnose iron deficiency in chronic disease: A review of current methods and potential marker for the outcome. Eur J Med Res. 2023 Jan 9;28(1):15. doi: 10.1186/s40001-022-00922-6.
  41. Naveed K, Goldberg N, Shore E, Dhoot A, Gabrielson D, Goodarzi Z, Lin Y, Pai M, Pardy NA, Robinson S, Andreou R, Sood M, Price V, Storm S, Verduyn A, Parker ML, Fralick M, Beriault D, Sholzberg M. Defining ferritin clinical decision limits to improve diagnosis and treatment of iron deficiency: A modified Delphi study. Int J Lab Hematol. 2023 Jun;45(3):377-386. doi: 10.1111/ijlh.14016.
  42. Parker ML, Storm S, Sholzberg M, Yip PM, Beriault DR. Revising Ferritin Lower Limits: It's Time to Raise the Bar on Iron Deficiency. J Appl Lab Med. 2021 Apr 29;6(3):765-773. doi: 10.1093/jalm/jfaa152.
  43. Sholzberg M, Hillis C, Crowther M, Selby R. Diagnosis and management of iron deficiency in females. CMAJ. 2025 Jul 1;197(24):E680-E687. doi: 10.1503/cmaj.240570.
  44. Martens K, DeLoughery TG. Sex, lies, and iron deficiency: a call to change ferritin reference ranges. Hematology Am Soc Hematol Educ Program. 2023 Dec 8;2023(1):617-21. doi: 10.1182/hematology.2023000494. 
  45. Trentino KM, Lloyd A, Swain SG, Trentino L, Gross I. Data and Metrics for Patient Blood Management: A Narrative Review and Practical Guide. Anesth Analg. 2025 Nov 1;141(5):942-949. doi: 10.1213/ANE.0000000000006557.
  46. Derzon JH, Clarke N, Alford A, Gross I, Shander A, Thurer R. Restrictive Transfusion Strategy and Clinical Decision Support Practices for Reducing RBC Transfusion Overuse. Am J Clin Pathol. 2019 Oct 7;152(5):544-557. doi: 10.1093/ajcp/aqz070. 
  47. Mullis BH, Mullis LS, Kempton LB, Virkus W, Slaven JE, Bruggers J. Orthopaedic Trauma and Anemia: Conservative versus Liberal Transfusion Strategy: A Prospective Randomized Study. J Orthop Trauma. 2024 Jan 1;38(1):18-24. doi: 10.1097/BOT.0000000000002696.
  48. Callum JL, Lin Y, Cope S, Karkouti K, Lieberman L, Pendergrast JM, Robitaille N, Tinmouth AT, Webert KE. Bloody Easy 5.1: Blood Transfusions, Blood Alternatives and Transfusion Reactions: A guide to Transfusion Medicine (5th edition) [Internet]. Ontario Regional Blood Coordinating Network; 2003 [updated 2023 Jul; cited 2026 Feb]. Available from: https://transfusionontario.org/wp-content/uploads/2022/10/BloodyEasy5.1_English_Final_2023_Interactive-June-28.pdf 
  49. Prick BW, Jansen AJ, Steegers EA, Hop WC, Essink-Bot ML, Uyl-de Groot CA, Akerboom BM, van Alphen M, Bloemenkamp KW, Boers KE, Bremer HA, Kwee A, van Loon AJ, Metz GC, Papatsonis DN, van der Post JA, Porath MM, Rijnders RJ, Roumen FJ, Scheepers HC, Schippers DH, Schuitemaker NW, Stigter RH, Woiski MD, Mol BW, van Rhenen DJ, Duvekot JJ. Transfusion policy after severe postpartum haemorrhage: a randomised non-inferiority trial. BJOG. 2014 Jul;121(8):1005–14. doi: 10.1111/1471-0528.12531.
  50. Shih A, Schnell G, Belley-Côté EP, Lett R, Peretz-Larochelle M, Tinmouth A. Canadian Cardiovascular Society and National Advisory Committee on Blood and Blood Products Joint Statement on Blood Utilization and Transfusion for Patients With Acute Coronary Syndromes. Cad J Cardiol. 2025 Oct;41(10):1875-84.
  51. Moro P, Andrighetti M, Siconolfi G, Borioni MS, Di Bonaventura C, Toni D, Cerulli Irelli E. Transfusion Thresholds and Neurological Functional Outcome After Acute Brain Injury: An Updated Systematic Review and Meta-Analysis of Randomized Clinical Trials. J Clin Med. 2025 May 16;14(10):3487. doi: 10.3390/jcm14103487.
  52. Chao HX, Zack T, Leavitt AD. Screening Characteristics of Hemoglobin and Mean Corpuscular Volume for Detection of Iron Deficiency in Pregnancy Obstet Gynecol. 2025 Jan 1;145(1):91-94. doi: 10.1097/AOG.0000000000005753.
  53. Jenča D, Melenovský V, Mrázková J, Šramko M, Kotrč M, Želízko M, Adámková V, Piťha J, Kautzner J, Wohlfahrt P. Iron deficiency and all-cause mortality after myocardial infarction. Eur J Intern Med. 2024 Aug;126:102-108. doi: 10.1016/j.ejim.2024.04.020.
  54. Masini G, Graham FJ, Pellicori P, Cleland JGF, Cuthbert JJ, Kazmi S, Inciardi RM, Clark AL. Criteria for Iron Deficiency in Patients With Heart Failure. J Am Coll Cardiol. 2022 Feb 1;79(4):341-351. doi: 10.1016/j.jacc.2021.11.039.
  55. Babitt JL, Berns JS, Bozkurt B, Cheung Khedairy RS, Cuevas Y, Effa EE, Eisenga MF, Fishbane S, Ginzburg YZ, Haase VH, Hedayati SS, Kim S, Moura-Neto JA, Nagler EV, Rossignol P, Sahay M, Tanaka T, Yee-Moon Wang A, Wheeler DC, Robinson KA, Wilson LM, Wilson RF, Earley A, Akl EA, Tonelli M. Executive Summary of the KDIGO 2026 Clinical Practice Guideline for the Management of Anemia in Chronic Kidney Disease (CKD). Kidney Int. 2026 Jan;109(1):44-56. doi: 10.1016/j.kint.2025.06.005.
  56. Mesgarpour B, Heidinger BH, Roth D, Schmitz S, Walsh CD, Herkner H. Harms of off‐label erythropoiesis‐stimulating agents for critically ill people. Cochrane Database of Syst Rev. 2017 Aug 25;8(8):CD010969. doi: 10.1002/14651858.CD010969.pub2.
  57. Colapinto CK, O’Connor DL, Tremblay MS. Folate status of the population in the Canadian Health Measures Survey. CMAJ. 2011 Feb 8;183(2):E100–6. doi: 10.1503/cmaj.100568.
  58. Chan YM, MacFarlane AJ, O’Connor DL. Modeling Demonstrates That Folic Acid Fortification of Whole-Wheat Flour Could Reduce the Folate Inadequacy in Canadian Whole-Wheat Consumers. J Nutr. 2015 Nov;145(11):2622–9. doi: 10.3945/jn.115.217851.
  59. Choorapoikayil S, Baron DM, Spahn DR, Lasocki S, Boryshchuk D, Yeghiazaryan L, Posch M, Bisbe E, Metnitz P, Reichmayr M, Zacharowski K, Meybohm P; German Society of Anaesthesiology and Intensive Care (GSAIC) Trials Group; SFAR research network; Supportive Anaesthesia Trainee-led Audit and Research Network (SATURN); ALICE study collaborators. The aetiology and prevalence of preoperative anaemia (ALICE study): an international, prospective, observational cohort study. Lancet Glob Health. 2025 Dec;13(12):e2041–50. doi: 10.1016/S2214-109X(25)00320-1.
  60. MacFarlane AJ, Greene-Finestone LS, Shi Y. Vitamin B-12 and homocysteine status in a folate-replete population: results from the Canadian Health Measures Survey. Am J Clin Nutr. 2011 Oct;94(4):1079–87. doi: 10.3945/ajcn.111.020230.
  61. Pfisterer KJ, Sharratt MT, Heckman GG, Keller HH. Vitamin B12 status in older adults living in Ontario long-term care homes: prevalence and incidence of deficiency with supplementation as a protective factor. Appl Physiol Nutr Metab. 2016 Feb;41(2):219–22. doi: 10.1139/apnm-2015-0565.
  62. Silverstein W, Cheung M, Lin Y. Vitamin B12 deficiency. CMAJ. 2022 Jun 20;194(24):E843. doi: 10.1503/cmaj.220306.
  63. O’Keefe GE, Shelton M, Qiu Q, Araujo-Lino JC. Increasing Enteral Protein Intake in Critically Ill Trauma and Surgical Patients. Nutr Clin Pract. 2019 Oct;34(5):751–9. doi: 10.1002/ncp.10256.
  64. Klevay LM. Is the Western diet adequate in copper? J Trace Elem Med Biol. 2011 Dec;25(4):204–12. doi: 10.1016/j.jtemb.2011.08.146.
  65. Bagheri Moghaddam A, Raouf-Rahmati A, Nemati A, Niroumand S, Mashreghi AR, Gholami M, Bahramizadeh Sajjadi R. Vitamin deficiency, a neglected risk factor for post-anesthesia complications: a systematic review. Eur J Med Res. 2025 Feb 12;30(1):97. doi: 10.1186/s40001-025-02288-x.
  66. Muñoz M, Acheson AG, Bisbe E, Butcher A, Gómez-Ramírez S, Khalafallah AA, Kehlet H, Kietaibl S, Liumbruno GM, Meybohm P, Rao Baikady R, Shander A, So-Osman C, Spahn DR, Klein AA. An international consensus statement on the management of postoperative anaemia after major surgical procedures. Anaesthesia. 2018 Nov;73(11):1418-31. doi: 10.1111/anae.14358.
  67. Lim J, Joo J, MacLean B, Richards T. The use of iron after surgery: a systematic review and meta-analysis. Anaesthesia. 2025 Aug;80(8):988-996. doi: 10.1111/anae.16605.
  68. Brameier DT, Tischler EH, Ottesen TD, McTague MF, Appleton PT, Harris MB, Weaver MJ, Suneja N. Use of Direct Oral Anticoagulants Among Patients With Hip Fracture Is Not an Indication to Delay Surgical Intervention. J Orthop Trauma. 2024 Mar 1;38(3):148-154. doi: 10.1097/BOT.0000000000002753.
  69. Sachdev D, Khalil L, Gendi K, Brand J, Cominos N, Xie V, Mehran N. Perioperative Management of Traditional and Direct Oral Anticoagulants in Hip Fracture Patients. Orthop Rev (Pavia). 2024 May 13;16:115605. doi: 10.52965/001c.115605.
  70. Weihs V, Humenberger M, Sturz G, Martin C, Pausch A, Duma A, Frossard M, Hajdu S. Early surgical fixation of proximal femur fractures under active direct oral anticoagulation (DOAC) therapy does not increase the postoperative blood loss. Results from a prospective cohort study with a matched-pair analysis. Arch Orthop Trauma Surg. 2025 Apr 12;145(1):243. doi: 10.1007/s00402-025-05870-4.
  71. Zhou X, Zhang C, Wang Y, Yu L, Yan M. Preoperative Acute Normovolemic Hemodilution for Minimizing Allogeneic Blood Transfusion: A Meta-Analysis. Anesth Analg. 2015 Dec;121(6):1443-55. doi: 10.1213/ANE.0000000000001010.
  72. Barile L, Fominskiy E, Di Tomasso N, Alpìzar Castro LE, Landoni G, De Luca M, Bignami E, Sala A, Zangrillo A, Monaco F. Acute Normovolemic Hemodilution Reduces Allogeneic Red Blood Cell Transfusion in Cardiac Surgery: A Systematic Review and Meta-analysis of Randomized Trials. Anesth Analg. 2017 Mar;124(3):743-752. doi: 10.1213/ANE.0000000000001609.
  73. De Araújo L, Garcia L. Acute Normovolemic Hemodilution: A Practical Approach. Open J Anesth. 2013 Jan;3(1):38-43. doi: 10.4236/ojanes.2013.31011.
  74. Martel G, Carrier FM, Wherrett C, Lenet T, Mallette K, Brousseau K, Monette L, Workneh A, Ruel M, Sabri E, Maddison H, Tokessy M, Wong PBY, Vandenbroucke-Menu F, Massicotte L, Chassé M, Collin Y, Perrault MA, Hamel-Perreault É, Park J, Lim S, Maltais V, Leung P, Gilbert RWD, Segedi M, Khalil JA, Bertens KA, Balaa FK, Ramsay T, Tinmouth A, Fergusson DA. Hypovolaemic phlebotomy in patients undergoing hepatic resection at higher risk of blood loss (PRICE-2): a randomised controlled trial. Lancet Gastroenterol Hepatol. 2025 Feb;10(2):114-124. doi: 10.1016/S2468-1253(24)00307-8.
  75. Kaufman M, Jahr JS, Klompas AM, Perelman S, Raphael J, Tan GM, Frank SM, Waters JH, Warner MA. Exploring Myths of Perioperative Autologous Red Blood Cell Salvage. Anesthesiology. 2025 Nov 1;143(5):1357-1370. doi: 10.1097/ALN.0000000000005586.
  76. Roberts I, Murphy MF, Moonesinghe R, Grocott MPW, Kalumbi C, Sayers R, Toh CH; UK Royal Colleges Tranexamic Acid in Surgery Implementation Group. Wider use of tranexamic acid to reduce surgical bleeding could benefit patients and health systems BMJ. 2024 Jun 12;385:e079444. doi: 10.1136/bmj-2024-079444.
  77. Prokopchuk-Gauk O, Shih A, Nahirniak S, Shabani-Rad MT, Pavenski K. NAC Statement on Fibrinogen Concentrate Use in Acquired Hypofibrinogenemia [Internet]. Ottawa: National Advisory Committee on Blood and Blood Products; 2014 Dec 15 [updated 2025 Feb 26; cited 2026 Feb 24] Available from: https://nacblood.ca/en/resource/nac-statement-fibrinogen-concentrate-use-acquired-hypofibrinogenemia 
  78. Shih A, Nahirniak S, Pavenski K, Prokopchuk-Gauk O, Shabani-Rad MT, Webert K. Recommendations for Use of Prothrombin Complex Concentrates in Canada [Internet]. Ottawa: National Advisory Committee on Blood and Blood Products; 2008 Sep 16 [updated 2023 Feb 21; cited 2026 Feb 24]. Available from: https://nacblood.ca/en/resource/recommendations-use-prothrombin-complex-concentrates-canada 
  79. Lin Y. Preoperative anemia screening clinics. Hematology Am Soc Hematol Educ Program 2019 Dec 6;2019(1):570-576. doi: 10.1182/hematology.2019000061.
  80. Ontario Nurse Transfusion Coordinators (ONTraC). Preoperative Hemoglobin Optimization and Anemia Management [Image on the Internet]. Ontario Transfusion Coordinators. 2007 [updated 2021; cited 2026 Feb]. Available from: https://www.ontracprogram.com/ckupload/files/103/Revised%20PBM%20algorithm%202021(6).pdf 
  81. Otten N. Technology Overview Issue 1: Economic Evaluation of Erythropoietin Use in Surgery [Internet]. Canadian Coordinating Office for Health Technology Assessment. 1998 Oct [cited 2026 Feb]. Available from: https://www.cda-amc.ca/sites/default/files/pdf/eposurgery_ov_e.pdf
  82. Inflation Calculator [Internet]. Bank of Canada. [cited 2026 Feb. Available from: https://www.bankofcanada.ca/rates/related/inflation-calculator/ 
  83. Spahn DR, Schoenrath F, Spahn GH, Seifert B, Stein P, Theusinger OM, Kaserer A, Hegemann I, Hofmann A, Maisano F, Falk V. Effect of ultra-short-term treatment of patients with iron deficiency or anemia undergoing cardiac surgery: a prospective randomized trial. Lancet. 2019 Jun 1;393(10187):2201-2212. doi: 10.1016/S0140-6736(18)32555-8.
  84. Rotin L, Mack J. Professional Education Chapter 2: Blood Components [Internet]. Canadian Blood Services; 2025 Apr 22 [cited 2026 Feb 24]. Available from: https://professionaleducation.blood.ca/en/transfusion/clinical-guide/blood-components
  85. Lagerquist O, Poseluzny D, Werstiuk G, Slomp J, Maier M, Nahirniak S, Clarke G. The cost of transfusing a unit of red blood cells: a costing model for Canadian hospital use. Vox Sang. 2017 Jun 5;12(3):375-380. doi: 10.1111/voxs.12355.
  86. Amin M, Fergusson D, Wilson K, Tinmouth A, Aziz A, Coyle D, Hébert P. The societal unit cost of allogenic red blood cells and red blood cell transfusion in Canada. Transfusion. 2004 Oct;44(10):1479-1486. doi: 10.1111/j.1537-2995.2004.04065.x.
  87. Alleyne M, Horne MK, Miller JL. Individualized treatment for iron-deficiency anemia in adults. Am J Med. 2008 Nov;121(11):943–948. doi: 10.1016/j.amjmed.2008.07.012.
  88. Moe S, Grill AK, Allan GM. Newer iron supplements for anemia. Can Fam Physician. 2019 Aug;65(8):556. PMID: 31413026
  89. Canada’s Drug Agency (previously Canadian Agency for Drugs and Technologies in Health – CADTH). CADTH Common Drug Review: Canadian Drug Expert Committee Recommendation Iron isomaltoside 1000 (Monoferric) [Internet]. Canada’s Drug Agency; 2020 Mar 27 [cited 2026 Feb]. Available from: https://www.cda-amc.ca/sites/default/files/cdr/complete/SR0622%20Monoferric%20-%20CDEC%20Final%20%20Recommendation%20March%2027%2C%202020%20for%20posting.pdf 
  90. Pharmacoeconomic Review Report: Iron Isomaltoside 1000 (Monoferric): (Pharmacosmos A/S): Indication: For the treatment of iron deficiency anemia in adult patients who have intolerance or unresponsiveness to oral iron therapy [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2020 May. Appendix 5, Reviewer Worksheets. Available from: https://www.ncbi.nlm.nih.gov/books/NBK564172/ 
  91. Cançado RD, de Figueiredo PO, Olivato MC, Chiattone CS. Efficacy and safety of intravenous iron sucrose in treating adults with iron deficiency anemia. Rev Bras Hematol Hemoter. 2011;33(6):439-443. doi:10.5581/1516-8484.20110119.
  92. Canada’s Drug Agency (previously Canadian Agency for Drugs and Technologies in Health – CADTH). Reimbursement Recommendation: Ferric Carboxymaltose (Ferinject) [Internet]. Can J Health Tech. 2025 May;5(5):1-40. Available from: https://www.cda-amc.ca/sites/default/files/DRR/2025/SR0852-Ferinject_FINAL_Recommendation.pdf
  93. Cortesi P, Mazzaglia G, Rethmeier L, Nottmeier M, EE254 A Cost-Utility Analysis of Ferric Derisomaltose Versus Ferric Carboxymaltose in Patients With Inflammatory Bowel Disease in Italy. Value in Health. 2022 Dec;25(12):S103. doi: 10.1016/j.jval.2022.09.502.
  94. Iqbal TH, Kennedy N, Dhar A, Ahmed W, Pollock RF. Cost-utility analysis of ferric derisomaltose versus ferric carboxymaltose in patients with inflammatory bowel disease and iron deficiency anemia in England. J Med Econ. 2024 Jan;27(1):392-403. doi: 10.1080/13696998.2024.2313932.
  95. Saskatchewan Drug Plan [Internet]. Government of Saskatchewan: Drug Plan and Extended Benefits Branch. 2026 [cited 2026 Feb]. Available from: https://formulary.drugplan.ehealthsask.ca/SearchFormulary/BG/706942 
  96. Janssen Inc. EPREX [product monograph]. Janssen Inc; 2017 Oct 18 [cited 2026 Feb]. available from: https://pdf.hres.ca/dpd_pm/00041771.PDF 
  97. Pantopoulos K. Oral iron supplementation: new formulations, old questions. Haematologica. 2024 Sep 1;109(9):2790-2801. doi: 10.3324/haematol.2024.284967.
  98. Rimon E, Kagansky N, Kagansky M, Mechnick L, Mashiah T, Namir M, Levy S. Are we giving too much iron? Low-dose iron therapy is effective in octogenarians. Am J Med. 2005 Oct;118(10):1142-7. doi: 10.1016/j.amjmed.2005.01.065.
  99. Stoffel NU, Cercamondi CI, Brittenham G, Zeder C, Geurts-Moespot AJ, Swinkels DW, Moretti D, Zimmermann MB. Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two open-label, randomised controlled trials. Lancet Haematol. 2017 Nov;4(11):e524-e533. doi: 10.1016/S2352-3026(17)30182-5.
  100. Düzen Oflas N, Demircioğlu S, Yıldırım Doğan N, Eker E, Kutlucan A, Doğan A, Aslan M, Demir C. Comparison of the effects of oral iron treatment every day and every other day in female patients with iron deficiency anaemia. Intern Med J. 2020 Jul;50(7):854-858. doi: 10.1111/imj.14766.
  101. Mehta S, Sharma BS, Gulati S, Sharma N, Goyal LK, Mehta S. A Prospective, Randomized, Interventional Study of Oral Iron Supplementation Comparing Daily Dose with Alternate Day Regimen Using Hepcidin as a Biomarker in Iron Deficiency Anemia. J Assoc Physicians India. 2020 May;68(5):39-41. PMID: 32610864.
  102. Kaundal R, Bhatia P, Jain A, Jain A, Nampoothiri RV, Mishra K, Jandial A, Goni D, Sandal R, Jindal N, Meshram A, Sharma R, Khaire N, Singh C, Khadwal A, Prakash G, Das R, Varma N, Varma S, Malhotra P, Lad DP. Randomized controlled trial of twice-daily versus alternate-day oral iron therapy in the treatment of iron-deficiency anemia. Ann Hematol. 2020 Jan;99(1):57-63. doi: 10.1007/s00277-019-03871-z.
  103. Kaynar LA, Gökçen S, Can F, Yeğin ZA, Özkurt ZN, Yağcı M. Comparison of daily oral iron replacement therapy with every other day treatment in female reproductive age patients with iron-deficiency anemia. Ann Hematol. 2022 Jul;101(7):1459–1464. doi: 10.1007/s00277-022-04835-6.
  104. Pasupathy E, Kandasamy R, Thomas K, Basheer A. Alternate day versus daily oral iron for treatment of iron deficiency anemia: a randomized controlled trial. Sci Rep. 2023 Feb 1;13(1):1818. doi: 10.1038/s41598-023-29034-9.
  105. Kinlin L, Talarico S, Kirby M, Parkin, P. A toddler with iron deficiency anemia unresponsive to oral iron treatment. CMAJ. 2020 Apr 14;192(15):E393-E396. doi: 10.1503/cmaj.191008.
  106. Powers JM, Buchanan GR, Adix L, Zhang S, Gao A, McCavit TL. Effect of Low-Dose Ferrous Sulfate vs Iron Polysaccharide Complex on Hemoglobin Concentration in Young Children With Nutritional Iron-Deficiency Anemia: A Randomized Clinical Trial. JAMA. 2017 Jun 13;317(22):2297-2304. doi: 10.1001/jama.2017.6846.
  107. Gupta A, Gandhi A, Vishwas K, Gupta-Baltazar K, Tu K. Comparative Study of Ferrous Fumarate, Ferrous Ascorbate, and Polysaccharide Iron for Treating Iron Deficiency Anemia in Adults. Can Prim Care Today. 2025 Aug 26;3(2):5-13. doi: 10.58931/cpct.2025.3243.
  108. Liu TC, Lin SF, Chang CS, Yang WC, Chen TP. Comparison of a combination ferrous fumarate product and a polysaccharide iron complex as oral treatments of iron deficiency anemia: a Taiwanese study. Int J Hematol. 2004 Dec;80(5):416-20. doi: 10.1532/ijh97.a10409.
  109. Li N, Zhao G, Wu W, Zhang M, Liu W, Chen Q, Wang X. The Efficacy and Safety of Vitamin C for Iron Supplementation in Adult Patients With Iron Deficiency Anemia: A Randomized Clinical Trial. JAMA Netw Open. 2020 Nov 2;3(11):e2023644. doi: 10.1001/jamanetworkopen.2020.23644.
  110. Tarng DC, Hung SC, Huang TP. Effect of intravenous ascorbic acid medication on serum levels of soluble transferrin receptor in hemodialysis patients. J Am Soc Nephrol. 2004 Sep;15(9):2486-93. doi: 10.1097/01.ASN.0000137884.59308.E7.
  111. Teucher B, Olivares M, Cori H. Enhancers of iron absorption: ascorbic acid and other organic acids. Int J Vitam Nutr Res. 2004 Nov;74(6):403-19. doi: 10.1024/0300-9831.74.6.403.
  112. Brune M, Rossander-Hulten L, Hallberg L, Gleerup A, Sandberg AS. Iron absorption from bread in humans: inhibiting effects of cereal fiber, phytate and inositol phosphates with different numbers of phosphate groups. J Nutr. 1991 Mar;122(3):442–449. doi: 10.1093/jn/122.3.442.
  113. Gillooly M, Bothwell TH, Torrance JD, MacPhail AP, Derman DP, Bezwoda WR, Mills W, Charlton RW, Mayet F. The effects of organic acids, phytates and polyphenols on the absorption of iron from vegetables. Br J Nutr. 1983 May;49(3):331–342. doi: 10.1079/bjn19830042.
  114. Hoppe M, Önning G, Berggren A, Hulthén L. Probiotic strain Lactobacillus plantarum 299v increases iron absorption from an iron-supplemented fruit drink: a double-isotope cross-over single-blind study in women of reproductive age. Br J Nutr. 2015 Oct 28;114(8):1195-202. doi: 10.1017/S000711451500241X.
  115. Yang Q, Jian J, Katz S, Abramson SB, Huang X. 17β-Estradiol inhibits iron hormone hepcidin through an estrogen responsive element half-site. Endocrinology. 2012 Jul;153(7):3170-8. doi: 10.1210/en.2011-2045.
  116. Hennigar SR, McClung JP, Hatch-McChesney A, Allen JT, Wilson MA, Carrigan CT, Murphy NE, Teien HK, Martini S, Gwin JA, Karl JP, Margolis LM, Pasiakos SM. Energy deficit increases hepcidin and exacerbates declines in dietary iron absorption following strenuous physical activity: a randomized-controlled cross-over trial. Am J Clin Nutr. 2021 Feb 2;113(2):359-369. doi: 10.1093/ajcn/nqaa289.
  117. Badenhorst CE, Dawson B, Cox GR, Laarakkers CM, Swinkels DW, Peeling P. Acute dietary carbohydrate manipulation and the subsequent inflammatory and hepcidin responses to exercise. Eur J Appl Physiol. 2015 Dec;115(12):2521-30. doi: 10.1007/s00421-015-3252-3.
  118. Brittenham GM. Short-term periods of strenuous physical activity lower iron absorption. Am J Clin Nutr. 2021 Feb 2;113(2):261-262. doi: 10.1093/ajcn/nqaa365.
  119. Skarpańska-Stejnborn A, Basta P, Trzeciak J, Szcześniak-Pilaczyńska Ł. Effect of intense physical exercise on hepcidin levels and selected parameters of iron metabolism in rowing athletes. Eur J Appl Physiol. 2015 Feb;115(2):345-51. doi: 10.1007/s00421-014-3018-3.
  120. Newlin MK, Williams S, McNamara T, Tjalsma H, Swinkels DW, Haymes EM. The effects of acute exercise bouts on hepcidin in women. Int J Sport Nutr Exerc Metab. 2012 Apr;22(2):79-88. doi: 10.1123/ijsnem.22.2.79.
  121. McCormick R, Moretti D, McKay AKA, Laarakkers CM, Vanswelm R, Trinder D, Cox GR, Zimmerman MB, Sim M, Goodman C, Dawson B, Peeling P. The Impact of Morning versus Afternoon Exercise on Iron Absorption in Athletes. Med Sci Sports Exerc. 2019 Oct;51(10):2147-2155. doi: 10.1249/MSS.0000000000002026.
  122. Barney DE, Ippolito JR, Berryman CE, Hennigar SR. A Prolonged Bout of Running Increases Hepcidin and Decreases Dietary Iron Absorption in Trained Female and Male Runners. J Nutr. 2022 Sep 6;152(9):2039-2047. doi: 10.1093/jn/nxac129.

Appendices

Appendix A: Table 1 & 2 Notes and Assumptions
Notes:

Table 1: Cost comparisons of anemia strategies

  • Increased hospital time, morbidity, and mortality associated with RBC transfusion are not considered in this table.
  • A change in Hb does not imply equal efficacy. One unit of transfused RBCs temporarily improves Hb levels, but suppresses endogenous erythropoiesis, and cells are broken down more rapidly than endogenous cells. Conversely, endogenous RBCs produced with appropriate supplementation are expected to have a normal lifespan.
  • Comparison of epoetin dosing on an accelerated daily schedule near the time of operation versus the weekly schedule for one month pre-operatively underscores the need for system design to allow for early intervention. Anemia management is more cost effective with six-week pre-operative planning. However, even a single dose of epoetin may be adequate to prevent the need for transfusion.83

Table 2: Inflation cost of erythropoietin

  • While orthopaedic surgery is close to meeting the quality-adjusted life years cutoff defined in the 1998 Economic Evaluation of Erythropoietin Use in Surgery report,81 cardiovascular surgery has already met the cutoff, moreover the cost increase of RBCs (123%) is nearly double that of the cost increase of 20,000 units of epoetin (67%).
  • All dollar ($) values given are CAD.

 

Assumptions (Table 1 only):

General

  • All dollar ($) values given are CAD.
  • Unless otherwise indicated in the sections below, the cost of:
    • Infusion chair time per minute = $0.71.
    • Nurse time per hour = $37.00.
    • Laboratory testing per infusion treatment cycle = $28.47.
    • Infusion set-up per infusion = $7.94.

Regarding red blood cells:

  • Cost per one unit of RBCs was provided by Canadian Blood Services.
  • One transfused unit of RBC raises Hb levels by 10g/L.84
  • Additional costs of RBC administration in Canada have been estimated to total $243.10,85 however these costs may be higher (up to $522.78).86 To keep comparisons similar, the total additional costs for RBC administration was calculated as follows: $243.10+(120min×$0.71)=$328.30

Regarding oral iron salts (ferrous sulphate, ferrous fumarate):

  • Cost per dose of iron salts was provided by a local pharmacy in Saskatchewan and is between $0.17-$0.28. The total acquisition cost was determined using the higher cost in this range and the duration of therapy is 20 weeks (14 weeks to improve Hb levels and an additional 6 weeks for iron stores).
  • Anemia treatment with oral iron salts raises Hb levels by 28g/L.87,88

Regarding IV iron (iron sucrose, ferric derisomaltose, ferric carboxymaltose):

  • There is 100mg of iron present in 200mL of whole blood, which equates to 30g Hb; in a 70kg adult with a blood volume of 70mL/kg, this rise equates to a 6.1g/L increase in Hb per 100mg of iron administered, but the effects are not linear.
  • Additional costs for administration of each IV iron were calculated based off Canada’s Drug Agency’s Pharmacoeconomics Review,89 specifically Table 10 of Appendix 5,90 which considers further cost details such as the amount of attention required of nursing staff per type of infusion. Each was calculated taking into account nursing, infusion set-up, chair time and laboratory testing costs.
  • The increase of Hb levels after the completion of therapy is between 32.9 45.8g/L.91 The average, 39g/L increase in Hb, was used.
  • Iron sucrose:
    •  Per Canada’s Drug Agency, the cost of iron sucrose is $37.50/100mg.89
  • Ferric derisomaltose:
    • Per Canada’s Drug Agency, the cost of ferric derisomaltose (referred to as iron isomaltoside by Canada’s Drug Agency) is $45.00/100mg.89
  • Ferric carboxymaltose:
    • Cost of ferric carboxymaltose was provided by Canada’s Drug Agency Reimbursement Recommendation.92
    • The total dose for ferric carboxymaltose is 1200mg, but the maximum dose at one time is 1000mg resulting in two required visits. The first visit is approximately one hour in length, and the second is shorter.
    • For anemia treatment with ferric carboxymaltose there’s significantly higher risk of hypophosphatemia.93,94 To account for the cost of hypophosphatemia treatment, $272 was included in the additional cost calculation for ferric carboxymaltose. This was based off an Italian review that found that the costs for hypophosphatemia treatment and follow up to be €169 (approximately $272 at the time of writing) per patient treated with ferric carboxymaltose.93 Additionally, a British review found that hypophosphatemia treatment and follow up to be £226 (approximately $414 at the time of writing).94 A formal Canadian review has not been done, and Canada’s Drug Agency did not evaluate this risk in their review.

Regarding epoetin alfa:

  • Cost of epoetin alfa as per the Saskatchewan Drug Formulary is $14.25/1000U up to 20,000 units, and $12.17/1000U for 40,000 units.95
  • Additional costs of epoetin alfa were calculated based off 30 minutes of nursing time and one minute of chair time per dose administered.
  • Change in Hb in healthy patients is 31g/L with the dosing schedule of either 150U/kg three times/week or 40,000U/week.96
  • Change in Hb in pre-operative orthopedics is 14.4g/L on average using 600U/kg/week and 7.3g/L on average using 300U/kg for 10 days pre-operatively, and 4 days post operatively.96
     
Appendix B: Improving Iron Absorption

Oral iron salts:

  •  Oral iron salts (gluconate, sulfate, fumarate, ascorbate, bisglycinate) are first line choices due to low cost and good efficacy.97
  • Using a lower dose iron salt (40mg elemental iron or less) may reduce side effects compared to higher dose iron salts. In octogenarians, 15mg elemental iron is adequate given enough time.98
  • Given twice the length of time, every other day dosing of an iron salt is as effective at correcting iron deficiency anemia as daily dosing.99-104

Comparisons to other oral iron supplements:

  •  Iron polysaccharide claims to have better gastrointestinal tolerance but has vastly inferior results at resolving iron deficiency anemia.97 Gastrointestinal effects are similar or higher in some randomized control trials for iron polysaccharides.
  • There is one case report involving a toddler with severe iron deficiency anemia where switching from Feramax (an iron polysaccharide) to Palafer (oral iron salt ferrous fumarate) resolved her anemia.105
  • Comparative studies have been done with the following results:
    • NovaFerrum (iron polysaccharide) versus ferrous sulfate (oral iron salt): iron deficiency anemia resolution 6% versus 29%.106
    • Feramax (iron polysaccharide) versus ferrous fumarate (oral iron salt) versus ferrous ascorbate (oral iron salt): Hb change 3.56g/L versus 11.59g/L versus 17.14g/L.107
    • Niferex (iron polysaccharide) versus ferrous fumarate (oral iron salt): Hb change 6g/L versus 28.4g/L.108
  • For dietary iron, heme iron is better absorbed (such as liver; 15-35% bioavailability) than non-heme iron (such as spinach; 1.4-7% bioavailability).97

Facilitators of iron absorption:

  •  The addition of vitamin C to iron salts does not improve iron absorption when ferritin is low,109 but may facilitate iron utilization in the body especially when inflammation is present.110 It may also improve absorption when higher levels of inhibitors (phytates, etc.) are present.111
    • Vitamin C aids in the conversion of ferric iron (Fe3+) to ferrous iron (Fe2+). Ferric iron is found in plants, but most iron supplements contain ferrous iron which is why no change is observed when adding vitamin C to iron salts. The addition of vitamin C may increase uptake in those who are strict vegetarians who do not take iron salts or in those who only supplement with “plant-based iron” such as Floradix.
  • Additional nutrients present in food (especially heme sources such as vitamin A, zinc, copper, protein, and magnesium) may facilitate improved absorption.112,113
  • Fermented foods increase iron absorption.114
  • Lactobacillus plantarum (and Bifidobacterium lactis) as a probiotic supplement improves absorption and reduces gastrointestinal side effects.114
  • Estrogen supplementation decreases hepcidin and may improve iron absorption.115

Inhibitors of iron absorption:

  • Concomitantly consuming calcium, tea, coffee, eggs, soy, antacid/proton pump inhibitors, or foods high in phytates or oxalates (some vegetables and grains) decreases iron absorption.
  • Energy (calorie) restriction and/or low carbohydrate diets decrease iron absorption.116,117
  • Strenuous exercise (VO2 max or equivalent training to failure) increases inflammation (and Interleukin-6 and hepcidin) and may interfere with iron absorption.118-120 The timing in relation to exercise and time of day shows that iron is best absorbed in the morning and very shortly after exercise (hepcidin peaks three to six hours after exercise).121 One hour of running has half the hepcidin elevation as two hours of running.122
Appendix C: Previous Authors
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2026-06-23 Appendix C - Previous Authors