Severe Iron Deficiency Anemia: Red blood cell transfusion or intravenous iron?

Iron deficiency (ID) is considered to affect two billion people worldwide¹ and iron deficiency anemia (IDA) remains the common cause of anemia in both economically developed and underdeveloped countries.^2,3 Groups at risk for ID and IDA are preschool children, adolescents, especially female, females during the reproductive years, pregnant females and the elderly. The mechanisms of IDA differ between developed and underdeveloped countries and between the groups at risk in developed countries. More details on these aspects are available elsewhere.^4–9 IDA can be determined by standard laboratory testing¹⁰ and the extent of the iron deficit measured using the Ganzoni formula (iron deficit (mg) = patient weight (Kg) × (target – actual hemoglobin) × 2.4 + 500) or a derivative of this formula.¹² It needs to be emphasized that IDA is not a diagnosis but rather a secondary manifestation of the presence of an underlying abnormality, the cause of which needs also to be elucidated.¹³ Treatment needs to be directed at both iron repletion and correction of the causative abnormality.

Severe IDA has no clear threshold hemoglobin and may or may not be associated with the classic features of anemia such as fatigue and pallor. Severe IDA, however, is relevant to Transfusion Medicine since it raises the specter of using allogeneic red blood cells as the source of iron repletion. A unit of red blood cells supplies between 150–200 mg of elemental iron but also hemoglobin allowing, in principle, a more rapid correction of microvascular hypoxemia. For this reason, red blood cell transfusion is commonly administered when patients with severe IDA present with angina, neurologic symptoms, clinical features indicative of heart failure or are hemodynamically unstable. The use of red blood cells in some of these scenarios may paradoxically be detrimental.^14–16

An alternative approach is to treat patients with severe IDA with intravenous iron.¹⁷ Several preparations of intravenous iron are available. Historically, there was a reluctance to use iron dextran formulations because of concerns regarding hypersensitivity reactions, particularly anaphylaxis. The newer preparations are far less likely to be associated with such reactions,¹⁸ if at all. Several formulations are available in the US. In terms of elemental iron, Iron sucrose (Venofer®) can provide 300mg per single infusion over 60 minutes; ferric gluconate (Ferlecit®) 250 mg over 60 minutes; low molecular weight iron dextran (INFeD®) 1000mg over 4 hours; ferumoxytol (Feraheme®) 510 mg over 60 minutes and ferric carboxymaltose (Injectafer®) 750 mg over 15 minutes. Thus, both the maximum amount of iron repletion and the minimum duration of infusion differs between preparations. It would seem preferable to use those preparations which can deliver a higher dose per infusion over the shortest time period, but not unexpectedly, such preparations are more costly on a per mg elemental iron infused basis. General unfamiliarity with these newer preparations, the historical concern regarding anapylactoid reactions and problems with commercial insurance reimbursement have been barriers to the more widespread use of these agents in the treatment of severe IDA. Physicians have defaulted to prescribing red blood cells, a more familiar product. However, red blood cells carry the risk of Transfusion Associated Circulatory Overload (TACO),¹⁹ hemolysis,²⁰ alloimmunization²¹ and transfusion related acute lung injury²² and overall represent a less safe alternative. The devil you know may not be better than the devil you know less well!

In this issue of Transfusion, Khadadah, et al provides an interesting report regarding the use of interventions targeted to the Emergency Department (ED) to reduce the use of red blood cell transfusion in the management of severe IDA and substitute with intravenous iron. This is a niche area of Patient Blood Management (PBM). The input interventions included ED physician education, development of an algorithm on IDA management in the ED and availability of a Transfusion Specialist for consultation. The algorithm (Figure 1) is particularly well thought out and should be generalizable to other institutions. The primary output measure was the percentage of patients with IDA who were appropriately managed based on the algorithm. They observed an improvement from 53% in the preintervention period to over 80% during the intervention period and an associated increased monthly use of intravenous iron from one dose administered in the 3 month preintervention period to between 2.6 and 4.7 doses per month in the intervention period. Of note, iron sucrose was the intravenous iron preparation available in the preintervention period and ferumoxytol became available 3 months into the intervention period. This latter formulation is capable of providing a far greater dose of iron per infusion (vide supra). Two reactions were observed: one patient receiving red blood cells had TACO and a second patient who received intravenous iron had a syncopal episode attributed to the infusion. There was a clear bias for the ED physician to transfuse red cells in the context of gastrointestinal bleeding. Younger female patients who presented with IDA caused by heavy menstrual bleeding were well represented in the intravenous iron only group which is particularly gratifying in that red cell transfusion was avoided with its potential for alloimmunization.²¹ The only concern regarding this report is the lack of short term and longer term follow up of the cohorts. In particular, younger females with severe IDA associated with heavy menstrual bleeding should be evaluated for von Willebrand’s disease²³ or at least considered candidates for empiric tranexamic acid which has been shown to reduced menstrual blood loss in this population.²⁴

This report is also another good illustration of what Transfusion Medicine Specialists can achieve when intra-institutional transfusion practices are examined and prescribing physicians educated and actively engaged.²⁵ Transfusion Service Directors need to discourage poor transfusion practices as part of a PBM program and shift the intra-institutional culture to transfusion avoidance, where appropriate.²⁶ This can substantially impact the volume of red blood cells transfused,^27–30 and the safest blood remains the unit which is never transfused.