REVIEW ARTICLE

Acta Haematologica Polonica 2022

Number 4, Volume 53, pages 249–257

DOI: 10.5603/AHP.a2022.0016

ISSN 0001–5814

e-ISSN 2300–7117

Anemia of critical illness: a narrative review

Piotr F. Czempik●iD*Łukasz J. Krzych●iD
Department of Anesthesiology and Intensive Care, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Katowice, Poland

*Address for correspondence: Piotr F. Czempik, Department
of Anesthesiology and Intensive Care, Faculty of Medical Sciences
in Katowice, Medical University of Silesia, Medyków 14, 40–752 Katowice,
Poland, e-mail: pczempik@sum.edu.pl

Received: 09.02.2022 Accepted: 09.04.2022

Abstract
The prevalence of anemia in patients admitted to the intensive care unit (ICU) reaches 66%. Moreover, numerous patients develop anemia during ICU hospitalization. In fact, anemia is the most common hematologic disease in the ICU.
The majority of patients hospitalized in the ICU present with acute systemic inflammation, so called systemic inflammatory response syndrome (SIRS). These patients may develop anemia of inflammation (AI). In crtitically ill patients AI may present acutely (acute systemic inflammation) or chronically (comorbidities associated with prolonged systemic inflammation), here we describe both presentations of AI as ‘anemia of critical illness’ (ACI). The second most frequent type of anemia in critically ill patients is iron-deficiency anemia (IDA). A mixed type of anemia (ACI + IDA) may also be present in these patients.
The three major pathophysiological mechanisms leading to ACI are: iron restriction, decreased erythropoiesis, and decreased erythrocyte lifespan. Cytokines synthesized during SIRS induce the production of hepcidin that inhibits the only transmembrane iron exporter (ferroportin) present in the duodenum and macrophages.
Etiological classification of anemia in critically ill patients poses a significant challenge to clinicians, as there is a multitude of tests available, and there are various reference ranges for these tests reported in the literature in the patient population in question. Pure ACI or mixed ACI + IDA can be diagnosed using a single laboratory test — complete blood count with analysis of reticulocytes — which provides Hb concentration in erythrocyte and reticulocyte.
The management of ACI incorporates discontinuation with erythropoiesis-stimulating agent causing anemia, reduction of iatrogenic blood loss, parenteral iron, and combined therapy of parenteral iron with erythropoiesis-stimulating agents in approved indications.
Key words: anemia of inflammation, anemia of critical illness, critically ill patients, hepcidin, iron-deficiency anemia, intensive care unit, reticulocyte hemoglobin equivalent
Acta Haematologica Polonica 2022; 53, 4: 249–257

Introduction

The prevalence of anemia in patients admitted to the intensive care unit (ICU) reaches 60–66% [1, 2]. Moreover, numerous patients develop anemia during ICU hospitalization, which is caused by disease processes, but may also be iatrogenic (e.g. phlebotomy, extracorporeal treatment procedures). By day 3 of ICU hospitalization, up to 90% of patients are anemic [3]. Lower hemoglobin (Hb) concentrations are associated with higher mortality rates and longer stays in the ICU, and in hospital in general [4].

The majority of patients hospitalized in the ICU present with acute systemic inflammation (SI), so called systemic inflammatory response syndrome (SIRS). These patients may develop anemia of inflammation (AI). AI, previously known as anemia of chronic disease (ACD), is also the most common type of anemia in hospitalized chronically ill patients [5] and may be present in the following conditions: infection, autoimmune disease [6], cancer [7], chronic kidney disease (CKD), congestive heart failure, chronic obstructive pulmonary disease, pulmonary arterial hypertension, chronic liver disease, obesity, advanced atherosclerosis, and old age [8]. The prevalence of AI in different chronic conditions is presented in Table I [7, 9–14]. Patients with the aforementioned diseases are frequently hospitalized in the ICU. These factors make AI the most common type of anemia in critically ill patients [15]. In critically ill patients AI can present acutely (acute systemic inflammation) or chronically (comorbidities associated with prolonged systemic inflammation), so we decided to call both presentations of AI in critically ill patients ‘anemia of critical illness’ (ACI). The second most frequent type of anemia in critically ill patients is iron-deficiency anemia (IDA). A mixed type of anemia (ACI + IDA) may also be present in these patients.

Table I. Prevalence of anemia of inflammation in chronic conditions

Study

Year

Patient population

Anemia [%]

Birgegård et al. [9]

2006

Cancer (lymphoma + multiple myeloma)

72.9

Macciò et al. [7]

2015

Cancer (solid tumors)

63

Ambrosy et al. [10]

2019

Heart failure

57.1

Coiffier et al. [11]

2001

Cancer (chemotherapy)

54.1

Gaskell et al. [12]

2008

Older people (>65 years)

17-47

St Peter et al. [13]

2018

Chronic kidney disease (dialysis)

6.7–22.2

Boutou et al. [14]

2013

Chronic obstructive pulmonary disease

15.6

Moreover, deficiency of vitamin B12, folic acid, and vitamin D, may also be present in critically ill patients.

The aim of this work was to summarize the current know­ledge on the pathophysiology, diagnosis, and management of ACI, and to present our perspectives on this important topic.

Pathophysiology

There are three major pathophysiological mechanisms leading to ACI: iron restriction, decreased erythropoiesis, and decreased erythrocyte lifespan.

Iron-restricted erythropoiesis

The activation of immune cells leads to synthesis of cytokines. The most important here are interleukin (IL) 6 and 1β as they induce the production of hepcidin in the liver, which is the master regulator of the iron metabolism [16]. Hepcidin is a 25-amino acid protein that exerts its effects by inhibiting the only transmembrane iron exporter — ferroportin, either through internalization [17] or direct occlusion [18]. These ILs also decrease production of the only iron-transporting protein — transferrin. Bacterial lipopolysaccharide (LPS) and interferon gamma (IFN-γ) also block the transcription of ferroportin [19]. Ferroportin is present in the duodenum where dietary iron is absorbed, and in macrophages from where over 90% of daily iron comes from. All these mechanisms lead to iron-restricted erythropoiesis (IRE) and its typical laboratory profile: low iron, low transferrin, and high ferritin.

Decreased erythropoiesis

This effect is mainly caused by decreased erythropoietin (EPO) production. EPO is produced by fibroblasts in the renal cortex. Decreased EPO is caused by the negative effect of IL-1 and tumor necrosis factor alpha (TNF-α) on EPO expression [20], and decreased erythropoietin biological activity caused by IL-1 and IL-6 [21]. Erythropoietin is responsible for proliferation and differentiation of erythrone and induces erythroferrone that inhibits hepcidin synthesis. Numerous cytokines (mainly IFN-γ) induce apoptosis of erythroid progenitor cells in the stem.

Decreased erythrocyte lifespan

This effect is caused by: enhanced phagocytosis by hepatic and splenic macrophages caused by deposition of antibody and complement on erythrocytes, activation of macrophages, and mechanical damage from fibrin deposits in microvasculature [22]. An overview of the pathophysiology of AI is presented in Figure 1 [23]. The organs involved are the bone marrow, liver, duodenum and kidneys, the most important regulator being hepcidin.

Czempik_01.jpg
Figure 1. Pathophysiology of anemia of inflammation [‘Pathophysiology of anemia of inflammation (created with Biorender)’ by Lanser et al. (no modification), available at: https://doi.org/10.3390/nu13113732, under licence CC BY 4.0]

There can be other causes of anemia in critically ill patients, including mineral (iron) and vitamin (vitamin B12, folic acid, vitamin D) deficiency. Iron deficiency (ID) leads to impaired erythropoiesis, vitamin B12 and folic acid deficiency (megaloblastic anemia) leads to impaired erythropoiesis and hemolysis, and vitamin D increases hepcidin concentration leading to even greater IRE.

Etiological classification of anemia

The World Health Organization defines anemia as a condition in which the number of erythrocytes, or their oxygen-carrying capacity, is insufficient to meet the body’s physiological needs [24]. The diagnostic criterion for anemia is a Hb concentration <12 g/dL for women and <13 g/dL for men. In clinical scenarios with potential blood loss (e.g. the perioperative period), there is a consensus to use a Hb cut-off value of <13 g/dL for both sexes, as women have lower blood volumes, yet bleed as much as men [25, 26].

Exclusion of nutrient deficiencies

ACI is a diagnosis of exclusion, so as a first step other causative/contributory factors of anemia ought to be excluded. These include at least mineral (iron) and vitamin (vitamin B12, folic acid, vitamin D) deficiencies, as these can be easily remedied.

The order of laboratory tests in diagnosis of ACI is presented below.

Erythrocyte parameters

Complete blood count (CBC) is the first line test to diagnose anemia. It is the only test that should be used to precisely determine Hb concentration. Assessment of Hb concentration, both in capillary blood [27, 28] and non-invasively [28], is not accurate and should be avoided. Anemia of critical illness typically presents as normocytic and normochromic anemia, IDA as microcytic and hypochromic anemia, and megaloblastic as macrocytic and normochromic anemia, however analysis of erythrocyte indices is not conclusive. Low mean cell volume (MCV), mean cell hemoglobin (MCH), and mean cell hemoglobin concentration (MCHC) can be seen in thalassemias, however these conditions are quite rare and their prevalence varies by geographical region. MCV has been found to be within a reference range in up to 40% of patients with ID or mixed hematinic deficiency [29]. MCV is affected by pre-analytical factors such as sample temperature or storage time [30]. To conclude, in the absence of thalassemia, low MCV, MCH or MCHC suggest ID, whereas their normal values do not exclude ID. CBC should be the first test for screening and preliminary classification of anemia [26].

Reticulocytes

A decreased number of reticulocytes is present in ACI, IDA, megaloblastic anemia, and bone marrow aplasia/hypoplasia. An increased number is present in hemolysis, polycythemia, hemorrhage, and when hematopoietic agents are used.

Reticulocyte Hb content

The name of the test varies with the analyzer: reticulocyte Hb equivalent — Ret-He (Sysmex XE/XN), mean reticulocyte Hb content — MCHr (Abbott Sapphire), reticulocyte Hb equivalent — RHE (Mindray BC6800), and reticulocyte Hb content calculated — RHCc (ABX-Horiba Petra) [31]. Reticulocytes circulate in the peripheral blood for 1–2 days and then they mature into erythrocytes. Determination of reticulocyte Hb shows if there is enough iron available for erythropoiesis at the time. Due to the short lifespan of reticulocytes, these parameters change within a few days and can be used to monitor iron availability and treatment progress. In patients with CKD, CHr can predict response to iron even when ferritin is increased as high as 800 µg/L [32]. Patients with sepsis or septic shock with serum ferritin even above 800 µg/L with low Ret-He, can positively respond to parenteral iron (unpublished data, clinicaltrials.gov identifier: NCT05217836). The Ret-He test was introduced in 2005. This test generally is rapid, convenient and cost-effective. It has been used to identify IDA in inflammatory conditions: rheumatoid arthritis [33], cancer [34], chronic disease [35], and gastroenterological disease [36]. CHr cannot distinguish IDA from thalassemia; however, in populations with a low prevalence of thalassemia, the Mentzer index may be used to identify thalassemia [37]. The Mentzer index is calculated by dividing MCV by RBC, with a value <13 suggesting thalassemia with a sensitivity of 98% [38]. Different cut-off values of reticulocyte Hb have been proposed for diagosis of IDA: 25 pg [39], 28 pg [40], 29 pg [32], and 30 pg [41, 36]. The current guidelines recommend a cut-off value of 29 pg in adults (excluding pregnancy) and children, until further data is available [42].

Iron studies (iron, transferrin, transferrin saturation, ferritin)

Serum iron determination is required for the calculation of transferrin saturation (TSAT) and, due to high diurnal variability, should not be measured in isolation. Transferrin concentration variability is lower than for iron. Nevertheless, transferrin synthesis is impaired in malnutrition and chronic disease, therefore specificity of transferrin in diagnosis of ID remains inadequate. TSAT is the ratio of serum iron to transferrin. ACI presents as low iron, transferrin and variable TSAT. IDA presents as low iron, increased transferrin, and low TSAT. The most useful differentiating parameter here is serum ferritin. Whereas a ferritin level <30 µg/L signifies typical IDA, ferritin 30–100 µg/L and TSAT <20% may suggest ID. Patients with ACI may present with normal or increased ferritin levels (>100 µg/L); the degree of elevation depends on the underlying condition. With ferritin >100 µg/L and TSAT >20%, we still cannot be sure if there is ID accompanying ACI [43]. Ferritin and transferrin are acute response proteins, and therefore they lose their diagnostic utility in the critically ill. Ferritin and transferrin saturation cannot be used for a precise diagnosis of absolute (ACI + IDA) or functional (ACI) ID in critically ill patients [44]. A wide range (20–85%) of patients with AI have absolute ID (AI + IDA) which may be caused by bleeding episodes related/unrelated to primary diagnosis and/or iatrogenic blood loss, mainly associated with laboratory sampling or extracorporeal procedures [45].

Hepcidin

As hepcidin is the master regulator of iron metabolism, its concentration may be useful to discriminate between IDA and AI. In AI, there is increased concentration of hepcidin, whereas in IDA its concentration is low. There is variation in hepcidin concentration depending on fasting status, circadian rhythm, and the time of the day [46]. Moreover, renal function influences hepcidin concentration, as hepcidin is also produced by the kidneys and clearance of hepcidin is through the kidneys [47]. There are different hepcidin assays available. Mass-spectrometry and radioimmunoassays are specific, but lack adequate sensitivity [48]. Enzyme-linked immunosorbent assays (ELISA) seem to overcome these problems and are more widely available. Although serum hepcidin may help differentiate AI from AI + IDA, for a precise diagnosis it should be combined with biochemical markers (ferritin) [49] or hematological indices (CHr) [33]. Hepcidin and Ret-He are used in a two-step diagnostic pathway in gastroenterology in- and outpatients. Based on hepcidin concentration, anemia has been classified as IDA (low hepcidin <6 ng/mL), IDA and/or AI (normal hepcidin 6–46 ng/mL), or AI (high hepcidin >46 ng/mL). Then, in the second mixed group, Ret-He was determined and further differentiation into IDA (Ret-He <30 pg) or AI (Ret-He >30 pg) was possible [36]. Hepcidin cannot be used for a preliminary differentiation between AI and AI + IDA in dialysis patients because its level is increased due to impaired renal excretion [50]. Moreover, hepcidin can be used to predict response to oral iron in patients with IDA [51, 52]. There have been no studies using hepcidin to identify ID in critically ill patients. This interesting topic deserves further investigation in a prospective clinical manner (clinicaltrials.gov identifier: NCT05217836).

Other tests used in anemia diagnostics are presented in Table II.

Table II. Other laboratory tests in anemia diagnostics

Laboratory test

Definition

Usefulness

Limitations

Percentage of hypochromic erythrocytes (%HypoHe)

Percentage of erythrocytes with Hb content ≤17 pg (subpopulation of mature erythrocytes with insufficient iron content)

Used to identify absolute ID in patients with AI (AI + IDA) with a cut-off value of 1.8% [35]

Relates to iron status in last three months, does not reflect acute changes in iron availability

Percentage of microcytic erythrocytes (% MicroR)

Percentage of erythrocytes with MCV <60 fL (subpopulation of mature erythrocytes with insufficient iron content)

Can be used to identify IDA in patients with AI with a cut-off value of <25.0% [35]

This parameter does not reflect acute changes in iron availability

Zinc protoporphyrin (ZPP)

Lack of iron leads to incorporation of zinc into porphyrin during hemosynthesis

Not recommended for diagnosis of ID (IIB) [42]

Limitations due to measurement technique (hyperbilirubinemia; CKD); false increase with Hb <100 g/L

Soluble transferrin receptor (sTfR)

Elevated concentration in majority of IDA and AI + IDA, within reference range in pure AI, decreased sTfR provides reliable diagnosis of IDA

Not recommended to identify ID [42]

Increased concentration may be associated with hemolytic anemia, deficiency of vitamin B12 or folic acid, hematological malignancies; confounded by inflammation — several cytokines affect sTfR levels independently of iron status

Ferritin index

Calculated as sTfR/log ferritin

Some discrimination between AI (<1) and AI + IDA (>2) [53]

Overlap between values

Management of anemia of critical illness

The best treatment for ACI would be resolution of the primary condition that led to ACI. Disease-specific treatments can correct anemia in certain conditions, e.g. anti-TNF agents in inflammatory bowel disease [54] or rheumatoid arthritis [55].

Parenteral iron

It is imperative to identify patients who are iron-deficient because these patients would benefit from iron supplementation. Indiscriminate use of iron supplementation should not be used because mild anemia and ID may be beneficial in patients with infectious diseases [56]. The contraindications for parenteral iron, according to the manufacturers, include: hypersensitivity, decompensated cirrhosis and/or hepatitis, and acute or chronic infection. This latter contraindication is questionable, as causative anemia treatment is recommended by numerous organizations (e.g. British Society of Gastroenterology, American Gastroenterological Association, National Blood Authority Australia), and transfusion of allogeneic erythrocytes leads to increased morbidity and mortality, including sepsis and infection [57, 58]. Increased risk of infection with parenteral iron remains a theoretical threat unsupported by studies [59]. Parenteral iron has been shown to successfully correct ID in different populations of AI patients [60]. There have been calls to revise approval for parenteral iron and widen its indications [61]. The parenteral iron formulations available in Poland are set out in Table III. Different doses of these formulations have been used in critically ill patients: iron sucrose 100 mg three times per week [62], iron sucrose 1,000 mg (single dose) [63], ferric carboxymaltose 500 mg once every five days [64], and ferric carboxymaltose 1,500 mg (single dose) [63]. In the setting of infection, divided doses (e.g. 200 mg) as opposed to single total doses of intravenous iron, should be preferred.

Table III. Parenteral iron formulations available in Poland

Iron formulation

Pharmacological agent

Brand name (manufacturer)

Iron-carbohydrate

Ferric gluconate

No i.v. agent available

Iron(III)-hydroxide sucrose complex

Venofer® (Vifor)

Iron(III)-hydroxide dextran complex

CosmoFer® (Pharmacosmos)

Ferrum Lek® (Sandoz)

Glycan-
-coated

Iron(III)-hydroxide carboxymaltose complex

Ferinject® (Vifor)

Iron(III)-derisomaltose

Diafer® (Pharmacosmos)

Monover® (Pharmacosmos)

Ferumoxytol

No i.v. agent available

Agents affecting erythropoietin and proinflammatory cytokines

Higher mortality with erythropoiesis-stimulating agents (ESA) has been reported in cancer patients [65], in dialysis patients not responding to ESA [66], and in pre-dialysis patients [67]. The official approval for ESA in the European Union market is for preoperative autologous donation, pre-dialysis/dialysis end stage CKD, and chemotherapy-induced anemia. There are calls to revise the approval for ESA and widen its indications, as commonly reported complications may in fact be attributable to other factors [68]. Hypoxia-inducible factors stabilizers (prolyl hydroxylase inhibitors) (clinical trials) act through endogenous erythropoietin formation and iron delivery from enterocytes and macrophages, and may be a viable therapeutic option in AI [69].

Allogeneic red blood cell transfusion

Red blood cell (RBC) transfusion is an allogeneic tissue transplantation and should be viewed as a treatment of last resort in anemic critically ill patients. It is associated with multiple complications: sepsis, infection, multi-organ dysfunction, thromboembolic events, cardiac events, respiratory failure, acute kidney injury, and prolonged hospitalization [58]. RBC transfusion at a restrictive Hb threshold is safe and potentially reduces in-hospital mortality in critically ill adults compared to a liberal strategy (transfusion at Hb <7 g/dL vs. <9 g/dL) [70]. As transfusion of RBC at restrictive triggers still may not improve oxygen delivery in some patients, and may in fact be deleterious, so called ‘physiological transfusion triggers’ have started to be used in RBC transfusion decision making [71]. Even elderly patients may tolerate very low Hb concentrations [72].

Direct hepcidin inhibitors and agents preventing binding of hepcidin to ferroportin (clinical trials)

These agents may act through different mechanisms: inhibition of hepcidin production, neutralization of circulating hepcidin, protection of ferroportin from hepcidin inhibition, and inhibition of hepcidin-inducing signals (e.g. IL-6) [73].

Potential role of erythroferrone (pre-clinical investigation)

Erythroferrone (ERFE) inhibits liver hepcidin synthesis during stress erythropoiesis, ensuring sufficient iron supply for bone marrow erythroblasts, and therefore ERFE has been suggested to protect against AI [74]. Some experimental research has confirmed the inhibitory effect of ERFE on hepcidin [75], however the inhibitory effect of ERFE on hepcidin was not evident in a population of rheumatoid arthritis patients [76].

Contributory factors

It is wise to correct modifiable patient factors contributing to anemia. Vitamin deficiencies should be replenished: vitamin B12, folic acid, and vitamin D. However, we must remember that vitamin deficiencies are rare in patients hospitalized in the ICU: in one study only 2% of patients had a vitamin B12 deficiency and another 2% had a folic acid deficiency [77], while in another study 2.4% of surgical patients had a vitamin B12/folic acid deficiency [26]. If possible, pharmacological agents leading to anemia should be discontinued: nonsteroidal anti-inflammatory drugs, antiplatelet agents, heparins, angiotensin-converting enzyme inhibitors, proton pump inhibitors, neuroleptics, penicillin derivatives (e.g. piperacillin), cephalosporins (e.g. ceftriaxone), and trimethoprim-sulphametoxazole [78, 79].

Iatrogenic blood loss (e.g. phlebotomy, stress-related gastrointestinal bleeding) is an important factor in the ICU and should be minimized. Phlebotomy blood loss can be reduced by ordering fewer laboratory tests (only tests that potentially could change the clinical management of patients) [80], by using low-volume sampling tubes [81], by drawing the minimum amount of blood for a particular test, by applying in-line blood conservation devices allowing reinfusion of blood that would otherwise be wasted [82], by the more common use of point-of-care micro-analytic tests, and by non-invasive monitoring [83].

Conclusions

The high prevalence of anemia in critically ill patients should encourage clinicians to implement proactive measures to prevent, detect, diagnose and treat anemia. In fact, anemia is the most common hematologic disease in the ICU. Taking into account the availability of tests, their limitations, uncertainty, cost, and iatrogenic blood loss, a diagnosis of pure ACI or mixed ACI + IDA can be established using solely complete blood count with analysis of reticulocytes (a standard 2 mL EDTA test tube) which provides Hb concentration in erythrocyte and reticulocyte. Before reticulocyte Hb content can be used as an indicator of ID, thalassemia should be excluded either by checking the patient’s history or by calculating the Mentzer index (MCV/RBC). The management of ACI should incorporate discontinuation of pharmacological agents causing anemia, reduction of iatrogenic blood loss, dividing doses of parenteral iron when reticulocyte Hb content is below the reference range, and combined therapy of divided doses of parenteral iron with ESA in approved indications. Reticulocyte Hb content, determined twice a week, is useful for monitoring treatment. Transfusion of RBC should remain a treatment of last resort.

Authors’ contributions

PC — conceptualization; writing of paper. ŁK — revision, writing of paper.

Conflict of interest

The authors declare no conflict of interest.

Financial support

The authors declare no financial support for this work.

Ethics

The work described in this article has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans; EU Directive 2010/63/EU for animal experiments; uniform requirements for manuscripts submitted to biomedical journals.

References

  1. Vincent JL, Baron JF, Reinhart K, et al. ABC (Anemia and Blood Transfusion in Critical Care) Investigators. Anemia and blood transfusion in critically ill patients. JAMA. 2002; 288(12): 1499–1507, doi: 10.1001/jama.288.12.1499, indexed in Pubmed: 12243637.
  2. Corwin HL, Gettinger A, Pearl RG, et al. The CRIT study: anemia and blood transfusion in the critically ill — current clinical practice in the United States. Crit Care Med. 2004; 32(1): 39–52, doi: 10.1097/01.CCM.0000104112.34142.79, indexed in Pubmed: 14707558.
  3. Gattinoni L, Chiumello D. Anemia in the intensive care unit: how big is the problem? Transfus Altern Transfus Med. 2002; 4(4): 118–120, doi: 10.1111/j.1778-428x.2002.tb00072.x.
  4. Sakr Y, Lobo S, Knuepfer S, et al. Anemia and blood transfusion in a surgical intensive care unit. Crit Care. 2010; 14(3): R92, doi: 10.1186/cc9026, indexed in Pubmed: 20497535.
  5. Kassebaum NJ, Jasrasaria R, Naghavi M, et al. A systematic analysis of global anemia burden from 1990 to 2010. Blood. 2014; 123(5): 615–624, doi: 10.1182/blood-2013-06-508325, indexed in Pubmed: 24297872.
  6. Weiss G, Schett G. Anaemia in inflammatory rheumatic diseases. Nat Rev Rheumatol. 2013; 9(4): 205–215, doi: 10.1038/nrrheum.2012.183, indexed in Pubmed: 23147894.
  7. Macciò A, Madeddu C, Gramignano G, et al. The role of inflammation, iron, and nutritional status in cancer-related anemia: results of a large, prospective, observational study. Haematologica. 2015; 100(1): 124–132, doi: 10.3324/haematol.2014.112813, indexed in Pubmed: 25239265.
  8. Stauder R, Valent P, Theurl I. Anemia at older age: etiologies, clinical implications, and management. Blood. 2018; 131(5): 505–514, doi: 10.1182/blood-2017-07-746446, indexed in Pubmed: 29141943.
  9. Birgegård G, Gascón P, Ludwig H. Evaluation of anaemia in patients with multiple myeloma and lymphoma: findings of the European CANCER ANAEMIA SURVEY. Eur J Haematol. 2006; 77(5): 378–386, doi: 10.1111/j.1600-0609.2006.00739.x, indexed in Pubmed: 17044835.
  10. Ambrosy AP, Gurwitz JH, Tabada GH, et al. RBC HEART Investigators. Incident anaemia in older adults with heart failure: rate, aetiology, and association with outcomes. Eur Heart J Qual Care Clin Outcomes. 2019; 5(4): 361–369, doi: 10.1093/ehjqcco/qcz010, indexed in Pubmed: 30847487.
  11. Coiffier B, Guastalla JP, Pujade-Lauraine E, et al. Predicting cancer-associated anaemia in patients receiving non-platinum chemotherapy. Eur J Cancer. 2001; 37(13): 1617–1623, doi: 10.1016/s0959-8049(01)00169-1.
  12. Gaskell H, Derry S, Andrew Moore R, et al. Prevalence of anaemia in older persons: systematic review. BMC Geriatr. 2008; 8: 1, doi: 10.1186/1471-2318-8-1, indexed in Pubmed: 18194534.
  13. St Peter WL, Guo H, Kabadi S, et al. Prevalence, treatment patterns, and healthcare resource utilization in Medicare and commercially insured non-dialysis-dependent chronic kidney disease patients with and without anemia in the United States. BMC Nephrol. 2018; 19(1): 67, doi: 10.1186/s12882-018-0861-1, indexed in Pubmed: 29544446.
  14. Boutou AK, Karrar S, Hopkinson NS, et al. Anemia and survival in chronic obstructive pulmonary disease: a dichotomous rather than a continuous predictor. Respiration. 2013; 85(2): 126–131, doi: 10.1159/000338792, indexed in Pubmed: 22759351.
  15. Napolitano LM. Anemia and red blood cell transfusion: advances in critical care. Crit Care Clin. 2017; 33(2): 345–364, doi: 10.1016/j.ccc.2016.12.011, indexed in Pubmed: 28284299.
  16. Muckenthaler MU, Rivella S, Hentze MW, et al. A red carpet for iron metabolism. Cell. 2017; 168(3): 344–361.
  17. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004; 306(5704): 2090–2093, doi: 10.1126/science.1104742, indexed in Pubmed: 15514116.
  18. Aschemeyer S, Qiao Bo, Stefanova D, et al. Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin. Blood. 2018; 131(8): 899–910, doi: 10.1182/blood-2017-05-786590, indexed in Pubmed: 29237594.
  19. Guida C, Altamura S, Klein FA, et al. A novel inflammatory pathway mediating rapid hepcidin-independent hypoferremia. Blood. 2015; 125(14): 2265–2275, doi: 10.1182/blood-2014-08-595256, indexed in Pubmed: 25662334.
  20. Jelkmann W. Regulation of erythropoietin production. J Physiol. 2011; 589(6): 1251–1258, doi: 10.1113/jphysiol.2010.195057.
  21. Okonko DO, Marley SB, Anker SD, et al. Erythropoietin resistance contributes to anaemia in chronic heart failure and relates to aberrant JAK-STAT signal transduction. Int J Cardiol. 2013; 164(3): 359–364, doi: 10.1016/j.ijcard.2011.07.045, indexed in Pubmed: 21821297.
  22. Libregts SF, Gutiérrez L, de Bruin AM, et al. Chronic IFN-γ production in mice induces anemia by reducing erythrocyte life span and inhibiting erythropoiesis through an IRF-1/PU.1 axis. Blood. 2011; 118(9): 2578–2588, doi: 10.1182/blood-2010-10-315218, indexed in Pubmed: 21725055.
  23. Lanser L, Fuchs D, Kurz K, et al. Physiology and inflammation driven pathophysiology of iron homeostasis-mechanistic insights into anemia of inflammation and its treatment. Nutrients. 2021; 13(11), doi: 10.3390/nu13113732, indexed in Pubmed: 34835988.
  24. World Health Organization (WHO). Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin and Mineral Nutrition Information System. World Health Organization, Geneva 2011.
  25. Muñoz M, Acheson AG, Auerbach M, et al. International consensus statement on the peri-operative management of anaemia and iron deficiency. Anaesthesia. 2017; 72(2): 233–247, doi: 10.1111/anae.13773, indexed in Pubmed: 27996086.
  26. Czempik P, Czepczor K, Czok M, et al. Simplified diagnostic algorithm for classification of preoperative anaemia based on complete blood count and its application in elective gastrointestinal surgery. Pol Przegl Chir. 2019; 91(4): 24–28, doi: 10.5604/01.3001.0013.2569, indexed in Pubmed: 31481643.
  27. Larson LM, Braat S, Hasan MI, et al. Preanalytic and analytic factors affecting the measurement of haemoglobin concentration: impact on global estimates of anaemia prevalence. BMJ Glob Health. 2021; 6(7), doi: 10.1136/bmjgh-2021-005756, indexed in Pubmed: 34330759.
  28. Shah N, Osea EA, Martinez GJ. Accuracy of noninvasive hemoglobin and invasive point-of-care hemoglobin testing compared with a laboratory analyzer. Int J Lab Hematol. 2014; 36(1): 56–61, doi: 10.1111/ijlh.12118, indexed in Pubmed: 23809685.
  29. Bermejo F, García-López S. A guide to diagnosis of iron deficiency and iron deficiency anemia in digestive diseases. World J Gastroenterol. 2009; 15(37): 4638–4643, doi: 10.3748/wjg.15.4638, indexed in Pubmed: 19787826.
  30. Joshi A, McVicker W, Segalla R, et al. Determining the stability of complete blood count parameters in stored blood samples using the SYSMEX XE-5000 automated haematology analyser. Int J Lab Hematol. 2015; 37(5): 705–714, doi: 10.1111/ijlh.12389, indexed in Pubmed: 26053195.
  31. Buttarello M. Laboratory diagnosis of anemia: are the old and new red cell parameters useful in classification and treatment, how? Int J Lab Hematol. 2016; 38(Suppl 1): 123, doi: 10.1111/ijlh.12500.
  32. Padhi S, Glen J, Pordes BAJ, et al. Guideline Development Group. Management of anaemia in chronic kidney disease: summary of updated NICE guidance. BMJ. 2015; 350: h2258, doi: 10.1136/bmj.h2258, indexed in Pubmed: 26044132.
  33. van Santen S, van Dongen-Lases EC, de Vegt F, et al. Hepcidin and hemoglobin content parameters in the diagnosis of iron deficiency in rheumatoid arthritis patients with anemia. Arthritis Rheum. 2011; 63(12): 3672–3680, doi: 10.1002/art.30623, indexed in Pubmed: 22127690.
  34. Peerschke EIB, Pessin MS, Maslak P. Using the hemoglobin content of reticulocytes (RET-He) to evaluate anemia in patients with cancer. Am J Clin Pathol. 2014; 142(4): 506–512, doi: 10.1309/AJCPCVZ5B0BOYJGN, indexed in Pubmed: 25239418.
  35. Torino AB, Gilberti Md, da Costa E, et al. Evaluation of red cell and reticulocyte parameters as indicative of iron deficiency in patients with anemia of chronic disease. Rev Bras Hematol Hemoter. 2014; 36(6): 424–429, doi: 10.1016/j.bjhh.2014.09.004, indexed in Pubmed: 25453653.
  36. Svenson N, Bailey J, Durairaj S, et al. A simplified diagnostic pathway for the differential diagnosis of iron deficiency anaemia and anaemia of chronic disease. Int J Lab Hematol. 2021; 43(6): 1644–1652, doi: 10.1111/ijlh.13666, indexed in Pubmed: 34288431.
  37. Mentzer WC. Differentiation of iron deficiency from thalassaemia trait. Lancet. 1973; 1(7808): 882, doi: 10.1016/s0140-6736(73)91446-3, indexed in Pubmed: 4123424.
  38. Vehapoglu A, Ozgurhan G, Demir AD, et al. Hematological indices for differential diagnosis of Beta thalassemia trait and iron deficiency anemia. Anemia. 2014; 2014: 576738, doi: 10.1155/2014/576738, indexed in Pubmed: 24818016.
  39. Canals C, Remacha AF, Sardá MP, et al. Clinical utility of the new Sysmex XE 2100 parameter-reticulocyte hemoglobin equivalent — in the diagnosis of anemia. Haematologica. 2005; 90(8): 1133–1134.
  40. Tantawy AA, Ragab IA, Ismail EA, et al. Reticulocyte hemoglobin content (Ret He): a simple tool for evaluation of iron status in child-hood cancer. J Pediatr Hematol Oncol. 2020; 42(3): e147–e151.
  41. Chinudomwong P, Binyasing A, Trongsakul R, et al. Diagnostic performance of reticulocyte hemoglobin equivalent in assessing the iron status. J Clin Lab Anal. 2020; 34(6): e23225, doi: 10.1002/jcla.23225, indexed in Pubmed: 32043622.
  42. Fletcher A, Forbes A, Svenson N, et al. A British Society for Haematology Good Practice Paper. Guideline for the laboratory diagnosis of iron deficiency in adults (excluding pregnancy) and children. Br J Haematol. 2022; 196(3): 523–529, doi: 10.1111/bjh.17900, indexed in Pubmed: 34693519.
  43. Goodnough LT, Schrier SL. Evaluation and management of anemia in the elderly. Am J Hematol. 2014; 89(1): 88–96, doi: 10.1002/ajh.23598, indexed in Pubmed: 24122955.
  44. Czempik PF, Pluta M, Krzych Ł. Ferritin and transferrin saturation cannot be used to diagnose iron-deficiency anemia in critically ill patients. Acta Haematol Pol. 2021; 52(6): 566–570, doi: 10.5603/ahp.2021.0091.
  45. Weiss G, Ganz T, Goodnough LT. Anemia of inflammation. Blood. 2019; 133(1): 40–50, doi: 10.1182/blood-2018-06-856500, indexed in Pubmed: 30401705.
  46. Grebenchtchikov N, Geurts-Moespot AJ, Kroot JJC, et al. High-sensitive radioimmunoassay for human serum hepcidin. Br J Haematol. 2009; 146(3): 317–325, doi: 10.1111/j.1365-2141.2009.07758.x, indexed in Pubmed: 19500086.
  47. Malyszko J, Malyszko JS, Pawlak K, et al. Hepcidin, iron status, and renal function in chronic renal failure, kidney transplantation, and hemodialysis. Am J Hematol. 2006; 81(11): 832–837, doi: 10.1002/ajh.20657, indexed in Pubmed: 16929540.
  48. Young MF, Glahn RP, Ariza-Nieto M, et al. Serum hepcidin is significantly associated with iron absorption from food and supplemental sources in healthy young women. Am J Clin Nutr. 2009; 89(2): 533–538, doi: 10.3945/ajcn.2008.26589, indexed in Pubmed: 19073788.
  49. Thomas C, Kobold U, Thomas L. Serum hepcidin-25 in comparison to biochemical markers and hematological indices for the differentiation of iron-restricted erythropoiesis. Clin Chem Lab Med. 2011; 49(2): 207–213, doi: 10.1515/CCLM.2011.056, indexed in Pubmed: 21143009.
  50. Wish JB, Aronoff GR, Bacon BR, et al. Positive iron balance in chronic kidney disease: how much is too much and how to tell? Am J Nephrol. 2018; 47(2): 72–83, doi: 10.1159/000486968, indexed in Pubmed: 29439253.
  51. Bregman DB, Morris D, Koch TA, et al. Hepcidin levels predict nonresponsiveness to oral iron therapy in patients with iron deficiency anemia. Am J Hematol. 2013; 88(2): 97–101, doi: 10.1002/ajh.23354, indexed in Pubmed: 23335357.
  52. Prentice AM, Doherty CP, Abrams SA, et al. Hepcidin is the major predictor of erythrocyte iron incorporation in anemic African children. Blood. 2012; 119(8): 1922–1928, doi: 10.1182/blood-2011-11-391219, indexed in Pubmed: 22228627.
  53. Weiss G. Anemia of chronic disorders: new diagnostic tools and new treatment strategies. Semin Hematol. 2015; 52(4): 313–320, doi: 10.1053/j.seminhematol.2015.07.004, indexed in Pubmed: 26404443.
  54. Koutroubakis IE, Ramos-Rivers C, Regueiro M, et al. The influence of anti-tumor necrosis factor agents on hemoglobin levels of patients with inflammatory bowel disease. Inflamm Bowel Dis. 2015; 21(7): 1587–1593, doi: 10.1097/MIB.0000000000000417, indexed in Pubmed: 25933393.
  55. Papadaki HA, Kritikos HD, Valatas V, et al. Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti-tumor necrosis factor-alpha antibody therapy. Blood. 2002; 100(2): 474–482, doi: 10.1182/blood-2002-01-0136, indexed in Pubmed: 12091338.
  56. Gwamaka M, Kurtis JD, Sorensen BE, et al. Iron deficiency protects against severe Plasmodium falciparum malaria and death in young children. Clin Infect Dis. 2012; 54(8): 1137–1144, doi: 10.1093/cid/cis010, indexed in Pubmed: 22354919.
  57. Vincent JL, Jaschinski U, Wittebole X, et al. ICON Investigators. Worldwide audit of blood transfusion practice in critically ill patients. Crit Care. 2018; 22(1): 102, doi: 10.1186/s13054-018-2018-9, indexed in Pubmed: 29673409.
  58. Shander A, Javidroozi M, Ashton E. Drug-induced anemia and other red cell disorders: a guide in the age of polypharmacy. Current Clinical Pharmacology. 2011; 6(4): 295–303, doi: 10.2174/­157488411798375895.
  59. Torres S, Kuo YH, Morris K, et al. Intravenous iron following cardiac surgery does not increase the infection rate. Surg Infect (Larchmt). 2006; 7(4): 361–366, doi: 10.1089/sur.2006.7.361, indexed in Pubmed: 16978079.
  60. Cappellini MD, Comin-Colet J, de Francisco A, et al. IRON CORE Group. Iron deficiency across chronic inflammatory conditions: International expert opinion on definition, diagnosis, and management. Am J Hematol. 2017; 92(10): 1068–1078, doi: 10.1002/ajh.24820, indexed in Pubmed: 28612425.
  61. Shander A, Spence RK, Auerbach M. Can intravenous iron therapy meet the unmet needs created by the new restrictions on erythropoietic stimulating agents? Transfusion. 2010; 50(3): 719–732, doi: 10.1111/j.1537-2995.2009.02492.x, indexed in Pubmed: 19919555.
  62. Pieracci FM, Stovall RT, Jaouen B, et al. A multicenter, randomized clinical trial of IV iron supplementation for anemia of traumatic critical illness*. Crit Care Med. 2014; 42(9): 2048–2057, doi: 10.1097/CCM.0000000000000408, indexed in Pubmed: 24797376.
  63. Onken JE, Bregman DB, Harrington RA, et al. Ferric carboxymaltose in patients with iron-deficiency anemia and impaired renal function: the REPAIR-IDA trial. Nephrol Dial Transplant. 2014; 29(4): 833–842, doi: 10.1093/ndt/gft251, indexed in Pubmed: 23963731.
  64. Litton E, Baker S, Erber WN, et al. IRONMAN Investigators, Australian and New Zealand Intensive Care Society Clinical Trials Group. Intravenous iron or placebo for anaemia in intensive care: the IRONMAN multicentre randomized blinded trial : A randomized trial of IV iron in critical illness. Intensive Care Med. 2016; 42(11): 1715–1722, doi: 10.1007/s00134-016-4465-6, indexed in Pubmed: 27686346.
  65. Tonia T, Mettler A, Robert N, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev. 2012; 12: CD003407, doi: 10.1002/14651858.CD003407.pub5, indexed in Pubmed: 23235597.
  66. Solomon SD, Uno H, Lewis EF, et al. Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) Investigators. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med. 2010; 363(12): 1146–1155, doi: 10.1056/NEJMoa1005109, indexed in Pubmed: 20843249.
  67. Macdougall IC, Provenzano R, Sharma A, et al. PEARL Study Groups. Peginesatide for anemia in patients with chronic kidney disease not receiving dialysis. N Engl J Med. 2013; 368(4): 320–332, doi: 10.1056/NEJMoa1203166, indexed in Pubmed: 23343062.
  68. Bennett CL, Silver SM, Djulbegovic B, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA. 2008; 299(8): 914–924, doi: 10.1001/jama.299.8.914, indexed in Pubmed: 18314434.
  69. Tanaka T, Eckardt KU. HIF activation against CVD in CKD: novel treatment opportunities. Semin Nephrol. 2018; 38(3): 267–276, doi: 10.1016/j.semnephrol.2018.02.006, indexed in Pubmed: 29753402.
  70. Zhang W, Zheng Y, Yu K, et al. Liberal transfusion versus restrictive transfusion and outcomes in critically Ill adults: a meta-analysis. Transfus Med Hemother. 2021; 48(1): 60–68, doi: 10.1159/000506751, indexed in Pubmed: 33708053.
  71. Fogagnolo A, Taccone FS, Vincent JL, et al. Using arterial-venous oxygen difference to guide red blood cell transfusion strategy. Critical Care. 2020; 24: 160, doi: https://doi.org/10.1186/s13054-020-2827-5.
  72. Czempik PF, Wojnarowicz O, Krzych ŁJ. Let us use physiologic transfusion triggers: favorable outcome in an 86-year-old Jehovah’s witness with a haemoglobin nadir of 44g L. Transfus Apher Sci. 2020; 59(2): 102718, doi: 10.1016/j.transci.2020.102718, indexed in Pubmed: 31926739.
  73. Sebastiani G, Wilkinson N, Pantopoulos K. Pharmacological targeting of the hepcidin/ferroportin axis. Front Pharmacol. 2016; 7: 160, doi: 10.3389/fphar.2016.00160, indexed in Pubmed: 27445804.
  74. Arezes J, Foy N, McHugh K, et al. Erythroferrone inhibits the induction of hepcidin by BMP6. Blood. 2018; 132(14): 1473–1477, doi: 10.1182/blood-2018-06-857995, indexed in Pubmed: 30097509.
  75. Kautz L, Jung G, Du X, et al. Erythroferrone contributes to hepcidin suppression and iron overload in a mouse model of β-thalassemia. Blood. 2015; 126(17): 2031–2037, doi: 10.1182/blood-2015-07-658419, indexed in Pubmed: 26276665.
  76. Youssef SR, Hassan EH, Morad CS, et al. Erythroferrone expression in anemic rheumatoid arthritis patients: is it disordered iron trafficking or disease activity? J Inflamm Res. 2021; 14: 4445–4455, doi: 10.2147/JIR.S327465, indexed in Pubmed: 34522114.
  77. Rodriguez RM, Corwin HL, Gettinger A, et al. Nutritional deficiencies and blunted erythropoietin response as causes of the anemia of critical illness. J Crit Care. 2001; 16(1): 36–41, doi: 10.1053/jcrc.2001.21795, indexed in Pubmed: 11230723.
  78. Shander A, Javidroozi M, Ozawa S, et al. What is really dangerous: anaemia or transfusion? Br J Anaesth. 2011; 107(Suppl 1): i41–i59, doi: 10.1093/bja/aer350, indexed in Pubmed: 22156270.
  79. Weiss G, Ganz T, Goodnough LT. Anemia of inflammation. Blood. 2019; 133(1): 40–50, doi: 10.1182/blood-2018-06-856500, indexed in Pubmed: 30401705.
  80. Shaffer C. Diagnostic blood loss in mechanically ventilated patients. Heart Lung. 2007; 36(3): 217–222, doi: 10.1016/j.hrtlng.2006.09.001, indexed in Pubmed: 17509428.
  81. Dolman HS, Evans K, Zimmerman LH, et al. Impact of minimizing diagnostic blood loss in the critically ill. Surgery. 2015; 158(4): 1083––1087; discussion 1087, doi: 10.1016/j.surg.2015.05.018, indexed in Pubmed: 26164619.
  82. Page C, Retter A, Wyncoll D. Blood conservation devices in critical care: a narrative review. Ann Intensive Care. 2013; 3: 14, doi: 10.1186/2110-5820-3-14, indexed in Pubmed: 23714376.
  83. McEvoy MT, Shander A. Anemia, bleeding, and blood transfusion in the intensive care unit: causes, risks, costs, and new strategies. Am J Crit Care. 2013; 22(6 Suppl): eS1–13; quiz eS14, doi: 10.4037/ajcc2013729, indexed in Pubmed: 24186829.

Copyright © 2022

The Polish Society of Haematologists and Transfusiologists,
Insitute of Haematology and Transfusion Medicine.

All rights reserved.

Regulations

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

By VM Media Group sp. z o.o., Grupa Via Medica, ul. Świętokrzyska 73, 80–180 Gdańsk, Poland
phone: +48 58 320 94 94, fax: +48 58 320 94 60, e-mail: viamedica@viamedica.pl