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Is blood of uncomplicated hemochromatosis patients safe and effective for blood transfusion? A systematic review

Open AccessPublished:June 01, 2012DOI:https://doi.org/10.1016/j.jhep.2012.04.040

      Summary

      Hemochromatosis is a disorder of the iron metabolism, characterized by high body iron content, necessitating frequent phlebotomies to remove excess iron. In some countries, this blood is discarded and not used for blood transfusion because of the non-voluntary character of this donation, and because a potential risk of microbial contamination of the donor blood is assumed.
      A systematic review was performed in order to collect and critically examine solid evidence with regard to the effectiveness and safety of blood for transfusion when derived from hemochromatosis patients who do not suffer from complications or organ damage. Using three databases (The Cochrane Library, MEDLINE, and Embase) we searched for studies from date of inception until January 2012.
      Out of 3470 articles, 80 references that were relevant to our question were selected, including many opinion pieces, comments, letters, and narrative reviews. Based on our selection criteria, we finally retained only six observational studies, so evidence on this subject is scarce and furthermore, the strength of the available evidence is low to very low, due to poor study designs. We found no evidence that red blood cell concentrates from hemochromatosis patients without complications of iron overload do not comply with the physiological quality requirements for transfusion, nor that their blood would present a greater risk to recipient safety than blood from non-hemochromatosis donors. However, in vitro findings from two studies suggest that iron-overloaded patients would be more susceptible to bacterial growth, but future in vivo studies are warranted to confirm this.
      Based on this, we call for harmonization of the blood donor selection policy among countries allowing hemochromatosis patients who do not suffer from complications of iron overload to donate blood, once iron levels are normalized.

      Keywords

      Introduction

      European Association for the Study of the LiverHemochromatosis is characterized by entry of iron into the blood stream in excess of that required for erythropoiesis. The excess iron can accumulate in parenchymal cells of liver, heart, endocrine glands, and other tissues, and result in organ damage. Hemochromatosis is in most cases inherited (‘primary or hereditary hemochromatosis’) as an autosomal recessive disorder, but can also be acquired. It arises from alterations in genes that regulate the synthesis of hepcidin, the latter downregulating the entry of iron into the blood stream, and many genotypes exist. Approximately 12.5% of individuals of Northern European descent are heterozygous for a mutation in the HFE gene (High Fe) and almost one in two to three hundred white people are homozygous. Based on genetic testing, it became clear that although homozygotes most often display abnormally high iron levels (high biochemical penetrance, ‘biochemical hemochromatosis’), only a small number of them develop complications and organ damage (low clinical penetrance, ‘clinical hemochromatosis’) [
      • Pietrangelo A.
      Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment.
      ,
      • Adams P.C.
      • Barton J.C.
      Haemochromatosis.
      ,
      • Waalen J.
      • Felitti V.
      • Gelbart T.
      • Ho N.J.
      • Beutler E.
      Penetrance of hemochromatosis.
      ].
      The standard medical treatment for hemochromatosis is removal of iron by regular therapeutic phlebotomy, either weekly to return to safe blood levels of iron (iron depletion therapy) or 1–4 times a year (maintenance therapy) [
      • Adams P.C.
      • Barton J.C.
      How I treat hemochromatosis.
      ].
      For many years, there has been a debate whether blood from patients with hemochromatosis can be accepted for transfusion. The two frequently raised arguments against the use of blood from hemochromatosis patients are that: (1) the blood would be unsafe and (2) the donation is not voluntary [
      • Conry-Cantilena C.
      Phlebotomy, blood donation, and hereditary hemochromatosis.
      ,
      • De Gonzalez G.L.
      Hereditary haemochromatosis and blood donation.
      ]. Concerning the safety of the blood, there is fear of possible contamination with siderophilic bacteria, such as Vibrio sp., Salmonella sp., and Yersinia sp. [
      • Nouel O.
      • Voisin P.M.
      • Vaucel J.
      • Dartois-Hoguin M.
      • Le B.M.
      Yersinia enterocolitica septicemia associated with idiopathic hemochromatosis and deferoxamine therapy. A case.
      ,
      • Cauchie P.
      • Vincken W.
      • Peeters O.
      • Charels K.
      Hemochromatosis and Yersinia enterocolitica septicemia.
      ,
      • Boelaert J.R.
      • van Landuyt H.W.
      • Valcke Y.J.
      • Cantinieaux B.
      • Lornoy W.F.
      • Vanherweghem J.L.
      • et al.
      The role of iron overload in Yersinia enterocolitica and Yersinia pseudotuberculosis bacteremia in hemodialysis patients.
      ,
      • Piroth L.
      • Meyer P.
      • Bielefeld P.
      • Besancenot J.F.
      Yersinia bacteremia and iron overload.
      ], especially as Yersinia enterocolitica has been identified with increased frequency as a causative agent of post-transfusion septic shock with possible fatal outcome [
      • Leclercq A.
      • Martin L.
      • Vergnes M.L.
      • Ounnoughene N.
      • Laran J.F.
      • Giraud P.
      • et al.
      Fatal Yersinia enterocolitica biotype 4 serovar O:3 sepsis after red blood cell transfusion.
      ]. Because iron overload can impair the host immune system, and viruses can interact with the iron metabolism to cause infection (e.g., by altering the expression of proteins involved in iron homeostasis), there is also a potential higher susceptibility for viral infections [
      • Walker E.M.
      • Walker S.M.
      Review: Effects of iron overload on the immune system.
      ,
      • Khan F.A.
      • Fisher M.A.
      • Khakoo R.A.
      Association of hemochromatosis with infectious diseases: expanding spectrum.
      ,
      • Drakesmith H.
      • Prentice A.
      Viral infection and iron metabolism.
      ]. The second argument deals with the fact that hemochromatosis patients that donate blood are not considered to be voluntary non-remunerated donors because they benefit from the donation. Since the phlebotomy is free of charge, becoming blood donor may be a cheap alternative for physician visits thus providing a financial incentive. In addition, the necessity of phlebotomy does not qualify this donation as “voluntary” [
      • Pennings G.
      Demanding pure motives for donation: the moral acceptability of blood donations by haemochromatosis patients.
      ].
      The management and cost of hemochromatosis treatment and the use of blood obtained via phlebotomy vary strongly throughout the Western world [
      • Butzeck B.
      • Rialland J.
      • Brissot P.
      • Porto G.
      • Courtois F.
      Management, costs of phlebotomies and use of removed blood in haemochromatosis varies throughout Europe.
      ]. In many countries, mainly Europe, blood from hemochromatosis patients is drawn only for therapeutic reasons and cannot be used for blood transfusion because of both arguments described above. The concern with regard to the voluntary nature of the donation however, can be addressed by rigorous use of the donor medical questionnaire, rejecting the blood for further use if the criteria applicable to any other donor are not met. In addition, making all phlebotomies free to hemochromatosis patients could eliminate any financial incentives and thus the non-voluntary character of the donation.
      Figure thumbnail fx3

      Materials and methods

      Search strategy

      All searches for evidence were performed between December 2011 and January 2012. The following sources were searched: The Cochrane Database of Systematic Reviews, The Database of Abstracts of Reviews of Effects, The Cochrane Central Register of Controlled Trials, MEDLINE (using the PubMed interface), and Embase (using the Embase.com interface).
      The following search formula was used for searching MEDLINE:
      • 1.
        “Hemochromatosis” [Mesh] OR “hemochromatosis” [TIAB] OR “haemochromatosis” [TIAB]
      • 2.
        “Blood Donors” [Mesh] OR “Blood Transfusion” [Mesh]
      • 3.
        “Blood Safety” [Mesh] OR “Blood-Borne pathogens” [Mesh] OR “infection” [TIAB] OR “safety” [TIAB]
      • 4.
        “Virus Diseases” [Mesh] OR “transfusion transmissible” [TIAB]
      • 5.
        “Bacterial Infections” [Mesh] OR “Bacteremia” [Mesh]
      • 6.
        “Erythrocytes” [Mesh] OR “Erythrocyte Indices” [Mesh] OR “Erythrocyte Count” [Mesh] OR “quality” [TIAB] OR “mean corpuscular volume” [TIAB] OR “mean cell volume” [TIAB] OR “cell count” [TIAB] OR “mean cell hemoglobin” [TIAB] OR “MCV” [TIAB] OR “MCH” [TIAB]
      • 7.
        2–6 OR
      • 8.
        1 AND 7
      The following search formula was used in Embase:
      • 1.
        ‘hemochromatosis’/exp OR hemochromatosis:ab:ti OR haemochromatosis:ab:ti
      • 2.
        ‘blood donor’/exp OR ‘blood transfusion’/exp
      • 3.
        ‘blood safety’/exp OR infection:ab:ti OR safety:ab:ti
      • 4.
        ‘virus infection’/exp OR ‘transfusion transmissible’:ab:ti
      • 5.
        ‘bloodborne bacterium’/exp OR ‘bacterial infection’/exp OR ‘bacteremia’/exp
      • 6.
        ‘erythrocyte’/exp OR ‘mean corpuscular volume’/exp OR ‘erythrocyte count’/exp OR quality:ab:ti OR ‘mean corpuscular volume’:ab:ti OR ‘mean cell volume’:ab:ti OR ‘cell count’:ab:ti OR ‘mean cell hemoglobin’:ab:ti OR ‘MCV’:ab:ti OR ‘MCH’:ab:ti
      • 7.
        2–6 OR
      • 8.
        1 AND 7
      Selection of the studies was performed in parallel by two independent reviewers (E.D.B., N.S.P.). Titles and abstracts of the studies identified by the search were scanned. When a study met the eligibility criteria, full text articles were obtained. Studies that did not meet the in- and exclusion criteria were excluded. The citation lists of included studies were searched for additional related articles, the first 20 related items in PubMed were scanned for other potentially relevant studies, and the references by which the included studies were cited were screened. The final selection of articles was compared among the two reviewers. Disagreement on the selection of studies was resolved by discussion or by involving a third reviewer (T.D.).

      Study selection/inclusion and exclusion criteria

      Language

      Studies in English and French were included.

      Types of studies

      Randomized controlled trials, controlled clinical trials, cohort studies, case–control studies, and case-series were included. In vitro studies were included if a control group was used and if the blood or serum sample was tested in unprocessed form (no incubation or cultivation of specific cell types). Excluded study designs were narrative reviews, commentaries, letters and opinions.

      Types of participants

      We included studies with a population that represents our target population: hemochromatosis patients without complications of iron overload that need phlebotomies to treat or maintain their condition and that are eligible as a blood donor. In detail, the included population consists of hereditary hemochromatosis patients without organ damage but having abnormal serum ferritin levels or undergoing iron depletion or maintenance therapy (‘biochemical hemochromatosis’). Excluded population: patients with complications of iron overload or organ damage (‘clinical hemochromatosis’); people with positive genetic testing for hemochromatosis, but without any indication of increased iron levels; patients with secondary, neonatal or juvenile hemochromatosis.

      Intervention and comparison

      Intervention: Blood from hemochromatosis patients; Comparison: Blood from healthy donors; blood from hemochromatosis patients at different time points.

      Types of outcome measures

      Primary outcomes: (1) safety: markers of transfusion-transmissible diseases or viral or bacterial infections in blood from persons who receive blood from a hemochromatosis patient; (2) effectiveness: erythrocyte properties/hematologic variables in blood from blood acceptors who receive blood from a hemochromatosis patient. Secondary outcomes: (1) safety: markers of transfusion-transmissible diseases or viral or bacterial infections in blood from hemochromatosis patients; (2) effectiveness: erythrocyte properties/hematologic variables in blood or serum samples from hemochromatosis patients.

      Data collection

      Data concerning study design, study population, outcome measures and study findings were extracted and tabulated in addition to the limitations in study design by two independent reviewers (E.D.B., N.S.P.). In case of disagreement a third reviewer was involved (T.D.).

      Quality of evidence

      The GRADE approach was used to grade the overall quality of evidence included in this review. GRADE considers limitations in study design of the included studies, inconsistency between the different studies (due to differences in populations, interventions or outcomes), indirectness (of population, intervention or outcome), imprecision and publication bias. Limitations in study design were analyzed by evaluating the presence of eligibility criteria, adequate control of confounding, design-specific sources of bias and correct measurement of exposure and outcome. The quality of evidence can be downgraded for each of the previous quality criteria and finally results in high, moderate, low or very low grade of evidence [
      • Atkins D.
      • Best D.
      • Briss P.A.
      • Eccles M.
      • Falck-Ytter Y.
      • Flottorp S.
      • et al.
      Grading quality of evidence and strength of recommendations.
      ].

      Results

      Study characteristics

      Fig. 1 provides a flowchart of the identification and selection of studies. The reviewers screened 3470 citations, including 164 duplicates and one triplicate. Evaluation of titles and abstracts resulted in 80 references. After full text evaluation, 74 studies were excluded because selection criteria were not met. It is remarkable that half of the studies that were selected for full text evaluation did not meet the criteria because of the study design. Many reviews, comments, letters and case reports are published on this subject, but very few studies exist to support them. Table 1 displays an overview of all studies that were excluded based on the criteria for population, intervention or outcome, with the reason for exclusion [
      • Adams P.C.
      • Deugnier Y.
      • Moirand R.
      • Brissot P.
      The relationship between iron overload, clinical symptoms, and age in 410 patients with genetic hemochromatosis.
      ,
      • Barton J.C.
      • Grindon A.J.
      • Barton N.H.
      • Bertoli L.F.
      Hemochromatosis probands as blood donors.
      ,
      • Barton J.C.
      • Bertoli L.F.
      • Rothenberg B.E.
      Peripheral blood erythrocyte parameters in hemochromatosis: evidence for increased erythrocyte hemoglobin content.
      ,
      • Bell H.
      • Thordal C.
      • Raknerud N.
      • Hansen T.
      • Bosnes V.
      • Halvorsn R.
      • et al.
      Prevalence of hemochromatosis among first-time and repeat blood donors in Norway.
      ,
      • Beutler E.
      • Gelbart T.
      Helicobacter pylori infection and HFE hemochromatosis.
      ,
      • Blacklock H.A.
      • Dewse M.
      • Bollard C.
      • Hudson P.
      • Barnhill D.
      • Jackson S.
      Blood donation by healthy individuals with haemochromatosis.
      ,
      • Bove M.
      • Aurizi C.
      • Biolcati G.
      • Sorge F.
      • Colasanti M.
      • Serra F.
      Screening for hereditary hemochromatosis in blood donors.
      ,
      • Brandao M.
      • Oliveira J.C.
      • Bravo F.
      • Reis J.
      • Garrido I.
      • Porto G.
      The soluble transferrin receptor as a marker of iron homeostasis in normal subjects and in HFE-related hemochromatosis.
      ,
      • De Filippi F.
      • Fraquelli M.
      • Conte D.
      • Soffredini R.
      • Prati D.
      • Ronchi G.
      • et al.
      High prevalence but low pathogenicity of hepatitis G virus infection in Italian patients with genetic haemochromatosis.
      ,
      • De Gobbi M.
      • D’Antico S.
      • Castagno F.
      • Testa D.
      • Merlini R.
      • Bondi A.
      • et al.
      Screening selected blood donors with biochemical iron overload for hemochromatosis: a regional experience.
      ,
      • Del Castillo A.
      • Gordo S.
      • Aldamiz T.
      • De La Calle F.
      • Varez-Sala L.A.
      Infectious diseases in diagnosed patients of genetic hemochromatosis.
      ,
      • Deugnier Y.
      • Battistelli D.
      • Jouanolle H.
      • Guyader D.
      • Gueguen M.
      • Loreal O.
      • et al.
      Hepatitis B virus infection markers in genetic haemochromatosis. A study of 272 patients.
      ,
      • Edwards C.Q.
      • Griffen L.M.
      • Drummond C.
      • Skolnick M.H.
      • Kushner J.P.
      Screening for hemochromatosis in healthy blood donors. Preliminary results.
      ,
      • Feeney G.P.
      • Carter K.
      • Masters G.S.
      • Jackson H.A.
      • Cavil I.
      • Worwood M.
      Changes in erythropoiesis in hereditary hemochromatosis are not mediated by HFE expression in nucleated red cells.
      ,
      • Levstik M.
      • Adams P.C.
      Eligibility and exclusion of hemochromatosis patients as voluntary blood donors.
      ,
      • Mah Y.H.
      • Kao J.H.
      • Liu C.J.
      • Chen C.L.
      • Chen P.J.
      • Lai M.Y.
      • et al.
      Prevalence and clinical implications of HFE gene mutations (C282Y and H63D) in patients with chronic hepatitis B and C in Taiwan.
      ,
      • McLaren C.E.
      • Barton J.C.
      • Gordeuk V.R.
      • Wu L.
      • Adams P.C.
      • Reboussin D.M.
      • et al.
      Determinants and characteristics of mean corpuscular volume and hemoglobin concentration in white HFE C282Y homozygotes in the Hemochromatosis and Iron Overload Screening Study.
      ,
      • McDonnell S.M.
      • Preston B.L.
      • Jewell S.A.
      • Barton J.C.
      • Edwards C.Q.
      • Adams P.C.
      • et al.
      A survey of 2,851 patients with hemochromatosis: symptoms and response to treatment.
      ,
      • Olakanmi O.
      • Schlesinger L.S.
      • Britigan B.E.
      Hereditary hemochromatosis results in decreased iron acquisition and growth by Mycobacterium tuberculosis within human macrophages.
      ,
      • Lee P.L.
      • Ho N.J.
      • Olson R.
      • Beutler E.
      The effect of transferrin polymorphisms on iron metabolism.
      ,
      • Power T.E.
      • Adams P.C.
      Hemochromatosis patients as voluntary blood donors.
      ,
      • Rosvik A.S.
      • Ulvik R.J.
      • Wentzel-Larsen T.
      • Hervig T.
      Blood donors with hereditary hemochromatosis.
      ,
      • Sendi H.
      • Ghaziani T.
      • Zali M.R.
      • Adibi P.
      • Agah M.
      • Jazayeri M.
      • et al.
      Hemochromatosis mutations in Iranians with hepatitis B virus infection.
      ,
      • Shan Y.
      • Lambrecht R.W.
      • Bonkovsky H.L.
      Association of hepatitis C virus infection with serum iron status: analysis of data from the third national health and nutrition examination survey.
      ,
      • Silva I.S.S.
      • Perez R.M.
      • Oliveira P.V.
      • Cantagalo M.I.
      • Dantas E.
      • Sisti C.
      • et al.
      Iron overload in patients with chronic hepatitis C virus infection: clinical and histological study.
      ,
      • Wise M.
      • Finelli L.
      • Sorvillo F.
      Prognostic factors associated with hepatitis C disease: a case–control study utilizing U.S. multiple-cause-of-death data.
      ]. Only six references [
      • Luten M.
      • Roerdinkholder-Stoelwinder B.
      • Rombout-Sestrienkova E.
      • De Grip W.J.
      • Bos H.J.
      • Bosman G.J.
      Red cell concentrates of hemochromatosis patients comply with the storage guidelines for transfusion purposes.
      ,
      • Leitman S.F.
      • Browning J.N.
      • Yau Y.Y.
      • Mason G.
      • Klein H.G.
      • Conry-Cantilena C.
      • et al.
      Hemochromatosis subjects as allogeneic blood donors: a prospective study.
      ,
      • Sanchez A.M.
      • Schreiber G.B.
      • Bethel J.
      • McCurdy P.R.
      • Glynn S.A.
      • Williams A.E.
      • et al.
      Prevalence, donation practices, and risk assessment of blood donors with hemochromatosis.
      ,
      • Jolivet-Gougeon A.
      • Loreal O.
      • Ingels A.
      • Danic B.
      • Ropert M.
      • Bardou-Jacquet E.
      • et al.
      Serum transferrin saturation increase is associated with decrease of antibacterial activity of serum in patients with HFE-related genetic hemochromatosis.
      ,
      • Jolivet-Gougeon A.
      • Ingels A.
      • Danic B.
      • Ussant-Bertel F.
      • Ferec C.
      • Loreal O.
      • et al.
      No increased seroprevalence of anti-Yersinia antibodies in patients with type 1 (C282Y/C282Y) hemochromatosis.
      ,
      • Bullen J.J.
      • Spalding P.B.
      • Ward C.G.
      • Gutteridge J.M.C.
      Hemochromatosis, iron, and septicemia caused by Vibrio vulnificus.
      ] met the inclusion criteria and were available for analysis (Table 2). All included studies were observational studies, three of them were performed in the United States, two in France and one in The Netherlands. One study measured blood effectiveness by determining hematologic variables [
      • Luten M.
      • Roerdinkholder-Stoelwinder B.
      • Rombout-Sestrienkova E.
      • De Grip W.J.
      • Bos H.J.
      • Bosman G.J.
      Red cell concentrates of hemochromatosis patients comply with the storage guidelines for transfusion purposes.
      ]. Five studies measured safety (agents of viral or bacterial transfusion-transmissible disease). Among the latter, two studies investigated the prevalence of viral infections [
      • Leitman S.F.
      • Browning J.N.
      • Yau Y.Y.
      • Mason G.
      • Klein H.G.
      • Conry-Cantilena C.
      • et al.
      Hemochromatosis subjects as allogeneic blood donors: a prospective study.
      ,
      • Sanchez A.M.
      • Schreiber G.B.
      • Bethel J.
      • McCurdy P.R.
      • Glynn S.A.
      • Williams A.E.
      • et al.
      Prevalence, donation practices, and risk assessment of blood donors with hemochromatosis.
      ], including one screening 52,650 blood donors (hemochromatosis patients and regular donors) and another investigating 130 hemochromatosis patients before and after blood donation (without control group). Furthermore, three studies were included evaluating the prevalence of bacterial infections in hemochromatosis patients and healthy people (not donating blood) [
      • Jolivet-Gougeon A.
      • Loreal O.
      • Ingels A.
      • Danic B.
      • Ropert M.
      • Bardou-Jacquet E.
      • et al.
      Serum transferrin saturation increase is associated with decrease of antibacterial activity of serum in patients with HFE-related genetic hemochromatosis.
      ,
      • Jolivet-Gougeon A.
      • Ingels A.
      • Danic B.
      • Ussant-Bertel F.
      • Ferec C.
      • Loreal O.
      • et al.
      No increased seroprevalence of anti-Yersinia antibodies in patients with type 1 (C282Y/C282Y) hemochromatosis.
      ,
      • Bullen J.J.
      • Spalding P.B.
      • Ward C.G.
      • Gutteridge J.M.C.
      Hemochromatosis, iron, and septicemia caused by Vibrio vulnificus.
      ]. Study characteristics and a detailed description of the populations can be found in Table 2.
      Figure thumbnail gr1
      Fig. 1Flowchart of identification and selection of studies.
      Table 1Excluded studies based on the selection criteria for population (P), intervention (I) or outcome (O), with the reason for exclusion.
      Table 2Characteristics and main results of included studies.

      Quality of evidence

      All included studies were observational studies, including one case-series, which results in an initial ‘low level of evidence’. In three out of the six studies, risk of bias was found because of limitations in design: one study had high risk of recall bias [
      • Sanchez A.M.
      • Schreiber G.B.
      • Bethel J.
      • McCurdy P.R.
      • Glynn S.A.
      • Williams A.E.
      • et al.
      Prevalence, donation practices, and risk assessment of blood donors with hemochromatosis.
      ], another had lack of clearly defined in-/exclusion criteria [
      • Bullen J.J.
      • Spalding P.B.
      • Ward C.G.
      • Gutteridge J.M.C.
      Hemochromatosis, iron, and septicemia caused by Vibrio vulnificus.
      ], and a third study did not include a control group (case-series) [
      • Leitman S.F.
      • Browning J.N.
      • Yau Y.Y.
      • Mason G.
      • Klein H.G.
      • Conry-Cantilena C.
      • et al.
      Hemochromatosis subjects as allogeneic blood donors: a prospective study.
      ]. We did find consistency across the different studies. We also addressed indirectness: all studies included the study population of interest, but two of the six studies were in vitro studies, and all studies included secondary outcomes. Due to the limited number of included studies, it was difficult to evaluate publication bias. Because of limitations in design in three out of the six studies and the case-series design in one study, we did not upgrade the strength of the body of evidence. Overall, the strength of the body of evidence, based on the GRADE approach, is low to very low. An overview of the limitations in design of the individual studies is summarized in Table 2.

      Synthesis of findings

      One study evaluated parameters that give an indication of the effectiveness of blood of hemochromatosis patients for the purpose of blood transfusion [
      • Luten M.
      • Roerdinkholder-Stoelwinder B.
      • Rombout-Sestrienkova E.
      • De Grip W.J.
      • Bos H.J.
      • Bosman G.J.
      Red cell concentrates of hemochromatosis patients comply with the storage guidelines for transfusion purposes.
      ]. In this study, cell concentrates from hemochromatosis patients and regular donors were collected and stored up to 50 days. Samples were taken for analysis at the beginning and weekly thereafter. The outcome of interest was the mean cell volume (MCV): it was shown that red blood cells (RBCs) of hemochromatosis patients at time of collection had a larger MCV (mean, 99.4 fL; range, 87.4–105.6 fL) than the RBCs of regular donors (MCV; mean, 92.3 fL; range, 86.1–98.1 fL). This is probably due to the overall younger cell age of RBCs of hemochromatosis patients. In addition, during storage, the MCV of RBCs increased in both groups in a similar way with 10–15%. No clinically relevant significant differences could be found between the two groups for a large number of biochemical and biophysical variables including extracellular glucose concentration, extracellular concentration of sodium and potassium ions, intracellular 2,3-DPG levels, cellular ATP concentration, total adenylate content, pO2, pCO2, pH, and bicarbonate. Based on this study, it can be concluded that there is no evidence that blood derived from hemochromatosis patients does not comply with the quality requirements, and therefore is suitable for the purpose of blood transfusion from a hemato-physiological point of view.
      With regard to the safety of the blood, two studies evaluated transfusion-transmissible viral infections, one study measured antibacterial antibodies and two other in vitro studies tested susceptibility of the blood against bacteria. Based on an email survey filled in by blood donors from eight different US blood centers [
      • Sanchez A.M.
      • Schreiber G.B.
      • Bethel J.
      • McCurdy P.R.
      • Glynn S.A.
      • Williams A.E.
      • et al.
      Prevalence, donation practices, and risk assessment of blood donors with hemochromatosis.
      ], it was concluded that there is no statistically significant different prevalence of unreported deferrable risks (risk factors for transfusion-transmissible viral infections that should result in deferral if reported during donor screening) between hemochromatosis donors (during maintenance therapy) and donors reporting no medical conditions necessitating phlebotomy (prevalence 2.0% versus 3.1%, respectively). Based on laboratory screening tests, including screening for antibody to hepatitis B core antigen, syphilis, human immunodeficiency virus, hepatitis C virus, hepatitis B surface antigen, and human T-lymphotropic virus, no statistically significant difference could be found for hemochromatosis donors versus regular donors (overall prevalence of positive screening test results of 1.3% versus 1.6%, respectively).
      A second study analyzed 130 hemochromatosis patients with laboratory evidence of iron overload. Of these, 76% met FDA eligibility criteria applied for blood donation. Based on the ferritin level, phlebotomy was performed weekly to every 8 weeks, during a study period of 27 months. In every blood sample, serologic testing for (not specified) agents of transfusion-transmissible disease was performed and no incident seroconversions for agents of transfusion-transmissible disease occurred during this period [
      • Leitman S.F.
      • Browning J.N.
      • Yau Y.Y.
      • Mason G.
      • Klein H.G.
      • Conry-Cantilena C.
      • et al.
      Hemochromatosis subjects as allogeneic blood donors: a prospective study.
      ]. The findings from the latter two studies suggest that hemochromatosis patients do not present a greater risk to blood safety than other donors, at least with regard to viral infections.
      In three observational studies, including two in vitro studies, antibacterial activity of blood of hemochromatosis patients was compared with blood of regular donors. No significant increase in antibodies against several serogroups of Yersinia pseudotuberculosis (I to V) and Yersinia enterocolitica (O:3, O:9, O:5.27) could be found in the serum of hemochromatosis patients without complications (average iron concentration of 25 μmol/L (5.2–48) and ferritin 235 μg/L (6–4520), absence of diabetes, cardiomyopathy, inflammatory state, concomitant infection or immunity deficiency) as compared to control blood donors [
      • Jolivet-Gougeon A.
      • Ingels A.
      • Danic B.
      • Ussant-Bertel F.
      • Ferec C.
      • Loreal O.
      • et al.
      No increased seroprevalence of anti-Yersinia antibodies in patients with type 1 (C282Y/C282Y) hemochromatosis.
      ]. Furthermore, in blood samples from iron-depleted hemochromatosis patients, antibacterial activity against Salmonella typhimurium LT2 was shown to be the same as in samples from healthy donors [
      • Jolivet-Gougeon A.
      • Loreal O.
      • Ingels A.
      • Danic B.
      • Ropert M.
      • Bardou-Jacquet E.
      • et al.
      Serum transferrin saturation increase is associated with decrease of antibacterial activity of serum in patients with HFE-related genetic hemochromatosis.
      ]. In contrast, it was shown that there is a statistically significant decreased antibacterial activity against S. typhimurium LT2 and a better survival of Vibrio vulnificus in blood from iron-overloaded hemochromatosis patients when compared with samples from healthy people [
      • Jolivet-Gougeon A.
      • Loreal O.
      • Ingels A.
      • Danic B.
      • Ropert M.
      • Bardou-Jacquet E.
      • et al.
      Serum transferrin saturation increase is associated with decrease of antibacterial activity of serum in patients with HFE-related genetic hemochromatosis.
      ,
      • Jolivet-Gougeon A.
      • Ingels A.
      • Danic B.
      • Ussant-Bertel F.
      • Ferec C.
      • Loreal O.
      • et al.
      No increased seroprevalence of anti-Yersinia antibodies in patients with type 1 (C282Y/C282Y) hemochromatosis.
      ,
      • Bullen J.J.
      • Spalding P.B.
      • Ward C.G.
      • Gutteridge J.M.C.
      Hemochromatosis, iron, and septicemia caused by Vibrio vulnificus.
      ].
      In summary, there is no evidence showing that blood from uncomplicated hemochromatosis patients would be unsafe to use as donor blood. Moreover, the available evidence supports the use of blood from hemochromatosis patients for blood transfusions, at least after normalization of their ferritin status. Since two in vitro studies suggest that blood obtained from iron-overloaded patients would be more susceptible for bacterial growth, further studies are warranted here. An overview of the findings per study can be found in Table 2.

      Discussion

      Hemochromatosis patients need frequent therapeutic phlebotomies. In some countries, this blood is discarded and not used for transfusions because of the non-voluntary character of the donation and the assumption that this blood would be less safe with regard to the possible presence of viral or bacterial contaminations. In this article, we show that there is no evidence that this blood after normalization of the iron level is not safe for blood transfusion. Study selection was limited to studies describing the target population, i.e. hemochromatosis patients that apart from their known diagnosis, would otherwise be eligible to donate blood based on the other exclusion criteria for donors in general. Since irreversible organ damage is such an exclusion criterion, we did not take this subgroup of hemochromatosis patients into account.
      Evidence is scarce concerning this subject: from 3470 potentially relevant studies, we selected 80 studies that were relevant to the question, and retained only six studies that met the selection criteria. The reason for the low number of published studies may be (1) the low prevalence of transfusion-related infections, which necessitates large scale and long term studies, (2) logistic problems, implicating the follow-up of patients receiving the blood, or may be (3) ethical, because potentially unsafe blood should be transfused.
      Furthermore, the quality of the evidence available in the six included studies is low to very low. We downgraded the level of evidence due to indirectness, because all studies measured secondary outcomes. It would have been of greater interest to measure outcomes in patients receiving the blood (which we defined as primary outcome), however, such studies are lacking in the literature. One study measured blood effectiveness by determining hematologic variables, and for this study there were no limitations in design [
      • Luten M.
      • Roerdinkholder-Stoelwinder B.
      • Rombout-Sestrienkova E.
      • De Grip W.J.
      • Bos H.J.
      • Bosman G.J.
      Red cell concentrates of hemochromatosis patients comply with the storage guidelines for transfusion purposes.
      ]. Two studies measured the prevalence of viral infections [
      • Leitman S.F.
      • Browning J.N.
      • Yau Y.Y.
      • Mason G.
      • Klein H.G.
      • Conry-Cantilena C.
      • et al.
      Hemochromatosis subjects as allogeneic blood donors: a prospective study.
      ,
      • Sanchez A.M.
      • Schreiber G.B.
      • Bethel J.
      • McCurdy P.R.
      • Glynn S.A.
      • Williams A.E.
      • et al.
      Prevalence, donation practices, and risk assessment of blood donors with hemochromatosis.
      ], including a study without control group (case-series), testing blood samples from 130 hemochromatosis patients [
      • Leitman S.F.
      • Browning J.N.
      • Yau Y.Y.
      • Mason G.
      • Klein H.G.
      • Conry-Cantilena C.
      • et al.
      Hemochromatosis subjects as allogeneic blood donors: a prospective study.
      ]. Taking into account the very low incidence of transfusion-transmissible viral infections, this represents a very low number of test persons, which is a serious limitation in design. The other three selected studies evaluated the prevalence of bacterial infections, and at first sight the results of these studies were not consistent. In two in vitro studies it was shown that a higher risk for bacterial contamination is present in blood from iron-overloaded, but not from iron-depleted patients [
      • Jolivet-Gougeon A.
      • Loreal O.
      • Ingels A.
      • Danic B.
      • Ropert M.
      • Bardou-Jacquet E.
      • et al.
      Serum transferrin saturation increase is associated with decrease of antibacterial activity of serum in patients with HFE-related genetic hemochromatosis.
      ,
      • Bullen J.J.
      • Spalding P.B.
      • Ward C.G.
      • Gutteridge J.M.C.
      Hemochromatosis, iron, and septicemia caused by Vibrio vulnificus.
      ]. In a third study, the presence of anti-Yersinia antibodies in the blood of uncomplicated hemochromatosis patients was compared to control blood donors, and no significant difference could be found [
      • Jolivet-Gougeon A.
      • Ingels A.
      • Danic B.
      • Ussant-Bertel F.
      • Ferec C.
      • Loreal O.
      • et al.
      No increased seroprevalence of anti-Yersinia antibodies in patients with type 1 (C282Y/C282Y) hemochromatosis.
      ]. In this study, it is not clearly stated whether the included patients where iron-overloaded or iron-depleted. Because none of them had complications, presumably only a minority of the study group is in the iron-overloaded stage, and thus the results are in agreement with these of the other studies. Based on in vitro findings with iron-overloaded patients, and in the absence of more solid evidence concerning the risk of viral and bacterial infections in this subset of hemochromatosis patients, conclusions about accepting hemochromatosis patients as blood donors should be cautious and take into account the normalization of the iron level.
      In addition to the evidence, current practice also seems to support this finding. Because of the high prevalence of hereditary hemochromatosis in the general population, there is no doubt that in current practice of blood donations (with no routine testing of hemochromatosis parameters, as ferritin and transferrin saturation, nor of genetic testing), a substantial number of donations originate from carriers of the hemochromatosis gene. Until now, this practice has never resulted in documented serious adverse events in patients transfused with these blood products.
      Apart from concerns with regard to the safety of the blood of hemochromatosis patients, the non-altruistic character of the donation remains a potential argument for exclusion of hemochromatosis patients [
      • Conry-Cantilena C.
      Phlebotomy, blood donation, and hereditary hemochromatosis.
      ,
      • De Gonzalez G.L.
      Hereditary haemochromatosis and blood donation.
      ]. However, using the donor medical questionnaire in a rigorous way, rejecting the blood for further use if all donor criteria are not met, should address this concern. One way to eliminate potential financial incentives is by making all phlebotomies free to hemochromatosis patients, a measure that is already taken in some countries [
      • Pennings G.
      Demanding pure motives for donation: the moral acceptability of blood donations by haemochromatosis patients.
      ].
      In recent years, the British, French, German, and Swedish transfusion services already changed their policy with regard to hemochromatosis patients who require continued phlebotomies. In France, a multidisciplinary working group studied the subject in 2001, and re-evaluated the eligibility criteria for hemochromatosis patients as blood donors, because the discovery of the HFE gene in 1996 made it clear that hemochromatosis exists in many different variants [
      • Courtois F.
      • Danic B.
      Genetic hemochromatosis and blood donation.
      ]. Similar measures have been taken, outside Europe, in the US, Canada, and Australia [
      • Adams P.C.
      • Barton J.C.
      How I treat hemochromatosis.
      ,
      • Radojska S.
      • Hengeoz O.
      • Gathof B.
      Hereditary hemochromatosis patients/carriers as blood donors – a single center experience.
      ,
      • Buring M.L.
      Haemochromatosis: red cross blood service policy.
      ,

      Guidelines for the Blood Transfusion Services in the United Kingdom. seventh ed. London: TSO (The Stationary Office); 2005.

      ,

      Ministrial Order of the Government of France. Arrêté du 12 janvier 2009 fixants les critères de selection des donneurs de sang 2009.

      ], where hemochromatosis donor blood is being used for transfusion. However, increased hemovigilance is required in their operating policies and because of these logistical consequences, collection of hemochromatosis donor blood is still not implemented worldwide [

      U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research (CBER). Guidance for industry Variances for Blood Collection from Individuals with Hereditary Hemochromatosis 2001. Available from: http://www.fda.gov/cber/guidelines.htm.

      ].
      Figure thumbnail fx4
      Figure thumbnail fx5

      Conflict of interest

      The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
      All authors are working for the Belgian Red Cross-Flanders and receive no other funding. V.C. and P.V. are employees of the Belgian Red Cross-Flanders Blood Service.

      Acknowledgments

      P.V. and V.C. proposed the concept and question of the literature review and critically revised the manuscript. E.D.B. and N.S.P. performed the literature review and drafted the manuscript. T.D. was the third reviewer in case of disagreements and wrote the methodology section. All authors read and approved the final manuscript.
      This work came about partly because of years of perseverance of Prof. Johan Fevery, who as a hepatologist has always been an advocate for his patients.
      The authors would like to thank Martine Baeten (MD), Jan Carlier (MD) and José Coene (MD) from the Belgian Red-Cross Flanders Blood Service for their feedback on the first draft of the manuscript. In addition, we thank Johan Fevery (MD, PhD), Frederik Nevens (MD, PhD) and David Cassiman (MD, PhD), from the Department of Internal Medicine, Hepatology from the University Hospital of Leuven, Belgium, for their expert opinion on this subject and reading a draft of the manuscript.

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