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Original article
Transfusion of D positive red cells to selected D-negative patients
Transfusión de hematíes D positivo a pacientes seleccionados D negativo
Saoia Zalba Marcosa, María Luisa Antelo Caamañoa, Arkaitz Galbete Jiménezb, Pablo Rodriguez Wilhelmia, Alicia Aranguren Azparrena, José Antonio García Ercec,d,e,
Corresponding author
a Servicio de Hematología y Hemoterapia, Complejo Hospitalario de Navarra, Pamplona, Navarra, Spain
b Unidad de Metodología, Fundación Miguel Servet, NAVARRABIOMED-Centro de Investigación Biomédica, Unidad de Metodología, Pamplona, Navarra, Spain
c Banco de Sangre y Tejidos de Navarra, Servicio Navarro de Salud, Osasunbidea, Pamplona, Navarra, Spain
d Grupo de Trabajo de la Sociedad Española de Transfusión Sanguínea «Hemoterapia basada en sentido común», Spain
e Grupo Español de Rehabilitación Multimodal (GERM), Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">A routine practice in Transfusion Services &#40;TS&#41; is to transfuse ABO and D-compatible packed red blood cells &#40;PRBCs&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> However&#44; in situations of D-negative shortage&#44; it is a universally accepted resource to transfuse D-positive components into patients without expression of said antigen in their red cells&#46; The RHD-gene codes for the expression of the RhD protein in which the D antigen is detected&#46; D-negative patients in contact with D-positive red blood cells can develop isoimmunisation and produce anti-D alloantibodies&#46; The standards of the Accreditation Committee for Blood Transfusion&#44; Cell and Tissue Therapy indicate that TS must have a protocol for the use of D-positive PRBCs in D-negative receivers&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Although this measure has no additional risks during transfusion&#44; as already mentioned&#44; in some cases it can induce sensitization against the D &#40;Rh1&#41; antigen&#46; For this reason&#44; this change in D compatibility should only be used in patients who have not been previously sensitized and within a protocol or clinical care pathway&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The development of irregular antibodies could cause haemolysis in the patient in case of new exposure to the D antigen&#44; both due to a subsequent transfusion and to pregnancies&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> For this reason&#44; it is vitally important to avoid transfusion of D-positive PRBCs into D-negative childbearing age women&#44; because transfusion-stimulated D immunization can cause severe haemolytic disease of the new-born in subsequent pregnancies with a D-positive fetus&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Likewise&#44; it is also recommended to avoid this transfusion practice in negative D patients in whom chronic or subsequent transfusion support is foreseen&#44; to minimize the risks of isoimmunisation in these cases&#46; In these patients&#44; the probability of isoimmunisation increases due to continued exposure&#44; therefore it is preferable to avoid this practice&#44; which could later also facilitate the development of other alloantibodies in addition to anti-D&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In this article&#44; we report the experience of a clinical care pathway of a tertiary centre&#46; Unlike other articles related to this topic&#44; an analysis of the survival of patients treated with a D-positive PRBCs transfusion is also provided&#44; looking for predictive mortality and isoimmunisation factors&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Objectives</span><p id="par0025" class="elsevierStylePara elsevierViewall">To analyze the incidence of isoimmunisation and the medium and long-term survival in a selected group of D-negative patients transfused with one or more D-positive leukoreduced PRBCs in a public reference health centre&#46; Analyze those D-negative patients who have anti-D isoimmunisation and analyze their survival comparing them with the general population&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Patients and methods</span><p id="par0030" class="elsevierStylePara elsevierViewall">A retrospective analysis is performed from a monitoring record of all D-negative patients who required the administration of at least one D-positive PRBC unit in a tertiary hospital centre&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">In this analysis&#44; medium and long-term mortality was assessed&#44; as well as the presence of &#8220;<span class="elsevierStyleItalic">isoimmunisation</span>&#8221; or demonstration of the presence of D-antigen-specific antibodies in the serum of D-negative patients transfused with D-positive red blood cells&#44; previously negative for said antigenic specificity&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Data source</span><p id="par0040" class="elsevierStylePara elsevierViewall">The records of the transfusion management software app&#46; &#40;e-Delphyn&#174; version 8&#46;0&#46;17&#46;2 from Hemasoft&#59; Valladolid&#44; Spain&#41; and clinical data&#44; collected in the electronic medical records &#40;owned by the Navarre Health Service-Osansunbidea&#41; were used as sources of information&#46; The e-Delphyn&#174; app&#46; collects the transfusion history of all donors and patients of the Public Network of the Comunidad Foral de Navarra&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The haemovigilance record of the data quality management program module &#40;BDI 9000&#44; from Tecnoquality&#174;&#44; Madrid Spain&#41; was also reviewed&#46; The databases of the National Institute of Statistics &#40;INE&#59; <a href="https://www.ine.es/dyngs/INEbase/es/operacion.htm?c=Estadistica_C%26cid=1254736177004%26menu=ultiDatos%26idp=1254735573002">https&#58;&#47;&#47;www&#46;ine&#46;es&#47;dyngs&#47;INEbase&#47;es&#47;operacion&#46;htm&#63;c&#61;Estadistica&#95;C&#38;cid&#61;1254736177004&#38;menu&#61;ultiDatos&#38;idp&#61;1254735573002</a>&#41; and the Navarre Statistical Institute &#40;&#40;na&#41; stat&#59; <a href="https://administracionelectronica.navarra.es/gn.institutoestadistica.web/InformacionEstadistica.aspx?R=1%26E=1">https&#58;&#47;&#47;administracionelectronica&#46;navarra&#46;es&#47;gn&#46;institutoestadistica&#46;web&#47;InformacionEstadistica&#46;aspx&#63;R&#61;1&#38;E&#61;1</a>&#41; for the mean mortality age of the reference population were consulted&#46; The last isoimmunisation review was performed on 31st December 2018&#44; through the site&#39;s transfusion management program &#40;e-Delphyn&#41;&#46; Mortality was recorded on the same date through access to the demographic data of the electronic medical records&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Time period</span><p id="par0050" class="elsevierStylePara elsevierViewall">All D-positive PRBCs transfusion cases carried out to D-negative patients in the Hospital Complex of Navarre from 1st January 2001 to 31st December 2018 &#40;from 2001 to October 2014&#44; old Hospital of Navarre&#44; which after this date joined Hospital Virgen del Camino&#44; creating the current Hospital Complex of Navarre&#41; have been reviewed&#46; Currently&#44; the Complex has about 1000 beds and its transfusion activity is around 15&#44;000 PRBCs per year&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Source</span><p id="par0055" class="elsevierStylePara elsevierViewall">Our only provider is the Navarre Blood and Tissue Bank&#44; which keeps the available stock updated on a daily basis and notifies the TS in the event that the D-negative PRBCs stock is insufficient to maintain the agreed minimum based on average consumption&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Protocol</span><p id="par0060" class="elsevierStylePara elsevierViewall">The clinical care protocol was prepared by the TS of the Hospital de Navarre and approved by the head of the Haematology and Hemotherapy Service of said centre in 2001&#46; Likewise&#44; it was submitted and approved by the Hospital Transfusion Committee in the same year &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">When one or more units of D-positive PRBCs have been transfused into a D-negative patient&#44; in case of receiving a new request for blood components&#44; in addition to typing and irregular antibody screening &#40;IAS&#41; established as standard &#40;RD 1088&#47;2005&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> in our laboratory&#44; an extended screening was carried out in a ficin enzyme medium &#40;using the Surgiscreen 0&#46;8&#37; and BioVue 0&#46;8&#37; from Ortho Clinical Diagnostics&#174;&#44; Ortho Clinical Diagnostics Spain&#44; S&#46;L&#46;&#41;&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">The prescribing doctors responsible for the transfused patients were responsible for obtaining the informed consent for the transfusion&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Variables</span><p id="par0075" class="elsevierStylePara elsevierViewall">Total PRBCs transfused&#44; number of patients&#44; D-negative patients&#44; transfusion rate per transfused patient&#44; and mean age of the transfused population were reviewed&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">In addition&#44; demographic variables were recorded&#58; age&#44; volume or number of D-positive PRBCs &#40;diagnosis&#44; irregular antibody screening and number of plasma units or D-positive platelets received by these patients&#41;&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Detected <span class="elsevierStyleItalic">de novo</span> isoimmunisations were collected &#40;in patients who required pretransfusion testing after the transfusion of D-positive PRBCs to D-negative patient&#41;&#46; Possible notifications of alloimmune haemolysis reaction &#40;acute or delayed&#41; were reviewed in the records of the Haemovigilance System&#46; The medical and administrative records in the files of all the patients of the transfusion management software app&#46; were reviewed and no reaction of alloimmune haemolysis&#44; acute or delayed&#44; was collected in these patients&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">In addition&#44; end-follow-up survival data and annual post-transfusion mortality rates were obtained&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Statistical analysis</span><p id="par0095" class="elsevierStylePara elsevierViewall">The variables collected were&#58; gender&#44; age&#44; diagnosis&#44; reason for transfusion&#44; components transfused&#44; seroconversion &#40;yes&#47;no&#41;&#44; haemolysis &#40;yes&#47;no&#41;&#44; mortality &#40;yes&#47;no&#41; and time to event&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">The age variable has been described with mean and range&#44; and also categorically and showing frequency and percentages&#46; The number of PRBCs has been summarized by mode for the total and mean sample &#40;standard deviation &#91;SD&#93;&#41; to compare the seroconversion groups&#46; The rest of the variables have been described using frequencies and percentages&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The association of age and number of PRBCs with seroconversion was studied using the <span class="elsevierStyleItalic">t</span> test and the association of global mortality with the variables age groups&#44; number of PRBCs&#44; diagnosis&#44; screening for irregular antibodies and plasma&#47;platelets calculating Kaplan&#8211;Meier survival curves and log-rank test&#46; A multivariate Cox model has been adjusted for global mortality including all the variables studied in the univariate analysis&#46; A significance level of 0&#46;05 has been considered and the analyses have been performed with R software v&#46;3&#46;4&#46;3 and IBM SPSS statistics&#44; v&#46; 25&#46;0 &#40;Navarre Biomed License&#59; IBM Corporation&#44; Somers&#44; NY&#44; USA&#41;&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Ethics</span><p id="par0110" class="elsevierStylePara elsevierViewall">As it was a clinical care protocol and due to the nature of the registry &#40;anonymized&#41;&#44; its retrospective search and high mortality&#44; it was not necessary to request a specific informed consent for this study&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The study was presented to members of the Clinical Research Ethics Committee of Navarre&#44; who did not consider it necessary to process any additional report by this committee given the nature of the study and the fact that all the data were pooled&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Results</span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Global transfusion activity 2001&#8211;2018</span><p id="par0120" class="elsevierStylePara elsevierViewall">During the analyzed period&#44; 225&#44;132 PRBCs were transfused into 45&#44;350 patients&#59; 8719 patients were group D-negative &#40;19&#46;23&#37;&#41; &#40;annual range 13&#8211;23&#37;&#41; &#40;Appendix B&#44; supplementary Table 1&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; The annual iso-D transfusion rate exceeds 95&#37;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0125" class="elsevierStylePara elsevierViewall">The mean age of transfused patients in the historical series is 70 years &#40;mode 70&#41;&#44; remaining stable throughout the years of the study for the global cohort of patients&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Description of patients included in the transfusion protocol from D-positive PRBCs to patient D-negative</span><p id="par0130" class="elsevierStylePara elsevierViewall">Since 2001&#44; a total of 797 D-positive PRBCs have been transfused into 252 D-negative patients&#59; this has represented 0&#46;35&#37; of the total PRBCs transfused in the period studied&#46; Of all 8719 transfused D-negative patients&#44; only 252 &#40;2&#46;9&#37; of D-negative and 0&#46;55&#37; of the entire series&#41; of them could not receive PRBCs D-negative at some given time&#46; Three patients were excluded from the statistical analysis because not all the study data were available&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Most of the patients were male&#58; 158 compared to 94 women&#46; The mean age was 74&#46;9 years and the mode 81 years &#40;minimum 41 and maximum 94&#41; in men&#46; The mean was 79&#46;8 years and the mode 83 years for women &#40;minimum 52 and maximum 98&#41;&#46; The age distribution was&#58; 59 &#40;23&#46;4&#37;&#41; under the age of 70&#59; 97 &#40;38&#46;5&#37;&#41; between 70 and 80 years old&#44; and 96 &#40;38&#46;1&#37;&#41; over 80 years old&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">The reason or disease of the transfused patients is shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; 38&#46;7&#37; &#40;96&#41; of patients were transfused in the context of <span class="elsevierStyleItalic">elective surgery</span>&#44; with <span class="elsevierStyleItalic">orthopaedic-trauma surgery</span> being the most common within this group&#44; with 32 patients&#44; the majority having undergone hip surgery&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0145" class="elsevierStylePara elsevierViewall">The mode of units transfused was 2 D-positive PRBCs per patient&#44; 131 patients &#40;52&#46;6&#37;&#41; transfused with 2 PRBCs&#44; 97 patients &#40;39&#37;&#41; received more than 2 PRBCs&#44; with a maximum of 24 PRBCs and a mean of 3&#46;2 PRBCs&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Regarding the main blood groups&#44; 139 patients were group O and 108 group A&#44; 3 group B and 2 group AB&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Twenty-five of these D-positive PRBCs transfused patients also received D-positive plasma or platelets&#44; which is 10&#37;&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Isoimmunisation</span><p id="par0160" class="elsevierStylePara elsevierViewall">No new blood components were required by 54&#46;3&#37; of the patients included in the analyzed registry during the post-transfusion observation period in any public hospital in our community&#46; Pretransfusion testing was requested after at least 3 months of exposure for 31&#46;7&#37; of patients &#40;<span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>80&#41;&#44; 32 &#40;40&#37;&#41; of whom developed irregular antibodies &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0165" class="elsevierStylePara elsevierViewall">Thirteen patients were isoimmunised exclusively against antigen D &#40;Rh1&#41;&#44; 8 patients against antigens D and C &#40;Rh2&#41;&#44; 3 patients against antigens D and E &#40;Rh3&#41; and 3 other patients against antigens D&#44; E and C&#46; Furthermore&#44; in 5 patients&#44; additional isoimmunisations were detected besides the one developed against the Rh system &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Five of the <span class="elsevierStyleItalic">isoimmunised</span> patients had also received D-positive platelets &#40;15&#37;&#41;&#44; compared to only 2 patients in the <span class="elsevierStyleItalic">non-immunized</span> group &#40;4&#37;&#41;&#46; In no case was anti-RhD gamma globulin administered after D-platelet transfusion&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">The mean D-positive PRBCs transfused in the immunized group was higher than that of the <span class="elsevierStyleItalic">non-immunized</span> group&#58; 3&#46;9 PRBCs on average &#40;SD 2&#46;6&#41; versus 2&#46;6 PRBCs &#40;SD 1&#46;7&#41;&#44; statistically significant difference &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;019&#41;&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">The mean age in the <span class="elsevierStyleItalic">immunized</span> patient group is 71&#46;7 years &#40;SD 11&#46;0&#41;&#44; lower than in the group of <span class="elsevierStyleItalic">non-immunized</span>&#44; which is 75&#46;4 years &#40;SD 9&#46;4&#41;&#44; a non-statistically significant difference &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;112&#41;&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Despite the fact that 32 patients were immunized and that 26 of them needed to be transfused again&#44; there was no difficulty in transfusing units lacking the antigens against which they had created antibodies&#46; Post-transfusion haemolytic anaemia was not detected in any case&#46; Neither was delayed haemolysis nor acute transfusion haemolytic reaction recorded or reported&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Breach of protocol</span><p id="par0190" class="elsevierStylePara elsevierViewall">It is not possible to estimate how many patients were not included in the protocol&#44; even when they met the criteria for it&#46; In contrast&#44; 2 D-negative patients were transfused with D-positive&#44; although there was no evidence of a shortage of negative D-unit stock&#46; In 2015&#44; a 75-year-old woman with iron deficiency anaemia&#44; who had not received subsequent transfusions and whose <span class="elsevierStyleItalic">isoimmunisation</span> status was unknown&#44; was still alive&#46; And in 2016&#44; an 81-year-old man suffering from myelodysplastic syndrome who had not been isoimmunised after one month and who died 2 months after the transfusion&#46; Both cases were reported as &#8220;<span class="elsevierStyleItalic">component administration</span><span class="elsevierStyleItalic">error</span>&#8221; to the autonomous haemovigilance registry&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Survival results</span><p id="par0195" class="elsevierStylePara elsevierViewall">Median survival was 36&#46;6 months &#40;95&#37; CI&#44; 26&#46;9&#8211;54&#46;7&#41;&#46; The median follow-up time was 37 months &#40;3&#46;1 years&#41;&#44; with a total follow-up of 1010 people&#47;year&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Of the 249 D-positive PRBCs transfused patients&#44; 171 &#40;68&#46;7&#37;&#41; died during follow-up&#46; The 1-year mortality rate was 35&#46;9&#37; &#40;29&#46;6&#8211;41&#46;6&#41; and 59&#46;1&#37; &#40;52&#46;4&#8211;64&#46;9&#41; at 5 years&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">Mortality in patients aged &#8804;80 years was less than 60&#37; vs&#46; 84&#37; in those over 80 years of age &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>a shows the survival curve according to age group&#46; There is a clear difference in the survival of the different age groups&#44; the group over 80 years is the one with the highest mortality&#44; with the difference being statistically significant&#46; There are no significant differences between those below 70 and those between 70 and 80 years of age&#46; A statistically significant difference in mortality &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41; was also observed according to the diagnostic group &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>a and b&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0210" class="elsevierStylePara elsevierViewall">Differences are observed in the survival curves regarding the different groups of the IAS variable &#40;<span class="elsevierStyleItalic">p</span> long-rank test value<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;037&#41;&#46; The group of patients with positive IAS has a longer survival than the group with negative or unknown IAS&#44; which behave similarly&#46; If we exclusively compare the <span class="elsevierStyleItalic">immunized</span> group &#40;IAS-positive&#41; with the <span class="elsevierStyleItalic">non-immunized</span> group &#40;IAS-negative&#41;&#44; it shows a statistically significant difference &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;005&#59; chi squared&#41;&#44; greater survival in <span class="elsevierStyleItalic">immunized</span> patients &#40;77&#46;1&#37; vs&#46; 43&#46;8&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0215" class="elsevierStylePara elsevierViewall">Conversely&#44; no survival differences were found between patients who had received another blood component compared to those who had not &#40;68&#37; vs&#46; 68&#37;&#41;&#59; nor according to the number of PRBCs units transfused&#58; &#8220;2 or less&#8221; vs&#46; &#8220;more than 2&#8221; &#40;68&#46;4&#37; vs&#46; 69&#46;1&#37;&#41; &#40;<span class="elsevierStyleItalic">p</span> value<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;18&#41;&#46; There were also no differences in survival between patients who were transfused with platelets or plasma in addition to PRBCs compared with those who only received PRBCs &#40;<span class="elsevierStyleItalic">p</span> value<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;65&#41;&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Multivariate analysis</span><p id="par0220" class="elsevierStylePara elsevierViewall">The results are very similar to those obtained in the univariate analysis&#46; Age &#40;now as continuous&#44; for adjustment purposes&#41;&#44; diagnosis and IAS appear as significant variables in the model&#46; Correlations between groups are also maintained&#46; The risk of mortality increases by 3&#37; for each patient&#39;s age year&#46; Compared with elective surgery&#44; haematology-oncology patients have 4 times more risk of mortality &#40;HR 3&#46;95&#44; 95&#37; CI &#91;2&#46;50&#8211;6&#46;26&#93;&#41;&#44; those of massive transfusion almost 2 times more&#44; those of gastrointestinal disease 2&#46;6 times more and those of other anaemias 2&#46;3 times more &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> and Appendix B&#44; supplementary Table 2&#41;&#46;</p></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Discussion</span><p id="par0225" class="elsevierStylePara elsevierViewall">The results shown demonstrate the feasibility and safety of our protocol for transfusing D-positive red blood cells into a selected D-negative patient population&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">During the last 18 years&#44; 45&#44;132 patients &#40;8719 D-negative patients&#41; have been transfused&#44; with more than 225&#44;000 PRBCs&#46; D-positive PRBCs transfusions were needed in less than 3&#37; of D-negative patients&#46; Of the patients who developed antibodies against the D system after the application of this protocol&#44; only 0&#46;35&#37; required a new transfusion&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">Regarding the probability of isoimmunisation&#44; 31 D-negative patients developed anti-D alloantibodies&#44; a figure that represents 12&#46;3&#37; of D-negative patients who received D-positive PRBCs&#46; However&#44; if we consider the patients studied as a representative sample of our global population&#44; we could conclude that 40&#37; of D-positive PRBCs transfused patients are immunized&#46; This explains why only 31&#46;7&#37; of D-negative patients transfused with D-positive underwent a subsequent IAS&#46; This percentage is similar to that detected by other authors&#44; although there are few studies and the degree of variability is important&#44; being lower in hospitalized patients &#40;20&#8211;41&#46;7&#37;&#41; compared to the healthy population&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#8211;9</span></a> This high variability could be due to the different alloantibody identification methods&#46; In our case&#44; the additional use of an enzyme medium &#40;ficin&#41; increases detection sensitivity&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">Taking into account the basic principles of immunohematology&#44; the antigenic capacity of the RhD antigen<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> and that the protocol is based on selecting patients with a lower risk of developing alloantibodies against D antigen&#44; the results obtained have been in line with our objective&#46; There have been no subsequent problems with transfusion support in isoimmunised patients&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">The highest incidence of isoimmunisation has been detected against the D antigen &#40;Rh1&#41;&#44; clearly higher than for the rest of the Rh system antigens&#46; Although this data is expected according to the immunogenicity <span class="elsevierStyleItalic">score</span> already known for the D antigen&#44; it is true that we do not know the phenotypic differences regarding the rest of the antigens between the recipient and the transfused PRBCs&#46; Primary immunization of a D-negative patient&#44; after transfusion of D-positive PRBCs&#44; usually leads to the occurrence of an anti-D alloantibody in approximately 80&#8211;90&#37; of cases in studies with healthy volunteers&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#8211;13</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">The group of patients with the highest probability of isoimmunisation are the youngest and with the highest number of transfused PRBCs&#58; more immunocompetent and with greater antigenic exposure&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;15</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">Isoimmunisation against D antigen after exposure to D-positive platelet units is also described&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> The percentage of platelet-related isoimmunisation is also highly variable according to the literature&#44; from 0&#8211;7&#37;<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17&#44;18</span></a> up to 19&#37;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#8211;21</span></a> &#40;variability related to the type of platelets and the clinical condition of the patient&#44; as well as the use of anti-D gammaglobulin prophylaxis&#41;&#46; However&#44; in our study&#44; the fact that more isoimmunisations were observed among patients who also received D-positive platelets may be due to a bias for the number of PRBCs transfused &#40;according to the multivariate analysis&#41;&#46; We did not consider that it was due to the administration of platelets contaminated with D-positive red blood cells&#44; but rather&#44; because they were polytransfused patients &#40;in the context of massive transfusion&#41;&#44; with a higher risk of isoimmunisation&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">One of the main objectives when selecting patients who could receive D-positive PRBCs even though they were D-negative was that they were less likely to need transfusions in the future&#46; The 135 patients who did not require a subsequent transfusion &#40;53&#46;6&#37; of the 252 patients who were included in the protocol&#41; are the ideal candidates to transfuse without D-compatibility compliance in cases of need&#46; We consider that the patient selection criterion was correct&#44; given that more than half of the patients did not require a subsequent transfusion&#44; and also because the isoimmunisation rate was low&#44; without any reported haemolytic reaction&#46; This group of patients does not have higher mortality than those subsequently transfused &#40;68&#37; vs&#46; 71&#37;&#41;&#44; so this would not be the cause&#46; Most of these patients belong to the group of elective surgeries&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">The great commitment of TS professionals to compliance with the protocol has led to the detection of protocol deviation in only 2 patients &#40;2 transfusion errors reported&#41;&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">The survival differences that we have detected when doing the analysis by diagnostic groups &#40;<span class="elsevierStyleItalic">p</span> value<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41; are also consistent with what is expected in any other population with similar characteristics and to which this protocol would not have been applied&#46; Thus&#44; patients with elective surgery had a greater survival than the other groups&#46; Haematology-oncology patients were the ones with the lowest survival&#44; followed by massive transfusions&#44; in which higher mortality was also detected&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">Erythrocytic isoimmunisation is not a risk factor for increased mortality in the patients studied&#46; In fact&#44; the isoimmunised group has a greater survival compared to the non-immunized group&#46; This&#44; more than a predictive factor&#44; is possibly a bias because the patients of elective non-cancer surgery&#44; as well as those of massive transfusion&#44; were younger and more immunocompetent than those of older age &#40;with shorter life expectancy&#41;&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">Fortunately&#44; the high donation rate in our community has meant having to implement the protocol on very few occasions&#46; Furthermore&#44; the need would have probably been reduced with the current &#8220;restrictive criteria&#8221; for transfusion&#44; or for a &#8220;single unit&#8221; &#40;<span class="elsevierStyleItalic">one at a time and with re-evaluation</span>&#41;&#44; something that we cannot affirm&#44; since transfusion adequacy has not been analysed&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#8211;28</span></a> Blood transfusion is one of the most overused medical interventions&#44; with the highest number of &#8220;Do not do&#8221; recommendations&#46; The dissemination and application of these universally accepted recommendations&#44; together with the implementation of &#8220;Patient Blood Management&#8221; programs&#44;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> possibly makes it not necessary to apply protocols similar to ours on a regular basis&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">30&#44;31</span></a></p><p id="par0285" class="elsevierStylePara elsevierViewall">In summary&#44; and as strengths of this study&#44; we want to highlight the high number of transfusions analyzed and the long-term follow-up&#46; Furthermore&#44; thanks to the fact that in the Autonomous Community of Navarre there is a computer system for the management of transfusion&#44; common to all public hospitals&#44; which has facilitated optimal patient monitoring &#40;being able to obtain information on the results of immunohematology studies and of the transfusions of the patients who had been included in the protocol regardless of whether they had subsequently been treated in a different hospital&#44; within the autonomous community&#41;&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall">A possible weakness of our study is the fact that we do not have immunological monitoring data for patients who did not require a pretransfusion study after applying this measure&#46;</p><p id="par0295" class="elsevierStylePara elsevierViewall">As final findings&#44; we consider that the results of this study allow us to conclude that the transfusion policy of this protocol in our centre is correct&#44; taking into account the acceptable isoimmunisation rate&#44; the absence of haemolytic reactions and the lack of increased mortality in these patients&#46; For this reason&#44; in those centres where obtaining D-negative blood represents a problem&#44; they can transfuse with D-positive blood based on a clinical care protocol in selected patients&#44; especially in older patients&#44; without an increase in morbidity and mortality being detected&#46;</p><p id="par0300" class="elsevierStylePara elsevierViewall">To the best of our knowledge&#44; unless otherwise stated&#44; this would be the study with the longest follow-up time &#40;18 years&#41; and the largest number of patients included&#44; which also analyses the risks of isoimmunisation&#44; possible haemolysis&#44; and especially the impact of these policies in terms of survival applicable to the general population of hospitalized patients&#46; For these reasons we consider that it adds value to the subject under study&#46;</p><p id="par0305" class="elsevierStylePara elsevierViewall">Haemotherapy is considered by some authors as the first example of &#8220;<span class="elsevierStyleItalic">personalized&#8221;</span> medicine &#40;Dr&#46; Pereira&#44; personal communication&#41;&#46; The identification of patients with low risk of isoimmunisation allows us to apply a clinical protocol for the selection of adequate blood components&#44; in case exposure to highly immunogenic antigens is necessary&#44; when there is a shortage of allogeneic blood&#44; a very limited commodity&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Ethical responsibilities</span><p id="par0310" class="elsevierStylePara elsevierViewall">No animal testing has been carried out&#46; The Declaration of Helsinki was observed&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Funding</span><p id="par0315" class="elsevierStylePara elsevierViewall">Nil&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Conflict of interests</span><p id="par0320" class="elsevierStylePara elsevierViewall">The authors have no conflict of interest to declare&#46;</p></span></span>"
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              "titulo" => "Global transfusion activity 2001&#8211;2018"
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              "titulo" => "Description of patients included in the transfusion protocol from D-positive PRBCs to patient D-negative"
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              "identificador" => "sec0070"
              "titulo" => "Isoimmunisation"
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              "identificador" => "sec0075"
              "titulo" => "Breach of protocol"
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    "fechaRecibido" => "2019-03-20"
    "fechaAceptado" => "2019-07-18"
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          "clase" => "keyword"
          "titulo" => "Keywords"
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            0 => "D-negative"
            1 => "Red cell blood transfusion"
            2 => "Compatibility"
            3 => "Pretransfusional crossmatch"
            4 => "Alloimmunisation"
            5 => "Mortality"
            6 => "Haemovigilance"
            7 => "Do not do"
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          "palabras" => array:8 [
            0 => "D negativo"
            1 => "Transfusi&#243;n sangu&#237;nea"
            2 => "Compatibilidad"
            3 => "Pruebas de compatibilidad"
            4 => "Aloinmunizaci&#243;n"
            5 => "Mortalidad"
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      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To transfuse packed red blood cells isogroup ABO D is a usual transfusion practice&#46; However&#44; when there is not enough D-negative blood available&#44; we can transfuse positive red blood cells to negative patients&#46; Immunocompetent D-negative individuals may develop serologically detectable anti-D antibodies within 3 months after exposure to D-positive red blood cells&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and method</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Over the last 18 years&#44; we have experienced situations of D-negative blood cell scarcity&#46; In these situations&#44; we have applied a clinical assistance protocol&#44; selecting patients with lower risk of alloimmunization and chronic transfusion requirements&#46; We have retrospectively evaluated this policy for the use of D-positive red blood cells in D-negative patients&#44; focussing on alloimmunization and mortality&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Applying the protocol&#44; 3&#37; of D-negative patients were transfused with D-positive units&#44; with an alloimmunization rate of 12&#46;3&#37;&#46; The rate of alloimmunization was higher in the younger age group and in those transfused with more units&#46; No haemolytic reactions were reported&#46; Mortality in the alloimmunized group was lower&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The use of D-positive red blood cells in selected D-negative patients does not induce adverse reactions&#44; is a safe practice and allows saving of a product that is sometimes limited&#46;</p></span>"
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          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Background"
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          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Material and method"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La transfusi&#243;n isogrupo ABO D es la pr&#225;ctica transfusional habitual&#44; sin embargo&#44; cuando no se dispone de sangre D negativo puede ser preciso transfundir concentrados de hemat&#237;es D positivo a pacientes D negativo&#46; Estos pacientes pueden desarrollar aloanticuerpos anti-D en los siguientes 3 meses a la exposici&#243;n&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todo</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">En los &#250;ltimos 18 a&#241;os&#44; hemos experimentado situaciones de escasez de sangre D negativo&#44; en las que hemos aplicado un protocolo cl&#237;nico asistencial&#44; seleccionando s los pacientes seg&#250;n el riesgo de aloinmunizaci&#243;n y de requerimientos transfusionales cr&#243;nicos&#46; Se realiz&#243; una recogida prospectiva de estos pacientes&#44; analizando principalmente la aloinmunizaci&#243;n y la mortalidad&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Tras las aplicaci&#243;n del protocolo se han transfundido unidades D positivo al 3&#37; de los pacientes D negativo&#44; con una tasa de aloinmunizaci&#243;n conocida del 12&#44;3&#37;&#44; siendo mayor en los pacientes m&#225;s j&#243;venes y en aquellos que han recibido mayor n&#250;mero de unidades&#46; No se detectaron complicaciones secundarias a la inmunizaci&#243;n y la mortalidad en este grupo fue menor&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La transfusi&#243;n de hemat&#237;es D positivo a pacientes D negativo no solo es una pr&#225;ctica segura para pacientes seleccionados&#44; sino que adem&#225;s permite optimizar el uso de un producto en situaciones de escasez&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Zalba Marcos S&#44; Antelo Caama&#241;o ML&#44; Galbete Jim&#233;nez A&#44; Rodriguez Wilhelmi P&#44; Aranguren Azparren A&#44; Garc&#237;a Erce JA&#46; Transfusi&#243;n de hemat&#237;es D positivo a pacientes seleccionados D negativo&#46; Med Cl&#237;n&#46; 2020&#59;154&#58;425&#8211;432&#46;</p>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">D-positive to D-negative patient transfusion protocol&#46;</p>"
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Mortality according to the development or not of irregular antibodies&#46;</p>"
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                  \t\t\t\t">1&#46;30 &#40;0&#46;93&#8211;1&#46;81&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;123&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diagnosis</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Elective surgery&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ref&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Haematology-oncology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;95 &#40;2&#46;50&#8211;6&#46;26&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Massive transfusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;92 &#40;1&#46;02&#8211;3&#46;63&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Non-neoplastic gastrointestinal pathology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;58 &#40;1&#46;61&#8211;4&#46;12&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Other anaemias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;28 &#40;1&#46;48&#8211;3&#46;51&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IA screening</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ref&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;48 &#40;0&#46;25&#8211;0&#46;89&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;002&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;32 &#40;0&#46;90&#8211;1&#46;93&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Multi-component</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ref&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#46;32 &#40;0&#46;71&#8211;2&#46;43&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;375&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No&#46; of pat&#46; isoimmunised&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">D<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>E&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">D<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>C<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>E&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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    "bibliografia" => array:2 [
      "titulo" => "References"
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          "identificador" => "bibs0015"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Guide for transfusi&#243;n of blood components Sociedad Espa&#241;ola de Transfusi&#243;n Sangu&#237;nea"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46; Ortiz"
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                            2 => "M&#46; Lozano"
                            3 => "M&#46;A&#46; Vesga"
                            4 => "J&#46;R&#46; Grifols"
                            5 => "A&#46; Castrillo"
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                        "tituloSerie" => "Med Clin &#40;Barc&#41;"
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                        "paginaInicial" => "389"
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                      "titulo" => "Est&#225;ndares en transfusi&#243;n sangu&#237;nea&#46; CAT"
                    ]
                  ]
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                    0 => array:1 [
                      "Libro" => array:4 [
                        "edicion" => "4th ed&#46;"
                        "fecha" => "2016"
                        "editorial" => "Grupo Acci&#243;n M&#233;dica"
                        "editorialLocalizacion" => "Barcelona"
                      ]
                    ]
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                ]
              ]
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                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Inmunohematolog&#237;a b&#225;sica y aplicada"
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