efs.sante.fr The best blood donor and blood product for each patient: an evolving role for haemovigilance? Pierre Tiberghien Etablissement Français du

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1 The best blood donor and blood product for each patient: an evolving role for haemovigilance? Pierre Tiberghien Etablissement Français du Sang, St-Denis Université de Franche-Comté, Besançon France

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6 Transfusion thresholds A large number of studies have highlighted that low/restrictive (vs high/liberal) RBC transfusion thresholds in most clinical settings are not only not associated with increased morbidity or mortality, but may possibly associated with improved outcome.

7 Transfusion thresholds A large number of studies have highlighted that low/restrictive (vs high/liberal) RBC transfusion thresholds in most clinical settings are not only not associated with increased morbidity or mortality, but may possibly associated with improved outcome. Clinicaltrials comparing the effects of restrictive versus liberaltransfusion on 30-day mortality (Carson et al, NEJM, 2017) Despite these findings, insuring adequate hemoglobin thresholds for RBC transfusion through education and reporting of deviation to appropriate guidelines are not presently a mainstay of a majority of hemovigilance programs.

8 Thresholds require specificity. NEJM, patients with severe acute upper gastrointestinal bleeding and randomly assigned to a restrictive strategy (transfusion when the hemoglobin level fell below 7 g per deciliter) or a liberal strategy (transfusion when the hemoglobin fell below 9 g per deciliter) Kaplan Meier estimates of the 6-week survival rate in the two groups. The probability of survival was significantly higher in the restrictive-strategy group than in the liberal-strategy group. The gray arrows indicate the day on which data from a patient were censored. The inset shows the same data on an enlarged y axis.

9 NEJM, children with sickle cell anemia randomized to receive regular blood transfusions (transfusion group) or standard care (observation group). Conclusion: regular blood-transfusion significantly reduced the incidence of recurrence of cerebral infarct in children with sickle cell anemia.

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11 Critical Care, 2010 Physiologic transfusion triggers should progressively replace arbitrary Hb-based transfusion triggers. Goal-directed erythrocyte transfusions to promote and optimize therapeutic adequacy while saving blood and avoiding unwanted adverse effects These physiologic transfusion triggers can be based on signs and symptoms of impaired global (lactate, SvO2 or ScvO2) or, even better, regional tissue (such as EKG ST-segment or P300 latency) oxygenation as well as heart rate and mean arterial pressure or systolic arterial pressure.

12 Critical Care, 2010 Physiologic transfusion triggers should progressively replace arbitrary Hb-based transfusion triggers. Goal-directed erythrocyte transfusions to promote and optimize therapeutic adequacy while saving blood and avoiding unwanted adverse effects These physiologic transfusion triggers can be based on signs and symptoms of impaired global (lactate, SvO2 or ScvO2) or, even better, regional tissue (such as EKG ST-segment or P300 latency) oxygenation as well as heart rate and mean arterial pressure or systolic arterial pressure.

13 Vox Sanguinis, 2017 The provision of such assessment tools as well as their implementation under the surveillance and reporting by hemovigilance is essential to assess current blood products safety with regard to donor, product and recipient characteristics.

14 Vox Sanguinis, 2017 The provision of such assessment tools as well as their implementation under the surveillance and reporting by hemovigilance is essential to assess current blood products safety with regard to donor, product and recipient characteristics.

15 Less sophisticated, but essential: bleeding assessment Bleeding assessment in at-risk (central thrombocytopenia, massive bleeding, ) patients receiving blood products is most often not within hemovigilance surveillance

16 Transfusion, 2018 Curr Op Hematol, 2016

17 Transfusion, 2018 Curr Op Hematol, 2016 Whole-blood transfusion is associated with improved or comparable survival compared with acute life bleeding resuscitation with blood components while greatly facilitating transfusion logistics Furthermore, platelet-containing blood products stored at 4 C have superior hemostatic function, compared with platelet-containing blood products at 22 C.

18 NEJM, 2008

19 NEJM, patients were assigned to receive fresh red cells (freshblood group) and 1219 patients were assigned to receive standard-issue red cells (standard-blood group

20 NEJM, patients were assigned to receive fresh red cells (freshblood group) and 1219 patients were assigned to receive standard-issue red cells (standard-blood group

21 Vox Sanguinis, 2017

22 Hypothesis as to why short-term blood storage could be harmful (Ning et al, Transfusion Med Rev, 2017)

23 Lancet Haematol, 2017

24 Lancet Haematol, 2017

25 Lancet Haematol, 2017

26 NEJM, 2015

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28 Vox Sanguinis, 2011

29 Vox Sanguinis, 2011

30 Could anti-hyimmunity in female donors exposed to male antigens during pregnancy could be contributive? Anti-H-Y immunity (Nielsen et al, Human Reproduction, 2010) H-Y antigens are encoded by a number of genes on the Y chromosome and are ubiquitously expressed by male cells (Warren et al, 2000) Maternal immune recognition of H-Y antigens can be demonstrated in women following pregnancies with boys (Verdijk et al, 2004). Allogeneic hematopoietic cell transplantation (HCT) recipients of parous female grafts are more prone to develop graft-versus-host disease (GvHD) than recipients of either nulliparous female grafts or male grafts (Kollmanet al, 2001; Loren et al,2006). This increased risk of GvHDis believed to be due to the frequent development of a cytotoxic immune response against H-Y antigens (Gratwohlet al, 2001). H-Y antibodies also develop significantly more often in male recipients with female donors compared with male recipients of male donors (Miklos et al., 2004, 2005), and the presence of the H-Y antibodies correlates with chronic GvHD.

31 Human Reproduction, 2010 Birth of a boy is significantly more common than a girl prior to secondary recurrent miscarriage. High frequency of H-Y antibodies is found in women with secondary recurrent miscarriage. The presence of such antibodies in early pregnancy is associated with low number of male offspring Frequency of H-Y immunity in blood donors? Transfer of anti-h-y cellular immunity despite deleucocytation? Transfer of a sufficient amount of anti-h-y antibodies? capable of inducing long-term immuno-pathology?

32 JAMA, patients who received RBC transfusions exclusively from 1 of 3 types of donors (88% male; 6% ever-pregnant female; and 6% never-pregnant female)

33 JAMA, patients who received RBC transfusions exclusively from 1 of 3 types of donors (88% male; 6% ever-pregnant female; and 6% never-pregnant female) The highest HRs for death after transfusion of RBC from ever-pregnant female donors were observed in male recipients 50 years and younger

34 JAMA Int Med, 2016

35 JAMA Int Med, 201è transfusion recipients (Scandinavian donations and transfusions database) Hazard ratio of death: o Unadjusted model: o U-shaped association between age of the blood donor and recipient mortality, with a nadir in recipients for the most common donor age group (40-49 years) and increasing HRs among recipients of blood from donors of successively more extreme age groups o Higher mortality among recipients of blood from female donors o Adjusted model for number of transfusions with a linear term: o attenuated but persisting associations between donor age / gender and mortality Closer examination of the association between number of transfusions and mortality revealed a nonlinear pattern. After adjustments to accommodate nonlinearity, donor age and sex were no longer associated with patient mortality.

36 Additional statistical adjustment needed to accurately account for the non linear association between mortality risk and the total number of transfused blood products Adjustingwitha linearterm: distorsion for «rare» caracteristics? Impact on «no-mixture» or «single» blood studies cohort studies?

37 Similarly, a smaller study involving transfused cardiac surgery patients did not find an effect of donor sex (and storage duration) on outcome Transfusion, cardiac surgery patients no significant effect of storage duration or donor sex.

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