Rheologic behavior of sickle and normal red blood cell mixtures in sickle plasma: implications for transfusion therapy

BACKGROUND: Guidelines for transfusion in sickle cell disease usually define an upper hematocrit (Hct) limit of 0.30 to 0.35 to avoid blood hyperviscosity. In vitro viscosity studies of normal (AA) and sickle (SS) red blood cell (RBC) mixtures in buffer appear to confirm that this Hct limit is optimal for oxygen delivery to vascular beds as judged by the ratio of Hct to viscosity, with this ratio often termed "oxygen or RBC transport effectiveness." In the absence of plasma, however, effects due to RBC-RBC interactions mediated by plasma proteins cannot be assessed. STUDY DESIGNS AND METHODS: To investigate the optimal Hct-to-viscosity ratio of RBCs in plasma, the rheologic effects of Hct (0.20-0.40), the proportion of SS RBCs (0-100%), and shear rate (1-1000/sec) for mixtures of oxygenated and deoxygenated SS and AA RBCs were evaluated in sickle plasma at 37 degrees C. RESULTS: RBC suspension viscosity was shear-dependent (i.e., viscosity decreased with increasing shear rate) and increased with Hct and proportion of SS RBCs. An "optimal" Hct level (defined as a maximal of the Hct-to-viscosity ratio) was seen only at shear rates above 50/sec. At lower shear rates (e.g., 5/sec), where plasma-mediated RBC-RBC interactions predominate, any increment in Hct was offset by a proportionally greater increase in viscosity, thus leading to a lower Hct-to-viscosity ratio. CONCLUSION: These results indicate the importance of plasma-mediated RBC interactions and suggest that the benefits of transfusion may vary depending on local flow rates (i.e., shear rates) and organ-specific hemodynamics.     

Adverse events of red blood cell transfusions in patients with sickle cell disease

Blood transfusion is a common medical intervention for patients with sickle cell disease (SCD) and disease related complications. While patients with SCD are at risk for all transfusion related adverse events defined by the National Healthcare Safety Network (NHSN) Biovigilance Component Hemovigilance Module Surveillance Protocol, they are uniquely susceptible to certain adverse events. This review discusses risk factors, mitigation strategies, and management recommendations for alloimmunization, hemolytic transfusion reactions, hyperviscosity and transfusion-associated iron overload in the context of SCD.     

Antigen-matched donor blood in the transfusion management of patients with sickle cell disease

BACKGROUND: Alloimmunization to red cell antigens is a significant risk in chronically transfused patients with sickle cell disease. Antigen matching, by decreasing the likelihood of alloantibody development, may significantly facilitate long-term management while decreasing morbidity. STUDY DESIGN AND METHODS: The transfusion records of 86 patients who underwent chronic transfusion for sickle cell disease at a tertiary-care medical center were reviewed retrospectively to determine the efficacy of an antigen-matching program in the prevention of alloimmunization to clinically significant red cell antigens. Recipients were phenotyped and given units matched for the K, C, E, S, and Fya or Fyb antigens. RESULTS: None (0%) of the 40 patients who received antigen-matched transfusions showed any evidence of alloimmunization, while 16 (34.8%) of the 46 patients who received both antigen-matched and non-antigen-matched transfusions developed clinically significant alloantibodies. The cost was 1.8 to 1.5 times that for a standard transfusion protocol. CONCLUSION: On the basis of this experience, it is recommended that transfusion centers engaged in the management of chronically transfused sickle cell anemia patients consider providing antigen-matched units for such patients. This is recommended not only because it prevents alloimmunization but also because such a program provides additional clinical benefits to the patient that may outweigh the higher costs of the process.     

Delayed hemolytic transfusion reaction in sickle cell disease patients: evidence of an emerging syndrome with suicidal red blood cell death

BACKGROUND: Delayed hemolytic transfusion reaction (DHTR) is a life-threatening complication in sickle cell disease (SCD) characterized by recurrence of disease complications, recipient red blood cell (RBC) destruction, and frequently no detectable antibody. Phosphatidylserine (PS) exposure signs suicidal RBC death or eryptosis and is involved in vasoocclusive crisis (VOC).
STUDY DESIGN AND METHODS: Transfusion was monitored in 48 SCD patients for up to 20 days. PS exposure was evaluated in vivo on patient RBCs (PS-RBCs) at five time points and in vitro after incubation of donor RBCs with pretransfusion plasma.
RESULTS: Three VOC patients displayed DHTR with recurrent SCD features and no detectable antibody in two cases. In vitro, PS-RBC percentage was significantly increased by incubating donor RBCs with pretransfusion plasma samples from DHTR patients with no detectable antibody. No such increase was observed with samples from other patients. This result indicates that donor RBCs may be damaged by the environment of SCD patients, increasing the physiologic clearance of apoptotic RBCs. In vivo, PS-RBC percentage increased in all three cases after destruction of transfused RBCs, indicating that DHTR induces PS-RBCs and, possibly, subsequent VOC and autologous RBC destruction.
CONCLUSION: This study clearly demonstrates that DHTR can occur in the absence of detectable antibody. In these cases, a mechanism of excessive eryptosis is proposed.     

Acquired hemoglobin variants and exposure to glucose‐6‐phosphate dehydrogenase deficient red blood cell units during exchange transfusion for sickle cell disease in a patient requiring antigen‐matched blood

Red blood cell exchange (RBCEx) is frequently used in the management of patients with sickle cell disease (SCD) and acute chest syndrome or stroke, or to maintain target hemoglobin S (HbS) levels. In these settings, RBCEx is a category I or II recommendation according to guidelines on the use of therapeutic apheresis published by the American Society for Apheresis. Matching donor red blood cells (RBCs) to recipient phenotypes (e.g., C, E, K‐antigen negative) can decrease the risk of alloimmunization in patients with multi‐transfused SCD. However, this may select for donors with a higher prevalence of RBC disorders for which screening is not performed. This report describes a patient with SCD treated with RBCEx using five units negative for C, E, K, Fya, Fyb (prospectively matched), four of which were from donors with hemoglobin variants and/or glucose‐6‐phosphate dehydrogenase (G6PD) deficiency. Pre‐RBCEx HbS quantification by high performance liquid chromatography (HPLC) demonstrated 49.3% HbS and 2.8% hemoglobin C, presumably from transfusion of a hemoglobin C‐containing RBC unit during a previous RBCEx. Post‐RBCEx HPLC showed the appearance of hemoglobin G‐Philadelphia. Two units were G6PD‐deficient. The patient did well, but the consequences of transfusing RBC units that are G6PD‐deficient and contain hemoglobin variants are unknown. Additional studies are needed to investigate effects on storage, in‐vivo RBC recovery and survival, and physiological effects following transfusion of these units. Post‐RBCEx HPLC can monitor RBCEx efficiency and detect the presence of abnormal transfused units. J. Clin. Apheresis 28:325–329, 2013. © 2013 Wiley Periodicals, Inc.     

Molecular blood typing augments serologic testing and allows for enhanced matching of red blood cells for transfusion in patients with sickle cell disease

BACKGROUND: Sickle cell disease (SCD) patients have dissimilar red blood cell (RBC) phenotypes compared to the primarily Caucasian blood donor base due, in part, to underlying complex Rh and silenced Duffy expression. Gene array–based technology offers high‐throughput antigen typing of blood donors and can identify patients with altered genotypes. The purpose of the study was to ascertain if RBC components drawn from predominantly Caucasian donors could provide highly antigen‐matched products for molecularly typed SCD patients. STUDY DESIGN AND METHODS: SCD patients were genotyped by a molecular array (HEA Beadchip, BioArray Solutions). The extended antigen phenotype (C, c, E, e, K, k, Jk^a, Jk^b, Fy^a, Fy^b, S, s) was used to query the inventory using different matching algorithms; the resulting number of products was recorded. RESULTS: A mean of 96.2 RBC products was available for each patient at basic‐level, 34 at mid‐level, and 16.3 at high‐level stringency. The number of negative antigens correlated negatively with the number of available products. The Duffy silencing mutation in the promoter region (67T>C) (GATA) was found in 96.5% of patients. Allowing Fy(b+) products for patients with GATA increased the number of available products by up to 180%, although it does not ensure prevention of Duffy antibodies in all patients. CONCLUSIONS: This feasibility study provides evidence that centers with primarily Caucasian donors may be able to provide highly antigen‐matched products. Knowledge of the GATA status expands the inventory of antigen‐matched products. Further work is needed to determine the most clinically appropriate match level for SCD patients.     

Pulmonary effects of red blood cell transfusion in critically ill,non‐bleeding patients

The aim of the study is to evaluate the effects of red blood cell (RBC) transfusions on pulmonary parameters in critically ill, non‐bleeding patients. Retrospective chart analysis was performed on critically ill patients without overt bleeding in the intensive care unit (ICU) of a university hospital. In 83 patients in a 5‐month period, who had received at least 1 RBC unit and stayed at least 24 h in the ICU, 199 transfusions of median 2 RBCs per transfusion (n = 504) were studied. Pulmonary parameters were retrieved during the period between 24 h before the start of transfusion and 24–48 h after transfusion. Outcome was assessed. The P_aO₂/F_IO₂ dose‐dependently decreased from 250 ± 105 at baseline to 240 ± 102 mmHg at 24 h after RBC transfusion (P = 0·003), irrespective of acute lung injury at baseline and RBC storage time. The lung injury score (LIS) also increased dose‐dependently, whereas, at 48 h, oxygenation and LIS largely returned to baseline. For every seven RBCs transfused, the LIS transiently increased by 1 unit. There were no changes in haemodynamics, lung mechanics or chest radiography. The total number of RBCs given in the ICU did not directly contribute to ICU and 1‐year mortality prediction. Transfusion of RBCs decreases oxygenation thereby increasing the LIS, dose‐dependently and transiently, in a heterogeneous population of critically ill, non‐bleeding patients, independent of prior cardiorespiratory status and RBC storage time. The effects are subtle, may go unseen and unreported and may represent subclinical transfusion‐related acute lung injury. They do not adversely affect outcome, even at 1‐year follow‐up.