Fertility after Curative Therapy for Sickle Cell Disease: A Comprehensive Review to Guide Care.

Curative therapy for sickle cell disease (SCD) currently requires gonadotoxic conditioning that can impair future fertility. Fertility outcomes after curative therapy are likely affected by pre-transplant ovarian reserve or semen analysis parameters that may already be abnormal from SCD-related damage or hydroxyurea treatment. Outcomes are also likely affected by the conditioning regimen. Conditioning with myeloablative busulfan and cyclophosphamide causes serious gonadotoxicity particularly among post-pubertal females. Reduced-intensity and non-myeloablative conditioning may be acutely less gonadotoxic, but more short and long-term fertility outcome data after these approaches is needed. Fertility preservation including oocyte/embryo, ovarian tissue, sperm, and experimental testicular tissue cryopreservation should be offered to patients with SCD pursing curative therapy. Regardless of HSCT outcome, longitudinal post-HSCT fertility care is required.

Preventing antibody positive delayed hemolytic transfusion reactions in sickle cell disease: Lessons learned from a case.

INTRODUCTION: Red blood cell (RBC) transfusions are important in the management of patients with sickle cell disease (SCD). However, a potentially catastrophic complication of transfusion in this population is the delayed hemolytic transfusion reaction (DHTR). The pathophysiology of all DHTRs is not understood, but some are known to be caused by an anamnestic resurgence of RBC alloantibodies. CASE PRESENTATION: A child with SCD transfused for acute chest syndrome re-presented a week after hospital discharge with severe anaemia, hemolysis, and a newly detected anti-E. This patient had been previously transfused years ago at an outside institution and the anti-E had not been previously documented. DISCUSSION: The presented case of an antibody positive DHTR illustrates several concepts critical to the prevention of this complication. RBC alloantibodies must be detected and this information must be shared. Prophylactic C/c, E/e, K antigen matching is helpful for patients with SCD, but systems must be in place to identify these patients. Patients transfused at multiple different hospitals are especially at risk for this complication and efforts are needed to prevent them from suffering a DHTR.

Impact of universal irradiation on chronic transfusion for sickle cell disease.

BACKGROUND: Irradiation of blood products prevents transfusion-associated graft-versus-host disease, but most patients do not require this modification which could have an adverse impact on transfusion outcomes. We hypothesized that irradiation may increase transfusion requirements for patients with sickle cell disease (SCD) receiving chronic transfusion. STUDY DESIGN AND METHODS: Our pediatric hospital implemented a new policy of universal blood product irradiation in May 2018. We conducted a retrospective chart review of patients with SCD receiving chronic red blood cell (RBC) transfusion throughout the year before and after institution of this policy. The primary outcome was the change in RBC transfusion volume per patient weight transfused during the pre- vs. post- universal irradiation period. Secondary outcomes were the change in median pretransfusion laboratory values. RESULTS: Among 17 patients, 8 (47%) received more RBCs the year before irradiation and 9 (53%) received more the year after irradiation. Implementation of universal irradiation did not significantly increase transfusion volumes needed to clinically manage this population (median change +1.7 ml/kg/year, p = .54). Additionally, there were no significant changes in absolute reticulocyte count, hemoglobin, hemoglobin S%, white blood cell count, lactate dehydrogenase, total bilirubin, serum potassium, and ferritin during the two time periods. CONCLUSION: In a cohort of patients with SCD receiving simple chronic transfusion, irradiation did not impact transfusion requirements or pertinent pretransfusion laboratory values. Irradiation does not appear to have clinically significant consequences for SCD chronic transfusion management.

Screening for new red blood cell alloantibodies after transfusion in patients with sickle cell disease.

BACKGROUND: Patients with sickle cell disease (SCD) are frequent recipients of red blood cell (RBC) transfusions and are at risk for RBC alloimmunization. RBC alloimmunization is diagnosed by identifying RBC alloantibodies as part of pre-transfusion testing, but this testing fails to detect alloantibodies that have evanesced. It may be beneficial to screen for new RBC alloantibody development after transfusion before possible antibody evanescence. STUDY DESIGN AND METHODS: Our institution started a new initiative for episodically transfused patients with SCD to obtain at least one antibody screen 2-6 months after transfusion as part of their clinical care. A database was created to prospectively track all transfused patients for 1 year and their post-transfusion antibody screen results. Patients received prophylactically CEK-matched RBC units. RESULTS: During the study year, 138 patients with SCD received a total of 242 RBC transfusions. Patients with a history of an RBC alloantibody (n = 13, 9.4%) had previously received more RBC units than non alloimmunized patients (median 11 vs. 2 RBC units, p = .0002). A total of 337 post-transfusion antibody screens were obtained in 127 patients (92.0%) with 110 patients (79.7%) having at least one antibody screen 2-6 months post-transfusion. With this prospective testing, two new RBC alloantibodies (anti-C and -M) were identified in two patients. CONCLUSION: It is feasible to test for new RBC alloantibody development in most episodically transfused patients with SCD as part of their routine care. The yield of this screening appears low with CEK matching, but it could still provide important information for individual patients.

The impact of pre-existing HLA and red blood cell antibodies on transfusion support and engraftment in sickle cell disease after nonmyeloablative hematopoietic stem cell transplantation from HLA-matched sibling donors: A prospective, single-center, observational study.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is curative for patients with sickle cell disease (SCD). Prior to HSCT, patients with SCD commonly receive RBC transfusions with some becoming RBC or HLA alloimmunized. This alloimmunization may impact post-HSCT transfusion requirements and donor engraftment. METHODS: The study population included patients with SCD transplanted on a single-center nonmyeloablative, HLA-matched sibling HSCT trial at the National Heart, Lung, and Blood Institute (NHLBI) who had a pre-HSCT sample available for HLA class I antibody testing. We evaluated transfusion requirements and engraftment outcomes comparing patients with and without pre-existing HLA and RBC antibodies. FINDINGS: Of 36 patients studied, 10 (28%) had HLA class I antibodies and 11 (31%) had a history of RBC alloantibodies. Up to day +45 post-HSCT, patients with HLA antibodies received more platelet transfusions (median 2.5 vs 1, p = 0.042) and those with RBC alloantibodies received more RBC units (median 7 vs 4, p = 0.0059) compared to respective non-alloimmunized patients. HLA alloimmunization was not associated with neutrophil engraftment, donor chimerism, or graft rejection. However, RBC alloimmunization correlated with a decreased donor T cell chimerism at 1 year (median 24% vs 55%, p = 0.035). INTERPRETATION: Pre-existing HLA and RBC alloantibodies are clinically significant for patients undergoing HLA-matched nonmyeloablative HSCT. Testing for both HLA and RBC antibodies is important to help estimate transfusion needs peri­HSCT. The association of lower donor T cell chimerism and pre-existing RBC alloantibodies needs further investigation. FUNDING: NIH Clinical Center and NHLBI Intramural Research Program (Z99 CL999999, HL006007-11) and the Thrasher Research Fund.

Parents of Children with Sickle Cell Disease Are Interested in Preimplantation Genetic Testing.

OBJECTIVE: To evaluate awareness of and attitudes toward preimplantation genetic testing (PGT) for sickle cell disease (SCD) among parents of children with SCD. STUDY DESIGN: Parents of children with SCD were given an educational handbook on PGT before a routine SCD clinic visit. After their clinic visit, parents were asked to complete an anonymous survey. RESULTS: Of 83 patents approached, 67 (81%) completed the survey. Only 16 of the 67 parents (24%) were previously aware of PGT for SCD. After our clinic-based education, 65 of the 67 parents (97%) indicated that it was important or very important for parents of children with SCD to know about PGT. Among parents interested in having more children, 29 of 32 (91%) would personally consider using PGT if covered by insurance. CONCLUSIONS: Parents of children with SCD are generally not aware of PGT. When educated in clinic, parents viewed information on PGT as valuable. Pediatricians and other health care professionals should inform parents of children with SCD about this reproductive option.

Characteristics and outcomes of osteomyelitis in children with sickle cell disease: A 10-year single-center experience.

BACKGROUND: Patients with sickle cell disease (SCD) are at increased risk for osteomyelitis (OM). Diagnosis of OM in SCD is challenging as the clinical presentation is similar to a vasoocclusive crisis (VOC) with no diagnostic gold standard. We report characteristics and outcomes of OM in SCD patients treated at our center over 10-year period. DESIGN/METHOD: We conducted a retrospective analysis of patients with SCD who were treated for OM at our center over a 10-year period (2006-2016). Cases were identified utilizing radiology data mining software. Radiology reports and medical charts of potential OM cases were reviewed. RESULTS: Twenty-eight children with SCD were treated for OM at our institution. Patients treated for OM were largely similar to patients treated for a VOC. However, patients treated for OM had significantly higher C-reactive protein (10 mg/dL vs 5.58 mg/dL, P = 0.03) and erythrocyte sedimentation rate (60 mm/h vs 47 mm/h, P = 0.02). Magnetic resonance imaging (MRI) findings were consistent with OM in 18 (64%) patients and indeterminate in the remaining. Based on clinical, laboratory, and radiological findings, the diagnosis of OM was considered confirmed in 3 patients, probable in 6 patients, and presumed in 19 patients. Nontyphoidal Salmonella was isolated from cultures in 9 (32%) patients, while no organism was identified in 19 (67%) patients. All patients were treated with antibiotics. Six patients (21%) required surgical interventions. CONCLUSIONS: OM continues to pose diagnostic challenges. Most patients are treated for OM without definitive confirmation. Nontyphoidal Salmonella was the only organism identified in our cohort.

Transcranial Doppler Screening Adherence among Children with Sickle Cell Anemia Seen in the Emergency Department.

OBJECTIVE: To evaluate adherence to annual transcranial Doppler ultrasound (TCD) screening to prevent stroke among patients with sickle cell anemia (SCA) seen in the emergency department (ED). STUDY DESIGN: This retrospective chart review included patients with SCA seen at a large pediatric ED over 64 weeks. Patients who did not need a TCD (age <2 or ≥16 years, on chronic transfusions, history of an inadequate TCD) or were not followed at the study institution were excluded. Patients who had received a TCD in the last 12 months (TCD adherent) were compared with patients who had not (TCD nonadherent). RESULTS: During the study period, 257 patients with SCA in need of an annual TCD were identified and 63 patients (25%) had not received an annual TCD, including 19 patients (7%) who had never had a TCD. All TCD adherent patients had a clinic visit in the last year compared with 75% of TCD nonadherent patients, P < .0001. The mean interval time since the last hematology clinic appointment from the ED encounter was greater for the TCD nonadherent group: 70 vs 270 days, P < .0001. Demographics including markers of socioeconomic status were not significantly different between the 2 groups. CONCLUSIONS: Patients with SCA who present to the ED and are nonadherent to TCD screening guidelines are less likely to have had a recent hematology clinic visit. Future interventions to improve screening for stroke in SCA should target this patient population seen in the ED but not clinic.

Targeted Hydroxyurea Education after an Emergency Department Visit Increases Hydroxyurea Use in Children with Sickle Cell Anemia.

OBJECTIVE: To evaluate the impact of an initiative to increase hydroxyurea use among children with sickle cell anemia (SCA) who presented to the emergency department (ED). STUDY DESIGN: This observational cohort study included children with SCA not taking hydroxyurea who presented to the ED with pain or acute chest syndrome and then attended a Quick-Start Hydroxyurea Initiation Project (Q-SHIP) session. A Q-SHIP session includes a hematologist-led discussion on hydroxyurea, a video of patients talking about hydroxyurea, and a direct offer to start hydroxyurea. RESULTS: Over 64 weeks, 112 eligible patients presented to the ED and 59% (n = 66) participated in a Q-SHIP session a median of 6 days (IQR 2, 20 days) after ED or hospital discharge; 55% of participants (n = 36) started hydroxyurea. After a median follow-up of 49 weeks, 83% (n = 30) of these participants continued hydroxyurea. Laboratory markers of hydroxyurea adherence were significantly increased from baseline: median mean corpuscular volume +8.6 fL (IQR 5.0, 17.7, P < .0001) and median hemoglobin F +5.7% (IQR 2.5, 9.8, P = .0001). Comparing Q-SHIP participants to nonparticipants, 12 weeks after ED visit, participants were more likely to have started hydroxyurea than nonparticipants (53% vs 20%, P = .0004) and to be taking hydroxyurea at last follow-up (50% vs 20%, P = .001). Two years after the implementation of Q-SHIP the overall proportion of eligible patients on hydroxyurea presenting to our ED increased from 56% to 80%, P = .0069. CONCLUSIONS: Participation in a clinic to specifically address starting hydroxyurea after a SCA complication increases hydroxyurea use.

Ethical Challenges in Hematopoietic Cell Transplantation for Sickle Cell Disease.

Hematopoietic cell transplantation (HCT) using an HLA-identical sibling donor offers a very high likelihood of cure with good outcomes for patients with sickle cell disease (SCD), and alternative donor HCT for SCD is an area of active clinical research. Thus, HCT is a potential option for a growing number of patients with SCD. This expanded use of HCT has raised several ethical questions. Who is eligible for HCT, in terms of both disease severity and psychosocial factors? Should affected children with matched sibling donors undergo HCT only when they have declared themselves as having significant symptomatology? Regarding donors, special ethical challenges include the use of preimplantation genetic diagnosis to conceive an HLA-identical sibling. In this review, we critically analyze various ethical challenges related to HCT for SCD, and offer recommendations to guide clinical care.

Infusion hemolysis after pediatric major ABO-mismatched bone marrow transplant: Comparison of two red blood cell depletion techniques.

BACKGROUND: During major ABO-mismatched bone marrow transplant (BMT), the infusion of incompatible red blood cells (RBCs) that are present in the bone marrow graft can cause adverse events from hemolysis. RBC depletion of the bone marrow graft can decrease this risk, but the optimal method to prevent hemolysis is unclear. PROCEDURE: We conducted a retrospective cohort study of patients who underwent major ABO-mismatched BMT at a pediatric center and had RBC depletion with either hydroxyethyl starch (HES) sedimentation or Ficoll density gradient separation. Postinfusion hemoglobinuria and creatinine values were compared. RESULTS: Between 2002 and 2016, 37 patients received HES-treated and 16 patients received Ficoll-treated major ABO-mismatched bone marrow grafts. The median residual volume of RBCs was significantly greater with HES-treated grafts (HES 21.0 ml vs. Ficoll 1.4 ml, P < 0.0001). Patients who received HES-treated grafts had a higher prevalence of postinfusion hemoglobinuria (HES 57% vs. Ficoll 6%, P = 0.0009), but renal impairment was rare. Considering only HES-treated grafts, the volume of RBCs was not associated with either postinfusion hemoglobinuria or a creatinine increase. CONCLUSIONS: Ficoll density gradient separation achieves smaller RBC volumes and less postinfusion hemoglobinuria than HES sedimentation, but both can prevent significant hemolysis. Further studies are needed to determine the residual incompatible RBC volume threshold in major ABO-mismatched BMT.

Leukoreduced red blood cell transfusions do not induce platelet glycoprotein antibodies in patients with sickle cell disease.

BACKGROUND: Alloimmunization to red blood cell (RBC) antigens after transfusion is well described in patients with sickle cell disease (SCD). We recently demonstrated that leukocyte-reduced RBC transfusions appeared to induce human leukocyte antigen (HLA) antibodies in some children with SCD; now, we hypothesize that residual platelets contained in transfused RBC products may lead to platelet glycoprotein antibody formation. STUDY DESIGN AND METHODS: A cross-sectional study was conducted among never pregnant pediatric patients with SCD who either had received many RBC transfusions or had never received any transfusions. Serum was tested for antibodies to platelet-specific glycoproteins using a commercial enzyme immunoassay. RESULTS: Platelet-specific glycoprotein antibodies were found in 12 of 90 patients (13%) in the transfused group versus 5 of 24 patients (21%) in the never transfused group (p = 0.35). The prevalence of antibodies as well as the median standardized optical density for these two groups was not significantly different for any of the studied platelet glycoprotein antigens. There was no association with the presence of platelet-specific glycoprotein antibodies with either RBC or HLA antibodies. CONCLUSIONS: Leukocyte-reduced RBC transfusions do not appear to induce platelet-specific glycoprotein antibodies. The positive platelet-specific glycoprotein antibody results from this study may represent platelet autoantibodies, platelet alloantibodies, or false-positive reactions. A better understanding of the immunobiology of patients with SCD at baseline and after blood product exposure may help improve future transfusion and transplantation.

Improved Splenic Function After Hematopoietic Stem Cell Transplant for Sickle Cell Disease.

BACKGROUND: Splenic dysfunction is a significant complication of sickle cell disease (SCD). Hematopoietic stem cell transplant (HSCT) is a proven cure for SCD; however, its long-term effect on splenic function is not well characterized. PROCEDURE: We conducted a retrospective cohort study of pediatric patients who had HSCT for SCD at two transplant centers. (99m) Tc liver-spleen (LS) scans were blindly reviewed and classified as demonstrating absent, decreased, or normal splenic uptake. RESULTS: Considering all engrafted nonsplenectomized Hb SS and Sß(0) -thalassemia patients with LS scans available, at a median of 2.0 years post-HSCT (range 1.0-9.3 years) eight of 53 (15%) had normal, 40 of 53 (75%) decreased, and five of 53 (9%) absent splenic uptake. More patients had splenic uptake after HSCT: pre-HSCT 14/38 (37%) versus post-HSCT 34/38 (89%), P < 0.0001. Older age at HSCT was associated with worse splenic function post-HSCT (median age at HSCT for absent uptake 16.6 years vs. present uptake 8.0 years, P = 0.030). Extensive chronic GVHD was also more common in patients with absent splenic uptake compared to patients with present uptake (absent 40% vs. present 6%, P = 0.064). CONCLUSIONS: HSCT significantly improves splenic function for most pediatric patients with SCD, but older patient age at time of HSCT and extensive chronic GVHD appear to be risk factors for poor post-HSCT splenic function.

Impact of red blood cell alloimmunization on sickle cell disease mortality: a case series.

BACKGROUND: Although red blood cell (RBC) transfusion represents an integral component of sickle cell disease (SCD) care, transfusion support for some patients can result in alloimmunization to RBC antigens. Alloimmunized patients with SCD appear to experience worse survival compared to nonalloimmunized patients. While this difference in mortality may in part be due to underlying immunologic differences related to disease severity, it may also reflect direct clinical consequences of RBC alloimmunization. Alloimmunized patients have an increased risk of serious hemolytic transfusion reactions (HTRs) and may not receive adequate RBC transfusion support due to lack of compatible RBC units. CASE REPORT: This study reports on five RBC alloimmunized patients with SCD who died, to illustrate the concept that RBC alloimmunization itself contributes to premature death. RESULTS: The clinical course for each of the reported patients provides insight into the direct and indirect consequences of RBC alloimmunization, where patients experienced delayed HTRs or did not receive needed RBC transfusions. CONCLUSION: Future work examining the clinical impact of RBC alloimmunization should not only consider HTRs but should also address the potential consequences associated with difficulties in obtaining compatible blood.

Neonatal Transfusion Medicine: Five Major Unanswered Research Questions for the Twenty-First Century.

Blood component transfusions are important to the care of preterm neonates; however, their use in clinical practice often is not based on high levels of evidence. Five major questions for neonates are discussed: (1) What is the optimal red blood cell (RBC) transfusion threshold? (2) What is the optimal platelet transfusion threshold? (3) Does the storage age of an RBC unit affect outcomes? (4) Does RBC transfusion contribute to the pathogenesis of necrotizing enterocolitis? and (5) Which new practices should be used to prevent transfusion-transmitted infections? Although definitive answers to these questions do not exist, future research should help answer them.