Urgent use of voxelotor in sickle cell disease when immediate transfusion is not safe.

The use of blood transfusions to improve anemia resulting from sickle cell disease (SCD) is often limited by alloimmunization, which occurs due to exposure to incompatible antigen present on donor red blood cells (RBCs). This complication occasionally manifests as delayed hemolytic transfusion reactions (DHTRs) that cause hemolysis of the recipient's own RBCs and can lead to fatal anemia. In this case study, we report a patient with SCD who experienced a DHTR following chronic transfusion and was successfully treated with voxelotor, an orally administered sickle hemoglobin (HbS) polymerization inhibitor for the treatment of SCD. Laboratory tests following admission indicated pan-reactivity in antigens, and a rare donor registry was used to locate acceptable units. The patient experienced the DHTR 3 days after admission, which limited laboratory tests due to profound hemolysis. Alternative treatments were limited, and phenotypically matched units were incompatible, so voxelotor was selected as a last-resort treatment. Following initiation of voxelotor 1500 mg, the patient's hemoglobin levels returned to baseline (6 g/dl) within 10 days, with clinical improvements. This report provides evidence regarding the use of voxelotor in the treatment of profound anemia where other treatments could be unsafe or unavailable.

Harvesting autologous stem cells from a patient with red blood cell abnormalities of ß-thalassemia intermedia.

BACKGROUND: Autologous stem cell transplants in patients with hemoglobinopathies are limited. Previous reports used granulocyte-colony-stimulating factor (G-CSF) for mobilization of stem cells; there are no reported cases undergoing plerixafor mobilization. We report such a patient, providing guidance for peripheral blood stem cells collection when aberrant red blood cells (RBCs) disrupt normal separation. STUDY DESIGN AND METHODS: A patient with ß-thalassemia intermedia and hereditary persistence of fetal hemoglobin presented for peripheral blood stem cell collection for autologous transplant for myeloma. He underwent splenectomy for anemia secondary to hemoglobinopathy and chemotherapy, ceasing RBC transfusions. The patient was mobilized using plerixafor after collection with G-CSF failed. RESULTS: Collections were performed using an apheresis system, processing 24 L daily. Peripheral blood and apheresis product CD34 determinations were performed daily. On Day 1, the product yield was 0.04 × 10(6) CD34 cells/kg, less than expected based on white blood cell count and CD34-positive cells. Peripheral blood smear showed nucleated RBCs and RBC morphologic abnormalities. Changes in instrument variables were made after consultation with Terumo BCT to adjust for variable distribution of mononuclear and stem cells during centrifugation. Collecting stem cells at a deeper location and centrifuging faster improved collection, and a cumulative total of 4.40 × 10(6) CD34 cells/kg was achieved after four collections. The patient underwent tandem autologous transplantation and engrafted within 12 to 13 days of each transplant. CONCLUSIONS: Adjustments in apheresis variables allowed successful collection of peripheral blood stem cells from a patient with RBC anomalies of ß-thalassemia that interfered with standard stem cell harvesting.

Red blood cell alloimmunization in sickle cell disease: prevalence in 2010.

BACKGROUND: Transfusion of red blood cells (RBCs) is frequently required for care of individuals with sickle cell disease (SCD). Alloimmunization rates are high and may be reduced by matching for RBC antigens that can cause alloimmunization. STUDY DESIGN AND METHODS: During the PROACTIVE Feasibility Study, patients with SCD age 2 years or older admitted for pain without acute chest syndrome were enrolled for possible randomization to preventive blood transfusion or standard care. Transfusion and antibody histories were obtained at each site, and antibody screening was done, to assess transfusion burden and alloimmunization prevalence. Participating sites were surveyed regarding antigen matching practice. RESULTS: A total of 237 patients (169 SS, 42 SC, 15 Sß(0) -thalassemia, 11 Sß(+) -thalassemia), 118 males and 119 females, were enrolled. Mean age was 19.3 years (range, 2.0-68.0); there were 122 children and 115 adults. A total of 75.8% had received at least a single transfusion of RBCs before the study. Thirty-four patients (14.4%) had a history of at least one alloantibody and 17 of these had more than one. When surveyed, 19 sites (83% of responders) reported antigen matching to at least include C, E, and K for transfusion of all patients with SCD. CONCLUSION: Though antigen typing before transfusion of people with SCD and providing antigen-negative units is now widely employed by sickle cell centers, the alloimmunization rate remains quite high in contemporary sickle cell populations and may be due in large part to transfusions received at institutions not providing extended matching.

Refining the value of secretory phospholipase A2 as a predictor of acute chest syndrome in sickle cell disease: results of a feasibility study (PROACTIVE).

Acute chest syndrome (ACS) is defined as fever, respiratory symptoms and a new pulmonary infiltrate in an individual with sickle cell disease (SCD). Nearly half of ACS episodes occur in SCD patients already hospitalized, potentially permitting pre-emptive therapy in high-risk patients. Simple transfusion of red blood cells may abort ACS if given to patients hospitalized for pain who develop fever and elevated levels of secretory phospholipase A2 (sPLA2). In a feasibility study (PROACTIVE; ClinicalTrials.gov NCT00951808), patients hospitalized for pain who developed fever and elevated sPLA2 were eligible for randomization to transfusion or observation; all others were enrolled in an observational arm. Of 237 enrolled, only 10 were randomized; one of the four to receive transfusion had delayed treatment. Of 233 subjects receiving standard care, 22 developed ACS. A threshold level of sPLA2 ≥ 48 ng/ml gave optimal sensitivity (73%), specificity (71%) and accuracy (71%), but a positive predictive value of only 24%. The predictive value of sPLA2 was improved in adults and patients with chest or back pain, lower haemoglobin concentration and higher white blood cell counts, and in those receiving less than two-thirds maintenance fluids. The hurdles identified in PROACTIVE should facilitate design of a larger, definitive, phase 3 randomized controlled trial.

Investigation of heparin-related hypotensive adverse events during photopheresis: utility of a patient care database.

BACKGROUND: Extracorporeal photopheresis (ECP) is a procedure in which leukocytes are harvested from a patient's whole blood, treated with a DNA binding dye and ultraviolet light to inactivate lymphocytes, and then returned into the patient's circulation. In January 2008, we observed moderately severe anaphylactoid reactions in eight of 16 patients undergoing ECP. CASE STUDY: Each affected individual exhibited hypotension of sudden onset, usually with tachycardia, during the return of heparin-anticoagulated blood at the end of the first cycle of collection of leukocytes. A systematic investigation of possible contributing factors revealed that all reactions were associated with administration of a single new lot of heparin. RESULTS: Changing to a different manufacturer of heparin eliminated the occurrence of further such hypotensive reactions during ECP. Although the symptoms were initially attributed to vasovagal reactions or dehydration, their temporal association with exposure to a new lot of heparin suggested a procedure-related phenomenon. Of particular note, was the finding that of the eight patients who had reactions at any time, six had initial exposures without reactions, suggesting a process of sensitization. CONCLUSION: This study demonstrated the value of a patient database listing lot numbers of all medications and components used in each routine ECP procedure for facilitating rapid determination of common patient exposures, making it easier to determine the cause of adverse events, in this case, a particular lot of heparin responsible for the hypotensive adverse events.

Blood component preferences of transfusion services supporting infant transfusions: a University HealthSystem Consortium benchmarking study.

BACKGROUND: The extent of acceptability of red blood cells (RBCs) containing additive solutions (ASs) for low-volume neonatal transfusions among hospitals is unknown. Also unknown is whether hospitals have policies that address the risk of hyperkalemia associated with prolonged storage either with or without irradiation for neonatal transfusions. STUDY DESIGN AND METHODS: A benchmarking survey of University HealthSystem Consortium members included questions regarding the acceptability of RBC units containing ASs for low-volume neonatal transfusions, policies addressing the length of RBC storage in AS, and policies regarding storage periods after irradiation. RESULTS: Twenty-eight of 47 respondents (60%) accept the use of at least one AS (AS-1, AS-3, or AS-5). Twenty-one (45%) accept the use of all three ASs for neonatal transfusions. Thirty-seven of 45 respondents (82%) do not have a policy requiring washing of RBCs used for low-volume transfusions beyond a specified number of days of storage or days after irradiation. CONCLUSIONS: Although the majority of institutions will use ASs, a significant number of institutions will not. The reasons for these policies were not elicited. Most respondents did not have a policy requiring washing beyond a specified number of days of storage or days after irradiation. Since RBCs stored for prolonged periods of time after irradiation have increased plasma potassium, it is important to develop policies to prevent clinically significant posttransfusion hyperkalemia in at-risk patients when RBCs are irradiated and not used immediately. More work still needs to be done to resolve these fundamental precepts of neonatal transfusion.

Changes in Mean Corpuscular Volume and RBC Distribution Width Predict Erythrocyte Engraftment Following ABO-Incompatible Hematopoietic Stem Cell Transplantation.

OBJECTIVES: The purpose of this study was to identify laboratory parameters representing erythrocyte engraftment to be used as an indicator to change the recipient to donor ABO group and Rh type following an ABO-incompatible hematopoietic stem cell transplant (HSCT). Studies have shown that ABO incompatibility does not have an effect on outcome of HSCT; however, the serologic consequences of these ABO-incompatible transplants can make it difficult to decide when to begin support with donor ABO/Rh-type blood products. METHODS: This study explored the use of RBC distribution width (RDW), mean corpuscular volume, and hemoglobin as regularly tested laboratory parameters that could be used as surrogate markers for RBC engraftment in 65 patients who received ABO/Rh-incompatible HSCT. RESULTS: The appearance of engrafted donor RBCs correlated with a peak in RDW (P = .002). In addition, our findings suggest that serologic changes in ABO/Rh appear to correspond with a peak in RDW (P = .002). CONCLUSIONS: High values of RDW likely result from a substantial proportion of large, young erythrocytes from recent engraftment with smaller, older pretransplant erythrocytes from the recipient. Our findings suggest that peak RDW may be an indicator of erythrocyte engraftment, following an ABO/Rh-incompatible HSCT.

Comparisons of high versus low emergency department utilizers in sickle cell disease.

STUDY OBJECTIVE: Patients with sickle cell disease often receive a substantial amount of their health care in the emergency department (ED) and some come to the ED frequently, seeking treatment for pain. As a result, patients with sickle cell disease are often stigmatized as opioid-seeking ED overutilizers. We describe the proportion of sickle cell disease patients who are high utilizers of the ED and compare them with other sickle cell disease patients on demographics, pain characteristics, health data, psychosocial characteristics, and quality of life. METHODS: Two hundred thirty-two patients completed baseline data and at least 30 days of daily diary data. Baseline data included demographics, health data, and quality of life (Medical Outcome Study 36 Item Short Form). Daily diary data included ED utilization for sickle cell pain and descriptors of pain and distress. RESULTS: Eighty-two (35.5%) patients were found to be high ED utilizers. Clinically important and statistically significant differences were found between high ED utilizers and all other sickle cell disease patients: lower hematocrit level, more transfusions, more pain days, more pain crises, higher mean pain and distress, and worse quality of life on Medical Outcome Study 36 Item Short Form physical function summary scales. After controlling for severity and frequency of pain, high ED utilizers did not use opioids more frequently than other sickle cell disease patients. CONCLUSION: A substantial minority of sickle cell disease patients are high ED utilizers. However, high ED utilizers with sickle cell disease are more severely ill as measured by laboratory variables, have more pain, more distress, and have a lower quality of life.

Daily assessment of pain in adults with sickle cell disease.

BACKGROUND: Researchers of sickle cell disease have traditionally used health care utilization as a proxy for pain and underlying vaso-occlusion. However, utilization may not completely reflect the amount of self-reported pain or acute, painful episodes (crises). OBJECTIVE: To examine the prevalence of self-reported pain and the relationship among pain, crises, and utilization in adults with sickle cell disease. DESIGN: Prospective cohort study. SETTING: Academic and community practices in Virginia. PATIENTS: 232 patients age 16 years or older with sickle cell disease. MEASUREMENTS: Patients completed a daily diary for up to 6 months, recording their maximum pain (on a scale of 0 to 9); whether they were in a crisis (crisis day); and whether they used hospital, emergency, or unscheduled ambulatory care for pain on the previous day (utilization day). Summary measures included both simple proportions and adjusted probabilities (for repeated measures within patients) of pain days, crisis days, and utilization days, as well as mean pain intensity. RESULTS: Pain (with or without crisis or utilization of care) was reported on 54.5% of 31 017 analyzed patient-days (adjusted probability, 56%). Crises without utilization were reported on 12.7% of days and utilization on only 3.5% (unadjusted). In total, 29.3% of patients reported pain in greater than 95% of diary days, whereas only 14.2% reported pain in 5% or fewer diary days (adjusted). The frequency of home opiate use varied and independently predicted pain, crises, and utilization. Mean pain intensity on crisis days, noncrisis pain days, and total pain days increased as the percentage of pain days increased (P < 0.001). Intensity was significantly higher on utilization days (P < 0.001). However, utilization was not an independent predictor of crisis, after controlling for pain intensity. LIMITATIONS: The study was done in a single state. Patients did not always send in their diaries. CONCLUSION: Pain in adults with sickle cell disease is the rule rather than the exception and is far more prevalent and severe than previous large-scale studies have portrayed. It is mostly managed at home; therefore, its prevalence is probably underestimated by health care providers, resulting in misclassification, distorted communication, and undertreatment.

Depression and anxiety in adults with sickle cell disease: the PiSCES project.

OBJECTIVE: Depression and anxiety are common in sickle cell disease (SCD) but relatively little is known about their impact on SCD adults. This study measured prevalence of depression and anxiety in SCD adults, and their effects on crisis and noncrisis pain, quality-of-life, opioid usage, and healthcare utilization. METHODS: The Pain in Sickle Cell Epidemiology Study is a prospective cohort study in 308 SCD adults. Baseline variables included demographics, genotype, laboratory data, health-related quality-of-life, depression, and anxiety. Subjects completed daily diaries for up to 6 months, reporting sickle cell pain intensity, distress, interference, whether they were in a sickle cell crisis, as well as health care and opioid utilization. RESULTS: Two hundred thirty-two subjects who completed at least 1 month of diaries were studied; 27.6% were depressed and 6.5% had any anxiety disorder. Depressed subjects had pain on significantly more days than nondepressed subjects (mean pain days 71.1% versus 49.6%, p < .001). When in pain on noncrisis days, depressed subjects had higher mean pain, distress from pain, and interference from pain. Both depressed and anxious subjects had poorer functioning on all eight SF-36 subscales, even after controlling for demographics, hemoglobin type, and pain. The anxious subjects had more pain, distress from pain, and interference from pain, both on noncrisis pain days and on crisis days, and used opioids more often. CONCLUSIONS: Depression and anxiety predicted more daily pain and poorer physical and mental quality-of-life in adults with SCD, and accounted for more of the variance in all domains of quality-of-life than hemoglobin type.

Patient satisfaction in specialized versus nonspecialized adult sickle cell care centers: the PiSCES study.

BACKGROUND: Sickle cell disease (SCD) patients can receive their ambulatory care from either SCD specialists (caregivers with sickle cell-only clinics) or nonspecialized care centers. Patient satisfaction, an important factor that may influence compliance and outcome, can differ between the two groups because of the perceived quality of care, outcomes or practice style. METHODS: We administered a patient satisfaction survey to 308 participants in an SCD prospective cohort study. Of the 308 patients, 133 (43.2%) received the majority of their SCD care at specialized centers, 152 (49.3%) received their care from nonspecialized centers and 26 (7.5) did not provide information. The satisfaction surveys measured general satisfaction (GS), technical quality (TQ), interpersonal manner (IM), communication (CM), financial aspects (FA), time spent with doctor (TA), and accessibility and convenience (AC). Patients reported their levels of satisfaction using a five-point Likert scale. We compared unadjusted group means, as well as means adjusted for potential confounders such as marital status, on patient satisfaction between specialized and nonspecialized centers. RESULTS: SCD patients who received their care from specialized centers had significantly higher mean satisfaction scores, compared to those who received their care from nonspecialized centers: GS 4.00(+/-0.93) vs. 3.66 (+/- 01.16, p=0.0326), TQ 3.98 (+/- 0.77) vs. 3.65 (+/- 0.91, p=0.0058), AC 3.83 (+/-0.79) vs. 3.51 (+/- 1.02, p=0.0142) , FA 3.88 (+/-0.96) vs. 3.49 (+/-1.25, p=0.0120). There were no statistically significant group differences in IM, TA and CM. CONCLUSION: SCD patients who received most of their SCD care from specialized centers had somewhat higher satisfaction scores in some areas when compared with patients who received their care from nonspecialized centers.

Comorbidity, Pain, Utilization, and Psychosocial Outcomes in Older versus Younger Sickle Cell Adults: The PiSCES Project.

Background. Patients with SCD now usually live well into adulthood. Whereas transitions into adulthood are now often studied, little is published about aging beyond the transition period. We therefore studied age-associated SCD differences in utilization, pain, and psychosocial variables. Methods. Subjects were 232 adults in the Pain in Sickle Cell Epidemiology Study (PiSCES). Data included demographics, comorbidity, and psychosocial measures. SCD-related pain and health care utilization were recorded in diaries. We compared 3 age groups: 16-25 (transition), 26-36 (younger adults), and 37-64 (older adults) years. Results. Compared to the 2 adult groups, the transition group reported fewer physical challenges via comorbidities, somatic complaints, and pain frequency, though pain intensity did not differ on crisis or noncrisis pain days. The transition group utilized opioids less often, made fewer ambulatory visits, and had better quality of life, but these differences disappeared after adjusting for pain and comorbidities. However, the transition group reported more use of behavioral coping strategies. Conclusion. We found fewer biological challenges, visits, and better quality of life, in transition-aged versus older adults with SCD, but more behavioral coping. Further study is required to determine whether age-appropriate health care, behavioral, or other interventions could improve age-specific life challenges of patients with SCD.

Gender differences in pain and healthcare utilization for adult sickle cell patients: The PiSCES Project.

BACKGROUND: Many studies have found gender differences in frequency and intensity of pain. Women often report lower pain thresholds, higher pain ratings, and lower tolerance for pain. People with sickle cell disease (SCD) experience both chronic and acute pain throughout life. OBJECTIVES: To compare adult men and women with SCD in terms of reported pain, crises, healthcare utilization, and opioid usage. METHODS: Two hundred twenty-six adults with SCD in Virginia were enrolled in a prospective cohort study of pain and completed daily diaries for 1-6 months. Subjects reported for the previous day their maximum SCD-related pain, distress, and interference (0-9 scale), whether they were in a sickle cell crisis, had unplanned utilization (clinic, emergency room, or hospitalization), or used opioids. Episodes of pain, crisis, or utilization were defined as consecutive days of such. Men and women were compared, using analysis of covariance (ANCOVA), controlling for age, SCD genotype, depression, and education. RESULTS: There were no significant differences between men and women in the percentage of days subjects experienced pain (men 58.6% vs. women 56.5%) or the number of pain episodes/6 months (7.7 vs. 9.6). Mean pain scores were comparable, when subjects were in crisis (5.5 vs. 5.6) or not (2.5 vs. 2.2). Distress and interference results were similar. Men with the SS genotype reported a higher percentage of days with crisis(18.5% vs. 11.6%) and utilization (5.1% vs. 2.7%) than women with the SS genotype. CONCLUSIONS: Contrary to many studies of pain, particularly chronic pain, men and women with SCD reported generally similar pain experiences.

Developing a blood conservation program in cardiac surgery.

The beneficial effects of blood transfusions have been described and widely accepted. Multiple factors, including shortages, costs, infectious risks, immunologic risks, and the risk/benefit ratio to the patient, have made the medical community reassess the guidelines for transfusion. Cardiac surgery presents a unique subset of patients, because intervention at multiple stages in the care of these patients is possible to decrease the need for transfusion. An algorithm for a cardiac surgery program was developed and a reassessment performed. Once it was seen that no detrimental effect on patient care occurred, the program was expanded, was enhanced, and subsequently has been offered to the rest of the health care system. This program has resulted in a decrease in cost while maintaining patient outcomes. The success of the program is believed to be a result of the multidisciplinary approach taken, with a commitment from all members of the blood reduction team being the key component of this success.