According to the American Society of Hematology 2020 guidelines for sickle cell disease (SCD) specific to transfusion support, for patients with a delayed hemolytic transfusion reaction (DHTR) and ongoing hyperhemolysis, supportive care should be initiated in all patients, including erythropoietin (EPO) with or without intravenous (IV) iron, in addition to immunosuppressive therapy. The guidelines provide no additional discussion on use of EPO for other clinical scenarios (e.g., bloodless medicine or sickle cell nephropathy) nor optimal dosing regimen for DHTR. [1]
Given the associated risk with allogeneic blood transfusions and increased number of patients refusing transfusions, a 2014 review explored options for bloodless medicine, with the primary goal of treating anemia and minimizing blood loss. Though not specific to patients with SCD, use of erythropoiesis-stimulating agents (ESAs) as one of the modalities for bloodless medicine has been reported in clinical settings. Based on available evidence and institutional experiences, the authors proposed administration of IV iron and occasionally ESAs for patients with hemoglobins (Hb) <13-14 who are undergoing cardiac surgery after consultation with the cardiac surgeon to determine the lowest acceptable hemoglobin. Typically, standard erythropoietin (∼20,000-30,000 IU) is given 3 times before scheduled surgeries (usually administered 2-3 times weekly). Given the convenience of administration, outpatient ESA therapy is usually given subcutaneously at a standard erythropoietin dose of 20,000-30,000 IU, while IV administration may be preferred in patients undergoing hemodialysis. Overall, evidence evaluating routine use of ESA as bloodless medicine appeared to be limited. Again, such standardized ESA dosage may not apply to SCD patients when blood transfusions are not applicable. [2]
Recent review articles recognize sickle cell-related kidney disease or sickle cell nephropathy as a complication in SCD patients, likely due to polymerization of HbS and sickling of red blood cells (RBCs) at the kidney medulla, leading to microinfarcts and ischemic injury of the vasa recta and medullary interstitium. However, standardized management of kidney disease in SCD remains challenging, including the optimal use of ESAs in this setting. Theoretically, as kidney function continues to decline over time, the ability of the kidneys to synthesize erythropoietin also reduces, implying a useful role of ESAs in this setting. While a higher dose of ESA may be required in patients with concurrent chronic kidney disease and SCD compared to those without SCD, treatment should be individualized for each patient without a recommended ESA dosing regimen applicable to the overall patient population. Of note, when using ESA, it is important to avoid hyperviscosity and target a Hb of no more than about 9-10.0 g/dL. [3], [4]
End-stage renal disease (ESRD) due to SCD occurs in very few patients (<1%) receiving renal replacement treatment, and as such, data evaluating use of EPO in these patients are scarce. Unresponsiveness of EPO treatment but also EPO’s positive effects for extending blood transfusion intervals of such patients have been reported in studies with small sample sizes (1 to 3 patients). In a letter to the editor, a study of 8 patients with ESRD and SCD who received ESA agents is described. Four hemodialysis patients were treated with epoetin beta 75 U/kg/week after blood transfusions when hemoglobin levels rose to approximately 7-8 g/dL. Despite therapy, hemoglobin concentrations fell to 5-5.5 g/dL in 2 months. Epoetin beta dosage was then increased to 150 U/kg/week. Other patients received darbepoetin alfa 0.75 mcg/kg/week. No significant differences between average hemoglobin, ferritin levels, transferrin saturation indices, numbers of hospitalizations, and blood transfusion needs and rate were observed before and after EPO treatment. The lack of response to EPO therapy was hypothesized to be due to the fact that the precise cause of anemia in patients with ESRD and SCD is not EPO insufficiency. However, due to the fact that basal endogenous EPO levels in SCD patients are higher than in normal patients, the EPO requirement may also be higher than for other ESRD patients. [5]
A recent review published by the American Society of Hematology (ASH) in 2021 discussed the management of DHTRs in patients with SCD. Symptoms associated with DHTRs or the premature destruction of transfused RBCs, including pain and dark urine, typically start days to weeks following an RBC transfusion. In cases of hyperhemolysis, patients may experience a decrease in Hb lower than pretransfusion level, along with presence of RBC alloantibody in most cases. In a presented case of a 12-year-old girl with SCD experiencing whole-body pain, fatigue, and dark urine 15 days after being discharged from the hospital after an episode of acute chest syndrome, she had been transfused with 2 units of RBCs during the previous hospitalization. While Hb recovered to 11 g/dL upon discharge, current visit found an alarmingly low Hb (3.7 g/dL). As such, IV iron and erythropoietin (dose not specified) along with fluids and treatment for pain were initiated, leading to recovery of Hb to 6 g/dL and reticulocyte close to baseline of 300,000/µL at discharge. [6]
Based on a referenced review published in 2015, the mainstay of treatments for DHRTs included supportive care, optimization of erythropoiesis, consideration of immunomodulatory therapies (including complement inhibition, steroids, intravenous immunoglobulin, and/or B-cell depletion), and minimizing future transfusions if possible. More specifically, the 2015 review stated innate erythropoiesis can be maximized with a combination of an erythropoiesis-stimulating agent and IV iron. High-dose erythropoietin (250-800 u/kg/dose) three times weekly, with close monitoring for hypertension, thrombosis, and bone pain, has been suggested, and IV iron supplementation is indicated if transferrin iron saturation is <20%. Patients with current renal failure, in particular, may benefit from the higher doses without apparent side effects. Please refer to Table 2 for a summary of the case series discussing successful use of EPO in patients presenting with DHRTs. Based on available evidence, authors proposed use of high-dose EPO and IV iron as well as first-line immunosuppression in those who continue to deteriorate after supportive care. [6], [7]
Similarly, a 2018 review reported two patient cases involving the use of EPO for the management of DHTR, in a field in which evidence-based studies are sorely lacking. In the first case, a 26-year-old woman with SCD was admitted to the ICU for severe acute chest syndrome with pulmonary hypertension. Without a previous history of DHTR after multiple transfusions, the patient received two partial manual exchanges of crossmatch-compatible RBCs, leading to Hb recovery to 10 g/dL. However, on day 7, patient developed severe pain and dark urine with Hb of 6.6 g/dL, HbA % of 29, lactate dehydrogenase (LDH) of 3,082 IU/L, and total bilirubin of 64 mmol/L, and then diagnosed with DHTR. Treatment included intravenous immunoglobulin over 4 days, eculizumab 900 mg on day 8 and day 14, 1 unit of extended-matched RBCs (due to life-threatening anemia of 2 g/dL), rituximab, and progressive treatment with EPO. In the other case, a 30-year-old man was admitted to the ICU for severe acute chest syndrome and received 4 units of crossmatch-compatible RBCs over 2 days, leading to good recovery (posttransfusion Hb of 9.9 g/dL). However, 10 days posttransfusion, the patient developed new vasoocclusive pain events with Hb 8.6 g/dL, HbA% 5.9, and LDH 1,614 IU/L. With the diagnosis of DHTR, patient was monitored closely, and his Hb increased progressively after receiving EPO and supportive therapy. Based on clinical data from case reports, authors recommend initiating EPO in all patients with reticulocytopenia. Specifically, darbepoetin-α at a dose of 100 to 300 mcg (every 48 hours) or epoetin-alfa at 30,000 U (every other day) should be considered when reticulocyte count is below 200,000/mm3 and Hb <6 g/dL until reticulocyte count increase. [8]
With the anecdotal increased use of EPO in the management of SCD, a 2006 review evaluated the safety and efficacy of EPO in conjunction with hydroxyurea based on available clinical reports and clinical experiences at the National Institutes of Health (NIH). Published experiences with EPO use in 39 SCD patients (homozygous sickle beta, SS, n= 30; compound heterozygous sickle beta thalassemia, Sβ0 thal, n= 9) treated between 1990 to 1996 were included. An additional 13 individuals (Sickle Syndromes HbSS n= 12; compound heterozygous SC disease n= 1) were identified who received erythropoietin or darbepoetin (here cumulatively referred to as EPO) at the NIH since 2002. Data from the published series reported a median dose of EPO of > 200 units/kg/dose for SCD over a median of ≥ 3 months, which is higher compared to commonly used dosing regimens in ESRD. Overall, there was a minimal incidence of reported adverse events among evaluated cases. [9], [10]
Eleven out of 13 patients from the NIH cohort, at a median age of 51 years, were treated with both hydroxyurea and EPO for > 4 months (median of 11 months on EPO) without complication. Eight patients received erythropoietin, four received darbepoetin, and one received sequentially both agents. Patients were further categorized into three groups based on treatment histories and comorbidities: Group A High-risk SCD with hydroxyurea-intolerance (n=5); Group B: High-risk SCD with relative renal insufficiency (n=5): Group C Miscellaneous (n= 3). Those in Group A initiated EPO for hydroxyurea-associated reticulocytopenia (<100,000 reticulocytes/μL) in the absence of other toxicities. Most patients (4/5) received concurrent hydroxyurea and EPO due to pulmonary hypertension and eGFRs of <80 mL/min at presentation, at risk for delayed hydroxyurea-dose advancement. Impaired renal function and severe/symptomatic anemia have contributed to the use of EPO for the rest of the cases. Median EPO dose, corrected for patient size, frequency of dose, and preparation, was ≥ 963 (≥ 327 to 2,718) units/kg/week in Group A, and ≥ 589 (>107 to 734) units/kg/week in Group B. Nearly all patients received subcutaneous EPO, except for IV EPO in 2 patients. In eight evaluable patients from Groups A & B (and patient 12), total Hb rose from a median of 6.4 (4.7 to 8.6) g/dL to 8.5 (6.7 to 11.5) g/dL, with hemoglobin F in these patients increasing from a median of 5 (1.6-14)% to 13.5 (3.1-21)%. Median LDH, also a reflection of disease activity, tended to decrease, from 388 (222-929) to 327 (202-433) IU/L. Please refer to Table 3 for a detailed summary of individual patient characteristics and outcomes. [9], [10]
While limited treatment experiences at the NIH observed no obvious safety concerns of EPO therapy, use of EPO has been theoretically associated with the worsening of symptomatic sickle cell disease (likely due to increased hemoglobin S concentration), changes in ophthalmologic symptoms, clinical thromboses, and pure red cell aplasia or systemic hypertension. Despite the limited evidence, authors suggest EPO therapy may be useful in patients with SCD and renal insufficiency who are not tolerating, or likely to tolerate, hydroxyurea at 15 mg/kg. Additionally, concomitant use of EPO may allow for more aggressive hydroxyurea dosing and subsequent higher fetal hemoglobin levels (see Table 4 for proposed use criteria). Regardless, routine use of EPO in SCD patients, especially those with mild-to-moderate renal function, requires further investigation. [9], [10]
Several observational studies reported utilizing epoetin alpha among patients with SCD. A 2020 retrospective, single-center cohort among African American patients (N= 504) with ESKD and dialysis revealed patients received a median of 36,000 IU epoetin alpha equivalent dose per week (interquartile range, 15,560-65,324). Based on the results of multivariate analysis, high-dose erythropoietin (defined as an average weekly epoetin alfa dose of ≥ 20,000 IU/week) was suggested to be associated with the highest risk for mortality and hospitalization rate in SCD. Another retrospective analysis from 2016 evaluated the treatments and outcomes of DHTR as one of the complications of sickle-cell disease over 12 years. Management included recombinant erythropoietin as well as rituximab and/or immunosuppressants, with approximately half of the patients (47%) receiving high-dose EPO, including 150-300 mcg of darbepoetin-alpha, 10,000-60,000 IU for epoetin-alpha or epoetin-beta according to their reticulocyte count and Hb levels. While 35% of DHTR patients received transfusion again, 69% of patients were not diagnosed with DHTR at the time of the second transfusion, while their Hb concentrations were stable. Overall, prospective clinical evidence to support the routine use of epoetin alfa in sickle cell patients appears to be lacking. [11], [12]