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Hematological support of patients with significant anemia who decline red blood cell blood transfusion

To the Editor: Patients who decline blood transfusion either due to religious or personal objections pose challenges in the face of potentially lifethreatening acute anemia. Decreases in hemoglobin are associated with increased mortality risk in patients who decline blood transfusion in the perioperative setting. Therefore, implementation of now wellestablished preoperative protocols for this unique patient population involves varying doses of erythropoiesis-stimulating agents (ESA) and supplementation with iron, folate, and/or vitamin B12. Large studies involving preoperative cardiac surgery patients who decline blood transfusion have shown acceptable surgical outcomes. However, in real-world settings, severe anemia may arise in either the postoperative setting or with unexpected severe medical illness. There is no established treatment for these patients once severe anemia has developed and blood transfusions are declined. Various protocols have been recommended albeit with very limited patient data to support these practices outside of the preoperative indications. Our retrospective cohort study identified a patient population who declined blood transfusions, their baseline characteristics at the time of their severe anemia, the various treatment strategies implemented and patient outcomes. Utilizing this information, we propose a protocol for treating these severely anemic patients who decline blood transfusions. Patients included in this retrospective study were patients who self-identified as Jehovah's Witness and/or refused blood transfusion between 2015 and 2021. These patients were either seen by the inpatient hematology consultative team at the request by the primary team or referred to the outpatient hematology clinic once anemia had already developed. Patients were excluded if they did not ultimately receive ESA therapy, were already on ESA therapy for end stage renal disease, received blood transfusion, or were on therapy for an underlying hematological malignancy. Primary outcome was defined as the time to hemoglobin increase by 2 g/dl from the hemoglobin at time of ESA therapy initiation. Secondary outcome was defined as time to hemoglobin increase by 1 g/dl from the hemoglobin at time of ESA therapy initiation. Baseline characteristics are summarized in Table S1. Twenty-four patients (58.3% were female) meeting the study criteria were included. The mean age was 68.4 years and the majority of the patients, with the exception of one patient, self-identified as part of the Jehovah's Witness community. Twenty-three patients were evaluated by the inpatient hematology consult team and one patient was seen in the outpatient hematology clinic for consultation. Ten patients were in the perioperative setting. Eleven patients were identified as having iron deficiency with or without acute bleeding. Five patients had severe medical critical illness and prolonged ICU stays. Two patients developed anemia related to chemotherapy for their solid tumors. One patient was identified as having G6PD deficiency and developed brisk hemolysis secondary to rasburicase and this patient has been described in part elsewhere. No patient had B12 deficiency and three patients had a ferritin less than 30 mg/L. One of the 13 patients who had a folate value checked actually had folate deficiency. The mean baseline hemoglobin was 6.5 g/dl. The primary outcome (hemoglobin rise >2 g/dl) occurred (Figure 1A) after a median of 12 days (mean 14.6 days) with an interquartile range of 7–17 days. The secondary outcome (hemoglobin rise >1 g/dl) occurred a median of 5 days (mean 8 days) with the skewed distribution showing an interquartile range of 3–9 days (Figure 1A). Of those patients for whom data were available, 71% ultimately increased the hemoglobin by 2 g/dl after a median of 12 days. Out of the 23 inpatients, 22 patients were alive at discharge and 1 patient died. The average length of stay in the hospital was 18.6 days with a range between 2 days and 55 days. There was significant variation in some baseline laboratory values obtained for each patient (Table S1). For example, a baseline erythropoietin value was sent prior to ESA therapy in only five patients. Furthermore, as described in Table S2, ESA dosing and therapy showed marked variation in practice but all patients included in this study received at least one dose of ESA therapy. Many patients received additional nutritional support with oral iron (n = 2), IV iron (n = 19), folic acid (n = 17), and vitamin B12 (n = 12). Not all patients accept red blood cell transfusion. Prior studies have focused on those being prepared for elective surgery. In the presurgical protocols, ESAs such as epoetin alfa with doses of 40 000 units weekly along with oral or IV iron are typically started at least 21 days in advance of the planned operation date with reported mean increase in hemoglobin of 1.2 g/dl. Our study analyzed patients who developed severe anemia due to unexpected severe medical illness or surgery and pose considerable management challenges when blood transfusions are declined. The paucity of literature and lack of clear evidence guiding the treatment of acute, severe unexpected anemia led to multiple treatment approaches (Table S2) within our single academic institution. Our analysis shows that darbepoetin or erythropoietin alpha were used with dose ranges between 65 and 300 mcg or between 10 000 and 40 000 units, respectively, on varying schedules. Mean baseline Received: 6 June 2022 Revised: 22 August 2022 Accepted: 23 August 2022