Severe Hemolytic Crisis in Pediatric Patients with Sickle Cell Disease without History of Recent Transfusion: A Single Center, Multi-site Case Series

Research Article

Ann Hematol Oncol. 2025; 12(1): 1471.

Severe Hemolytic Crisis in Pediatric Patients with Sickle Cell Disease without History of Recent Transfusion: A Single Center, Multi-site Case Series

Garrett ER1,2* and Rollins MR1,2

1Department of Pathology and Laboratory Medicine, Children’s Healthcare of Atlanta, Atlanta, GA, USA

2Department of Pediatrics, Division of Hematology-Oncology, Emory University SOM, Atlanta, GA, USA

*Corresponding author: Erin R. Garrett, MS, MD, 2220 N. Druid Hills Rd, 3rd Fl Blood Bank, Atlanta, GA, USA Tel: 951)642-0603; Email: Erin.Garrett@choa.org

Received: January 23, 2025; Accepted: February 11, 2025; Published: February 13, 2025

Abstract

Antibody negative Delayed Hemolytic Transfusion Reaction [Ab(-) DHTR] is defined in patients with Sickle Cell Disease (SCD) as hemolysis within 21 days following red blood cell (RBC) transfusion in the absence of positive serologic testing (direct antiglobulin test (DAT) and/or new alloantibody). Hyperhemolysis (HH), or indiscriminate hemolysis of autologous and allogeneic RBCs, is a unique complication of Ab- DHTR in patients with SCD. With a constellation of lab findings including elevated LDH, reticulocytopenia and a rapid drop in hemoglobin below pre-transfusion and baseline level, Hyper-Hemolysis Syndrome (HHS) is an important complication of Ab(-) DHTR that can result in morbidity and mortality among patients with SCD. Despite associated lab and clinical findings, diagnosis and prompt intervention can be difficult due to the underlying pathophysiology of SCD with the added context of recent transfusion.

In this retrospective case review of five pediatric patients with SCD, we describe their courses during an inpatient hospital admission for management of suspected DHTR by the clinical team. Laboratory findings were supportive of Ab (-) DHTR complicated by HH, however, the patients were subsequently found not to have transfusion exposure within the 21 days prior to presentation. Considering HH in a patient with SCD a distinct clinical presentation without temporal relation to recent transfusion should be considered to prevent delay in appropriate management. While the mechanism of action of HH/HHS remains elusive, alternative inciting events and their mechanism of actions should continue to be explored to direct therapy and improve patient outcomes for patients with SCD.

Keywords: Hyper-hemolysis; Sickle Cell Disease

Abbreviations

Ab(-)DHTR: Antibody Negative DHTR; ACS: Acute Chest Syndrome; ASH: American Society of Hematology; AUS: Activity of Undetermined clinical Significance; CDC/NHSN: Center for Disease Control and Prevention’s National Healthcare Safety Network; DAT: Direct Antiglobulin Test; DHTR: Delayed Hemolytic Transfusion Reaction; DOS: Day(s) of Stay; FDA: Food and Drug Administration; Hct: Hematocrit; Hgb: Hemoglobin; HH: Hyper-hemolysis; HHS: Hyper-hemolysis Syndrome; HU: Hydroxyurea; LDH: Lactate Dehydrogenase; LOS: Length of Stay; MOD: Multi-organ Dysfunction; MTP: Massive Transfusion Protocol; PNH: Paroxysmal Nocturnal Hemoglobinuria; SCD: Sickle Cell Disease; RBCs: Red Blood Cells; TMA: Thrombotic Microangiopathy; VOC: Vaso-Occlusive Crisis

Introduction

Sickle cell disease (SCD) is a multisystem disease associated with episodes of acute illness and progressive organ damage; it is one of the most common severe monogenic disorders worldwide [1]. Since being first described in 1910, patient life span and quality have vastly improved due to increased knowledge of disease pathophysiology and technological advancements in pharmacology and gene therapy [2]. Despite these advancements, transfusion of allogeneic RBCs remains a pillar of therapy for a specific subset of patients to treat current or mitigate future disease related complications [3]. Allogeneic RBCs do, however, have associated risks, including alloimmunization, transfusion associated hemosiderosis, transfusion transmitted infection and other transfusion related adverse events as defined by the CDC/NHSN Hemovigilance Module [4].

Previous studies have shown that patients with SCD are at increased risk of developing alloimmunization as well as experiencing other transfusion related adverse events compared to the general population; specifically, DHTR [5]. DHTR is reported more frequently in patients with SCD but is believed to be underreported due to symptomology resembling VOC [6,7].

DHTR is defined by CDC/NHSN as a rapid fall in hemoglobin (Hgb) to pre-transfusion levels with positive direct antiglobulin test (DAT), and identification of new alloantibody occurring 24 hours to 28 days following transfusion. There is near total, or complete, destruction of allogeneic RBCs sparing autologous RBCs. Patients may present with symptoms of fever, chills, pain, hemoglobinuria, and jaundice from intravascular, antibody mediated hemolysis. They can also be asymptomatic, with destruction of allogeneic RBCs and unintentional detection of new alloantibody identified by screening labs performed for an unrelated reason. Neither presentation is unique for, nor specific to, patients with SCD. Treatment is typically supportive and additional transfusion of RBCs with avoidance of antigens to newly identified or historic alloantibody (-ies) is considered safe and appropriate management for future transfusion [5].

Ab(-)DHTR has been described in the literature with clinical symptoms identical to the CDC/NHSN defined DHTR absent the newly identified alloantibody and/or positive DAT [8]. The etiology and pathophysiology of this presentation remain obscure, making its prevalence difficult to quantify. ASH has implemented management guidelines for patients with SCD presumed to have Ab(-) DHTR presenting within 21 days of transfusion with signs of hemolysis and no serological evidence of DHTR [9]. In these cases, additional transfusion is not advisable due to the lack of alloantibody identification for antigen avoidance.

A reported consequence of severe Ab(-) DHTR is the development of potentially life-threatening HH. HH is defined as rapid decline of post-transfusion HgbA level to below pre transfusion levels. The mechanism of this “bystander” hemolysis, destruction of both allogeneic and autologous RBCs, has yet to be identified. In patients with SCD, HH has been characterized as an extreme complication of Ab(-) DHTR [8]. HHS is a constellation of laboratory findings including elevated LDH and reticulocytopenia in addition to the rapid drop in Hgb below pre-transfusion and baseline associated with HH, and severe pain out of proportion to previously reported VOC. Given the underlying pathophysiology of SCD, making a definitive diagnosis of Ab- DHTR or HH/HHS can be difficult in proximity to transfusion, and attempts to develop a diagnostic algorithm have had limited utility [7,10,11]. However, a unifying theme of prior history of transfusion within 21-28 days of presentation and/or symptom onset is consistent for Ab-DHTR and HH/HHS.

In 2006, Ballas and Marcolina described a subset of adult patients with SCD presenting with clinical and laboratory features of HH/HHS manifesting as “acute painful episodes [12].” Pain out of proportion to historical VOC has been reported as an associated feature of HH/HHS clinical presentation. Since patients in the study with history of transfusion within 44 months of presentation were excluded, the authors concluded that HH/HHS in these patients was a complication of underlying disease, not proximity to transfusion. A case reported by Jones et al in 2015, describes a single pediatric patient presenting with HH following a VOC and no lifetime history of transfusion exposure [13]. These cases support an alternative to transfusion as a trigger for or association with HH/HHS, suggesting it is acute on chronic disease related hemolysis not directly related to transfusion. It is also important to consider the clinical implications of correlating this presentation specifically with recent transfusion and the impact on time to diagnosis and management of those affected patients. Herein, we describe a cohort of pediatric patients with SCD presenting with severe hemolysis and no transfusion exposure within at least 28 days of presentation.

Methods

The Institutional Review Board of a single center, multi-site tertiary care pediatric hospital in the Southeastern US, waived a retrospective chart review conducted between November 2021 and January 2023. Patient inclusion criteria were: diagnosis of SCD (any genotype), admitted for documented concern for DHTR with date of last transfusion unknown at the time of admission, and a Transfusion Medicine consult for evaluation for DHTR. Patients with a confirmed history of no transfusion documented at our institution or outside institution >28 days prior to presentation with a negative antibody screen and DAT from admission to discharge were identified.

Patient demographics including age, admission diagnosis, SCD genotype, current disease modifying agents such as HU, history of allo-/autoimmunization, and date of last transfusion. The following immunohematology, hematologic and metabolic labs results were recorded during admission: blood type, antibody screen, antibody identification, DAT, Hgb electrophoresis, Hgb, Hct, platelet count, reticulocyte count (percentage and absolute), LDH, bilirubin, haptoglobin and plasma free Hgb. Medical interventions received during admission including transfusion, medications used for management of suspected hemolysis, and apheresis were also documented.

Results

Demographics

Five patients with a median age of 17y (15-19y) and 6 distinct encounters were identified. Two patients were siblings. Patient #5 had 2 encounters with <24hrs between discharge and re-admission. Three of 5 patients were HgbSS genotype. The majority of the patients were Black females (80%). All patients had a history of prior transfusion. Two of 5 patients (40%) had a history of alloimmunization and 1/5 (20%) had a history of AUS with all clinically significant alloantibodies ruled out. No patients had a history of autoantibodies. Three of 5 patients (60%) were on HU only; the other 2 patients were treated with Voxeletor in combination with HU or Crizanlizumab. Outpatient medication compliance was not evaluated. See Table 1 for additional demographic information.