Personalizing transfusion in sickle cell disease: where is the canary in the mine?

Red blood cell (RBC) transfusion is the cornerstone of therapy for sickle cell disease (SCD). The genetic mutation in SCD results in the production of hemoglobin (Hb) S. HbS polymerizes when deoxygenated and deforms the shape of the RBC, leading to hemolysis with resultant anemia, inflammation, and endovascular activation. Prior to hemolysis, though, HbS RBCs have increased aggregation and decreased deformability compared to HbA RBCs, increasing the viscosity of the blood and decreasing flow through the microcirculation. The goal of chronic transfusion therapy is to increase the number of RBCs with HbA and decrease the quantity of RBCs with HbS, which not only increases the oxygen carrying capacity of the blood through correction of the patient's anemia, but also improves flow through the microcirculation by decreasing aggregation and increasing the percentage of HbA RBCs with normal deformability.1 Most commonly, chronic transfusion is used as treatment for primary or secondary prevention of stroke in SCD. The neurocognitive complications of SCD are not surprising considering the high oxygen demand of the brain, requiring 20% of the cardiac output to fulfill its metabolic demand. Historically, approximately 10% of patients with HbSS disease had an overt stroke, associated with abnormalities on the bedside neurologic exam, by the age of 20 years.2 However, there is a 92% risk reduction with the initiation of chronic transfusion therapy for primary stroke prevention after identifying those at greatest stroke risk via screening transcranial Doppler ultrasound (TCD).3, 4 Unfortunately, a high percentage of patients with SCD still suffer from silent cerebral infarctions (small strokes that are associated with cognitive deficits, but not with abnormalities on the neurologic exam) in the modern treatment era with TCD screening. Approximately 40% of children with HbSS disease develop a silent cerebral infarct by the age of 18 years without a plateau in prevalence.5 The Silent Cerebral Infarct Multi-Center Clinical Trial showed that chronic transfusion significantly decreased the risk of recurrent stroke, silent or overt, in patients with a history of silent infarct.6 Lastly, chronic transfusion therapy is occasionally used as treatment in patients with other complications of SCD, such as severe sickle cell hepatopathy, or recurrent acute chest syndrome, vasoocclusive episodes, or priapism.7 The benefits from chronic transfusion therapy in SCD are partially offset by the side effects of this intervention. Even though automated exchange transfusions decrease iron burden when compared to simple transfusion or manual exchange, many patients still require chelation with potentially toxic medications for hemosiderosis.8 Alloimmunization remains a significant risk of chronic transfusion even in the setting of matching for Rh, D, E and K antigens and utilizing RBCs from African American donors, with up to 7%-59% of chronically transfused patients becoming alloimmunized.9 Approximately 1/3 of new alloantibodies in this setting are associated with a delayed hemolytic transfusion reaction.10 In this issue of TRANSFUSION, Kamyszek et al11 report the results of a retrospective cohort study investigating the association between HbA decrement between RBC exchange procedures with SCD-related clinical events in 21 adult SCD patients receiving chronic transfusion therapy for a variety of clinical indications. Within this cohort, they found that the subgroup of patients with increased SCD-related complications resulting in an emergency department visit or hospitalization had a significantly greater HbA decrement between exchange procedures compared to those with fewer complications of their disease. Kamyszek's study of HbA decrement may have important clinical implications, but further investigation will be required. The vast majority of research on chronic transfusion therapy for SCD has focused on monitoring HbS between transfusions. One other group, Yee and colleagues12 investigated the decrement of HbA in chronically transfused pediatric patients with SCD. However, this study focused on the relationship between HbA decrement, prior alloimmunization, and donor-recipient minor RBC antigen mismatches, rather than on the relationship between HbA decrement and clinical outcomes. The work of Kamyszek et al11 reiterates the positive impact of chronic transfusion therapy on the multitude of clinical complications associated with SCD, and together, these two studies highlight our lack of understanding of factors influencing survival of transfused RBCs, the best algorithms for monitoring chronic transfusion therapy, and the optimal transfusion goals required for this population, which receives a single therapeutic intervention for a variety of clinical indications. Current guidelines for chronically transfusing patients with SCD recommend targeting a pre-transfusion HbS less than 30%, with a post-transfusion Hb < 10 g/dL.7, 13 This recommendation was based on landmark trials, including the Stroke Prevention Trial in Sickle Cell Anemia (STOP), Stroke With Transfusions Changing to Hydroxyurea (SWiTCH), Silent Cerebral Infarct Multi-Center Clinical Trial (SIT), and TCD With Transfusions Changing to Hydroxyurea (TWiTCH), all of which required the pre-transfusion HbS remain less than 30% with varying recommendations for the post-transfusion hemoglobin, if guidance was provided at all for the post-transfusion hemoglobin. None of these trials stipulated pre- or post-transfusion HbA thresholds.4, 6, 14, 15 There are no studies, to date, specifically investigating the impact of different percent HbA or HbS goals in chronic transfusion therapy for stroke prevention or for any complication of SCD. The clinical trial designs requiring pre-transfusion HbS to be less than 30% were based on early literature investigating secondary stroke prevention with transfusion therapy.16-19 Of note, all subjects included in these early cohort studies had a history of overt stroke, and many of the participants had vasculopathy confirmed with arteriogram. Thus, we are imposing treatment regimens created for the most severely affected patients on all patients with SCD requiring chronic transfusion therapy. However, other earlier studies also suggest that subgroups of patients with SCD may receive neuroprotection from more liberal pretransfusion HbS thresholds of 40%-60%.20, 21 Currently, the field does not have sufficient evidence to guide clinicians in whether to modify a patient's transfusion schedule to adjust the pre-transfusion HbA or HbS, post-transfusion Hb, or a combination of all laboratory measures. Most studies of chronic transfusion therapy in SCD have focused on primary or secondary stroke prevention; almost no high-quality evidence exists to guide the use of chronic transfusion therapy to manage other complications of SCD. Considering the limited interventions available to these patients and the significant side effects of chronic transfusions highlighted above, these patients deserve better data to guide their care. While current transfusion guidelines potentially over-treat some patients with SCD, these same guidelines may be insufficient for patients with the most severe cerebrovascular disease. Hulbert et al reported that 45% of SCD patients receiving chronic transfusion therapy for secondary stroke prevention had recurrent or progressive infarction, with a strong association between cerebral vasculopathy and new infarction,22 suggesting that additional treatment is warranted for this subgroup of patients. An improved understanding of the impact of SCD pathophysiology on the brain is required to better stratify patients' stroke risk and determine the appropriate therapeutic intervention for each subgroup. Patients with SCD experience increased cerebral metabolic stress, as measured by an increase in magnetic resonance measures of cerebral blood flow and oxygen extraction fraction (percent of oxygen removed from the blood into the brain tissue), with the greatest increase in oxygen extraction fraction occurring in the border zone where cerebral blood flow nadirs and infarction is most likely to occur in SCD.23 Cerebral blood flow and oxygen extraction fraction are the brain's compensatory mechanisms that can be adjusted to meet the brain's demand for oxygen, based on its oxygen metabolism. Cerebrovascular reserve, the ability to increase cerebral blood flow as needed to meet the metabolic demands of the brain, is limited in patients with SCD due to their high resting cerebral blood flow, potentially placing patients at risk for infarction when they are unable to appropriately compensate during periods of increased metabolic demand.24 Chronic transfusion therapy has been shown to decrease cerebral blood flow and oxygen extraction fraction, suggesting that chronic transfusions mitigate stroke risk by relieving ongoing metabolic stress within the brain and allowing for a greater reserve of these compensatory mechanisms to use during times of increased metabolic demand.25 Furthermore, brain development has been shown to be impacted by SCD even if frank infarction has not occurred, as demonstrated in studies using magnetic resonance diffusion tensor imaging to evaluate white matter integrity and morphometry to measure white matter and gray matter volumes.26, 27 In addition to helping the field better understand the pathophysiology of SCD, these advanced imaging techniques could be leveraged to create a risk prediction algorithm to stratify SCD patients at risk for neurocognitive complications of the disease, permitting the creation of guidelines for treatment, including chronic transfusion therapy, specific to a patient's risk stratum. The high metabolic demand of the brain potentially makes it a bellwether for the multiorgan damage that patients with SCD are experiencing, meaning an improved biomarker of the neurocognitive complications of SCD may be the most sensitive screening tool for these patients. A better understanding of the chronic transfusion intervention itself, including the impact of aggregation, viscosity and deformability of RBCs on the clinical effects of SCD, how transfusion of HbA affects aggregation, viscosity and RBC deformability,1 and donor characteristics that affect RBC survival after transfusion12 will also be required to properly guide clinical care. In summary, SCD is a complex disorder affecting all organ systems. Unfortunately, disease-modifying therapies remain extremely limited, and many patients experience complications of SCD that warrant chronic transfusion therapy and outweigh the significant risks associated with this intervention. Current transfusion guidelines were developed from the protocols of large clinical trials, without thorough investigation into the most impactful targets for each transfusion or how best to monitor the intervention between transfusions. Additionally, there are little to no data to guide chronic transfusion therapy for prevention or treatment of complications of the disease besides stroke. A better understanding of the underlying pathophysiology of SCD and the impact of transfusion will ultimately be required to improve clinical outcomes for these patients.