American Society Of Hematology Guidelines Research Articles

Decision theoretical foundations of clinical practice guidelines: an extension of the ASH thrombophilia guidelines

AbstractDecision analysis can play an essential role in informing practice guidelines. The American Society of Hematology (ASH) thrombophilia guidelines have made a significant step forward in demonstrating how decision modeling integrated within Grading of Recommendations Assessment, Developing, and Evaluation methodology can advance the field of guideline development. Although the ASH model was transparent and understandable, it does, however, suffer from certain limitations that may have generated potentially wrong recommendations. That is, the panel considered 2 models separately: after 3 to 6 months of index venous thromboembolism (VTE), the panel compared thrombophilia testing (A) vs discontinuing anticoagulants (B) and test (A) vs recommending indefinite anticoagulation to all patients (C), instead of considering all relevant options simultaneously (A vs B vs C). Our study aimed to avoid what we refer to as the omitted choice bias by integrating 2 ASH models into a single unifying threshold decision model. We analyzed 6 ASH panel's recommendations related to the testing for thrombophilia in settings of “provoked” vs “unprovoked” VTE and low vs high bleeding risk (total 12 recommendations). Our model disagreed with the ASH guideline panels’ recommendations in 4 of the 12 recommendations we considered. Considering all 3 options simultaneously, our model provided results that would have produced sounder recommendations for patient care. By revisiting the ASH guidelines methodology, we have not only improved the recommendations for thrombophilia but also provided a method that can be easily applied to other clinical problems and promises to improve the current guidelines’ methodology.

Converting IMPROVE bleeding and VTE risk assessment models into a fast-and-frugal decision tree for optimal VTE prophylaxis

AbstractCurrent hospital venous thromboembolism (VTE) prophylaxis for medical patients is characterized by both underuse and overuse. The American Society of Hematology (ASH) has endorsed the use of risk assessment models (RAM) as an approach to individualize VTE prophylaxis by balancing overuse (excessive risk of bleeding) and underuse (risk of avoidable VTE). ASH has endorsed IMPROVE (International Medical Prevention Registry on Venous Thromboembolism) risk assessment models; the only RAM to assess short-term bleeding and VTE risk in acutely ill medical inpatients. ASH, however, notes that no RAMs have been thoroughly analyzed for their effect on patient outcomes. We aimed to validate the IMPROVE models and adapt them into a simple, fast-and-frugal (FFT) decision tree to evaluate the impact of VTE prevention on health outcomes and costs. We used 3 methods: the “best evidence” from ASH guidelines, a “learning health system paradigm” combining guideline and real-world data from the Medical University of South Carolina (MUSC), and a “real-world data” approach based solely on MUSC data retrospectively extracted from electronic records. We found that the most effective VTE prevention strategy used the FFT decision tree, guided by an IMPROVE VTE score of ≥2 or ≥4 and a bleeding score of <7. This method could prevent 45% of unnecessary treatments, saving ∼$5 million annually for patients such as the MUSC cohort. We recommend integrating IMPROVE models into hospital electronic medical records as a point-of-care tool, thereby enhancing VTE prevention in hospitalized medical patients.

Good engraftment after reduced intensity targeted busulfan-based conditioning and matched related donor hematopoietic cell transplantation in hemoglobinopathies.

Hematopoietic cell transplantation (HCT) is an established curative therapy for transfusion-dependent thalassemia (TDT) and sickle cell disease (SCD). The latest American Society of Hematology guidelines recommend myeloablative preparative regimen in patients under 18years of age. The objective was to demonstrate safety and efficacy of a reduced intensity conditioning (RIC) regimen including high-dose fludarabine, anti-thymocyte globulin, and targeted busulfan as a single alkylator to sub-myeloablative exposures. Between 2012 and 2021, 11 patients with SCD and five patients with TDT and matched related donor (MRD) HCT were included. The median age at transplantation was 8.3years (range: 3.7-18.8years). The median administered busulfan AUC was 67.4mg/L×h (range: 60.7-80mg/L×h). Overall survival was 93.8% and event-free survival 87.5% with one engrafted SCD patient with pre-existing moyamoya disease succumbing after drainage of a subdural hematoma. One SCD patient developed a secondary graft failure and was treated with a second HCT. Myeloid chimerism was full in all other patients with a median follow-up time of 4.1years (range: 2.0-11.1years), whereas T-cell donor chimerism was frequently mixed. This RIC conditioning followed by MRD HCT is sufficiently myeloablative to cure pediatric patients with hemoglobinopathies without the need for additional total body irradiation or thiotepa.

Inpatient thrombophilia workup; does hematology consult prevent unnecessary testing?

Hypercoagulable disorders are best described as a group of acquired and hereditary conditions that increase the risk for the development of thrombi within veins or arteries. In the setting of an unprovoked venous thromboembolism, common practice in the inpatient setting has been further investigation via a thrombophilia workup to establish an underlying cause. Current Hematology-Oncology guidelines argue against inpatient workup as the results rarely influence inpatient management. Following American Society of Hematology guidelines (Middledorp), the current study found that only 15% (11/72) of patients met appropriate criteria for thrombophilia testing. There was no relationship between appropriate thrombophilia testing and diagnosis of thrombophilia or initiation of anticoagulation. There was a relationship between appropriate thrombophilia testing and Hematology-Oncology consultation. This demonstrates the need for expert consultation if thrombophilia testing is being considered. The current study provides more evidence that a strong recommendation against inpatient testing should be made as testing does not aid in diagnosis or change management and is an overutilization of healthcare resources.

Rituximab versus Splenectomy in Chronic Primary ITP: Experience of a Single Hematology Clinic.

Immune thrombocytopenia (ITP) is an acquired immune-mediated disease that lacks an underlying etiology. Steroids are the main first-line treatment of ITP, while the second-line treatment consists primarily of splenectomy and rituximab. This study aimed to assess and compare the response to rituximab and splenectomy. This retrospective comparative study reviewed ITP patients treated at a single private hematology clinic from 2007 to 2019. Seventy-four ITP patients were recruited, 27 were on rituximab, and 47 had undergone splenectomy. The initial platelet counts and bleeding symptoms were recorded, and initial and long-term responses to treatment were evaluated based on the American Society of Hematology guidelines. The mean age of the patients was 42.1 years with a male-to-female ratio of 1:1.8. The initial mean platelet count was comparable between the rituximab and splenectomy groups (p = 0.749). The initial complete response (CR) differed significantly between the rituximab and splenectomy groups (44.4% versus 83%, p = 0.002). The five-year response rate was significantly higher in the splenectomy than in the rituximab group (74% versus 52%, log-rank 0.038). Splenectomy was the only significant predictive factor for long-term response (OR = 0.193, p = 0.006). The overall response revealed that splenectomy appeared superior to rituximab as a second-line treatment of ITP. Splenectomy was the only positive prognostic indicator of sustained response.

Anticoagulation management in patients tested for heparin-induced thrombocytopenia in the cardiothoracic intensive care unit diverges from expert guidelines

Abstract Heparin-induced thrombocytopenia (HIT) is a rare, life-threatening complication in patients receiving heparin products. Clinical scoring tools, such as the ‘4T’ score, aim to help identify patients at risk for HIT and are recommended by expert guidelines. For example, the American Society of Hematology (ASH) recommends that patients with an intermediate or high-risk 4T score are presumptively treated for HIT by withdrawing heparin and starting an alternative anticoagulant. At our institution, laboratory HIT testing involves an in-house latex immunoassay (LIA) that, if positive, reflexes to a send-out serotonin release assay (SRA) at the Blood Center of Wisconsin. This confirmation may take several days to result, underscoring the importance of presumptive treatment. Anecdotally, we have observed that clinicians have expressed reservations about the use of the 4T score in the cardiothoracic intensive care unit (CTICU). These reservations may lead to increased HIT testing in patients with low 4T scores and delays in the initiation of alternative anticoagulants. We set out to objectively determine if clinical practice in the CTICU is aligned with ASH guidelines. To do so, we used anticoagulant usage as a proxy for medical decisions made at the time of order for HIT laboratory testing. Data was extracted from the electronic medical records of all patients who were admitted to the CTICU between 5/2018 and 7/2022 and administered a heparin product (n = 1,602). Patients that were not tested for HIT (n = 1,449) were excluded. The remaining patients’ (n = 153) medication record timings were normalized such that the time of their first LIA was set to zero to allow for relative comparisons. 25 (16%) of the LIAs were positive, of which 5 (20%) were confirmed by SRA. Of the 153 patients, 136 (89%) received heparin within 24 hours prior to LIA order, while 6 (4%) were already on alternative anticoagulation (bivalirudin). Of the patients on heparin prior to LIA, 18 (13%) were switched to bivalirudin upon LIA order, 66 (49%) had heparin discontinued without an alternative, and 52 (39%) were continued on heparin. Our results suggest that the prevalence of HIT in this cohort is 3.3% by SRA, much lower than the expected pretest probability estimated for intermediate- and high-risk 4T scores in published meta-analyses. In addition, the observed anticoagulation practices varied widely and diverged from ASH guidelines, where only 17% of patients were on alternative anticoagulation when the testing was ordered. Future work will investigate these patterns across LIA positivity and 4T scores while attempting to address the clinical outcomes of these treatment decisions.

Comparison of Alloimmunization in Pregnant People with Sickle Cell Disease Receiving Chronic Versus on-Demand Transfusions: A Multinational Study

Introduction Despite exceptional maternal morbidity and mortality risk, people with sickle cell disease (SCD) lack firm indications for chronic transfusion therapy (CTT) during pregnancy. Alloimmunization may cause hemolytic transfusion reactions and can limit the safety of future blood transfusions; thus it is a rationale for restricting CTT during pregnancy. Little data quantifies this risk. The 2020 American Society of Hematology (ASH) Guidelines for SCD TransfusionSupport recommend CTT in some pregnancies, but adoption in clinical practice is unknown. This study's purpose is to use a large two-center SCD pregnancy cohort to describe alloimmunization rates in SCD pregnancies treated with CTT vs on-demand transfusion (ODT) and to determine the fraction of SCD pregnancies meeting the ASH Guideline to initiate CTT in pregnancy. Methods We reviewed SCD pregnancies delivered at Mt. Sinai Hospital, Toronto (1990-2017) and Johns Hopkins Hospital (2000-2021). We collected data on transfusions and SCD complications before and during pregnancy, delivery, and fetal outcomes. Analyses classified subjects and pregnancies as receiving CTT or ODT. We defined CTT as pregnancies treated with scheduled, prophylactic transfusions; ODT as pregnancies transfused as-needed, including no transfusions. Sinai routinely matched transfusions for Rh and K antigens while Hopkins matched Rh only. Both centers provided extended matching if an alloantibody was detected. The first analysis included singleton pregnancies to primigravida subjects. We compared new alloantibody development, SCD complications, and pregnancy outcomes in CTT vs. ODT groups and in genotype stratified groups. We used Chi-squared and Wilcoxon rank-sum tests for categorical and continuous variables; p &amp;lt; .05 was significant. The second analysis included all cohort pregnancies and identified which met criteria for CTT per ASH Transfusion Guidelines which advise CTT for (A) severe SCD complications before or during pregnancy here defined by acute chest syndrome (ACS) or pain requiring acute care in the year before or during pregnancy, any history of venous thromboembolism (VTE), stroke, or multi-organ failure or (B) features of high-risk pregnancy, defined by multiple gestation, pre-eclampsia, gestational hypertension, cardiac comorbidities, or preterm labor history. Results Among 145singleton, primigravida pregnancies, more received ODT than CTT (119 ODT vs 26 CTT). Among ODT subjects 46/119 received at least one transfusion during pregnancy. CTT subjects had more severe SCD than ODT subjects before pregnancy (Table 1). During pregnancy, SCD severity did not differ (Table 2). Before pregnancy, 18 subjects were alloimmunized and did not differ by treatment group (6/26 CTT vs 12/119 ODT, p=0.07). During pregnancy, six subjects developed an alloantibody and did not differ by treatment group (1/26 CTT vs 5/119 ODT, p=0.93). Half (3/6) had a history of alloimmunization before pregnancy (1 CTT vs 2 ODT, p=0.27) and three did not (0 CTT vs 3 ODT, p=0.27). All subjects with new antibodies during pregnancy and historic alloimmunization developed anti-K antibodies (1 CTT, 2 ODT) at both sites. Those without alloimmunization history developed anti-Jkantibodies (3 ODT) at Sinai. In the secondary analysis, we included 299 pregnancies to 203 subjects. Among them, 249 pregnancies (83%) met at least one ASH Guideline criteria for initiating CTT. This included all CTT pregnancies (61/61, 39 subjects) and 79% of ODT pregnancies (188/238, 164 subjects), 46% of which received at least one transfusion during pregnancy (86/188). Conclusions In this SCD pregnancy cohort, alloimmunization rates were low and did not differ between those treated with CTT versus ODT. As alloimmunization events were inconsistent with institutional matching practices, new antibody development may be attributable to transfusions from outside hospitals or pregnancy-associated alloimmunization. Antigen matching per ASH Transfusion Guidelines avoids C, E, K and Jk alloimmunization. Scheduled transfusions may reduce emergency transfusion which increases alloimmunization risk. Finally, all CTT and 79% of ODT pregnancies met ASH Guideline criteria for CTT in pregnancy, however the cohort predates ASH Guideline publication. Guideline adherence may lead to increased use of CTT during pregnancy. More discriminating tools are needed to inform CTT use in SCD pregnancy.

Prevalence and Time Trends of Oral Anticoagulant Utilization in Adults with Sickle Cell Disease

Background: Sickle cell disease (SCD) is an inherited red blood cell disorder, caused by a genetic mutation in the β-hemoglobin chain. SCD is associated with chronic activation of coagulation and an increased risk of venous thromboembolism (VTE). Although the American Society of Hematology guidelines recommend indefinite anticoagulation for unprovoked or recurrent provoked VTE, no guidance is given regarding choice of anticoagulant due to a paucity of data. Existing evidence on the use of anticoagulants in patients with SCD has been mostly focused on oral anticoagulants, was limited by small sample sizes, and did not clearly demonstrate the temporal utilization patterns. Real-world evidence on oral anticoagulant use in SCD from large population-based studies is largely lacking. This study examined the prevalence and time trends of oral anticoagulant utilization in patients with SCD in the United States (US). Methods: This retrospective, repeated cross-sectional study analyzed the Cerner Health Facts® database from January 1, 2011, to December 31, 2016, which captures longitudinal electronic medical records (EMR) of patient data from participating facilities in the US. To be included, patients were required to (1) have ≥ 1 inpatient or emergency department encounters with SCD, or 2 outpatient encounters that were 30 days apart in a calendar year from 2012 to 2016, (2) have ≥ 1 prescription records on the encounters with SCD, (3) aged ≥ 18 years at index, and (4) have ≥ 1 encounter with SCD in a year prior to the index. For patients with multiple encounters with SCD in the calendar year, we randomly selected one encounter with SCD and defined it as the index. In this design, a patient contributed only one observation per year but may contribute to multiple years of observations if meeting the selection criterion. The outcome was the use of anticoagulants, defined as any prescription drug encounter for an oral anticoagulant (Vitamin K antagonist [VKA]: warfarin; direct oral anticoagulants [DOACs]: apixaban, rivaroxaban, dabigatran, edoxaban) within a grace period of 7 days discharged from the index. The independent variable was each calendar year measured as dummy variables. Covariates were measured during the 12-month baseline period prior to the index, which included patient demographics, comorbidities and complications of SCD, and facility characteristics. Time trends on the proportions of eligible patients with anticoagulant use against the calendar years of the SCD diagnosis were plotted, and the significance on the crude trend was examined using Cochran-Armitage trend test. In the main analysis, a modified Poisson regression by using generalized estimating equations (GEEs) estimated the adjusted prevalence ratios (APRs) for the trends and covariates associated with any anticoagulant utilization. In subgroup analysis, we estimated the APRs of covariates for the use of DOACs versus VKA. Results: The cohort included 8,824 adult patients with SCD in 182 facilities using automated Cerner EMR system for the years 2012 to 2016. Prescription rates of all oral anticoagulants gradually increased from 2012 to 2014; the rates of VKA prescriptions substantially dropped from 11.1/1000 to 4.1/1000 persons between 2014 and 2016, whereas prescription rates of DOACs increased significantly from 12.0/1000 to 29.1/1000. Prevalence of VTE was stable at approximately 6.2/1000 to 7.5/1000 between 2012 and 2016. Prescription rates of DOACs were lower in patients with (versus without) VTE (6.1/1000 vs 7.3/1000), while a reversed prescription pattern was observed for VKA (VTE [yes vs no]: 4.4/1000 vs 1.8/1000). Controlling for covariates, our main analysis demonstrated that patients with a diagnosis of acute chest syndrome, pulmonary hypertension, and depression were 1.51, 2.30, and 1.57 times more likely to have oral anticoagulant prescription, respectively (all p &amp;lt;0.05). Subgroup analysis showed that having a diagnosis of VTE was associated with a decreased likelihood of DOACs prescription relative to VKA (APR= 0.75, 95%CI: 0.62-0.91). Conclusion: Prescription of oral anticoagulants in adults with SCD has significantly increased from 2012 to 2016 and the increase was dominated by DOACs. The treatment paradox of a lower relative rate of DOACs utilization versus VKA in adults with SCD requires more study to understand the reasons and additional clinical outcomes associated with the utilization patterns.

Standardized Clinical Pathways Improve Management of Vaso-Occlusive Episodes in the Pediatric Emergency Department

Introduction: Pain secondary to vaso-occlusive episodes (VOE) is one of the most common and debilitating complications of sickle cell disease (SCD). Although there are guidelines for pain management, these are often not well-followed. Pain management is entrenched in subjectivity and susceptible to implicit bias. Research has shown that clinical pathways improve care for patients which is especially important in vulnerable populations such as pediatric patients with SCD. Following a quality improvement project at our institution that resulted in significantly improved inpatient care for pediatric patients with SCD, the goal of this project was to create an accessible clinical pathway with multidisciplinary input to streamline management of VOE in the emergency department (ED) and assure equitable care for all. We aimed to improve time to analgesics, increase the percent of patients receiving pain medications within 30 minutes, and increase intranasal fentanyl and patient-controlled anesthesia (PCA) utilization in the pediatric ED. Methods: The care signature clinical pathway was created using a multidisciplinary approach with individuals representing the department of pediatric hematology-oncology, pediatric emergency, anesthesiology, pharmacy, and nurse management. The pathway was developed based on updated American Society of Hematology guidelines for pain management in pediatric VOE. The pathway became available for use via electronic medical record on July 12 th, 2022. Outcome measures regarding pain management were evaluated for one year prior to pathway publication and compared to outcomes one year after publication. Patients with a primary or secondary diagnosis of SCD presenting to the Yale pediatric ED with vaso-occlusive pain were included. Results: A total of 214 ED visits were evaluated. The pre-pathway cohort included 108 encounters from July 1 st, 2021 to June 30 th, 2022 and the post-pathway cohort included 106 ED encounters from August 1 st, 2022 to July 21 st, 2023. During the first year post implementation, a provider utilized the clinical pathway a total of 534 times (121 individuals) with an average of 1 time per day. An analgesic was ordered for 63 (58.3%) patients and administered for 31 (28.7%) patients within 30 minutes of arrival in the pre-pathway cohort. An analgesic was ordered for 73 (68.9%) and administered for 32 (30.2%) patients within 30 minutes of arrival in the post-pathway cohort. Comparing pre- and post-pathway cohorts, the median time to pain medication order was 22 vs 17 minutes and pain medication administration was 42 vs 40 minutes respectively. Intranasal fentanyl was used for 2 (1.9%) patients in the pre-pathway cohort and 12 (11.3%) patients in the post-pathway cohort. A total of 0 (0%) hydromorphone PCAs were administered in the ED in the pre-pathway cohort compared to 4 (3.8%) hydromorphone PCA administered in the ED in the post-pathway cohort. Conclusion: Standardizing pain management using a clinical pathway has shown improvement in ED management of VOE in the first year post implementation with increased utilization of intranasal fentanyl and PCAs. Our goal of increased percentage of patients receiving pain medication within 30 minutes and decreased time to first analgesic was not achieved, however this is an ongoing project and with education in implementation of the clinical pathway we hope to continue to see long term progress. Additionally, in the future, we plan to expand use of this pathway to additional sites within our health care system.

Determinants of Relapse and Treatment-Free Survival Following Splenectomy in Patients with Immune Cytopenias

Background: Splenectomy has historically been a treatment option for patients with immune cytopenia not responding to standard treatment. Despite being a highly effective treatment option, current guidelines recommend this strategy as a third-line treatment. There is a need for more evidence regarding predictive response factors that could help adequately select the ideal candidate for splenectomy, its effectiveness, and related complications. The study aims to identify factors associated with relapse in patients diagnosed with immune cytopenia who have undergone splenectomy. Methods: Retrospective cohort study including patients with immune cytopenia, including immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and Evans syndrome (ES), who underwent splenectomy between January 1990 and March 2023 in a tertiary referral center in Mexico City. Response criteria were based on the 2019 American Society of Hematology guidelines for ITP and the 2020 First International Consensus Meeting for AIHA. We defined early surgical complications as those occurring in the first 30 days from splenectomy; a durable response after splenectomy was described as lasting one year or more. Results: With a median follow-up of 100 months (interquartile range [IQR] 55.6 - 141.7 months), 173 patients were analyzed: 70% were female, 83% had primary ITP, 10% AIHA, and 7% ES. Only 15% had secondary autoimmune cytopenia: 4% systemic lupus erythematosus, 4% antiphospholipid antibody syndrome (APS), and 4% both; 3% had other autoimmune diseases; one (0.5%) patient had common variable immunodeficiency (CVI). Before splenectomy, all the patients received corticosteroids as first-line treatment, 13% rituximab, and 10% thrombopoietin receptor analogs (TPO-RA). Splenectomy was performed as the second-line treatment (2L) in 43% of the cases and as a third or later line of therapy (&amp;gt;2L) in 57%. When analyzing periods, there is a decline in the frequency of splenectomy as 2L: 62% from 1990-2010, 48% from 2011-2015, and 33% from 2016-2023. The median time from diagnosis to splenectomy was 6.3 months (IQR 2.6 - 19.9 months), 10.9 months (IQR 3.7 - 30.9 months), and 16.5 months (IQR 3.5 - 49.5 months) in the respective periods. The global response rate after splenectomy was 97.7%: complete response in 91.9%, partial response in 5.8%, and durable responses in 77.5%. The relapse rate after splenectomy was 32.0%, significantly lower in patients undergoing splenectomy as 2L vs. &amp;gt;2L: 20.0% vs. 40.8% (p&amp;lt;0.001). The relapse rate after splenectomy was the same in the different periods (p = 0.244). The number of patients free of a new line treatment after splenectomy at 100 months was significantly higher in patients undergoing splenectomy as 2L vs. &amp;gt;2L: 82.7% vs. 65.3% (p=0.014). When analyzing factors associated with relapse requiring a new line of treatment, splenectomy as the 2L (HR 0.403; 95% CI 0.206-0.788, p = 0.008) and post-splenectomy thrombocytosis (HR 0.301; 95% CI 0.144-0.6, p = 0.001) were associated with higher treatment-free survival in the multivariate analysis (See Table 1 and Figure 1). The rate of early surgical complications was 14%: severe infections (8.7%), bleeding (5.2%), and thrombosis (3.5%). Late surgical complications occurred in 8%: thrombosis (5.8%), infections (2.9%), and bleeding (2.3%). Five patients (3%) died during the follow-up period: 3 related to thrombocytopenia, one to splenectomy (abdominal sepsis in a patient with CVI), and one due to prostate adenocarcinoma. The use of TPO-RA before splenectomy and the diagnosis of APS were associated with post-surgical thrombosis in the multivariate analysis: OR 6.8 (95% CI 1.9 - 23.5, p = 0.002) and OR 4.3 (95% CI 1 - 17.8, p = 0.044), respectively. Conclusions: At our center, splenectomy is frequently employed as a very early 2L treatment. However, this tendency has diminished due to improved access to new drugs. Interestingly, splenectomy as 2L vs. &amp;gt;2L is associated with better outcomes which contrast with current recommendations. In a center where splenectomy is frequently performed, the procedure is associated with a reasonable rate of complications. In patients with immune cytopenia, splenectomy as a second-line treatment is a valid, effective, relatively safe, and cost-effective option, particularly in low-income areas with limited access to new therapies.

Hemoglobin S target of

Sickle cell disease (SCD) patients with a history of stroke are encouraged to receive chronic red blood cell exchange (RBCx) for stroke prevention. The American Society of Hematology guideline published in 2020 recommends an HbS target of <30%. However, this approach necessitates more frequent RBCx and more RBC units. UT Southwestern has devised a chronic exchange protocol that elevates the HbS target to <50% in patients with a low risk of stroke. This retrospective chart review study reviewed the medical records of patients receiving chronic RBCx with a target of HbS <50% over the past 10-year period to assess the safety of maintaining higher HbS targets in SCD patients with a low risk of cerebrovascular accidents (CVA). Among 49 SCD patients in the chronic RBCx program for secondary stroke prevention, 33 patients were maintained on an HbS target of <50% (average measured: 35.4%) for the duration of RBCx program enrollment (median 93.0 months, 95% CI, 83-99). Stroke or transient ischemic attack (TIA) clearly attributable to changing target HbS had not been identified among the 33 study subjects. Seven patients experienced conversion between the HbS targets of <50% and <30% HbS target. Significant reductions were observed in the frequency of RBCx and usage of blood volume in four of them. The findings suggest that liberalizing the HbS target could confer clinical flexibility without increasing the risk of CVA in a selective population. Further studies to fully evaluate the potential benefits of this approach are indicated.

Risk Stratification for Supratherapeutic Peak Anti-Xa Levels in Adult Patients on Therapeutic Enoxaparin.

The American Society of Hematology Guidelines for the management of venous thromboembolism recommend against the use of anti-Xa monitoring for assessing enoxaparin dosing based on a low level of evidence associating supratherapeutic levels with an increased risk of bleeding. However, institutions still utilize anti-Xa levels in select patient populations with altered volume of distribution and/or excretion to monitor and adjust therapy. The primary objective of this study was to identify risk factors associated with supratherapeutic peak anti-Xa levels (≥1.10 IU/mL) for patients receiving therapeutic enoxaparin. This was a retrospective single-center study performed at an academic tertiary care hospital. Patients who received enoxaparin at 1 mg/kg twice daily and peak anti-Xa monitoring were separated into supratherapeutic and therapeutic/subtherapeutic cohorts. A total of 436 patients were screened, and 215 were included, with a mean age of 62 years. There were 108 in the therapeutic/subtherapeutic cohort and 107 in the supratherapeutic cohort. Acute kidney injury (AKI), body mass index (BMI), weight, female sex, intensive care unit (ICU) service, Sequential Organ Failure Assessment (SOFA) score ≥4, and creatinine clearance at the time of peak anti-Xa level collection were associated with supratherapeutic anti-Xa levels in univariate models. Adjusted logistic regression models were created and identified BMI in the 30 to 34.9 kg/m2 (odds ratio [OR] 4.35; 95% confidence interval [CI] 1.70-11.13, P < 0.005) and ≥35 kg/m2 (OR 6.75; 95% CI 3.05-14.94, P < 0.005) and AKI (OR 2.62; 95% CI 1.04-6.62, P = 0.042) as significant risk factors for supratherapeutic anti-Xa levels. Our study identified BMI ≥ 30 kg/m2, AKI, female sex, ICU service, SOFA score ≥4, and creatinine clearance as risk factors for supratherapeutic anti-Xa levels in patients receiving 1 mg/kg twice daily dosing of enoxaparin. Further research should be done to provide evidence for the association between anti-Xa levels and bleeding risk.

American Society of Hematology, ABHH, ACHO, Grupo CAHT, Grupo CLAHT, SAH, SBHH, SHU, SOCHIHEM, SOMETH, Sociedad Panamena de Hematología, Sociedad Peruana de Hematología, and SVH 2023 guidelines for diagnosis of venous thromboembolism and for its management in special populations in Latin America.

Implementation of international guidelines in Latin American settings requires additional considerations (ie, values and preferences, resources, accessibility, feasibility, and impact on health equity). The purpose of this guideline is to provide evidence-based recommendations about the diagnosis of venous thromboembolism (VTE) and its management in children and during pregnancy. We used the GRADE ADOLOPMENT method to adapt recommendations from 3 American Society of Hematology (ASH) VTE guidelines (diagnosis of VTE, VTE in pregnancy, and VTE in the pediatric population). ASH and 12 local hematology societies formed a guideline panel comprising medical professionals from 10 countries in Latin America. Panelists prioritized 10 questions about the diagnosis of VTE and 18 questions about its management in special populations that were relevant for the Latin American context. A knowledge synthesis team updated evidence reviews of health effects conducted for the original ASH guidelines and summarized information about factors specific to the Latin American context. In comparison with the original guideline, there were significant changes in 2 of 10 diagnostic recommendations (changes in the diagnostic algorithms) and in 9 of 18 management recommendations (4 changed direction and 5 changed strength). This guideline ADOLOPMENT project highlighted the importance of contextualizing recommendations in other settings based on differences in values, resources, feasibility, and health equity impact.

Should Magnetic Resonance Angiography Be Used for Screening of Intracranial Aneurysm in Adults with Sickle Cell Disease?

Magnetic resonance imaging (MRI) is used in patients with sickle cell disease (SCD) to detect silent cerebral infarcts. MR angiography (MRA) can identify arterial stenoses and intracranial aneurysms (ICANs) associated with SCD. In this study, we aimed to estimate the prevalence of ICANs in asymptomatic adult patients with SCD referred from the SCD clinic for routine screening by MRI/MRA using a 3T-MRI scanner. Findings were independently reviewed by two neuroradiologists. Between 2016 and 2020, 245 asymptomatic adults with SCD were stratified according to genotype (SS/S-β0thalassemia and SC/Sβ+). ICANs were found in 27 patients (11%; 0.95 CI: 8-16%). ICANs were more frequent in SS/S-β0thalassemia patients (20/118 or 17%; 0.95 CI: 11-25%) than in SC/βb+ patients (7/127 or 6%; 0.95 CI: 2-11%; p = 0.007). Individuals with SCD (particularly SS/S-β0thalassemia) have a higher prevalence of ICANs than the general population. We believe that MRA should be considered in the current American Society of Hematology guidelines, which already contain a recommendation for MRI at least once in adult SCD patients. However, the clinical significance of preventive treatment of unruptured aneurysms remains controversial.

Standardizing the Diagnostic and Therapeutic Approach to Newly Diagnosed Children with ITP: Prospective Data from the ITP Consortium of North America (ICON) Quality Improvement Initiative

Background Pediatric immune thrombocytopenia (ITP) is an acquired autoimmune disorder which leads to a low platelet count and increased risk of bleeding. Despite published treatment guidelines, there is practice variation among clinicians and institutions due to the low grade of available evidence. The recommended management of newly diagnosed children at low risk of serious bleeding is observation; despite this, these patients are often treated with medication. These medications are only transiently effective with potential for side effects and excess lab monitoring as well as associated with increased costs and overuse of healthcare resources due to hospital admissions and encounters for medication-related side effects. Our objective is to report prospective data from a quality improvement (QI) project of the Pediatric ITP Consortium of North America (ICON) that was initiated in 2020 to improve consistency in clinical practice using national ITP guidelines. DESIGN/METHODS Within the ICON QI subcommittee, a standardized clinical care pathway for newly diagnosed childhood ITP was developed based on the American Society of Hematology (ASH) 2019 guidelines. Sites initially completed a retrospective analysis documenting the pre-QI pathway management of children, ages 1-16 years, diagnosed with ITP from January to December 2019. After local dissemination of the clinical care pathway, clinicians at all participating sites reviewed the pathway at the time of managing newly diagnosed children and completed a short survey documenting a modified Buchanan-Adix bleeding score and management decisions. Chart review was completed six months following ITP diagnosis to collect data regarding additional treatment or hospitalization. For retrospective data, total patients include those with available data. Results Retrospective data were collected from 7 centers for 205 patients managed for newly diagnosed ITP. In this pre-intervention cohort, 0.5% of patients (1/204) had a bleeding score documented at their initial visit. Most patients (63%,129/204) received initial medication treatment including intravenous immunoglobulin (54%), corticosteroids (9%), and anti-D/other (3%); 37% (75/204) were initially observed. In the 6 months after diagnosis, 11% (23/205) were admitted to the hospital for management of ITP. The ITP QI pathway was implemented prospectively in the care of 126 patients from 7 centers between November 2020 and July 2022. Of these patients,100% (126/126) had a bleeding score documented at their initial visit [Grade 0 (2%), Grade 1 (26%), Grade 2 (27%), Grade 3 (45%), Grade 4 (0%)]. Initial treatment included close observation in the majority (63%, 79/125) and medication treatment in 37% [corticosteroids (22%, 28/125) and IVIG/anti-D (14%, 18/125)] (Figure 1). Most patients were managed per the pathway according to their bleeding score (80%, 93/117). The most common reasons that providers deviated from the pathway were parent preference (50%, 12/24) and provider concern about bleeding risk (29%, 7/24). Of those with low level grade 3 bleeding, in whom the pathway suggested close observation, 62% (21/34) were observed and 38% of patients (13/34) were treated with medication (Figure 2). For patients with high level grade 3 bleeding, in whom the pathway suggested medication treatment, all patients except one were treated with medication. Of the 66 patients with 6 month follow up data, only 2 patients (3%, 2/66) were admitted to the hospital. DISCUSSION For children with newly diagnosed ITP and a platelet count <20 x 109/L who have no or mild bleeding, ASH guidelines suggest observation rather than treatment with corticosteroids. Implementation of an ITP clinical care pathway based on bleeding score led to an increase in the number of children observed. In contrast to the pre-intervention cohort, most patients treated with medication received corticosteroids rather than IVIG as per ASH guidelines. Despite the increase in patients managed with close observation, just 3% were admitted to the hospital within the first 6 months of diagnosis compared to 11% of the retrospective cohort. Our findings suggest that the use of a clinical care pathway based on objective assessment of bleeding symptoms increases management with close observation when indicated in the treatment of childhood ITP without a subsequent increase in hospitalization and increases adherence to national guidelines. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Dissemination and Implementation Looking at the Care Environment (DISPLACE) Study Evaluates Novel Interventions to Improve TCD (Sickle Stroke Screening) Implementation

Background: Stroke is a devastating complication of sickle cell anemia (SCA). The STOP (Stroke Prevention Trial in Sickle Cell Anemia) protocol was adopted in 2014 by the National Heart Lung and Blood Institute (NHLBI) guidelines for stroke-risk screening using transcranial Doppler ultrasound (TCD) and prevention with chronic red cell transfusion therapy (CRCT). These guidelines were upheld in the recent American Society of Hematology guidelines. Despite strong evidence supporting TCD screening (and CRCT initiation) in stroke prevention, wide scale implementation has not been achieved 4. DISPLACE (Dissemination and Implementation Looking at the Care Environment) is a multicenter, NHLBI-funded study conducted to identify barriers to TCD implementation and test novel methods for improving outcomes. DISPLACE is a 3-part study: 1) Retrospective assessment of current practice; 2) Assessment of barriers and facilitators; and 3) Implementation trial to improve TCD screening. This report focuses on Part 3. Methods: DISPLACE is a 28-center consortium across the US representing a range of: region (urban vs rural), size, and institution type (academic vs community). During Part 1, sites performed a rigorous retrospective chart review of children with SCA aged 2-16 years from 2012-2016 to collect baseline TCD rates. Part 2 included a rigorous mixed methods of the barriers and facilitators assessment to TCD screening was performed that resulted in 3 main interventions: 1.Re-branding TCD as Sickle Stroke Screen, a meaningful name selected by patients/families with SCD; 2. A Single Coordinator (SC) for each site's TCD screening, scheduling, and follow-up; 3. A newly designed application, Provider Minder (trademarked; PM). PMwas created to remind providers of patient appointments (versus reminders only sent to patients/families). Data entry in PM included birth date (to calculate age), city/state of residence, distance from SCD clinic and insurance. Date of last TCD was recorded to calculate date of next screen. When the TCD was due, the system alerted the provider to enter appointment completion or reason(s) why it was missed. TCD results were entered for PM to prompt for the next TCD date in a 10-14 month window (normal screens), 2-6 weeks (conditional screens), and intervention plan (abnormal screens): repeat scan in <2 weeks or other. If the provider failed to enter a patient's result, PM alerted the provider q3 days until the TCD was recorded as completed/rescheduled. Part 3 included 16 sites who successfully completed data entry in Part 1 and had the lowest TCD implementation rates. Part 3 inclusion criteria were the same as Part 1 except to specifically select children with SCA now aged 2-7 (the highest risk group to have an abnormal TCD in Part 1). All 28 sites received re-branding educational material (also disseminated to non-study sites). Cluster randomization was used to allocate sites to PM (8 sites) or PM + SC (8 sites). The primary outcome is which intervention results in the best TCD rates. Secondary outcomes include Part 3 sites’ improvement in TCD rates (compared to historical rates) and impact of the educational/rebranding of TCD to "Sickle Stroke Screen” in sites (4) that did not participate in Part 3. Stroke status, presence of CRCT after an abnormal TCD, missed TCD appointments, and medical decisions following TCD were also recorded. Results: Part 1 included 28 centers with 5223 individuals with SCA in the database. Of the 16 Part 3 sites, three could not implement the interventions due to a simultaneous change in hospital administration and site PI (1), inability to use PM due to institutional firewall (1) and inability to implement due to site specific issues (1). These 3 sites remained in the study as "control sites” and a fourth control site was added. Thus, 13 sites implemented the interventions with 877 patients; 520 were in sites using PM and 357 were in sites using PM+SC. Demographic data for the 877 children with SCA are in Table 1. The study ended on May 31, 2022. Calculations of TCD rates at all sites are in process and will be presented. Conclusions: Despite the benefit of TCD screening in children with SCA, guideline-based implementation remains poor. The range of barriers to screening has been previously reported by the DISPLACE study team and were used to design the study interventions. Results from this study will guide optimization of the intervention protocol proven to enhance TCD implementation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Benefits, Harms, and Cost-Effectiveness of Indefinite Anticoagulant Therapy for First Unprovoked Venous Thromboembolism: A Decision Analytic Modelling Study

Background: Anticoagulation for 3-6 months is the minimum required duration of treatment for patients with venous thromboembolism (VTE). Whether to extend treatment beyond the initial 3-6 months of anticoagulation in patients with a first unprovoked VTE has been debated. The American Society of Hematology guidelines suggest continuing anticoagulation indefinitely over discontinuing anticoagulation after completing 3-6 months of initial treatment for a first unprovoked VTE, except in patients who have a high risk for bleeding (Ortel T, Blood Adv 2018). However, the lifetime clinical benefits, harms, and cost-effectiveness of indefinite anticoagulation have not been formally assessed. While a randomized controlled trial (RCT) would be the optimal study design to provide evidence for or against continuing anticoagulation indefinitely in patients with a first unprovoked VTE, it is unlikely to be conducted due to the lifelong (i.e. until death) follow-up and extremely large sample size that would be required.Decision-analytic modelling can provide evidence to inform guidelines under circumstances in which RCTs are unfeasible. Objective: The aim of this modelling study was to compare the clinical benefits, harms, and cost-effectiveness of continuing versus discontinuing anticoagulation indefinitely after completing initial treatment for a first unprovoked VTE. Methods: We created a probabilistic Markov cohort simulation model [Figure 1] to simulate costs (adjusted to 2022 Canadian dollars) and outcomes (recurrent VTE, major bleeding, and quality-adjusted life-years [QALYs]) for two hypothetical cohorts of patients aged 55 years with a first unprovoked VTE that had completed 3-6 months of initial anticoagulant therapy - one cohort assigned to continue anticoagulation indefinitely with direct oral anticoagulants, and another assigned to discontinue anticoagulation indefinitely. The model adopted a cycle length of 1 month and a lifetime horizon. The economic analysis adopted a third-party payer perspective relating to the Canadian publicly-funded healthcare system. The long-term risks and case-fatality rates of recurrent VTE and major bleeding, with and without extended anticoagulation, were sourced from our recently published systematic reviews (Khan F, BMJ 2019;Khan F, Ann Intern Med 2021). Additional data related to transition probabilities, costs, and utility values were obtained from highest quality published sources identified through a targeted literature search. Future costs and QALYs were discounted at an annual rate of 1.5% as per Canadian guidelines. The model structure, input parameters, and assumptions were validated by clinical experts to ensure that they coincided with current clinical practice. Results: In a hypothetical cohort of 1000 patients, continuing anticoagulation indefinitely, compared to discontinuing anticoagulation, prevented 253 recurrent VTE events (number needed to treat = 4) and induced an additional 69 major bleeding events (number needed to harm = 15). Indefinite anticoagulation resulted in higher health system costs ($70,019.35 vs. $61,438.10 per person) and no improvement in QALYs (15.26 vs. 15.31 per person; incremental difference of -0.05 QALYs or -18.25 quality adjusted life-days) [Table 1]. Model results were most sensitive to the annual risk of major bleeding and case-fatality rate of major bleeding during extended anticoagulation however, in all one-way sensitivity analyses, discontinuing anticoagulation remained economically dominant (i.e., lower costs and similar QALYs) over continuing anticoagulation indefinitely, at a willingness-to-pay (WTP) threshold of Can$50,000 per QALY. In probabilistic analyses, the probability of indefinite anticoagulation being the cost-effective treatment strategy was 0% at a WTP threshold of Can$50,000 or Can$100,000 per QALY. Conclusions: Indefinite anticoagulation for a first unprovoked VTE is unlikely to either result in a net clinical benefit or be cost-effective. With no net gain in QALYs (albeit a small net loss), there is no rationale for continuing anticoagulation indefinitely in all (i.e., unselected) patients with a first unprovoked VTE. However, the clinical and cost-effectiveness of indefinite anticoagulation in subgroups of patients at high risk of recurrent VTE and low risk of major bleeding requires further investigation, and will be an important next step. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Mindfulness Practices for Chronic Pain in Sickle Cell Disease

Background: Patients with sickle cell disease (SCD) suffer from both acute and chronic pain that severely affects their quality of life. Pain is largely managed with opioids, which have significant side effects including dependence, adverse mood effects, and potential for opioid-induced hyperalgesia. The 2020 American Society of Hematology guidelines for SCD suggests cognitive and behavioral pain management strategies (including mind-body interventions). However, there remains low certainty in the evidence of these modalities. We chose to pursue mindfulness-based interventions given their proven efficacy in other chronic pain syndromes and associated mental health disorders. Objective: The purpose of our pilot study was to assess the feasibility and acceptability of weekly group yoga therapy sessions conducted virtually via videoconferencing software in patients with sickle cell disease and chronic pain, defined as pain on more than 15 days per month for the last 6 months. Design: Twenty patients with SCD were recruited for weekly virtual group yoga therapy sessions, which incorporated aspects of mindfulness meditation and low impact movements synchronized with breathing exercises (see Table 1). Results: Twenty out of 22 patients (92%) approached for the study agreed to participate. The median age of participants was 35 (IQR 26-43), with the majority being female (n=13 out of 19, 68%). The baseline survey revealed participants had frequent Emergency Department visits (median 3, IQR 1.25-4) and hospitalizations (median 2, IQR 0-2) in the 6 months prior to the intervention. The study population exhibited high levels of pain catastrophizing (median PCS 40.5, IQR 27.25-52.5, 93%tile), anxiety (median GAD-7 18.5, IQR 10.25-21.5), and depression (median PHQ-9 17, IQR 13.25-22.5). On average, 15% of participants (range 2-32%) attended each session. Barriers to participation included technologic difficulties, time conflicts, and inability to contact participants. The participants who consistently attended the sessions had positive feedback. One participant stated, "It went well for me. Meditation was helpful...[and] the yoga helped with my knee." Another participant commented, "I liked having a community with the other patients." Conclusions and Future Directions: This pilot study was among the first of its kind to examine mindfulness practices for chronic pain in adults with SCD. While there was a high rate of agreement to participate in the study, indicating a willingness and receptiveness to the study intervention, the overall participation per session was low. The study population had high rates of health care utilization despite most participants being on chronic opioid therapy and disease modifying medications, which illustrates the need for additional therapeutic strategies. A striking aspect of the baseline survey was the high rates of pain catastrophizing, anxiety, and depression, which directly impact chronic pain and thus require a holistic approach that includes mindfulness-based interventions. Our future research will draw upon lessons learned from the pilot study to address barriers to participation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Platelet Count Threshold Associated with Bleeding in Adult Patients with Immune Thrombocytopenia Treated with Antiplatelet Drugs. Results from the Carmen-France Registry

Introduction: In 2019, international guidelines for the management of immune thrombocytopenia (ITP) stated that ITP treatment is rarely indicated in case of platelet count >20 x109/L. The threshold associated with significant bleeding in ITP patients treated with antiplatelet agents is unknown, and 2019 American society of hematology guidelines for ITP management stressed the need for studies to determine it. This was the aim of this study. Methods: The source of data was the CARMEN-France registry, a prospective, real-world registry of incident ITP adults in the French Midi-Pyrénées region since June 2013, implemented in other centers of the French Autoimmune cytopenia referral center network since 2016. Inclusion criteria were adult patients (aged ≥18 years) newly diagnosed with ITP (platelet count <100 x 109/L and exclusion of other causes of thrombocytopenia). We designed a transversal study to correlate the platelet count to bleeding at ITP diagnosis, before any ITP treatment. Study population consisted in the patients included in the registry up to November 2021 and treated with antiplatelet agents at the time of ITP diagnosis, without concomitant exposure to anticoagulant. We quantified the percentages of patients with overall bleeding, cutaneous bleeding, non-serious mucosal bleeding and serious bleeding (defined by intracranial bleeding, gastro-intestinal bleeding or gross hematuria with anemia) by categories of platelet count (by 109/L up to 50 x 109/L then ≥50 x 109/L). Analyses were conducted by subgroups of antiplatelet agents due to suspected differences in pharmacological effect in patients with ITP who have a high platelet turn over: patients treated with clopidogrel and ticagrelor, two reversible ligands to P2Y12 receptor with longer half-life, may be at a higher risk of bleeding than those treated with acetylsalicylic acid alone, an irreversible ligand to COX-1. Results: Out of 1171 adult patients with incident primary ITP included in the registry during the study period, 143 (12.2%) were exposed to an antiplatelet drug at the time of ITP diagnosis: 108 to acetylsalicylic acid alone, 20 to clopidogrel alone and 15 to an association of antiplatelet agents (acetylsalicylic acid + clopidogrel, n=13; acetylsalicylic acid + ticagrelor, n=2). In the acetylsalicylic acid group, the median age was 75.5 years, 73 (67.6%) were men, median platelet count at ITP diagnosis was 15 x 109/L and 66 (61.1%) had bleeding: 60 (55.6%) a cutaneous bleeding, 35 (32.4%) a non-serious mucosal bleeding and 4 (3.7%) a serious bleeding (3 gastrointestinal bleeding with anemia and 1 gross hematuria with anemia). The pattern of bleeding by platelet count categories is shown in Figure 1. The frequency of overall bleeding was 97.6% (41/42) in the < 10 x 109/L group, 66.7% (14/21) in the 10 - 19 x 109/L group and 22.2% (10/45) in the ≥20 x 109/L group (similar pattern by all categories ≥20 x 109/L). The receiver operating characteristics curve had an area under the curve of 88.3% (95% confidence interval: 81.9-94.6%). The threshold of <20 x 109/L had a sensitivity of 83.3% and a specificity of 81.0%. The pattern for cutaneous and non-serious mucosal bleeding was similar (Figure 1). All four serious bleeding occurred in patients with a platelet count <20 x 109/L. In the clopidogrel and association of antiplatelet drug groups, bleeding was observed in 14 (70.0%) and 10 (66.7%) patients, respectively. No clear correlation with the platelet count was shown, limited by the low number of patients. One serious bleeding occurred in each group (two intracranial bleeding), in patients with platelet counts < 10 x 109/L. Conclusion: This study shows that the bleeding risk in ITP patients treated with acetylsalicylic acid alone is similar to other ITP patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

28-Year-Old Man With Joint Pain

A 28-year-old man presented to the emergency department with right shoulder pain that radiated to the right arm as well as pain of the right hip and lower back. His medical history is significant for sickle cell disease (SCD) with the HbSS genotype (homozygous for the S globin). He had a hemorrhagic stroke in the setting of venous sinus thrombosis 2 years earlier with no persisting neurologic deficits as well as osteonecrosis of bilateral hips and right knee requiring right total hip arthroplasty and right total knee arthroplasty. His pain started 3 days earlier after he exerted himself performing yard work and had progressively worsened. He described the pain as sharp, throbbing, and 10/10 in severity. The pain did not improve with acetaminophen or oxycodone. He also reported shortness of breath, which had resolved. He did not have fever, chills, chest pain, cough, abdominal pain, diarrhea, or recent trauma. Home medications included apixaban, l-glutamine, hydroxyurea, and folic acid. He had not missed any doses of his medications. He required 2 admissions in the past year for sickle cell pain crisis. Vital signs demonstrated an oral temperature of 37.7°C, blood pressure of 122/82 mm Hg, heart rate of 99 beats/min, respiratory rate of 19 breaths/min, and oxygen saturation of 94% on room air. Physical examination found tenderness to palpation of the right shoulder, right arm, and right hip with limited range of motion secondary to pain. There was no ecchymosis, erythema, or warmth of the shoulder or hip joints. Peripheral pulses were normal. Lungs were clear to auscultation bilaterally. Laboratory evaluation revealed the following (reference ranges provided parenthetically): hemoglobin, 9.0 g/dL (13.5 to 17.5 g/dL); hematocrit, 26.7% (38.3% to 48.6%); platelet count, 267 × 109/L (135 to 317 × 109/L); white blood cell count, 13.2 × 109/L (3.4 to 9.6 × 109/L); neutrophils, 10.29 × 109/L (1.56 to 6.45 × 109/L); lymphocytes, 1.51 × 109/L (0.95 to 3.07 × 109/L); monocytes, 1.09 × 109/L (0.26 to 0.81 × 109/L); eosinophils, 0.03 × 109/L (0.03 to 0.48 × 109/L); basophils, 0.06 × 109/L (0.01 to 0.08 × 109/L); sodium, 134 mmol/L (135 to 145 mmol/L); potassium, 4.1 mmol/L (3.6 to 5.2 mmol/L); bicarbonate, 25 mEq/L (22 to 29 mEq/L); blood urea nitrogen, 11 mg/dL (8 to 24 mg/dL); creatinine, 0.85 mg/dL (0.74 to 1.35 mg/dL); calcium, 9.8 mg/dL (8.8 to 10.2 mg/dL); glucose, 85 mg/dL (70 to 140 mg/dL); and procalcitonin, 0.17 ng/mL (≤0.15 ng/mL). Absolute reticulocyte count was 198 × 109/L (30.4 to 110.9 × 109/L) with a reticulocyte index of 3.1%. His baseline hemoglobin level ranged from 9 to 10 g/dL. Hemoglobin S percentage was 81.5%, which was increased from 69.8% at time of diagnosis. Radiographic examination of the right shoulder showed stable changes of the proximal humerus, suggesting chronic avascular necrosis (Figure). Radiographic examination of the hips and pelvis showed stable right total hip arthroplasty with well-seated components without evidence of loosening. In addition, there was unchanged sequela of left femoral head osteonecrosis. Chest film showed no focal consolidation, pleural effusion, or pneumothorax. Electrocardiographic findings were unremarkable, with no notable ischemic changes. High-sensitivity troponin level was normal.1.Which of the following is the most likely diagnosis?a.Acute avascular necrosisb.Acute coronary syndromec.Opioid-induced hyperalgesiad.Osteomyelitise.Vaso-occlusive crisis (VOC) On evaluation of a patient with SCD and acute pain, it is important to rule out common orthopedic complications of SCD, such as avascular necrosis.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar Radiography is the initial study of choice when avascular necrosis is suspected clinically. In this case, radiographs of the hips and right shoulder were obtained, which showed evidence of chronic avascular necrosis unchanged from prior films. Whereas this is likely to be a cause of chronic pain for our patient, it would not explain his acute pain. Acute coronary syndrome can be manifested as atypical chest pain or pain of the shoulder or arm. This was appropriately ruled out with a normal electrocardiogram and high-sensitivity troponin level. Opioid-induced hyperalgesia is a type of neuropathic pain that can occur with long-term opioid use.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar In addition to hyperalgesia (increased pain in response to a stimulus that should provoke pain), patients may also experience allodynia (pain in response to a stimulus that usually does not provoke pain) with escalating opioid dosages. This diagnosis is unlikely as the patient has not taken opioids long term for pain. Impaired immune function and functional asplenia place patients with SCD at risk for development of osteomyelitis.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar However, in the absence of fever, localized erythema, or swelling, this diagnosis is less likely. Our patient did have a mildly elevated white blood cell count on presentation. Leukocytosis can be seen in sickle cell patients without an infection. Vaso-occlusive crisis is the most likely diagnosis. Patients typically present with a sudden onset and throbbing and sharp pain involving the lower back, joints, or extremities.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar There is often a prodromal phase of 1 or 2 days with symptoms of numbness, paresthesia, or aches in the associated area.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar The patient was subsequently admitted to the hospital for management of VOC.2.What initial treatment should be given for this patient’s condition?a.Exchange transfusionb.Intravenous fluidsc.Nonsteroidal anti-inflammatory drugs (NSAIDs)d.Opioidse.Simple transfusion Exchange transfusion is not indicated for VOC alone; however, exchange transfusion is used in the setting of acute ischemic stroke, severe acute chest syndrome (ACS), multiorgan failure, acute sickle hepatopathy, and severe sepsis.2Howard J. Sickle cell disease: when and how to transfuse.Hematology Am Soc Hematol Educ Program. 2016; 2016: 625-631Crossref PubMed Scopus (62) Google Scholar There is a role for hydration with intravenous fluids if there is clinical evidence of dehydration to restore the patient to a euvolemic state.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar,3Brandow A.M. Carroll C.P. Creary S. et al.American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain.Blood Adv. 2020; 4: 2656-2701Crossref PubMed Scopus (51) Google Scholar Whereas hydration with intravenous fluids can be a useful adjunctive therapy, it should not preclude adequate pain management. American Society of Hematology guidelines for management of acute pain related to SCD issue a conditional recommendation for 5 to 7 days of NSAIDs in addition to opioids.3Brandow A.M. Carroll C.P. Creary S. et al.American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain.Blood Adv. 2020; 4: 2656-2701Crossref PubMed Scopus (51) Google Scholar It is important to consider potential harms of NSAID use, such as renal, vascular, and gastrointestinal toxic effects. Our patient takes apixaban for history of venous sinus thrombosis, and NSAIDs would increase bleeding risk. Thus, NSAIDs would not be appropriate or the first management option. The cornerstone of therapy for VOC is rapid (preferably within 30 minutes) and effective analgesia with opioid medications.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar An individualized approach based on baseline opioid therapy and prior effective therapy is recommended.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar,3Brandow A.M. Carroll C.P. Creary S. et al.American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain.Blood Adv. 2020; 4: 2656-2701Crossref PubMed Scopus (51) Google Scholar Intranasal and subcutaneous routes of administration should also be considered to prevent delay in administration of analgesia.3Brandow A.M. Carroll C.P. Creary S. et al.American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain.Blood Adv. 2020; 4: 2656-2701Crossref PubMed Scopus (51) Google Scholar Simple transfusion is indicated in the case of symptomatic anemia in SCD but not for isolated vaso-occlusive pain.2Howard J. Sickle cell disease: when and how to transfuse.Hematology Am Soc Hematol Educ Program. 2016; 2016: 625-631Crossref PubMed Scopus (62) Google Scholar Iron overload and increased risk of red blood cell (RBC) alloimmunization may result from frequent blood transfusions.2Howard J. Sickle cell disease: when and how to transfuse.Hematology Am Soc Hematol Educ Program. 2016; 2016: 625-631Crossref PubMed Scopus (62) Google Scholar,4Fasano R.M. Booth G.S. Miles M. et al.Red blood cell alloimmunization is influenced by recipient inflammatory state at time of transfusion in patients with sickle cell disease.Br J Haematol. 2015; 168: 291-300Crossref PubMed Scopus (150) Google Scholar He received treatment with a morphine patient-controlled analgesia pump. Subsequently, the morphine patient-controlled analgesia pump was transitioned to oral oxycodone as needed when his pain was better controlled. The following day, a fever developed, with temperature of 38.1°C. He also noted shortness of breath and pleuritic chest pain. Oxygen saturation on room air was 96%. Blood culture specimens were obtained. Electrocardiography revealed sinus tachycardia with a heart rate of 105 beats/min and no ST-segment changes.3.Which of the following is the next most appropriate diagnostic evaluation?a.Arterial blood gasb.Bronchoalveolar lavagec.Computed tomography pulmonary angiography (CTPA)d.D-dimere.Troponin With development of fever, shortness of breath, and pleuritic chest pain, there was clinical concern for ACS. Acute chest syndrome often develops after onset of severe pain and is defined as an acute illness characterized by fever or respiratory symptoms, with a new pulmonary infiltrate on chest imaging.5Howard J. Hart N. Roberts-Harewood M. Cummins M. Awogbade M. Davis B. BCSH CommitteeGuideline on the management of acute chest syndrome in sickle cell disease.Br J Haematol. 2015; 169: 492-505Crossref PubMed Scopus (84) Google Scholar Other signs and symptoms of ACS may include hypoxia, chest pain, skeletal pain, and hemoptysis.5Howard J. Hart N. Roberts-Harewood M. Cummins M. Awogbade M. Davis B. BCSH CommitteeGuideline on the management of acute chest syndrome in sickle cell disease.Br J Haematol. 2015; 169: 492-505Crossref PubMed Scopus (84) Google Scholar Arterial blood gas analysis is useful for confirming hypoxia but is not usually necessary in adult patients with oxygen saturation above 94% on room air, such as in our case. Bronchoalveolar lavage would not be done before confirming a pulmonary infiltrate and is typically needed only if patients are not responding to standard therapy. The appropriate next step is CTPA because chest imaging is needed to confirm the diagnosis of ACS. Whereas ACS can be diagnosed with chest radiography, CTPA can be useful in excluding pulmonary embolism and is recommended if there is a high clinical suspicion of pulmonary embolism.5Howard J. Hart N. Roberts-Harewood M. Cummins M. Awogbade M. Davis B. BCSH CommitteeGuideline on the management of acute chest syndrome in sickle cell disease.Br J Haematol. 2015; 169: 492-505Crossref PubMed Scopus (84) Google Scholar D-dimer testing is not helpful in SCD because levels are typically elevated.5Howard J. Hart N. Roberts-Harewood M. Cummins M. Awogbade M. Davis B. BCSH CommitteeGuideline on the management of acute chest syndrome in sickle cell disease.Br J Haematol. 2015; 169: 492-505Crossref PubMed Scopus (84) Google Scholar With an electrocardiogram showing no ischemic changes, acute coronary syndrome is unlikely, and troponin should be ordered only if other work-up is unrevealing. Our patient’s CTPA study found consolidative air space disease in the right lower lobe with no evidence of pulmonary embolism.4.What is the next most appropriate step in management of this patient’s condition?a.Exchange transfusionb.Bronchodilator therapyc.Corticosteroidsd.Antibiotic therapye.Inhaled nitric oxide A pulmonary infiltrate was identified along with symptoms of chest pain and shortness of breath, which meets criteria of ACS. Exchange transfusion is warranted for severe clinical features, such as worsening hypoxia, increased respiratory rate, thrombocytopenia, or multilobar disease on chest imaging.2Howard J. Sickle cell disease: when and how to transfuse.Hematology Am Soc Hematol Educ Program. 2016; 2016: 625-631Crossref PubMed Scopus (62) Google Scholar The decision to initiate exchange transfusion should be made only after consultation with a hematologist. Our patient had disease localized to 1 lobe and no significant hypoxia or oxygen requirements; therefore, exchange transfusion was deferred with careful monitoring of evidence of clinical deterioration. Simple transfusion is recommended to be administered early in the hypoxic or symptomatic patient to increase hemoglobin level to greater than 10 g/dL, and failure to improve after simple transfusion is another indication for exchange transfusion.2Howard J. Sickle cell disease: when and how to transfuse.Hematology Am Soc Hematol Educ Program. 2016; 2016: 625-631Crossref PubMed Scopus (62) Google Scholar Bronchodilators should be used only if patients have a history of asthma or evidence of bronchospasm.5Howard J. Hart N. Roberts-Harewood M. Cummins M. Awogbade M. Davis B. BCSH CommitteeGuideline on the management of acute chest syndrome in sickle cell disease.Br J Haematol. 2015; 169: 492-505Crossref PubMed Scopus (84) Google Scholar Corticosteroids are indicated only in the case of acute asthma exacerbation, and there is a risk of rebound sickling with corticosteroid use.5Howard J. Hart N. Roberts-Harewood M. Cummins M. Awogbade M. Davis B. BCSH CommitteeGuideline on the management of acute chest syndrome in sickle cell disease.Br J Haematol. 2015; 169: 492-505Crossref PubMed Scopus (84) Google Scholar Because clinicians can usually not distinguish causes of ACS, patients must be treated empirically for pneumonia, including coverage of atypical organisms such as Mycoplasma and Chalmydophila.5Howard J. Hart N. Roberts-Harewood M. Cummins M. Awogbade M. Davis B. BCSH CommitteeGuideline on the management of acute chest syndrome in sickle cell disease.Br J Haematol. 2015; 169: 492-505Crossref PubMed Scopus (84) Google Scholar Whereas case reports have found benefit with inhaled nitric oxide therapy, there are no randomized controlled trials to support its routine use for ACS.5Howard J. Hart N. Roberts-Harewood M. Cummins M. Awogbade M. Davis B. BCSH CommitteeGuideline on the management of acute chest syndrome in sickle cell disease.Br J Haematol. 2015; 169: 492-505Crossref PubMed Scopus (84) Google Scholar Our patient was prescribed moxifloxacin, a respiratory fluoroquinolone with pseudomonal coverage that can be used for hospital-acquired pneumonia. He also received 1 simple transfusion. During the next 48 hours, he showed improvement in symptoms, including resolution of fever, chest pain, and shortness of breath. On hospital day 4, he was discharged home, with follow-up in the hematology clinic arranged.5.Which of the following medications should be given to prevent recurrence of VOC?a.Crizanlizumabb.Aspirinc.Montelukastd.Rivaroxabane.Simvastatin Crizanlizumab is a humanized monoclonal antibody that inhibits P-selectin.6Ataga K.I. Kutlar A. Kanter J. et al.Crizanlizumab for the prevention of pain crises in sickle cell disease.N Engl J Med. 2017; 376: 429-439Crossref PubMed Scopus (339) Google Scholar The SUSTAIN trial reported that crizanlizumab is associated with significantly lower frequency of pain crises and similar incidence of serious adverse effects in patients with SCD compared with placebo,6Ataga K.I. Kutlar A. Kanter J. et al.Crizanlizumab for the prevention of pain crises in sickle cell disease.N Engl J Med. 2017; 376: 429-439Crossref PubMed Scopus (339) Google Scholar leading to its approval by the Food and Drug Administration (FDA) in 2019. Studies have investigated aspirin and montelukast for management of SCD, and neither drug was found to decrease the frequency or severity of VOC.7Greenberg J. Ohene-Frempong K. Halus J. Way C. Schwartz E. Trial of low doses of aspirin as prophylaxis in sickle cell disease.J Pediatr. 1983; 102: 781-784Abstract Full Text PDF PubMed Scopus (76) Google Scholar,8Field J.J. Kassim A. Brandow A. et al.Phase 2 trial of montelukast for prevention of pain in sickle cell disease.Blood Adv. 2020; 4: 1159-1165Crossref Scopus (1) Google Scholar Anticoagulants like rivaroxaban have a role in managing some complications of SCD, such as thrombotic events; however, there is no evidence to suggest that rivaroxaban prevents VOC. In addition, the patient was already taking apixaban for history of sinus venous thrombosis. Simvastatin is hypothesized to benefit SCD because of its ability to decrease inflammation and to improve endothelial function.9Hoppe C. Jacob E. Styles L. Kuypers F. Larkin S. Vichinsky E. Simvastatin reduces vaso-occlusive pain in sickle cell anaemia: a pilot efficacy trial.Br J Haematol. 2017; 177: 620-629Crossref PubMed Scopus (35) Google Scholar A small pilot study with 19 individuals reported reduction in sickle cell–related pain in patients treated with simvastatin for 3 months.9Hoppe C. Jacob E. Styles L. Kuypers F. Larkin S. Vichinsky E. Simvastatin reduces vaso-occlusive pain in sickle cell anaemia: a pilot efficacy trial.Br J Haematol. 2017; 177: 620-629Crossref PubMed Scopus (35) Google Scholar Larger, randomized controlled trials are needed to further evaluate the efficacy of simvastatin in reducing VOC and hospitalizations in SCD. He returned to the hematology clinic after his hospitalization and was subsequently prescribed monthly intravenous infusions of crizanlizumab. Three months later, he has not required hospitalization for any complication of SCD including VOC. Sickle cell disease, the most common hemoglobinopathy, is due to a mutation in the β-globin gene, producing hemoglobin S (HbS). This altered hemoglobin protein is more likely to polymerize in the deoxygenated state, causing reduced deformability and thus “sickling” of RBCs.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar,10Kapoor S. Little J.A. Pecker L.H. Advances in the treatment of sickle cell disease.Mayo Clin Proc. 2018; 93: 1810-1824Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Clinical manifestations of SCD are heterogeneous, depending on the specific genotype. Our patient had HbSS disease, which typically is manifested with severe features of multiorgan involvement. Infections, severe anemia, and VOC are acute complications of SCD that require prompt diagnosis and treatment. It is important to identify potential triggers of VOC, such as dehydration, hypoxia, significant physical or emotional stress, temperature extremes, infection, and select comorbidities.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar Our patient was a 28-year-old man who presented with VOC, which may have been triggered by his physically exerting himself while performing yardwork. It is also possible that a respiratory infection may have triggered VOC, leading to indiscernible consolidations on chest imaging. He initially had diffuse joint pain but quickly developed systemic symptoms concerning for ACS. This rapid progression of multiorgan involvement is explained by the underlying mechanisms of VOC. The polymerized sickled RBCs from HbSS disease adhere to vascular endothelium and induce chronic inflammation through chemokines. This chronic inflammation promotes microvascular occlusion, large-vessel intimal hyperplasia, thrombosis, bone marrow fat embolization, and ultimately tissue ischemia.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar Acute chest syndrome can develop when pulmonary tissue and vasculature are involved. Manifestations of ACS can include pulmonary infections, fat embolism, and infarction. The sequelae of ACS can induce a V/Q mismatch, leading to respiratory distress and persistent hypoxia.5Howard J. Hart N. Roberts-Harewood M. Cummins M. Awogbade M. Davis B. BCSH CommitteeGuideline on the management of acute chest syndrome in sickle cell disease.Br J Haematol. 2015; 169: 492-505Crossref PubMed Scopus (84) Google Scholar A mild form of ACS was suspected in our patient because of radiographic evidence of a pulmonary infiltrate, fever, and pleuritic chest pain. Our patient was not found to have significant hypoxia and did not require supplemental oxygen. Acute chest syndrome represents a spectrum of disease, ranging from a mild respiratory illness to respiratory failure, with severe hypoxia associated with a higher transfusion requirement and increased mortality.5Howard J. Hart N. Roberts-Harewood M. Cummins M. Awogbade M. Davis B. BCSH CommitteeGuideline on the management of acute chest syndrome in sickle cell disease.Br J Haematol. 2015; 169: 492-505Crossref PubMed Scopus (84) Google Scholar Because the clinical features of pneumonia also meet the criteria for ACS, treatment of coexisting entities was of utmost importance. In general, the management of SCD involves treating symptomatic anemia and preventing complications of SCD, such as VOC. Hydroxyurea was the first drug approved by the FDA for treatment of homozygous SCD.10Kapoor S. Little J.A. Pecker L.H. Advances in the treatment of sickle cell disease.Mayo Clin Proc. 2018; 93: 1810-1824Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Hydroxyurea works by increasing fetal hemoglobin production and decreasing intracellular HbS polymerization.10Kapoor S. Little J.A. Pecker L.H. Advances in the treatment of sickle cell disease.Mayo Clin Proc. 2018; 93: 1810-1824Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Adults with SCD treated with hydroxyurea have fewer episodes of VOC and ACS, require fewer blood transfusions, and have longer overall survival.10Kapoor S. Little J.A. Pecker L.H. Advances in the treatment of sickle cell disease.Mayo Clin Proc. 2018; 93: 1810-1824Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar l-Glutamine, an amino acid precursor for nicotinamide adenine dinucleotide, is another therapy for SCD approved by the FDA. Glutamine and glutathione levels are depleted in erythrocytes in patients with SCD, which is believed to be due to increased oxidation in sickle RBCs and higher l-glutamine consumption.10Kapoor S. Little J.A. Pecker L.H. Advances in the treatment of sickle cell disease.Mayo Clin Proc. 2018; 93: 1810-1824Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar l-Glutamine has been reported to decrease hospitalizations and frequency of VOC and ACS in patients with SCD.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar,10Kapoor S. Little J.A. Pecker L.H. Advances in the treatment of sickle cell disease.Mayo Clin Proc. 2018; 93: 1810-1824Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Crizanlizumab, a humanized monoclonal antibody, works by inhibiting P-selectin. P-selectin is responsible for initiating the process of leukocyte adhesion to the endothelium, which is known to contribute to abnormal blood flow in patients with SCD.6Ataga K.I. Kutlar A. Kanter J. et al.Crizanlizumab for the prevention of pain crises in sickle cell disease.N Engl J Med. 2017; 376: 429-439Crossref PubMed Scopus (339) Google Scholar The SUSTAIN trial compared crizanlizumab with placebo in 198 patients with SCD, reporting a lower rate of VOC in the high-dose crizanlizumab group (1.08 per year) compared with placebo (2.91 per year).6Ataga K.I. Kutlar A. Kanter J. et al.Crizanlizumab for the prevention of pain crises in sickle cell disease.N Engl J Med. 2017; 376: 429-439Crossref PubMed Scopus (339) Google Scholar Adverse effects of crizanlizumab include nausea, vomiting, arthralgias, pruritus, and chest pain.6Ataga K.I. Kutlar A. Kanter J. et al.Crizanlizumab for the prevention of pain crises in sickle cell disease.N Engl J Med. 2017; 376: 429-439Crossref PubMed Scopus (339) Google Scholar Voxelotor was the most recent drug to gain FDA approval in the treatment of SCD. Voxelotor is an oral agent that works by inhibiting sickled hemoglobin polymerization. The HOPE trial reported significant improvements in hemoglobin concentrations and reductions in hemolysis markers with voxelotor compared with placebo.11Howard J. Ataga K.I. Brown R.C. et al.Voxelotor in adolescents and adults with sickle cell disease (HOPE): long-term follow-up results of an international, randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Haematol. 2021; 8: e323-e333Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Future studies are needed to determine the impact of this drug on hospitalizations and mortality in SCD. Allogeneic hematopoietic stem cell transplant (HSCT) is a potentially curative therapy for SCD that works by replacing the patient’s hematopoietic stem cells with a donor’s cells, allowing normal RBC production.10Kapoor S. Little J.A. Pecker L.H. Advances in the treatment of sickle cell disease.Mayo Clin Proc. 2018; 93: 1810-1824Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar In patients with severe complications of SCD, such as stroke, recurrent episodes of VOC, ACS, recurrent priapism, osteonecrosis, or transfusion-associated alloimmunization, HSCT should be considered.10Kapoor S. Little J.A. Pecker L.H. Advances in the treatment of sickle cell disease.Mayo Clin Proc. 2018; 93: 1810-1824Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar The limited availability of suitable donors along with the risk of complications after transplant, such as infection, graft failure, and graft-vs-host disease, is a barrier to HSCT for most patients.10Kapoor S. Little J.A. Pecker L.H. Advances in the treatment of sickle cell disease.Mayo Clin Proc. 2018; 93: 1810-1824Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar In 2017, a 13-year-old boy with HbSS disease became the first person to be successfully treated with gene therapy.10Kapoor S. Little J.A. Pecker L.H. Advances in the treatment of sickle cell disease.Mayo Clin Proc. 2018; 93: 1810-1824Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Gene therapy, a rapidly evolving field, uses genetically modified autologous stem cells, eliminating the requirement for a donor.12Frangoul H. Altshuler D. Cappellini M.D. et al.CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia.N Engl J Med. 2021; 384: 252-260Crossref PubMed Scopus (311) Google Scholar Several clinical trials are currently underway to further study the safety and efficacy of gene therapy for SCD. Whereas newer therapies have helped to increase life expectancy and improve morbidity associated with SCD, gene therapy has the potential to soon revolutionize the management of SCD. The authors report no competing interests.