Sickle Cell Research Articles

Temporal summation of pain in sickle cell disease: comparison of adolescents and young adults with chronic vs. infrequent pain.

This study examined the role of central sensitization in the experience of pain among adolescents and young adults with the most severe genotypes of sickle cell disease (SCD). We hypothesized that adolescents and young adults with chronic SCD pain would demonstrate a higher perceptual response to repeated stimulation of identical intensity (i.e., temporal summation of pain, TSP) compared to counterparts with infrequent pain. We also examined psychological risk factors that can impact pain sensitivity. Patients ages 12-21 years, diagnosed with SCD type Hb SS or Hb S Beta0Thalasemia, who reported infrequent pain (≤2 pain days/month; n = 25) or met AAPT criteria for chronic SCD pain (n = 25) were enrolled. Patients were age- and sex-matched, with similar proportions receiving chronic blood transfusion and hydroxyurea. Patients completed static quantitative sensory testing (QST) and dynamic TSP testing to assess pain sensitivity. Patients and a caregiver completed demographic and psychological measures (depression, anxiety, pain interference, pain catastrophizing). Simple slope analysis revealed differentially elevated heat TSP among adolescents and young adults with chronic SCD pain (b = 3.14, p = .002) but not those with infrequent pain (b = 0.45, p = .61). Faster habituation was further observed for those with chronic compared to infrequent pain. Adolescents and young adults with chronic pain reported more frequent depression, anxiety, and pain interference symptoms; however, psychological symptoms and pain catastrophizing were not associated with QST or TSP (ps >.17). Current results demonstrate that a well-established, prognostic, QST risk marker (i.e., TSP) may distinguish chronic from infrequent pain subgroups of adolescents and young adults with SCD.

Determination of the Level of von Willebrand Factor, ADAMTS13, and Ratio of ADAMTS13:von Willebrand Factor in Sickle Cell Disease Patients.

Sickle cell anemia (SCA) is a hypercoagulable state characterized by a significant alteration in hemostatic parameters which may predispose an increased risk of vaso-occlusive crisis (VOC). Sickle cell disease (SCD) is the most common genetic disorder in sub-Saharan Africa. Nigeria bears a high disease burden with an estimated prevalence of 1%-3% of its population being affected by the disease. The study seeks to determine the role of von Willebrand factor (VWF), ADAMTS13, and the ratio of ADAMTS13:VWF antigen in the pathogenesis of VOC. The objective of this study is to evaluate the level of VWF, ADAMTS13, and their ratio in SCD subjects in Calabar and to determine their role in the pathogenesis of VOC. This is a comparative study carried out at the University of Calabar Teaching Hospital (UCTH), Calabar. Sixty SCA patients were evaluated in VOC and steady states as well as five parented healthy controls. VWF: Ag and ADAMTS13:Ag were evaluated using Assaypro enzyme-linked immunosorbent assay kits with Lot nos. 01751728 and 04222167R, respectively. Data were analyzed by IBM SPSS Chicago software version 21. The study was approved by the UCTH Institution Ethical Review Board. The mean ages of the SCA subjects and controls were 23.5 ± 7.2 years and 26.5 ± 5.6 years, respectively (P = 0.706). There were 23 (38.3%) males in the SCA group and 21 (42.0%) females in the controls. There was no significant difference in their sex distribution (P = 0.063). The mean (standard deviation [SD]) of VWF in VOC, steady state, and controls were 2.52 ± 0.34, 1.34 ± 0.23, and 1.41 ± 0.23 IU/mL, respectively. The differences in mean were significantly higher in VOC state (P = 0.003). The mean ± SD of ADAMTS13 in VOC, steady state, and controls were 0.61 ± 0.10, 0.44 ± 0.06, and 0.62 ± 0.10 μg/L, respectively. ADAMTS13 levels did not differ significantly across the groups (P = 0.270). Similarly, there was no significant difference between ADAMTS13:VWF ratios across the groups (P = 0.318). VWF level is elevated in VOC state and thus may be implicated in the pathogenesis of VOC. ADAMTS13 and the ratio of ADAMTS13:VWF are not significantly affected in VOC.

Prevention of stroke and cognitive decline in pediatric population in resource-limited settings

There is an increasing global burden of pediatric stroke especially in low- and middle-income countries (LMICs). This is worsened by the specific risk factors in these areas, including Sickle Cell Disease and endemic infections like Tuberculosis and Human Immunodeficiency disease. Stroke occurs 221–300 times more frequently in patients with SCD when compared to healthy children. Although established stroke units and acute stroke care can improve outcomes, these are often not available in resource-poor settings. Primary and secondary prevention of strokes become a very important strategy to reduce the mortality and debilitating physical and cognitive long-term effects of stroke. There are myriads of challenges with implementing already established global policies and guidelines for stroke care in LMICs. These include paucity of data on this subject, poor knowledge and awareness about the symptoms of childhood stroke, adverse cultural beliefs regarding strokes, lack of screening and diagnostic equipment, inadequately trained manpower as well as nonexistent evidence-based management guidelines in these regions. To address these challenges, simple, cost-effective, stroke care models that determine the process of care and how available services should be delivered have been proposed to suit the peculiarities of LMICs in the areas of stroke risk assessment, prevention, and management.

Improving Sickle Cell Patient Appointment Compliance in a Hospital-Based Pediatric Ophthalmology Clinic

This quality improvement initiative aimed to reduce the no-show rate at a hospital-based tertiary sickle cell ophthalmology clinic. Missed appointments place a significant burden on the healthcare system, resulting in prolonged waiting times and underutilized clinical resources that impact the quality of care provided. Individuals with sickle cell disease commonly require multiple appointments to address the myriads of comorbidities associated with their disease. Nevertheless, the sickle cell ophthalmology clinic experienced an alarmingly high no-show rate of 49% from June to September of 2021 despite offering same-day appointments with the hematology clinic. To address this issue, we conducted a study in which we compared the baseline no-show rate with the rate after relocating both clinics to the same floor, aiming to overcome patient-related barriers. Following 3.5 months of the clinics sharing the same floor, the no-show rate decreased to 39%, reflecting a 10% improvement from the baseline rate. In summary, co-locating two related clinics can alleviate patient burdens, foster communication between multidisciplinary specialties, and contribute to an overall improvement in the quality of care and treatment provided.

Associations of haematological and inflammatory biomarkers with brain volume in patients with sickle cell anaemia: A cross-sectional retrospective study.

Sickle cell disease is a genetic disorder characterised by abnormal haemoglobin production. This study aims to investigate the associations between haematological and inflammatory biomarkers and brain volumes in patients with sickle cell anaemia and compare brain structure between patients with sickle cell anaemia and healthy controls. This retrospective cross-sectional study included 130 participants (70 sickle cell anaemia patients and 60 healthy controls) who underwent brain MRI examinations at King Fahad Central Hospital between January 2010 and October 2022. Demographic data and haematological and inflammatory biomarkers were collected to examine their relationships with brain volumes. Brain volumes were measured using FreeSurfer. Specific haematological and inflammatory biomarkers were correlated with brain volume in patients with sickle cell anaemia, p < 0.05. Sickle cell anaemia patients exhibited smaller volumes in the brainstem, corpus callosum and amygdala compared to healthy controls. Males had significantly higher iron levels (p < 0.001) and larger various brain structure volumes (p < 0.05) than females. This study demonstrates significant associations between specific biomarkers and brain volume in sickle cell anaemia patients, underscoring the importance of monitoring these biomarkers for early detection and management of neurological complications in sickle cell anaemia.

Ascorbic acid regulates in vitro and in vivo toxicogenetic effects of hydroxyurea on eukaryotic cells

Hydroxyurea (HU) exerts unique and diverse biological effects as an anti-leukemic agent, irradiation sensitizer, and HbS inducer in patients with sickle cell anemia. Herein, we assessed the potential toxicogenic and/or oxidant effects of hydroxyurea associated with ascorbic acid by in vivo examinations in Allium cepa and human cancer cells and systemically on mice tissues. Growing A. cepa roots and HCT-116 colorectal tumor cells were examined after HU and HU plus ascorbic acid exposure. DNA damage and antioxidant enzymatic activity were quantified in peripheral blood mononuclear cells (PBMC), bone marrow leukocytes and livers of mice after 7 day-HU treatment (7.5, 15 and 30 mg/kg/day) and Vitamin C 2 μM. Hydroxyurea presented toxic effects on meristematic Allium cepa cells, causing chromosomal abnormalities and reduction of mitotic index, killed HCT-116 colorectal carcinoma cells and induced DNA injuries upon mice cells (hepatocytes, bone marrow leukocytes and PBMC). Simultaneously, hydroxyurea decreased levels of CAT and GSH activities and expand lipid peroxidation. All these biochemical and physiological changes were ameliorated when associated with ascorbic acid, indicating it restored antioxidant enzymes, decreased MDA levels, removed peroxides and, consequently, presented cytoprotection against HU-provoked cellular damage in normal cells. On the other hand, antioxidants compounds may interfere on effectiveness of HU during anticancer chemotherapies.

Adverse maternal and fetal outcomes among tribal pregnant women suffering from sickle cell disease: A retrospective cohort study in a community-based hospital situated in a tribal block of Gujarat, India.

The study presents the risk of the maternal-fetal morbidity and mortality among one of the largest cohort of sickle cell disease (SCD) pregnancies in India and reports the epidemiology of the maternal morbidity. This was a retrospective cohort study conducted at Kasturba Maternity Hospital, SEWA Rural, in the tribal area of Gujarat, India. All pregnant women admitted to the Hospital between 2016 and 2021 were screened for SCD, and their maternal-fetal morbidities were recorded throughout the pregnancy. We quantified risk of maternal-fetal morbidity and mortality among SCD, trait and normal pregnancies after adjusting for potential confounders using Poisson and logistic regression. A total of 24 256 delivered during the study period, with 354 (1.5%) and 4216 (17.4%) suffering from SCD and trait, respectively. After adjusting for potential confounders, the women with SCD pregnancy had higher risk of maternal death (adjusted-odds-ratio [AOR] 13.7, 95% CI: 4.5-42.7), anemia (AOR 6.8, 95% CI: 4.5-10.2), severe anemia (AOR 4.3, 95% CI: 3.3-5.6), preterm delivery (AOR 4.5, 95% CI: 3.6-5.7), cesarean section (AOR 5.5, 95% CI: 4.7-7.0), stillbirth (AOR 3.4, 95% CI: 2.3-5.3), and low birth weight (AOR 3.1, 95% CI: 2.4-39) compared to normal pregnancies. Maternal morbidities occurred throughout the pregnancy; however, the risk was highest during the last month of pregnancy. Pregnant women who had severe manifestation of SCD before the pregnancy were at higher risk of developing maternal morbidities. We concluded that SCD might be an independent risk-factor for developing maternal-fetal morbidities. The SCD pregnancies with prior severe manifestations must be carefully managed during the last month of pregnancy when the risk is highest.

Indian Council of Medical Research (ICMR)-Sickle Cell Disease (SCD) Stigma Scale for India (ISSSI): A Protocol for Scale Development.

Sickle cell disease (SCD) is a genetic blood disorder presenting a substantial public health challenge. India, holding the second-highest prevalence globally, exhibits diverse clinical manifestations. The recently launched National SCD Elimination Mission (NSEM) in India has contributed to an increased identification of cases. The national program should extend its services beyond screening and clinical management. The outcome of the disease is influenced by a multitude of factors impacting healthcare utilization, with stigma emerging as a major influencer. Addressing stigma at the right time is crucial to comprehensive disease care. Understanding and quantifying the type and level of stigma in the ecosystem are fundamental steps toward tackling this pressing issue, necessitating the development of a scale. The existing three scales developed and utilized in African and American contexts may not be suitable for the Indian SCD community due to phenotypic, socio-cultural, and contextual variations. Therefore, developing, modifying, and creating a locally applicable scale is imperative. This protocol paper outlines the process of developing, refining, and evaluating the Indian Council of Medical Research (ICMR)-SCD Stigma Scale for India (ISSSI), which will be developed by Indian researchers led by the ICMR.

Cyclosporin H Improves the Transduction of CD34+ Cells with an Anti-Sickling Globin Vector, a Possible Therapeutic Approach for Sickle Cell Disease.

Sickle cell disease (SCD) is a debilitating monogenic disease originating from mutations in the hemoglobin beta chain gene producing an abnormal hemoglobin HbS. The polymerization of HbS is responsible for the sickling of erythrocytes leading to anemia and vaso-occlusive events. Gene therapy is a promising treatment of SCD, and two different gene therapy drugs, using gene editing or gene transfer, have already reached the marketing stage. There is still a need to improve the efficacy of gene therapy in SCD, particularly when using anti-sickling beta-globin gene transfer strategies, which must outcompete the pathological HbS. One possibility is to increase transduction by inhibiting lentiviral restriction factors such as interferon-induced transmembrane proteins (IFITMs). This can be achieved by the addition of cyclosporin H (CsH) during the transduction process. This strategy was applied here in CD34+ hematopoietic progenitor and stem cells obtained from cord blood (CB). A first series of experiments with lentiviral vector coding for a green fluorescent protein (GFP) gene confirmed that the addition of CsH enhanced transgene expression levels and vector copy number per cell (VCN), while CD34+ cells remained viable and functional. Notably, the production of colony-forming cells (CFC) remained unaffected unless very high VCN values were reached. In a second step, CD34+ cells obtained from the CB of newborns with homozygous (n = 2) or heterozygous (n = 1) SCD mutations were transduced with the GLOBE-AS3 lentiviral vector coding for the HbAS3 anti-sickling beta globin. As with GFP, GLOBE-AS3 lentiviral transduction was clearly enhanced by CsH, leading to VCN > 2 and therapeutic levels of expression of the HbAS3. Moreover, the process did not affect the viability or functions of CFC. The combination of CB progenitors, the GLOBE-AS3 vector, and CsH is thus shown here to be a promising approach for the treatment of SCD.

Impact of Neighborhood Disadvantage on Preventive and Acute Care Utilization in Sickle Cell Disease.

Individuals with sickle cell disease (SCD) experience significant healthcare disparities; however, there is little known on the impact of psychosocial stressors and neighborhood disadvantage on preventive and acute care utilization in this population. A retrospective data collection was performed for all patients cared for at a comprehensive pediatric sickle cell center in the Midwest who had also completed the Psychosocial Assessment Tool (PAT), a validated caregiver-reported measurement of family psychosocial risk, from September 2021 through December 2022. Patient age, payor, primary language, frequency of acute and missed preventive care visits, as well as Area Deprivation Index (ADI) and Childhood Opportunity Index (COI) scores were collected for 256 patients. The average state ADI was 6.3 (±2.9), and the majority of patients were in the Very Low or Low COI categories. Total PAT score (p=0.003), state ADI (p<0.001), and state COI (p<0.001) were all significantly correlated with missed SCD clinic visits, with increased odds of a missed visit with increasing neighborhood disadvantage (OR 1.22, p<0.001). The odds of acute care were also increased in those with higher family psychosocial risk (OR 1.76, p<0.011), though this was not seen with ADI or COI, suggesting an additional effect of family stressors and resilience on acute care utilization. This highlights the importance of regular, universal social and psychological risk screening, as well as inclusion of psychosocial team members in SCD programs to identify and readily address risk factors that impact child outcomes in a minoritized chronic disease population.

Identification of small molecule agonists of fetal hemoglobin expression for the treatment of sickle cell disease.

Induction of fetal hemoglobin (HbF) has been shown to be a viable therapeutic approach to treating sickle cell disease and potentially other β-hemoglobinopathies. To identify targets and target-modulating small molecules that enhance HbF expression, we engineered a human umbilical-derived erythroid progenitor reporter cell line (HUDEP2_HBG1_HiBiT) by genetically tagging a HiBiT peptide to the carboxyl (C)-terminus of the endogenous HBG1 gene locus, which codes for γ-globin protein, a component of HbF. Employing this reporter cell line, we performed a chemogenomic screen of approximately 5000 compounds annotated with known targets or mechanisms that have achieved clinical stage or approval by the US Food and Drug Administration (FDA). Among them, 10 compounds were confirmed for their ability to induce HbF in the HUDEP2 cell line. These include several known HbF inducers, such as pomalidomide, lenalidomide, decitabine, idoxuridine, and azacytidine, which validate the translational nature of this screening platform. We identified avadomide, autophinib, triciribine, and R574 as novel HbF inducers from these screens. We orthogonally confirmed HbF induction activities of the top hits in both parental HUDEP2 cells as well as in human primary CD34+ hematopoietic stem and progenitor cells (HSPCs). Further, we demonstrated that pomalidomide and avadomide, but not idoxuridine, induced HbF expression through downregulation of several transcriptional repressors such as BCL11A, ZBTB7A, and IKZF1. These studies demonstrate a robust phenotypic screening workflow that can be applied to large-scale small molecule profiling campaigns for the discovery of targets and pathways, as well as novel therapeutics for sickle cell disease and other β-hemoglobinopathies.

Osteopathic Manipulative Treatment: A Safe and Feasible Adjunct in Sickle Cell Disease Pain Management.

Children and adolescents and young adults (CAYAs) with sickle cell disease (SCD) suffer from recurrent acute pain episodes that result in hospitalization and confer substantial morbidity. Pharmacologic pain control is often inadequate, thus non-pharmacologic modalities are needed. Osteopathic manipulative treatment (OMT) is a potentially valuable non-pharmacologic addition to pain management. We describe eight patients hospitalized with SCD pain who received OMT. OMT was safe, feasible, and a promising adjunctive option for management of SCD pain.

Executive Functioning Ratings and Responsibility for Hydroxyurea Treatment for Adolescents with Sickle Cell Disease

Executive Functioning Ratings and Responsibility for Hydroxyurea Treatment for Adolescents with Sickle Cell Disease

Coexistent sickle cell anemia and autoimmune hemolytic anemia in two adolescents

Coexistent sickle cell anemia and autoimmune hemolytic anemia in two adolescents

Longitudinal outcomes of chronically transfused adults with sickle cell disease and a history of childhood stroke.

Many children with sickle cell disease (SCD) who suffer a stroke receive chronic transfusion therapy (CTT) indefinitely; however, their adulthood neurologic outcomes have not been reported. Understanding these outcomes is critical to inform decisions regarding curative therapy in childhood. In this retrospective study, we described a cohort of adults with SCD and a history of childhood stroke who received care at a single center and compared their outcomes with matched subjects without childhood strokeusing chi2 and Mann-Whitney U tests. Of 42 subjects with childhood stroke, all received CTT for secondary stroke prophylaxis. Five (11%) developed recurrent stroke. The rate of stroke was similar in subjects with and without childhood stroke (0.7 vs. 1.1 per 100 person·years, p = .63). Both cohorts exhibited evidence of iron overload (median ferritin 2227 vs. 1409 ng/dL, p = .10) and alloimmunization (45% vs. 45%, p = 1.0), despite receiving care in a comprehensive SCD program. For adults with SCD who had a childhood stroke, our results suggest CTT returns the risk of stroke to that of age-matched stroke naïve patients with SCD.

Sickle cell disease in India: Not just a mild condition.

Sickle cell disease (SCD) is a common and life-threatening global health problem, with more than 500 000 affected infants born annually. The burden of SCD in sub-Saharan Africa is well established, but the comparably high prevalence in India is not well recognized and many consider SCD in India to be less severe. In their paper, a national study in India demonstrated the significant impact of SCD for patients, families and the healthcare system, supporting a call to action to recognize and address SCD as a serious and common health condition in India. Commentary on: Seth etal. Burden of vaso-occlusive crisis, its management, and impact on quality of life of Indian sickle cell disease patients. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19829.

Genetic Modifiers of Hemoglobin Expression from a Clinical Perspective in Hemoglobinopathy Patients with Beta Thalassemia and Sickle Cell Disease

Hemoglobinopathies, namely β-thalassemia and sickle cell disease (SCD), are hereditary diseases, characterized by molecular genetic aberrations in the beta chains of hemoglobin. These defects affect the normal production of hemoglobin with severe anemia due to less or no amount of beta globins in patients with β-thalassemia (quantitative disorder), while SCD is a serious disease in which a mutated form of hemoglobin distorts the red blood cells into a crescent shape at low oxygen levels (qualitative disorder). Despite the revolutionary progress in recent years with the approval of gene therapy and gene editing for specific patients, there is an unmet need for highlighting the mechanisms influencing hemoglobin production and for the development of novel drugs and targeted therapies. The identification of the transcription factors and other genetic modifiers of hemoglobin expression is of utmost importance for discovering novel therapeutic approaches for patients with hemoglobinopathies. The aim of this review is to describe these complex molecular mechanisms and pathways affecting hemoglobin expression and to highlight the relevant investigational approaches or pharmaceutical interventions focusing on restoring the hemoglobin normal function by linking the molecular background of the disease with the clinical perspective. All the associated drugs increasing the hemoglobin expression in patients with hemoglobinopathies, along with gene therapy and gene editing, are also discussed.

Biomarkers to Differentiate Acute Chest Syndrome From Vaso-Occlusive Crisis in Children With Sickle Cell Disease.

Acute Chest Syndrome (ACS) is the leading cause of death in children with sickle cell disease (SCD) in the US-about half of the children who develop ACS present initially with pain. Here, we studied biomarkers to differentiate ACS from vaso-occlusive crises (VOC) in children with SCD who presented with pain to the emergency department (ED). We conducted a prospective cohort study of consecutive patients who presented to the ED with pain and were discharged with ACS or VOC between March, 2017 and February, 2020. We identified 7 patients with ACS and 19 patients with VOC. The two groups were comparable in age and sex. All patients with ACS had asthma versus 42% of the VOC group. The ACS group had lower weight and BMI z-scores. Patients with ACS compared to VOC had significantly higher respiratory rates, lower O2 saturation, and longer hospital stays. They also had higher white blood cell count, glucose level (> 99 mg/dL), anion gap (> 9 mEq/L), sPLA2 (> 7 pg/mL), IFN-γ (> 17.8 pg/mL), IL-10 (1.54 pg/mL), and IL-12 (> 0.5 pg/mL) levels. We identified biomarkers associated with ACS development in children with SCD presenting with pain that allow for earlier ACS interventions to reduce mortality and morbidity.

A Novel One-Sample Mendelian Randomization Approach for Count-Type Outcomes That Is Robust to Correlated and Uncorrelated Pleiotropic Effects.

We propose two novel one-sample Mendelian randomization (MR) approaches to causal inference from count-type health outcomes, tailored to both equidispersion and overdispersion conditions. Selecting valid single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) poses a key challenge for MR approaches, as it requires meeting the necessary IV assumptions. To bolster the proposed approaches by addressing violations of IV assumptions, we incorporate a process for removing invalid SNPs that violate the assumptions. In simulations, our proposed approaches demonstrate robustness to the violations, delivering valid estimates, and interpretable type-I errors and statistical power. This increases the practical applicability of the models. We applied the proposed approaches to evaluate the causal effect of fetal hemoglobin (HbF) on the vaso-occlusive crisis and acute chest syndrome (ACS) events in patients with sickle cell disease (SCD) and revealed the causal relation between HbF and ACS events in these patients. We also developed a user-friendly Shiny web application to facilitate researchers' exploration of causal relations.

Association of Clinical and Paraclinical Factors with Pain Crisis Severity in Sickle-Thalassemia Patients in Iran

Objectives: This study aimed to evaluate the effects of several factors, including hospitalization frequency, inflammatory and hemolytic markers, and the numbers of blood transfusions and crises, on the severity of pain crises in sickle-thalassemia patients. Methods: Of all patients visiting hematologists in university-affiliated hospitals and clinics, only 75 sickle cell disease (SCD) and sickle-thalassemia patients met the inclusion criteria for this study. Disease severity was measured based on pain crises per year and laboratory markers, including hemolytic and inflammatory indicators, outpatient or inpatient status, the number of hospital admissions, and the number of blood units transfused over one year. Results: In sickle cell patients, a significant correlation was observed between hospital admission and WBC (0.01), ALP (0.001), MCHC (0.001), ferritin (0.021), and ESR (0.006). Additionally, pain crises were positively correlated with transferrin saturation (TS) (+0.28) and the number of transfused blood units (+0.49) and negatively correlated with Hb (-0.30) and total iron binding capacity (TIBC) (-0.23). Blood unit transfusions showed a positive correlation with serum iron (+0.44), RDW (+0.36), ferritin (+0.39), pain crises (+0.49), and TS (+0.49), along with a negative correlation with Hb (-0.75) and MCHC (-0.33). When categorizing pain crises into two groups, patients experiencing more frequent crises generally exhibited lower hemoglobin levels and a higher number of blood units transfused. Hemoglobin also showed a significant negative correlation with lactate dehydrogenase (LDH) level in both groups: -0.604 (P = 0.005) in patients with ≥ 3 crises per year and -0.368 (P = 0.006) in patients with &lt; 3 crises per year. Patients with hemoglobin levels of 7.5 or higher tended to maintain an LDH level below 1000. Among patients referred with pain crises, hemoglobin was negatively correlated with hemolytic markers such as LDH (-0.41) and retic (-0.29). Conclusions: Hemoglobin and LDH can serve as follow-up markers, as they are routinely measured in all sickle cell patients and, in this study, hemoglobin levels of 7.5 or higher and LDH levels below 1000 were associated with fewer and less severe pain crises. Regular monitoring of hemolytic markers may help in pain crisis prevention, as this study found that hemolytic crises frequently coincided with pain crises. Further research is needed to provide conclusive evidence in this area.