Inflammatory Polymorphisms Link the Risk of Acute Chest Syndrome with Asthma in Adults with Sickle Cell Disease

Abstract Abstract 1072 Acute chest syndrome (ACS) is a common cause of death among patients with sickle cell disease (SCD). There is increasing evidence that asthma may represent a significant risk factor for the development of ACS in children with SCD and it is associated with increased mortality (Newaskar, et al. 2010; Poulter, et al. 2011).The incidence of ACS in adolescent SCD patients is associated with the occurrence of asthma and genetic polymorphisms in NOS1 and NOS3 (Duckworth, et al. 2007). Polymorphisms in inflammatory genes, including IL-12A, IL-12B, and IL-4 receptor have been previously associated with the incidence and severity of asthma in non-SCD cohorts (Chen, et al. 2011; Mannino, et al. 2002; Caggana, et al. 1999). These data imply that the association of asthma with increased risk for ACS in adolescent SCD patients has a genetic component. However, the clinical and genetic associations among ACS, asthma, and inflammation have not been evaluated in adults with SCD. Our goals were (1) to identify clinical risk factors for ACS and (2) to identify single nucleotide polymorphisms (SNPs) in inflammatory genes associated with asthma and ACS in our population of adult SCD patients. All clinical data were collected using standardized report forms. Use of bronchodilators served as a surrogate for the occurrence of asthma. We analyzed 94 SNPs within 14 inflammatory genes in 675 DNA samples from SCD patients ascertained from Duke University, University of North Carolina-Chapel Hill, and Emory University. In order to achieve greater coverage in our genes of interest, SNP genotyping data was derived from two methods, Taqman genotyping assays from Applied Biosystems and genome-wide association studies (GWAS) using the Illumina-610 SNP array. Clinical and genetic associations with ACS and use of bronchodilators were examined using regression analysis (PROC LOGISTIC or GLM in SAS version 9.2, Cary, NC). The incidence of ACS in our population was 73%. Six percent of our population used bronchodilators, similar to the overall incidence of asthma in the US population (Newaskar et al., 2011). We observed a significant association between the use of bronchodilators and the incidence of ACS in our dataset, such that the percentage of patients with a history of ACS among bronchodilator users was 90% versus 73% in non-users (p=0.028). ACS was also associated with an increase in pain episodes (OR=1.6, p<0.0001), narcotics use (OR=1.5, p=0.0002), WBC counts (p=0.04), platelet counts (p=0.007), and higher mean hemoglobin (Hb) levels (p=0.003). ACS was also associated with decreased Hb F levels (p=0.05). After controlling for age, gender, and use of hydroxyurea, SNPs in IL-12A (rs568408; p=0.007), IL-12B (rs2195940; p=0.022), and IL-4R (rs3024537; p=0.049) were significantly associated with ACS. In addition, IL-12A (rs568408; p=0.037), IL-12B (rs2853694; p=0.009), and IL-4R (rs2283563; p=0.031) were significantly associated with the use of bronchodilators in our adult SCD cohort. None of the SNPs in IL=12B or IL-4R were found to be in linkage disequilibrium (LD) with each other. After multiple regression analysis, SNPs in IL-12A (rs568408; p=0.013), IL-12B (rs2195940; p=0.01), and IL-4R (rs3024537; p=0.02) remained significantly associated with ACS, and SNPs in IL-12A (rs568408; p=0.048), IL-12B (rs2853694; p=0.005), and IL-4R (rs2283563; p=0.01) remained significantly associated with use of bronchodilators. The functional significance of these SNPs is presently unknown. All of the polymorphisms are intronic except for rs568408, located in the 3'untranslated region of IL-12A. In summary, our findings in adult SCD patients support previous data in children demonstrating associations among inflammatory markers and asthma with the occurrence of ACS. Our data also support the association between asthma and increased risk of ACS. Finally, we have identified potential genetic risk factors for both asthma and ACS in adults with SCD. Our findings suggest that further investigation into the role of these inflammatory mediators in pulmonary dysfunction in SCD is warranted. Disclosures: No relevant conflicts of interest to declare.

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A case of severe multi-system disease in a sickle cell SC patient caused by parvovirus B19 infection

Journal of Clinical Images and Medical Case Reports ◽

10.52768/2766-7820/1314 ◽

2021 ◽

Vol 2 (5) ◽

Author(s):

Mohamed Almuqamam ◽

◽

Swetha Madhavarapu ◽

Nataly Apollonsky ◽

◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Parvovirus B19 ◽

Acute Infection ◽

Organ Injury ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Splenic Sequestration ◽

Increased Risk ◽

Parvovirus B19 Infection

Sickle Cell Disease (SCD) is an inherited hemoglobinopathy, which results in production of abnormal hemoglobin S. HbSC disease is a variant of SCD, which shares a similar clinical complication profile to HbSS disease, but often thought to be a milder condition. In patients with SCD, Hb S in deoxygenated state undergoes polymerization, leading to hemolysis, vaso-occlusive events, and eventually end-organ damage. Among other complications in patients with SCD is increased risk of complications caused by parvovirus B19. We present a case of a 14-year-old female with HbSC disease who presented to the emergency room with complaint of abdominal pain and found to have splenic sequestration. Splenic sequestration progressed rapidly, Hemoglobin (hb) dropped to 4.6 g/dl and acute chest syndrome (ACS) developed. She was treated following the ACS protocol, received 4 units of Packed Red Blood Cells (PRBC) and subsequently underwent a single volume PRBC exchange transfusion. Considering her unusual presentation, with severe ARDS from alveolar hemorrhage requiring mechanical ventilation and multi-organ injury, several autoimmune and infectious conditions with a cytokine storm component including COVID-19 disease, were considered. Results of viral testing revealed parvovirus B19 IgM antibodies signifying an acute infection. She fully recovered with supportive care and was discharged home. Multisystem involvement simulating connective tissue disorders or malignancies with acute parvovirus B19 infection has been reported and is considered extremely rare. To our knowledge, there were no reports of pediatric patients with SC disease presenting with splenic sequestration and ACS in the setting of parvovirus B19 multisystem disease. Keywords: sickle cell disease; acute respiratory distress syndrome; acute chest syndrome; parvovirus B19.

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Low‐risk factors for severe bacterial infection and acute chest syndrome in children with sickle cell disease

Pediatric Blood & Cancer ◽

10.1002/pbc.27667 ◽

2019 ◽

Vol 66 (6) ◽

pp. e27667 ◽

Cited By ~ 1

Author(s):

Elena María Rincón‐López ◽

María Luisa Navarro Gómez ◽

Teresa Hernández‐Sampelayo Matos ◽

Jesús Saavedra‐Lozano ◽

Yurena Aguilar de la Red ◽

...

Keyword(s):

Risk Factors ◽

Sickle Cell Disease ◽

Bacterial Infection ◽

Sickle Cell ◽

Low Risk ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Severe Bacterial Infection

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Identification of Clinical and Laboratory Parameters Associated with the Development of Acute Chest Syndrome during Vaso-Occlusive Episodes in Children with Sickle Cell Disease: A Preliminary Step before Assessing Specific and Early Treatment Strategies

Journal of Clinical Medicine ◽

10.3390/jcm8111839 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1839

Author(s):

Madhi ◽

Kamdem ◽

Jung ◽

Carlier-Gonod ◽

Biscardi ◽

...

Keyword(s):

Sickle Cell Disease ◽

Pain Score ◽

Sickle Cell ◽

Multivariate Model ◽

Red Blood Cell Transfusion ◽

Predictive Score ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Laboratory Parameters ◽

Increased Risk

This prospective observational study sought to ascertain clinical and laboratory parameters associated with the development of acute chest syndrome (ACS) during vaso-occlusive episodes (VOE) in children with sickle cell disease (SCD). It was performed at the pediatric department of the university Intercommunal Créteil hospital. All children with SCD (all sickle genotypes) consecutively admitted from November 2013 to December 2016 for painful VOEs and no evidence of ACS were included. Clinical and laboratory parameters collected at admission and within 48 h after admission were compared for children in whom ACS developed or not. Variables that were statistically significant on univariate analysis or considered to be clinically relevant were included in a multivariable model to ascertain the risk factors associated with the development of ACS during a VOE. The variables retained in the multivariate model were used to construct a predictive score for ACS. For each included child and during the study period, only data from the first VOE and/or the first ACS were analyzed. Among 191 hospitalizations for painful VOEs, for 176 children with SCD, ACS developed in 35 during hospitalization. Mean hospital stay was longer for children with ACS versus VOEs alone (7.6 (±2.3) vs. 3.3 (±1.8) days, p < 0.0001), and all children with ACS versus 28/156 (17.9%) with VOEs alone received red blood cell transfusion (p < 0.0001). The multivariate model retained pain score (≥9/10), pain localization (abdominal or spinal pain or involving more than two limbs), and high reticulocyte (≥260 × 109/L) and neutrophil (>10 × 109/L) counts, at admission, as independently associated with ACS development. The area under the receiver operating characteristic curve for the ACS predictive score was 0.82 (95% CI: 0.74–0.89), and the negative predictive value was 97.7%. The evolution profiles during the first 48 h differed between children with ACS and VOEs alone, with a more rapid decline of pain score and leucocytosis in children with VOEs. Clinical and laboratory measurements at admission may be simple parameters to identify children with increased risk of ACS development during VOEs and to facilitate early diagnosis of this respiratory complication. Also, the persistent elevation of leukocyte count on day 2 may be considered a sign of evolving ACS.

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Polymorphisms in TNFα Are Associated with Cerebrovascular Events in Sickle Cell Disease.

Blood ◽

10.1182/blood.v114.22.1540.1540 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1540-1540 ◽

Cited By ~ 1

Author(s):

Latorya A Barber ◽

Allison E Ashley-Koch ◽

Melanie E. Garrett ◽

Karen L Soldano ◽

Marilyn J. Telen

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Conflicts Of Interest ◽

Umbilical Vein ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Data Set ◽

Clinical Complications ◽

Cerebrovascular Events ◽

Increased Risk

Abstract Abstract 1540 Poster Board I-563 Tumor necrosis factor alpha (TNFα) is a pro-inflammatory cytokine that stimulates phagocytosis, neutrophil recruitment, and expression of adhesion molecule VCAM-1. Plasma levels of TNFα have been found to be increased in sickle cell disease (SCD), and in vitro studies show that TNFα causes increased adherence of sickle red blood cells to human umbilical vein endothelial cells. A polymorphism in the promoter region of the TNFα gene has previously been associated with stroke in children with SCD (Hoppe et al., 2007). The current study was designed to identify associations of additional TNFα single nucleotide polymorphisms (SNPs) with SCD clinical complications. We analyzed five SNPs in the TNFα gene in 509 DNA samples of SCD patients from Duke University, University of North Carolina at Chapel Hill, and Emory University. In our data set, cerebrovascular events (CVEs), including overt stroke, seizures, and transient ischemic attacks, occurred in 133 out of 509 SCD patients (26.1%). SNP genotyping was performed using Taqman genotyping assays from Applied Biosystems. Due to low minor allele frequencies (<0.05) for all the SNPs examined, genetic associations with SCD clinical complications were examined by using allele tests. After controlling for age, gender, and use of hydroxyurea, two of the five TNFα SNPs, rs2228088 and rs3093665, were significantly associated with CVEs (p=0.013 and 0.029, respectively). The odds that SCD patients with a G allele at rs2228088 suffered from CVEs were 0.485 times that for patients with the T allele, suggesting that the G allele had a protective effect. The odds of having the A allele at rs3093665 and suffering from CVEs was also reduced, at 0.45 compared to the C allele. Neither SNP was found to be in linkage disequilibrium (LD) with any of the other SNPs analyzed (r2≤0.002). There was also strong association of SNP rs2228088 with acute chest syndrome (ACS; p=0.003), occurring in 382 out of 509 SCD patients (75%). However, in this analysis, the G allele was associated with increased risk for ACS (OR=2.313). In addition to the association with CVEs, the SNP rs3093665 was also significantly associated with priapism (p=0.03), reported by 86 of 223 male SCD patients (38.6%). In this analysis, the A allele was protective, as had been observed for CVE (OR=0.188). Additionally, we found no difference in steady state plasma TNFα levels between genotypes for the two SNPs. The functional significance of these SNPs is presently unknown. SNP rs2228088 is a synonymous SNP located in the coding region, and rs3093665 is located in the 3' untranslated region of the TNFα gene. While the G to T change at SNP rs2228088 does not translate to a change in amino acid sequence, the A to C change at SNP rs3093665 may affect mRNA stability due to its location. It is also possible that one or both of these SNPs is in LD with another functionally relevant SNP. Our findings thus support previous data implicating TNFα polymorphisms in risk for central nervous system events. Interestingly, ACS has been previously associated with seizures, stroke and altered mental status in adults and children with SCD (Vinchinsky et al., 2000) and with silent cerebral infarcts and reversible posterior leukoencephalopathy syndrome in children with SCD (Henderson et al., 2003). However, in our dataset, ACS and the occurrence of CVEs were not associated (p=0.24). Further studies are required to elucidate these and other factors that potentially correlate with SCD clinical complications. Disclosures No relevant conflicts of interest to declare.

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Acute Chest Syndrome in Children with Sickle Cell Disease in Italy: Results of a National Survey from the Italian Association of Pediatric Hematology Oncology (AIEOP)

Blood ◽

10.1182/blood-2019-128215 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2301-2301

Author(s):

Vania Munaretto ◽

Raffaella Colombatti ◽

Serena Ilaria Tripodi ◽

Corti Paola ◽

Simone Cesaro ◽

...

Keyword(s):

Risk Factors ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Exchange Transfusion ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Italian Association ◽

Pediatric Hematology ◽

Frequent Event ◽

Regional Hospitals

Background: Acute Chest Syndrome (ACS) is the second cause of hospitalization in Sickle Cell Disease (SCD), burdened by significant morbidity and mortality. The guidelines regarding management of ACS are sometimes difficult to follow in the real world and the prevention and treatment strategies of ACS are often applied in an uneven manner in the various settings (community care, regional hospitals, reference university centers). Moreover, epidemiology, clinical phenotype and outcomes as well as risk factors could vary in different populations according to ethnicity, genotype or health care system organization. Aims and Methods: A retrospective multicenter observational study was conducted to investigate the epidemiology of ACS and to the evaluate the diagnostic and therapeutic pathways of ACS in children with SCD (age 0-18 years) in the 2013-2018 period, after the publication of the Italian Association of Pediatric Hematology Oncology (AIEOP) Guidelines for the Management of SCD in Childhood in Italy in 2012. Results: 126 children were recruited and 122 included in the analysis, with 208 evaluable episodes of ACS (range: 1-6 episodes /patient) from 11 AIEOP Centers. 73 M, 49 F. Mean age was 10.9 years. 85% patients were of African origin, 92% were HbSS/SB°; mean age at diagnosis of SCD of the entire cohort was 25,3 months (range 0-16,8). 44.2% of patients had more than one episode of ACS during the study period; 37% had had a previous episode before 2013. 58% had comorbidities, mostly respiratory (asthma or allergy). 75% of the patients underwent disease modifying treatment during study period (73% hydroxyurea, 2% chronic transfusion). The seasonality of ACS episodes was important in our country: 75% of episodes occured between October and March. 95% of ACS episodes were secondary to a Vaso-Occlusive Crisis. 76% of the admissions occurred in SCD reference centers, 24% in regional hospitals, but 30% later required transfer to reference centers for worsening of clinical conditions or need of exchange transfusion. The mean length of hospitalization was 9.6 days (range 1-46); one patient died of pneumococcal sepsis; 6 episodes required transfer to the Intensive Care Unit, mechanical ventilation was required in one episode. A good adherence to the AIEOP Guidelines was documented for some aspects: 99% of the patients were hospitalized, 98% performed chest X-ray for the diagnosis of ACS and in 99% antibiotic therapy was started. Others aspects were less satisfactory and in need of improvement: incentive spirometry was only performed in 19% of admissions; oxygen therapy was performed only in 75% of patients even if SatO2 was<95%; transfer to reference centers was not always timely. During 75% of ACS episodes a simple red cell transfusion was required for Hb>8g/dl, while in 16% an exchange transfusion was performed for severe respiratory distress (of these 71% were performed in patients transfered from regional hospitals); 38% required inhaled bronchodilators, 6% steroids. A preliminay evaluation of risk factors for recurrent ACS showed that in our cohort allergy to inhaled allergens (p 0.02) and enuresis (p 0.01) were associated with increased prevalence of recurrent ACS; patients with asthma/wheezing also presented more recurrent ACS compared to patients wihout them (23% vs 13%) but this data did not reach statistical significance. Conclusion: This study represents the first analysis in Italy of ACS, which is confirmed as a frequent event in our cohort, with a significant proportion of patients who experience recurrent ACS. Steps need to be undertaken to improve management of ACS and adherence to the AIEOP guidelines at a national level: stimulate the application of early preventive measures that are still under-utilized, increase the appropriateness of multidisciplinary specialist approach (transfusion specialist, acute care physicians, pneumologists, hematologists) strengthen the dissemination of information through training events for all the Hospitals of the network. Disclosures Colombatti: AddMedica: Consultancy; Global Blood Therapeutics: Consultancy; Novartis: Consultancy.

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Regulatory Genetic Variation at the S100B Gene Associates with Vaso-Occlusive Manifestations in Sickle Cell Disease

Blood ◽

10.1182/blood-2018-99-115395 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1063-1063 ◽

Cited By ~ 1

Author(s):

Xu Zhang ◽

Wei Zhang ◽

Santosh L. Saraf ◽

Sergei Nekhai ◽

Mark T Gladwin ◽

...

Keyword(s):

Linkage Disequilibrium ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Research Funding ◽

Genetic Regulation ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Thrombotic Risk ◽

Increased Risk

Abstract In sickle cell disease (SCD) polymerization of hemoglobin S under deoxygenated conditions causes vaso-occlusion, which can manifest as acute pain crisis and progressive bone/organ damage. Molecular studies have attributed vaso-occlusion to elevated vascular adhesion and inflammatory responses, whereas the genetic regulation has only recently been assessed. Genomic DNA isolated from peripheral blood mononuclear cells (PBMCs) was hybridized to Illumina Human 610-Quad SNP array for the PUSH and Walk-PHaSST cohorts and to Affrymetrix SNP 6.0 array for the Howard SCD expression cohort. Single nucleotide polymorphisms (SNPs) for 381 PUSH, 525 Walk-PHaSST, and 55 Howard patients were imputed to 1000 genomes project phase 3 data. Messenger RNA from PBMCs was profiled using Affymetrix Human Exon 1.0 ST Array for the Howard expression cohort and Affymetrix Human gene 2.0 ST array for the UIC expression cohort. Patients within the PUSH and Walk-PHaSST cohorts were classified to four groups according to a cumulative pain score, calculated based on pain frequency and questionnaire description of pain intensity. Pain grouping was examined for correlation with other SCD complications using Cochran Armitage test. History of acute chest syndrome (ACS, PUSH P=3.8×10-9, Walk-PHaSST P=2.4×10-5) and avascular necrosis (AVN, PUSH P=4.1×10-4, Walk-PHaSST P=3.7×10-5) were the most significant clinical manifestations that consistently associated with pain in the two cohorts. To investigate the genetic control of vaso-occlusive manifestations with appropriate power, we leveraged genetic association of pain, ACS, and AVN with genetic regulation of disease-specific gene expression. We mapped expression quantitative trait loci (eQTL) in the Howard expression cohort for SNPs<1 Mb away from gene ends per expression trait. At a permutation based false discovery rate of 5%, 1004 independent eQTL (linkage disequilibrium r2 ≤0.3 per trait) were identified for 880 genes. Focusing on 129 genes whose expression was altered in PBMCs in sickle cell anemia by at least 1.5-fold [1], we identified six eQTL for five differential genes (up-regulated: OSBP2, SLC14A1, RNF182, CCRL2; down-regulated: S100B). The six eQTL were assessed for association with pain, ACS, and AVN, using the Walk-PHaSST cohort for discovery and the PUSH cohort for validation. At a significance of Bonferroni corrected P=0.05 (nominal P=0.0083), an eQTL of S100B (rs2154586) significantly associated with AVN in the Walk-PHaSST cohort (OR=1.8, P=0.00061) and the association was replicated in the PUSH cohort (OR=2.7, P=0.0052). The A allele of the eQTL (frequency=0.18) associated with increased risk for AVN and increased expression level of S100B in the Howard expression cohort (β=0.40, P=1.6 ×10-6). In an additional 64 sickle cell anemia patients without hydroxyurea treatment from the UIC expression cohort, expression levels of S100B were significantly elevated in the individuals with AVN (β=0.28, P=0.029). The 24 SNPs in linkage disequilibrium with the eQTL (r2 >0.7) constituted the third most significant peak in a meta-analysis of genome-wide association of AVN in the PUSH and Walk-PHaSST cohorts. To test the hypothesis that genes involved in vaso-occlusion in SCD may affect thrombotic risk in non SCD individuals, we examined the association of the locus with venous thromboembolism (VTE) in the ARIC, JHS and CHS cohorts from dbGaP. The locus was imputed in African Americans and VTE was defined as being told by a doctor to have a blood clot in the leg or lung as answered in questionnaires during medical exams. The SNPs were associated with VTE using logistic linear regression adjusting for age, gender, enrollment site, and the first 15 principal components per cohort. The risk allele of the leading SNP for AVN consistently associated with increased risk of VTE across the cohorts, with a combined P=0.0041 and OR=1.4. S100B encodes a calcium sensor that appears to intervene in a variety of biological functions. S100B can mediate the inflammatory effects of damage-associated molecular pattern molecules (DAMPs) produced by erythrocyte hemolysis [2, 3]. Serum concentration of S100B correlates with LDH and with TCD-determined peak velocity of the left middle cerebral artery in thalassemia patients[4]. Polymorphisms of S100B that lead to increased serum levels are associated with increased risk of ischemic stroke in the Chinese population[5]. Disclosures Nekhai: NIMHD, NIH: Research Funding; NHLBI, NIH: Research Funding; NIAID, NIH: Research Funding.

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Corticosteroids and increased risk of readmission after acute chest syndrome in children with sickle cell disease

Pediatric Blood & Cancer ◽

10.1002/pbc.21336 ◽

2008 ◽

Vol 50 (5) ◽

pp. 1006-1012 ◽

Cited By ~ 66

Author(s):

John J. Strouse ◽

Clifford M. Takemoto ◽

Jeffrey R. Keefer ◽

Gregory J. Kato ◽

James F. Casella

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Increased Risk

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Pulmonary Complications of Sickle Cell Anemia

Chest Imaging ◽

10.1093/med/9780199858064.003.0025 ◽

2019 ◽

pp. 141-145

Author(s):

Constantine Raptis

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Community Acquired Pneumonia ◽

Pulmonary Complications ◽

Acute Chest Syndrome ◽

Globin Chain ◽

Cell Disease ◽

Risk Of Mortality ◽

Increased Risk ◽

History Of

“Sickle cell disease” describes the spectrum of pathology in patients with at least one HbS chain and one other abnormal β‎ globin chain. Although patients with sickle cell disease often present with a simple community acquired pneumonia, acute chest syndrome must be considered in patients presenting with chest pain and fever, as it carries an increased risk of mortality, especially in adults. A few other entities, including rib infarction and subdiaphragmatic pathologies, can mimic the symptoms of acute chest syndrome. Finally, the findings of sickle cell disease on chest radiography will be discussed. Radiologists must be familiar with these findings in order to accurately interpret imaging studies, especially when the history of sickle cell is not provided.

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Clinical, laboratory, and genetic risk factors for thrombosis in sickle cell disease

Blood Advances ◽

10.1182/bloodadvances.2019001384 ◽

2020 ◽

Vol 4 (9) ◽

pp. 1978-1986 ◽

Cited By ~ 1

Author(s):

Andrew Srisuwananukorn ◽

Rasha Raslan ◽

Xu Zhang ◽

Binal N. Shah ◽

Jin Han ◽

...

Keyword(s):

Risk Factors ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Genetic Risk ◽

Clinical Laboratory ◽

Genetic Risk Factors ◽

Cell Disease ◽

Thrombotic Risk ◽

Increased Risk ◽

Thrombotic Complications

Abstract Sickle cell disease (SCD) patients are at a four- to 100-fold increased risk for thrombosis compared with the general population, although the mechanisms and risk factors are not clear. We investigated the incidence and predictors for thrombosis in a retrospective, longitudinal cohort of 1193 pediatric and adult SCD patients treated at our institution between January 2008 and December 2017. SCD diagnosis and thrombotic complications were identified using International Classification of Diseases coding and verified through medical chart review. Clinical and laboratory data were extracted from the medical records. With a median follow-up of 6.4 years, 208 (17.4%) SCD patients experienced 352 thrombotic events (64 strokes, 288 venous thromboembolisms [VTE]). Risk factors for stroke included older age and HbSS/Sβ0-genotype and a lower hemoglobin (Hb) F% in the subset of HbSS/Sβ0-genotype patients (P < .05). VTE risk was independently associated with lower estimated glomerular filtration rate, hydroxyurea (HU) use, HbSS/Sβ0 genotype, and higher white blood cell (WBC) counts and Hb (P ≤ .03). Two thrombomodulin gene variants previously associated with thrombosis in the general African American population, THBD rs2567617 (minor allele frequency [MAF] 0.25; odds ratio [OR], 1.5; P = .049) and THBD rs1998081 (MAF, 0.24; OR, 1.5; P = .059), were associated with thrombosis in this cohort. In summary, thrombotic complications are common, and several traditional and SCD-specific risk factors are associated with thrombotic risk. Future studies integrating clinical, laboratory, and genetic risk factors may improve our understanding of thrombosis and guide intervention practices in SCD.

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