Sickle Cell Leg Ulcers Are Associated with Hyperuricemia, Hemolysis, Pulmonary Hypertension and Death.

Abstract Abstract 2583 Poster Board II-560 Background: Leg ulceration is a common, debilitating complication of sickle cell disease (SCD), affecting 8 to 50% of patients, and recently found to be associated with the hemolytic phenotype. We evaluated the relationship of leg ulceration history with estimated pulmonary artery systolic pressure, hemolytic rate and other clinical characteristics in a cohort of 396 adults with SCD. Materials and methods: All SCD patients were enrolled in a NHLBI-approved protocol and were screened for pulmonary hypertension with echocardiography at steady state. We collected a detailed past medical history, as well as a comprehensive set of laboratory tests. Comparisons between patients with and without a history of leg ulcers were made using Wilcoxon rank sum tests to compare medians of continuous variables. Associations between categorical variables and leg ulcer history in two groups were tested using the chi-square test of independence. Results: Eighteen % of all subjects had a history of leg ulceration. Patients affected were older, predominantly had homozygous SCD, and had markers of significantly more severe hemolysis, including low hemoglobin and high reticulocyte counts, LDH and AST. They also had a significantly higher prevalence of elevated tricuspid regurgitation velocities (TRV≥2.5 m/sec, 56% vs. 40%, p=0.02; TRV≥3 m/sec, 22% vs. 12%, p=0.006). High serum uric acid and lower serum albumin were significantly associated with a history of leg ulcers. A self-reported history of hepatitis also was associated with leg ulceration. None of the other parameters evaluated were significantly associated with leg ulceration, including history of pain, acute chest syndrome, stroke or priapism. Significantly, patients with a history of leg ulcers were more likely to have died by the time of data analysis (21% vs. 9%, P=0.02). Discussion: These data in SCD patients with a history of leg ulcers provide the first demonstration of an association with elevated serum uric acid and confirmation of published associations with elevated pulmonary pressures and markers of hemolytic severity. The uric acid association is more significant than that for serum creatinine or urea nitrogen, suggesting that uric acid is more than simply a marker of renal dysfunction. In patients without SCD, there is a growing literature implicating uric acid as a possible cause of hypertension and a marker of risk for cardiovascular disease, pulmonary hypertension, and early mortality. This is particularly interesting, in view of the epidemiological relationship between leg ulcers and pulmonary hypertension demonstrated here and previously by others. The results continue to support linkage of leg ulcers and pulmonary hypertension to a hyperhemolytic -vasculopathy subphenotype of SCD. Disclosures: No relevant conflicts of interest to declare.

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Association of MBL2 polymorphism with Leg Ulcers Development in Sickle Cell Anemia Patients

Blood ◽

10.1182/blood.v124.21.4912.4912 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4912-4912

Author(s):

Marcos André Cavalcanti Bezerra ◽

Isabela Cristina Farias ◽

Diego Arruda Falcão ◽

Igor de Farias Domingos ◽

Luana Laranjeira Prado ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Conflicts Of Interest ◽

Clinical Manifestations ◽

Monogenic Disease ◽

Prior History ◽

Leg Ulcers ◽

Immune Disorder ◽

History Of ◽

Mbl Deficiency

Abstract Leg ulcers are the most common clinical manifestations of sickle cell anemia (SCA), a monogenic disease with huge clinical diversity among patients. They affect 8% to 10% of SCA patients, reaching a percentage greater than 50% in patients residing in tropical areas. These ulcers occur due to vascular occlusion, tissue hypoxia, hemolysis and genetic factors, presenting a slow healing, high recurrence rate and huge susceptibility to infection. Recently, some studies have shown a positive relationship between the complement system and the development of some vascular diseases and injuries such as leg ulcers in non-SCA patients. Mannan-binding lectin (MBL) is an important component of the humoral innate immune system, and MBL possesses several characteristics indicating that it may play an essential role in wound healing; modulating inflammation and contributing to the clearance of microorganisms and apoptotic cells. In a recent study of chronic leg and foot ulcer patients, serum MBL levels were significantly different between wounds of different etiologies, with chronic venous leg ulcers patients having a higher frequency of MBL deficiency. Polymorphisms in the MBL2 are associated with a reduction in the MBL protein serum levels, increasing risk of developing leg ulcers and also the maintenance of these wounds, compromising the integrity of the immune defence and its response to potential invading pathogens. Here, we aimed to determine the frequency of polymorphisms in the promoter region -221 (Y / X) and -550 (H / L) and exon 1 of the MBL2 and assess the clinical impact of these variants in a northeastern Brazilian SCA population who presented leg ulcers. Two-hundred seventy-five unrelated SCA patients were included. According the leg ulcers presence, the total cohort was classified in patients presenting current or prior history of leg ulcers (n=100) and SCA patients above 18 years with no history of leg ulcers (n=175). Molecular analysis was performed by qPCR. Our population was in Hardy-Weinberg equilibrium. The allelic frequency of haplotypes associated with high MBL production (HYA, LYA) was 54.5% for cases and 62.9% in controls. The genotypes related to low MBL production (HYO, LYO) in cases and controls was 27.5% and 18.6%, respectively. The frequency of genotype related to intermediate MBL production (LXA) was 18% in cases and 18.5% in controls. We had no statistically significant results when we analyzed only the polymorphisms (P>0.05). However, the phenotypic analysis between high and low MBL production revealed that patients with leg ulcers have lower MBL protein levels (P=0.019). We focused specifically on a possible role of MBL deficiency on healing complications, based on the facts that MBL deficiency is the most common immune disorder, and that a common causality for prolonged healing of these ulcers is infection or colonization by bacteria. In our study, MBL deficiency appears to increase the risk of developing leg ulcers in SCA patients. Disclosures No relevant conflicts of interest to declare.

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Targeted Education after an Emergency Department Visit Increases Hydroxyurea Initiation in Children with Sickle Cell Anemia

Blood ◽

10.1182/blood.v130.suppl_1.868.868 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 868-868

Author(s):

Sarah Kappa ◽

Lydia Pecker ◽

Deepika S. Darbari ◽

Robert Nickel

Keyword(s):

Emergency Department ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Conflicts Of Interest ◽

National Health System ◽

Clinic Visit ◽

Acute Chest Syndrome ◽

Hemoglobin F ◽

History Of ◽

One Year

Abstract Introduction: Hydroxyurea decreases many complications of sickle cell anemia (SCA) but is underused in treatment-eligible patients. Barriers to hydroxyurea initiation occur on the health care system, provider, and patient level. Novel strategies to increase hydroxyurea use in patients with SCA are needed. To address this challenge at our center, we implemented the Quick Start Hydroxyurea Initiation Project (Q-SHIP). Methods: Patients with SCA were eligible to participate in Q-SHIP if they presented to the Children's National Health System (CNHS) emergency department (ED) for pain or acute chest syndrome and were not taking hydroxyurea. Patients <9 months old, on chronic transfusions, pregnant, or not followed by CNHS hematology were excluded. Eligible patients were referred to a weekly Q-SHIP clinic visit focused on hydroxyurea education and were offered initiating treatment at the visit's conclusion. Participants completed a pre-session questionnaire, discussed hydroxyurea with a hematologist using a handbook developed by CNHS, and watched videos featuring patients and parents of children with SCA sharing their experience with hydroxyurea. Subjects were classified as starting hydroxyurea if they had a clinic visit for hydroxyurea monitoring within 3 months of participation in a Q-SHIP session. Results: Over 13 months (2/1/2016 - 3/31/2017) 65 eligible patients participated in Q-SHIP a median of 5 days (IQR 2, 20 days) after ED or hospital discharge. Although 44% (28/64) of participants reported no previous hydroxyurea offer, provider clinic documentation indicated that 61% (17/28) of these families had declined a previous hydroxyurea offer. After Q-SHIP, 55% (36/65) of participants started hydroxyurea. Subjects who started hydroxyurea after Q-SHIP were similar to those who did not, except subjects who started were more likely have a history of an intensive care unit admission (Table 1). After a median follow-up of 11 months, 81% (29/36) of participants who started hydroxyurea after Q-SHIP continued on therapy. Among Q-SHIP participants continuing treatment, mean corpuscular volume increased by a median of 8.6 fL (IQR +5.4, +17.7, p<0.0001) and hemoglobin F increased by a median of 5.8% (IQR +3.0, +11.3, p<0.001). One year after implementation of Q-SHIP, the proportion of treatment-eligible patients with SCA who presented to the ED with pain or ACS who were receiving hydroxyurea increased; February 2016: 56% (32/57) vs. February 2017: 73% (43/59), p=0.059. Conclusion: Addressing indications for hydroxyurea therapy in a clinic encounter exclusively for this purpose soon after a SCA complication is a meaningful time to meet with families of children with SCA to initiate treatment. Disclosures No relevant conflicts of interest to declare.

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Interleukin 8 Level, Reticulocyte Counting and aPTT Ratio in Brazilian Sickle Cell Anemia Patients with Leg Ulcers

Blood ◽

10.1182/blood.v118.21.4835.4835 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4835-4835

Author(s):

Magnun N N Santos ◽

Eliel Wagner Faber ◽

Dulcinéia Martins Albuquerque ◽

Romulo Tadeu Dias Oliveira ◽

Marcos André Cavalcanti Bezerra ◽

...

Keyword(s):

Gene Expression ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Plasma Levels ◽

Conflicts Of Interest ◽

Organ Damage ◽

Northeastern Brazil ◽

Leg Ulcers ◽

Increased Risk ◽

History Of

Abstract Abstract 4835 Background: Sickle cell anemia (SCA) is characterized by a chronic inflammatory state in which oxidative stress, particularly in the endothelium, exerts a strong influence on the pathogenesis of vaso-occlusion and may be implicated in patients' clinical heterogeneity and survival. It has been suggested that the cytokine production profile of cells involved in the immune response may vary among patients with SCA. Leg ulcers (LU) represent a severe complication in these patients, and this condition has been associated with specific end-organ damage and an increase in morbidity and mortality. Recent studies have shown that venous obstruction, endothelial dysfunction, coagulopathy and infections are implicated in the complex pathogenesis of LU. Aims: To determine IL-1β, IL-6 and IL-8 plasma levels and gene expression rates as well as hematological and coagulation parameters and correlate these with the history of LU in adult SCA patients followed up at HEMOPE, in the state of Pernambuco, northeastern Brazil. Methods: Peripheral blood samples from 92 patients (median age 27 years; 42 female; 52 male; all Afro-descendants) in the steady state who had been diagnosed with SCA (HbSS), had not received a transfusion and were not using hydroxyurea were analyzed. Plasma levels of cytokines were determined by ELISA, and the gene expression rates by qRT-PCR. The patients' clinical and laboratorial characteristics were obtained from their medical charts. Statistical analysis was performed using the SAS System for Windows version 9.2. Results: Median age was higher in patients with a history of LU than in those without a history (33.1 vs. 28.4; p = 0.04). Although no statistically significant (p = 0.5) differences in IL-8 gene expression rates were observed, IL-8 plasma levels were significantly higher in patients with a history of LU than in patients without a history (23.8 vs. 7.7; p = 0.01) (Figure 1). Thus, patients with high levels of IL-8 had an increased risk for the occurrence of leg ulcers (OR = 1.01; 95% CI = 1.00–1.02). The ROC curve showed that IL-8 levels higher than 8.55 pg/mL could indicate the presence of LU (accuracy = 71.6%; sensitivity = 73.7%; specificity = 68.5%). The laboratory tests revealed reticulocyte counts and activated partial thromboplastin time (aPTT) ratios (R) that were significantly higher in patients with a history of LU than in those without a history (11.8 vs. 8.4, p = 0.01; 1.1 vs. 0.9, p = 0.04, respectively). Both the higher reticulocyte counts and R values were associated with increased risk for the occurrence of leg ulcers in these patients (OR = 1.12, 95% CI = 1.02 – 1.20; OR = 24.28, 95% CI = 1.20 – 486.09, respectively). Conclusion: In this study, patients who had had LU at some time in their lives showed significantly higher IL-8 levels, reticulocyte counts and R values than patients who had never had LU. Our results therefore suggest a relationship between the parameters described above and LU in patients with SCA. These parameters could perhaps be used, in association with different genetic modulators that may contribute to different clinical phenotypes observed in this disease, as markers of this clinical manifestation of SCA or of a propensity to develop it. Financial Support: CAPES (Brazil)/FAPESP/CNPq/INCTS Disclosures: No relevant conflicts of interest to declare.

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Association between Serum Uric Acid Levels and Perinatal Outcome in Women with Preeclampsia

Obstetrics and Gynecology International ◽

10.1155/2021/6611828 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Robinson Uchenna Ugwuanyi ◽

Irozuruike Munachiso Chiege ◽

Felix Eke Agwu ◽

George Uchenna Eleje ◽

Nonso Martin Ifediorah

Keyword(s):

Uric Acid ◽

Pregnant Women ◽

Serum Uric Acid ◽

Uric Acid Level ◽

Perinatal Outcome ◽

Acid Level ◽

Serum Uric Acid Level ◽

Elevated Serum ◽

Categorical Variables ◽

Multiple Gestation

Objectives. To compare serum uric acid levels with disease severity and perinatal outcome among preeclamptic and normal pregnant women. Materials and Methods. This was a case-control study carried out in Federal Medical Centre, Umuahia, Nigeria. Consenting pregnant women were consecutively recruited into two groups comprising pregnant women diagnosed with preeclampsia and normotensive nonproteinuric pregnant women. Exclusion criteria included pregnant women who were current smokers, took alcohol, and diagnosed with multiple gestation, diabetes mellitus, or renal failure. Associations between categorical variables such as preeclampsia severity and perinatal outcomes were done using logistic regression while means of continuous variables such as serum uric acid were compared using Student’s t-test. Data were presented using odds ratios (ORs) with 95% confidence intervals (95% CI) and a statistical significance level set at P value ˂ 0.05. Data analysis was done using Statistical Package for Social Sciences version 22. Results. One hundred and two participants were finally analysed. Fifty-one participants were recruited in each arm. Women with preeclampsia had significantly high serum uric acid level versus controls (6.08 ± 0.49 mg/dL vs. 5.20 ± 0.19; P < 0.001 ). Women with elevated serum uric acid levels (˃6 mg/dL) were found to be 4 times more likely to have severe preeclampsia ( P = 0.022 , OR = 4.00, 95% CI = 1.225–13.056), 66 times more likely to have APGAR score ˂7 in the first minute ( P < 0.001 , OR = 66.00, 95% CI = 6.991–623.128), and 3 times more likely to have lower birth weight ( P = 0.038 , OR = 3.400, 95% CI = 1.073–10.775) than those with normal serum uric acid levels. Conclusions. The mean serum uric acid level in a preeclamptic is higher than that of normal pregnant control, and higher levels are associated with severity of the disease and significantly associated with poorer perinatal outcome.

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Leg Ulcers among Patients with Sickle Cell Disease on Hydroxyurea Therapy.

Blood ◽

10.1182/blood.v104.11.1676.1676 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1676-1676

Author(s):

Suresh Mendpara ◽

Betsy Clair ◽

Mudusar Raza ◽

Lisa Daitch ◽

David Smith ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Therapeutic Agent ◽

Acute Chest Syndrome ◽

Prior History ◽

Leg Ulcers ◽

Cell Disease ◽

Number Of Patients ◽

Transfusion Requirements ◽

History Of

Abstract Leg ulcers remain a debilitating complication of Sickle Cell Disease (SCD): significant pain, tendency to polymicrobial infection, difficult to heal, and tendency to recur in ~ 50% of patients. According to CSSCD data, 2.5% of 2075 patients had leg ulcers at study entry; overall incidence was 9.97 per 100-person years in patients without concomitant alpha thalassemia (thal), and 5.73 per 100 person years in those with alpha thal. Hydroxyurea (HU) is an approved therapeutic agent for adults with SCD; it has been shown to decrease frequency of pain crises and acute chest syndrome and decrease transfusion requirements. Recently, HU was associated with a 40% reduction in mortality. There have been reports of an association between HU therapy and leg ulcers in patients with myeloproliferative disorders (MPD) and more recently with SCD. A retrospective study from the Mayo Clinic (Best et al, Ann. Intern. Med., 128:29, 1998) found that among 115 patients with various forms of MPD, 14 developed leg ulcers after an average HU exposure of 6 years; all ulcers healed after stopping HU, and 2 patients had recurrences of their ulcers after resuming HU. Chaine et al (Arch. Dermatol, 137: 467, 2001) reported that 5/17 (29%) patients with SCD on HU developed leg ulcers. If HU, the most effective available therapeutic agent for SCD is indeed causative of leg ulcers, this should raise serious concerns. In an effort to further clarify this problem, we performed a retrospective analysis. 421 adult SCD patients (age 16–60) formed the subject of this study. 152 were treated with HU for a minimum of 6 months. 269 patients were not exposed to HU. A total of 25 patients (5.9%) had leg ulcers; 17 were treated with HU, 8 were not. Thus, the frequency of leg ulcers was 11.2% among HU treated patients, as opposed to 2.9% among those who did not receive HU therapy (p<0.001). However, of the 17 patients with ulcers, 16(94%) had a history of ulcers prior to HU exposure. Only one patient developed ulcers for the first time after starting HU therapy. 6/17 patients experienced healing of their ulcers despite continuing HU. Among the patients treated with HU, those who had ulcers were more anemic (pre-treatment Hb 7.4 vs 8.2 g/dl, p=0.01) and were older (mean age 40.5 vs 33.0, p<0.001), confirming previous observations. Logistic regression analyses showed that only age and prior history of leg ulcers were significant risk factors for the development of ulcers in patients with SCD under HU therapy. Our data on a large number of patients does not suggest that HU therapy alone is causative of leg ulcers in SCD patients. The supporting evidence for this conclusion comes from our observations that 1) a vast majority of patients (16/17; 94%) who developed leg ulcers after starting HU had a previous history of ulcers. This is also true of the report by Chaine et al, where 4/5 patients with leg ulcers had a prior history; 2) in 6/17 patients (35.3%) ulcers healed with conventional therapy despite continuation of HU. Furthermore, it should be noted that patients with leg ulcers represent a more severe group and are thus more likely candidates for HU therapy. We conclude that HU therapy alone is not causative of leg ulcers in patients with SCD. In addition, HU does not appear to prevent recurrence of leg ulcers in patients with a prior history; nor does it expedite ulcer healing. Other as yet unknown factors, some of which are likely genetic, play an important role in determining the risk for developing leg ulcers.

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Are We Missing the Mark? Respiratory Symptoms, Cxr's and Acute Chest Syndrome (ACS) in Sickle Cell Disease (SCD)

Blood ◽

10.1182/blood.v124.21.1378.1378 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1378-1378

Author(s):

Sarah Gard Lazarus ◽

Olufolake A. Adisa ◽

Robert Hagbom ◽

April Zmitrovich ◽

Claudia R. Morris

Keyword(s):

Sickle Cell ◽

Clinical Assessment ◽

Respiratory Symptoms ◽

Conflicts Of Interest ◽

Average Length ◽

Physical Exam ◽

Normal Lung ◽

Acute Chest Syndrome ◽

History Of ◽

To Receive

Abstract Background: Acute chest syndrome (ACS) is a common complication of SCD detected by chest radiography (CXR) with significant morbidity and mortality. Previous studies show that clinical assessment alone grossly underestimates the presence of ACS. We evaluate whether abnormal respiratory signs and symptoms are predictive of ACS. Methods: Data was obtained by electronic medical record using ICD-9 codes linked to fever and SCD in the year 2013 in children 2 months to 18 years at two Children's Healthcare of Atlanta campuses (Egleston and Scottish Rite). Information on demographics, vital signs, respiratory symptoms on review of systems (ROS), physical exam (PE) findings and ACS diagnosis were obtained by direct chart review. Results: 610 visits of 356 patients with SCD/fever were included. 95 patients were excluded prior to analysis due to lack of measured fever, inaccurate sickle cell diagnosis, age, or CXR already completed by another institution. Mean age was 5.7±5 years & 178 (50%) were female. 67% had Hb-SS, 23% had Hb-SC, & 10% had other genotype. 379 CXR's (62%) were ordered, of which 66 (17%) were positive (Table 1). Of the patients who were admitted for ACS (n=64), the average length of stay was 4.4±3 days, 15 (23%) required oxygen, 3 required BIPAP (5 %) and 8 (12%) required transfusions. None required ICU level care. Five patients who were admitted with negative CXRs from the ED developed ACS on the ward (5%). One discharged patient was called back for a radiology diagnosis of ACS not noted by the ED physician. 63 (16%) additional patients discharged from the ED returned within 72 hours. 33/63 (52%) received CXRs on repeat visit and 7/63 (11%) had developed ACS. 6 of these patients had a negative CXR at their initial ED encounter. One patient who was discharged without a CXR returned within 24 hours with ACS. History of ACS (odds ratio=2.5, 95% CI: 1.4-4.4, p<0.01), tachypnea (OR=2.0, 95% CI: 1.1-3.4, p=0.03), and abnormal physical exam findings (OR=2.8, 95% CI: 1.5-5, p<0.01) were all associated with positive CXR finding and ACS. Conclusions: CXRs were ordered in only 62% of encounters of febrile children with SCD. The prevalence of ACS among patients evaluated by CXR at the initial ED encounter was 17%. Patients with a past history of ACS were more likely to receive CXR's & more likely to have ACS. Tachypneic patients were not more likely to receive CXR's, but were more likely to have ACS. Respiratory signs/symptoms & abnormal lung PE findings made physicians more likely to order CXR's, & also were predictive of ACS. Tachypnea & history of ACS are high risk factors for ACS in febrile children with SCD, in addition to abnormal ROS and PE. However, 62% of children with ACS had a normal lung exam. Clinical assessment alone is a poor predictor for ACS. Abstract 1378. TableNo CXRN=231 visitsCXR OrderedN=379 visitspPositive CXRN= 66Negative CXRN= 313pAge (years; mean±SD)5.2±4.56.0±4.70.065.7±3.76.0±4.80.60Fever (Tm Celcius±SD)39.1±0.539.3 ±3.30.3639.2±0.639.3±3.60.86Tachypnea (n, %) (age adjusted)71 (31%)119 (31%)0.8629 (44%)90 (29%)0.02H/O ACS (n, %)87 (38%)191 (50%)<0.0146 (70%)145 (46%)<0.01H/O Asthma (n, %)57 (25%)124 (33%)0.0326 (39%)98 (31%)0.20Abnormal ROS (n, %)86 (59%)301 (79%)<0.0161 (92%)240 (77)<0.01Abnormal Lung PE (n, %)7 (3%)84 (22%)<0.0125 (38%)59 (19%)<0.01Admissions (n, %)53 (23%)161 (43%)<0.0162 (94%)99 (32%)<0.01Length of Stay (days±SD)3.2±1.14.0±2.50.034.2±2.43.9±2.90.59Oxygen Use0 (0%)35 (9%)0.0415 (23%)20 (6%)<0.01BIPAP Use0 (0%)7 (2%)0.043 (5%)4 (1%)0.07Transfusion9 (4%)29 (8%)0.068 (12%)21 (7%)0.13 Disclosures No relevant conflicts of interest to declare.

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PADI4 Gene Polymorphism As a Risk Factor for Acute Chest Syndrome in Sickle Cell Anemia Patients

Blood ◽

10.1182/blood.v130.suppl_1.954.954 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 954-954 ◽

Cited By ~ 1

Author(s):

Francine Chenou ◽

Bidossessi Wilfried Hounkpe ◽

Dulcinéia Martins de Albuquerque ◽

Igor de Farias Domingos ◽

Aderson da Silva Araujo ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Gene Polymorphisms ◽

Conflicts Of Interest ◽

Inflammatory Diseases ◽

Clinical Manifestations ◽

Chronic Inflammatory Disease ◽

Acute Chest Syndrome ◽

Cycle Sequencing ◽

History Of

Abstract Introduction: Sickle cell anemia (SCA) is a chronic inflammatory disease with heterogeneous clinical features and the reasons for the heterogeneity of the clinical manifestations has not been fully elucidated. New mediators of the pathogenesis of SCA described recently include the formation of Neutrophil Extracellular Traps (NETs), which may contribute to the amplification of inflammation via the production of pro-inflammatory mediators. Peptidylarginine Deiminase 4 (PADI4) is a critical regulator of NETosis by mediating histone citrullination, an essential step for the generation of NETs. There appears to be a relationship between PADI4 gene polymorphisms and the pathophysiology of other inflammatory diseases in which NETosis seems to be relevant. Our aim was to investigate the association of PADI4 gene polymorphisms [rs874881(G>C), rs1748033(T>C), rs11203366(G>A), rs11203367 (T >C), rs2240340 (T>C)], which have been previously associated with increased PADI4 mRNA stability and with some clinical manifestations in cohorts of SCA patients. Methods: The study included 194 SCA patients (93 males and 101 females with mean age 33.29 ± 9.54 years) being followed up at the Hematology and Hemotherapy Foundation of Pernambuco (HEMOPE), Recife, Brazil. PADI4 gene polymorphisms were performed by Polymerase Chain Reaction (PCR) and their products were sequenced using the Big Dye Terminator Cycle Sequencing Ready Reaction Kit v3.1 (Applied Biosystems, CA, USA). These results obtained were compared with the clinical data obtained from the patients' records. Ethical approval was obtained from Ethics Committee of HEMOPE and all patients gave informed consent. Results: The frequencies of the genotypes found were as follows: rs874881 (22.2% GG, 50.5% GC, 27.3% CC); rs1748033 (17% TT, 42.3% TC, 40.7% CC); rs11203366 (21.1% GG, 50% GA, 28.9% AA); rs11203367 (20.6% TT, 49.5% TC, 29.9% CC); rs2240340 (24.7% TT, 46.4% TC, 28.9% CC). The distribution of the genotypes was in accordance with the Hardy-Weinberg equilibrium (p > 0.05). Twenty-four patients (12.4%) presented with a history of acute chest syndrome (ACS), 27 (13.9%) with stroke, 168 (86.6%) with vaso-occlusive crisis (VOC), and 81 (47.8%) with leg ulcers (LU). No association was observed between the polymorphisms studied and the history of LU, VOC and stroke in the patients (p > 0.05). However, for rs 874881 and 1748033 with the G and T alleles, respectively, were associated with a higher risk of ACS (OR: 2.96, p = 0.02 and OR: 4.75, p = 0.01, respectively). Conclusion: In the present study, we found an association between the wild type alleles (rs874881G and rs1748033T) and a history of ACS in our cohort of SCA patients. There is need for future studies on these polymorphisms in larger cohorts of SCA patients to affirm this association. Disclosures No relevant conflicts of interest to declare.

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Effect of Sickle Cell Disease Type, Age and Gender On the Prevalence of Chronic Organ Damage in Adults with Sickle Cell Disease.

Blood ◽

10.1182/blood.v114.22.4607.4607 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4607-4607

Author(s):

Raymond U. Osarogiagbon ◽

Syed N Haider ◽

Jun Tang

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Conflicts Of Interest ◽

Brain Mri ◽

Organ Damage ◽

Categorical Variables ◽

Acute Chest Syndrome ◽

Continuous Variables ◽

Cell Disease ◽

End Organ Damage

Abstract Abstract 4607 Introduction The high mortality risk that sickle cell disease (SCD) patients experience from infancy is cumulative through adulthood, largely because of the effect of cumulative end organ damage, which is a more powerful predictor of early mortality than frequency of painful episodes. The latter, though, gets more attention from patients and caregivers. Any vascular territory is susceptible to damage. The most common target organs are the brain, lungs, kidneys, retina and joints. We examined the prevalence of the full spectrum of end organ damage in a cohort upon entry into our adult SCD program and compared the clinical and laboratory characteristics of patients based on age, gender and SCD type. Patients and Methods Retrospective review of prospectively collected data on 118 adults upon entry into our program between February 2005 and October 2008. All patients underwent a standardized battery of tests to evaluate hematological and biochemical parameters at entry. Historical presence of episodes of acute chest syndrome, pneumonia, stroke, avascular necrosis, osteomyelitis, leg ulcers, priapism, and cholecystectomy and hydroxurea therapy was quantified. Pulmonary hypertension (PHT) was defined as a tricuspid regurgitant jet velocity (TRJV) ≥2.5 m/s on Doppler echocardiography; sickle cell nephropathy (SCN) as glomerular filtration rate, (GFR) < 90ml/min. and/or 24-hour protein>300mg and/or urine protein/creatinine ratio>0.3); cerebrovascular disease (CVD) as evidence of previous ischemic and/or hemorrhagic infarct and/or aneurysm formation on brain MRI/MR angiography; and sickle cell retinopathy (SCR) as background to proliferative retinopathy) on fluorescent retinal angiography. Characteristics of patients were evaluated with t-test for continuous variables and chi-square test for the categorical variables. Results The relevant statistically significant correlative variables in these 3 comparisons are shown in the following tables. Conclusions Our study highlights the various differences in the prevalence of sickle cell disease-related end organ damage and morbidity among different age, gender and two major sickle cell disease categories. It shows the significant progression of organ damage with advancing age and the more severe nature of SS/Sβ0 phenotype. Further expansion of this assessment may help identify specific high risk groups that can be targeted as candidates for more intensive preventive interventions. Disclosures: No relevant conflicts of interest to declare.

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Clinical Characteristics Associated with Survival in Adult Sickle Cell Disease

Blood ◽

10.1182/blood.v120.21.3229.3229 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3229-3229

Author(s):

Hany Elmariah ◽

Melanie E. Garrett ◽

Kenneth I. Ataga ◽

Allison E Ashley-Koch ◽

Marilyn J. Telen

Keyword(s):

Pulmonary Hypertension ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Survival Data ◽

Conflicts Of Interest ◽

Cox Proportional Hazards Model ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Cerebrovascular Events ◽

Hydroxyurea Therapy

Abstract Abstract 3229 Background: Sickle cell disease (SCD) greatly decreases survival of affected patients, and significant advances will be necessary to decrease the gap in expected survival between SCD patients and non-affected individuals. We examined the relationship of clinical differences among SCD patients to survival, in order to gain greater understanding of major contributors to early mortality. Identification of such factors could guide development of therapeutic options. Methods: Survival data were obtained for 417 adult subjects previously enrolled in a study of clinical outcome modifying genes in SCD from Duke University Medical Center and the University of North Carolina at Chapel Hill. All subjects were ≥18 years at the time of enrollment and were followed for a mean of 7.9 years (range 2.3–10 years). At enrollment, a number of clinical parameters were collected, including hemoglobin (Hb) genotype (SS, SC, Sβ0 thalassemia, or Sβ+thalassemia), baseline laboratory values (Hb, WBC, platelets, reticulocytes, fetal Hb, LDH, MCV, proteinuria), comorbidities (cerebrovascular events, pulmonary hypertension, history of acute chest syndrome, avascular necrosis, priapism, and pain crises - defined as number of hospitalizations in the past 12 months, among others), and medication status (hydroxyurea, narcotics, and others). Levels of soluble adhesion molecules (sICAM, sVCAM, sE-selectin, sP-selectin), NT-proBNP, TNF-α, and interleukins-6, -8, and -10 were measured for a subset of 87 subjects. Regression analysis based on the Cox proportional hazards model was employed to determine the effect of clinical phenotypes on survival time using PROC PHREG in SAS v9.2 (SAS Systems, Cary, NC). All models were adjusted for gender and age at enrollment. Results: Mean age at enrollment was 34 years (range 18 to 84 years). The mean age at death was 45 years (range 24 to 86 years). Subjects with HbSβ0 had the worst prognosis (p=0.0001), followed by subjects with SS, SC, and Sβ+. Lower glomerular filtration rate (GFR, hazard ratio [HR]=1.087 per each ml/min decrease in GFR, p<0.0001), incidence of pain crises (HR=2.038, p=0.005), pulmonary hypertension (HR=2.269, p=0.005), cerebrovascular events (HR=1.875, p=0.008), proteinuria (HR=1.922, p=0.011), seizures (HR=2.138, p=0.012), short-acting narcotics use (HR=1.693, p=0.033) and TIAs (HR=2.407, p=0.043) were significantly associated with decreased survival. Lower baseline Hb was also associated with decreased survival (HR=1.259 per g/dl decrease, p=0.0047), but after controlling for GFR, was no longer significant (p=0.274). Additionally, increased NT-proBNP (HR=1.617, p=0.0004) and sVCAM-1 (HR=2.032, p=0.0003) were associated with decreased survival. Fifty percent of patients were on hydroxyurea therapy, which was not associated with a change in survival (p=0.503). Conclusion: SCD continues to reduce life expectancy for affected individuals, particularly those with Hb Sβ0 and SS. Surprisingly, we found that Sβ0 had a significantly worse survival compared to SS. Cerebrovascular events, pulmonary hypertension, proteinuria, decreased GFR, and more frequent pain crises were also strongly associated with poorer survival. Not only were these comorbidities individually associated with decreased survival, but an additive effect was observed, such that subjects with a greater number of negative endpoints had worse survival (p<0.0001). These traits may provide some utility in predicting prognosis of SCD patients. More importantly, aggressive management of these comorbidities may produce a survival benefit. The association of higher sVCAM-1 levels with decreased survival suggests that targeted therapies to reduce endothelial damage and inflammation may also be beneficial. In contrast to prior studies, hydroxyurea therapy had no influence on survival. This may reflect a failure in some patients to reach the maximum tolerated dose, lack of compliance, or more severe baseline disease in those patients who were treated. Disclosures: No relevant conflicts of interest to declare.

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High Frequency of Asthma, Sepsis and Acute Chest Syndrome in Children with Sickle Cell Disease and Pulmonary Hypertension.

Blood ◽

10.1182/blood.v110.11.3782.3782 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3782-3782

Author(s):

Claudia R. Morris ◽

Ward Hagar ◽

Jennifer Gardner ◽

Jennifer Michlitsch ◽

Elliott Vichinsky

Keyword(s):

Pulmonary Hypertension ◽

Sickle Cell Disease ◽

Lung Disease ◽

Sickle Cell ◽

Obstructive Lung Disease ◽

Acute Chest Syndrome ◽

Screening Methods ◽

Cell Disease ◽

Co Morbidity ◽

History Of

Abstract Pulmonary hypertension (PH) is an important co-morbidity in sickle cell disease (SCD). Despite increasing research in adults, the prevalence and implication of this condition in children is unknown. Charts of 362 SCD patients followed at Children’s Hospital & Research Center Oakland were reviewed in order to determine clinical associations of PH in adults and children with SCD. Patients with underlying lung abnormalities or those on chronic transfusions were more likely to have echocardiograms in this cohort, however the diagnosis of PH was often unrecognized. Of the 110 pediatric patients, 61 were screened by an echocardiogram with 15 meeting echocardiogram criteria for PH (24.6%.) The ages of children with PH ranged from 7 to 17 years (mean 12.7±3 years). Of the 252 adults, 148 were screened and 81 were considered to have PH (53.7%). Only 52% of patients with PH based on abnormal echocardiography were identified by a clinician as having PH, and although 38 (46.9%) were receiving chronic transfusions, only 4% were specifically treated for PH. Of the 15 children with PH, only 9 carried that diagnosis of PH in their charts, and none were on therapy geared towards PH. A different clinical phenotype for PH in adults versus children was identified. Associations with PH for adults included age, renal and lung disease, Hepatitis C, chronic transfusions, and a history of acute chest syndrome (ACS), with ACS being protective (OR [95% CI]: 0.40 [0.16 – 1.00], p <0.05). For children, a history of sepsis (7.00 [1.29 – 39.7], p= 0.01), ACS (8.2 [1.04 – 367], p<0.05) or obstructive lung disease suggestive of asthma (4.70 [1.4 – 16.4], p=0.01) was associated with PH, possibly reflecting distinct aspects of endothelial dysfunction. Logistic regression of their 3 significant univariant variables found that only a history of sepsis (adjusted OR 2.16; 95% CI 1.2–28.3, p=0.031) remained significant, with the history of asthma or obstructive lung disease nearly so (adjusted OR 1.86; 95% CI 0.93 −14.9, p=0.062) with an area of the receiver operator curve of 0.80. It is well documented that asthma and ACS are associated with complications in SCD, and these data demonstrate an association of these conditions with PH in children with SCD as well. This is the first report to identify a relationship between bacteremia or sepsis and PH in children with SCD. Asthma, sepsis and ACS are all conditions associated with arginine dysregulation and low nitric oxide bioavailability, a shared mechanism with hemolysis-associated PH. PH is a common complication in SCD that affects children as well as adults. The diagnosis is often missed, even with echocardiographic evidence of PH, likely related to lower pulmonary pressures occurring in patients with SCD, compared to levels typically associated with PH. Children with PH have a different profile of complications than adults with PH, suggesting alternate mechanisms of disease pathogenesis in children that may require different screening methods and potentially even different treatment approaches. Since PH is associated with high mortality and morbidity, universal screening by Doppler echocardiagram should target children as well as adults. Increased awareness is essential to identify patients at risk, and new therapies are critically needed.

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