Elevated plasma levels of fibrinopeptide a during sickle cell anemia pain crisis–evidence for intravascular coagulation

Impaired polymorphonuclear neutrophil (PMN) functions during sickle cell anemia (SCA) may have a pathogenic role in the onset of vasoocclusive events. We used flow cytometry to study, in whole blood, the adhesion molecule expression and respiratory burst of PMNs from children with SCA. Three different clinical groups were studied: (1) patients with no history of vasoocclusive events (n = 15); (2) patients with a history of vasoocclusive events (n = 17); and (3) patients receiving hydroxyurea therapy for severe vasoocclusive events (n = 9). Unstimulated PMNs showed decreased L selectin expression and increased H2O2 production whatever the severity of the disease, reflecting PMN activation. This could contribute to endothelial activation reflected by abnormal plasma levels of soluble adhesion molecules (soluble intercellular adhesion molecule-1, sE selectin, and sL selectin). After stimulation with bacterial N-formyl peptides (N-formyl-methionyl-leucyl-phenylalanine [fMLP]), PMNs from untreated patients with a history of vasoocclusive events showed dysregulated L selectin shedding and increased H2O2 production. Furthermore, in these patients, tumor necrosis factor priming followed by fMLP stimulation induced an H2O2 production significantly higher than in the other patient groups and controls. These impairments could immobilize PMNs on the endothelium, thereby inducing reduced blood flow and fostering microvascular occlusion and vascular damage. In contrast, children treated with hydroxyurea showed near-normal basal and poststimulation H2O2 production as well as normal L selectin shedding after stimulation but no change in plasma levels of soluble adhesion molecules. To our knowledge, this is the first report showing major qualitative changes of PMN abnormalities upon hydroxyurea treatment in SCA patients. This strongly suggests that PMNs are a primary target of this drug.

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Concurrent Primary Pneumococcemia, Disseminated Intravascular Coagulation, and Sickle Cell Anemia

Southern Medical Journal ◽

10.1097/00007611-197807000-00032 ◽

1978 ◽

Vol 71 (7) ◽

pp. 858-859 ◽

Cited By ~ 5

Author(s):

CHRISTOPHER R. McDONALD ◽

EDWARD R. EICHNER

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Disseminated Intravascular Coagulation ◽

Intravascular Coagulation

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ADULT SICKLE CELL ANAEMIA PATIENTS IN BONE PAIN CRISIS HAVE ELEVATED PRO-INFLAMMATORY CYTOKINES

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2018.017 ◽

2018 ◽

Vol 10 (1) ◽

pp. e2018017 ◽

Cited By ~ 4

Author(s):

Adekunle Emmanuel Alagbe ◽

John Ayodele Olaniyi ◽

Oladapo Wale Aworanti

Keyword(s):

Steady State ◽

Sickle Cell ◽

Plasma Levels ◽

Bone Pain ◽

Sickle Cell Anaemia ◽

Cross Sectional Study ◽

Cross Sectional ◽

Tnf Α ◽

Pain Crisis ◽

State Group

Background and Objective: Inflammatory markers that influence bone pain crisis (BPC) and other complications of sickle cell anaemia (SCA) are numerous and play various roles. This study determined the plasma levels of tumour necrosis factor (TNF) - α, interleukin - 8 (IL-8), and endothelin - 1 (ET-1) in adult SCA patients during BPC and in steady state. In addition, the plasma levels of these cytokines were correlated with the severity of BPC of the patients.Methods and Materials: Sixty adult SCA patients (30 during BPC and 30 during steady state) and 30 haemoglobin A controls were enrolled for this cross-sectional study. The severity of BPC was assessed clinically, and questionnaires were filled. Plasma levels of TNF- α, IL-8 and ET-1 were quantified by ELISA, and haematological parameters were determined using a 5-part auto-analyzer. Plasma levels were correlated with the severity of bone pain crisis. Results were considered statistically significant if p<0.05.Results: Plasma TNF-α, IL-8, and ET-1 were significantly elevated in the BPC group than in the steady state group and the controls. Plasma TNF-α, IL-8 and ET-1 were markedly higher in the severe BPC groups than the steady state and control groups, There was a positive correlation between TNF-α and ET-1 in the bone pain crisis group.Conclusion: Elevated levels of plasma TNF-α, IL-8, and ET-1 further establish the chronic inflammatory state in SCA and equally affirm their significant contribution, not only to pathogenesis but also to the severity of pain in SCA. Keywords: Sickle cell anaemia, Cytokines, Bone pain crisis, Severity, Steady state.

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Epidemiology and Risk Factors for Pain In Children and Adolescent with Sickle Cell Anemia.

Blood ◽

10.1182/blood.v116.21.1651.1651 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1651-1651 ◽

Cited By ~ 1

Author(s):

Deepika Darbari ◽

Onyinye Onyekwere ◽

Mehdi Nouraie ◽

Gregory J. Kato ◽

Caterina Minniti ◽

...

Keyword(s):

Risk Factors ◽

Confidence Interval ◽

Children And Adolescents ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Odds Ratio ◽

Severe Pain ◽

History Of ◽

Pain Crisis ◽

Thalassemia Trait

Abstract Abstract 1651 Background: Pain crises are the most common symptom experienced by individuals with sickle cell anemia (SCA). Frequency of pain crises varies significantly and high rate is a risk factor for higher mortality in adults with SCA. The risk factors for pain crises in children and adolescents with SCA are not completely understood. To determine factors associated with frequent severe pain crises, we analyzed the cohort of children and adolescents with SCA who were enrolled in the prospective study “The Pulmonary Hypertension and the Hypoxic Response in SCD (PUSH)”. All children were evaluated in their steady, non-crisis state. Methods: Family-reported history of number of severe pain crises in the preceding 12 months was recorded prospectively in 365 children and adolescents with SCA. Severe pain crises were defined as painful vaso-occlusive episodes requiring evaluation in Emergency Department (ED) or in-patient hospitalization. Lifetime history of red cell transfusions, echocardiography, and laboratory studies were obtained. Clinical and laboratory characteristics of study subjects who had ≥3 severe pain crises in the preceding year were compared to subjects with < 3 severe pain crises. Results: Study subject ranged in age from 3–20 years and 175 (48%) were female. Seventy two children (20 %) had ≥3 severe pain crises in the preceding year (frequent pain crisis group); 293 (80%) children had < 3 severe pain crises (infrequent pain crisis group), including 224 (61%) subjects who had no admissions/ ED visits for pain. Associated factors for frequent pain crisis included older age (odds ratio 1.2; 95% confidence interval 1.12–1.35; P <0.001) and α-thalassemia trait (odds ratio 3.22; 95% confidence interval 1.55–6.69; P =0.002) while higher steady state serum lactate dehydrogenase (LDH) was associated with infrequent pain crisis (odds ratio 0.35; 95% confidence interval 0.13–0.98; P =0.045). In a group of patients without α-thalassemia trait, older age and low LDH were linked to frequent pain crisis. Subjects in the frequent pain crisis group had higher median hemoglobin (9.0 vs. 8.5 gm/dL; p=0.003) and higher ferritin (median 455 vs. 191 ng/mL; p=0.008). Higher ferritin in the frequent pain crisis group was mirrored by the higher percentage who reported >10 lifetime transfusions (42% vs. 22%; p=0.001). Median tricuspid regurgitation jet velocity (TRV) was higher in the frequent pain crisis group (2.41 vs. 2.31; p= 0.001) but the proportion of children with TRV>2.5 was not different (19.4% vs.11.5% in infrequent crises group; p=0.09). Hydroxyurea use was not different between the groups (51% vs. 40%; p=0.08) nor was fetal hemoglobin (10% vs. 12%; p=0.2). Conclusions: The occurrence of severe pain crisis varies among children and adolescents with SCA with a large number of children experiencing no severe painful episodes. Consistent with the Cooperative Study of Sickle Cell Disease report, the risk of severe pain crisis increases with age. Individuals with α-thalassemia trait are likely to experience more frequent pain crises possibly related to higher hemoglobin concentration and viscosity. However, even after controlling for α-thalassemia trait, children and adolescents who reported more frequent severe pain crises showed evidence of less hemolysis, consistent with a hypothetical model associating the hemolytic subphenotype of SCA with less frequent vasoocclusive pain crises. Further studies are indicated to identify the molecular mechanisms of pain in sickle cell anemia. Disclosures: No relevant conflicts of interest to declare.

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Health Care Utilization for Painful Events Is Associated with Early Mortality in a Contemporary Population of Adults with Sickle Cell Anemia

Blood ◽

10.1182/blood.v118.21.2115.2115 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2115-2115

Author(s):

Deepika S. Darbari ◽

Mariana Hildeshem ◽

Caterina Minniti ◽

Gregory J. Kato ◽

James G. Taylor

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Severe Pain ◽

Early Mortality ◽

Care Utilization ◽

Cell Disease ◽

History Of ◽

Pain Crisis ◽

Ed Visits ◽

Painful Events

Abstract Abstract 2115 Background: Painful vaso-occlusive crises are the most common symptom associated with sickle cell anemia (SCA) and show a large inter-patient variability in the frequency and severity. Historically a high rate of admissions for pain is associated with early mortality in SCA adults. Modern day management of SCA includes screening for life threatening complications such as pulmonary hypertension and disease modifying therapies such as hydroxyurea and chronic blood transfusions. It has also become clear that all acute painful events including some self reported crisis do not lead to ED visit/ hospitalization therefore use of healthcare utilization may underestimate the actual frequency of painful vaso-occlusive crises. The present study determined if ED visit/ hospitalizations for painful vaso-occlusive crises remain a marker of early mortality in the modern era. Methods: To determine the relative contribution of pain and other established risk factors for death in a contemporary adult cohort with sickle cell anemia, we analyzed data of SCA individuals who were evaluated at NIH between February 2001 and June 2007 for screening of the IRB approved protocol to study pulmonary hypertension in sickle cell disease. Self reported history of vaso-occlusive painful events requiring visit to an emergency department (ED) or in-patient hospitalization in 12 months preceding the enrollment was used to stratify study subjects into no-ED visit/ hospitalization or ED visit/hospitalization group. Characteristics between the groups were compared. Doppler echocardiography was used to estimate systolic pulmonary artery pressure through measurement of the tricuspid regurgitation velocity (TRV). Study subjects were followed prospectively and age at death was recorded. Results: One hundred and four (40%) SCA subjects reported no ED visit/ hospitalization while 160 (60%) reported at least one ED visit/ hospitalization in 12 months preceding the enrollment. Although not statistically significant, a higher proportion of study participants in the ED visit/ hospitalization group were on hydroxyurea (38 vs. 69%; P=0.4), and more likely to have received > 10 red cell transfusions (37 vs. 48%; P= 0.09). The no-ED/ hospitalization group and ED/ hospitalization groups were not different in median age (33 vs. 31; P=0.1) or fetal hemoglobin concentration (7.7 vs. 6.9%; P=0.3). Overall forty (15.1%) individuals died during the median follow-up period of 5 years. Cox proportional hazards analysis was performed to determine if severe pain crisis requiring ED visits/hospitalizations were associated with early mortality after adjusting for other known risk factors for mortality (Table 1). Risk for mortality was significantly associated with a history of severe pain crisis requiring ED visit/hospitalization in preceding year (RR 2.81, 95% CI: 1.2–6.4, P= 0.04), elevated TRV ≥ 3 m/s (RR 4.07, 95% CI: 1.3–12.8, P= 0.02) and elevated ferritin (RR 2.31, 95% CI: 1.0–5.0, P= 0.04). Conclusions: Severe painful episodes requiring health care utilization are associated with premature mortality and despite likely underestimation of actual frequency of pain, remain a marker of disease severity. Elevated TRV a marker of elevated pulmonary arterial pressure and early mortality has a cumulative effect with pain on reduced survival. Consistent with Cooperative Study of Sickle Cell Disease (CSSCD) report, higher hemoglobin (and lower LDH) was associated with reports of ED visit/ hospitalization likely related to increased viscosity. We conclude that as a group, SCA patients reporting severe pain requiring ED visits /hospitalization and elevated TRV are at the highest risk for shortened survival. Disclosures: No relevant conflicts of interest to declare.

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2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia

Blood ◽

10.1182/blood.v96.7.2379.h8002379_2379_2384 ◽

2000 ◽

Vol 96 (7) ◽

pp. 2379-2384

Author(s):

Mabel Koshy ◽

Louise Dorn ◽

Linda Bressler ◽

Robert Molokie ◽

Donald Lavelle ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Complete Blood Count ◽

Fetal Hemoglobin ◽

Therapeutic Benefit ◽

Additional Treatment ◽

Acute Chest Syndrome ◽

F Cells ◽

Pain Crisis ◽

Globin Synthesis

Augmentation of the fetal hemoglobin (HbF) levels is of therapeutic benefit in patients with sickle cell anemia. Hydroxyurea (HU), by increasing HbF, lowers rates of pain crisis, episodes of acute chest syndrome, and requirements for blood transfusions. For patients with no HbF elevation after HU treatment, augmentation of HbF levels by 5-aza-2′-deoxycytidine (5-aza-CdR, decitabine) could serve as an alternate mode of treatment. Eight adult patients participated in a dose-escalating phase I/II study with 5-aza-CdR at doses ranging from 0.15 to 0.30 mg/kg given 5 days a week for 2 weeks. HbF, F cell, F/F cell, γ-globin synthesis ratio, complete blood count, and chemistry were measured. The average γ-globin synthesis relative to non-α-globin synthesis prior to therapy was 3.19% ± 1.43% and increased to 13.66% ± 4.35% after treatment. HbF increased from 3.55% ± 2.47% to 13.45% ± 3.69%. F cells increased from 21% ± 14.8% to 55% ± 13.5% and HbF/F cell increased from 17% to 24%. In the HU nonresponders HbF levels increased from 2.28% ± 1.61% to 2.6% ± 2.15% on HU, whereas on 5-aza-CdR HbF increased to 12.70% ± 1.81%. Total hemoglobin increased by 1 g/dL in 6 of 8 patients with only minor reversible toxicities, and all patients tolerated the drug. Maximum HbF was attained within 4 weeks of treatment and persisted for 2 weeks before falling below 90% of the maximum. Therefore 5-aza-CdR could be effective in increasing HbF in patients with sickle cell anemia who failed to increase HbF with HU. Demonstration of sustained F levels with additional treatment cycles without toxicity is currently being performed.

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Elevated plasma D-dimer levels in children with sickle cell anemia in steady state attending state specialist hospital Maiduguri, Borno State, Nigeria

Nigerian Journal of Medicine ◽

10.4103/njm.njm_118_20 ◽

2020 ◽

Vol 29 (4) ◽

pp. 634

Author(s):

SalisuAhmed Ibrahim ◽

IsyakuGwarzo Mukhtar ◽

AbdulhamidBuhari Mohammed ◽

KabiruAhmed Mohammed ◽

Tanko Yusuf

Keyword(s):

Steady State ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Elevated Plasma ◽

D Dimer

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Altered Functional Properties of Eosinophils In Sickle Cell Anemia and Effects of Hydroxyurea Therapy

Blood ◽

10.1182/blood.v116.21.2656.2656 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2656-2656

Author(s):

Flavia Rubia Pallis ◽

Nicola Conran ◽

Kleber Yotsumoto Fertrin ◽

Sara T. Olalla-Saad ◽

Fernando Ferreira Costa ◽

...

Keyword(s):

Functional Properties ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Peripheral Blood ◽

Plasma Levels ◽

Transgenic Animal ◽

Healthy Controls ◽

Eosinophil Peroxidase

Abstract Abstract 2656 The pathophysiology of sickle cell anemia (SCA) is now recognized to include a chronic inflammatory condition that contributes to the recurrent episodes of vaso-occlusion that characterize this disease. The vaso-occlusive process is a multi-step process that involves different cell types, such as red blood cells, reticulocytes, activated endothelial cells, platelets and leukocytes. In vivo transgenic animal studies indicated that the neutrophil appears to be the most important leukocyte in vaso-occlusion in previous transgenic animal in vivo studies; however, eosinophils (EOs) may also participate in this phenomenon in humans. EOs are found in significantly elevated numbers in sickle cell disease individuals and, in static adhesion assays, demonstrate augmented adhesive properties suggesting an activated state of these cells. However, the role of EOs in the pathophysiology of SCD and the effect of hydroxyurea (HU) therapy on the functional properties of these cells are not well understood. The aim of this study was to evaluate EO adhesion, migration and degranulation in SCA patients and the effect of HU therapy on these cells. EOs were purified from the peripheral blood of healthy controls (CON) (n≥10), steady-state SCA patients (n≥12) and SCA patients on HU therapy (n≥15), using Percoll gradient separation, followed by immunomagnetic sorting. EO adhesion was determined by static adhesion assays and degranulation was evaluated by measurement of eosinophil peroxidase activity. Migration of EOs was determined in 96-multiwell chemotaxis chamber assays. Plasma levels of Eotaxin-1, 2 and RANTES, important eosinophil attracting chemokines, were determined by ELISA. The absolute number of EOs in the peripheral blood of SCD patients not treated with HU was significantly higher compared to control individuals (0.504±0.09 vs 0.188±0.04; P=0.01, respectively). SCA patients taking HU presented significantly lower numbers of EOs (0.200±0.05, P = 0.01). Basal adhesion of EOs from SCA patients was significantly higher than in healthy controls (22.8±2.6 vs 13.7±1.7%, respectively, P = 0.004). Furthermore, the EOs from SCA patients on HU therapy demonstrated a significantly lower adhesion to fibronectin (12.5±2.0%, P=0.002). Spontaneous EO chemotaxis was significantly increased in SCA patients, compared to healthy controls (12.9±1.56 vs 6.97±0.8 × 105/ml, respectively, P=0.009). Interestingly, the chemotatic response of EOs isolated from SCA patients taking HU was also higher than that of control EOs (12.1± 1.9 × 105/ml). EO chemotaxis in response to RANTES, Eotaxin and IL5 was significantly augmented in all groups compared to spontaneous chemotaxis (RANTES: CON: 15.3± 2.3; SCA: 19.9±3.0; SCAHU: 25.0±4.7; Eotaxin: CON: 18.7±3.0; SCA: 24.5±4.2; SCAHU: 24.0±5.2; IL5: CON: 13.4±2.4; SCA: 18.8±3.0, SCAHU: 16.6±4.5, P<0.05). Baseline eosinophil peroxidase release was higher in SCA EOs, compared to CON EOs (0.4±0.04 vs 0.2±0.02, respectively, P=0.001), but patients on HU presented a lower EOs degranulation than SCA not on HU (0.19±0.03, P=0.003). Plasma levels of Eotaxin-1 and RANTES were significantly higher in SCA individuals, compared to CON individuals (124±7; 1057±125 vs 78±7; 540±50.2 pg/ml, P=0.0002; P=0.0009, respectively). HU therapy was not associated with any change in Eotaxin-1 and RANTES plasma levels (117.9±9.7; 1175±126.2 pg/ml, respectively). Eotaxin-2 plasma levels did not vary among groups (485±80.8, 450±34, 398±47.8 pg/ml for CON, SCA and SCAHU, respectively). EOs of patients with SCA demonstrate a higher capacity for spontaneous migration, stimulated migration and degranulation. Therapy with HU is associated with reduced adhesion and degranulation of EOs in these patients, but had no effect on the chemotactic ability of these cells or chemokine levels. The presence of relative eosinophilia along with altered functional properties in SCA patients warrants further investigation of the role of EOs in the vaso-occlusive process. In particular, complications associated with allergic reactions, such as acute thoracic syndrome and asthma in SCA children, in which EO adhesion and degranulation may be more important, should be studied. The characteristics of the effect of HU on EO also suggest that SCA events in which EO chemotaxis plays a role are likely to respond poorly to HU therapy, and should lead to the development of alternative therapeutic strategies. 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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