Effect of hydroxyurea therapy on intravascular hemolysis and endothelial dysfunction markers in sickle cell anemia patients

2021 ◽  
Vol 100 (11) ◽  
pp. 2669-2676
Author(s):  
Francine Chenou ◽  
Bidossessi Wilfried Hounkpe ◽  
Igor de Farias Domingos ◽  
Wouitchékpo Vincent Tonassé ◽  
Thais Helena Chaves Batista ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Intravascular Hemolysis ◽  
Hydroxyurea Therapy

scholarly journals Evaluation of Markers of Intravascular Hemolysis and Endothelial Dysfunction in Sickle Cell Anemia Patients with and without Hydroxyurea Therapy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4826-4826
Author(s):  
Francine Chenou ◽  
Bidossessi Wilfried Hounkpe ◽  
Igor de Farias Domingos ◽  
Thais Helena Chaves Batista ◽  
Rodrigo Marcionilo Santana ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Plasma Levels ◽  
Activity Levels ◽  
Adamts13 Activity ◽  
Intravascular Hemolysis ◽  
Endothelin 1 ◽  
Thrombospondin 1 ◽  
Hydroxyurea Therapy

Background: Sickle cell anemia (SCA) is characterized by chronic hemolysis and endothelial dysfunction (ED). Plasma hemoglobin (pHb) and its heme component released from intravascular hemolysis (IH) are among the most important factors contributing to ED. Unfortunately, the importance of IH to the development of an ED and the effects of hydroxyurea therapy on IH and ED in SCA remains unclear. Aims: We evaluated plasma levels of IH and ED markers among Brazilian SCA patients not receiving hydroxyurea therapy (HbSS), and compared with those of hydroxyurea-treated SCA patients (HbSS_HU) and healthy controls (HbAA). Methods: A cross-sectional study of 60 SCA consenting patients (32 HbSS and 28 HbSS_HU; 19-42 years) in steady state, who are being followed up at the Blood Center, Pernambuco (HEMOPE) and 32 HbAA controls. The IH markers were serum Lactate Dehydrogenase [LDH] and total heme measured by enzymatic colorimetric tests, and pHb measured by enzyme-linked immunosorbent assay (ELISA). The ED markers were plasma von Willebrand factor (vWF:Ag) and vWF ristocetin cofactor activity (vWF:Rco) levels measured by the latex enhanced immunoassay. The other ED markers were the antigen of vWF-cleaving protease (ADAMTS13:Ag), thrombospondin-1 and endothelin-1 levels measured by ELISA, and ADAMTS13 Activity (ADAMTS13:Act) measured by FRETS-VWF73 method. The study was approved by the Ethics Committee of the State University of Campinas and HEMOPE under protocol No: 1.863.428. Data were analyzed using GraphPad Prism 6. Results: The pHb and LDH were significantly increased in HbSS than HbSS_HU patients (Figures 1A and 1B). Plasma levels of vWF:Ag, vWF:Rco, serum levels of total heme, thrombospondin-1 and endothelin-1 were significantly increased in HbSS and HbSS_HU patients compared to HbAA controls (Figures 1C and 2A, 2B, 2E, 2F), while serum level of thrombospondin-1 level was elevated in HbSS than HbSS_HU patients (Figure 2E). Similarly, ADAMTS13:Ag levels and ADAMTS13 activity were significantly lower in HbSS and HbSS_HU patients than HbAA controls, while ADAMTS13 activity levels were significantly elevated in HbSS_HU patients compared to HbSS patients (Figure 2D). In HbSS_HU patients, the ADAMTS13:Act was negatively correlated with heme and LDH [r = -0.47, p = 0.013; and r = -0.44, p = 0.023 respectively]. In additional, heme was positively correlated with vWF:Ag and LDH [(r = 0.47, p = 0.017) and (r = 0.56, p = 0.003) respectively]. In HbSS patients, LDH and pHb were positively correlated (r = 0.44, p = 0.014). Conclusions: Hydroxyurea therapy was associated with a reduced levels of LDH, pHb and thrombospondin-1 levels, and increased levels of ADAMTS13 activity in SCA patients. Increased ADAMTS13 activity levels may be attributed to reduction of pHb and thrombospondin-1 levels because previous invitro studies have shown that thrombospondin-1 or pHb are bound to vWF. Thus, vWF is restrained from ADAMTS13 activity and cleavage, and hyperreactive vWF might accumulate as a consequence of inhibition of ADAMTS13 activity. Increased thrombospondin-1, pHb and hyperreactive vWF levels are proposed to participate in sickle cell adhesion and promote thrombotic complications. Therefore, our results demonstrate an additional clinical benefit for the use of hydroxyurea in these patients. Disclosures No relevant conflicts of interest to declare.

Adhesion Molecules Interaction with Markers of Lipid Metabolism, Hemolysis, Endothelial Dysfunction and Medical Histories Among Steady-State Sickle Cell Anemia Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2553-2553
Author(s):  
Bruno Antônio Veloso Cerqueira ◽  
Wendell Vilas Boas ◽  
Jorge Clarêncio ◽  
Daniela Andrade ◽  
Angela MD Zanette ◽  
...  
Keyword(s):  
Steady State ◽  
Lipid Metabolism ◽  
Endothelial Dysfunction ◽  
Adhesion Molecules ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Density Lipoprotein ◽  
Control Group ◽  
Intravascular Hemolysis ◽  
Soluble Adhesion Molecules

Abstract Abstract 2553 Poster Board II-530 Introduction: Sickle cell anemia (SCA) results from the homozygous form of hemoglobin S (Hb S). Vaso-occlusive pain episodes underlie most of the acute and chronic clinical complications of disease and it is correlated with activation of red blood cells, leukocytes, platelets and endothelial cells that express several adhesion molecules and ligand. The aim of the present study was investigates the levels of soluble ICAM-1 and VCAM-1 adhesion molecules associating with biochemical markers, expression of neutrophils adhesion molecule and medical history of sickle cell anemia patients. Patients and Methods. We studied 53 SCA patients in steady-state (25 men, 28 women, mean age: 21.17 ± 14.12 years) from northeast Brazil diagnosed with SCA in attendance of the outpatients clinic of the Foundation of Hematology and Hemotherapy of Bahia (HEMOBA). The control group was compound by 22 healthy Brazilian, with AA hemoglobin pattern matched by age, years and ethnic origin. Biochemical analyses were measured by colorimetric methods, surface adhesion molecules expressions by flow cytometry, soluble adhesion molecules by ELISA and the complete medical history was obtained by patients' record. Results: Our results show a higher serum levels of VCAM-1(s) in patients than control group (p=0.006). Moreover, in this study we found low expression of neutrophils CD18 in patients with high levels of VCAM-1(s). Total cholesterol and low density lipoprotein (LDL-C) were significantly negative associated with VCAM-1(s) (r=−0.312, p=0.023; r=−0.282, p=0.041 respectively) and the high density lipoprotein (HDL-C) was significantly negative associated with ICAM-1(s) (r=−0.348; p=0.011). Intravascular hemolysis markers such as aspartate transferase (AST) and lactate dehydrogenase (LDH) were significantly positive associated with VCAM-1(s) (r=0.459, p=0.001 and r=0.281, p=0.041, respectively). Sickle cell anemia individuals that developed necrosis and leg ulcers exhibited high serum level of VCAM-1(s) (p=0.017 and p=0.021 respectively) and patients that presented priapism had low levels of ICAM-1(s) (p=0.046). Conclusion: The presence of high levels of ICAM-1(s) and VCAM-1(s) adhesion molecules and its association with markers of intravascular hemolysis, endothelial dysfunction and lipid metabolism may indicate a differentiated mechanism of these molecules in sickle cell anemia pathogenesis, with a complex involvement of cellular, endothelial and proinflammatory interactions. The measurement of soluble adhesion molecules is of easy determination and may be an important biomarker of prognosis among sickle cell anemia patients. Additional studies should be carried out in order to explore the contribution of ICAM-1 (s) and VCAM-1 (s) in other signal pathways. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Methemoglobin measure in adult patients with sickle-cell anemia: influence of hydroxyurea therapy

2014 ◽  
Vol 50 (3) ◽  
Author(s):  
Marilia Rocha Laurentino ◽  
Teresa Maria de Jesus Ponte Carvalho ◽  
Talyta Ellen de Jesus dos Santos ◽  
Maritza Cavalcante Barbosa ◽  
Thayna Nogueira dos Santos ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Adult Patients ◽  
Hydroxyurea Therapy

Clinical outcome and laboratory parameters in sickle cell anemia patients of pediatric age group post hydroxyurea therapy (Preprint)

2021 ◽  
Author(s):  
Nihar Gupta
Keyword(s):  
Clinical Outcome ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Age Group ◽  
Pediatric Age ◽  
Cell Disease ◽  
Laboratory Parameters ◽  
Pediatric Age Group ◽  
Group Post ◽  
Hydroxyurea Therapy

BACKGROUND Sickle cell anemia or SCA is a homozygous condition of Sickle cell disease or SCD, in which patients presents with a chronic and progressive condition which is characterised by hemolytic anemia, recurrent vaso-occlusive events, along with complications like organ dysfunction. Hydroxyurea has emerged as a break-through in treatment of Sickle cell anemia. Currently it is the only FDA approved drug which has shown disease modifying results. OBJECTIVE To determine the clinical outcome and laboratory parameters in SCA patients of pediatric age group post-hydroxyurea therapy. METHODS A total of 30 patients who were diagnosed as Sickle cell anemia(SCA) patients in Sickle cell anemia OPD of Pediatric department were included in the study. RESULTS Hydroxyurea therapy is expected to increase HbF% levels and improve the clinical outcome and laboratory parameters in sickle cell anemia patients of pediatric age group. CONCLUSIONS Hydroxyurea use increases HbF%, decrease painful crises, blood transfusion, and days of hospitalisation.

scholarly journals Optimizing hydroxyurea therapy for sickle cell anemia

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 436-443 ◽  
Author(s):  
Russell E. Ware
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Fetal Hemoglobin ◽  
Maximum Tolerated Dose ◽  
Sub Saharan Africa ◽  
Future Research ◽  
Published Evidence ◽  
Treatment Indications ◽  
Hydroxyurea Treatment ◽  
Hydroxyurea Therapy

Abstract Hydroxyurea has proven efficacy in numerous clinical trials as a disease-modifying treatment for patients with sickle cell anemia (SCA) but is currently under-used in clinical practice. To improve the effectiveness of hydroxyurea therapy, efforts should be directed toward broadening the clinical treatment indications, optimizing the daily dosage, and emphasizing the benefits of early and extended treatment. Here, various issues related to hydroxyurea treatment are discussed, focusing on both published evidence and clinical experience. Specific guidance is provided regarding important but potentially unfamiliar aspects of hydroxyurea treatment for SCA, such as escalating to maximum tolerated dose, treating in the setting of cerebrovascular disease, switching from chronic transfusions to hydroxyurea, and using serial phlebotomy to alleviate iron overload. Future research directions to optimize hydroxyurea therapy are also discussed, including personalized dosing based on pharmacokinetic modeling, prediction of fetal hemoglobin responses based on pharmacogenomics, and the risks and benefits of hydroxyurea for non-SCA genotypes and during pregnancy/lactation. Another critical initiative is the introduction of hydroxyurea safely and effectively into global regions that have a high disease burden of SCA but limited resources, such as sub-Saharan Africa, the Caribbean, and India. Final considerations emphasize the long-term goal of optimizing hydroxyurea therapy, which is to help treatment become accepted as standard of care for all patients with SCA.

Pulmonary Hypertension as a Risk Factor for Death in Patients with Sickle Cell Anemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4819-4819
Author(s):  
Rodolfo D Cancado ◽  
Maria Cristina A Olivato ◽  
Newton Nunes Lima Filho ◽  
Orlando Campos ◽  
Carlos Chiattone
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Pulmonary Artery ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Systolic Pressure ◽  
Pulmonary Artery Systolic Pressure ◽  
Cell Disease ◽  
Risk Of Death ◽  
Hydroxyurea Therapy

Abstract Pulmonary hypertension develops in most forms of hereditary and chronic hemolytic anemia, including sickle cell disease, thalassemia, hereditary spherocytosis, and paroxysmal nocturnal hemoglobinuria, suggesting that there is a clinical syndrome of hemolysis-associated pulmonary hypertension. Retrospective studies from tertiary care referral centers suggest a prevalence of pulmonary hypertension in adults with sickle cell disease ranging from 20 to 40%. Despite the fact the elevations in pulmonary artery pressures are slight, morbidity and mortality are high. In adult sickle cell anemia patients, pulmonary hypertension is emerging as a major risk factor for death. We performed Doppler echocardiographic assessments of pulmonary-artery systolic pressure in 80 consecutive patients (20 men and 60 women; mean [±SD] age, 30 ± 10.8 years) between 1/20/2006 and 1/20/2008. The genotype on the basis of hematologic and hemoglobin characteristics was hemoglobin SS in all patients. Pulmonary hypertension was prospectively defined as a tricuspid regurgitant Jet velocity (TFJV) of at least 2.5 m per second. Patients were followed for a mean of 18 months (6–24 months), and data were censored at the time of death or loss to follow-up. Doppler-defined pulmonary hypertension occurred in 37.5 percent of patients (30/80). Multiple logistic-regression analysis, with the use of the dichotomous variable of a tricuspid regurgitant jet velocity of less than 2.5 m per second or 2.5 m per second or more, identified age, female sex, deferasirox therapy, left ventricular mass index, pulmonary artery systolic pressure, reticulocytes, white-cell count, platelet count, lactate dehydrogenase (a marker of hemolysis), blood urea nitrogen, creatinine, uric acid and self-reported history of cardiovascular complication, billiary stones, retinopathy and acute chest syndrome, as significant independent correlates of pulmonary hypertension. The hemoglobin level, fetal hemoglobin level, hydroxyurea therapy and serum ferritin level were unrelated to pulmonary hypertension. Hazard rate for death according to the TFJV of at least 2.5 m per second, as compared with a velocity of less than 2.5 m per second, was associated with an increased risk of death (0.00 versus 2.54; P=0.998). Mortality rate in 24 months was 6.7% (2/30) for patients with TRJ velocity ≥ 2.5 m/sec versus 0.0% (0/50) for patients without pulmonary hypertension. Pulmonary hypertension, diagnosed by Doppler echocardiography, is common in adults with sickle cell disease. It appears to be a complication of chronic hemolysis, is resistant to hydroxyurea therapy, and confers a high risk of death. Large trials evaluating the effects of treatment for pulmonary hypertension in the sickle cell anemia population are indicated.

Serum Transferrin: An Independent Predictor of Mortality in Sickle Cell Anemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2126-2126
Author(s):  
Zahra Pakbaz ◽  
Mariana E Hildesheim ◽  
Shoaib Alam ◽  
Darlene Allen ◽  
Caterina Minniti ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Sickle Cell ◽  
Serum Ferritin ◽  
Sickle Cell Anemia ◽  
Conflicts Of Interest ◽  
Independent Predictor ◽  
Stable Condition ◽  
Acute Chest Syndrome ◽  
Serum Transferrin ◽  
Significant Difference

Abstract Abstract 2126 Introduction: Serum ferritin (SF), the most convenient marker of iron burden in sickle cell anemia (SCA), is potentially confounded by effects of inflammation in SCA. Serum transferrin (STF) has been described as one of the independent predictors of elevated tricuspid regurgitant velocity (TRV) in SCA. Therefore in this report we investigate the potential predictive role of STF in morbidity and mortality of individuals with SCA. Methods: Patients with sickle cell disease documented by high-pressure liquid chromatography were eligible for the study. Four hundred and sixty SCA patients were recruited in this study from the community through multimedia advertisements, community outreach, and regional clinics. All evaluated patients were screened by history taking, physical examination, laboratory studies, and transthoracic echocardiography. All patients provided written informed consent. The advertisements and protocol were approved by the institutional review boards of the National Heart, Lung, and Blood Institute and Howard University. Only outpatients in stable condition were included; patients who had had a vaso-occlusive crisis within the previous two weeks or an episode of acute chest syndrome within the previous four weeks were excluded. Results: Two hundred and sixty two participants with HbSS were included in the data analysis. Forty-seven percent were male. Median age was 32 years old. Median TRV in this cohort was 2.4 m/s. Forty nine percent of participants had TRV≥2.5 m/s and 19% had TRV≥3 m/s. Patients with lower STF (<164 mg/dl) were older (p=0.01), had more blood transfusions in the past (p<0.0001) and did not have more complications of sickle disease (priapism, acute chest syndrome, leg ulcers or emergency room visits, all p>0.05), but all-cause death rate was higher (22% vs. 6%, p=0.0001). Hemoglobin, CRP, alkaline phosphatase, uric acid, placenta growth factor (<0.001), SF and iron saturation were found to be higher and kidney function was worse. Patients with lower STF level were also more likely to have TRV≥3.0 m/s (32% vs. 13%, p<0. 001) but there was no significant difference in BNP and ejection fraction. Patients with lower STF had endothelial dysfunction, as indicated by a blunted forearm blood flow (FBF) response to infusion of acetylcholine into the brachial artery (p<0.01). Among age, gender, BNP, TRV,GFR,WBC, STF, systolic blood pressure and fetal hemoglobin, the Cox proportional analysis of mortality found TRV, GFR and STF the independent significant predictors of mortality in this cohort. Kaplan-Meier survival curve showed that patients with transferrin <164 mg/dl had significantly lower survival (p<0.001). Conclusion: In this cohort of adults with sickle cells anemia, STF is found to be an independent predictor of endothelial dysfunction, high TRV and mortality. It may be a more sensitive predictor than serum ferritin. We propose that iron overload may induce a state of endothelial dysfunction that is a risk factor for clinical vasculopathy and death. Disclosures: No relevant conflicts of interest to declare.

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