scholarly journals Thromboinflammatory mechanisms in sickle cell disease - challenging the hemostatic balance

Haematologica ◽  
2020 ◽  
Vol 105 (10) ◽  
pp. 2380-2390 ◽  
Author(s):  
Nicola Conran ◽  
Erich V. De Paula
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Ischemia Reperfusion ◽  
Organ Damage ◽  
Acute Chest Syndrome ◽  
Cellular Interactions ◽  
Innate Immune Responses ◽  
Cell Disease ◽  
Inflammatory Processes ◽  
Abnormal Hemoglobin

Sickle cell disease (SCD) is an inherited hemoglobinopathy that is caused by the presence of abnormal hemoglobin S (HbS) in red blood cells, leading to alterations in red cell properties and shape, as the result of HbS dexoygenation and subsequent polymerization. SCD pathophysiology is characterized by chronic inflammatory processes, triggered by hemolytic and vaso-occlusive events, which lead to the varied complications, organ damage and elevated mortality seen in individuals with the disease. In association with activation of the endothelium and leukocytes, hemostatic alterations and thrombotic events are well-documented in SCD. Here we discuss the role for inflammatory pathways in modulating coagulation and inducing platelet activation in SCD, due to tissue factor activation, adhesion molecule expression, inflammatory mediator production and the induction of innate immune responses, amongst other mechanisms. Thromboinflammatory pathways may play a significant role in some of the major complications of SCD, such as stroke, venous thromboembolism and possibly acute chest syndrome, besides exacerbating the chronic inflammation and cellular interactions that trigger vaso-occlusion, ischemia-reperfusion processes, and eventually organ damage.

scholarly journals New insights into the pathophysiology and development of novel therapies for sickle cell disease

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 493-506 ◽  
Author(s):  
Scott Moerdler ◽  
Deepa Manwani
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cell Disease ◽  
Oxidant Damage ◽  
Emerging Treatments ◽  
Heterotypic Interactions ◽  
Abnormal Hemoglobin ◽  
Selection Of

Abstract Although the seminal event in sickle cell disease is the polymerization of abnormal hemoglobin, the downstream pathophysiology of vasoocclusion results from heterotypic interactions between the altered, adhesive sickle cell red blood cells, neutrophils, endothelium, and platelets. Ischemia reperfusion injury, hemolysis, and oxidant damage all contribute to heightened inflammation and activation of the hemostatic system. These various pathways are the focus of emerging treatments with potential to ameliorate disease manifestations. This review summarizes the considerable progress in development of these agents despite challenges in selection of study end points and complex pathophysiology.

scholarly journals Beyond the Definitions of the Phenotypic Complications of Sickle Cell Disease: An Update on Management

2012 ◽  
Vol 2012 ◽  
pp. 1-55 ◽  
Author(s):  
Samir K. Ballas ◽  
Muge R. Kesen ◽  
Morton F. Goldberg ◽  
Gerard A. Lutty ◽  
Carlton Dampier ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Point Mutation ◽  
Sickle Cell ◽  
Globin Gene ◽  
Single Point ◽  
Acute Chest Syndrome ◽  
Single Point Mutation ◽  
Cell Disease ◽  
Exon 1 ◽  
Abnormal Hemoglobin

The sickle hemoglobin is an abnormal hemoglobin due to point mutation (GAG → GTG) in exon 1 of theβglobin gene resulting in the substitution of glutamic acid by valine at position 6 of theβglobin polypeptide chain. Although the molecular lesion is a single-point mutation, the sickle gene is pleiotropic in nature causing multiple phenotypic expressions that constitute the various complications of sickle cell disease in general and sickle cell anemia in particular. The disease itself is chronic in nature but many of its complications are acute such as the recurrent acute painful crises (its hallmark), acute chest syndrome, and priapism. These complications vary considerably among patients, in the same patient with time, among countries and with age and sex. To date, there is no well-established consensus among providers on the management of the complications of sickle cell disease due in part to lack of evidence and in part to differences in the experience of providers. It is the aim of this paper to review available current approaches to manage the major complications of sickle cell disease. We hope that this will establish another preliminary forum among providers that may eventually lead the way to better outcomes.

scholarly journals Iron Overload in Sickle Cell Disease

2010 ◽  
Vol 2010 ◽  
pp. 1-9 ◽  
Author(s):  
Radha Raghupathy ◽  
Deepa Manwani ◽  
Jane A. Little
Keyword(s):  
Sickle Cell Disease ◽  
Iron Overload ◽  
Sickle Cell ◽  
Organ Damage ◽  
Endothelial Damage ◽  
Red Cells ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Treatment And Prevention ◽  
Oxygen Carrying Capacity

In sickle cell disease transfusions improve blood flow by reducing the proportion of red cells capable of forming sickle hemoglobin polymer. This limits hemolysis and the endothelial damage that result from high proportions of sickle polymer-containing red cells. Additionally, transfusions are used to increase blood oxygen carrying capacity in sickle cell patients with severe chronic anemia or with severe anemic episodes. Transfusion is well-defined as prophylaxis (stroke) and as therapy (acute chest syndrome and stroke) for major complications of sickle cell disease and has been instituted, based on less conclusive data, for a range of additional complications, such as priapism, vaso-occlusive crises, leg ulcers, pulmonary hypertension, and during complicated pregnancies. The major and unavoidable complication of transfusions in sickle cell disease is iron overload. This paper provides an overview of normal iron metabolism, iron overload in transfused patients with sickle cell disease, patterns of end organ damage, diagnosis, treatment, and prevention of iron overload.

scholarly journals A cautionary note regarding hydroxyurea in sickle cell disease

Blood ◽  
1994 ◽  
Vol 83 (4) ◽  
pp. 1124-1128
Author(s):  
EP Vichinsky ◽  
BH Lubin
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Clinical Course ◽  
Fetal Hemoglobin ◽  
Organ Damage ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Transfusion Therapy ◽  
History Of ◽  
Hbf Level

Hydroxyurea can increase fetal hemoglobin (HbF) and improve the clinical course of sickle cell disease (SCD) patients. However, several issues of hydroxyurea therapy remain unresolved, including differences in patients' drug clearance, predictability of drug response, reversibility of sickle cell disease-related organ damage by hydroxyurea, and the efficacy of elevated HbF. We treated two patients with hydroxyurea for periods of 1 to 4 years, monitoring clinical course and laboratory parameters at regular intervals. The first patient (patient A) had a history of chronic pain and extensive hospitalizations. The second patient (patient B) had a history of stroke and refused to continue with chronic transfusion therapy and chelation. Both patients showed a fivefold to tenfold increase in HbF (5% to 25%, 3% to 31%). However, patient A developed an acute chest syndrome, despite an HbF level of 20%. After red blood cell transfusions for hypoxia, the HbF level decreased to 5%. When hydroxyurea dosage was increased, pancytopenia developed and was not resolved until 2 months after hydroxyurea was discontinued; Patient B developed a cerebral hemorrhage on hydroxyurea; he died shortly thereafter. His HbF level was 21% before death. We noted an increase in HbF and a general improvement in the two patients. However, both experienced major SCD-related complications despite HbF levels over 20%. Our findings also suggest that the progressive vascular changes associated with SCD are unlikely to be dramatically affected by increased HbF levels. Because neither the efficacy nor the toxicity of hydroxyurea have been thoroughly investigated, physicians should be cautious in prescribing hydroxyurea for patients with SCD before completion of the National Clinical Trial.

Sickle Cell Disease

2018 ◽  
Author(s):  
Ann Ng ◽  
Erin S. Williams
Keyword(s):  
African American ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Sickle Cell Trait ◽  
Organ Damage ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Systemic Involvement ◽  
History Of

Sickle cell anemia (sickle cell disease) is a common hemoglobinopathy with anywhere from 90,000 to 100,000 Americans affected. This chronic condition has a predominance in populations of African descent, occurring in approximately 1 out of 365 African American births, compared to 1 out of 16,300 Hispanic births. The sickle cell trait can be detected in 1 of 13 African American births. One of the most common complications associated with sickle cell anemia, vaso-occlusive crises by sickled cells, results in severe pain. Other issues associated with this condition include acute chest syndrome, lung infections, end organ damage, and stroke. With improvements in the management and prevention of pain crises, infection, and other systemic involvement, these patients are living longer, thus increasing the potential for surgical needs. Whether it is for routine surgeries or surgeries that are due to the natural history of the disease; the pediatric anesthesiologist must be knowledgeable of the management of these patients in order to prevent morbidity and mortality.

Keap1-Nrf2 System: Potential Role in Prevention of Sickle Cell Disease Organs Damages and Inflammation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 411-411 ◽  
Author(s):  
Nadine Keleku-Lukwete ◽  
Mikiko Suzuki ◽  
Akihito Otsuki ◽  
Kouhei Tsuchida ◽  
Saori Katayama ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Ischemia Reperfusion ◽  
Organ Damage ◽  
The Other ◽  
Cell Disease ◽  
Indirect Bilirubin ◽  
Sickle Cells ◽  
Nrf2 Activation ◽  
Free Heme

Abstract Chronic hemolysis in sickle cell disease (SCD) gives rise to intermittent vessel occlusion. Recurrent ischemia-reperfusion generates high levels of reactive oxygen species (ROS) that leads to cell damage. On the other hand, lysed red blood cells (RBC) released free heme into blood stream, which contributes to generation of oxidant microenvironment. ROS burden generated by heme and ischemia-reperfusion injury contributes to endothelial cell activation that promotes inflammatory response with activation of inflammatory mediators. Sickle cell patients bearing high white blood cell (WBC) count develop severe complications of the disease. Nrf2 is a transcription factor that mediates adaptation to oxidative stress and cell defense. Under homeostatic conditions, Nrf2 is trapped by Keap1 and degraded by proteasome pathway. Upon exposure to stress stimuli, such as ROS and electrophiles, Nrf2 is stabilized and activates transcription of cytoprotective and antioxidants genes. Therefore, we hypothesized that Nrf2 activation might be important for tissue protection in SCD. To evaluate the therapeutic effect of Nrf2 activation on SCD, we used a SCD knock-in mouse model bearing human mutated globin loci. Since Keap1 negatively regulated Nrf2 in normal conditions, we crossed the SCD model mice with Keap1 hypomorphic knockdown (Keap1F/-) mice to generate compound mutant (SCD::Keap1F/-) mice, in which Nrf2 was constitutively activated. Histological analysis of the liver and lung revealed that congestive reaction and necrotic area observed in the SCD mice were significantly reduced in the SCD::Keap1F/- mice. Moreover, liver damage marker alanine transferase (ALT) were also decreased in SCD::Keap1F/- mice compared with SCD mice. We further examined inflammation status using human IL6 reporter mouse system and found that inflammation, which was mainly observed in lung of SCD mice, was markedly improved in the SCD::Keap1F/- mice. Expression levels of inflammatory cytokines IL6 and IL1β in the lung as well as adhesion molecules VCAM and P-selectin in the aorta of SCD::Keap1F/- mice were lower than those of the SCD mice. These results indicate that Nrf2 activation improves organ damage and inflammation in the SCD mice. On the other hand, hemolysis of sickle cells and compensatory stress erythropoiesis did not change substantially between the SCD and the SCD::Keap1F/- mice. These results indicate that Nrf2 activation improves organ damage and inflammation independently from improvement of hemolysis. Previous reports show that free heme released from sickle cells gives rise to ROS-mediate pathological process as inflammation and organ damage in SCD. We therefore measured plasma free heme and downstream product indirect bilirubin in the SCD::Keap1F/- mice, and found that both heme and indirect bilirubin was decreased in the SCD::Keap1F/- mice. These results demonstrate that Nrf2 activation improves SCD symptoms at least in part by elimination of free heme. To determine whether chemical compounds that serve as Nrf2 inducers have a protective potential of SCD mice organs, we treated 6-weeks aged mice with an Nrf2 inducer CDDO-Im (20 μmol/kg) 3 times per week for 3 weeks. CDDO-Im administration progressively reduced WBC numbers in the SCD::Keap1F/- mice. Also we observed decrease in the expression level of IL6 and IL1β in the lung and necrotic area in the liver in CDDO-Im-treated SCD::Keap1F/- mice. These results indicate that administration of a chemical Nrf2 inducer relieves inflammation and organ damage in the SCD mice. Collectively, these data provide the evidence that Nrf2 activation improves ROS-mediated organ damages and inflammation. Associated in the therapy of SCD, Nrf2 inducers could be of benefit to SCD patients. Disclosures No relevant conflicts of interest to declare.

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

Blood ◽  
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.

Systematic Evaluation Of Chronic Organ Damage In Adult Sickle Cell Patients. A Seven-Year Follow-Up Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4683-4683
Author(s):  
Charlotte F.J. van Tuijn ◽  
Marein Schimmel ◽  
Eduard J. van Beers ◽  
Bart J. Biemond
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Outpatient Clinic ◽  
Organ Damage ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Avascular Osteonecrosis ◽  
Tertiary Teaching

Introduction The occurrence of organ damage in sickle cell disease (SCD) is a crucial determinant for both medical treatment and prognosis. In a previous study, we systematically analyzed the prevalence of SCD related organ damage and complications in adult sickle cell patients in a tertiary teaching hospital in the Netherlands. We now describe a seven-year follow-up of this patient cohort, to provide an insight into the course of the various forms of organ damage and SCD related complications. Methods At baseline in 2006, 110 adult patients visiting the outpatient clinic of our hospital were enrolled. All enrolled patients from the primary analysis were included for follow-up. Patients were screened for sickle cell related manifestations during visits to the outpatient clinic biannually. Various forms of sickle cell related organ damage and complications (presence of microalbuminuria, renal failure, pulmonary hypertension retinopathy, iron overload, cholelithiasis, avascular osteonecrosis, leg ulcers, acute chest syndrome, stroke, priapism and admissions for painful crises) were routinely screened according to international guidelines. Patients with genotype HbSS/HbSβ0 and HbSC/HbSβ+were grouped for further analysis. Results Of all originally included patients (N=110), nine were lost to follow-up (N=9). The mean age of the current study cohort is 37 years (IQR 27-46). Overall, 59 patients (58%) developed a new form of organ damage or new complication since baseline analysis, including eight patients who deceased (7 due to a sickle cell disease related death). In the HbSS/HbSβ0 genotype group (N=60) we found an increase in the percentage of patients who have had an Acute Chest Syndrome (29% to 47%) or have been diagnosed with avascular osteonecrosis (15% to 24%), retinopathy (23% to 34%) or pulmonary hypertension (31% to 48%). In the HbSC/HbSβ+ (N=35) group we found an increase in the occurrence of avascular osteonecrosis (9% to 14%), retinopathy (59 % to 70%) and pulmonary hypertension (9% to 19%). Furthermore, the use of hydroxycarbamide increased in both genotype groups and the frequency of admissions for painful crises remained stable for both genotype groups. Conclusion In the past period of seven years 58% of the patients in a previously well descript cohort of adult SCD patients developed a new sickle cell related complication. For some forms of organ damage or complications a substantial increase occurred dependent of a patient’s genotype. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A cautionary note regarding hydroxyurea in sickle cell disease

Blood ◽  
1994 ◽  
Vol 83 (4) ◽  
pp. 1124-1128 ◽  
Author(s):  
EP Vichinsky ◽  
BH Lubin
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Clinical Course ◽  
Fetal Hemoglobin ◽  
Organ Damage ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Transfusion Therapy ◽  
History Of ◽  
Hbf Level

Abstract Hydroxyurea can increase fetal hemoglobin (HbF) and improve the clinical course of sickle cell disease (SCD) patients. However, several issues of hydroxyurea therapy remain unresolved, including differences in patients' drug clearance, predictability of drug response, reversibility of sickle cell disease-related organ damage by hydroxyurea, and the efficacy of elevated HbF. We treated two patients with hydroxyurea for periods of 1 to 4 years, monitoring clinical course and laboratory parameters at regular intervals. The first patient (patient A) had a history of chronic pain and extensive hospitalizations. The second patient (patient B) had a history of stroke and refused to continue with chronic transfusion therapy and chelation. Both patients showed a fivefold to tenfold increase in HbF (5% to 25%, 3% to 31%). However, patient A developed an acute chest syndrome, despite an HbF level of 20%. After red blood cell transfusions for hypoxia, the HbF level decreased to 5%. When hydroxyurea dosage was increased, pancytopenia developed and was not resolved until 2 months after hydroxyurea was discontinued; Patient B developed a cerebral hemorrhage on hydroxyurea; he died shortly thereafter. His HbF level was 21% before death. We noted an increase in HbF and a general improvement in the two patients. However, both experienced major SCD-related complications despite HbF levels over 20%. Our findings also suggest that the progressive vascular changes associated with SCD are unlikely to be dramatically affected by increased HbF levels. Because neither the efficacy nor the toxicity of hydroxyurea have been thoroughly investigated, physicians should be cautious in prescribing hydroxyurea for patients with SCD before completion of the National Clinical Trial.

Prevalence and Predictors of Chronic Organ Damage in Adults with Sickle Cell Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4624-4624
Author(s):  
Syed N Haider ◽  
Jun Tang ◽  
Raymond U. Osarogiagbon
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Organ Damage ◽  
Early Mortality ◽  
Categorical Variables ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Early Management ◽  
End Organ Damage ◽  
Objective Evidence

Abstract Abstract 4624 Introduction Sickle cell disease (SCD) affects about 80,000 individuals in the US and about 1 of every 400 African Americans. Although SCD is characterized by acute painful crisis events, pain rates are a weak indicator of mortality risk. The main determinants of early mortality in adults are painless events such as sickle cell nephropathy (SCN), stroke due to cerebrovascular disease (CVD) and pulmonary hypertension (PHT). Sickle cell retinopathy (SCR) is a common cause of morbidity. There is a powerful correlation between end organ damage and early mortality. The prevalence of preclinical target organ damage has not been fully elucidated. We examined the prevalence of the full spectrum of end organ damage in a cohort at entry to our adult SCD program. We also contrasted the clinical and laboratory characteristics of patients with and without organ dysfunction. Patients and Methods Retrospective review of data on 118 adults (mean age 26.48±11.85 years) gathered upon entry into our program between February 2005 and October 2008. Historical presence of episodes of acute chest syndrome, pneumonia, stroke, avascular necrosis, osteomyelitis, leg ulcers, priapism, and cholecystectomy was quantitated. All patients underwent a standardized battery of tests to evaluate hematological and biochemical parameters at entry. Objective evidence of end organ damage was defined as follows: PHT, tricuspid regurgitant jet velocity (TRJV) ≥2.5 on echocardiography; SCN, glomerular filtration rate (GFR) < 90ml/min. and/or 24-hour protein>300mg and/or urine protein/creatinine ratio>0.3, all measured or calculated from 24 hour urine sample; CVD, evidence of previous ischemic and/or hemorrhagic infarct and/or aneurysmal dilatation on brain MRI or MR angiogram; SCR, background to proliferative retinopathy on fluorescent retinal angiography. Characteristics of patients were evaluated using t-test for continuous and the chi-square test for the categorical variables. Results There were 58 (49%) males and 60 (51%) females (p-value 0.85). Hemoglobin genotype: 74(63%) had SS/Sβ0, 27(23%) had SC, 11(9%) had Sβ+ while 5(4%) had S/hereditary persistence of fetal hemoglobin (S/HPFH).Of the patients who were tested for individual end organ damage 26% (24/91) had PHT, 52% (48/92) had nephropathy, 40% (31/78) had CVD while 38% (26/68) had retinopathy. The relevant statistically significant correlative variables for each type of end organ damage are shown in the table: Conclusions End organ damage was highly prevalent in this cohort of adults with SCD. Objective clinical and laboratory factors may predict the risk for end organ damage. This information can be used to develop an objective scoring system for disease severity based on early organ damage which may enable identification of patients at highest risk for severe morbidity and early mortality who might be candidates for more intensive evaluation and early management with disease-modifying interventions, beyond treatment of acute painful events. Disclosures: No relevant conflicts of interest to declare.

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