Abnormalities In Sickle Cell Disease Research Articles

Pulmonary function, CT and echocardiographic abnormalities in sickle cell disease

ObjectivesTo test the hypothesis that vascular abnormalities on high-resolution CT (HRCT) would be associated with echocardiographic changes and lung function abnormalities in patients with sickle cell disease (SCD) and the...

Hemostatic abnormalities in sickle cell disease

Although it has long been recognized that sickle cell disease (SCD) and other hemoglobinopathies are associated with a state of chronic hyperactivation of coagulation, the study of the epidemiology of venous thromboembolic (VTE) complications in SCD is only now beginning to evolve. In parallel, mechanistic studies of the hypercoagulable state in humans and mouse models implicate an increasingly important causative role of hemolysis. The case for SCD as a thrombophilic state has been strengthened by the recent literature. In an attempt to better understand the underlying mechanism(s), global assays of coagulation (thromboelastography and thrombin generation assays) have been utilized by several groups, but thus far, the results have been inconsistent, probably because of the technical differences. However, global assays continue to support the case for an important role of peripheral blood cells and their derived microparticles in promoting coagulation activation. VTE is an underappreciated and potentially morbid complication of SCD. The mechanisms underlying this hypercoagulable state are complex. A greater understanding of these pathways may lead to the rational selection of therapies that not only prevent thrombosis, but also impact on many of the other vaso-occlusive complications of SCD.

Increased left ventricular trabeculation in individuals with sickle cell anaemia: Physiology or pathology?

Left ventricular non-compaction (LVNC) cardiomyopathy is a relatively novel cardiomyopathy that is characterized by increased left ventricular trabeculation and inter-trabecular recesses communicating with the left ventricular cavity. The disease is rare amongst Caucasians but studies in heart failure patients of African/Afro-Caribbean origin (black) demonstrate that a high proportion fulfil criteria for LVNC [ [1] Kohli S.K. Pantazis A.A. Shah J.S. et al. Diagnosis of left-ventricular non-compaction in patients with left-ventricular systolic dysfunction: time for a reappraisal of diagnostic criteria?. Eur Heart J. 2008; 29: 89-95 Crossref PubMed Scopus (337) Google Scholar ]. Recent observations in athletes have also demonstrated a 3-fold greater prevalence of increased LV trabeculation amongst black athletes compared with Caucasian athletes, with almost 15% fulfilling echocardiographic LVNC criteria [ [2] Gati S. Chandra N. Bennett R.L. et al. Increased left ventricular trabeculation in highly trained athletes: do we need more stringent criteria for the diagnosis of left ventricular non-compaction in athletes?. Heart. 2013; PubMed Google Scholar ]. Given the high prevalence of LVNC compared with other primary cardiomyopathies implicated in the general population, it is unclear whether the myocardial morphology observed in black individuals is representative of LVNC or merely an epiphenomenon associated with increased cardiac preload. Chronic anaemia of sickle cell disease is associated with an increased LV preload and a high cardiac output. Although published data describing the cardiovascular adaptation in patients with sickle cell anaemia [ [3] Gladwin M.T. Sachdev V. Cardiovascular abnormalities in sickle cell disease. J Am Coll Cardiol. 2012; 59: 1123-1133 Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar ] include LV dilatation and eccentric hypertrophy, the co-existence of increased LV trabeculation or indeed, the presence of LVNC criteria has not been reported. The issue is pertinent since dyspnoea and chest pain are common to both sickle cell anaemia and LVNC.

Comments on renal abnormalities of sickle cell disease

Comments on renal abnormalities of sickle cell disease

Evaluation of renal function in sickle cell disease patients in Brazil

The objective of this study was to investigate renal function in a cohort of 98 patients with sickle cell disease (SCD) followed up at a tertiary hospital in Brazil. Clinical and laboratory characteristics at the time of the most recent medical examination were analyzed. Renal function was evaluated by the estimation of glomerular filtration rate (GFR) by the criteria of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). We compared patients with normal GFR to patients with decreased GFR (<60 mL·min−1·(1.73 m2)−1) and hyperfiltration (>120 mL·min−1·(1.73 m2)−1). Comparison between patients according to the use of hydroxyurea and comparison of clinical and laboratory parameters according to GFR were also carried out. Average patient age was 33.8 ± 13.3 years (range 19-67 years), and 57 (58.1%) patients were females. The comparison of patients according to GFR showed that patients with decreased GFR (<60 mL·min−1·(1.73 m2)−1) were older, had lower levels of hematocrit, hemoglobin and platelets and higher levels of urea and creatinine. Independent risk factors for decreased GFR were advanced age (OR = 21.6, P < 0.0001) and anemia (OR = 39.6, P < 0.0001). Patients with glomerular hyperfiltration tended to be younger, had higher levels of hematocrit, hemoglobin and platelets and lower levels of urea and creatinine, with less frequent urinary abnormalities. Hydroxyurea, at the dosage of 500-1000 mg/day, was being administered to 28.5% of the patients, and there was no significant difference regarding renal function between the two groups. Further studies are required to establish the best therapeutic approach to renal abnormalities in SCD.

Musculoskeletal manifestations of sickle cell disease, diagnosis with whole body MRI

PurposeThe aim of work is to define the musculoskeletal abnormalities in patients with sickle-cell disease using whole body MRI. Patients and methodsTwenty-seven patients with known sickle cell disease were included in this study complaining of acute painful vaso-occlusive crisis. All the patients complaining of bony pain in different body regions. Some patients complaining of bony swellings and joint pain. Whole body (W.B) MRI studies were performed for all the patients .Three coronal (T1, T2, and STIR) sequences were performed for whole-body MR imaging. In selected cases, dedicated examination of certain body parts was performed. ResultsPersistent red marrow, intramedullary bone hyperplasia and bone infarcts were seen in all patients. Vertebral bone infarcts were found in 23 patients. Bilateral proximal femoral head epiphysis avascular necrosis were found in 9 patients. Osteomylitis was diagnosed in 6 patients and septic arthritis in 2 patients. ConclusionWhole body MRI can help identifying muscloskeletal abnormalities in sickle cell disease in a single session. MRI is a useful imaging tool in distinguishing acute osteomylitis and bone infarct. Knowledge of the range of imaging findings is crucial in order to accurately depict the complication and initiate appropriate therapy.

Kidney abnormalities in sickle cell disease.

Patients with sickle cell disease exhibits numerous kidney structural and functional abnormalities, changes that are seen along the entire length of the nephron. Changes are most marked in patients with homozygous sickle cell anemia, but are also seen in those with compound heterozygous states and the sickle cell trait. The renal features of sickle cell disease include some of the most common reasons for referral to nephrologists, such as hematuria, proteinuria, tubular disturbances and chronic kidney disease. Therapy of these conditions requires specialized knowledge of their distinct pathogenic mechanisms. Spanish Haemathology and Hemotherapy Association has recently publicated their Clinical Practice Guidelines of SCD management. Renal chapter is reproduced in this article for Nefrología difussion.

Chronic Liver Abnormalities in Sickle Cell Disease: A Clinicopathological Study in 70 Living Patients

Background and Aim: The present study aimed to evaluate the incidence and etiology of chronic liver abnormalities in 70 living patients with sickle cell disease from the Hematology and Hemotherapy Center of the State University of Campinas. Methods: Clinical and laboratory investigations, including liver function tests, serological tests for viral hepatitis and abdominal ultrasound, were performed in all patients. Additionally, liver biopsies were taken from 20 patients. Results: Sixty-seven (96%) patients had some liver abnormality; these included abnormal liver function tests, viral hepatitis, liver ultrasonographic changes or cholelithiasis. The sickling process was the only explanation for the abnormal liver function tests or liver ultrasonographic changes in 24% of these patients. One or more defined reasons, including viral hepatitis, cholelithiasis, clinical hemosiderosis, alcoholism or diabetes, justified the liver abnormalities in 76% of the patients. Nineteen of the 20 liver biopsies presented some degree of vascular lesion; other histological findings were associated with hemosiderosis, viral hepatitis or cholestasis. Conclusions: In patients with sickle cell disease, chronic liver abnormalities are frequent and seem to be a multifactorial phenomenon, depending on overlapping factors such as cholelithiasis, viral damage, iron overload and also the primary disease itself.

Fisiopatologia das doenças falciformes: da mutação genética à insuficiência de múltiplos órgãos

The most important pathophysiological abnormalities of sickle cell disease are reviewed, taking into account three levels: a) molecules and cells, b) tissues, c) organism as a whole. We dedicated especial attention to the chronic inflammatory phenomena, abnormally expressed adhesion molecules, the interaction among sickle cells, endothelial cells, leukocytes and platelets, and their role in the pathophysiology of vaso-occlusion. The clinical manifestations, like anemia, pain crises and multiorgan dysfunction are covered. Factors that modulate disease severity, like the co-inheritance of a-thalassemia, gene mutations related to thrombophilia and the elevation of fetal hemoglobin are discussed.

Different findings in Tc-99m MDP bone scintigraphy of patients with sickle cell disease: report of three cases

Sickle cell anemia is an inherited disorder caused by abnormal hemoglobin, the S hemoglobin. Although vaso-occlusive crises can occur virtually in any organ, they are particularly common in the bony skeleton of affected patients. Bone marrow necrosis, bone infarcts, osteomyelitis, and aseptic necrosis are common complications in patients with sickle cell disease. Beside these abnormalities of the skeletal system, diffuse micro or macro calcification resulting from both splenic infarction and repeated vaso-occlusive episodes in the kidneys can be shown by technetium-99m methylenediphosphonate (Tc-99m MDP) bone scintigraphy. We present here the different osseous and extraosseous abnormalities noted on bone scintigraphies of three patients with sickle cell anemia. Whole-body bone scan was performed after injecting 740 MBq of Tc-99m MDP in three patients with sickle cell disease. Tc-99m MDP whole-body image of the first patient showed non-uniform uptake in the anterior and posterior aspects of multiple ribs and bilateral femurs and tibias that was attributed to repetitive infarcts. Additionally, increased activity in shoulders, right elbow, and right knee was consistent with arthritis. Tc-99m MDP image of the second patient demonstrated avascular necrosis of the left femoral head and diffuse activity in the enlarged kidneys. Increased activity in the spleen that was attributed to repetitive infarcts was visualized in bone scan of the third patient. In light of the findings in these cases, bone scintigraphy is a reliable imaging method in detecting both osseous and extraosseous abnormalities of sickle cell disease and may be used initially.

Computed tomography and pulmonary function abnormalities in sickle cell disease

The aim of this study was to determine whether patients with sickle cell disease (SCD) in steady state had pulmonary abnormalities seen on high-resolution computed tomography (HRCT) and whether any abnormalities correlated with contemporaneously diagnosed lung function abnormalities. A subsidiary question was whether the results of a noninvasive measure of haemolysis (end-tidal carbon monoxide (ETCO) levels) correlated with pulmonary function abnormalities. Thirty three patients with SCD, median (range) age 36 yrs (17-67 yrs) were examined. The degree of lobar volume loss and ground-glass opacification and prominence of central vessels on HRCT were quantitatively assessed. Pulmonary function was assessed by measurements of lung volumes, spirometry, gas transfer and oxygen saturation. ETCO levels were measured using an end-tidal CO monitor. Forced expiratory volume in one second (FEV1), forced vital capacity and total lung capacity significantly correlated with HRCT findings, particularly lobar volume loss. ETCO levels significantly negatively correlated with FEV1, vital capacity measured using a plethysmograph, specific airway conductance and arterial oxygen saturation measured by pulse oxymetry. In conclusion, the present results suggest that high-resolution computed tomography noninvasive assessment of haemolysis might be useful to identify sickle cell disease patients with respiratory function impairment.

Blood Lipid Abnormalities in Sickle Cell Disease Are Pancellular and Clinically Important.

In a previous study, we observed that high expression of the adhesion molecules L-selectin and αMβ2 integrin on leukocyte membranes is associated with severe sickle cell disease (Eur J Haem. 2002; 69: 135– 144). The lipid composition of cell membranes affects adhesion molecule expression, cell integrity and function (Calder P Lipids. 2003; 38: 343–352). Omega-3 fatty acids (FA) such as docosahexaenoic (DHA) and eicosapentaenoic (EPA) are vital for the structure and function of cell membranes. Sickling perturbs the normal asymmetry of erythrocyte membrane lipids. Choline phosphoglycerides (CPG) move from the outer to inner leaflet. Ethanolamine (EPG) and serine (SPG) phosphoglycerides shift from the inner to the outer layer. Exposure of the highly reactive SPG to plasma promotes clotting, rbc adhesion to vascular endothelium, wbcs and platelets; vaso-occlusion, and ischaemic organ damage. Loss of lipid asymmetry impairs the structure of rbc membranes, causes abnormal ion flux and exacerbates haemolysis. Although rbc and plasma lipid abnormalities are recognised, there is little data on occurrence and clinical relevance of leukocyte or platelet FA anomalies in SCD. The aim of this study is to find out if the FA constitution of blood cell membranes modulates the clinical features of SCD. The FA composition of blood cells and plasma was analysed in 68 HbSS and 9 HbSC patients in steady-state (40M, 37F, age 11–52 yr, mean 26 yr); and 58 healthy, age, sex and race matched HbAA controls from the same environment. We excluded cigarette smokers, anyone who had blood transfusion or pregnancy in the previous 4 months, and SCD patients with co-morbidities or HbF ≥ 10%. Steady-state Hb level in HbSS patients showed highly significant positive correlation with the proportions of DHA in erythrocyte membrane CPG (p<0.001, r = 0.42); and of EPA in membrane EPG (p<0.01, r = 0.57). There was very significant reduction of red cell and plasma EPA of HbSS patients compared to HbSC and HbAA individuals (p<0.001). Similarly, DHA and EPA were significantly reduced in leukocytes and platelets of HbSS patients relative to controls (p<0.005). Compared to HbSS patients who had no complications of SCD (n=9), those with complications (n=19) had markedly reduced DHA and total omega-3 fatty acids in erythrocytes (p<0.005), and platelets (p<0.05). Since EPA and DHA are essential structural and functional components of cell membranes, and precursors of potent anti-inflammatory eicosanoids and cytokines, decrease in their proportions exacerbates haemolysis, inflammation, vaso-occlusion and organ damage in SCD. Tomer et al (Thromb. Hemost. 85; 966–974) and our group observed reduction in the number of sickle cell crisis during pilot clinical trials of EPA and DHA. The current study and pilot trials suggest that omega-3 FA therapy has considerable potential in SCD. As natural constituents of fish oil omega-3 FA are eaten safely world-wide, and are affordable in developing countries where majority of SCD patients live. Unlike hydroxyurea, they are not cytotoxic, teratogenic or immunosuppressive. Unlike regular blood transfusions, there is no risk of HIV or other infections. Omega-3 FA are beneficial in cardiovascular and multi-organ chronic inflammatory conditions. There are sufficient grounds for a large clinical trial of EPA and DHA in the multi-system disorder that is SCD.

Transgenic Sickle Mice Are Markedly Sensitive to Renal Ischemia-Reperfusion Injury

Ischemic injury is invoked as a mechanism contributing to end-organ damage and other complications of sickle cell disease (SCD). However, the intrinsic sensitivity of tissues in SCD to ischemic insults has never been addressed. We examined the effect of renal ischemia in a transgenic mouse expressing human sickle hemoglobin. Twenty-four hours after bilateral, total renal artery occlusion for 15 minutes, transgenic sickle mice exhibited worse renal function and more marked histological injury. With bilateral renal ischemia of greater duration (22.5 minutes), and after 6 hours, transgenic sickle mice exhibited massive vascular congestion, sickling of red blood cells, more marked histological injury in the kidney, and more prominent congestion in the capillary beds in the lungs and heart. Additionally, serum amyloid P-component, the murine homologue of C-reactive protein, was markedly increased in transgenic sickle mice as compared to wild-type mice. Twenty-four hours after bilateral renal ischemia for 22.5 minutes, transgenic sickle mice exhibited 28% mortality, with no mortality observed in any other group. With bilateral renal ischemia of short or long duration, renal expression of caspase-3 was most prominent in transgenic sickle mice subjected to ischemia. Thus, renal ischemia in this murine model induces more severe renal injury and extrarenal complications. We conclude that tissues in SCD exhibit heightened vascular congestion and sensitivity to ischemia and that clinically apparent or silent episodes of ischemia may contribute to the complications of SCD.

The contribution of endothelial cell P-selectin to the microvascular flow of mouse sickle erythrocytes in vivo

AbstractMicrovascular occlusion in sickle cell disease can be initiated by adhesion of sickle red blood cells (RBCs) to the endothelium. Our objective in this study was to verify the relevance in vivo of our discovery that sickle RBCs adhere abnormally to endothelial P-selectin in vitro. We used computer-assisted intravital microscopy to characterize RBC flow velocity (VRBC) in mice. We found faster VRBC of sickle RBCs in P-selectin knock-out and control mice than in sickle cell mice, which have increased endothelial cell P-selectin expression. Agonist peptide for murine protease-activated receptor-1 (PAR-1), which selectively activates mouse endothelial cells but not platelets, was used to assess the effects of endothelial cell P-selectin on microvascular flow. Suffusion of venules with this agonist stopped flow promptly in normal and sickle mice but not in P-selectin knock-out mice or in control mice pretreated with anti-P-selectin monoclonal antibody or unfractionated heparin (UFH). Agonist-induced slowing of flow was reversed rapidly by suffusion with UFH, provided flow had not already stopped. We conclude that endothelial cell P-selectin contributes to the microcirculatory abnormalities in sickle cell disease and that blocking P-selectin may be useful for preventing painful vasoocclusion in sickle cell disease. (Blood. 2004;104:3378-3385)

Echocardiographic abnormalities in sickle cell disease.

Echocardiographic abnormalities in patients with sickle cell disease (SCD) were determined, and pulmonary arterial systolic pressure (PASP) was estimated. Clinical data and echocardiograms of 38 adult hospitalized patients with SCD at two tertiary care hospitals were reviewed. Fisher's exact test was performed to determine correlation between pulmonary hypertension and various clinical variables. Pulmonary hypertension was the most common abnormality identified in 22 (58%) patients. The estimated mean PASP was 37.5 +/- 10.9 mmHg. Older age and prior history of acute chest syndrome were significantly correlated with an increased prevalence of pulmonary hypertension (P < 0.05). Patients with hemoglobin levels <8 g/dL had PASP 43.2 +/- 0.5 compared to a mean PASP of 33.3 +/- 6.0 in patients with hemoglobin > or =8 g/dL (P = 0.01). Eight (21%) patients had evidence of a hyperdynamic left ventricle. Left heart abnormalities included dilated atrium in 14 (37%), dilated ventricle in 5 (13%), ventricle hypertrophy in 5 (13%), and ventricle dysfunction in 3 (9%) patients. Right heart abnormalities included dilated atrium in 9 (24%), dilated ventricle in 6 (16%), and ventricle dysfunction in 3 (9%) patients. Despite an increased incidence of abnormal flow across the valves on Doppler analysis, no patient had structurally abnormal valves. A majority of patients with SCD had evidence of pulmonary hypertension, which correlated with older age and history of acute chest syndrome. Other structural and functional echocardiographic abnormalities were less common.

Microvascular abnormalities in sickle cell disease: a computer-assisted intravital microscopy study

The conjunctival microcirculation of 18 homozygous sickle cell disease (SCD) patients during steady-state, painful crisis, and postcrisis conditions was recorded on high-resolution videotapes using intravital microscopy. Selected videotape sequences were subsequently coded, frame-captured, studied, and blindly analyzed using computer-assisted image analysis protocols. At steady-state (baseline), all SCD patients exhibited some of the following morphometric abnormalities: abnormal vessel diameter, comma signs, blood sludging, boxcar blood flow phenomenon, distended vessels, damaged vessels, hemosiderin deposits, vessel tortuosity, and microaneurysms. There was a decrease in vascularity (diminished presence of conjunctival vessels) in SCD patients compared with non-SCD controls, giving the bulbar conjunctiva a "blanched" avascular appearance in most but not all SCD patients during steady-state. Averaged steady-state red cell velocity in SCD patients was slower than in non-SCD controls. During painful crisis, a further decrease in vascularity (caused by flow stoppage in small vessels) and a 36.7% +/- 5.2% decrease in large vessel (mostly venular) diameter resulted. In addition, the conjunctival red cell velocities either slowed significantly (6.6% +/- 13.1%; P <.01) or were reduced to a trickle (unmeasurable) during crisis. The microvascular changes observed during crisis were transient and reverted to steady-state baseline after resolution of crisis. When combined, intravital microscopy and computer-assisted image analysis (computer-assisted intravital microscopy) represent the availability of a noninvasive tool to quantify microvascular abnormalities in vascular diseases, including sickle cell disease. The ability to identify and relocate the same conjunctival vessels for longitudinal studies uniquely underscores the applicability of this quantitative real-time technology.

Renal abnormalities in sickle cell disease

Renal abnormalities in sickle cell disease

Renal abnormalities in sickle cell disease

Renal abnormalities in sickle cell disease

Renal abnormalities in sickle cell disease.

Sickle cell anemia and the related hemoglobinopathies are associated with a large spectrum of renal abnormalities. The patients have impaired urinary concentrating ability, defects in urinary acidification and potassium excretion, and supranormal proximal tubular function. The latter is manifest by increased secretion of creatinine and by reabsorption of phosphorus and beta(2)-microglobulin. Young patients with sickle cell disease (SCD) have supranormal renal hemodynamics with elevations in both effective renal plasma flow (ERPF) and glomerular filtration rate (GFR). These parameters decrease with age as well as following the administration of prostaglandin inhibitors. Proteinuria, a common finding in adults with sickle cell disease, may progress to the nephrotic syndrome. Proteinuria, hypertension, and increasing anemia predict end-stage renal disease (ESRD). While ESRD can be managed by dialysis and/or renal transplantation, there may be an increased rate of complications in renal transplant recipients with SCD. Hematuria is seen in individuals with all of the SCDs as well as with sickle cell trait. In most cases the etiology of the hematuria turns out to be benign. However, there does appear to be an increased association between SCD and renal medullary carcinoma. Therefore, those SCD patients who present with hematuria should initially undergo a thorough evaluation in order to exclude this aggressive neoplasm. Papillary necrosis may occur due to medullary ischemia and infarction. Erythropoietin levels are usually lower than expected for their degree of anemia and decrease further as renal function deteriorates. An abnormal balance of renal prostaglandins may be responsible for some of the changes in sickle cell nephropathy. Acute renal failure is a component of the acute multiorgan failure syndrome (MOFS). Finally, progression of sickle cell nephropathy to ESRD may be slowed by adequate control of hypertension and proteinuria. However, the prevention of the renal complications of SCD will require a cure for this genetic disorder.

Renal abnormalities in sickle cell disease

Renal abnormalities in sickle cell disease. Sickle cell nephropathy is indicated by sickled erythrocytes, with the consequent effects of decreased medullary blood flow, ischemia, microinfarct and papillary necrosis. Impaired urinary concentrating ability, renal acidification, hematuria, and potassium secretion are also found. There may be a causal relationship between an increase in nitric oxide synthesis and experimental sickle cell nephropathy, and some studies have indicated that the progression of sickle cell nephropathy is hemodynamically mediated. Although there are many studies showing that proteinuria, nephrotic syndrome, chronic progressive renal failure, and acute renal failure syndromes are the outcome of this disease, the pathogenic mechanism(s) and potential therapies remain to be elucidated. Survival of patients with sickle cell nephropathy who progress to end-stage renal disease (ESRD) is equal to non-diabetic ESRD patients, and graft survival rates are also similar for those who undergo renal transplantation. This article presents a historical review of the glomerular and tubular disorders associated with sickle cell nephropathy, and reviews therapeutic indications to slow its progression. Further research is needed.