Platelet Nucleation on Arrested Neutrophils Drives Vaso-Occlusion in Sickle Cell Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 414-414
Author(s):  
Maritza A. Jimenez ◽  
Prithu Sundd ◽  
Enrico M Novelli ◽  
Gregory J Kato
Keyword(s):  
Endothelial Cells ◽  
Sickle Cell Disease ◽  
Fluorescence Microscopy ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Genetic Disorder ◽  
Epifluorescence Microscopy ◽  
Cellular Interactions ◽  
Cell Disease ◽  
Neutrophil Aggregation

Abstract Introduction: Sickle Cell Disease (SCD) is an autosomal recessive genetic disorder that leads to sickling and hemolysis of RBCs under hypoxic conditions. As a result of chronic hemolysis, SCD is associated with a hyper-inflammatory and hyper-coagulation state, which accounts for enhanced adhesion of leukocytes, platelets, RBCs and vascular endothelial cells leading to vaso-occlusion. Acute vaso-occlusive pain crisis (VOC) is the primary reason for emergency medical care by SCD patients. Although neutrophils have been shown to play a role in the on-set of vaso-occlusion by interacting with sickle RBCs and platelets in cremaster venules of transgenic SCD mice, the cellular, molecular and biophysical mechanisms that promote vaso-occlusion in SCD patients is not completely understood. Materials and Methods: Freshly collected heparinized blood from steady-state SCD (SS) patients and race matched control subjects was perfused through polydimethylsiloxane (PDMS) based microfluidic flow channels (30 µm x 500 µm) with a glass bottom coated with either human microvascular endothelial cells or a cocktail of recombinant human P-selectin, ICAM-1 and IL-8 at a physiological shear stress (6 dyn cm-2). Fluorescent Abs against CD16 and CD49b were added to the blood for in-situ staining of neutrophils and platelets, respectively. Cellular interactions were recorded using quantitative microfluidic fluorescence microscopy (qMFM)1, which is a combination of quantitative dynamic footprinting1 and epifluorescence microscopy. Results and Discussion: Neutrophils in SS blood were observed to roll, arrest and then capture freely flowing platelets leading to the formation of vaso-occlusive aggregates. RBCs were observed getting trapped within the platelet-neutrophil aggregates. The number of platelet-neutrophil interactions, lifetime of these interactions and the extent of platelet-neutrophil aggregation were several folds higher in SS than control subject blood. Bacterial lipopolysaccharide (LPS; 500 ng/ml) pretreatment led to enhanced platelet-neutrophil aggregations in SS but not control blood. The enhanced platelet-neutrophil aggregations in SS blood (+/-LPS) was attenuated to the level observed in control blood by simultaneous blockage of P-selectin on platelets and Mac-1 on neutrophils with functional blocking Abs. Conclusion: Our data demonstrates that the vaso-occlusive pathophysiology in SCD involves sequential steps of neutrophil arrest, nucleation of platelets on arrested neutrophils, formation of platelet-neutrophil aggregates and trapping of RBCs in these aggregates. The inflammatory milieu of SS patient blood sets a lower threshold for bacterial endotoxin induced platelet-neutrophil aggregation than control blood. Vaso-occlusion can be ameliorated in SS blood by simultaneous inhibition of platelet P-selectin and neutrophil Mac-1. Understanding the molecular mechanism of vaso-occlusion will enable the development of therapies that can prevent VOC in SS patients. References: 1. Jimenez MA, Tutuncuoglu E, Barge S, Novelli EM, Sundd P. Quantitative microfluidic fluorescence microscopy to study vaso-occlusion in Sickle Cell Disease. Haematologica, 2015. 2 Sundd, P. et al. Quantitative dynamic footprinting microscopy reveals mechanisms of neutrophil rolling. Nat Methods 7, 821-824, doi:10.1038/nmeth.1508 (2010). Disclosures No relevant conflicts of interest to declare.

scholarly journals Neutrophil-Platelet Aggregation Enables Vaso-Occlusion in Sickle Cell Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1295-1295 ◽  
Author(s):  
Maritza A. Jimenez ◽  
Gregory J Kato ◽  
Prithu Sundd
Keyword(s):  
Platelet Aggregation ◽  
Sickle Cell Disease ◽  
Fluorescence Microscopy ◽  
Single Cell ◽  
Sickle Cell ◽  
Genetic Disorder ◽  
Cellular Interactions ◽  
Cell Disease ◽  
Microfluidic Flow ◽  
Neutrophil Aggregation

Introduction: Sickle Cell Disease (SCD) is an autosomal-recessive-genetic disorder that leads to sickling and hemolysis of red blood cells (RBCs). Acute vaso-occlusive pain crisis (VOC) is the predominant pathophysiology faced by SCD patients and the primary reason for emergency medical care. Although neutrophils have been shown to play a role in vaso-occlusion by interacting with sickle RBCs in the cremaster venules of transgenic SCD mice, the cellular, molecular and biophysical mechanisms that promote vaso-occlusion in SS patients is not completely understood. Materials and Methods: Freshly collected heparinized blood from steady-state SS patients and race matched control (AA) subjects was perfused through silicone based microfluidic flow channels with a glass bottom coated a cocktail of recombinant human P-selectin, ICAM-1 and IL-8 at a physiological wall shear stress (6 dyn cm-2). Fluorescent Abs against CD16 and CD49b were added to the blood for in-situ staining of neutrophils and platelets, respectively. Cellular interactions were recorded at a single cell-resolution using quantitative microfluidic fluorescence microscopy (qMFM)1, which allows quantitative assessment of vaso-occlusive events at an unprecedented single cell resolution2. Results: Vaso-occlusion in the microfluidic channel involved neutrophil arrest followed by nucleation of platelets on arrested neutrophils, formation of neutrophil-platelet-aggregates (NPA) and partial occlusion of the microfluidic flow channel. Remarkably, the number of platelet-neutrophil interactions and the lifetime of these interactions were several folds higher in SS patient than control AA blood. Surprisingly, preincubation with 250 ng/ml of bacterial lipopolysaccharide (LPS) led to a significant increase in the number and lifetime of platelet-neutrophil interactions in SS but not AA blood. This enhanced NPA formation in SS patient blood was attenuated to the level observed in AA blood by simultaneous blockage of P-selectin on platelets and Mac-1 on neutrophils as well as pretreatment with a small molecule inhibitor of toll-like-receptor-4 (TLR4) signaling pathway. Conclusion: Our data shows that the vaso-occlusive pathophysiology in SCD involves sequential steps of neutrophil arrest, nucleation of platelets on arrested neutrophils, formation of large NPAs and obstruction of blood flow. Platelet-neutrophil aggregation can be ameliorated by the simultaneous blockage of P-selectin on platelets and Mac-1 on neutrophils. The inflammatory milieu of SS patient blood sets a lower threshold for bacterial endotoxin induced neutrophil-platelet aggregation than control blood. The enhanced platelet-neutrophil aggregation in SS blood is dependent on activation of TLR-4 pathway. Understanding the molecular mechanism of vaso-occlusion will enable the development of therapeutics to prevent VOC in SS patients. References: 1 Jimenez MA, Tutuncuoglu E, Barge S, Novelli EM, Sundd P. Quantitative microfluidic fluorescence microscopy to study vaso-occlusion in sickle cell disease. Haematologica. 2015;100(10):e390-e393. doi:10.3324/haematol.2015.126631. 2 Sundd, P. et al. Quantitative dynamic footprinting microscopy reveals mechanisms of neutrophil rolling. Nat Methods7, 821-824, doi:10.1038/nmeth.1508 (2010). Disclosures Kato: Mast Therapeutics: Consultancy; Bayer: Research Funding.

scholarly journals Neutrophil-Platelet Micro-Emboli Enable Vaso-Occlusion in Sickle Cell Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2695-2695
Author(s):  
Prithu Sundd ◽  
Maritza Jimenez ◽  
Enrico M Novelli ◽  
Mark T Gladwin
Keyword(s):  
Endothelial Cells ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Cellular Adhesion ◽  
Epifluorescence Microscopy ◽  
Single Point Mutation ◽  
Cellular Interactions ◽  
Cell Disease ◽  
Cellular Adhesion Molecule

Abstract Introduction: Sickle Cell Disease (SCD) is an autosomal-recessive-hemolytic disorder caused by a single point mutation in the β-globin gene that leads to sickling of RBCs under deoxygenated condition. Sickle RBCs (sRBCs) are not only rigid but also express adhesion molecules, which are not normally expressed on RBCs. The sticky and rigid sRBCs are believed to get trapped in blood vessels along with leukocytes to cause vaso-occlusion, which is the predominant pathophysiology underlying acute pain crisis in SCD patients. The process of sickling and vaso-occlusion leads to sRBC hemolysis, which releases hemoglobin, ADP and other RBC contents into the blood giving rise to a pro-inflammatory and pro-coagulant state, characterized by activated leukocytes, platelets, endothelial cells (ECs), tissue factor (TF) and enhanced adhesion of these cells to each other. Leukocyte–endothelium adhesion starts with leukocyte rolling mediated by P-selectin-glycoprotein-ligand (PSGL)-1 on leukocytes binding to P-selectin on endothelium. Rolling is followed by firm arrest, which is mediated by activated β­2-integrins (LFA-1 and Mac-1) on the leukocytes binding to inter-cellular-adhesion-molecule (ICAM)-1 on endothelium. Although neutrophils have been shown to play a role in the onset of vaso-occlusion by interacting with sRBCs and platelets in cremaster venules of SCD mice; the cellular, molecular and biophysical mechanisms that enable vaso-occlusion in SCD patients are not known. Materials and Methods: Freshly collected heparinized blood from SCD patients and race matched control subjects was perfused through a polydimethylsiloxane (PDMS) based microfluidic flow chamber with a glass bottom coated with either human micro-vascular endothelial cells or a cocktail of recombinant human P-selection, ICAM-1 and IL-8 at a venular/arteriolar wall shear stress. Fluorochrome conjugated Abs against CD16, CD235a and CD49b were added to the blood to stain neutrophils, sRBCs and platelets, respectively, and cellular interactions were recorded using multi-color Quantitative Dynamic Footprinting (qDF; Sundd et al Nature Methods 2010) or epifluorescence microscopy. Specificity of cellular interactions was tested using function blocking Abs against human Mac-1, LFA-1, P-selectin and PSGL-1. Results: SCD patients had much higher number of circulating neutrophils than control patients. Neutrophils rolled, arrested and then captured free flowing platelets in both SCD and control blood. However, significantly larger number of neutrophils rolled and arrested in SCD blood than control blood. As a result, much higher number of platelets was captured by arrested neutrophils in SCD blood than control blood, which led to the formation of neutrophil-platelet micro-emboli. The micro-emboli formation was mediated by a unique biophysical mechanism, which involved PSGL-1 and Mac-1 on neutrophils binding to P-selectin and GPIbα on platelets, respectively. Conclusion: Vaso-occlusion involves a cascade of adhesive events. First, neutrophils roll and arrest at the site of vaso-occlusion. Second, arrested neutrophils capture free flowing platelets and RBCs to form micro-emboli. Third, eventually these micro-emboli give rise to micro-thrombi, which cause stasis of blood flow. Acknowledgments: This study is supported by 11SDG7340005 from the American Heart Association (P.S.), VMI start-up funds (P.S.) and CBTP-T32 fellowship HL076124 (M.J). Disclosures No relevant conflicts of interest to declare.

Platelet-Neutrophil Aggregates Promote Pulmonary Arteriole Microembolism in Sickle Cell Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2162-2162
Author(s):  
Margaret F. Bennewitz ◽  
Ravi Vats ◽  
Egemen Tutuncuoglu ◽  
Mark T. Gladwin ◽  
Prithu Sundd
Keyword(s):  
Sickle Cell Disease ◽  
Molecular Mechanism ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Genetic Disorder ◽  
Acute Chest Syndrome ◽  
Cellular Trafficking ◽  
Anatomical Site ◽  
Cell Disease ◽  
Pulmonary Microcirculation

Abstract Introduction: Sickle cell disease (SCD) is an autosomal recessive genetic disorder that affects ~100,000 Americans and millions of people worldwide. The acute chest syndrome (ACS), a form of acute lung injury, is a major cause of morbidity among SCD patients. The current treatment for ACS is primarily supportive and the molecular mechanism remains largely unknown. SCD patients hospitalized with vaso-occlusive pain crisis (VOC) often develop ACS within the ensuing days, suggesting a role for pulmonary vaso-occlusion in the onset of ACS. However, the cellular and molecular mechanism and the anatomical site of pulmonary vaso-occlusion are still elusive. Materials and Methods: Intravenous (IV) bacterial lipopolysaccharide (LPS) was used to induce VOC in SCD mice. Intravital multiphoton excitation (MPE) fluorescence microscopy was used to study the blood cell trafficking within the pulmonary microcirculation of live SCD or control mice. Fluorochrome-conjugated anti-mouse Ly-6G, Ter-119, and CD49b antibodies were administered IV for in vivo staining of circulating neutrophils, red blood cells and platelets, respectively. Cellular trafficking was recorded at baseline and 2 hours after IV challenge with LPS. Image sequences were analyzed to identify vaso-occlusion, which was defined as cellular aggregation and stasis of blood flow within the pulmonary blood vessels. Results and Discussion: Preliminary data using MPE imaging in transgenic SCD mice revealed that vaso-occlusion was absent at baseline in unchallenged SCD mice and the cellular trafficking within the pulmonary microcirculation was comparable in SCD and control mice. Doses of IV LPS (0.01-5 mg/kg of body weight), which were innocuous to control mice were found to be lethal to SCD mice. Remarkably, MPE imaging of the lung microcirculation revealed that IV LPS led to microembolism of the pre-capillary pulmonary arterioles by platelet-neutrophil aggregates in SCD but not control mice. The microembolism involved either entrapment of circulating platelet-neutrophil aggregates or in situ aggregation through sequential steps of neutrophil arrest on the arteriolar endothelium, followed by platelet nucleation on arrested neutrophils and microthrombus formation. Conclusions: Initial findings demonstrate that pulmonary vaso-occlusion in SCD mice involves microembolism of the pre-capillary pulmonary arterioles by platelet-neutrophil aggregates. Future studies will determine the molecular interactions responsible for pulmonary arteriolar microembolism. Acknowledgments: This study is supported by the 11SDG7340005 from the American Heart Association (P.S.) and the VMI startup account (P.S.). M.F.B is supported by the NIH NHLBI VMI T32 training grant T32HL110849. Disclosures No relevant conflicts of interest to declare.

Analysis of Calcium Profile and Bone Mineral Density in Patients with Sickle Cell Disease

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4810-4810
Author(s):  
Lucila Macedo Gonçalves ◽  
Rodolfo Cancado ◽  
Tarissa Beatrice Zanata Petry ◽  
Murilo Rezende Melo ◽  
João Eduardo Salles ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Bone Mineral ◽  
Conflicts Of Interest ◽  
Genetic Disorder ◽  
Urinary Calcium ◽  
Cell Disease ◽  
Mineral Density ◽  
Subsequent Increase

Abstract Abstract 4810 Introduction: Sickle Cell Disease (SCD) is a genetic disorder where the red blood cells assume an abnormal, rigid, sickle shape, causing tissue hypoxia with subsequent increase of osteoclastic activity, originating osteopenia and osteoporosis. The prevalence of the osteoporosis in the SCD can vary from 25 a 50%, affecting more commonly the children. There are few data regarding the prevalence of bone mineral low density in adults. Our objective was to analyse the calcium profile and bone mineral density (BMD) of pacients with SCD and describe the prevalence of osteopenia in this group. Material and Methods: We have studied 49 patients with SCD analysing the serum and 24 hours urinary calcium, serum ferritin, LDH, parathyroid hormone (PTH) and BMD in the lombar vertebrae and proximal femoral. Results: From the 49 patients, 21(42.9%) were males and 28(57.1%) females, mean age of 27 years old (16-51 yr), 55.1% (27) of the patients presented osteopenia and 26.5% (13) osteoporosis, considering lombar vertebrae BMD. Only 18.4% (9) had normal BMD. Mean ± DP PTH was 85.3 ± 79.32 and mean ± DP serum calcium of 8.9 ± 0.44. Mean ± DP LDH was 970.8 ± 492.36 and we have observed significant correlation between this variable and low BMD (p<0.02). Conclusion: The prevalence of osteopenia and osteoporosis was extremely high (81.6%) in the studied patitents. The secondary hyperparatireoidism was present in many patients and we did not find hypoparathyroidism. The hemolysis appears as a factor that contributes for the low BMD. Disclosures: No relevant conflicts of interest to declare.

Oxidation Of Von Willebrand Factor and ADAMTS13 In Patients With Sickle Cell Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2304-2304 ◽  
Author(s):  
Junmei Chen ◽  
Yi Wang ◽  
Tahsin Ozpolat ◽  
Colette Norby ◽  
Xiaoyun Fu ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Von Willebrand Factor ◽  
Conflicts Of Interest ◽  
Human Umbilical Cord ◽  
Cell Disease ◽  
Normal Plasma ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Sickle cell disease (SCD) is a hemoglobinopathy characterized by vaso-occlusive episodes and hemolysis. We previously showed that SCD patients at disease baseline have elevated levels of von Willebrand factor (VWF) and enhanced VWF adhesive activity (Chen et al. Blood, 2011, 117:3680-3683). The total active VWF (quantity times relative adhesive activity compared to pooled plasma) correlated with the degree of hemolysis. VWF is an adhesive protein capable of binding platelets, erythrocytes, and leukocytes, especially in its newly released form, a portion of which remains attached to the endothelium until it is cleaved off by the plasma metalloprotease ADAMTS13. Here, we explored the mechanisms that could account for increased total active VWF in SCD patients, including increased endothelial secretion, ADAMTS13 inhibition, and VWF oxidation. Previously, we showed that the neutrophil oxidant hypochlorous acid (HOCl), oxidized VWF at the ADAMTS13 cleavage site (Met1606) rendering it uncleavable, and at other sites that increased its platelet-binding activity (Chen et al. Blood, 2010, 115:706-712 and Fu et al. Blood, 2011, 118: 5283-5291). We have also found that HOCl can inactivate ADAMTS13 by oxidizing Met249 in the Met-turn of the metalloprotease domain. We first examined whether patient plasma could activate endothelial cells to secrete VWF strings using plasma from 8 patients at disease baseline. Patient plasma was incubated with monolayers of human umbilical cord vein endothelial cells (HUVECs) in a parallel-plate flow chambers for 20 min at 37°C before fixed platelets were perfused through the chamber to decorate the VWF strings. HUVECs incubated with either normal pooled plasma or phorbol myristate acetate were the negative and positive controls, respectively. The data are expressed as a percent of the strings seen in the positive control. SCD plasma activated HUVECs to secrete more VWF strings than did normal plasma (11% – 31% for patient plasma compared to 1% – 6% for normal plasma). We also measured the concentration of myeloperoxidase (MPO) in the plasma from these patients. Almost all (16 of 17) had elevated MPO concentration, ranging from 1.3 to 16.2 times the control. MPO released from activated neutrophils converts hydrogen peroxide to HOCl in the presence of chloride ion. We therefore have begun to evaluate the extent of VWF and ADAMTS13 oxidation in patient plasma using tandem mass spectrometry. In the one patient examined for VWF oxidation, we found 2.8% and 4.6% % oxidation at M1606 and M1385, respectively, versus 0.2% and 0.5% in the control. Although this is only a small percent of all the vulnerable Met residues, this extent of oxidation was accompanied by a marked defect in the ability of the patient’s endogenous ADAMTS13 to cleave endogenous VWF, even though the ADAMTS13 activity was normal when tested with small A2 peptide substrate. We have also examined ADAMTS13 oxidation in two other SCD patients at disease baseline. Here too, oxidation of Met249 was increased compared to control (4.0% and 4.8% vs 2.5% in the control). In summary, in studies of several patients with SCD at disease baseline, we have found: elevated levels of VWF and ADAMTS13 oxidation, defective cleavage of endogenous VWF by endogenous ADAMTS13, and activation of endothelial cells with release of VWF by patient plasma. These findings all suggest that oxidative stress associated with SCD contributes to worsening the vaso-occlusive and hemolytic aspects of the disease and increases the risk for thrombosis. We are expanding these studies to include more patients at baseline, and patients in acute crisis, where we expect the oxidative signature to be even higher. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Mass Spectrometry of Urine Proteins for Early Detection of Renal Complications in Sickle Cell Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2714-2714
Author(s):  
Elena A Adjei ◽  
Namita Kumari
Keyword(s):  
Renal Failure ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Genetic Disorder ◽  
Globin Gene ◽  
Cell Disease ◽  
Renal Complications ◽  
Potential Biomarker ◽  
Urine Proteins

Abstract PURPOSE: Sickle cell disease (SCD) is an autosomal recessive genetic disorder caused by a single G6V mutation in the β-globin gene. SCD patients have various complications including chronic renal failure and nephrotic syndrome which can develop in 30-50% of sickle cell patients. Currently there are no reliable methods to identify the risk for renal complications in the early stages for the subset of people who will develop renal failure. It is essential that new noninvasive prognostic biomarkers be discovered to help assess patients for risk of renal failure which may lead to early intentions and greater survival rates among SCD patients. METHODS: Urine samples were collected from 25SCD patients and 6 healthy controls. Trypsin digests of urine proteins were analyzed by nano LC coupled in-line to LTQ Orbitrap XL tandem mass spectrometer. Proteins identified with Proteome Discoverer software were further quantified using SIEVE 2.1 (Thermo). RESULTS: About 80 proteins were detected in urine. Among those, about 10 proteins were found at higher levels in SCD patients, including seruloplasmin, transferring and alpha-1-acid glycoprotein precursor. CONCLUSION: Several of the detected proteins may cause early changes in glomerular permeability and be a potential biomarker for early renal manifestations in SCD. Further studies are needed to form a more conclusive relationship between renal complications and the proteins present in urine of SCD patients. SUPPORT: NIH Research Grants 8G12MD007597 and P50HL118006-01. Disclosures No relevant conflicts of interest to declare.

scholarly journals Targeting pain at its source in sickle cell disease

2018 ◽  
Vol 315 (1) ◽  
pp. R104-R112 ◽  
Author(s):  
Kanika Gupta ◽  
Om Jahagirdar ◽  
Kalpna Gupta
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Genetic Disorder ◽  
Somatosensory System ◽  
Organ Damage ◽  
Mast Cell Activation ◽  
Cell Disease ◽  
Central Nervous Systems

Sickle cell disease (SCD) is a genetic disorder associated with hemolytic anemia, end-organ damage, reduced survival, and pain. One of the unique features of SCD is recurrent and unpredictable episodes of acute pain due to vasoocclusive crisis requiring hospitalization. Additionally, patients with SCD often develop chronic persistent pain. Currently, sickle cell pain is treated with opioids, an approach limited by adverse effects. Because pain can start at infancy and continue throughout life, preventing the genesis of pain may be relatively better than treating the pain once it has been evoked. Therefore, we provide insights into the cellular and molecular mechanisms of sickle cell pain that contribute to the activation of the somatosensory system in the peripheral and central nervous systems. These mechanisms include mast cell activation and neurogenic inflammation, peripheral nociceptor sensitization, maladaptation of spinal signals, central sensitization, and modulation of neural circuits in the brain. In this review, we describe potential preventive/therapeutic targets and their targeting with novel pharmacologic and/or integrative approaches to ameliorate sickle cell pain.

scholarly journals Prevalence of Sickle Cell Disease and Other Haemoglobin Variants in Calabar, Cross River State, Nigeria

2019 ◽  
pp. 1-6
Author(s):  
Akaba Kingsley ◽  
Ofem Enang ◽  
Ofonime Essien ◽  
Annette Legogie ◽  
Omini Cletus ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Genetic Disorder ◽  
Globin Gene ◽  
Specific Gene ◽  
Cell Disease ◽  
Cellulose Acetate Electrophoresis ◽  
Genetic Changes ◽  
Female Ratio ◽  
Cross River State

Background: Sickle cell disease (SCD) is the commonest genetic disorder worldwide with a global prevalence of 20-25 million. About 12-15 million affected persons are in Sub-Sahara Africa with Nigeria bearing the highest burden of people living with sickle cell disease. SCD is a disease characterized as an autosomal, recessive, heterogeneous, and a monogenetic disorder caused by an A-to-T point mutation in the β-globin gene responsible for the production of abnormal hemoglobin S (HbS), which polymerizes in the deoxygenated state and results in the sickling of erythrocytes.  Haemoglobin variants are mutant forms of haemoglobin in a population usually occurring as a result of genetic changes in specific genes, or globins that causes change on alterations in the amino acid. They could affect the structure, behavior, the production rate and the stability of the specific gene. Well-known haemoglobin variants such as sick-cell anaemia are responsible for diseases and are considered haemoglobinopathies. Other variants cause no detectable pathology and are thus considered as non-pathological variants. Aim: The study is aimed at evaluating the burden of sickle cell disease and other haemoglobin variants in Calabar, South-South Nigeria. Methods: This is a retrospective study done at the haematology laboratory of University of Calabar Teaching Hospital, Calabar. Cellulose acetate electrophoresis at alkaline pH was used for the evaluation of haemoglobinopathies. The data were entered into Microsoft Excel 2016 spreadsheet and analysed with the IBM SPSS Version 22. Data were summarized into percentage of different phenotypes. Results: Results of the total 3648 haemoglobin electrophoresis recorded, 1368 (37.50%) were male while the remaining 2280 (62.5%) females given a male to female ratio of 1:1.7. Five haemoglobin phenotypes were identified as HbAA, HbAS, HbAC, HbSC and HbSS. The overall average values of their prevalence were HbAA 64.78%, HbAS 32.62%, HbSS 2.14%, HbAC 0.33%, HbSC 0.14%. Thus, the prevalence of SCD (Prevalence of HbSS+HbSC) was 2.28%. The highest proportion of SCD was observed in 2011 with least in 2016 and 2017 respectively. Conclusion: The prevalence of SCD and other haemoglobin variants in Calabar is similar to that of the national prevalence rate. There is need for continuous enlightenment and premarital counselling on the pattern of inheritance of SCD most especially with the increased burden of sickle traits in the environment has reported in this study.

scholarly journals Case Report: Acute Stroke in Young Adult Patient with Moyamoya Syndrome Secondary to Sickle Cell Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-13
Author(s):  
Oladipo Cole ◽  
Asia Filatov ◽  
Javed Khanni ◽  
Patricio Espinosa
Keyword(s):  
Case Report ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Moyamoya Disease ◽  
Conflicts Of Interest ◽  
Acute Chest Syndrome ◽  
African American Female ◽  
Moyamoya Syndrome ◽  
Cell Disease ◽  
Radiographic Findings

Moyamoya disease, well described in literature, is a chronic cerebrovascular occlusive disorder. It is characterized by progressive stenosis/occlusion of the terminal portions of the internal carotid arteries (ICA) and the proximal portions of the middle cerebral arteries (MCA). Less frequently described is Moyamoya syndrome, the name given to radiographic findings consistent with Moyamoya disease, but with an identifiable cause. The diseases associated with Moyamoya Syndrome include Sickle Cell Disease (SCD), Thalassemias, and Down's Syndrome to name a few. Common complications of Moyamoya include both ischemic and hemorrhagic strokes. Upon literature review, Moyamoya syndrome caused by SCD is not well described. When it is, the discussion is centered around the pediatric patient population and surgical management. Our case report describes a 22-year-old African American female with SCD who initially presented with Acute Chest Syndrome. Her hospital course was complicated by development of overt debilitating neurologic deficits. Subsequently, she was found to have Moyamoya Syndrome on neuroimaging. She was successfully treated with medical management without any surgical intervention. This case highlights the necessity of thorough examination, differential diagnosis, imaging findings, and consideration of predisposing syndromes in the work-up for Moyamoya syndrome; especially individuals with Sickle Cell Disease. Disclosures No relevant conflicts of interest to declare.

scholarly journals Utility of Procalcitonin in Differentiating Acute Chest Syndrome from Vaso-Occlusive Crisis in Sickle Cell Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-11
Author(s):  
Satish Maharaj ◽  
Simone Chang ◽  
Karan Seegobin ◽  
Marwan Shaikh ◽  
Kamila I. Cisak
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Complete Blood Count ◽  
Conflicts Of Interest ◽  
Statistical Significance ◽  
Acute Chest Syndrome ◽  
Adult Males ◽  
Cell Disease ◽  
Unequal Variances ◽  
Recorded Data

Background: Acute chest syndrome (ACS) frequently complicates sickle cell disease (SCD) and is a leading cause of hospitalization and mortality. Many factors have been implicated in ACS, including infections, thrombosis, fat and pulmonary emboli. However, a clear etiology is not defined in 50% of the cases and ACS is considered a clinical endpoint for different pathogenic processes (Vichinsky et al 2000). The non-specific nature of ACS makes diagnostic tests challenging, and there are no serum tests clinical used to aid diagnosis. Procalcitonin (PCT) is a prohormone of calcitonin and serum PCT rises within hours of an inflammatory stimulus. PCT has clinical utility as a marker of severe systemic inflammation, infection, and sepsis (Becker et al. 2008). Few studies have evaluated PCT as a biomarker for ACS in patients presenting with vaso-occlusive crises (VOC). Two studies have reported no difference in PCT (Biemond et al. 2018 and Stankovic et al 2011), while one study reported higher PCT between ACS and VOC (Patel et al 2014). Methods: We retrospectively reviewed 106 patients with SCD who presented to the emergency department with fever and painful crises during 2015-2019. The patients were divided into two categories based on discharge diagnoses - patients with VOC only (n=88) and patients with ACS (n=18). Inclusion criteria for both groups were patients with SCD, 17 years and older and PCT measurement on presentation. Exclusion criteria were defined as patients who had received empiric antibiotics prior to PCT testing. Data collected on presentation included genotype, age, gender, complete blood count, PCT, creatinine, total bilirubin and hydroxyurea use. Length of stay was recorded. Data was analyzed between the two groups using descriptive statistics and accounting for unequal variances, withp-value set at 0.05 for significance. Results: Demographics and clinical characteristics are summarized in Table 1 (Figure). The sample included primarily adult males (77%), with about two-thirds on hydroxyurea. Genotype HbSS (73.6%) was most prevalent followed by HbSC (22.6%) and HbSβ (3.8%). The ACS group had a higher percentage of HbSS, lower use of hydroxyurea and higher mean bilirubin. Mean PCT for the ACS group was 0.52 ng/mL (range, 0.05-2.04), compared to 0.31 ng/mL (range, 0.02-6.82) in the VOC group; withp=0.084. ROC analysis showed a PCT&gt;0.5ng/mL had 39% sensitivity and 85% specificity for ACS in this sample. Conclusion: In this sample, PCT on presentation was higher in those with ACS compared to VOC, but this difference did not achieve statistical significance. Further study in a larger population would be useful to evaluate this finding. Disclosures No relevant conflicts of interest to declare.

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