scholarly journals Current and novel therapies for the prevention of vaso-occlusive crisis in sickle cell disease

2020 ◽  
Vol 11 ◽  
pp. 204062072095500
Author(s):  
Ifeyinwa Osunkwo ◽  
Deepa Manwani ◽  
Julie Kanter
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Severe Pain ◽  
Management Strategies ◽  
Organ Damage ◽  
Care Utilization ◽  
Cell Disease ◽  
High Resource ◽  
Emerging Treatments

Individuals with sickle cell disease (SCD) are living further into adulthood in high-resource countries. However, despite increased quantity of life, recurrent, acute painful episodes cause significant morbidity for affected individuals. These SCD-related painful episodes, also referred to as vaso-occlusive crises (VOCs), have multifactorial causes, and they often occur as a result of multicellular aggregation and vascular adherence of red blood cells, neutrophils, and platelets, leading to recurrent and unpredictable occlusion of the microcirculation. In addition to severe pain, long-term complications of vaso-occlusion may include damage to muscle and/or bone, in addition to vital organs such as the liver, spleen, kidneys, and brain. Severe pain associated with VOCs also has a substantial detrimental impact on quality of life for individuals with SCD, and is associated with increased health care utilization, financial hardship, and impairments in education and vocation attainment. Previous treatments have targeted primarily SCD symptom management, or were broad nontargeted therapies, and include oral or parenteral hydration, analgesics (including opioids), nonsteroidal anti-inflammatory agents, and various other types of nonpharmacologic pain management strategies to treat the pain associated with VOC. With increased understanding of the pathophysiology of VOCs, there are several new potential therapies that specifically target the pathologic process of vaso-occlusion. These new therapies may reduce cell adhesion and inflammation, leading to decreased incidence of VOCs and prevention of end-organ damage. In this review, we consider the benefits and limitations of current treatments to reduce the occurrence of VOCs in individuals with SCD and the potential impact of emerging treatments on future disease management.

scholarly journals How I treat and manage strokes in sickle cell disease

Blood ◽  
2015 ◽  
Vol 125 (22) ◽  
pp. 3401-3410 ◽  
Author(s):  
Adetola A. Kassim ◽  
Najibah A. Galadanci ◽  
Sumit Pruthi ◽  
Michael R. DeBaun
Keyword(s):  
Sickle Cell Disease ◽  
Blood Transfusion ◽  
Sickle Cell ◽  
Exchange Transfusion ◽  
Management Strategies ◽  
Cell Disease ◽  
Transfusion Therapy ◽  
Hematopoietic Stem ◽  
Neuro Imaging

Abstract Neurologic complications are a major cause of morbidity and mortality in sickle cell disease (SCD). In children with sickle cell anemia, routine use of transcranial Doppler screening, coupled with regular blood transfusion therapy, has decreased the prevalence of overt stroke from ∼11% to 1%. Limited evidence is available to guide acute and chronic management of individuals with SCD and strokes. Current management strategies are based primarily on single arm clinical trials and observational studies, coupled with principles of neurology and hematology. Initial management of a focal neurologic deficit includes evaluation by a multidisciplinary team (a hematologist, neurologist, neuroradiologist, and transfusion medicine specialist); prompt neuro-imaging and an initial blood transfusion (simple followed immediately by an exchange transfusion or only exchange transfusion) is recommended if the hemoglobin is >4 gm/dL and <10 gm/dL. Standard therapy for secondary prevention of strokes and silent cerebral infarcts includes regular blood transfusion therapy and in selected cases, hematopoietic stem cell transplantation. A critical component of the medical care following an infarct is cognitive and physical rehabilitation. We will discuss our strategy of acute and long-term management of strokes in SCD.

scholarly journals Morphine for the Treatment of Pain in Sickle Cell Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Mihir Gupta ◽  
Lilian Msambichaka ◽  
Samir K. Ballas ◽  
Kalpna Gupta
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Clinical Studies ◽  
Severe Pain ◽  
Organ Damage ◽  
Cell Disease ◽  
Organ Function ◽  
Specific Effects ◽  
Organ Specific ◽  
Chronic Use

Pain is a hallmark of sickle cell disease (SCD) and its treatment remains challenging. Opioids are the major family of analgesics that are commonly used for treating severe pain. However, these are not always effective and are associated with the liabilities of their own. The pharmacology and multiorgan side effects of opioids are rapidly emerging areas of investigation, but there remains a scarcity of clinical studies. Due to opioid-induced endothelial-, mast cell-, renal mesangial-, and epithelial-cell-specific effects and proinflammatory as well as growth influencing signaling, it is likely that when used for analgesia, opioids may have organ specific pathological effects. Experimental and clinical studies, even though extremely few, suggest that opioids may exacerbate existent organ damage and also stimulate pathologies of their own. Because of the recurrent and/or chronic use of large doses of opioids in SCD, it is critical to evaluate the role and contribution of opioids in many complications of SCD. The aim of this review is to initiate inquiry to develop strategies that may prevent the inadvertent effect of opioids on organ function in SCD, should it occur, without compromising analgesia.

scholarly journals Voxelotor: alteration of sickle cell disease pathophysiology by a first-in-class polymerization inhibitor

2021 ◽  
Vol 12 ◽  
pp. 204062072110011
Author(s):  
Alexander K. Glaros ◽  
Reza Razvi ◽  
Nirmish Shah ◽  
Ahmar U. Zaidi
Keyword(s):  
Sickle Cell Disease ◽  
Hemolytic Anemia ◽  
Sickle Cell ◽  
Clinical Stage ◽  
Pharmaceutical Research ◽  
Organ Damage ◽  
Cell Disease ◽  
Disease Modifying Drugs ◽  
Long Term Follow Up

Sickle cell disease, despite its recognition as a severely debilitating genetic condition affecting hundreds of thousands of neonates throughout the world each year, was not a target of pharmaceutical research focus for most of its 100-year existence in the medical consciousness. This has changed in recent years as many novel therapeutics are currently under investigation, with three new disease-modifying drugs achieving FDA approval in the last 4 years. One of these drugs, voxelotor, is especially encouraging as an inhibitor of sickling for its ability to safely improve the chronic hemolytic anemia of sickle cell disease. This was demonstrated during all clinical phases of investigation by an average improvement in hemoglobin of greater than 1 g/dL, as well as statistically significant improvements in established markers of hemolysis. While anemia itself represents a potential cause of morbidity, it is more importantly a marker of the hemolysis known to cause the long-term vascular and organ damage that makes sickle cell disease so debilitating and frequently fatal early in life. Given the recency of the approval, there has not been sufficient long-term follow-up to demonstrate improvement in the chronic sequelae of sickle cell disease as a result of voxelotor-induced improvements in hemolytic anemia. There is hope, however, based on the experience with hydroxyurea improving morbidity and mortality via reductions in sickling and improved rheology, that voxelotor may have similar long-term benefits by positively manipulating the kinetics of hemoglobin polymerization. This review aims to summarize the targeted pathobiology of sickle cell disease, the mechanism of action of voxelotor, and the safety and efficacy data from preclinical to late clinical stage investigations of this long-awaited medication, in the hopes of better informing the decision-making process behind prescribing or not prescribing it for patients in need of intervention.

scholarly journals International Differences in Outpatient Pain Management: A Survey of Sickle Cell Disease

2019 ◽  
Vol 8 (12) ◽  
pp. 2136
Author(s):  
Nadirah El-Amin ◽  
Paul Nietert ◽  
Julie Kanter
Keyword(s):  
Pain Management ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Management Strategies ◽  
Sampling Strategy ◽  
The United States ◽  
Care Utilization ◽  
Snowball Sampling ◽  
Cell Disease ◽  
Prescribing Practices

Vaso-occlusive pain crises are the hallmark of sickle cell disease (SCD) and the primary reason for health care utilization. Both national and international guidelines recommend aggressive intravenous opioids, intravenous fluids and anti-inflammatory therapy as the mainstay of treatment for acute SCD pain. However, many vaso-occlusive crises are managed at home with oral medication and supportive care. There are no guidelines on home medication management of SCD-related pain, likely due to the lack of well-defined endpoints for acute events and the lack of funding for already approved pain medications. Amplifying this issue is the growing concern for opioid abuse and misuse in the United States (US) and internationally. This study aimed to evaluate differences in opioid prescribing practices among providers treating SCD in the US and internationally. A survey was disseminated electronically to known providers using a combination of purposive and snowball sampling strategy. There were 127 responses and 17 countries represented. US providers were more likely to prescribe opioids (p < 0.001) and were more likely to be “very comfortable” prescribing opioids than non-US prescribers (p < 0.001). US providers also tended to prescribe more tablets per patient of stronger opioids than non-US physicians. US physicians were more likely to be concerned that patients were abusing opioids than non-US physicians (32% vs. 27%, p < 0.05). There are significant variations in how different parts of the world manage pain in the outpatient setting for SCD. Identifying optimal home pain management strategies is necessary to improve care and long-term outcomes in SCD.

scholarly journals High Molecular Weight Kininogen Contributes to End-Organ Damage and Mortality in a Mouse Model of Sickle Cell Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 268-268 ◽  
Author(s):  
Erica Sparkenbaugh ◽  
Kathryn Wilson ◽  
Malgorzata Kasztan ◽  
David M. Pollock ◽  
Keith R. McCrae ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Bone Marrow ◽  
Sickle Cell Disease ◽  
High Molecular Weight ◽  
Sickle Cell ◽  
Thrombin Generation ◽  
Organ Damage ◽  
High Molecular Weight Kininogen ◽  
Cell Disease

Abstract Introduction: Recent advances in preventive care, such as hydoxyurea and prophylactic antibiotics, have reduced the mortality of children with sickle cell disease (SCD) s in developed countries. Yet, the chronic hemolytic anemia and recurrent vaso-occlusive crises result in systemic inflammation and coagulopathy. Markers of coagulation activation correlate with painful crises, acute chest syndrome, stroke, venous thromboembolism, pulmonary hypertension, left ventricular diastolic heart disease, and sickle nephropathy. These complications result in end-organ failure that causes increased morbidity and mortality in adult SCD patients. We have shown that tissue factor (TF), the primary initiator of extrinsic coagulation, contributes to inflammation and coagulation in mouse models of SCD. (1,2). It has also been demonstrated that long-term reduction in thrombin protects from cardiopulmonary dysfunction and reduces mortality of sickle cell mice (3). Recent work from our laboratory demonstrates that high molecular weight kininogen (HK) promotes thrombin generation and inflammation in sickle mice. HK is proteolytically cleaved into bradykinin and cleaved HK fragments (HKf) by kallikrein and other proteases. HKf induces TF expression and activity on monocytes dependent on Mac-1 (CD11b/CD18). We found that Mac-1 inhibition attenuates thrombin generation and inflammation in sickle cell mice. Hypothesis: Long-term HK deficiency in sickle cell mice will attenuate TF-mediated coagulation and inflammation, and protect against end-organ damage and mortality. Methods and Results: To evaluate the effect of long-term HK deficiency on outcomes in sickle cell disease, we used bone marrow from Townes sickle (SS) and wild type (AA) mice to generate chimeras in lethally irradiated HK+/+ (WT) and HK-/- (KO) mice to create AA/WT, AA/KO, SS/WT, and SS/KO mice. Efficient reconstitution of bone marrow was confirmed by hemoglobin electrophoresis. Eight months after chimeras were generated, endpoints were assessed. SS/WT mice had early mortality (median survival 209 days, 6/23 mice survived to 250 days); HK deficiency significantly prolonged survival in SS mice (median survival 240 days, 24/29 mice survived to 250 days; p<0.01). Plasma levels of interleukin-6 were significantly higher in SS/WT mice compared to AA/WT controls (21 ± 3.7 ng/mL vs 6.6 ± 2.2 ng/mL in AA/WT, p<0.001); HK deficiency attenuated this increase (5.1 ± 1.2 ng/mL, p<0.001). The neutrophil-lymphocyte ratio was also elevated in SS/WT mice (0.47 ± 0.004 vs 0.3 ± 0.05 in AA/WT, p<0.05), yet not in the SS/KO group (0.25 ± 0.07, p<0.05), indicating that HK deficiency protects against inflammation in SS mice. Analysis of urine for renal injury markers revealed that SS/WT mice had elevated urine albumin/creatinine ratios (652 ± 34 mg albumin/g creatinine vs. 276 ± 54, p<0.01), which was significantly decreased in SS/KO mice (321 ± 49, p<0.01). Moreover, SS/WT mice had significantly reduced urine osmolality compared to AA/WT controls (2116 mOsm/kg vs 1208 mOsm/kg, p<0.05), which was reversed in SS/KO mice (1842 mOsm/kg, p<0.05). This suggests that HK deficiency protects against kidney injury and preserves urinary concentrating ability. We also observed increases in the relative left ventricle (LV+S/BW; 4.9 ± 0.2 vs 3.3 ± 0.1, p<0.05) and right ventricle (RV/BW; 1.4 ± 0.4 vs 0.99 ± 0.09, p<0.05) size in SS/WT mice compared to AA/WT controls, which was prevented in SS/KO mice (LV+S/BW: 4.0 ± 0.2, p<0.05 and RV/BW: 1.1 ± 0.06, p<0.05). Conclusions: These data indicate that HK deficiency attenuates chronic inflammation, kidney failure, and heart hypertrophy, and improves survival of sickle cell mice. Disclosures No relevant conflicts of interest to declare.

scholarly journals Feasibility of an mHealth self-management intervention for children and adolescents with sickle cell disease and their families

2021 ◽  
Author(s):  
Shannon Phillips ◽  
Julie Kanter ◽  
Martina Mueller ◽  
Amy Gulledge ◽  
Kenneth Ruggiero ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Rating Scale ◽  
Management Strategies ◽  
Self Management ◽  
Cell Disease ◽  
Vessel Occlusion ◽  
Feasibility Assessment ◽  
Management Intervention ◽  
Scale Scores

Abstract Sickle cell disease (SCD) is an inherited hemoglobinopathy that leads to blood vessel occlusion and multiorgan complications, including pain, that may be experienced daily. Symptom management often begins at home, and tools are needed to support self-management strategies that can be implemented by children with SCD and families. The purpose of this study was to assess the feasibility of the mHealth self-management intervention (application) Voice Crisis Alert V2 for children with SCD and families. Feasibility assessment was guided by the Reach, Efficacy, Adoption, Implementation, and Maintenance framework. Data were collected with 60 dyads (children with SCD/caregivers) at four time points. Self-management data were collected via application use, and postintervention interviews were conducted. Analyses included descriptive statistics and constant comparison with directed content analysis. Recruitment was completed in 28 weeks, with 82% retention at end-of-intervention. Mobile Application Rating Scale scores and interview data indicated high satisfaction. From baseline to mid-intervention, 94% of dyads used the application (75% of total use); 45% used the application from mid-intervention to the end-of-intervention. Dyads made 2,384 actions in the application; the most commonly used features were recording health history and recording and tracking symptoms. Few reported issues with the application; most issues occurred early in the study and were corrected. After the intervention period was completed, 37% continued to use the application. Feasibility was confirmed by meeting recruitment and retention goals, high adoption of the application, and high reported satisfaction with the application. Challenges with sustained use were encountered, and areas for improvement were identified.

scholarly journals Sickle Cell Disease: Role of Oxidative Stress and Antioxidant Therapy

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 296
Author(s):  
Rosa Vona ◽  
Nadia Maria Sposi ◽  
Lorenza Mattia ◽  
Lucrezia Gambardella ◽  
Elisabetta Straface ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Globin Gene ◽  
Organ Damage ◽  
Cell Disease ◽  
Vessel Occlusion ◽  
Antioxidant Agents ◽  
Oxidant Status

Sickle cell disease (SCD) is the most common hereditary disorder of hemoglobin (Hb), which affects approximately a million people worldwide. It is characterized by a single nucleotide substitution in the β-globin gene, leading to the production of abnormal sickle hemoglobin (HbS) with multi-system consequences. HbS polymerization is the primary event in SCD. Repeated polymerization and depolymerization of Hb causes oxidative stress that plays a key role in the pathophysiology of hemolysis, vessel occlusion and the following organ damage in sickle cell patients. For this reason, reactive oxidizing species and the (end)-products of their oxidative reactions have been proposed as markers of both tissue pro-oxidant status and disease severity. Although more studies are needed to clarify their role, antioxidant agents have been shown to be effective in reducing pathological consequences of the disease by preventing oxidative damage in SCD, i.e., by decreasing the oxidant formation or repairing the induced damage. An improved understanding of oxidative stress will lead to targeted antioxidant therapies that should prevent or delay the development of organ complications in this patient population.

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.

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