scholarly journals Phase-I Study of ETA Receptor Antagonist Ambrisentan in Sickle Cell Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 617-617
Author(s):  
Abdullah Kutlar ◽  
Jennifer Pollock ◽  
Steffen E. Meiler ◽  
Ryan Harris ◽  
Xu Hongyan ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Inflammatory Cytokines ◽  
Sickle Cell ◽  
Research Funding ◽  
Receptor Blockade ◽  
Tubular Injury ◽  
Cell Disease ◽  
Pressure Pain ◽  
Eta Receptor

Endothelin-1 (ET1) is a potent vasoconstrictor, mitogen, proinflammatory mediator and a mediator of nociception. Its synthesis is increased by hypoxia, ischemia, shear stress, oxidative stress and reduced nitric oxide (NO) bioavailability, all of which are well documented mechanisms in the pathophysiology of sickle cell disease. Two distinct receptors, ETA and ETB mediate opposing actions of ET1; while ETA mediates vasoconstriction, inflammation, cellular adhesion and vascular remodeling, ETB stimulation leads to increased NO production, vasodilatation, anticoagulation and anti-adhesion. We studied the role of ET1 in SCD in transgenic mouse models, and showed that selective ETA receptor blockade with ambrisentan provides renal protection by preventing the development of glomerular hyperfiltration, and preventing proteinuria (Kasztan et al, 2017; Taylor et al, 2019; Kasztan & Pollock, 2019).Additionaly, ETA receptor blockade was shown to decrease pulmonary inflammation in response to different stimuli, including hypoxia/reoxygenation and LPS (Meiler et al). Lutz et al (2018) showed that pharmacologic inhibition, or neuron specific knockdown of ETA receptor in primary sensory neurons of dorsal root ganglia in Berk mice alleviated basal and post-hypoxia evoked pain hypersensitivity. We then conducted a Phase 1, double blind, placebo controlled study to elucidate the role of ET-1 in 26 patients with SCD (SS or Sb0thal); patients were randomized to either ambrisentan 5 mg/day (N=13) or placebo (N=13) for 12 weeks. The primary end point was safety and tolerability. We also measured microalbuminuria, pressure pain threshold, transcranial doppler (TCD), echocardiograms (TR jet velocity), vascular endothelial function by flow mediated dilation (FMD), and inflammatory cytokines. Urine specimens were collected for measurement of markers of glomerular and tubular injury (NGAL, KIM-1, netrin and nephrin) at baseline and at the end of study (Day 85). Ambrisentan was well tolerated without any adverse events or fluid retention. No change in systolic and diastolic blood pressures were observed in either group (p=0.88, and p=049, respectively). No significant change in weight or serum creatinine was observed in the ambrisentan group (69.1→68.6 Kg, p=0.99, and 0.74→0.69 mg/dl, p=0.43). In the ambrisentan group, there was a tendency toward reduced microalbuminuria, (-36.6 mg/g Cr, vs +91.6), especially in the subgroup of patients who had been on a stable dose of ACE or ARB for 6 months (n=6, 286.1 mg/g Cr at baseline to 197.7 mg/g on day 85, p=0.06). FMD measurements showed increased arterial diameter, and improved microvascular function. Data collected for secondary end points including, TCD, TRV, inflammatory cytokines, markers of glomerular and tubular injury, quantitative sensory testing (QST) with pressure pain measurements, and von Frey monofilament readings, as well as quality of life measures (ASCQMe) are in the process of being analyzed. These data suggest that ETA receptor blockade is safe, well tolerated and has the potential to impact various aspects of disease pathophysiology in SCD. Disclosures Kutlar: Novartis: Consultancy; Global Blood Therapeutics, Inc. (GBT): Research Funding; Bluebird Bio: Other: DSMB Member; Novo Nordisk: Research Funding; Micelle Biopharma: Other: DSMB Chair. OffLabel Disclosure: Ambrisentan is an approved FDA drug used for treatment of another condition but it is expected that it will also help improve and/or prevent kidney damage that can be caused by sickle cell disease.

scholarly journals Use of Thromboprophylaxis for Central Venous Access Devices in Patients with Sickle Cell Disease: A Survey of Canadian Providers

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4173-4173
Author(s):  
Kristine Matusiak ◽  
Stephanie Forte ◽  
Jameel Abdulrehman ◽  
Madeleine Verhovsek ◽  
Kevin H.M. Kuo
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Research Funding ◽  
Central Venous Access ◽  
Venous Access ◽  
Cell Disease ◽  
Central Venous ◽  
Advisory Committees ◽  
History Of

Abstract Background: Sickle cell disease (SCD) induces a chronic prothrombotic state, with a cumulative incidence of venous thromboembolism (VTE) reported to be 11% by age 40. Central venous access devices (CVAD) are commonly used for chronic transfusions and iron chelation in this patient population.The presence of a CVAD is an additional risk factor for venous thromboembolism (VTE), with a catheter related thrombosis rate of 24%. Despite this high risk of VTE, the role of thromboprophylaxis in this setting is uncertain due to a lack of high quality data. Methods: A survey was administered in March 2021 to physicians caring for adult sickle cell disease patients via the Canadian Haemoglobinopathy Association (CanHaem), covering nine SCD comprehensive care centers in Canada. One reminder email was distributed after 3 weeks to encourage participation. Questions were directed at characterizing the practice size, number of patients with CVADs, and the role of thromboprophylaxis for CVADs. Physicians were also surveyed about their willingness to enroll their SCD patients with CVADs in a randomized trial of thromboprophylaxis versus placebo. Items were generated and selected based on face and content validity. Results are reported in medians and percentages, where applicable. Results: Responses were collected from 14 physicians who care for a median of 100 (IQR 185) adult sickle cell disease patients in practices across Canada. Physicians reported approximately 5% of their patients currently require a CVAD, and physicians estimated no CVAD patients are lost to follow up. Respondents use a variety of CVADs, including port-a-caths (75%), followed by PICC lines (58%), tunneled (25%) and non-tunneled CVCs (25%) (Figure 1). Duration of venous access was reported to be <1 month (17%), 1-3 months (8%), 3-6 months (0%), 6-12 months (8%), and >12 months (67%). Fifty percent of respondents indicated they do not use thromboprophylaxis for CVADs. Responses varied with respect to choice and dose of antiplatelet or anticoagulant in cases where thromboprophylaxis is used (Figure 2). Forty-two percent of physicians indicated they were not very confident or not at all confident in choice of prophylaxis. Past history of VTE was the most cited factor influencing the choice to use thromboprophylaxis. Physicians were generally in favour of enrolling patients in an RCT using thromboprophylaxis for CVADs. The exception was that 69% answered "No" when asked about enrolling patients with a prior history of VTE who are not currently on anticoagulation. One-hundred percent of physicians agreed that an RCT would improve their confidence in decision-making around thromboprophylaxis in their patients with CVADs. Conclusions: While there is evidence for an increased risk of VTE for SCD patients with CVADs, our results suggest there remains clinical equipoise with respect to the use of thromboprophylaxis. Thromboprophylaxis options were variable when physicians chose to use them, as there is no evidence to support specific antithrombotic regimens. All physicians surveyed are supportive of an RCT to clarify this management approach, and many would enroll their patients. As a result of this survey, a Canadian multicenter pilot RCT addressing this question is currently underway. Figure 1 Figure 1. Disclosures Forte: Pfizer: Research Funding; Canadian Hematology Society: Research Funding; Novartis: Honoraria. Verhovsek: Vertex: Consultancy. Kuo: Alexion: Consultancy, Honoraria; Celgene: Consultancy; Bluebird Bio: Consultancy; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Apellis: Consultancy. OffLabel Disclosure: This survey explored the use of LMWH, direct oral anticoagulants, warfarin and ASA for prophylaxis among patients with sickle cell disease using a central venous access device.

scholarly journals ETA Receptor Blockade and Vascular Function in Patients with Sickle Cell Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 25-26
Author(s):  
Daniel Adamkiewicz ◽  
Hongyan Xu ◽  
Latanya Bowman ◽  
Leigh Wells ◽  
Niren Patel ◽  
...  
Keyword(s):  
Blood Flow ◽  
Sickle Cell Disease ◽  
Synergistic Effect ◽  
Phase I ◽  
Flow Velocity ◽  
Vascular Function ◽  
Research Funding ◽  
Receptor Blockade ◽  
Cell Disease ◽  
Eta Receptor

Endothelin-1 (ET1) is a potent vasoconstrictor, mitogen, proinflammatory mediator, and a mediator of nociception, whose synthesis is increased by hypoxia, ischemia, shear stress, oxidative stress and reduced nitric oxide (NO) bioavailability, all of which are well documented mechanisms in the pathophysiology of sickle cell disease (SCD). We earlier reported on our studies on the role of ET-1 in SCD, and in transgenic mouse models showed that ETA receptor blockade with ambrisentan provides renal protection by preventing the development of glomerular hyperfiltration and proteinuria (Kasztan et al, 2017, Taylor et al, 2019, Kasztan and Pollock, 2019). ETA receptor blockade was also shown to decrease pulmonary inflammation in response to hypoxia/reoxygenation and LPS (Meiler et al.). Additionally, Lutz et al (2018) showed that pharmacologic inhibition or neuron specific knockdown of ETA receptor in primary sensory neurons of dorsal root ganglia in Berk mice alleviated basal and post-hypoxia evoked pain sensitivity. More recently (Kutlar et al, Blood 2019, 617,130036) we reported the preliminary results of a placebo controlled, double-blind phase I trial of ambrisentan in 26 subjects with SCD (SS and S-ß0 thalassemia) and microalbuminuria, and showed that the drug was well tolerated without any dose limiting toxicities and patients on ambrisentan had a reduction in microalbuminuria, especially in the subgroup who had been on concomitant ACEi/ARB therapy at a stable dose for at least six months (n=6, 286.1 mg/g Cr at baseline to 197.7 mg/g on day 85, p=0.06). FMD measurements showed increased arterial diameter, and improved microvascular function. We analyzed data collected on secondary end points during the phase I study, including Tricuspid regurgitant jet velocity (TRV), Transcranial Doppler (TCD) velocities in distal internal carotid (dICA) and middle cerebral (MCA) arteries, and eGFR (calculated with CKD-Epi formula). Fig. 1a shows eGFRs in ambrisentan and placebo groups; Fig. 1b and Fig. 1c show a breakdown of ambrisentan and placebo groups based on concomitant ACEi/ARB usage. There is a reduction in glomerular hyperfiltration in the ambrisentan group compared to placebo, more pronounced in the subgroup who have not been on ACEi/ARBs. Fig. 1d depicts the change in flow velocity in MCA (TAMMV, Time Averaged Mean Maximal Velocity, cm/sec) between the ambrisentan and placebo groups; similarly, Fig. 1e and 1f show the breakdown of baseline and Day 85 TAMMVs in MCA according to ACEi/ARB usage. A similar trend is also observed in dICA flow (fig. 1g-1i), and suggests a synergistic effect of ETA receptor blockade with ACEi/ARBs in preventing an increase in blood flow velocities. TRV was available on 7 subjects, 6 of which were in the ambrisentan group. Fig. 1j shows the change in TRV in the ambrisentan group, and again is suggestive of a synergistic effect of ambrisentan and ACEi/ARBs in decreasing TRV. These data are clearly very preliminary, and are obtained on a small number of subjects, and as such, do not warrant any conclusions and or speculations. Nevertheless, an interesting observation is the apparent interaction of ETA receptor blockade and ACEi/ARBs in altering vascular flow/function in SCD patients. Decrease in microalbuminuria has been reported with ACEi and ARBs in SCD (Yee et al, 2018), without any effect on GFR. A reduction in hyperfiltration would likely have a significant renoprotective effect, at an earlier stage in the development of sickle nephropathy. ETA receptor antagonists are approved for the treatment of pulmonary arterial hypertension; thus, a decrease in TRV would have a beneficial effect. Increase in blood flow velocity in major intracranial vessels is a well established risk factor for ischemic stroke in children with SCD; however, much less is known in adults. In summary, the effect of ETA receptor blockade with or without ACEi/ARB, may have a significant effect on vascular function/blood flow in different organ systems, and should be explored in a large, multi-center phase II trial, with and without concomitant and or serial ACEi/ARBs, for a longer period of time, with a dose escalation, to further clarify the pleiotropic effects on multiple aspects of SCD pathology. Figure 1 Disclosures Kutlar: NIH/NHLBI (SCDIC): Research Funding; Global Blood Therapeutics: Research Funding, Speakers Bureau; Micelle Biopharma: Consultancy; Novartis Pharmaceuticals: Consultancy, Research Funding; Novo Nordisk: Research Funding; Forma Therapeutics: Research Funding; REACH: Other: DSMB Member; NOHARM: Other: DSMB Member; Bluebird Bio: Other: DSMB Member.

scholarly journals Antiphospholipid Antibodies in Sickle Cell Disease: A Systematic Review and Exploratory Meta-Analysis

2021 ◽  
Vol 27 ◽  
pp. 107602962110029
Author(s):  
Mira Merashli ◽  
Alessia Arcaro ◽  
Maria Graf ◽  
Matilde Caruso ◽  
Paul R. J. Ames ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Antiphospholipid Antibodies ◽  
Meta Analysis ◽  
Age Groups ◽  
Anticardiolipin Antibodies ◽  
Cell Disease ◽  
Pooled Prevalence ◽  
The Relationship

The relationship between antiphospholipid antibodies (aPL) and sickle cell disease (SCD) has never been systematically addressed. Our aim was to evaluate potential links between SCD and aPL in all age groups. EMBASE/PubMed was screened from inception to May 2020 and Peto odds ratios for rare events were calculated. The pooled prevalence (PP) of IgG anticardiolipin antibodies (aCL) was higher in individuals with SCD than in controls (27.9% vs 8.7%, P < 0.0001), that of IgM aCL was similar in the two groups (2.9% vs 2.7%); only individuals with SCD were positive for lupus anticoagulant (LA) (7.7% vs 0%, P < 0.0001). The PP of leg ulcers was similar between aPL positive and negative individuals (44% vs 53%) and between patients in acute crisis and stable patients (5.6% vs 7.3%). Reporting of aPL as a binary outcome and not as a titer precluded further interpretation. The results indicate that a prospective case-control study with serial measurements of a panel of aPL in SCD patients might be warranted, in order to understand further the possible pathogenic role of aPL in SCD.

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.

Role of Adhesion Molecules and Vascular Endothelium in the Pathogenesis of Sickle Cell Disease

Hematology ◽  
2007 ◽  
Vol 2007 (1) ◽  
pp. 84-90 ◽  
Author(s):  
Marilyn J. Telen
Keyword(s):  
Sickle Cell Disease ◽  
Red Blood Cells ◽  
Adhesion Molecules ◽  
Sickle Cell ◽  
Vascular Endothelium ◽  
Blood Cells ◽  
Cell Disease ◽  
Adhesive Interactions ◽  
Lines Of Evidence

AbstractA number of lines of evidence now support the hypothesis that vaso-occlusion and several of the sequelae of sickle cell disease (SCD) arise, at least in part, from adhesive interactions of sickle red blood cells, leukocytes, and the endothelium. Both experimental and genetic evidence provide support for the importance of these interactions. It is likely that future therapies for SCD might target one or more of these interactions.

Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 362-369 ◽  
Author(s):  
Deepa Manwani ◽  
Paul S. Frenette
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Targeted Therapies ◽  
Therapeutic Intervention ◽  
Fetal Hemoglobin ◽  
Cell Disease ◽  
The Past ◽  
Symptomatic Management

Abstract Recurrent and unpredictable episodes of vaso-occlusion are the hallmark of sickle cell disease. Symptomatic management and prevention of these events using the fetal hemoglobin–reactivating agent hydroxyurea are currently the mainstay of treatment. Discoveries over the past 2 decades have highlighted the important contributions of various cellular and soluble participants in the vaso-occlusive cascade. The role of these elements and the opportunities for therapeutic intervention are summarized in this review.

scholarly journals Influence of Haptoglobin Polymorphism on Stroke in Sickle Cell Disease Patients

Genes ◽  
2022 ◽  
Vol 13 (1) ◽  
pp. 144
Author(s):  
Olivia Edwards ◽  
Alicia Burris ◽  
Josh Lua ◽  
Diana J. Wilkie ◽  
Miriam O. Ezenwa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Blood Cells ◽  
Cell Disease ◽  
Free Hemoglobin ◽  
Cerebral Tissue ◽  
Sickle Hemoglobin ◽  
Haptoglobin Polymorphism

This review outlines the current clinical research investigating how the haptoglobin (Hp) genetic polymorphism and stroke occurrence are implicated in sickle cell disease (SCD) pathophysiology. Hp is a blood serum glycoprotein responsible for binding and removing toxic free hemoglobin from the vasculature. The role of Hp in patients with SCD is critical in combating blood toxicity, inflammation, oxidative stress, and even stroke. Ischemic stroke occurs when a blocked vessel decreases oxygen delivery in the blood to cerebral tissue and is commonly associated with SCD. Due to the malformed red blood cells of sickle hemoglobin S, blockage of blood flow is much more prevalent in patients with SCD. This review is the first to evaluate the role of the Hp polymorphism in the incidence of stroke in patients with SCD. Overall, the data compiled in this review suggest that further studies should be conducted to reveal and evaluate potential clinical advancements for gene therapy and Hp infusions.

scholarly journals Causal role of L-glutamine in sickle cell disease painful crises: a Mendelian randomization analysis

2019 ◽  
Author(s):  
Yann Iboudo ◽  
Melanie E. Garrett ◽  
Pablo Bartolucci ◽  
Carlo Brugnara ◽  
Clary B. Clish ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Small Molecules ◽  
Causal Relationship ◽  
Sickle Cell ◽  
Drug Targets ◽  
Mendelian Randomization ◽  
Cell Disease ◽  
Aseptic Necrosis ◽  
Randomization Analysis

ABSTRACTIn a recent clinical trial, the metabolite L-glutamine was shown to reduce painful crises in sickle cell disease (SCD) patients. To confirm this observation and identify other metabolites implicated in SCD clinical heterogeneity, we profiled 129 metabolites in the plasma of 705 SCD patients. We tested correlations between metabolite levels and six SCD-related complications (painful crises, cholecystectomy, retinopathy, leg ulcer, priapism, aseptic necrosis) or estimated glomerular filtration rate (eGFR), and used Mendelian randomization (MR) to assess causality. We found a causal relationship between L-glutamine levels and painful crises (N=1,278, odds ratio (OR) [95% confidence interval] = 0.68 [0.52 – 0.89], P=0.0048). In two smaller SCD cohorts (N=299 and 406), the protective effect of L-glutamine was observed (OR=0.82 [0.50-1.34]), although the MR result was not significant (P=0.44). We identified 66 significant correlations between the levels of other metabolites and SCD-related complications or eGFR. We tested these correlations for causality using MR analyses and found no significant causal relationship. The baseline levels of quinolinic acid was associated with prospectively ascertained survival in SCD patients, and this effect was dependent on eGFR. Metabolomics provide a promising approach to prioritize small molecules that may serve as biomarkers or drug targets in SCD.

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