A novel, effective, and efficient strategy for treating sickle cell vaso-occlusive events in the infusion center setting.
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ABSTRACT:
SUBMITTER: Peslak SA
PROVIDER: S-EPMC9979427 | biostudies-literature | 2023 Feb
REPOSITORIES: biostudies-literature
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A novel, effective, and efficient strategy for treating sickle cell vaso-occlusive events in the infusion center setting.
Peslak Scott A SA Akins Alexis Brimm AB Foxwell Anessa M AM Iannelli Marie M Grande Carolyn C Breen Delisha D Russell J Eric JE Uritsky Tanya J TJ Sayani Farzana A FA
Blood advances 20230201 3
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Project description:Painful vaso-occlusive crisis (VOC) remains the most common reason for presenting to the Emergency Department and hospitalization in patients with sickle cell disease (SCD). Although two new agents have been approved by the Food and Drug Administration for treating SCD, they both target to reduce the frequency of VOC. Results from studies investigating various approaches to treat and shorten VOC have so far been generally disappointing. In this paper, we will summarize the complex pathophysiology and downstream events of VOC and discuss the likely reasons for the disappointing results using monotherapy. We will put forward the rationale for exploring some of the currently available agents to either protect erythrocytes un-involved in the hemoglobin polymerization process from sickling induced by the secondary events, or a multipronged combination approach that targets the complex downstream pathways of VOC.
| S-EPMC8454100 | biostudies-literature
Project description:Hematopoietic stem cell transplantation (HSCT) is potentially curative for patients with sickle cell disease (SCD). Patients with stable donor engraftment after allogeneic HSCT generally do not experience SCD-related complications; however, there are no published data specifically reporting the change in vaso-occlusive events (VOE) after HSCT. Data regarding the number of VOEs requiring medical attention in the 2 years before allogeneic HSCT were compared with the number of VOEs in the 2 years (0-12 months and 12-24 months) after allogeneic HSCT in patients with SCD. One-hundred sixty-three patients with SCD underwent allogeneic HSCT between 2005 and 2019. The average age at the time of HSCT was 21 years (range, 7 months - 64 years). Most patients underwent nonmyeloablative conditioning (75% [N = 123]) and had a matched sibling donor (72% [N = 118]). The mean number of VOEs was reduced from 5.6 (range, 0-52) in the 2 years before HSCT to 0.9 (range, 0-12) in the 2 years after HSCT (P < .001). Among the post-HSCT events, VOE was more frequent during the first 12 months (0.8 [range, 0-12]) than at 12 to 24 months after HSCT (0.1 [range, 0-8) (P < .001)). In patients who had graft rejection (12%, N = 20), VOEs were reduced from 6.6 (range, 0-24) before HSCT to 1.1 (range, 0-6) and 0.8 (range, 0-8) at 0 to 12 months and 12 to 24 months after HSCT, respectively (P < .001). VOEs requiring medical care were significantly reduced after allogeneic HSCT for patients with SCD. These data will inform the development of novel autologous HSCT gene therapy approaches.
| S-EPMC9860452 | biostudies-literature
Project description: Not available
| S-EPMC10362533 | biostudies-literature
Project description:IntroductionVaso-occlusive crisis (VOC) is one of the main causes of hospital admission in patients with sickle cell disease (SCD). Ketamine is often used as an adjuvant to opioids to control sickle cell crisis; however, there is a lack of evidence about its safety and efficacy for VOC in SCD patients.ObjectiveTo synthesize evidence from published reports about the efficacy and safety of ketamine in the management of acute painful VOC in both pediatric and adult SCD patients.MethodsA systematic literature search of PubMed, Scopus, Web of Science, EBSCO and Cochrane Library was conducted, up to March 2019. Studies reporting the analgesic effects and side effects of ketamine in the management of acute painful VOC in pediatric and adult SCD patients were included. The primary outcome measure was improvement in pain scale, and the secondary outcomes were reduction in opioid utilization and side effects. Studies were narratively summarized in this review.ResultsFourteen studies (with a total of 604 patients) were included in the final analysis. Several case reports and case series showed that ketamine significantly reduced pain scales and opioid utilization in both populations. The only randomized controlled trial available showed that ketamine was noninferior to morphine in reducing pain scores, but had a higher incidence of nonlife-threatening, reversible adverse effects. However, a retrospective study of 33 patients showed a higher pain score in the ketamine group with an acceptable short-term adverse effect.ConclusionKetamine has a potentially comparable efficacy with other opioids in reducing the pain during VOC in SCD patients. However, it also likely has a higher rate of transient adverse events. Owing to the lack of published randomized controlled trials, current evidence is not sufficient to confirm the safety and efficacy of ketamine. Future well-designed randomized controlled trials are strongly recommended.
| S-EPMC7839575 | biostudies-literature
Project description:Acute vaso-occlusive crisis (VOC) in sickle cell disease (SCD) is an important cause of end-organ damage. It is estimated that 10-39% of VOC occurs with hepatic involvement. Current assessments of hepatic involvement during VOC are unsatisfactory. We investigated transient elastography (TE) as a marker of hepatic involvement, its relationship with histology, and biochemical markers during VOC. SCD patients were evaluated with biochemical markers and TE at steady-state and during VOC. Change in TE and biochemical markers were correlated with length of hospital stay. When available, liver biopsy and tricuspid regurgitation velocity (TRV) at steady-state were correlated with TE. Twenty-three patients were evaluated (mean age = 34.3 years, standard deviation = 7.96). In 15 patients with liver biopsies, TE correlated with fibrosis (P = 0.01) and TRV (P = 0.0063), but not hepatic iron. Hemolysis biomarkers changed during VOC (P < 0.022), but not alanine aminotransferase (ALT). Paired comparison of TE at steady-state and during VOC showed an increased from 6.2 to 12.3 kPa (P = 0.0029). Increasing TE during VOC associated with increasing ALT and alkaline phosphatase (P = 0.0088 and 0.0099, respectively). At steady-state, increasing inflammation on biopsy (P = 0.0037) and TRV (P = 0.0075) correlated with increasing TE during VOC. Increased hospital stay was associated with higher ALT (P = 0.041), lower albumin (P = 0.046), hemoglobin/hematocrit (P < 0.0021) but not TE. TE may identify patients with hepatic involvement during VOC independent of biochemical measures. Increase in TE may reflect both hepatic passive congestion and hepatic involvement during VOC. TE may serve as a physiological biomarker for hepatic features of VOC.
| S-EPMC3808506 | biostudies-literature
Project description:Pain is an hallmark of sickle-cell-related acute clinical manifestations as part of acute vaso-occlusive crisis (VOC). In SCD pain has different origins such as vascular or neuropathic pain, which requires multimodal analgesia. This is based on the administration of drugs with different pharmacological mechanisms of action, maximizing analgesia and minimizing their adverse events and the risk of drug-addition in patients experiencing acute-recurrent pain events as in SCD. Ketorolac is a potent non-narcotic analgesic, being relatively safe and effective during pain-management in children and adults. Up to now, there is a lack of safety information on continuous infusion ketorolac as used to control acute pain in patients with SCD, and the benefits/risks ratio needs to be investigated. Here, we report for the first time the safety profile of ketorolac in the special population of patients with SCD. We confirmed that ketorolac in combination with tramadol, an opioid like molecule, is effective in pain control of adult patients with SCD experiencing acute severe VOCs defined by pain visual analog scale. Our study shows that short term (72 h) continuous infusion of ketorolac plus tramadol is not associated with adverse events such as liver or kidney acute disfunction or abnormalities in coagulation parameters during patients' hospitalization and within 30 days after patients discharge. This is extremely important for patients with SCD, who should have access to multimodal therapy to control recurrent acute pain crisis in order to limit central sensitization a fearsome issue of undertreated recurrent acute pain and of chronic pain.
| S-EPMC10801952 | biostudies-literature
Project description:Pain is an hallmark of sickle-cell-related acute clinical manifestations as part of acute vaso-occlusive crisis (VOC). In SCD pain has different origins such as vascular or neuropathic pain, which requires multimodal analgesia. This is based on the administration of drugs with different pharmacological mechanisms of action, maximizing analgesia and minimizing their adverse events and the risk of drug-addition in patients experiencing acute-recurrent pain events as in SCD. Ketorolac is a potent non-narcotic analgesic, being relatively safe and effective during pain-management in children and adults. Up to now, there is a lack of safety information on continuous infusion ketorolac as used to control acute pain in patients with SCD, and the benefits/risks ratio needs to be investigated. Here, we report for the first time the safety profile of ketorolac in the special population of patients with SCD. We confirmed that ketorolac in combination with tramadol, an opioid like molecule, is effective in pain control of adult patients with SCD experiencing acute severe VOCs defined by pain visual analog scale. Our study shows that short term (72 h) continuous infusion of ketorolac plus tramadol is not associated with adverse events such as liver or kidney acute disfunction or abnormalities in coagulation parameters during patients' hospitalization and within 30 days after patients discharge. This is extremely important for patients with SCD, who should have access to multimodal therapy to control recurrent acute pain crisis in order to limit central sensitization a fearsome issue of undertreated recurrent acute pain and of chronic pain.
| S-EPMC10801952 | biostudies-literature
Project description:Heme, released from red blood cells in sickle cell disease (SCD), interacts with toll-like receptor 4 (TLR4) to activate NF-κB leading to the production of cytokines and adhesion molecules which promote inflammation, pain, and vaso-occlusion. In SCD, TLR4 inhibition has been shown to modulate heme-induced microvascular stasis and lung injury. We sought to delineate the role of endothelial verses hematopoietic TLR4 in SCD by developing a TLR4 null transgenic sickle mouse. We bred a global Tlr4-/- deficiency state into Townes-AA mice expressing normal human adult hemoglobin A and Townes-SS mice expressing sickle hemoglobin S. SS-Tlr4-/- had similar complete blood counts and serum chemistries as SS-Tlr4 +/+ mice. However, SS-Tlr4-/- mice developed significantly less microvascular stasis in dorsal skin fold chambers than SS-Tlr4 +/+ mice in response to challenges with heme, lipopolysaccharide (LPS), and hypoxia/reoxygenation (H/R). To define a potential mechanism for decreased microvascular stasis in SS-Tlr4-/- mice, we measured pro-inflammatory NF-κB and adhesion molecules in livers post-heme challenge. Compared to heme-challenged SS-Tlr4 +/+ livers, SS-Tlr4 -/- livers had lower adhesion molecule and cytokine mRNAs, NF-κB phospho-p65, and adhesion molecule protein expression. Furthermore, lung P-selectin and von Willebrand factor immunostaining was reduced. Next, to establish if endothelial or hematopoietic cell TLR4 signaling is critical to vaso-occlusive physiology, we created chimeric mice by transplanting SS-Tlr4 -/- or SS-Tlr4 +/+ bone marrow into AA-Tlr4 -/- or AA-Tlr4 +/+ recipients. Hemin-stimulated microvascular stasis was significantly decreased when the recipient was AA-Tlr4-/- . These data demonstrate that endothelial, but not hematopoietic, TLR4 expression is necessary to initiate vaso-occlusive physiology in SS mice.
| S-EPMC7851052 | biostudies-literature
Project description:The search for predictive indicators of disease has largely focused on molecular markers. However, biophysical markers, which can integrate multiple pathways, may provide a more global picture of pathophysiology. Sickle cell disease affects millions of people worldwide and has been studied intensely at the molecular, cellular, tissue, and organismal level for a century, but there are still few, if any, markers quantifying the severity of this disease. Because the complications of sickle cell disease are largely due to vaso-occlusive events, we hypothesized that a physical metric characterizing the vaso-occlusive process could serve as an indicator of disease severity. Here, we use a microfluidic device to characterize the dynamics of "jamming," or vaso-occlusion, in physiologically relevant conditions, by measuring a biophysical parameter that quantifies the rate of change of the resistance to flow after a sudden deoxygenation event. Our studies show that this single biophysical parameter could be used to distinguish patients with poor outcomes from those with good outcomes, unlike existing laboratory tests. This biophysical indicator could therefore be used to guide the timing of clinical interventions, to monitor the progression of the disease, and to measure the efficacy of drugs, transfusion, and novel small molecules in an ex vivo setting.
| S-EPMC3633235 | biostudies-literature
Project description:Inhibition of leukocyte adhesion to the vascular endothelium represents a novel and important approach for decreasing sickle cell disease (SCD) vaso-occlusion. Using a humanized SCD-mouse-model of tumor necrosis factor-?-induced acute vaso-occlusion, we herein present data demonstrating that short-term administration of either hydroxyurea or the phosphodiesterase 9 (PDE9) inhibitor, BAY73-6691, significantly altered leukocyte recruitment to the microvasculature. Notably, the administration of both agents led to marked improvements in leukocyte rolling and adhesion and decreased heterotypic red blood cell-leukocyte interactions, coupled with prolonged animal survival. Mechanistically, these rheologic benefits were associated with decreased endothelial adhesion molecule expression, as well as diminished leukocyte Mac-1-integrin activation and cyclic guanosine monophosphate (cGMP)-signaling, leading to reduced leukocyte recruitment. Our findings indicate that hydroxyurea has immediate beneficial effects on the microvasculature in acute sickle-cell crises that are independent of the drug's fetal hemoglobin-elevating properties and probably involve the formation of intravascular nitric oxide. In addition, inhibition of PDE9, an enzyme highly expressed in hematopoietic cells, amplified the cGMP-elevating effects of hydroxyurea and may represent a promising and more tissue-specific adjuvant therapy for this disease.
| S-EPMC3466969 | biostudies-literature