scholarly journals Impact of Autoimmune Disease and Its Treatment on Adults with Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4182-4182
Author(s):  
Jennel Zeppieri ◽  
Desmond Aroke ◽  
Alice J. Cohen
Keyword(s):  
Autoimmune Disease ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Low Dose ◽  
Adult Patients ◽  
High Dose ◽  
Complement Pathway ◽  
Cell Disease ◽  
Pain Crisis ◽  
Ed Visits

Abstract Background: Sickle cell disease (SCD) is one of the most common inherited diseases worldwide. Within the United States, it affects 1 in 100,000 people and 1 in 365 African American births. Management requires a comprehensive team dedicated to improving quality of life by minimizing the frequency of pain crisis, hospitalizations and infections that ultimately can reduce mortality. Susceptibility to infections among SCD patients is partly attributed to impaired host defense from chronic activation of the alternative complement pathway. This complement pathway dysregulation has also been suggested to predispose SCD patients to an array of autoimmune diseases (AID). It has been reported that the prevalence of AID in SCD teens and adults is 1.8%. The overlapping clinical manifestations and hematological abnormalities represent a challenge in diagnosing a coexisting AID among SCD patients and likely contribute to an under-reporting of its prevalence in the literature. Once coexistence is established, optimizing the management of each disease is challenging as the therapeutic treatment particularly the use of high dose steroids may exacerbate complications of SCD. The aim of this study was to assess the impact of AID and its treatment on SCD outcomes. Methods: In our retrospective review of 300 adult patients cared for in the adult SCD center from 2016-2021 we identified four patients (1.3%) who met the criteria of SCD and a confirmed diagnosis of an AID. Data that was reviewed included: age, type of SCD, type of AID, treatments of both, number of hospitalizations and ED visits and complications. Results: Four patients, all women between the ages of 38-42 years at the time of AID diagnosis, were identified. The coexisting SCD type and AID were as follows: HbSS with hereditary persistent of HbF(HPFH) and systemic lupus erythematous (SLE), HbSC and SLE with Sjogren's disease, S beta thalessemia+ and SLE with Raynaud's phenomena and HbSS with rheumatoid arthritis (RA). None of the patients were on hydroxyurea. None of the patients were treated with high dose steroids for their AID. Patient 1: HbSS/HPFH with infrequent hospitalizations for vasoocclusive pain crisis (VOC) A rash noted during her second pregnancy prompted a skin biopsy, revealing cutaneous SLE for which treatment with hydroxychloroquine (HC) was initiated. She had one admission for VOC pain crisis at 34 weeks of gestation. Her HC was discontinued prior to delivery. She had an elective C-section at 39 weeks and delivered a healthy 7 lb. baby. 6 weeks post partum she developed severe joint pains and fatigue. She experienced symptom relief with resumption of HC and a low dose prednisone (P) 10 mg. No additional immunosuppressive therapy was started as she continues to breast-feed. Patient 2: HbSC, with SLE and Sjogrens disease with frequent ED visits and admissions for VOC prior to her AID diagnosis. At AID diagnosis she was started on HC and pilocarpine resulting in a prompt reduction in ED visits for pain. She then began to experience worsening arthropathy presumed to be secondary to SLE and was started on methotrexate (MTX). She was hospitalized for community-acquired pneumonia /acute chest syndrome with pleural effusion and pulmonary infiltrates. After no response to antibiotics, she was started on P 30 mg with relief. Because of SLE flare with steroid taper and concern for high dose steroids she was started on rituximab 375 mg/m2 weekly x4. Her pulmonary infiltrates resolved. She continues to have frequent ED/admissions for pain events for VOC. Patient 3: HbSS with frequent ED/admissions for VOC prior to her diagnosis of RA, AVN and pulmonary hypertension. Her AID was treated with MTX and low dose P. Because of RA progression she started etanercept. She had 1 episode of sepsis and septic arthritis and continues to have frequent VOC. Patient 4: Sb+thalassemia with infrequent VOC diagnosed with SLE with Raynaud phenomena. She has been treated with HC without VOC but frequent urinary tract infections. Conclusion: Optimal treatment of adult patients with coexisting SCD and an AID is challenging. In this small group of patients, treatment with a variety of immunosuppressive agents other than high dose steroids, has led to control of the autoimmune disease but no clear improvement of sickle cell pain events and some atypical infections have occurred. Continued tracking of cases of SCD with AID should be done to better understand management and long term outcomes. Disclosures No relevant conflicts of interest to declare.

Oral Administration of Low-Dose Decitabine and Tetrahydrouridine In Combination Increases Fetal Hemoglobin to Therapeutic Levels In the Absence of Cytotoxicity and Reduces Inter-Individual Drug Bioavailability In Baboons

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2147-2147
Author(s):  
Donald Lavelle ◽  
Kestutis Vaitkus ◽  
Maria Armila Ruiz ◽  
Cassandra List ◽  
Tatiana Kouznetsova ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Sickle Cell Disease ◽  
Oral Administration ◽  
Sickle Cell ◽  
Low Dose ◽  
Fetal Hemoglobin ◽  
High Dose ◽  
Cell Disease ◽  
Drug Bioavailability ◽  
Increased Risk

Abstract Abstract 2147 Increased fetal hemoglobin (HbF) levels alleviate the symptoms and improve survival of patients with sickle cell disease and β-thalassemia. Because therapeutic options remain limited for a large group of patients refractory to hydroxyurea (HU) therapy, alternative therapeutic agents to increase HbF are urgently needed. Decitabine (DAC) increases HbF to therapeutic levels in sickle cell disease patients refractory to HU. Oral administration of DAC would ease administration, increase compliance, and lower costs. Previous studies showed that oral administration of high doses of DAC increased HbF levels in baboons (Lavelle et al Am J Hematol 82:981, 2007). The oral bioavailability of DAC is limited by the degradative action of cytidine deaminase (CDA), and patients with CDA polymorphisms associated with reduced CDA activity may exhibit increased risk of cytotocity. We hypothesized that oral administration of low-dose DAC in combination with the CDA inhibitor THU would improve the DAC concentration-time profile while avoiding high peak drug levels likely to cause DNA damage and cytotoxicity and reduce risks of cytotoxicity in patients with CDA polymorphisms. Pharmacokinetics (PK) analysis in six baboons following oral administration of high-dose DAC alone showed that a dose (10mg/kg) previously shown sufficient to induce maximal (62.3–72%) HbF levels in 3 of 5 baboons when administered daily for ten days was associated with a mean AUC value of 355min*ng/ml. PK analysis following administration of varying doses of DAC in combination with THU showed that this AUC of 355min*ng/ml was attained with a 0.5 mg/kg DAC dose administered orally in combination with THU. The effect of oral low-dose DAC in combination with THU on HbF was then evaluated in four baboons. Initially, a single baboon (7482) was treated at 0.5mg/kg/d 3X/week for 3 weeks followed by 2X/week for an additional 5 weeks. Three additional baboons (7484, 7472, and 7470) were treated with either 0.25 or 0.5mg/kg/d 2X/week for eight weeks. Results (Table 1) showed significant increases in HbF associated with modest decreases in ANC and increases in platelets in all animals.AnimalDecitabine dose (mg/kg/d)SchedulePre-treatment HbF (%)Maximal HbF (%)ΔHbFANC nadirPlt max(x103)74820.53Xwk/3wks 2Xwk/5wks3.523.820.32580100474840.52Xwk/8wks4.223.118.91680102974720.252Xwk/8wks12.830.117.3146060074700.252Xwk/8wks9.929.319.42130895 Decreased DNA methylation in the 5' γ-globin gene region was observed in post-treatment BM samples by quantitative MassARRAY DNA methylation analysis. PK analysis showed that DAC bioavailability following oral administration of high-dose DAC alone differed 33 fold between 7470 and 7484 but only 1.3 fold following oral administration of low-dose DAC in combination with THU. Thus co-administration of low-dose DAC with THU reduced inter-individual variability of drug bioavailability and this was consistent with the similar HbF responses observed in these animals. Importantly, the ability of oral low dose DAC-THU to increase HbF to similar levels in the absence of cytotoxicity in two baboons differing in DAC bioavailability following oral administration of high-dose DAC alone predicts that oral low-dose DAC-THU in combination will reduce risks of cytotoxicity in patients with differences in DAC bioavailability due to CDA polymorphisms. These experiments have determined a dose and schedule of oral low-dose DAC in combination with THU that effectively increases HbF to therapeutic levels in the absence of cytotoxic effects in baboons and thus provide critical information important for the design of a future clinical trial of this drug combination in patients with sickle cell disease refractory to hydroxyurea therapy. Disclosures: No relevant conflicts of interest to declare.

Low-Dose Ketamine Infusion In Adult Patients With Sickle Cell Disease – Impact On Management Of Acute Painful Episodes

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2249-2249
Author(s):  
Michel Gowhari ◽  
Aileen Chu ◽  
Julie Golembiewski ◽  
Robert E. Molokie
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Pain Control ◽  
Low Dose ◽  
Conflicts Of Interest ◽  
Adult Patients ◽  
Cell Disease ◽  
Ketamine Infusion ◽  
The Past ◽  
Painful Episode

Abstract Introduction Acute painful (vaso-occlusive) episode is the clinical hallmark of sickle cell disease (SCD). Individuals with SCD may experience acute episodes of severe debilitating pain that requires an acute care/emergency room visit and/or hospitalization. While parenteral opioids are the mainstay of treatment, the use of these agents may be complicated by toxicity, tolerance, and opioid-induced hyperalgesia. Additionally, using one medication/mode of treatment may be inadequate to achieve optimal safe pain control. Ketamine as an adjuvant treatment (administered in low sub-anesthetic doses) has been recognized for its utility in the management of a variety of painful conditions, ranging from oncologic to post-operative pain. However, there is limited literature supporting its use in treating acute sickle painful episodes. Here we have undertaken a retrospective analysis of adult patients with SCD who were treated with low-dose ketamine infusion during an acute painful episode in order to determine its effects of lowering opioid requirements. Methods A retrospective chart and database review was conducted on all patients with SCD who received low-dose ketamine infusion during an acute painful episode in the past three years at a single institution. After a review of inpatient pharmacy records, thirty unique subjects with SCD were identified to have received low-dose ketamine infusion during an acute painful episode in the past three years. For each of these subjects, total and daily (24hr) opioid requirements were determined for the admissions of a vaso-occlusive episode where ketamine infusion was used as an adjuvant for pain control and compared to the prior admission. For the ketamine admission, opioid requirements before, during, and after infusion were also compared. The opioid requirement was converted to intravenous morphine equivalents for standardized comparison. Total opioid and daily (24hr) requirements were determined for each admission. Results Full analysis of all thirty subjects (uncomplicated and complicated pain crises, ketamine infusion of any duration) revealed that the opioid requirement was significantly lower after ketamine compared to before ketamine was started (Wilcoxon signed-rank test P=0.029). The total opioid requirement during the entire ketamine admission, however, was not significantly different from the total opioid requirement during the non-ketamine admission (P=0.088). When a sub-analysis was performed on subjects receiving a ketamine infusion for greater than 24 hours (N=22), the 24hr opioid requirement was significantly lower after ketamine compared to before ketamine was started (P=0.0397). The total opioid requirement during the entire ketamine admission was not significantly different from the total opioid requirement during the non-ketamine admission (P=0.194). When a sub-analysis was performed on subjects with an uncomplicated vaso-occlusive episode (N=17), 24hr opioid requirement was significantly lower after ketamine compared to before ketamine was started (P=0.036). Additionally, the average daily opioid requirement throughout the entire ketamine admission was significantly lower than the average daily opioid requirement during the non-ketamine admission (P=0.001). The total opioid requirement during the entire ketamine admission was not significantly different from the total opioid requirement during the non-ketamine admission (P=1). For the full and subgroup analyses of opioid requirements during the ketamine admission, there was a significantly greater amount of opioid required before the ketamine was started compared to during and after ketamine infusion. Conclusion The use of low-dose infusion of ketamine as an adjuvant for pain control in patients with SCD during vaso-occlusive episode resulted in a significant decrease in opioid requirements. Hence it appears that a low-dose ketamine infusion has utility in the treatment of acute pain crises in adult patients with sickle cell disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Vitamin D and Inflammatory Markers in Children with Sickle Cell Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2312-2312
Author(s):  
Margaret T. Lee ◽  
Adiba Ashrafi ◽  
Mady Hornig ◽  
Amelia Boehme ◽  
Nancy S. Green ◽  
...  
Keyword(s):  
Vitamin D ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Vitamin D3 ◽  
Dose Group ◽  
Low Dose ◽  
High Dose ◽  
Cell Disease ◽  
Immune Markers ◽  
Group Time

Background: Vitamin D, in addition to its role in calcium and bone homeostasis, is a multifunctional regulator of inflammation and of innate and adaptive immune responses. Deficiencies are prevalent in sickle cell disease. We conducted a randomized double- blind active-controlled clinical trial comparing high- (100,000 IU/month) and low-dose (12,000 IU/month) oral vitamin D3 in 62 children with sickle cell disease to reduce respiratory complications including infection, asthma exacerbation and acute chest syndrome (ViDAS trial: Vitamin D for sickle cell respiratory complications; NCT01443728). A secondary aim was to examine the effects of vitamin D on immune function and inflammation. Methods: Using stored serum samples collected from subjects at steady state, we examined hsCRP (single-plex assay) and key cytokines and markers of vascular activation (20-plex immunoassay) at baseline and year-1 in a subset of 36 subjects with HbSS (high-dose: n=17; low-dose: n=19), mean age 7.8 years, 53% females and 67% on hydroxyurea. Immune markers included IL1β, IL1RA, IL2, IL4, IL10, IL18, IL22, IFNγ, TNFα, TNFβ, sFasL, CXCL1, CXCL8 (IL8), PDGFBB, VEGFA, serpin E1 (PAI1), sICAM1, VCAM1, TGFα and TGFβ. Raw immune data were transformed using Box-Cox transformations and standardized; markers with persistently skewed (non-Gaussian) distributions after transformation were dichotomized for analysis. Continuous immune variables were analyzed by repeated measures ANOVA (unadjusted) and ANCOVA (adjusted for baseline covariates of age, sex and baseline total 25-hydroxyvitamin D3 and D2). Dichotomized biomarkers were analyzed using generalized linear mixed-effects models. Secondary analyses stratified on hydroxyurea status were also pursued. For these exploratory biomarker discovery-focused analyses, all significance tests were performed 2-tailed without adjustment for multiple comparisons, with α=0.1 for main effects and 0.2 for interactions. Results: Independent of vitamin D3 dose, serum concentrations of immune markers declined from baseline to the 1-year timepoint for the pro-inflammatory markers IL2, CXCL8 (IL8), IFNγ, TGFα, CXCL1 and PDGFBB and the counter-regulatory molecule, IL10. Among all subjects, interactions of dose group*time were found for IL2, sICAM1 and hsCRP; subjects on hydroxyurea additionally demonstrated dose group*time interactions for serpin E1 (PAI1), IFNγ and TNFα. Subjects on hydroxyurea in the high-dose group also demonstrated decreases over 1-year follow-up in serum IL2, serpin E1, IFNγ, TNFα, sICAM1 and hsCRP whereas serum levels of these immune markers increased among subjects in the low-dose group taking hydroxyurea. This crossover pattern in direction of the dose group*time interaction effect was also observed for the larger study population for sICAM1 and hsCRP. Table 1 shows the markers that tested significantly for main effects and/or interactions. Effects for the rest of the markers were not statistically significant. Conclusions: Our data support the immunomodulatory properties of vitamin D, with variable responses to high and low doses. Effects involved several salient immune and vascular markers for sickle cell disease, including IL2, serpin E1, IFNγ, TNFα, sICAM1 and hsCRP, and appeared to be more pronounced among subjects on high-dose vitamin D3 who were also taking hydroxyurea. Table 1 Disclosures Brittenham: Nestec, Inc.: Consultancy; Novartis International: Consultancy; Tesseract Health, Inc.: Consultancy; Vifor Fresenius Medical Care: Consultancy; Ambys Medicines: Consultancy; Dispersol Technologies: Consultancy; Rockwell Medical, Inc.: Consultancy.

Exchange Transfusion In Adult Patients With Sickle Cell Disease With Refractory Vaso-Occlusive Crises

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4689-4689 ◽  
Author(s):  
Padmini Moffett ◽  
Bryan K Moffett
Keyword(s):  
African American ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Exchange Transfusion ◽  
Iron Chelation ◽  
Adult Patients ◽  
Cell Disease ◽  
Psychological Burden ◽  
Ed Visits

Sickle cell disease occurs in 1/500 African-American births. Pain is one of the most common complications of sickle cell disease and is associated with depression, anxiety, decreased quality of life and poor sleep patterns. Vaso-occlusive crises resulting in three or more hospitalizations per year occur in 48% of patients with sickle cell disease (Annals of Emergency Medicine - May 2009 (Vol. 53, Issue 5, Pages 587-593). Hydroxyurea has been shown to ameliorate the frequency of painful vaso-occlusive crises in sickle cell anemia (Charache et al, Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia NEJM. 1995), unfortunately many eligible patients are not treated due to psychosocial reasons and fear of teratogenicity or malignancy or have painful crisis refractory to hydroxyurea. A panel of experts has suggested that RBC exchange transfusion in these patients may decrease ED visits and subsequent hospitalizations based on anecdotal evidence [Best practices for transfusion for pateitns with sickle cell disease. T Wun, K Hagel. Hematology Review 2009, July 1; 1(22); e22]. We present the case of a 31 year old African-American male with Hgb S/beta thalassemia + with complications of sickle cell disease including Parvovirus B19 induced aplastic anemia, iron overload secondary to multiple simple transfusions, multiple vaso-occlusive crises as well as a left lower extremity ulcer precipitated by treatment with hydroxyurea. He was treated with folic acid as well as deferasirox for iron chelation. He began PRBC exchange transfusions every 6 weeks in March of 2011. In the one year prior to exchange transfusion initiation he had 13 ED visits and 4 hospitalizations for vaso-occlusive crises. After initiation of exchange transfusions he had 11 ED visits and 2 hospitalizations for vaso-occlusive crises the following year. An elevated WBC is associated with poor outcomes in sickle cell disease (Miller et al Predictors of adverse outcomes in children with sickle cell disease. N Engl J Med 2000). His average WBC level was 13 x 109/L, which decreased to 11 x 109/L after initiation of exchange transfusion. The patient underwent extended typing for E,C, and Kell RBC antigens to minimize development of antibodies. Though monthly exchange transfusions are costly and carry the attendant risk of antibody formation, this may be offset by reducing the financial and psychological burden of frequent hospitalizations for management of refractory vaso-occlusive crises. Exchange transfusion may also ameliorate the cost associated with long-term iron chelation. Further investigation is warranted to determine whether a program of monthly exchange transfusions can curtail ED visits and hospitalizations in adult patients with sickle cell disease and multiple, refractory vaso-occlusive crises. Disclosures: No relevant conflicts of interest to declare.

Fever In Hospitalized Adult Patients with Sickle Cell Disease

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2652-2652
Author(s):  
Deepa Jeyakumar ◽  
Matthew Zibelman ◽  
Ryan Hurth ◽  
Lani Krauz ◽  
Santosh Saraf ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Hospital Setting ◽  
Adult Patients ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Indwelling Catheters ◽  
Upper Limit ◽  
Pain Crisis

Abstract Abstract 2652 Background: Sickle cell disease is complicated by veno-occlusive crises leading to pain crises, chronic end-organ damage and early mortality. With recent advances in the management of sickle cell disease in childhood, sickle cell patients are living longer. However, our understanding of the clinical course of adult sickle cell disease remains limited and is based largely on extrapolation of knowledge from children with sickle cell disease. Unfortunately, adult patients remain at an elevated risk of infections due to encapsulated organisms in the setting of functional asplenia. This risk is exacerbated by possible indwelling catheters and exposure to the health care environment. Fever in these patients can herald a serious infection. Alternatively, brisk hemolysis can be associated with fever. Wierenga, et. al. (2001) described that fevers to 39F in children were associated with acute chest syndrome (21%), painful vaso-occlusive crisis (27%), and bacteremia in 6%. To our knowledge, no such review of fever in hospitalized adult sickle cell patients has been published in the medical literature. Therefore, the clinician is placed in a diagnostic dilemma regarding the management of fever in adult patients with sickle cell disease. Objective: To determine the etiologies of fevers in hospitalized adult patients with sickle cell disease in an urban tertiary hospital setting. Methods: We performed an IRB-approved retrospective analysis of 143 admissions between 1995–2008 with sickle cell pain crisis and had a fever greater than 38.5C during the admission. The aim was to determine the prevalence of fevers due to infectious versus hemolysis-related causes in the population of interest. Elevated white blood cell count (defined as greater than 1.5x upper limit of normal), radiologic and/or culture data were used to classify a fever as due to infection. Elevated LDH and total bilirubin (defined as greater than 2x upper limit of normal) were used to classify a fever as due to hemolysis. The risks of infection in patients on hydroxyurea as well as indwelling catheters (including central lines and foley catheters) were assessed. We also evaluated the risk of hemolysis in patients on hydroxyurea. Finally, the use of antibiotics and duration of the fever in patients with hemolysis and infection were also evaluated. Results: Among patients admitted with sickle cell pain crisis and had a fever during their hospitalization, we found evidence of infection in 65% and hemolysis in 58%. Interestingly, 35% had evidence of both infection and hemolysis. Approximately, 11.8% had no significant evidence of infection or hemolysis. Antibiotics were used in 66% of all patients with pain crisis and fever. Among the patients who received antibiotics, 81% had evidence of infection and 19% had no evidence of infection. Approximately 1/5 patients with fevers received antibiotics despite the absence of evidence of infection. Infections were not increased among hydroxyurea users (61.5% with fever) over non-hydroxyurea users (67.9% with fever), p = 0.4. Fevers due to documented infections were found in 78% of patients with indwelling catheters compared with 62% of patients without catheters, p≤0.05. The risk of fever due to hemolysis was not significantly different between hydroxyurea and non-hydroxyurea users at 58% versus 57% respectively, p=0.9. Of patients with fevers for more than one day, infection was found in 69% of patients compared with 31% of patients who had no evidence of infection p=0.5. Whereas, of patients with fevers for more than one day, hemolysis was found in 57% of patients compared with 42% of patients who did not have evidence of hemolysis with p=0.9. Conclusions: Among adult sickle cell patients hospitalized with pain crisis and fever, hemolysis accounted for 58% of cases while infections accounted for 65% with 35% evidence of both. Infections were not increased among hydroxyurea users. Indwelling catheters did increase the risk of fevers due to infection. The risk of fever due to hemolysis was not significantly increased among patients on hydroxyurea. Finally, in patients with fevers for more than one day, hemolysis accounted for 57% of cases and infection accounted for 45%. These findings provide initial investigation of the etiologies of fevers in adult hospitalized sickle cell patients and further studies are necessary to confirm these findings. Disclosures: No relevant conflicts of interest to declare. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A Pilot Study of High-Dose N-Acetylcysteine Infusion in Patients with Sickle Cell Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1299-1299 ◽  
Author(s):  
Hasan Tahsin Ozpolat ◽  
Junmei Chen ◽  
Xiaoyun Fu ◽  
Shelby A Cate ◽  
Jennie Le ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Endothelial Cells ◽  
Sickle Cell Disease ◽  
Platelet Activation ◽  
Sickle Cell ◽  
Low Dose ◽  
High Dose ◽  
Oxidized Glutathione ◽  
Cell Disease ◽  
Reduced And Oxidized Glutathione

Abstract We have completed a clinical trial evaluating the safety of N-acetylcysteine (NAC) infusion in adult patients with sickle cell disease (SCD) at disease baseline (NCT01800526). This trial was inspired by the hypothesis that von Willebrand factor (VWF) has an important role in the pathophysiology of vaso-occlusion and hemolysis in SCD and that NAC can reduce signs and symptoms of the disease by reducing the activity of VWF. A secondary hypothesis was that NAC could also act by reversing or preventing some of the oxidative changes associated with SCD. VWF is stored in the Weibel-Palade bodies of endothelial cells and α-granules of platelets and released from endothelial cells upon activation and mediates the attachment of platelets to the vessel wall, and secondarily, of erythrocytes and leukocytes. We previously showed that VWF levels and adhesive activity in SCD plasma were elevated and that total active VWF correlated with the extent of hemolysis (determined by plasma LDH levels), suggesting that VWF participates in the pathophysiology of SCD (Chen et al, Blood. 2011; 117:3680‐3). In another study, we showed that NAC was able to reduce VWF multimer size and platelet-binding activity ex vivo in human plasma and in vivo in mice (Chen et al, JCI, 2011, 121:522). In this clinical trial, we enrolled 5 subjects at disease baseline, 4 with SCD and 1 with sickle trait. All subjects received two high-dose NAC infusions: initially 150 mg/kg and 4 weeks later 300 mg/kg. NAC infusion was administered in subjects 1 and 2 as a bolus infusion of half of the dose in the 1sthour and the remaining half in 7 hr. Subjects 3-5 received NAC as constant infusion for 8 hr. Blood was collected immediately before infusion, during infusion (at 1 and 4 hr), immediately after infusion (8 hr), and 24 and 72 hr after infusion. We examined blood for red blood cell (RBC) fragments, dense cells, platelet activation status, platelet-monocyte complexes and the concentrations of reduced and oxidized glutathione. We also examined plasma for VWF concentration and multimer distribution, ADAMTS13 antigen and activity, and evaluated plasma redox status by measuring the concentrations of NAC and cysteine in their reduced, oxidized, and mixed disulfide forms, as well as the concentration of protein-bound cysteine. The small molecule thiols were measured by mass spectrometry. Results:1) All subjects tolerated NAC infusion well, except that subjects 1 and 2 experienced pruritus during the bolus infusion at the 300 mg/kg dose. We therefore changed the protocol to deliver the drug over 8 hr by continuous infusion for subjects 3 through 5. 2) During NAC infusion, the percentage of dense cells and concentration of RBC fragments decreased rapidly (average decrease: low dose 44%; high dose 31%) and the change persisted up to 72 hr. 3) Platelet activation also decreased, as determined by reduced P-selectin expression (low dose, 7.7 ± 0.7% to 5.0 ± 1.9%; high dose, 17.8 ± 0.07% to 7.3% ± 0.4), PAC-1 binding (evaluates activated αΙΙbβ3), and formation of platelet-monocyte complexes (monocytes with attached platelets: low dose, 52 ± 16% to 27 ± 12%; high dose, 77 ± 12% to 50 ± 17%). 4) The highest molecular weight VWF multimers transiently disappeared during the NAC infusion and recovered by 24 hr. There were no appreciable changes in VWF antigen or ADAMTS13 antigen or activity with NAC infusion. 5) With NAC infusion, the concentrations of Cys and NAC increased in plasma, both total and reduced forms, with a concomitant decrease in protein-bound Cys in the one patient studied (free thiol Cys increased 23 fold with the high dose infusion at 8 hr; protein-bound Cys decreased 87%). Similarly, the concentrations of reduced and oxidized glutathione increased in whole blood. Summary: NAC infusion in SCD patients at disease baseline appears safe and is well tolerated. NAC infusion decreases RBC fragments, dense cells, and the size of large VWF multimers, and inhibits platelet activation and formation of platelet-monocyte complexes. In addition, NAC infusion increases the total and free-thiol concentrations of cysteine and glutathione in blood, relieving oxidative stress in SCD. Our data suggest that NAC may be of benefit for SCD patients during vaso-occlusive crisis through a variety of mechanisms, which include improvements in red cell parameters, decreased platelet adhesion, reduced adhesive activity of VWF, and protection against oxidative damage. Disclosures No relevant conflicts of interest to declare.

scholarly journals Effects of N-Acetylcysteine in Patients with Sickle Cell Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4173-4173 ◽  
Author(s):  
Tahsin Özpolat ◽  
Junmei Chen ◽  
Xiaoyun Fu ◽  
Shelby A Cate ◽  
Jennie Le ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Low Dose ◽  
High Dose ◽  
Red Cell ◽  
Cell Disease ◽  
Bolus Infusion ◽  
Dose Infusion ◽  
Time Point

Abstract We previously showed that the plasma of patients with sickle cell disease (SCD) contains an elevated quantity of von Willebrand factor (VWF) with high specific adhesive activity (as measured by the binding of nanobody AU/VWFa-11). Total active VWF (VWF antigen multiplied by VWF specific activity) correlated with the extent of hemolysis in these patients (Chen J. et al., Blood, 2011, 117:3680). In another study, we showed that N-acetylcysteine (NAC) reduced VWF size and activity ex vivo and broke down platelet–VWF aggregates in vivo in mice (Chen J. et al, JCI, 2011, 121:522). Given the possibility that VWF is involved in the pathophysiology of sickle cell disease, we are examining whether NAC can benefit these patients. We are first conducting a pilot clinical trial to determine the safety profile of infused NAC and its effects on laboratory endpoints. Five SCD patients at disease baseline and not recently transfused will be enrolled. To date, two patients have completed intravenous infusion of NAC at a low dose of 150 mg/kg with a bolus infusion of 75 mg/kg for the 1st hr and 75 mg/kg for 7 hr. Approximately one month after the low-dose infusion, these patients received another infusion of 300 mg/kg given as a bolus infusion of 150 mg/kg for the 1st hr and 150 mg/kg for 7 hr. Blood was collected for analysis immediately before the infusion, at 1 hr (after bolus infusion), 8 hr, 24 hr, and 72 hr after infusion. Among the parameters examined were plasma VWF, red blood cell concentration, density, and size (to look for fragments), and the concentrations of NAC, cysteine and glutathione and their oxidized and mixed disulfide forms. In these two patients, the NAC infusion was well tolerated except that both patients experienced pruritus during the higher-dose bolus infusion. We measured the concentrations of reduced and oxidized NAC, cysteine, and glutathione in whole blood in the first study subject by mass spectrometry. NAC concentrations were 725 μM and 1.58 mM at the 1 hr time point at the low and high doses, respectively. Compared to the baseline (before NAC infusion), the concentration of total cysteine in blood was increased 2.4 fold for low dose and 2.9 fold for high dose at 1 hr and returned to baseline at 8 hr. The concentration of total glutathione in whole blood was increased 1.5 fold and 1.3 fold at 24, and 72 hr, respectively, for the high dose infusion but did not change much at the low dose infusion. The size of high molecular weight VWF multimers decreased with the high dose infusion, the effect being obvious at 1 hr. In addition, NAC infusion markedly reduced the concentration of red cell fragments and dense cells. Both of these effects were very rapid, being observable at the 1 hr time point. In summary, NAC infusion in sickle cell patients at disease baseline appears safe. NAC increases the concentrations of total cysteine and glutathione in blood, reduces high molecular weight VWF multimers, and decreases the number of dense red blood cells and the extent of red cell fragmentation. Disclosures No relevant conflicts of interest to declare.

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