scholarly journals The Oxygenscan Provides Clinically Relevant Biomarkers for Treatment Efficacy That Are Associated with Frequency of Vaso-Occlusive Crisis in Sickle Cell Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2275-2275
Author(s):  
Minke A.E. Rab ◽  
Richard van Wijk ◽  
Celeste K. Kanne ◽  
Brigitte A. van Oirschot ◽  
Jennifer Bos ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Research Funding ◽  
Clinical Severity ◽  
Patient Specific ◽  
Cell Disease ◽  
Significant Difference ◽  
Before And After ◽  
Oxygen Concentrations ◽  
Rbc Deformability

Background: In sickle cell disease (SCD), hemoglobin S (HbS) polymerizes upon deoxygenation, reducing red blood cell (RBC) deformability. RBC deformability can be measured over a range of oxygen concentrations using a Laser Optical Rotational Red Cell Analyzer (Lorrca) ektacytometer (RR Mechatronics, Zwaag, the Netherlands) with Oxygenscan module. The Oxygenscan measures 3 key parameters: 1) EImax, RBC deformability at normoxia; 2) EImin, RBC deformability upon deoxygenation; and 3) the point of sickling (PoS): the oxygen tension at which a 5% decrease in normoxic EI is observed during deoxygenation, reflecting the patient-specific pO2 at which sickling begins (Figure 1A). Previously we showed that Oxygenscan parameters correlate with measures of SCD disease severity and hemolysis (absolute reticulocyte count, %fetal hemoglobin, %HbS, total Hb, %dense RBC, (Rab et al. Blood 2018). In this study, we investigated the relationship between oxygenscan parameters and incidence of vaso-occlusive crisis (VOC), and we tested the ability of the Oxygenscan parameters to assess response to hydroxyurea (HU) and chronic transfusion (CTF) in patients with SCD. Methods: We analyzed 2 cohorts: a European cohort (EUC) of 62 SCD patients (all HbSS or HbS/β-thalassemia), enrolled at either University Medical Center Utrecht (UMCU, n= 42) or Hospital Lyon (LIBM, n=20), and a US cohort (USC) of 97 SCD patients enrolled at Texas Children's Hospital (TCH). Differences in Oxygenscan parameters in SCD patients without/with VOC (requiring a doctor's evaluation) in the past 2 years were measured in 46 adult EUC SCD patients and 80 pediatric USC SCD patients. EUC patients without VOC (n=18, median age 40.6 years (y); 11 female (F), 44% on HU, 6% on CTF, 28% on both treatments), were compared to patients with a positive history of VOC (n=28, median age 23.9y, 13F, 39% on HU, 11% on CTF and 11% on both). Patients without VOC in the USC (n= 34, median age 8.0y, 15F, 53% on HU, 15% on CTF and 21% on both treatments) were compared to patients with VOC (n=46, median age 11.8y, 20F, 74% on HU, 13% on CTF and 11% on both treatments). To establish treatment related Oxygenscan parameter changes, we analyzed RBCs from 9 SCD patients from UMCU (median age 19y, 5F), before and during HU treatment (measurements performed at baseline, and 1, 3 and 6 months after starting HU), 7 SCD patients from UMCU (median age 26.7y; 6F) before and after transfusion and 17 SCD patients from TCH (median age 10.8y; 6F) on HU before and after transfusion. Results: In the EUC, PoS differed significantly between patients without VOC in the last 2 years (median 41.6mmHg) and patients with VOC in the last 2 years (median 53.7 mmHg, p<0.001, Figure 1B). In the USC, PoS was also lower in patients without VOC compared to those with a VOC in past 2 years (p<0.05, Figure 1C). EImin in both cohorts was significantly lower in patients who experienced VOC (p<0.05). EImax did not show a significant difference in both cohorts. Correlation of PoS with VOC episodes was significant in the EUC (r=0.447, p<0.01, Figure 1D) and USC (r=0.228, p<0.05), indicating that RBCs start to sickle at a higher pO2 in patients where VOC occur more often. Differences found in median PoS between EUC and USC could be due to differences in treatment (EUC 30% no treatment, USC 5% no treatment), difference in age (EUC median age 28.5y, USC median age 11.6y), genetic background or technical differences between Oxygenscan devices. Transfusion improved EImax, EImin, and PoS (USC: p<0.001, p<0.0001, and p<0.01, EUC: all parameters p<0.05 Figure 1E). HU treatment improved all parameters after 3 and 6 months compared to baseline (p<0.05 and p<0.0001 Figure 1F). Conclusion: Our results show that RBC from SCD patients without VOC in the last two years were able to tolerate lower oxygen concentrations before sickling (PoS). RBCs from patients without VOC were also more deformable when deoxygenated (EImin) compared to patients who had experienced one or more VOCs in the last two years. In contrast, RBC deformability, when oxygenated (EImax) was not different in patients with or without VOC in the last two years. All 3 Oxygenscan parameters significantly improved with standard of care SCD treatments, namely CTF and/or HU. We therefore conclude that the PoS, EImax and EImin are useful biomarkers of clinical severity and treatment response, and may be essential in monitoring novel SCD treatments as part of a clinical trial as a surrogate endpoint. Disclosures Rab: RR Mechatronics: Research Funding. van Wijk:Agios Pharmaceuticals: Consultancy, Research Funding; RR Mechatronics: Research Funding. Bos:RR Mechatronics: Research Funding. Nur:Novartis Pharmaceuticals: Consultancy. Cnossen:NWO: Other: Governmental grants , ZonMW, Innovation fund and Nationale Wetenschapsagenda 2018; Roche: Other: Travel Grants; Takeda: Other: Travel Grants, Research Funding; Shire: Other: Travel Grants, Research Funding; Baxter: Other: Travel Grants, Research Funding; Sobi: Research Funding; CSL Behring: Other: Travel Grants, Research Funding; Nordic Pharma: Research Funding; Novo Nordisk: Research Funding; Bayer: Other: Travel Grants, Research Funding; Pfizer: Other: Travel Grants, Research Funding. van Beers:Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding.

scholarly journals Naloxone Use for Opioid Reversal in Patients with Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2038-2038
Author(s):  
Mahir Khan ◽  
Jin Han ◽  
Santosh L. Saraf ◽  
Robert E. Molokie
Keyword(s):  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Opioid Overdose ◽  
Cell Disease ◽  
Advisory Committees ◽  
Significant Difference ◽  
Before And After ◽  
Time Periods

Abstract Patients with sickle cell disease (SCD) are known to require increased dosing of drugs including opioids due to differences in renal and hepatic metabolism. While it is known that SCD patients require higher opioid doses to achieve the same degree of analgesia, it is not clear if this is associated with a similar increase in drug toxicities. A significant risk of opioid use is respiratory depression, and naloxone is used for rapid reversal of this adverse effect. In the setting of a nationwide opioid shortage in 2018, our institution established a policy requiring the use of patient-controlled analgesia (PCA) rather than intravenous push (IVP) for hospitalized SCD patients. This coincided with a mandate for end tidal carbon dioxide (ETCO) monitoring with PCA use, effectively implementing ETCO in the routine care of this population. In this study, we describe our experience using naloxone for opioid reversal in hospitalized SCD patients. We studied naloxone use in patients admitted to the University of Illinois at Chicago for two 24-month time periods (July 31, 2015 - July 31, 2017 and May 1, 2018 - May 1, 2020). These dates were chosen to compare naloxone use before and after implementation of ETCO monitoring. A pharmacy reporting tool was used to identify every dose of naloxone administered within the hospital during these dates. We isolated patients on the inpatient sickle cell service and compared the proportion of SCD patients between study periods using Fisher's exact test. For SCD patients who received naloxone, we obtained baseline patient characteristics and divided doses into episodes when multiple doses were given within a day. For each episode, we studied analgesic regimens, details of the hospitalization, and laboratory values. Given the small data sample, we used descriptive statistics for analysis. Among 931 total naloxone doses given in the two time periods, 35 were given to SCD patients. Out of 580 total distinct patients, there were 14 patients admitted to the sickle cell service. There were 5 out of 279 (1.8%) SCD patients who received 12 out of 443 (2.7%) doses between July 2015 and July 2017. There were 10 out of 309 (3.2%) SCD patients who received 23 out of 488 (4.7%) doses between May 2018 and May 2020. There was no significant difference in naloxone use by SCD patients before and after implementation of ETCO. For the two time periods combined, there were 14 out of 580 (2.4%) SCD patients who received 35 out of 931 (3.8%) doses. We were able to manually confirm 10 SCD patients and 17 episodes of naloxone use by chart review. Among these, 2 patients who only had 1 episode each received naloxone in the absence of opioid overdose. One patient with multiple episodes had an episode of receiving naloxone for opioid overdose not involving hospital-administered medications. Among the remaining 8 SCD patients who appropriately received naloxone for opioid reversal in the hospital, 100% were black or African American race. Seven (87.5%) out of 8 had Hgb SS genotype, and male-to-female ratio was 1:1. Six out of 14 (42.9%) episodes occurred when patients were not receiving their usual pain regimen. Vaso-occlusive crisis was a diagnosis for 13 out of 14 (92.9%) episodes. A median of 2 doses of naloxone were given per episode. Median creatinine clearance was 20.85 mL/min, and several cases coincided with acute kidney injury. Median sedation scale score prior to naloxone dose was 1 (minimally sedated). One patient was treated with a naloxone continuous infusion. Our study highlights the relatively low use of naloxone in patients with SCD despite generally high usage of opioids. Nearly every patient admitted to the sickle cell service utilizes opioid pain medications, but the proportion of naloxone use in SCD patients is small. There was no significant difference in naloxone use after policy changes instituted the use of ETCO, but this may be due to sample size. The low rates of naloxone use in SCD patients may be related to mechanisms of hyperfiltration that necessitate increased opioid dosing. Our results suggest that the higher observed opioid dosages are not associated with worsened toxicities in SCD patients. With techniques such as ETCO, SCD patients can more safely be treated for pain using opioid medications, and providers should be mindful of pertinent pharmacological factors when caring for this population. Disclosures Saraf: Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Safety and Efficacy of Sildenafil Therapy for Doppler-Defined Pulmonary Hypertension in Patients with Sickle Cell Disease: Preliminary Results of the Walk-PHaSST Clinical Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 571-571 ◽  
Author(s):  
Roberto F Machado ◽  
Robyn J Barst ◽  
Nancy A Yovetich ◽  
Kathryn L Hassell ◽  
Jonathan C. Goldsmith ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Adverse Events ◽  
Arterial Pressure ◽  
Sickle Cell ◽  
Research Funding ◽  
Cell Disease ◽  
Safety And Efficacy ◽  
Preliminary Results ◽  
Significant Difference

Abstract Abstract 571 Background: Pulmonary hypertension (PH) is associated with increased mortality in patients with sickle cell disease (SCD). Methods: Walk-PHaSST (treatment of Pulmonary Hypertension and Sickle cell disease with Sildenafil Therapy) is a multi-center (10 United States and United Kingdom Centers), placebo-controlled, double-blind 16-week trial evaluating the safety and efficacy of oral sildenafil for the treatment of Doppler-defined PH (tricuspid regurgitant jet velocity [TRV] ≥2.7m/s) in adults and children (aged >12 years) with SCD. The primary endpoint was the six-minute walk distance (6MWD). The study was designed with a planned screening of approximately 1000 subjects, to enroll 132 subjects for inclusion in the nested Main Interventional Trial (MIT). In the screening trial, subjects were evaluated by history and physical examination, laboratory screening, transthoracic Doppler echocardiography and 6MWD. Randomized subjects were stratified by TRV (2.7-2.9 m/s and ≥3.0 m/s), and those in upper strata underwent a right heart catheterization (RHC). Preliminary Results: Of the 722 screened subjects, 150 (26%) had both a TRV ≥2.7 m/s AND 6MWD of 150-500 meters (m), qualifying for MIT enrollment. A total of 74 subjects (13%) were randomized into the MIT. The study was prematurely stopped due to a statistically significant increase in serious adverse events (SAEs) in the sildenafil arm after 33 subjects had completed the 16 week assessments and 74 subjects (37 sildenafil: 23 female, 47 ± 12 years, TRV 3.0 ± 0.4 m/s, 6MWD 378 ± 93 m; 37 placebo: 23 female, 44 ± 14 years, TRV 2.9 ± 0.3 m/s, 6MWD 381 ± 75 m) had been randomized in the MIT. To evaluate safety and efficacy, all 74 subjects were evaluated, with pre-defined primary and secondary endpoint analysis and imputation rules for missing data. Baseline gender, hemoglobin phenotype, TRV and 6MWD were similar between sildenafil and placebo (all p>0.05). There was a significant increase in SAEs in the sildenafil arm (46% vs. 22% of randomized subjects; p=0.048) but no significant difference in adverse events (AEs; 76% vs. 68%; p=0.607). Sickle cell anemia with crisis (hospitalization defining the SAE) accounted for the significant difference in SAEs (35% vs. 11%; p=0.025). In reference to AEs, patients on sildenafil tended to have more headache (27% vs. 14%; p=0.247) and more blurred vision (11% vs. 3%; p=0.358). No other SAEs or AEs by organ system or preferred term were significantly different (all p > 0.43). There were no AEs classified as life-threatening and there was one death in the placebo arm. To assess potential efficacy, all 33 subjects with TRV of ≥3.0 m/s underwent RHC and received a single test dose of 60 mg of sildenafil; data are currently availabel for 22 of those subjects. Although this dose of sildenafil acutely decreased mean pulmonary arterial pressure (p=0.01), and mean systemic arterial pressure (p<0.01), the change in pulmonary vascular resistance was not significant. There were no apparent safety issues with the acute sildenafil dosing (e.g. priapism). After 16 weeks of sildenafil, there was no difference in the change in TRV (adjusted mean change from baseline: sildenafil -0.10 ± 0.08 m/s, placebo -0.13 ± 0.8 m/s; p=0.7) or in 6MWD (adjusted mean change from baseline: sildenafil -17 ± 20.9 m, placebo +1.4 ± 21.8 m; p=0.47). On the Brief Pain Inventory (BPI), sildenafil subjects reported worsening pain during walking (p=0.07; p=0.17) and less enjoyment of life (p=0.09; p=0.04) vs. placebo at the interim visits (6 and 10 week, respectively). For subjects in the sildenafil group, no difference was detected in 6MWD for those experiencing a VOC vs. those without a VOC (adjusted mean 386 ± 15.9 m; 372 ± 11.7 m; p=0.39). Preliminary Conclusions: In conclusion, sildenafil significantly increased rates of VOCs requiring hospitalization vs. placebo. The premature study termination for safety concerns limited the sample size for efficacy assessments; however, further investigation may be warranted in a more select group of patients with optimized hydroxyurea and transfusion therapy. Based on the completed analyses, no relationship has been established between experiencing pain (via serious VOC) and 6MWD. Additional analyses will focus on determining whether pain (as measured by BPI) is correlated with change in 6MWD. Finally, these data suggest a potential role for the cyclic cGMP axis in the pathobiology of VOC and sickle cell disease related pain. Disclosures: Barst: Pfizer: Consultancy, Research Funding. Gibbs:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Girgis:Pfizer: Research Funding. Badesch:Pfizer: Consultancy, Research Funding.

scholarly journals Nocturnal Hypoxemia Rather Than Obstructive Sleep Apnea Is Associated With Decreased Red Blood Cell Deformability and Enhanced Hemolysis in Patients With Sickle Cell Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Emeric Stauffer ◽  
Solène Poutrel ◽  
Giovanna Cannas ◽  
Alexandra Gauthier ◽  
Romain Fort ◽  
...  
Keyword(s):  
Obstructive Sleep Apnea ◽  
Pulmonary Hypertension ◽  
Sleep Apnea ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Clinical Severity ◽  
Cell Disease ◽  
Nocturnal Hypoxemia ◽  
Obstructive Sleep ◽  
Rbc Deformability

Background: Although obstructive sleep apnea (OSA) could act as a modulator of clinical severity in sickle cell disease (SCD), few studies focused on the associations between the two diseases.Research Question: The aims of this study were: (1) to explore the associations between OSA, nocturnal oxyhemoglobin saturation (SpO2) and the history of several acute/chronic complications, (2) to investigate the impact of OSA and nocturnal SpO2 on several biomarkers (hematological, blood rheological, and coagulation) in patients with SCD.Study Design and Methods: Forty-three homozygous SCD patients underwent a complete polysomnography recording followed by blood sampling.Results: The proportion of patients suffering from nocturnal hypoxemia did not differ between those with and those without OSA. No association between OSA and clinical severity was found. Nocturnal hypoxemia was associated with a higher proportion of patients with hemolytic complications (glomerulopathy, leg ulcer, priapism, or pulmonary hypertension). In addition, nocturnal hypoxemia was accompanied by a decrease in RBC deformability, enhanced hemolysis and more severe anemia.Interpretation: Nocturnal hypoxemia in SCD patients could be responsible for changes in RBC deformability resulting in enhanced hemolysis leading to the development of complications such as leg ulcers, priapism, pulmonary hypertension or glomerulopathy.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03753854.

scholarly journals Hypoxia Enhanced Red Cell Adhesion in Vitro May Identify Patients at Risk for Vasculopathy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3672-3672
Author(s):  
Charlotte Yuan ◽  
Erina Quinn ◽  
Sargam Kapoor ◽  
Myeongseop Kim ◽  
Erdem Kucukal ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Research Funding ◽  
Cell Disease ◽  
Hypoxic Conditions ◽  
Significant Difference ◽  
History Of ◽  
Male Subjects

Abstract Background: Priapism is a serious complication associated with Sickle Cell Disease (SCD) that may be a manifestation of underlying vasculopathy. The Centers for the Study of Complex Diseases of Childhood (CSCCD), comprising independent Comprehensive Sickle Cell Centers, demonstrated an association of priapism with hemolysis.1 Previously, we identified two groups of people with SCD based on red blood cell (RBC) adhesion under hypoxic conditions: those patients whose RBCs showed hypoxia-enhanced adhesion (HEA) and those whose did not (non-HEA).2 Patients with HEA had evidence for more hemolysis in vivo. Here, we aimed to examine (1) the association of HEA with hypoxia in vivo, and (2) RBC adhesion in normoxic and hypoxic conditions in male patients with or without a history of priapism. Methods: This retrospective study was conducted at the Adult Sickle Cell Disease Clinic at the University Hospitals Seidman Cancer Center, in Cleveland, OH between 2015 to 2018. Blood samples were obtained from 26 male subjects (29 samples, 25 HbSS and 1 HbSS HPFH). Adhesion experiments were performed as previously reported by passing surplus whole blood through LN-immobilized microchannels at physiological conditions under both normoxic and hypoxic conditions.2,3 Adherent RBCs were then quantified with microscope after a wash step. The median value was used for data analyses from multiple samples obtained from an individual. Chart review was conducted to examine results of hypoxia testing obtained in vivo as part of routine clinical care. Results: Male subjects with HbSS and a history of priapism had higher HEA in comparison to subjects without a history of priapism (3268 ± 5647 vs. 122 ± 1218, p=0.016). However, there was no significant difference between RBC adhesion of the two groups under normoxic conditions (529 ± 1528 vs. 402 ± 280). More male subjects with priapism had hypoxia in vivo (10 out of 14) than subjects without priapism (5 out of 12). Compared to male subjects with a history of priapism, those without a history of priapism had lower lactate dehydrogenase levels (474 ± 267 vs. 290 ± 215, p=0.008). Conclusions: Our data showed that subjects with a history of priapism had a higher HEA and tended to have more evidence for hypoxia in vivo than did subjects without a history of priapism. Further, male subjects with hypoxia in vivo had more HEA than did those without hypoxia in vivo (not shown). Hypoxia in vivo may cause increased RBC damage (reflected by HEA), hemolysis, nitric oxide depletion, and consequent vasculopathy, resulting in priapism. Hypoxia may be treatable, when identified in subjects with a history priapism in vivo or possibly with HEA in vitro. This could plausibly modify disease severity in some cases. References: Nolan VG, Wyszynski DF, Farrer LA, Steinberg MH. Blood. 20015 Nov;106(9):3264-7. doi: 10.1182/blood-2005-04-1594 Kim M, Alapan Y, Adhikari A, Little JA, Gurkan Microcirculation. 2017 Jul;24(5). doi: 10.1111/micc.12374. Alapan Y, Kim C, Adhikari A, Gray KE, Gurkan-Cavusoglu E, Little JA, Gurkan Transl Res. 2016 Jul;173:74-91.e8. doi: 10.1016/j.trsl.2016.03.008. Epub 2016 Mar 19. Disclosures Little: NHLBI: Research Funding; PCORI: Research Funding; Hemex: Patents & Royalties: Patent, no honoraria; Doris Duke Charitable Foundations: Research Funding.

scholarly journals Use of Marijuana in Patients with Sickle Cell Disease Increased the Frequency of Hospitalization for Acute Painful Vaso-Occlusive Crises

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2498-2498
Author(s):  
Samir K. Ballas
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Drug Screening ◽  
Marijuana Use ◽  
Clinical Severity ◽  
Questionnaire Study ◽  
Cell Disease ◽  
Significant Difference ◽  
Urine Drug ◽  
Urine Drug Screening

Introduction : Recently, there has been general interest in using marijuana as an analgesic for various types of pain. Cannabis is known to relieve severe nausea and vomiting. Anecdotally, medical marijuana has analgesic effects in patients with chronic and neuropathic pain other than sickle cell pain, decreases the frequency of migraine headache, has anti-spastic effect in multiple sclerosis, and may relieve some of the signs and symptoms of amyotrophic lateral sclerosis and Crohn's disease. Its role in epilepsy is controversial. On the negative side long-term cannabis use is associated with periodontal disease, maternal marijuana use at 20 weeks gestation was strongly associated with spontaneous pre-term birth independent of maternal cigarette smoking and illegal synthetic cannabinoids (K2/spice) were associated with catatonia and myocardial infarction in adolescents. Studies in the transgenic sickle cell mouse showed that cannabinoid receptor-specific mechanisms ameliorate pain via inhibition of mast cell activation and neurogenic inflammation. A questionnaire study from the United Kingdom showed that 36% of the patients with sickle cell disease (SCD) have used cannabis in the previous 12 months to relieve symptoms. Another longitudinal questionnaire study in Jamaica found that marijuana was not related to the clinical severity of SCD. The objective of this study is to report the epidemiological and clinical features of the patients with SCD who were found to be taking marijuana by using random urine drug screening from 1994 to 2009. The frequency of vaso-occlusive crises (VOCs) in these patients was compared to patents with SCD whose urine drug screening showed no marijuana. The terms marijuana and cannabinoid will be used interchangeably in this Abstract. Patients & Methods: A total of 270 random urine drug screen tests were done on 72 patients representing 10% of our patients with SCD during the period of the study. Written consent was obtained from the patients for enrollment in the study that was approved by the IRB. Types of SCD were determined by routine lab tests. Urine samples, collected randomly, were analyzed for the presence of amphetamine, benzodiazepines, opiates, barbiturate, cannabinoid, propoxyphene, methadone and phencyclidine. Samples were classified as either positive or negative for cannabinoid. Statistical analysis included the two-tailed student's t, Fisher exact and the Chi Square tests. Results: Thirty-seven of the 72 patients tested positive for cannabinoid in their urine and 35 patients tested negative. Table 1 shows the major epidemiological and clinical feature of the patients studied. There was no significant difference in ages of men and women who used or did not use marijuana (p > 0.05). However, males who used marijuana were significantly younger (p < 0.001) than males who did not (Table 1). Moreover, the ages of females who tested positive for cannabinoid were not significantly different from women who tested negative (Table 1). The patients who tested positive for cannabinoids also tested positive for other illicit drugs more often than patients who tested negative. Positivity for benzodiazepines, cocaine and phencyclidine were significantly higher in patients who used marijuana than the nonusers. Notably, there was no significant difference in the use of opioids consumed by users and non-users of marijuana. Similarly, there was no significant difference in the frequency of complications of SCD between users and non-users of marijuana (Table 1). The most important aspect of the study is the effect of marijuana use on the frequency of utilization of medical facilities. Patients in the marijuana cohort were admitted to the hospital for VOCs more frequently (Table 1) than the control group: 2,443 versus1,602 admissions respectively (p < 0.05). Conclusion: Together these data suggest that patients in the marijuana cohort were more often in severe pain that required treatment in the hospital for VOCs than non-users. This difference could be due to the quality of the marijuana used, the neuronal effects of marijuana and the severity of pain in the users of marijuana. The role of marijuana in the treatment of sickle cell pain seems more complex than thought. Further controlled trials are needed to clarify this issue. Table 1 Table 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Oxygenscan: A Rapid and Reproducible Test to Determine Patient-Specific, Clinically Relevant Biomarkers of Disease Severity in Sickle Cell Anemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2360-2360
Author(s):  
Minke A.E, Rab ◽  
Celeste K Kanne ◽  
Brigitte A. van Oirschot ◽  
Jennifer F. Bos ◽  
Maite Elizabeth Houwing ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Disease Severity ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Research Funding ◽  
Patient Specific ◽  
Advisory Committees ◽  
Laboratory Parameters ◽  
Oxygen Concentrations ◽  
Rbc Deformability

Abstract Background: In sickle cell anemia (SCA), hemoglobin S (HbS) polymerizes upon deoxygenation, resulting in sickling of red blood cells (RBCs). These deoxygenated RBCs have strongly reduced deformability, which contributes to the etiology of vaso-occlusive crises and chronic hemolytic anemia. There are no widely available clinical laboratory tests to directly monitor effects of disease modifying therapies (i.e. hydroxyurea) on RBC deformability. RBC deformability can be measured using a Laser Optical Rotational Red Cell Analyzer (Lorrca) ektacytometer (RR Mechatronics, the Netherlands), which measures RBC deformability over a range of osmolalities. Recently, a new module was added which consists of a method to measure RBC deformability, expressed as Elongation Index (EI), during controlled deoxygenation. This test, termed oxygenscan, has 3 key read out parameters: 1) EImax, which represents RBC deformability at normoxia; 2) EImin represents deformability upon deoxygenation; and 3) the point of sickling (PoS), the point at which a >5% decrease in EI is observed during deoxygenation, reflecting the patient-specific pO2 at which sickling begins (Figure 1). In this study, we correlated laboratory parameters associated with SCA disease severity with oxygenscan parameters to establish the clinical utility of this test. Methods: The discovery cohort consisted of 15 SCA patients (median age 22.0 years, 33.3% on hydroxyurea (HU)) enrolled at University Medical Center Utrecht (UMCU). The validation cohort consisted of 21 patients with SCA (median age 12.5 years, 76.2% on HU) from Texas Children's Hematology Center (TCHC). Oxygenscans were carried out in duplicates at both sites. Percentage dense RBC (%DRBC) were measured using an ADVIA hematology analyzer (Siemens) at TCHC only. In this study, we used Pearson's correlation to test for linear correlations between oxygenscan parameters EImax, EImin and PoS and clinically relevant laboratory parameters: total hemoglobin (Hb), absolute reticulocyte count (ARC), %HbS and %HbF, and %DRBC. Results: In both cohorts PoS significantly positively correlated with ARC (Figure 2A-B). In the UMCU cohort, total Hb levels also significantly positively correlated with EImax (Figure 2C), which was validated in the TCHC cohort (Figure 2D). HbF positively correlated with the EImin in both cohorts (Figure 2E-F). EImin also significantly negatively correlated with HbS (r=-0.828 p=<0.001 in the UMCU cohort, r=-0.936, p=<0.001 in the TCHC cohort data not shown). EImax showed a strong negative correlation with the %DRBC (Figure 2G) in the TCHC cohort. Individual test results were highly reproducible at both sites, with a median coefficient of variability of all tested parameters below 3%. Conclusion: The oxygenscan is a semi-automated, inexpensive, highly reproducible, and rapid test to fully characterize patient-specific RBC deformability under a range of oxygen concentrations. Key oxygenscan measurements- PoS, EImin, and EImax- correlated with known measures of SCA disease severity, namely ARC, HbF, HbS, total Hb and %DRBC. Patients with higher reticulocyte counts showed a clinically unfavorable increase of oxygen concentration at which RBCs start to sickle (termed PoS), than patients with lower ARC. Patients with higher HbF had more deformable RBCs even at the lowest oxygen concentrations, or EImin, while patients with higher HbS had lower EImin (low values indicate poor deformability under deoxygenated conditions). Patients with high %DRBC had lower EImax, indicating poor RBC deformability at normoxic conditions. Conversely, patients with high total Hb had high EImax. The very strong correlations of key oxygenscan measurements with different measures of SCA disease severity suggest that these parameters could be exploited as useful biomarkers of clinical severity and in the follow-up and treatment of SCA patients and warrant further investigation. Disclosures Rab: RR Mechatronics: Research Funding. Bos:RR Mechatronics: Research Funding. Cnossen:Roche: Research Funding; CSL Behring: Research Funding; Novartis: Research Funding; Novo Nordisk: Research Funding; Bayer: Research Funding; Shire: Research Funding; Pfizer: Research Funding. Schutgens:Bayer: Research Funding; CSL Behring: Research Funding; Pfizer: Research Funding; Uniqure BV: Research Funding; Novo Nordisk: Research Funding; Baxalta/Shire: Research Funding. van Wijk:Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; RR Mechatronics: Research Funding. van Beers:RR Mechatronics: Research Funding; Bayer: Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Erythrocytapheresis in Sickle Cell Disease Lead to An Elective Reduction of Erythrocytes-Derived Blood Microparticles

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2657-2657
Author(s):  
Emna Mahfoudhi ◽  
Yann Lecluse ◽  
Françoise Driss ◽  
Claire Flaujac ◽  
Nicole Casadevall ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Conflicts Of Interest ◽  
Red Cells ◽  
Cell Disease ◽  
Positive Effects ◽  
Significant Difference ◽  
Before And After ◽  
The Mean ◽  
Student Test

Abstract Abstract 2657 Introduction: Erythocytapheresis is a highly effective procedure used in the management of both acute and chronic complications of sickle cell disease (SCD). Indeed, exchange transfusion is recommended as a part of the initial treatment of vaso-occlusive stroke in children. Red cells exchange can also be proposed in primary and secondary stroke prevention in order to maintain a low level of HbS. Microparticles (MPs) are small vesicles released from cells after activation or apoptosis. Microparticles number is increased in SCD both at the steady state and during crisis. The majority of these microparticles are originated from erythrocytes and platelets. In SCD, erythrocytes MPs are strongly correlated with hemolysis and activation of coagulation. In this study, we aimed to measure the level of total, platelets-derived and erythrocytes-derived MPs in patients with SCD undergoing erythrocytapheresis; we compared the level of MPs before and after red cells exchange in order to evaluate if the reduction of stroke observed in patients undergoing erythrocytapheresis could be due to a specific decrease in erythrocytes-derived MPs known to be implicated in coagulation activation in this disease. Materials and Methods: After informed consent, 24 samples were harvested on a tube containing buffered sodium citrate from 22 patients with SCD undergoing erythrocytapheresis. For each patient, a sample was collected before and just after the exchange. 20 samples from donor with neither anemia nor coagulation disorders were used as controls. Each sample was centrifugated at 1500g during 15 mn, the supernatant was collected and centrifugated 2mn at 13000g at 20°C and then frozen at -80°C until analysis. For MPs detection, 38mL of the thawed supernatant was labelled with 5mL of 10X Annexine V buffer, 1mL of Annexine V-FITC, 1 mL of anti-GPA-PE and 5 mL of anti-CD41-APC. 5mL of calibrated beads at known concentration were added to 345 mL of 1X Annexine buffer just before analysis on the MoFlow cytometer (Beckman Coulter). The Megamix beads system was used in order to delimitate the FSC/SSC gate of MPs. Results: Total number of plasma MPs (1755/mL vs 273), erythrocytes-derived MPs (174/mL vs 8) and platelets-derived MPs (1520/mL vs 236) were significantly increased in SCD patients in comparison with controls. For SCD patients undergoing erythrocytapheresis, the mean HbS level was respectively 52% and 24% before and after red cells exchange. No significant difference in the total hemoglobin concentration was noted. The mean number of MPs did not differ before and after the exchange (1755/mL versus 1940/mL respectively, student test p>0.05). The mean number of platelets-derived MPs remained stable before and after the exchange (1520/mL versus 1250mL, student test, p>0.05). In sharp contrast, we observed a significant clearance of the erythrocytes-derived MPs in the plasma of SCD patients after red cells exchange (mean number of GPA+-MPs: 174/mL before exchange versus 77mL after, student test, p<0.05). However, we could also observe a great variation of the number of erythrocytes and platelets-derived MPs between the different patients. Conclusion: The number of erythrocytes-derived MPs decreased specifically after red cells exchange, in contrast with the total and the platelets-derived MPs which remained stable; this selective decrease in the GPA+-MPs of SCD patients could be due to a reduction in the total number of red cells containing a high HbS content in the circulation, because of their replacement by normal erythrocytes that have a far lower capacity to produce MPs. It has been recently shown that in SCD, GPA+-MPs are specifically correlated with coagulation and fibrinolysis activation, underlying the fact that a direct link exists between hemolysis, erythrocytes- derived MPs liberation and procoagulant state. The specific clearance of the GPA+-MPs after red cells exchange could partially explain the positive effects of this procedure in primary and secondary prevention of stroke in SCD. However, that GPA+-MPs remained statistically increased after red cells exchange in comparison with controls; whether a low number of post-exchange MPs could be correlated with a better outcome is actually under investigation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals COVID Symptoms and COVID Anxiety in Sickle Cell Disease

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 16-17
Author(s):  
Wally R Smith ◽  
Benjamin Jaworowski ◽  
Shirley Johnson ◽  
Thokozeni Lipato ◽  
Daniel M Sop
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Research Funding ◽  
Telephone Survey ◽  
Cell Disease ◽  
Weighted Mean ◽  
The Us ◽  
Associated Symptoms ◽  
At Home

Background Even before the US upswing of the current COVID pandemic, the number of sickle cell disease (SCD) patients coming to hospitals and EDs appeared to fall drastically. This happened despite SCD patients having often been heavy utilizers of the ED and hospital for their iconic vaso-occlusive crises (VOC). Though ambulatory SCD clinics quick converted largely to telehealth in order to comply with stay-at-home orders designed to suppress person-to-person transmission, some SCD patients appeared to avoid care, delay care, or refuse doctors' invitations for care. Presumably patients did so out of COVID fears, but this has not been confirmed in the literature. Further, whether these patients had COVID symptoms but stayed at home has not been studied. As part of quality improvement (QI) to conduct COVID surveillance in an adult sickle cell program, we sought to explain and predict SCD health care utilization patterns we were observing, as well as to determine urgent physical and mental health needs of patients who appeared to be avoiding care. Methods Fifteen staff in the Adult Sickle Cell Medical Home at Virginia Commonwealth University, a large urban academic medical center, conducted a telephone survey ("wellness check"was used when we talked to patients) of all known adults with SCD over 19 days in 2020. A staff member confirmed the patient had SCD, asked permission to proceed, then asked about symptoms consistent with COVID-19. At the end of the telephone survey, respondents wer invited to complete an email survey of sickle cell and COVID-19 utilization attitudes (19-33 items, depending on the response pattern, either drawn from the National Health Interview Survey, from the Adult Sickle Cell Quality of Life Measurement quality of care survey, or drafted by the authors), the Sickle Cell Stress Survey-Adult (SCSS-A, a 10-item previously validated survey), and anxiety and depression (PHQ9 of the PRIME-MD). Results Of 622 adults approached by phone call, 353 responded to the following yes/no screening questions regarding the prior 14 days: fever over 100 F 0/353 (0.00%); cough 3/353(0.01%); difficulty breathing 0/353(0.00%); unexplained shortness of breath 2/353(0.01%); sore throat 2/353 (0.01%); unexplained muscle soreness 2/353(0.01%);contact with anyone who tested positive for COVID-19 2/353(0.01%); testing for COVID 19 6/353(0.02%). For QI purposes, we set a threshold of three or more COVID-associated symptoms or the presence of fever as criteria requiring intense telephone or in-person staff monitoring for the following week. Only three patients met criteria. A total of 219/353 had email surveys sent. Of 63 patients (28.8%) who returned email surveys by June 10, 2020, 35.9% had already managed a "pain attack" at home 4 or more times in the prior 12 months, and 45.5% of these said their bad ER experiences were very or somewhat important in that decision. In the prior 14 days, although 30/64 reported a crisis for at least one day, only 4/64 had visited the Emergency Department for pain. On a 0-10 scale, 21/61 patients endorsed "0" for worry that they would be COVID-infected by going for medical care (weighted mean 3.9), but 18/59 endorsed "10" for worry they were more at risk of COVID because of SCD (weighted mean 6.31), and 22/60 endorsed "10" for worry they would fare worse than others if COVID infected (weighted mean 6.97). Many patients forwent "needed" care (16/62) or delayed "needed" care by at least a day (36/61). Eleven patients met criteria for moderately severe to severe depression on the PHQ-9, and 28/63 somewhat or strongly agreed with the statement "death is always on the back of my mind" on the SCSS-A. Conclusions In adolescents and adults with SCD, many were already reticent to come to the ED for pain, but a significant portion reported delays or avoidance of needed care during the early stages of the US COVID pandemic, and few reported using the ED despite over half reporting at least one crisis day in 14. Patients nonetheless reported very few COVID-associated symptoms. Fears of COVID infection/susceptibility may limit visits for needed sickle cell care among adults. Acknowledgements: Mica Ferlis RN, FNP, Caitlin McManus, RN, FNP, Emily Sushko, RN, FNP, Justin West, RN, Kate Osborne, RN, Stefani Vaughan-Sams, Marla Brannon, BS, Nakeiya Williams, BS Disclosures Smith: GlycoMimetics, Inc.: Consultancy; Emmaeus Pharmaceuticals, Inc.: Consultancy; Novartis, Inc.: Consultancy, Other: Investigator, Research Funding; Global Blood Therapeutics, Inc.: Consultancy, Research Funding; Shire, Inc.: Other: Investigator, Research Funding; NHLBI: Research Funding; Patient-Centered Outcomes Research Institute: Other: Investigator, Research Funding; Health Resources and Services Administration: Other: Investigator, Research Funding; Incyte: Other: Investigator; Pfizer: Consultancy; Ironwood: Consultancy; Novo Nordisk: Consultancy; Imara: Research Funding; Shire: Research Funding.

scholarly journals Clinical and Biomarker Predictors for Avascular Necrosis in Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3091-3091
Author(s):  
Michael Rabaza ◽  
Maria Armila Ruiz ◽  
Liana Posch ◽  
Faiz Ahmed Hussain ◽  
Franklin Njoku ◽  
...  
Keyword(s):  
Risk Factors ◽  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Avascular Necrosis ◽  
Sickle Cell ◽  
Research Funding ◽  
Medical Attention ◽  
Cell Disease ◽  
Advisory Committees ◽  
Early Management

Abstract Introduction Sickle cell disease (SCD) affects 1 in 365 African Americans and approximately 25 million people world-wide. A common skeletal system complication is avascular necrosis (AVN), which can cause substantial pain and a reduced quality of life. While early management of AVN is focused on increasing range of motion with physical therapy and pain relief, there are no clear predictors for who is more likely to develop AVN and earlier institution of these preventive measure could help decrease disease progression. Vascular endothelial growth factor (VEGF) is a biomarker of endothelial injury and may indicate reduced vascular supply to the femoral or humeral head. Here we describe potential risk factors and biologic pathways for AVN in SCD, as understanding these may lead to improvements in future monitoring, early detection, and early intervention practices. Methods We investigated clinical and laboratory risk factors associated with AVN in a cohort of 435 SCD patients from our center. Blood samples, clinical, and laboratory data were collected at the time of enrollment during a clinic visit. Genotyping for alpha thalassemia was performed by PCR and the serum concentration of VEGF was measured by ELISA. AVN status was confirmed by review of the medical record and available imaging. We conducted a cross-sectional analysis comparing categorical and linear variables by AVN status using the chi-square and Kruskal-Wallis test, respectively. The independent association of the clinical and laboratory variables with AVN status was determined by logistic regression analysis. The initial model included variables with a P-value &lt; 0.1 on univariate analysis and the final model was ascertained by stepwise forward and backward selection. Median values and interquartile range (IQR) are provided. Results The median age of the cohort was 32 (IQR, 24 - 43) years, 57% (250/435) were female, and 46% (198/435) were on hydroxyurea. AVN was observed in 34% (149/435) of SCD patients. SCD patients with AVN were older, had more frequent vaso-occlusive crises requiring medical attention, and had a higher body mass index (Table I) (P ≤ 0.002). We measured VEGF in 241 of the SCD patients with serum samples available at the time of enrolment. Serum VEGF concentrations trended higher in SCD patients with versus without AVN (420 vs. 359 pg/mL, respectively; P = 0.078). In the multivariate analysis model, AVN was independently associated with increased number of vaso-occlusive crises (OR 1.1, 95% CI: 1.0 - 1.14; P = 0.02), AST concentration (natural log OR 0.5, 95% CI: 0.2 - 0.9; P = 0.03), VEGF concentration (natural log OR 1.4, 95% CI: 1.0 - 1.9; P = 0.047), and tobacco use (OR 1.9, 95% CI: 0.9 - 3.7; P = 0.078). Discussion In conclusion, we demonstrate a high prevalence of AVN in an adult cohort of SCD patients. The presence of AVN was independently associated with a greater frequency of vaso-occlusive pain episodes, which may demonstrate a shared pathophysiology between AVN and vaso-occlusion that merits further investigation. We demonstrate that serum VEGF concentrations are higher in SCD patients with AVN and may be a clinical tool to identify those at high-risk and for earlier intervention for this complication. Figure 1 Figure 1. Disclosures Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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