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.

Tricuspid Regurgitant Jet Velocity Is Significantly Associated with Hemolysis in the Evaluation of Pulmonary Hypertension in Children and Young Adults with Sickle Cell Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1211-1211
Author(s):  
Robert I. Liem ◽  
Nichele M. Willingham ◽  
Luciana T. Young ◽  
Alexis A. Thompson
Keyword(s):  
Pulmonary Hypertension ◽  
Young Adults ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Reticulocyte Count ◽  
Cell Disease ◽  
Significant Difference ◽  
Children And Young Adults ◽  
Jet Velocity ◽  
Tricuspid Regurgitant Jet Velocity

Abstract Pulmonary hypertension (PHT) has emerged as a frequent cause of increased morbidity and mortality in adults with sickle cell disease (SCD). However, the incidence, prevalence and etiology of PHT in children with SCD are currently unknown. An elevated tricuspid regurgitant jet velocity (TRJV) ≥ 2.5 m/sec on Doppler echocardiogram (ECHO) in adults may predict PHT usually diagnosed by traditional cardiac catheterization. We hypothesized that routinely measuring TRJV in children and young adults with SCD was feasible and that TRJV correlated with degree of baseline hemolysis. Methods Using a standard protocol, we prospectively measured steady state TRJV in a convenience, cross-sectional sample of 43 patients (mean age 14.2±2.8 years, range 10 to 20) with hemoglobin (Hb) SS, SC or S-β0 thalassemia at our institution as part of a PHT screening initiative beginning December 2005. Patients on chronic transfusions were excluded. The relationship between TRJV and same day laboratory studies and clinical data obtained from patient charts was examined. Results TRJV was not measurable in 5 of 43 (12%) patients, due presumably to normal pulmonary artery systolic pressures. Neither right ventricular hypertrophy nor decreased septal wall motion, both suggestive of PHT, was present when TRJV could not be determined. In the remaining 38 studies in which TRJV could be quantified (mean 2.34 m/sec±0.44), TRJV was ≥ 2.5 m/sec in 13 patients. Using Pearson’s correlation coefficient, we found a significant correlation between TRJV and LDH (r=0.54, p=0.01), with higher TRJV associated with higher LDH. There were also significant, though more modest, positive correlations between TRJV and WBC (r=0.37, p=0.05) and reticulocyte count (r=0.40, p=0.05) and a significant negative correlation between TRJV and Hb (r= -0.46, p=0.01). Using t-test for independent samples, we found a significant difference in mean LDH (458 IU/L±192 vs. 338 IU/L±144, p=0.037), Hb (8.7 g/dL±1.3 vs. 10.2 g/dL±1.6, p=0.008) and reticulocyte count (17.3%±10.3 vs. 10.7%±6.9, p=0.027) between patients with TRJV ≥ 2.5 and &lt;2.5 m/sec. A difference approaching significance in total WBC (11.4 x103/μL±5.3 vs. 8.3 x103/μL ±3.2, p=0.075) was also observed between the two groups. We found neither a significant difference in mean values between the two groups nor significant relationships with TRJV when we examined platelet count, plasma free Hb, percent fetal Hb or total bilirubin. Using Fisher’s Exact Test, we did not demonstrate in our small cohort a difference in the proportion of patients with TRJV ≥ 2.5 or &lt; 2.5 m/sec who had a history of hydroxyurea use, acute chest syndrome, frequent pain, asthma, splenectomy, gallstones, priapism, exchange transfusion, heart disease or tonsilloadenoidectomy. Conclusions We conclude that TRJV by ECHO is quantifiable in most children and young adults being evaluated for PHT and that a higher LDH and reticulocyte count and a lower Hb at baseline are observed more frequently with elevated TRJV. Larger cohort studies are needed to test the predictive value of one or more of these markers of hemolysis. Although long term outcomes associated with elevated TRJV, as an indication of PHT, in children with SCD remains unclear, decreasing hemolysis in this population may represent an early therapeutic target in the prevention of future clinically significant PHT.

scholarly journals Efficacy and Safety of 1500 mg Voxelotor in a Phase 2a Study (GBT440-007) in Adolescents with Sickle Cell Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 509-509 ◽  
Author(s):  
Clark Brown ◽  
Carolyn Hoppe ◽  
Adlette Inati ◽  
Miguel R. Abboud ◽  
Winfred Wang ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Adverse Events ◽  
Flow Velocity ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Genetic Disorder ◽  
Cell Disease ◽  
Advisory Committees ◽  
Clinical Measures

Abstract Background: Sickle cell disease (SCD) is a genetic disorder caused by a mutated hemoglobin S (HbS) that polymerizes in the deoxygenated state and triggers the downstream effects of red blood cell deformation (sickling), hemolysis, vaso-occlusion, and inflammation. Injury from SCD starts in infancy and accumulates over a lifetime causing end-organ damage and ischemic tissue injury, leading to fatigue, pain (vaso-occlusive crisis), and other clinical complications that are underrecognized, undertreated, and associated with early death. Voxelotor is an oral, once-daily therapy that modulates hemoglobin (Hb) affinity for oxygen, thereby inhibiting Hb polymerization. GBT440-007 is a phase 2a study designed to assess the safety, pharmacokinetics (PK), and efficacy of voxelotor in pediatric patients with SCD (HbSS or HbSβ0 thalassemia). Methods: This ongoing study is evaluating multiple doses of voxelotor at 2 dose levels, 900 mg/day and 1500 mg/day, for 24 weeks in adolescents aged 12 to 17 years. The primary objective is to assess the effect of voxelotor on anemia. Secondary objectives include the effects on clinical measures of hemolysis, PK (PK parameters determined using population PK analysis), cerebral blood flow as assessed by transcranial doppler ultrasound (TCD), and safety. Results: Results for adolescents treated with 900 mg/day have been previously reported. As of June 18, 2018, partial data are available for 13 patients (9 females and 4 males). The median age was 14 years (range, 12-17 years) and median weight was 47 kg (range, 31-72 kg). All participants were on hydroxyurea (HU), and 46% had 2 or more painful crises (range, 2-15) in the year prior to enrollment. The median baseline TCD flow velocity was 112 cm/s (range, 92-177 cm/s), and all were less than 135 cm/s at baseline except for 1 with a baseline of 177 cm/s. Data for measures of hemolysis and TCD are available for 5 adolescents who received voxelotor for 12 weeks. The median increase in Hb was 1.0 g/dL at 12 weeks (Table). Median reductions in reticulocytes and indirect bilirubin were 29% and 18%, respectively (Table), consistent with previously reported results of voxelotor in adults with SCD. Preliminary data suggest linear PK up to 1500 mg, the highest dose evaluated. The adolescent with a baseline conditional TCD (177 cm/s of the bifurcation of the internal carotid artery) on background HU at the maximum tolerated dose (29 mg/kg) had a reduction in TCD flow velocity of 20 cm/s with a concordant increase in Hb of 1.7 g/dL at week 24 with voxelotor compared to baseline and a decrease in reticulocytes from 16.45% to 10.4% (Figure). TCD flow velocities in all other arterial segments showed an overall decline at week 24. All treatment-related adverse events were grade 1 or 2, and there were no treatment-related serious adverse events. Data for all adolescents treated with voxelotor 1500 mg/day for up to 24 weeks will be presented at the conference. Conclusions: Preliminary results indicate that voxelotor at 1500 mg/day was well tolerated. Data from 5 adolescents at 12 weeks show a marked improvement in Hb and reductions in clinical measures of hemolysis. Importantly, hematologic improvements are seen in adolescents already managed at the maximally tolerated dose of HU. Compared to previously reported data at 900 mg/day, this indicates a dose-dependent improvement in hemolytic anemia. One adolescent with conditional TCD, despite background HU, achieved normalized TCD flow velocity after voxelotor therapy. Overall, these results are consistent with in vivo inhibition of HbS polymerization by voxelotor and support the ongoing clinical evaluation of voxelotor as a potential disease-modifying therapy for adolescents with SCD. Disclosures Brown: Global Blood Therapeutics: Consultancy, Research Funding. Inati:Global Blood Therapeutics: Research Funding; Astra Zeneca: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Woods:Global Blood Therapeutics: Research Funding; Pfizer: Research Funding; Guidepoint: Honoraria; Putman: Honoraria; Children's Mercy Hospital: Employment, Membership on an entity's Board of Directors or advisory committees. Hsu:Global Blood Therapeutics: Research Funding; Astra Zeneca: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ironwood: Research Funding; Emmi: Consultancy; Hilton Publishing: Consultancy; Gerson Lehman Group: Consultancy; Guidepoint: Consultancy. Piccone:Novartis: Consultancy. Fong:Global Blood Therapeutics: Employment. Dixon:Global Blood Therapeutics: Employment. Tonda:Global Blood Therapeutics: Employment. Washington:Global Blood Therapeutics: Employment. Lehrer-Graiwer:Global Blood Therapeutics: Employment.

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.

Mutations and Polymorphisms Influencing Hemolysis in Hemoglobin Genes and Risk of Pulmonary Hypertension in Sickle Cell Disease: Effect of Hemoglobin SC.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1206-1206
Author(s):  
James G. Taylor ◽  
Diana Ackah ◽  
Crystal Cobb ◽  
Oswaldo Castro ◽  
Gregory J. Kato ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Survival Data ◽  
Strong Predictor ◽  
Pulmonary Vasculature ◽  
Cell Disease ◽  
Intravascular Hemolysis ◽  
Hepatic Congestion ◽  
Significant Difference

Abstract Pulmonary hypertension (PH) is an increasingly recognized phenotypic manifestation of sickle cell disease (SCD) and a leading cause of death among adults with SCD. Chronic intravascular hemolysis is a central pathologic event with release of hemoglobin into plasma and leads to nitric oxide consumption. A resulting NO deficiency state is hypothesized to produce vasoconstriction within the pulmonary vasculature, ultimately becoming manifest as symptomatic PH. We have hypothesized that genetic factors may influence the risk for developing PH in SCD. As an initial step in identifying PH susceptibility loci, the allelic spectrum of mutations and polymorphisms in the hemoglobin genes have been examined with respect to PH in adults with SCD. Echocardiography was used to phenotype 261 unrelated subjects for PH, where cases were prospectively defined by a triscuspid regurgitant jet velocity &gt; 2.5 m/s. The entire HBB gene was sequenced, and genotypes for SNPs flanking the β and α-globin loci were determined. HBB sequence analysis identified 66 (25.3%) compound heterozygotes for 1 of 13 different mutations (16.1% Hb SC or 9.2% β+ thalassemia, β0 thalassemia, or another hemoglobinopathy). A significant difference in genotype distributions between PH cases and cohort controls (3 x 2 table, P=0.026) suggested that individual mutations within the locus may be associated with PH. When analyzed individually, the prevalence of HbSC between cases (7.4%) and controls (21.1%) suggested that the HbC allele is associated with protection from PH (Odds Ratio=0.35, 95% CI 0.15–0.78, P=0.009). HbSS is only a mild risk factor (OR=2.01, 95% CI 1.07–3.78, P=0.026). In contrast, there was no association between 5′ or 3′ β globin locus haplotypes defined by combinations of 16 common SNPs and PH in patients with either SCD or HbSS. When the α-globin locus was examined using 3 haplotype tagged SNPs flanking the HBA2 and HBA1 genes, no PH associations were observed. An analysis of α-thalassemia mutations has not yet been completed, thus no definitive conclusions can be made for the influence of the α-globin locus on PH. Finally, the HbSC association was explored further by comparing laboratory markers of hemolysis and survival data within the HbSC group. Between SC PH cases and controls, anemia was the only significant characteristic of PH (P=0.0027) without other labs suggestive of excessive hemolysis. In contrast, other clinical findings observed in association with SCD PH, including hepatic congestion, iron overload and renal insufficiency, were present in HbSC PH group. While an overall association with protection from PH was observed for HbSC, a preliminary 40 month survival analysis suggests that PH in SC patients remains a significant marker associated with a risk for death (Hazard Ratio=7.89, P=0.007) which is comparable to overall SCD survival with PH. We conclude that the HbSC genotype is associated with protection from the development of PH in SCD, possibly due a smaller relative contribution of intravascular hemolysis. However, this diagnosis remains a strong predictor for death in SCD independent of HBB genotype. Further study of large populations of HbSC patients are warranted for defining optimal PH therapies and may be useful for elucidating the genetic basis for the non-hemolytic mechanisms contributing to secondary PH in SCD.

Risk Factors for Death in 632 Patients with Sickle Cell Anemia in the United States and United Kingdom

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3240-3240 ◽  
Author(s):  
Mark T Gladwin ◽  
Robyn J Barst ◽  
J. Simon R. Gibbs ◽  
Marianna Hildesheim ◽  
Vandana Sachdev ◽  
...  
Keyword(s):  
Risk Factors ◽  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Research Funding ◽  
Proportional Hazards ◽  
The United States ◽  
Right Heart Catheterization ◽  
Heart Catheterization ◽  
Cell Disease

Abstract Abstract 3240 The role of pulmonary hypertension as a common and attributable cause of mortality in patients with sickle cell disease remains controversial. To assess this question and explore risk factors for death in patients with sickle cell disease we evaluated 632 patients in the Walk-PHASST pulmonary hypertension screening cohort, recruited from nine different study sites in the United States and one site in the United Kingdom. Methods: Patient characteristics and their associations with mortality were analyzed with Cox proportional hazards regression analysis. Based on data from three right heart catheterization screenings studies that have recently been published, we defined the presence of pulmonary hypertension for this analysis by a Doppler-echocardiographic measurement of the tricuspid regurgitant jet velocity (TRV) ≥ 3.0 m/s, which has a 67–75% positive predictive value for a mean pulmonary artery pressure ≥ 25 mm Hg by right heart catheterization. This therefore represents a very conservative threshold for a large population screening study. Among subjects with a measurable TRV (n=572), 64 (11.2%) had measurements of ≥ 3.0 m/sec. Among those with measurable NT-proBNP (n=582), 140 (24.1%) had measurements ≥160 pg/mL, a value associated with both pulmonary hypertension and mortality. A total of 39 (7.4%) had both high TRV (≥3.0 m/sec) and high NT-proBNP (≥160 pg/mL). Results: Over a median follow-up time of 29 months, we observed 22 deaths. 50% (N=11) of these patients had a TRV≥ 3.0 m/sec. At 24 months the cumulative survival was 83% for patients with TRV ≥ 3.0 m/sec and 98% for patients with TRV < 3.0 m/sec (p<0.0001). The unadjusted hazard ratios for death were 11.14 (95% CI 4.1–30.1; p<0.0001) for patients with TRV above and below 3.0 m/sec and 4.55 (95% CI 1.8–11.3; p=0.001) for patients with NT-proBNP above and below 160 pg/mL. For patients with both high TRV (≥ 3.0 m/sec) and high NT-proBNP (≥ 160 pg/mL), the unadjusted hazard ratio was 14.86 (95% CI 5.5–39.9; p<0.0001). Overall, an increased risk of death was observed for both age and gender, with males at higher risk relative to females (HR=2.48, 95% CI 1.0–6.1; p=0.05), and patients older than 47 years (HR=2.02, 95% CI 1.1–3.8; p=0.03). Associations with mortality were also observed for chronic transfusions (HR=3.00, 95% CI 1.2–7.8; p=0.02) and a NYHA/WHO class value or III or IV (HR=4.52, 95% CI 1.4–14.3; p=0.01). Other variables associated with mortality in our cohort included a high hemolytic component, aspartate aminotransferase (AST), ferritin, and creatinine. Variables not associated with mortality included current hydroxyurea use, SC disease, self-reported history of painful episodes, and six-minute walk distance. In stepwise multiple proportional hazards regression analysis, the association between TRV and mortality remained significant after adjustment for all other risk factors, including ferritin, AST, creatinine and even NT-proBNP (HR 4.27, 95%CI 1.3–14.1; p=0.04). Conclusions: Using a more conservative cut-off value of TRV ≥ 3.0 m/sec as defining PH in a large screening population of sickle cell disease patients, PH occurs in approximately 10% of unselected screened patients and is associated with the highest unadjusted and adjusted risk for death of any measured variable. Disclosures: Gladwin: Bayer Corp: Consultancy, Research Funding; NIH and NHLBI: Research Funding; Gilead Sciences: Research Funding. Barst:Ventripoint: Stock options Other; Actelion, Eli Lilly, Gilead, Glaxo Smith-Kline (GSK), Medtronics, Bayer, Ikaria, Pfizer, Novartis, VentriPoint: Consultancy, Honoraria. Girgis:NIH/NHLBI: Research Funding, Travel support Other. Rosenzweig:NIH: Research Funding. Badesch:NIH: Research Funding. Lanzkron:NIH: Research Funding.

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.

A Comparison of Chronic Manual and Automated Red Blood Cell Exchange Transfusion in Sickle Cell Disease Patients From Two Comprehensive Care Centres in the United Kingdom

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3430-3430 ◽  
Author(s):  
Kevin H.M. Kuo ◽  
Richard Ward ◽  
Jo Howard ◽  
Paul Telfer
Keyword(s):  
Sickle Cell Disease ◽  
Adverse Events ◽  
Blood Cell ◽  
Sickle Cell ◽  
Red Blood Cell ◽  
Antibody Formation ◽  
Individual Variability ◽  
Cell Disease ◽  
Significant Difference ◽  
Manual Group

Abstract Abstract 3430 Chronic transfusion is indicated in the treatment and prevention of sickle cell disease (SCD) related-complications. Red blood cell exchange (RBCX) is preferred over top-up transfusion as it enables iron balance and rapid reduction of sickle hemoglobin (HbS) without increasing blood viscosity. RBCX can be done manually by sequential phlebotomy and transfusion or by automated apheresis, but the two methods have not been formally compared. Bart's Health NHS Trust (BHT) performs manual RBCX and Guy's and St. Thomas NHS Trust (GSTT) automated RBCX. Manual RBCX consists of isovolumetric exchange 15 to 20 mL/kg of venesected blood for normal saline and packed RBC, generally at a 1:1 ratio. Automated RBCX utilizes the Spectra Optia Apheresis System with a fractional cell remaining between 24 and 44, end Hct within 0.02 of pre-RBCX Hct, and a fluid replacement balance of 100%. The indications for RBCX and pre-RBCX HbS or hemoglobin SC (HbSC) target (30% or 50%, depending on indication) are the same in both units. All packed RBC were leukodepleted, HbS negative, ≤ 7 days old, and phenotypically matched for C, D, E, and Kell. A retrospective observational cohort study as part of a quality assurance audit was conducted examining all SCD patients attending regular RBCX at BHT and GSTT between 1 May 2011 and 30 April 2012. Fifty-one patients (21 manual, 30 automated), totaling 401 RBCX sessions were included. Ten patients in the manual group and 7 patients in the automated group targeted an HbS of < 30%, while the rest were targeted to < 50%. There was no significant difference in baseline characteristics between the two groups. Peripheral vein was the most common method of cannulation in manual RBCX while temporary central venous catheterization was most common in automated RBCX (P < 0.0001). Time interval differed between manual and automated RBCX (median 4.4 vs. 7.1 weeks, P < 0.0001). Both groups consistently achieved a post-RBCX Hct < 0.350. More patients on automated RBCX were able to consistently achieve their prescribed HbS or HbSC target (defined as > 2/3 of RBCX sessions) than on manual RBCX (37% vs. 10%, unadjusted OR 5.5, 95% CI 1.07 – 28.22, P = 0.048). When adjusted for the prescribed pre-RBCX HbS or HbSC target, the Mantel-Haenszel OR estimate was 4.72 (95% CI 0.885 – 25.17). Older age was also associated with consistently achieving the prescribed HbS or HbSC target (P = 0.010 on multivariable logistric regression). Although the yearly volume of RBC and donor units used were significantly higher in the automated group (241.1 mL/kg/year and 55 units/year) compared to the manual group (127 mL/kg/year and 32 units/year), there was no difference in the rate of allo-antibody formation. There was no difference in the mean ferritin trend between manual and automated RBCX in non-chelated patients (−0.068 ± 1.439 vs. −0.297 ± 2.027 ug/L/day, P = 0.439). Automated RBCX was better at maintaining a near zero iron balance than manual RBCX due to considerable individual variability in the manual group (kurtosis statistic 13.221 ± 0.935 SE vs. 0.398 ± 1.121 SE). It took a significantly longer time to perform a manual RBCX session than an automated one (257 min. vs. 115 min.). There was no significant difference in the number of adverse events. The number of RBCX sessions that had to be converted to top-up transfusions in the manual group because of low pre-RBCX haematocrit far exceeded that of the automated group (11 vs. 0 sessions). None of the patients in either group had new or progressive neurological events. Manual RBCX, despite an optimized protocol and strict adherence to treatement, is inferior to automated RBCX in being able to consistently achieve the prescribed HbS target, although consistent adherence with automated RBCX can also be challenging. Automated RBCX requires less time to perform than manual RBCX, but involves higher RBC use and more donor exposure. Adverse events and antibody formation are the same for both methods. Automated RBCX can maintain a near zero iron balance in most patients without the use of iron chelation and with less individual variability than manual RBCX. The results suggest that automated RBCX is the preferred RBC exchange method in controlling HbS in SCD patients. Further longitudinal study is required to determine whether a better control of HbS translates into differences in patient-related outcomes. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Targeted Proteomics of Pulmonary Hypertension in Sickle Cell Disease

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 981-981
Author(s):  
Varshini Babu ◽  
Jane A. Little ◽  
Claudia R. Morris ◽  
Roberto Machado ◽  
J Simon R Gibbs ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Negative Correlation ◽  
Neutrophil Count ◽  
Tricuspid Regurgitation ◽  
Research Funding ◽  
Cell Disease ◽  
Protein Biomarkers ◽  
False Discovery

Abstract BACKGROUND AND AIM: Hemolysis, inflammation and coagulopathy associated with sickle cell disease (SCD) can lead to pulmonary hypertension. More than 15% of adult patients with SCD are affected by pulmonary hypertension as measured by a tricuspid regurgitation velocity (TRV) ≥ 2.9 m/sec (Nouraie, M. et al., Validation of a composite vascular high-risk profile for adult patients with sickle cell disease. American Journal of Hematology, 94:E312-E314. 2019). Moreover, sickle cell disease patients with pulmonary hypertension have a much higher mortality risk than those without pulmonary hypertension. There is little knowledge on the proteomic profile of pulmonary hypertension in SCD. Our aim was to conduct a proof-of-concept study to explore targeted serum protein biomarkers that are differentially expressed in SCD patients with elevated tricuspid regurgitation velocities and explore their corresponding pathways. MATERIAL AND METHODS: Data from the Walk-PHaSST study was used for this study. The Walk-PHaSST was a multicenter study to assess the effect of sildenafil for SCD patients with pulmonary hypertension (Gladwin, M. T. et al., Risk factors for death in 632 patients with sickle cell disease in the United States and United Kingdom. PLoS One, 9:e99489. 2014). In the screening phase of the study, 720 patients with SCD were recruited. Study participants underwent clinical and lab examinations, as well as an echocardiography. We selected two groups of patients: one group of patients with a TRV≤2.6 m/sec and another with TRV≥2.9 m/sec (N =35 in each). The serum concentration of 92 protein biomarkers was measured using an OLINK cardiovascular panel. This panel assess a range of biological process including inflammatory response, angiogenesis, cell adhesion, coagulation, and response to hypoxia. T-tests were performed between the aforementioned groups for each of the serum biomarkers. The Hochberg method was used to calculate the false discovery rate. A volcano plot was created using the Bonferroni correction. Finally, we tested the correlation of the differentially expressed biomarkers with clinical variables measured in blood samples of the participants. These variables include white blood cell (WBC), neutrophil count, thrombospondin-1 (TSP as measure of coagulation), PIGF and VEGF (growth factors involved in angiogenesis), and NT-proBNP (elevated in pulmonary hypertension). RESULTS: Using a false discovery rate of 0.01, we discovered 14 significantly expressed proteins. Six of them passed a Bonferroni corrected overall critical p value &lt; 0.00054 (Figure 1). These included T-cell surface glycoprotein (CD4), lymphotactin (XCL1), SLAM family member 7 (SLAMF7), galectin-9 (GAL9), TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2), and tumor necrosis factor receptor superfamily member 11A (TNFRSF11A). We observed up to a 1.2-fold increase in these 6 protein biomarker levels in the high TRV groups. The correlogram (Figure 2) indicated that there is a slightly positive correlation between WBC and CD4, GAL9, TRAILR2, and TNFRSF11A (r &gt; 0.20). For neutrophil count, we observed significantly negative correlation with selected markers including TNFRSF11A levels (r = -0.51), GAL9 (r = -0.35), XCL1 (r = -0.27), SLAMF7 (r = - 0.21), and CD4 (r &lt; - 0.24). A significantly negative correlation between TSP and GAL9 levels (r = -0.31) was also observed. Finally, we observed a strong, positive correlation between all proteins and serum NT-proBNP levels (r &gt; 0.44). CONCLUSION: Circulatory protein markers of immune response and coagulation are highly expressed in SCD patients with elevated TRV. This provides evidence that these protein biomarkers have potential to be utilized as prognostic markers for pulmonary hypertension in patients with SCD. Figure 1 Figure 1. Disclosures Little: Biochip Labs: Patents & Royalties; Hemex Health, Inc.: Patents & Royalties. Gibbs: Acceleron Pharma: Consultancy, Other: lecture fees; Actelion: Consultancy, Other: lecture fees; Aerovate: Consultancy, Other: lecture fees; Bayer: Consultancy, Other: lecture fees; Compexia: Consultancy, Other: lecture fees; Janssen: Consultancy, Other: lecture fees; MSD: Consultancy, Other: lecture fees ; Pfizer: Consultancy, Other: lecture fees; United Therapeutics: Consultancy, Other: lecture fees. Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Nouraie: Phoenicia BioScience Inc.: Consultancy.

The Relationship of Pulmonary Hypertension and Survival in Sickle Cell Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1665-1665 ◽  
Author(s):  
Kenneth I. Ataga ◽  
Susan Jones ◽  
Oludamilola Olajide ◽  
Dell Strayhorn ◽  
Alice Lail ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Right Atrial ◽  
Reference Ranges ◽  
Cell Disease ◽  
Risk Of Death ◽  
Increased Risk ◽  
Significant Difference

Abstract Introduction: Pulmonary hypertension (PHT) is a common complication of sickle cell disease (SCD). Most SCD patients who have PHT appear to have only mild elevations in their pulmonary artery systolic pressure (PASP). Although SCD patients with PHT have been reported to have an increased mortality, the effect of mild PHT on survival in patients with SCD remains uncertain. Methods: The study subjects represent a cohort of patients followed at the Sickle Cell Clinic at UNC, Chapel Hill. Doppler echocardiography was used to estimate the PASP. The PASP was determined by applying the modified Bernoulli equation (PASP = 4V2 + right atrial pressure), if an adequate tricuspid regurgitant velocity was observed. A subject was considered to have PHT if his/her PASP exceeded the upper limits of normal in the age- and body mass index-adjusted reference ranges. Subjects with PHT were sub-classified into mild (above normal values up to 44 mm Hg), moderate (45 – 74 mm Hg) or severe pulmonary hypertension (≥ 75 mm Hg). Patients’ data were censored at the time of their death or loss to follow-up. Results: The 60 subjects enrolled in this study have been followed for a period of 9 to 47 months (mean [± SD] of 29.8 ± 10.7 months). Pulmonary hypertension was observed in 18 subjects on initial evaluation, while the remaining 34 subjects had no evidence of PHT. The 18 subjects with PHT have been followed for 24.9 ± 10.6 months, while the 34 subjects without PHT have been followed for 31.8 ± 10.1 months. Six patients have died to date. All of these 6 patients had evidence of PHT, with estimated PASP values of 44, 44, 48, 54, 74 and 84 mm Hg (mean = 58 mm Hg) respectively. The presence of PHT was strongly associated with an increased risk of death (p = 0.0001). No other variables were associated with the risk of death in these patients. Although more patients with moderate and severe PHT died when compared to patients with mild PHT, the difference was not statistically significant. Conclusion: Pulmonary hypertension is strongly associated with an increased risk of death in patients with SCD. While our study did not find a significant difference in the risk of death when patients with mild PHT were compared to patients with more severe disease, the number of patients followed was relatively small and the duration of follow-up was short. More patients and a longer period of follow-up would be required to ascertain whether the effect of mild pulmonary hypertension on mortality is different from that of more severe PHT in patients with SCD. Figure Figure

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