Systematic Evaluation Of Chronic Organ Damage In Adult Sickle Cell Patients. A Seven-Year Follow-Up Study

Introduction The occurrence of organ damage in sickle cell disease (SCD) is a crucial determinant for both medical treatment and prognosis. In a previous study, we systematically analyzed the prevalence of SCD related organ damage and complications in adult sickle cell patients in a tertiary teaching hospital in the Netherlands. We now describe a seven-year follow-up of this patient cohort, to provide an insight into the course of the various forms of organ damage and SCD related complications. Methods At baseline in 2006, 110 adult patients visiting the outpatient clinic of our hospital were enrolled. All enrolled patients from the primary analysis were included for follow-up. Patients were screened for sickle cell related manifestations during visits to the outpatient clinic biannually. Various forms of sickle cell related organ damage and complications (presence of microalbuminuria, renal failure, pulmonary hypertension retinopathy, iron overload, cholelithiasis, avascular osteonecrosis, leg ulcers, acute chest syndrome, stroke, priapism and admissions for painful crises) were routinely screened according to international guidelines. Patients with genotype HbSS/HbSβ0 and HbSC/HbSβ+were grouped for further analysis. Results Of all originally included patients (N=110), nine were lost to follow-up (N=9). The mean age of the current study cohort is 37 years (IQR 27-46). Overall, 59 patients (58%) developed a new form of organ damage or new complication since baseline analysis, including eight patients who deceased (7 due to a sickle cell disease related death). In the HbSS/HbSβ0 genotype group (N=60) we found an increase in the percentage of patients who have had an Acute Chest Syndrome (29% to 47%) or have been diagnosed with avascular osteonecrosis (15% to 24%), retinopathy (23% to 34%) or pulmonary hypertension (31% to 48%). In the HbSC/HbSβ+ (N=35) group we found an increase in the occurrence of avascular osteonecrosis (9% to 14%), retinopathy (59 % to 70%) and pulmonary hypertension (9% to 19%). Furthermore, the use of hydroxycarbamide increased in both genotype groups and the frequency of admissions for painful crises remained stable for both genotype groups. Conclusion In the past period of seven years 58% of the patients in a previously well descript cohort of adult SCD patients developed a new sickle cell related complication. For some forms of organ damage or complications a substantial increase occurred dependent of a patient’s genotype. Disclosures: No relevant conflicts of interest to declare.

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Progression of Pulmonary Hypertension in Patients with Sickle Cell Disease.

Blood ◽

10.1182/blood.v106.11.3187.3187 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3187-3187 ◽

Cited By ~ 3

Author(s):

Kenneth I. Ataga ◽

Charity Moore ◽

Susan Jones ◽

Oludamilola Olajide ◽

Dell Strayhorn ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Left Ventricular ◽

Right Atrial ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Original Cohort ◽

The Mean

Abstract Introduction: The prevalence of pulmonary hypertension (PHT) is high in patients with sickle cell disease (SCD). Although most patients have only mild increases in their pulmonary artery systolic pressure (PASP), the presence of PHT is strongly associated with an increased risk of death. While PHT seen in SCD is thought to progress over time, both the rate of development of PHT and the factors that affect disease progression remain unknown. Methods: The 41 subjects in this study were drawn from an original cohort of 60 patients followed in the Sickle Cell Clinic at UNC-Chapel Hill. All patients were previously evaluated for PHT (defined using an age-, sex-, and BMI-adjusted reference range). Of the 60 patients in the original cohort, six are now deceased and 13 others were not available for repeat evaluation. The PASP was determined using Doppler echocardiography and then applying the modified Bernoulli equation (PASP = 4V2 + right atrial pressure). Individuals were not studied if they: 1) showed clinical evidence of left ventricular failure; 2) had a recent acute illness (e.g., vaso-occlusive crisis); or 3) had experienced an episode of acute chest syndrome within the preceding 4 weeks. Means and standard deviations were calculated for all measures at the time of initial evaluation and at the time of follow-up. Results: Of the 41 subjects in our study, PHT was originally present in 12, while no evidence of PHT was present in 29. Of the 29 subjects who initially had no evidence of PHT, 4 (or 14%) have now developed PHT (mean follow-up period of 3.3 ± 0.4 years). In these 4 subjects, the mean PASP at the time of initial and follow-up evaluations respectively were: 37.0 ± 2.0 mm Hg vs. 55.8 ± 11.0 mm Hg. The patients who developed PHT during the course of the study had lower systolic BP (143 ± 12 mm Hg vs. 128 ± 12 mm Hg), lower fetal hemoglobin levels (6.2 ± 5.7 % vs. 4.2 ± 3.7 %), and higher platelet counts (276 ± 119 X 103/μL vs. 426 ± 96 X 103/μL) at the time of their follow-up analyses. By contrast, 3 of the 12 subjects (or 25%) who were thought to have PHT at the time of their original evaluations were found to have normal PASP determinations at the time of their repeat echocardiograms (mean follow-up period of 3.2 ± 0.6 years). In these latter 3 subjects, the mean PASP values at the time of the initial and follow-up evaluations respectively were: 40.0 ± 4.6 mm Hg vs. 33.7 ± 4.7 mm Hg. Conclusion: In this small group of patients with SCD, we found that PHT developed in 14% of subjects who had no evidence of PHT 3 years earlier. Based on this observation, it seems that periodic echocardiograms to screen for the development of PHT would be appropriate. On the other hand, our observation that some patients initially classified as having PHT failed to have elevated PASP measurements at the time of follow-up illustrates the limitation of a single echocardiographic evaluation in establishing this diagnosis. Because of the increase in PASP that occurs during acute vaso-occlusive episodes, and the difficulty usually encountered in distinguishing steady state from crisis, the initial elevation of the PASP in these patients could have resulted from sub-clinical crisis states. For these reasons, a patient found to have an elevated PASP at the time of a screening echocardiogram should have a repeat study, and perhaps a right heart catheterization, before the diagnosis of PHT is firmly established.

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Natriuretic Peptide Levels Correlate with Pulmonary Pressures and Prospective Mortality in SCD: Use of This Biomarker To Identify Prevalence and Mortality of Pulmonary Hypertension in the MSH Cohort.

Blood ◽

10.1182/blood.v106.11.1.1 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1-1

Author(s):

Roberto Machado ◽

Martin Steinberg ◽

Duane Bonds ◽

Samir Ballas ◽

William Blackwelder ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Cell Disease ◽

Risk Of Death ◽

Cox Proportional Hazards Regression ◽

Proportional Hazards Regression

Abstract Pulmonary hypertension [PH-tricuspid regurgitant jet velocity (TRV) ≥2.5 m/s] is a common complication of sickle cell disease associated with high mortality. Identification of biomarkers of PH and mortality could facilitate screening and risk stratification in this population. Validated biomarkers would provide methods for retrospective evaluation of the prevalence and prognosis of PH in large historical cohorts of patients such as the Multicenter Study of Hydroxyurea in Sickle Cell Anemia(MSH). Because brain natriuretic peptide(BNP) is released from the ventricles during pressure strain, we hypothesized that BNP levels would correlate with the severity of PH and prospective risk of death in patients with SCD. BNP was measured in 45 African-American control subjects and 230 patients with SCD. Median (interquartile range) BNP(pg/ml) was higher in patients with PH than patients without PH or controls[+PH: 206(81–701),-PH: 47(26–104), C: 29, P<0.001]. BNP levels directly correlated with age (R=0.32, P<0.001), creatinine (R=0.22, P<0.001), LDH(R=0.31, P<0.001), TRV (R=0.5, P<0.001), pulmonary vascular resistance (R=0.5, P=0.001); and inversely with hemoglobin(R=0.41, P<0.001), cardiac output(R=0.47, P= 0.003) and 6-minute walk distance(R=0.51, P=0.001). The area under the ROC for BNP and the diagnosis of pulmonary hypertension was 0.84 (P<0.001). A cutoff value of 160 pg/ml (corresponding to the 75th percentile for the population) had 58% sensitivity and 98% specificity for the diagnosis of PH. Cox proportional hazards regression identified BNP as an independent predictor of mortality(RR 2.17,95% CI 1.2–3.8, P =0.001) with clear mortality break point at the 75th percentile(160 pg/ml). To independently explore the prevalence and associated risk of PH in patients with sickle cell disease, a BNP value of 160 pg/ml was used as an indicator of PH. BNP levels were then measured in plasma samples collected in 121 patients who were enrolled in the MSH patient’s follow-up study that started in 1996. These patients had received hydroxyurea or placebo for two years, had moderately severe disease based on study entry criteria, and had 9-years of comprehensive follow-up. An abnormal BNP level ≥160 pg/ml was present in 30% of patients in the MSH cohort. BNP levels correlated directly with age(R=0.35, P<0.001) and creatinine (R=0.24, P<0.001), and inversely with hemoglobin(R=−0.54, P<0.001). There was no correlation between BNP and rate of painful episodes or acute chest syndrome, use of hydroxyurea or leukocyte count. A high BNP level in the MSH cohort was associated with mortality by logistic regression(OR 3.04,95% CI 1.2–7.6, P = 0.018) and Cox proportional hazards regression analysis(RR 2.87, P=0.017). The relationship remained significant for continuous log- transformed BNP values and after adjustment for other covariates. These studies confirm that PH is common, mechanistically linked to hemolytic anemia and the major risk factor for death in SCD. Provocatively, the MSH analysis suggests that rates of pain episodes in this small sample of seriously ill patients were unrelated to risk of death: this risk was largely determined by a high BNP level, which is probably explained by undiagnosed hemolysis-associated PH.

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Severity of Sickle Cell Disease: Modeling Interrelationships among Hemolysis, Pulmonary Hypertension and Risk of Death.

Blood ◽

10.1182/blood.v108.11.786.786 ◽

2006 ◽

Vol 108 (11) ◽

pp. 786-786

Author(s):

Paola Sebastiani ◽

Vikki G. Nolan ◽

Clinton T. Baldwin ◽

Maria M. Abad-Grau ◽

Ling Wang ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Sickle Cell Disease ◽

Disease Severity ◽

Hemolytic Anemia ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Clinical Severity ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Risk Of Death

Abstract A single point mutation in the β hemoglobin gene causes sickle cell disease (SCD), but patients have extremely variable phenotypes. Hemolysis-related complications include pulmonary hypertension (PHT), priapism, stroke and leg ulceration; blood viscosity and sickle vasoocclusion are associated with painful episodes, acute chest syndrome and osteonecrosis. Predicting who is at highest risk of death would be useful therapeutically and prognostically. Applying Bayesian network modeling that describes complex interactions among many variables by factorizing their joint probability distribution into modules, to data from 3380 SCD patients, we constructed a disease severity score (DSS: 0, least severe; 1, most severe), defining severity as risk of death within 5 years. A network of 24 variables described complex associations among clinical and laboratory complications of SCD. The analysis was validated in 140 patients whose SCD severity was assessed by expert clinicians and 210 adults where severity was also assessed by the echocardiographic diagnosis of PHT and death. Information about PHT allowed a comparison of the DSS with the tricuspid regurgitant jet velocity (TRJV), an objective marker of PHT and an independent risk factor for death. DSS and three indices of clinical severity (severity ranking of individuals by expert clinicians; objective measurement of the presence and severity of PHT; risk of prospective death) were correlated. Among living subjects, the median score was 0.57 in 135 patients without PHT, 0.64 in 40 patients with mild PHT and 0.86 in 15 patients with severe PHT. The difference in average score between living patients with and without PHT is significant. The same increasing trend was noticeable in the subjects who died during follow-up: 0.60 in subjects without PHT; 0.68 in subjects with mild PHT; 0.79 in subjects with severe PHT. The utility of the DSS is also supported by the ability to assign a score to subjects for whom the TRJV cannot be measured. Surprisingly, besides known risk factors like renal insufficiency and leukocytosis, we identified the intensity of hemolytic anemia and clinical events associated with hemolytic anemia as contributing to risk for death. Priapism, an excellent reflection of the hemolytic anemia-related complications of SCD, is associated with PHT and its association with death was unexpected. Laboratory variables predictive of disease severity included LDH and reticulocytes that reflect the intensity of hemolytic anemia. Elevated systolic blood pressure increased the odds of death by 3.4, consistent with hypertension as a marker of early death in SCD. Subjects with sickle cell anemia are at greatest risk compared with subjects with sickle cell anemia-α thalassemia and with subjects with HbSC disease. Our model suggests that the intensity of hemolytic anemia, estimated by LDH, reticulocyte count and AST, and shown previously to be associated with PHT, priapism, leg ulceration and possibly stroke, is an important contributor to death. This model can be used to compute a personalized measure of disease severity that might be useful for guiding therapeutic decisions and designing clinical trials.

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A North American Experience Of Hemoglobin SC Disease, Its Complications, and Management

Blood ◽

10.1182/blood.v122.21.2221.2221 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2221-2221 ◽

Cited By ~ 1

Author(s):

Veronique Naessens ◽

Richard Ward ◽

Kevin H.M. Kuo

Keyword(s):

Sickle Cell Disease ◽

Avascular Necrosis ◽

Sickle Cell ◽

Care Center ◽

Comprehensive Care ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Baseline Hemoglobin ◽

Hemoglobin Sc Disease

Background The phenotype of hemoglobin SC (HbSC) disease is distinct from sickle cell anemia (SCA) (HbSS and S/b0) but management of adults is mostly derived from studies of the latter group. Longitudinal observational studies on the complications and outcomes of hemoglobin SC disease are largely confined to centers outside North America. The unique ethnic composition of our cohort, consisting of mostly Western Africans and West Indians, permits further characterization of the HbSC phenotype. Objective to describe the baseline characteristics and long-term complications of a cohort of adult HbSC patients followed in a Canadian sickle cell comprehensive care center. Methods A retrospective observational cohort study was conducted on all adult patients with HbSC disease attending a sickle cell comprehensive care center in Toronto, Canada from 1994 to 2013. Baseline demographics, acute and chronic complications attributable to sickle cell disease, and laboratory data were collected. Medians were used to describe continuous variables, while percentages or ratios for categorical variables. Logistic regression was used to examine factors influencing the main clinical complications. Results 104 patients were included in the analysis, comprising of 38.5% males and 61.5% females. Median length of follow-up was 3.5 years (1 - 19) and median age at last recorded visit was 35 years (18 - 68). Median baseline hemoglobin was 119 g/L (82 - 153 g/L), hematocrit 0.340 (0.250 - 0.440), and fetal hemoglobin (HbF) fraction 1% (0 - 7.7%). Most frequent complications encountered were retinopathy (55.8%) and symptomatic avascular necrosis (27.9%), followed by painful vaso-occlusive crises requiring emergency room visit (23.1%). Presence of retinopathy was associated with higher baseline hemoglobin (OR 2.72 for every 10 g/L of hemoglobin, p = 0.037) and older age (OR 2.72 for every decade, p < 0.001). Acute chest syndrome (7.7%), priapism (7.5% of men), and renal involvement (8.2%), were less common than reported in the literature, while the rates of venous thromboembolism (8.7%), symptomatic infarctive or hemorrhagic stroke (2.9%) were slightly more common. Median right ventricular systolic pressure on 2D-transthoracic echocardiogram was 29 mmHg (17 – 43 mmHg). No patient underwent a right heart catheterization. Two patients died from septic shock, both at the age of 29. Disease-modifying therapy most often consisted of hydroxyurea (28.8%), followed by exchange transfusion (6.7%) and phlebotomies (5.8%). Hydroxyurea significantly increased the median HbF fraction (from 1% to 2.75%, p = 0.004 by related-samples Wilcoxon signed rank test). Conclusion In this large North American cohort of adult patients, we have again shown that HbSC disease is not as benign as traditionally thought. As such, patients with HbSC disease warrant similar follow-up to that provided to SCA. Retinopathy, avascular necrosis and painful vaso-occlusive crises were the most common complications in our study, albeit lower than in other reported cohorts. The frequent use of hydroxyurea in this cohort is quite unique compared to other sickle cell comprehensive care centers reported in the literature. However, therapeutic phlebotomy is less often used compared to the European experience. We also observed a lower frequency of retinopathy, avascular necrosis, painful vaso-occlusive crises, priapism and acute chest syndrome. Whether this observation is due to hydroxyurea use or to other genetic or environmental factors remains to be determined. Further studies are also required to develop a more evidence-based therapeutic strategy for this genotype of Sickle Cell Disease. Disclosures: No relevant conflicts of interest to declare.

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Incidence and Risk of Delayed Hemolytic Transfusion Reaction in Sickle Cell Disease Patients Based on a Prospective Study

Blood ◽

10.1182/blood.v128.22.95.95 ◽

2016 ◽

Vol 128 (22) ◽

pp. 95-95 ◽

Cited By ~ 1

Author(s):

France Pirenne ◽

David Narbey ◽

Philippe Chadebech ◽

Armand Mekontso-Dessap ◽

Pablo Bartolucci ◽

...

Keyword(s):

Sickle Cell Disease ◽

Prospective Study ◽

Sickle Cell ◽

Acute Chest Syndrome ◽

Transfusion Reaction ◽

Cell Disease ◽

Hemolytic Transfusion Reaction ◽

Delayed Hemolytic Transfusion Reaction ◽

Prospective Longitudinal

Abstract Background Delayed hemolytic transfusion reaction (DHTR) is a life threatening complication of transfusion in sickle cell disease (SCD). This syndrome is underestimated because of a clinical picture that resembles a vaso-occlusive crisis (VOC) and the frequent absence of detectable antibodies. Several retrospective studies have evaluated the frequency of DHTR based on case reports. We conducted a prospective, longitudinal, single center study to determine the incidence of DHTR and the risk of developing DHTR depending on the transfusion regimen: chronic versus punctual. Methods and patients SCD patients aged over 18 years, undergoing a transfusion, were enrolled in this study. A total of 697 transfusion episodes (TE) in 312 patients were included during 30 months. Some patients had multiple TE during the period. The post transfusion outcome of the patients was assessed up to one month after the included TE. DHTR was confirmed based on the rapid disappearance of HbA (> 50% 15 days post-transfusion) associated with two of the following criteria up to three weeks after transfusion: VOC symptoms, dark urine, worsening anemia, increased LDH. Transfusion episodes were divided into chronic (336 TE in 111 patients) and punctual (361 TE in 201 patients). Chronic transfusions were defined as regular transfusions to treat chronic complications or for primary/secondary prevention of complications. Short transfusion program during pregnancy was considered as punctual transfusions if patients were not previously regularly transfused. The study obtained approval of the local Ethics Committee. Results Follow-up of the patients after transfusion showed 15 DHTR during the study. They all developed in punctually transfused patients. Thus, patients who are transfused punctually have a significantly higher risk of developing DHTR than those in a regular transfusion program (p < 0.001). When considering only punctual transfusions, the incidence of DHTR is 4.2% per transfusion episode (IC 95% [2.6; 6.9]) and 7.5% per patient during the 30 months of the study (IC 95% [4.6; 12.4]). In these DHTR cases, the transfusion indication was surgery (n = 6), pregnancy (n = 3), acute chest syndrome (n = 3), stroke (n = 1), profound anemia (n = 1), and VOC prevention before a school exam (n = 1 case). Two patients died of multi-organ failure following severe intravascular hemolysis. The median hemoglobin decrease for all DHTR cases after the triggering transfusion was 4.4 g/dl [IQR 3.6-5.2]; the highest LDH level was 879 [IQR 680-1423]. Ten patients developed newly formed antibodies, but only five among them displayed antibodies with significant serological features (anti-Fya, anti-S, anti-Jka, anti-HI). In the five other cases, the antibodies were of unspecified specificity or auto antibodies in the RH blood group (the genetic RH background was known). Finally, antibodies were undetectable for five cases, confirmed by long-term patient follow up. Conclusion This prospective study demonstrates, for the first time, that DHTR is a frequent reaction in adult SCD patients, developing only in occasionally transfused patients. This finding highlights that adult patients with regular transfusion who did not previously encountered DHTR are not susceptible to developing this severe reaction. A mechanism linked to acute situations can be suggested as already shown for the induction of allo-immunization. However, many cases developed without detectable antibodies, confirming the complex pathophysiology of this syndrome. A bio-clinical scoring system to predict DHTR, based on this study, is under development and will be presented. Disclosures Michel: Roche: Research Funding.

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Five years of experience with hydroxyurea in children and young adults with sickle cell disease

Blood ◽

10.1182/blood.v97.11.3628 ◽

2001 ◽

Vol 97 (11) ◽

pp. 3628-3632 ◽

Cited By ~ 132

Author(s):

Alina Ferster ◽

Parvine Tahriri ◽

Christiane Vermylen ◽

Geneviève Sturbois ◽

Francis Corazza ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Laboratory Data ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Significant Difference ◽

History Of ◽

Ischemic Attack

The short-term beneficial effect of hydroxyurea (HU) in sickle cell disease (SCD) has been proven by randomized studies in children and adults. The Belgian registry of HU-treated SCD patients was created to evaluate its long-term efficacy and toxicity. The median follow-up of the 93 patients registered is 3.5 years; clinical and laboratory data have been obtained for 82 patients at 1 year, 61 at 2 years, 44 at 3 years, 33 at 4 years, and 22 after 5 years. On HU, the number of hospitalizations and days hospitalized dropped significantly. Analysis of the 22 patients with a minimum of 5 years of follow-up confirm a significant difference in the number of hospitalizations (P = .0002) and days in the hospital (P < .01), throughout the treatment when compared to prior to HU therapy. The probabilities of not experiencing any event or any vaso-occlusive crisis requiring hospitalization during the 5 years of treatment were, respectively, 47% and 55%. On HU, the rate per 100 patient-years of severe events was estimated to be 3.5% for acute chest syndrome, 1.2% for aplastic crisis, 0.4% for splenic sequestration; it was 0% for the 9 patients with a history of stroke or transient ischemic attack followed for an average of 4 years. No important adverse effect occurred. Long-term chronic treatment with HU for patients with SCD appears feasible, effective, and devoid of any major toxicity; in patients with a history of stroke, HU may be a valid alternative to chronic transfusion support.

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Impact of Alloimmunization in Patients with Sickle Cell Disease

Blood ◽

10.1182/blood-2021-152829 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3251-3251

Author(s):

Dipanjan Debnath ◽

Hedy P Smith ◽

Cathy Conry-Cantilena ◽

Valentina Baez Sosa

Keyword(s):

Pulmonary Hypertension ◽

Sickle Cell Disease ◽

Iron Overload ◽

Health System ◽

Sickle Cell ◽

Organ Damage ◽

Cell Disease ◽

Academic Health ◽

End Organ Damage ◽

The Mean

Abstract INTRODUCTION Blood transfusion is an essential therapeutic and prophylactic component in the management of sickle cell disease (SCD) and associated complications. Prolonged transfusion therapy can lead to the development of antibodies to the donor's RBC antigens (alloimmunization), causing complications such as delayed hemolytic transfusion reactions, hyperhemolysis, worsening vaso-occlusive episodes, and end-organ damage. There have been only a few case series highlighting the impact of RBC alloimmunization on SCD morbidity and mortality, proposing a pathway involving RBC alloimmunization and decreased survival associated with hemolytic reactions or difficulty obtaining compatible blood when needed. However, apart from the consequences of iron overload, there is no long-term data for alloimmunization highlighting the clinical consequences, multiorgan damage, or associated morbidity in sickle cell patients. AIM The primary aim is to investigate the incidence of alloimmunization in SCD patients in an academic health system. The secondary aim is to elucidate the differences in demographics, frequency of vaso-occlusive crisis, end-organ damage, and inflammatory markers between alloimmunized and non-alloimmunized SCD patients. METHODS We conducted a retrospective multicentric descriptive study, including all sickle cell patients treated in an academic health system from January 1st, 2009, to December 31st, 2020, in Maryland, Virginia, and Washington, DC. An exemption from the Institutional Review Board for obtaining individual subjects' consent was procured. Patients included in the study were older than 18 years and diagnosed with sickle cell disease. Patients who did not have sickle cell disease were excluded from the study. Statistical analysis was reported using means for descriptive data, t-test for continuous variables, and chi-square for categorical variables. RESULTS A total of 94 patients with sickle cell disease were included in the study. Of these, 24 (25.5%) patients were found to have alloimmunization, whereas 70 (74.4%) patients did not. Of the alloimmunized patients, the average age, BMI and BSA were 30.15 years (p=0.037), 23.15 kg/m2 (p=0.040), and 1.65 m2 (p=0.003) compared to 37.07 years, 26.17 kg/m2 and, 1.84 m2 respectively among the non-alloimmunized group. 83% of the alloimmunized patients had sickle cell anemia (Hb SS), and 17% had a sickle thalassemia phenotype (p=0.005). A lower baseline hemoglobin (Hb) value of 8.01 g/dL was seen among alloimmunized patients compared to a higher Hb value of 9.63 g/dL (p=0.001) among the non-alloimmunized. Alloimmunized patients had an average of 5.55 alloantibodies. The average number of vaso-occlusive crises per year and related hospitalizations was statistically significantly higher in the alloimmunized group with 4.82 and 3.78, respectively, compared to 2.34 (p=0.035) 1.01 (p=0.0005) in the non-alloimmunized group. Similarly, the incidence of other sickle cell-related complications were higher among the alloimmunized patients, such as priapism (29% vs. 9%; p=0.0139), pulmonary hypertension (38% vs. 9%; p=0.0038) with no statistical difference in the iron overload (25% vs. 11%; p=0.150) or ferritin levels (. 83% of alloimmunized patients had a history of narcotic use vs. 34% among the non-alloimmunized (p=0.0001). Higher use of disease-modifying therapies including hydroxyurea (71% vs. 31%; p=0.0009) and voxelotor (13%vs0; p=0.0029), were also seen among alloimmunized patients. While no statistically significant difference was seen in the mean number of lifetime transfusions, there was a difference in the mean number of lifetime exchanges (3.67 vs. 0.0; p=0.0208). CONCLUSION The prevalence of alloimmunization in sickle cell patients in our study population (25.5%) was higher than in the literature (7- 59%) and the general population (2%). An increase in alloimmunization was associated with an increased number of exchanges but not with simple transfusions. Independent from the iron overload, alloimmunization was associated with increasing end-organ damage and sickle cell complications such as priapism, pulmonary hypertension. Strategies to decrease alloimmunization are needed to prevent these complications. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Glycocalyx Perturbation in Patients with Sickle Cell Disease: Association with Disease Morbidity.

Blood ◽

10.1182/blood.v108.11.1204.1204 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1204-1204

Author(s):

Eduard J. Beers van ◽

Pearl Landburg ◽

Max Nieuwdorp ◽

Ashley L. Duits ◽

Hans Vink ◽

...

Keyword(s):

Sickle Cell Disease ◽

Disease Severity ◽

Sickle Cell ◽

Matrix Metalloproteases ◽

Endothelial Glycocalyx ◽

Acute Chest Syndrome ◽

Diabetic Patients ◽

Cell Disease ◽

Avascular Osteonecrosis ◽

Morbidity Score

Abstract Activated endothelium plays a pivotal role in the pathogenesis of sickle cell disease (SCD). The activation of the endothelium is caused by hypoxia reperfusion damage, high shear rates and pro-inflammatory mediators, like thrombin and TNF-alpha. The central role of the glycocalyx (a layer of hyaluronan and proteoglycans covering the endothelium) has been established as an antithrombotic and antiadhesive endothelial barrier. Recently, a technique to determine the total systemic volume of the endothelial glycocalyx in humans has been validated. Using this technique, we demonstrated that the glycocalyx volume is strongly diminished in diabetic patients and even more in diabetic patients with microangiopathy. In the present study, we measured the glycocalyx volume in 20 sickle cell patients (14 HbSS/Sβ0 and 6 HbSC) and 10 carriers of sickle cell disease. To assess whether the glycocalyx perturbation may also contribute to disease morbidity in SCD, disease morbidity score (DMS) was calculated according to predefined criteria. In addition, we determined plasma levels of the matrix metalloproteases (MMP-2 and MMP-9) and the tissue inhibitors of MMP (TIMP-1 and TIMP-2) and compared these levels with the glycocalyx volume. The total systemic glycocalyx volume was measured by subtracting the intravascular distribution volume of a glycocalyx impermeable tracer (autologous labelled erythrocytes) from that of a glycocalyx permeable tracer (dextran 40). DMS was calculated by adding up individual prevalence (present or absent) of organ damage (microalbuminuria, pulmonary hypertension, retinopathy, perceptive hearing loss, iron overload, avascular osteonecrosis, renal failure and leg ulcers) and history of sickle cell related complications (acute chest syndrome, stroke, > 2 vaso-occlusive crises/year, and cholelithiasis ). Patients with SCD (HbSS/Sβ0 and HbSC) demonstrated to have a significant reduced glycocalyx volume compared to sex and age-matched sickle cell traits 0.48 ± 0.14 and 0.5 ± 0.36 versus 1.26 ± 0.27 liters (mean ± SEM), p=0.025. Interestingly, the glycocalyx volume was associated with DMS. Patients with high (severe)DMS had a significant lower glycocalyx volume than patients with a low(mild) DMS (0.81 ± 0.26 versus 0.18 ± 0.26 liters, p=0.047). No associations between glycocalyx volume and serum levels of MMP-2, MMP-9, TIMP-1 or TIMP-2 were found. The strongly diminished glycocalyx volume in sickle cell patients resembles the chronic state of activation of the endothelium in SCD that may also may be responsible for the enhanced adhesion of leukocytes and erythrocytes as well as the prothrombotic state of these patients Since the glycocalyx layer serves as an important barrier between the endothelium and the circulating blood cells to prevent the adhesion of leukocytes, therapies that may restore or preserve glycocalyx function are warranted in SCD. Figure. Disease severity and glycocalyxvolum Figure. Disease severity and glycocalyxvolum

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Pulmonary Hypertension Is Not Associated with An Increased Risk of Death in Children with Sickle-Cell Disease Followed for a Mean of 3 Years.

Blood ◽

10.1182/blood.v112.11.1443.1443 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1443-1443

Author(s):

Margaret T. Lee ◽

Tania Small ◽

Muhammad Amar Khan ◽

Erika Berman Rosenzweig ◽

Robyn J. Barst ◽

...

Keyword(s):

Alkaline Phosphatase ◽

Pulmonary Hypertension ◽

Platelet Count ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Cell Disease ◽

Risk Of Death ◽

Increased Risk ◽

History Of

Abstract To determine if pulmonary hypertension (PH) is associated with increased mortality in children with sickle-cell disease (SCD), we prospectively followed 88 pediatric patients for a mean of 3 years after echocardiographic screening for PH. Subjects (45 males, 43 females) were 5–20 years old (median 13) at initial screening and included 59 SS, 23 SC, 4 S/β0Thalassemia, 1 S/β+Thalassemia and 1 S/HPFH. PH was defined as tricuscipid regurgitant jet velocity (TRV) of ³2.5 m/s. Of the 88 subjects, 18 (20%) had TRV ³2.5 m/s (median 2.6, range 2.5–3.1). Subjects with PH ranged from 7 to 19 years old (median 15), were predominantly male (12 of 18) and included 14 (78%) SS, 2 SC, 2 S/β0Thalassemia. After a mean follow-up of 36.3 ± 9.4 (SD) months, all 18 patients with PH were alive. None had received specific treatment for PH; one had undergone a successful bone marrow transplant from a matched sibling donor. After a mean follow-up of 33.5 ± 13.3 months, 67 subjects with normal TRV were alive; 3 had been lost to follow-up. To compare risk factors for PH in our children with those reported for adults, we reviewed the clinical data for our subjects. Children with PH had significantly increased serum lactate dehydrogenase (LDH; P=0.04), higher platelet count (P=0.02), and, in males, a history of priapism (P=0.009). No significant differences were observed with respect to age, gender, sickle-cell type, white blood cell count, hemoglobin, reticulocyte count, bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, creatinine, ferritin, history of painful crisis, acute chest syndrome, asthma, splenectomy, or hydroxyurea therapy. To further examine the association of PH and hemolysis, a subanalysis was done excluding 18 chronically transfused patients because transfusion can alter laboratory indicators of hemolysis. Independent variables with P≤0.1 on univariate analysis (LDH, female gender, and platelet count) were entered into a logistic regression model. Only LDH was independently associated with PH (Odds Ratio=1.6, 95% CI=1.2–2.1, P=0.004). Our results show that PH diagnosed by Doppler echocardiography was not associated with an increased risk of death in children with SCD followed for a mean of 3 years. A greatly increased risk of death (rate ratio, 10.1) has been reported in adults followed for a mean of 1.5 years (N Eng J Med2004;350:886–95). In our children, as in the adults, increased LDH, a marker of hemolysis, and, in males, a history of priapism were associated with PH. By contrast, our children with PH did not have increases in serum creatinine, direct bilirubin, alkaline phosphatase and ferritin that have been linked epidemiologically to PH in adults with SCD (Pediatr Hematol Onc2007;24:159–70). These findings suggest that PH of itself may not be a direct cause of death in SCD. Rather, PH may be a manifestation of progressive, cumulative organ damage resulting from chronic hemolysis and systemic vasculopathy that ultimately leads to increased mortality in adulthood. Early recognition and preventive therapy for increased hemolysis may be needed to avert premature death in adults with SCD.

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Association of Pulmonary Hypertension with Sickle Cell Disease Subtypes

Blood ◽

10.1182/blood.v112.11.4824.4824 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4824-4824

Author(s):

Alice J. Cohen ◽

Chaim Tuckman-Vernon

Keyword(s):

Pulmonary Hypertension ◽

Sickle Cell Disease ◽

Hemolytic Anemia ◽

Sickle Cell ◽

Doppler Echocardiography ◽

Beta Thalassemia ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Hemoglobin C ◽

Baseline Hemoglobin

Abstract Pulmonary hypertension (PH) is a common complication of sickle cell disease (SD) and a significant cause of morbidity and mortality. PH, measured by Doppler echocardiography and defined as a tricuspid regurgitant jet velocity (TRV) > 2.5 m per second (m/s), is hypothesized to be related to the chronic hemolytic anemia of SD, but causality is unproven. If so, the presence of hemoglobin C, which reduces hemolysis, would be expected to have a reduced likelihood of PH. This study reviewed the prevalence of PH in 3 categories of patients with SD: homozygous S (SS), sickle-beta thalassemia (SB), and SC. Methods: Sickle cell disease patients registered at a state funded community comprehensive care adult sickle cell center were routinely screened for PH by Doppler echocardiography. The presence of PH, the incidence of a related complication, acute chest syndrome (ACS), and baseline hemoglobin (hgb) were reviewed. Results: 16 patients with SC type, 30 with SS and 39 with SB disease underwent screening. The prevalence of PH, ACS and hgb are listed in the table below. Conclusion: SC patients have PH and ACS similar to patients with SS and SB patients. These patients have higher baseline hemoglobin and may have hyperviscosity as a cause of PH and ACS as opposed to hemolytic anemia. Further study of PH and ACS in SC patients is warranted. SC SS SB p value PH 6/16 (38%) 12/40 (40%) 11/39 (28%) p= NS ACS 7/16 (44%) 10/30 (33%) 19/39 (49%) p=NS PH + ACS 4/16 (25%) 5/30 (17%) 4/39 (10%) p=NS ACS in PH patients 4/6 (67%) 5/12 (42%) 4/11 (36%) p-=NS Hgb 10.8 7.89 8.57 p=0.000

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