scholarly journals Mortality of covid19 in sickle cell disease systematic review

2021 ◽  
Vol 12 (2) ◽  
pp. 151-156
Author(s):  
Waseem Bader Al Talalwah ◽  
Shorok Ali Al Dorazi
Keyword(s):  
Sickle Cell Disease ◽  
Clinical Features ◽  
Sickle Cell ◽  
Pulmonary Arteries ◽  
Beta Thalassemia ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Fourth Decade ◽  
Radiological Changes

The covid19 infection is pandemic disease are more commonly in chronic diseases. As covid19 case pulmonary infection, the current study focuses on sickle cell disease patients are suitable to acute chest syndrome. It will clarify the risk factors for covid19 infection and its clinical features in sickle cell disease. It also reviews the radiological findings to gain more data on this pandemic disease. The current study includes 44 cases of sickle cell disease having covid19 infection. The entire cases include sickle cell disease only in 89% whereas the other sickle cell disease cases are coexisted with beta- thalassemia in 9.1%. The fourth decade is the highest peak incidence. There are several complications found to be in sickle cell disease are acute chest syndrome, chronic leg ulcer, renal failure exceeding 10%. The bronchial asthma found to be in 6.9% and avascular necrosis found to be 11.4% whereas the cerebrovascular accident found to be in 13.8%. The radiological changes include lung tissues, alveoli, pleural cavities and pulmonary arteries in different rate. The incidence of recovery found to be in 93% whereas the death found to be in 7%. It found to be involving in respiratory and gastrointestinal systems result in different clinical features in different rate. This study compares the clinical features, findings investigation and complications between sex and decades. Further, this study clarifies recovery and mortality rate between sex and decades. Knowing and understanding covid19 infection in sickle cell disease, physicians will be able to provide high quality of medical services.

scholarly journals Clinical events in the first decade in a cohort of infants with sickle cell disease. Cooperative Study of Sickle Cell Disease [see comments]

Blood ◽  
1995 ◽  
Vol 86 (2) ◽  
pp. 776-783 ◽  
Author(s):  
FM Gill ◽  
LA Sleeper ◽  
SJ Weiner ◽  
AK Brown ◽  
R Bellevue ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Clinical Course ◽  
The United States ◽  
Beta Thalassemia ◽  
Acute Chest Syndrome ◽  
Cooperative Study ◽  
Cell Disease ◽  
Splenic Sequestration ◽  
Clinical Events

Within the Cooperative Study of Sickle Cell Disease, 694 infants with confirmed sickle cell disease were enrolled at less than 6 months of age. Information about the nature and frequency of complications was collected prospectively over a 10-year period. Painful crises and acute chest syndrome were the most common sickle cell-related events in homozygous sickle cell anemia (SS), hemoglobin SC disease (SC), and S beta thalassemia patients (overall incidence in SS patients of 32.4 and 24.5 cases per 100 person-years, respectively). Bacteremia occurred most frequently in SS children under 4 years of age and in SC patients less than 2 years of age. The mortality rate was low in this cohort compared with that found in previous reports. Twenty children, all with Hb SS, died (1.1 deaths per 100 person-years among SS patients). Infection, most commonly with Streptococcus pneumoniae and Hemophilus influenzae, caused 11 deaths. Two children died of splenic sequestration, 1 of cerebrovascular accident, and 6 of unclear causes. Two patients underwent cholecystectomies, and 17 underwent splenectomies after one or more splenic sequestration crises. The experience of this cohort should reflect closely the true clinical course of those children with Hb SS and Hb SC disease who are observed in sickle cell centers in the United States.

Outcomes of Chronic Automated RBC Exchange Program in Omaha, Nebraska 2015-2020

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 21-22
Author(s):  
Aleh Bobr ◽  
Scott A Koepsell ◽  
Julie Eclov ◽  
Omar Abughanimeh ◽  
Steven Ebers ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Blood Cell ◽  
Iron Overload ◽  
Sickle Cell ◽  
Red Blood Cell ◽  
Beta Thalassemia ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Before And After ◽  
Ed Visits

Background: Red blood cell exchange (RBCX) is an effective therapy in the treatment of different hemoglobinopathies. The University of Nebraska Medical Center (UNMC) established a chronic RBCX program in November 2015, which took care of patients with multiple hemoglobinopathies. In this study, we aim to evaluate the outcomes of this program. Methods: This is a retrospective study. After an IRB approval, we reviewed the charts of patients who were enrolled in the chronic RBCX program between 11/2015-7/2020 at UNMC. Data was collected to evaluate indications of RBCX, types of hemoglobinopathies, hemoglobinopathies' complications before and after the enrollment in the program, and assessment of hospital visits before and after enrollment in the program. Results: In November 2015, the chronic RBCX program was established in Nebraska. Since the start, 24 patients came through the program and 20 patients are still actively enrolled and undergoing regular exchange transfusions. The four patients who left the program did it for the following reasons: moving out of state, stem cell transplant and change to different treatment modality. Four of 24 patients were beta thalassemia patients (two of them with combined HbE/beta thalassemia). Twenty patients had sickle cell disease with two of them having combined beta thalassemia and HbS and one with alpha thalassemia and HbS. The indications ranged from history of stroke, intracranial vascular stenosis, acute chest syndrome (ACS), iron overload, multiple vascular occlusive crises (VOC) and intolerance of medications with most of the patients having multiple indications from the list above (Figure 1). There are several positive outcomes from being on the program. In the patients who had been on the program for at least one year (n=11), nine started the program with iron overload and all of them had a significant decrease in serum ferritin (average 751 ng/mL) with three patients returning to normal range. In the patients who had been in the program at least six months (n=16), 13 patients started with iron overload with five returning to normal range and average decrease in ferritin of 585 ng/mL. Another positive outcome is the number of emergency department (ED) visits for pain crisis. We noted reduction in ED visits in all patients who were in the program for at least six months (n=14), with the exception of one patient where the visits were likely the part of drug seeking behavior. In fact 12 of 13 patients had one or no ED visits within one year after starting on the chronic exchange program having had from 2-11 visits a year prior. None of the patients in the program experienced more severe complications of sickle cell disease, like stroke and acute chest syndrome, while on the program. Due to high volumes of transfusion, there is a big concern about developing red blood cell antibodies in sickle cell disease patients who in general have higher red blood cell antibody burden. Out of 24 patients in the program, six had pre-existing antibodies. For the duration of the program, no new alloantibodies were discovered in the chronically exchanged patients despite high transfusion volumes (range 14L-30L/year). The transfused blood was matched for Rh and Kell antigens for the patients with no antibody history. The patients with previous antibody history had additional matching for the antigen to which antibody was directed. Conclusion:Automated chronic RBCX transfusion program is safe to perform. It leads to significant reduction in volume overload and ED visits. Performing high volume transfusions outside of acute sickle cell crisis and with Rh and Kell matched units prevents formation of RBC antibodies Disclosures Gundabolu: BioMarin:Consultancy;Bristol Myers Squibb pharmaceuticals:Consultancy.

Association of Pulmonary Hypertension with Sickle Cell Disease Subtypes

Blood ◽  
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

scholarly journals Evaluation of Outcomes and Quality of Care in Children with Sickle Cell Disease Diagnosed by Newborn Screening: A Real-World Nation-Wide Study in France

2019 ◽  
Vol 8 (10) ◽  
pp. 1594 ◽  
Author(s):  
Brousse ◽  
Arnaud ◽  
Lesprit ◽  
Quinet ◽  
Odièvre ◽  
...  
Keyword(s):  
Quality Of Care ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Pneumococcal Vaccination ◽  
Marrow Transplant ◽  
Beta Thalassemia ◽  
Cell Disease ◽  
Curative Therapy ◽  
Probability Of Survival

This study’s objective was to assess, on a national scale, residual risks of death, major disease-related events, and quality of care during the first five years in children diagnosed at birth with sickle cell disease (SCD). Data were retrospectively collected from medical files of all children with SCD born between 2006–2010 in France. Out of 1792 eligible subjects, 1620 patients (71.8% SS or S/beta°-thalassemia -SB°-) had available follow-up data, across 69 centers. Overall probability of survival by five years was 98.9%, with 12/18 deaths related to SCD. Probability of overt stroke by five years in SS/SB° patients was 1.1%, while transcranial Doppler (TCD) was performed in 81% before three years of age. A total of 26 patients had meningitis/septicemia (pneumococcal in eight cases). Prophylactic penicillin was started at a median age of 2.2 months and 87% of children had received appropriate conjugate pneumococcal vaccination at one year. By five years, the probability of survival without SCD-related events was 10.7% for SS/SB° patients. In contrast, hydroxyurea was prescribed in 13.7% and bone marrow transplant performed in nine patients only. In this study, residual risks of severe complications were low, probably resulting from a good national TCD, vaccination, and healthcare system coverage. Nonetheless, burden of disease remained high, stressing the need for disease-modifying or curative therapy.

Sickle Cell Disease in Central India: High Prevalence of Sickle/Beta Thalassemia and Severe Dsiease Phenotype

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4588-4588 ◽  
Author(s):  
Dipty Jain ◽  
Vinit Warthe ◽  
Roshan Colah ◽  
Graham Roger Serjeant
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Hospital Admissions ◽  
Conflicts Of Interest ◽  
Central India ◽  
Beta Thalassemia ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Beta Thalassaemia ◽  
Alpha Thalassaemia

Abstract Objectives: To assess the clinical, haematological and molecular features of sickle cell disease in central India where the disease has been reported to be more severe than the mild clinical course usually observed in the Asian haplotype of homozygous sickle cell (SS) disease. Methods: A cross-sectional assessment of 91 consecutive patients with sickle cell disease attending clinics at the Akola Government Medical College, Akola, Maharastra State, India. Results: Of the 91 patients, who were predominantly of the scheduled caste community, 49 had SS disease, 6 had sickle cell-HbD Punjab, and 36 had sickle cell-beta thalassaemia. Of the patients with sickle cell-beta thalassaemia, the beta thalassemia mutation was IVS1-5 G>C mutation in 25 patients (69%) while the rest had one of seven other molecular mutations identified (Table1). Contrary to commonly held beliefs, alpha thalassaemia occurred in only 9/90 (10%) of subjects but fetal haemoglobin (HbF) levels were markedly elevated with mean and median levels of 24.4%. All except 3 SS disease patients had the Xmn1(+/+) polymorphism. These patients exhibited many of the severe manifestations of sickle cell disease. Comparison of SS disease and sickle cell-beta thalassaemia showed no differences in the prevalence of dactylitis, bone pain crisis, acute chest syndrome, haemoglobin level, reticulocyte counts or hydroxyurea usage but patients with sickle cell-beta thalassaemia had significantly more hospital admissions, blood transfusions, and greater frequencies of splenomegaly and hepatomegaly. Conclusions: Many of the patients with sickle cell disease in central India appear to have relatively severe manifestations. This appears to be due to much lower frequencies of alpha thalassaemia and more frequent sickle cell-beta thalassaemia. There is a need for assessment of the indications and policies for blood transfusion and for hydroxyurea. Table 1. Beta Thalassemia mutations associated with HbS/Beta Thalassemia in Akola Mutation Expression Number IVS 1-5 (G>C) severe b+ 22 IVS 1-1 (G>A) bo 3 Cd 15 (-T) bo 2 Cd 30 (G>C) bo 2 Cd 15 (G>A) bo 1 Cd 39 (C>T) bo 1 Cd 41/42 (-CTTT) bo 1 619 bp deletion bo 1 Total 36 Disclosures No relevant conflicts of interest to declare.

scholarly journals The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease

Blood ◽  
1994 ◽  
Vol 84 (2) ◽  
pp. 643-649 ◽  
Author(s):  
O Castro ◽  
DJ Brambilla ◽  
B Thorington ◽  
CA Reindorf ◽  
RB Scott ◽  
...  
Keyword(s):  
Risk Factors ◽  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Disease Incidence ◽  
National Study ◽  
Beta Thalassemia ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Age Related

Abstract The acute chest syndrome (ACS), a pneumonia-like illness in sickle cell patients, is one of the most frequent causes of their morbidity and hospitalizations. Repeated ACS events may predict the development of chronic lung disease. ACS is reported as a frequent cause of death in these patients. We examine here the incidence and risk factors of ACS in 3,751 patients with sickle cell disease who were observed prospectively for at least 2 years (19,867 patient-years [pt-yrs]) as part of a multicenter national study group. The ACS, defined by a new pulmonary infiltrate on x-ray, occurred at least once in 1,085 patients (2,100 events). ACS incidence was higher in patients with homozygous sickle cell disease (SS; 12.8/100 pt-yrs) and in patients with sickle cell-beta(0) -thalassemic (9.4/100 pt-yrs), and lower in patients with hemoglobin (Hb) SC disease (5.2/100 pt-yrs) and patients with sickle cell-beta(+) thalassemia (3.9/100 pt-yrs). alpha-Thalassemia did not affect the rate of ACS incidence in SS patients. Within each Hb type the incidence was strongly but inversely related to age, being highest in children 2 to 4 years of age (25.3/100 pt-yrs in SS) and decreasing gradually to its lowest value in adults (8.8/100 pt-yrs in SS). In SS children (< 10 years of age), we documented an age-related within- person reduction in ACS attack rates. Adults with a higher ACS rate had a higher rate of mortality (from all causes) than those with low ACS rates. This increased rate of mortality might also have contributed to the decline in ACS rate with age. In multivariate analysis, other factors affecting incidence in SS patients were degree of anemia (lower ACS rates in patients with lower steady-state Hb levels) and fetal Hb (lower rates in patients with high fetal Hb). There was also a positive association between ACS rate and steady-state leukocyte count. The relationship of ACS rate to higher steady-state Hb levels in SS patients is unexplained but might be caused by increased blood viscosity.

scholarly journals What is the evidence that hydroxyurea improves health-related quality of life in patients with sickle cell disease?

Hematology ◽  
2012 ◽  
Vol 2012 (1) ◽  
pp. 290-291 ◽  
Author(s):  
Deepika S. Darbari ◽  
Julie A. Panepinto
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Well Being ◽  
Clinic Visit ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Related Quality ◽  
Health Related

Abstract A 10-year-old male patient with homozygous sickle cell disease presents for a follow-up clinic visit after a recent hospitalization for a painful vasoocclusive event. His parents mention that in the past year he has had 4 hospitalizations for vasoocclusive events, 2 of which were complicated by the development of acute chest syndrome that resulted in transfer to the intensive care unit. He has missed many school days and may be retained a grade this year. He feels particularly sad about missing the school field trip that occurred during his last hospitalization. He also reports that he is not able to keep up with his friends when participating in physical activities at school. The child's parents are worried that he may be depressed. You as the provider discuss the option of hydroxyurea therapy. His parents ask if hydroxyurea would improve his overall well-being and functioning.

scholarly journals The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease

Blood ◽  
1994 ◽  
Vol 84 (2) ◽  
pp. 643-649 ◽  
Author(s):  
O Castro ◽  
DJ Brambilla ◽  
B Thorington ◽  
CA Reindorf ◽  
RB Scott ◽  
...  
Keyword(s):  
Risk Factors ◽  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Disease Incidence ◽  
National Study ◽  
Beta Thalassemia ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Age Related

The acute chest syndrome (ACS), a pneumonia-like illness in sickle cell patients, is one of the most frequent causes of their morbidity and hospitalizations. Repeated ACS events may predict the development of chronic lung disease. ACS is reported as a frequent cause of death in these patients. We examine here the incidence and risk factors of ACS in 3,751 patients with sickle cell disease who were observed prospectively for at least 2 years (19,867 patient-years [pt-yrs]) as part of a multicenter national study group. The ACS, defined by a new pulmonary infiltrate on x-ray, occurred at least once in 1,085 patients (2,100 events). ACS incidence was higher in patients with homozygous sickle cell disease (SS; 12.8/100 pt-yrs) and in patients with sickle cell-beta(0) -thalassemic (9.4/100 pt-yrs), and lower in patients with hemoglobin (Hb) SC disease (5.2/100 pt-yrs) and patients with sickle cell-beta(+) thalassemia (3.9/100 pt-yrs). alpha-Thalassemia did not affect the rate of ACS incidence in SS patients. Within each Hb type the incidence was strongly but inversely related to age, being highest in children 2 to 4 years of age (25.3/100 pt-yrs in SS) and decreasing gradually to its lowest value in adults (8.8/100 pt-yrs in SS). In SS children (< 10 years of age), we documented an age-related within- person reduction in ACS attack rates. Adults with a higher ACS rate had a higher rate of mortality (from all causes) than those with low ACS rates. This increased rate of mortality might also have contributed to the decline in ACS rate with age. In multivariate analysis, other factors affecting incidence in SS patients were degree of anemia (lower ACS rates in patients with lower steady-state Hb levels) and fetal Hb (lower rates in patients with high fetal Hb). There was also a positive association between ACS rate and steady-state leukocyte count. The relationship of ACS rate to higher steady-state Hb levels in SS patients is unexplained but might be caused by increased blood viscosity.

scholarly journals Soluble P-Selectin Levels in Patients with Sickle Cell Disease Reflect Platelets' Activation Rather Than Endothelial Dysfunction

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4829-4829
Author(s):  
Ersi Voskaridou ◽  
Mantzou Aimilia ◽  
Pagona Flevari ◽  
Maria Dimopoulou ◽  
Veroniki Komninaka ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Sickle Cell Disease ◽  
Clinical Features ◽  
Sickle Cell ◽  
Research Funding ◽  
Iron Accumulation ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Soluble P

Background: Vascular occlusion is a major cause of the morbidity associated with sickle-cell disease (SCD). The tendency of sickle red blood cells to adhere to the vascular endothelium is believed to be a major contributor and possibly primary cause of the vaso-occlusive process. Therefore mediators of adhesion have become a potential new target for pharmacological therapy to combat the complications of SCD. One of the molecules involved in this process is P-Selectin or CD62P, a cell adherence molecule that is rapidly and chronically expressed on the surface of endothelial cells and platelets when activated. P-Selectin is found in the plasma of normal individuals at ng/mL concentrations. Circulating soluble P-Selectin (sP-Selectin) appears to be slightly smaller than native P-Selectin. An alternatively spliced mRNA encoding a form of human P-Selectin lacking the transmembrane anchoring domain has been reported for both megakaryocytes and endothelial cells, and evidence suggests that the majority of circulating sP-Selectin arises in this manner. We and others have reported elevated sP-Selectin levels in SCD even in steady phase. Recently, a humanized monoclonal antibody that binds to P-Selectin and blocks its interaction with P-selectin glycoprotein ligand 1 (PSGL-1) has been administered to patients with SCD, resulting in an amelioration of painful VOC. In this context we aimed to explore if sP-Selectin levels could be used to choose among the SCD patients those who might benefit from the new therapy. Patients and Methods: Eighty adult Caucasian patients with HbS/βthal at steady phase [40 patients under hydroxyurea (HU+) treatment and 40 patients without hydroxyurea (HU-) treatment] were included in this study, while 20 apparently healthy individuals of similar age and gender served as controls. Along with sP-Selectin levels, measured with the same method as reported previously (Human sP-Selectin/CD62P Immunoassay, R&D Systems, Minneapolis, MN, USA), other parameters of hemolysis, inflammation, endothelial dysfunction, iron accumulation and clinical features of the disease were evaluated. Results are expressed as median values ± SEM. Results: We found that sP-Selectin levels were elevated in 45/80 (56%) patients with HbS/βthal compared to controls (108.2±6.3 vs. 69.3±4.1ng/mL, respectively, p<0.001), independently of patients' βthal genotype and correlated strongly with PLT count (r=0.760, p<0.001). Regarding HU treatment, sP-Selectin levels did not differ between (HU+) and (HU-) patients (112.5±9.8 vs. 100.3±7.4ng/mL, respectively, p>0.07). No significance correlation was found between sP-Selectin levels and markers of: hemolysis (RPI: r=0.191, p>0.100); LDH: r=0.103, p>0.360 and bilirubin: r=0.171, p>0.130); inflammation (hs-CRP: r= 0.002, p>0.842); endothelial dysfunction (vWF:antigen: r=0.141, p>0.210 and ADAMTS-13: r=0.089, p>0.507). Regarding iron accumulation no correlation was found between sP-Selectin and ferritin levels (r=0.090, p>0.438), while a weak negative correlation was found with hepcidin-25 levels (r=-0.283, p=0.018). Furthermore, no correlation was found between sP-Selectin levels and history of clinical complications such as VOC (p>0.795), acute chest syndrome, venous and arterial thrombosis and mean pulmonary artery pressure values, (p>0.402). Conclusion: In this study, we proceeded with an external validation procedure of sP-Selectin determination in patients with HbS/βthal (keeping the same methodology in a different cohort of patients), and we found elevated levels of sP-Selectin with the evidence of PLTs' secretion origin, as no correlation found with other markers of endothelial dysfunction and inflammation. Interestingly, we failed to find a significant link of sP-Selectin levels with other markers of disease severity and/or clinical features of SCD. Thus, we consider that the use sP-Selectin as a biomarker of assessment and treatment of endothelial dysfunction in patients with SCD is of almost negligible importance. Disclosures Voskaridou: Genesis: Consultancy, Research Funding; Protagonist: Research Funding; Celgene Corporation: Consultancy, Research Funding; Acceleron: Consultancy, Research Funding; Addmedica: Membership on an entity's Board of Directors or advisory committees.

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