Current Prevalence of Specific Clinical Outcomes in Adult Patients with Hb SS or Hb Sβ0 Thalassemia.

Abstract Over the last five years, we have enrolled 541 unrelated adult patients (age >18) with HbSS or HbSβ0 at three major comprehensive sickle cell centers in a study designed to identify factors associated with clinical outcomes in sickle cell disease. Our database includes demographic, clinical, and laboratory data on all participants. Medical history was obtained by both patient interview and review of medical records. The average age of patients enrolled was 34.0 yrs, median age 31.9, and 61 were ≥ 50 yrs; 54% were female. 81% of patients had finished high school, and 35% smoked tobacco products. History of SCD-related complications was as follows: acute chest syndrome - 76%, priapism (males only) - 41%, stroke - 16%, TIA - 5%, seizure - 12%, AVN of shoulders or hips - 30%, leg ulcers - 26%, heart failure - 7%, gallstones - 66%, and retinopathy - 22%. 68% of patients had undergone cholecystectomy, 11% splenectomy, and 11% major joint replacement. 136 patients had echocardiography data reported, and of these 39% had findings consistent with pulmonary hypertension, as defined as TRjet ≥ 2.5 m/s. 7% were receiving chronic transfusion therapy, and 6% were receiving iron chelation therapy. Significant proteinuria (≥ 1+) was present in 27% of patients, while only 4% had hematuria. Review of medication usage revealed that 40% were taking hydroxyurea (HU) at the time of enrollment, and 23% used long-acting narcotics daily. 14% of patients took medication for hypertension, 9% took antidepressants, and 6% used bronchodilators. Interviews and review of records showed that 21% had not required hospitalization during the past year, while 25% were hospitalized only once, 46% were hospitalized 2–4 times, and 8% were hospitalized >4 times during the past year. Hematologic values and HU status were available for 433 patients. Hematologic Values On HU Not On HU Mean Std Dev N Mean Std Dev N p value Hb 8.9 1.62 174 8.29 1.46 259 <0.001 Hct 25.85 4.62 174 24.25 4.39 259 0.0003 WBC 10.52 4.06 173 12.31 5.04 259 0.0001 Platelets 409.03 142.03 173 405.61 144.21 258 0.75 Patients not on HU had significantly higher total bilirubin values (3.51±2.66 vs 2.91±2.93, p=0.02) and insignificantly higher ferritin levels (1297±2118 vs 1089±1535, p=0.5). However, patients taking HU had higher LDH (p=0.0019) and uric acid levels (p<0.0001). In summary, despite frequent use of HU, resulting in statistically higher hemoglobin levels and lower WBC, the prevalence of end-organ complications associated with SCD remains high. More than half of all patients were hospitalized at least twice annually, and almost one-quarter required daily long-acting narcotics. 30% of patients have AVN, and more than 10% of patients had already undergone major joint surgery. Further research into HU prescribing patterns and patient compliance might lead to improvement in patient outcomes, but other interventions are likely to be required in order to ameliorate the persistently high complication rate of SCD.

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Alloimmunization Does Not Modify the Clinical Profile of Sickle Cell Disease Patients from Salvador-Brazil

Blood ◽

10.1182/blood.v112.11.4799.4799 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4799-4799

Author(s):

Angela Zanette ◽

Karla O. Mota ◽

Marilda Souza Goncalves ◽

Laise Vilasboas Schettini ◽

Lais Magalhaes Aguiar ◽

...

Keyword(s):

Sickle Cell Disease ◽

Clinical Outcomes ◽

Sickle Cell ◽

Laboratory Data ◽

Clinical Profile ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Hemoglobin S ◽

Hemoglobin C ◽

Significant Difference

Abstract Introduction: The hemoglobinopathies are the most common monogenic disorders known. A mutation in the gene for β globin gave origin to hemoglobin S, an abnormal hemoglobin originated in Africa. Sickle cell disease (SCD) is characterized by the presence of hemoglobin S, which results in vasoocclusion episodes and hemolytic anemia throughout patients life. Vascular occlusion leads to acute events and progressive disabling organ damage. Sickle cell anemia is the homozygous state SS, while hemoglobinopathy SC is a doubly heterozygous state, where hemoglobin S occurs in combination with hemoglobin C. Brazil has a prominent African ancestry and SCD is highly prevalent in some regions of the country. In Bahia State, for example, neonatal screening data have shown that, from every 650 children born alive, one has SCD, mostly homozygous SS. Among other therapeutic measures, packed red blood cells (RBC) play a prominent role in SCD management. In situations such as acute chest syndrome (ACS), primary and secondary prevention of stroke, splenic or hepatic sequestration crisis, severe anemia, complicated pregnancy, isquemic organ damages and others, the transfusions may save lives. Although RBC may contribute to reduce morbidity and improve quality of life in SCD patients, there still are risks. Among other risk categories, alloimmunization may result from transfusions and occurs in 5 % to 50 % of SCD patients. It is still not known whether allosensibilization significantly affects the clinical outcomes in SCD. Objecive: The purpose of this study was to compare the clinical profile of multitransfused adult SCD patients who developed alloantibodies (ALO) to patients with the same disease, coming from the same population who did not become alloimmunized (non-ALO). Methods: This is a cross sectional study where medical records of SCD patients, referred to a reference center of Salvador, the capital of Bahia State, Brazil, were reviewed. Only SCD patients 18 years of age or older were included. They had received at least 3 RBC transfusions from 2004 to 2007, or had any alloantibody identified during this period. Patient characteristics, clinical findings, number of transfusions, frequency and specificity of alloantibodies, laboratory data, and the main clinical outcomes were reviewed. Results: a hundred and eight patients were included: 105 SS and 3 SC. The pre-transfusional RBC matching was done to ABH, D,C,c,E,e and Kell antigens. 56 patients developed alloantibodies (53 SS and 3 SC). Anti-E, anti-K, and anti-C were the most prevalent alloantibodies identified (39,3 %, 21,4 % and 16,1 %, respectively). Among the variables addressed in this study, age (higher in non-ALO, .041) and antiglobulin test positivity, more prevalente in ALO (.0001), depicted statistically significant difference. A few patients developed immune hemolysis, controlled successfully with corticosteroids. Alloimmunization was more prevalent among women, although no statistically significant difference was reached between ALO and non-ALO Other variables such as number of transfusions, hematological profile, biochemical data and complications such as stroke, leg ulcers, osteonecrosis, renal disease, abnormal cardiac features, and pulmonary hypertension did not show significant difference between both groups. Conclusion: his study shows that, although alloimmunization is a potential dangerous consequence of RBC transfusions, it did not modify the clinical profile of SCD alloimmunized patients. The concomitance of allosensibilization and autoantibodies in SCD leads to additional difficulties in the RBC matching for transfusion and may exacerbate hemolysis. In order to address autoimmunity in SCD, prospective studies with larger samples are needed.

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Clinical Complications in Adult Patients with Sickle Cell Anemia and β-Thalassemia-Sickle Cell Disease

Blood ◽

10.1182/blood.v120.21.4767.4767 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4767-4767

Author(s):

Giovanna Graziadei ◽

Alessia Marcon ◽

Martina Soldarini ◽

Ilaria Gandolfi ◽

Luisa Ronzoni ◽

...

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Acute Chest Syndrome ◽

P Value ◽

Cell Disease ◽

Transfusion Therapy ◽

Clinical Complications ◽

Significant Difference ◽

The Mean

Abstract Abstract 4767 Background. Sickle-Cell Disease (SCD) is one of the most common severe monogenic inherited disorders worldwide, due to hemoglobin S (HbS), with reduced affinity for the oxygen. HbS polymerization, leading to erythrocyte rigidity, vaso-occlusion and hemolytic anemia, is central in the pathophysiology and crucial for the clinical outcome. The term SCD refers to Sickle Cell Anemia (SCA) due to homozygosis for βS allele, HbS/β-thalassemia (T-SCD) due to compound of β-thal and βS allele, and HbSC disease, owing to the coinheritance of βS and βcalleles. SCD is a multiorgan disease characterized by recurrent acute events and progressive organ damage, worsening during the life. Aims. This is a retrospective monocentric study aimed to assess and compare the clinical complications among 59 adult SCD patients, followed at the Hereditary Anemia Centre of the Foundation IRCCS “Ca Granda” Ospedale Maggiore Policlinico, in Milan, Italy. Methods. Mutation analysis of the b globin gene was established by direct DNA sequencing on the ABI Prism 310 genetic analyzer. Clinical and hematological features were evaluated by routine tests and physical examination, with special attention to the erythropoiesis stress parameters as LDH values and extramedullary erythropoietic (EE) masses. Results. Fifty-nine adult SCD patients, 16 SCA and 43 T-SCD, were evaluated. In T-SCD patients detected b-mutations were severe (b°) in 69.8%, and moderate or mild (b+-b++) in 30.2%. The mean age of SCA patients was 36±9 and 41±11 years for T-SCD patients. For both groups the mean follow-up was 20±6 years, while the mean age at the presentation in our Centre was 32±8 years in SCA patients and 31±10 years in T-SCD ones. Five out of 16 (31.2%) SCA patients and 16/43 (37.2%) T-SCD patients were male. HbF mean levels were 6.9±5.1% and 10.1±7.2%, respectively in SCA and T-SCD group; surprisingly Hb mean levels were lower in SCA (9.3±1.3 g/dl) than in T-SCD (9.9±1.4 g/dl) patients. Comparing SCA and T-SCD, there was statistically significant difference in splenic features: splenectomy was performed in 2/16 (12.5%) SCA patients vs 21/43 (48.8%) T-SCD patients (p-value < 0.01). Splenomegaly was absent in SCA, while was detected in 11/22 (50%) T-SCD (p-value < 0.0001); all SCA patients had functional asplenia, not observed in T-SCD patients; splenic infarctions were absent in SCA patients and were detected in 7/22 (31.8%) T-SCD patients, of whom 5 had splenomegaly and 2 had normal spleen size (pvalue <0.001). On the other side, there was not statistically significant difference in the prevalence of stroke, acute chest syndrome (ACS), bone pain crisis, sepsis, leg ulcers and priapism. However, we observed some clinical differences, even if not statistically significant. Cholecistectomy was performed in 4/16 (25%) SCA patients vs 17/43 (39.5%) T-SCD patients, and gallstones were detected respectively in 5/12 (41.7%) and in 14/26 (53.8%) of SCA and T-SCD patients. Thrombotic events were absent in SCA patients, compared to 4/43 (9.3%) T-SCD patients. Furthermore, we detected EE in 3/16 (18.6%) SCA and in 3/43 (7%) T-SCD, all carrying b° thal mutations. We underlie that Hb levels and LDH values were higher in SCA than in T-SCD patients (823±295 vs 689±209 U/L). About the treatment, 14/16 (87.5%) SCA and 31/43 (72%) T-SCD underwent to top-up transfusion; 5/43 (11.6%) T-SCD were regularly transfused. Seven out of 16 (43.8%) SCA and 18/43 (41.8%) T-SCD patients were treated with Hydroxycarbamide (HU). Criteria for transfusion therapy were: painful crisis not responsive to HU, major clinical complications, such as stroke or ACS, extramedullary erythropoietic masses associated with high LDH levels and low Hb values. Conclusions. These data suggest that SCA and T-SCD patients have similar clinical course. Splenomegaly is present only in T-SCD patients, probably due to the increased amount of extravascular hemolysis. Surprisingly, SCA patients showed EE and lower Hb levels with higher LDH values compared to T-SCD ones. This could be related to the prevalence of intravascular hemolysis, that can lead to erythropoietic stress in SCA, even if tissues are better oxygenated in these patients because of biochemical characteristic of HbS in terms of decreased oxygen affinity. These observations could be important to evaluate transfusion and HU treatment. Disclosures: Cappellini: Novartis: Research Funding.

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Clinical epidemiology of individuals with Sickle cell anemia using Hydroxyurea at Muhimbili National Hospital, Dar Es Salaam, Tanzania

Tanzania Medical Journal ◽

10.4314/tmj.v31i1.346 ◽

2020 ◽

Vol 31 (1) ◽

pp. 106-119

Author(s):

Elisha Osati ◽

Edward Kija ◽

Florence Urio ◽

Magdalena Lyimo ◽

Siana Nkya ◽

...

Keyword(s):

Clinical Outcomes ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Severe Pain ◽

Clinical Epidemiology ◽

Fetal Hemoglobin ◽

Dar Es Salaam ◽

Acute Chest Syndrome ◽

Muhimbili National Hospital ◽

National Hospital

Background: The pathophysiology of sickle cell disease (SCD) is complex and involves nitric oxide depletion, increased inflammation/adhesion molecules and vaso-occlusion in addition to the chronic hemolytic anemia. This pathophysiology results in systemic clinical complications including recurrent episodes of severe pain, stroke, acute chest syndrome (ACS) and an increased susceptibility to infection. SCD severity varies among individuals and fetal hemoglobin (HbF) is known as a major modulator of the disease. To date, hydroxyurea (HU) is a known intervention that acts by increasing HbF in individuals with SCD. The increase in HbF reduces the risk of ‘sickling’ events and improves clinical outcomes. This is the first study on the use of HU in individuals with SCA in Tanzania.Methods: A case-control study to determine the proportion, indications, clinical and laboratory outcomes of SCD patients with HU use was conducted at Muhimbili National Hospital in Dar Es Salaam, Tanzania.Results: Forty-two patients with Sickle cell anemia (SCA) on HU treatment and 32 patients with SCA not on HU treatment were enrolled. The proportion of HU use by individuals with SCA at Muhimbili National Hospital was 10 per 1000. The mean HbF % was 9.8 ± 2.4 vs 6.2 ±1.4 for controls (P <0.001). Thirty (71.4%) were enrolled for HU treatment due to central nervous system (CNS) events, frequent painful crises 11(26.2%) and recurrent anemia 1(2.4%). Thirty-two SCA patients (76.2%) reported improvements after being on HU for at least six months. Of these, 91% reported no history of severe pain that required hospitalizations since they started HU. Twenty patients (66.7%) out of those with CNS events reported not to have experienced convulsions after HU initiation.Conclusions: HbF was higher in patients who were on HU and had positive correlation with clinical outcomes. Further clinical trials are required to evaluate more effects of HU use among SCA individuals in Tanzania. Keywords: Sickle cell anemia, HU, Fetal hemoglobin, Tanzania.

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Efficacy of Allogeneic Hematopoietic Cell Transplantation (HCT) in Sickle Cell Disease: Results of a Systematic Review/Meta-Analysis

Blood ◽

10.1182/blood-2019-124955 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2106-2106

Author(s):

Madiha Iqbal ◽

Tea Reljic ◽

Ernesto Ayala ◽

Hemant S. Murthy ◽

Ambuj Kumar ◽

...

Keyword(s):

Systematic Review ◽

Sickle Cell Disease ◽

Clinical Outcomes ◽

Sickle Cell ◽

Pediatric Patients ◽

Medical Literature ◽

Meta Analysis ◽

Adult Patients ◽

Cell Disease ◽

Allogeneic Hct

Background: Sickle cell disease (SCD) is an inherited hemoglobinopathy which affects over 300,000 children born each year worldwide. In spite of improvement in supportive care in recent years, there is still a lack of effective treatment options. SCD leads to debilitating and cyclic episodes of erythrocyte sickling with progressive organ injury, contributing to lifetime morbidity and shortened life expectancy. Allogeneic HCT (allo-HCT) is a potentially curative therapy for SCD because engraftment is associated with resolution of the clinical phenotype of the disease and abrogation of its complications. Medical literature on allo-HCT for SCD is largely limited to children. Recent studies have evaluated the efficacy of allo-HCT in the adult population. Here, we conduct a systematic review/meta-analysis to assess the totality of evidence pertaining to the efficacy (or lack thereof) of allo-HCT in children and adults. Materials and methods: We performed a comprehensive search of the medical literature using PubMed/Medline, EMBASE and Cochrane library on July 3rd, 2019. We extracted data on clinical outcomes related to benefits (overall [OS] and disease free/event free survival [EFS/DFS]) and harms (non-relapse mortality [NRM] and graft failure [GF]), independently by two authors. Our search strategy identified 1001 references but only 30 studies (n= 1995 patients) were included in this systematic review/meta-analysis. We also performed a sub analysis on clinical outcomes for studies that included only pediatric patients (defined as <18 years) and those in patients ≥18 years of age. Results: Median age for patients enrolled in all the studies was at 10 years. Recurrent veno-occlusive crises represented the most common indication for allo-HCT followed by acute chest syndrome and stroke; nevertheless, most patients had more than one indication. Matched related donors (MRD) were the most common donor source (93%). Bone marrow was the most common source of hematopoietic stem cells (77%). Majority of patients underwent conditioning with myeloablative regimens (77%). Pooled OS rates (n=29 studies, 1681 patients) after allogeneic HCT was 95% (95%CI=93-96%) with low heterogeneity (I2=6.4%) among included studies (Figure 1). Pooled EFS/DFS rates (n=29 studies, 1894 patients) post-allografting was 90% (95%CI=87-93%) with moderate heterogeneity (I2=54%). Pooled NRM rates from 30 studies (1995 patients) was 4% (95%CI=2-6%) with low heterogeneity (I2=29.4%). Pooled GF rates from 28 studies (1851 patients) was 4% (95%CI=2-6%) with moderate heterogeneity (I2=55%). A subset analysis specifically for pediatric patients (n= 11 studies, 1009 patients, median age at 9.7 years) showed a pooled OS rate of 96% (95%CI=94-97%) with low heterogeneity (I2=0%); and for adult patients (n=3 studies, 51 patients, median age at 33.4 years) the pooled OS was 94% (95%CI=80-100%) with moderate heterogeneity (I2=52%). Pooled EFS/DFS for pediatric patients (n= 11 studies, 1009 patients) was at 89 %( 95%CI=84-93%) with moderate heterogeneity (I2=55.1%); and for adult patients (n=2 studies, 30 patients) was at 95% (95%CI=83-100%) with high heterogeneity (I2=96.5%). Pooled NRM from 10 studies with pediatric patients (281 patients) was at 6 % (95%CI=3-10%) with low heterogeneity (I2=0%); and from 3 studies with adult patients (51 patients) was at 1% (95%CI=0-7%) with low heterogeneity (I2=15.1%). Pooled GF from 10 studies with pediatric patients (281 patients) was at 3 % (95%CI=1-7%) with moderate heterogeneity (I2=40%); and from 2 studies with adult patients (30 patients) was at 5% (95%CI=0-17%) with high heterogeneity (I2=95.4%). Conclusions: The results of our systematic review/meta-analysis show excellent OS, EFS/DFS in children and adults undergoing allo-HCT with pooled OS rates exceeding 90%. The main limitation to offering an allo-HCT in SCD remains the availability of a suitable donor as 85% of patients meeting criteria do not have a MRD. We anticipate that with emergence of haploidentical transplantation the number of allo-HCT will increase in the future. GF remains a significant concern in this population and future studies should focus on novel immune suppression strategies to help reduce GF. Disclosures Kharfan-Dabaja: Pharmacyclics: Consultancy; Daiichi Sankyo: Consultancy.

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Non-crisis related pain occurs in adult patients with sickle cell disease despite chronic red blood cell exchange transfusion therapy

Transfusion and Apheresis Science ◽

10.1016/j.transci.2021.103304 ◽

2021 ◽

pp. 103304

Author(s):

Susanna A. Curtis ◽

Balbuena-Merle Raisa ◽

John D. Roberts ◽

Jeanne E. Hendrickson ◽

Joanna Starrels ◽

...

Keyword(s):

Sickle Cell Disease ◽

Blood Cell ◽

Sickle Cell ◽

Red Blood Cell ◽

Exchange Transfusion ◽

Adult Patients ◽

Cell Disease ◽

Transfusion Therapy

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Sickle crisis in the critically ill

10.1093/med/9780199600830.003.0275 ◽

2016 ◽

Author(s):

Shilpa Jain ◽

Mark T. Gladwin

Keyword(s):

Sickle Cell Disease ◽

Blood Cell ◽

Sickle Cell ◽

Red Blood Cell ◽

Systemic Infection ◽

Red Blood Cell Transfusion ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Ischaemia Reperfusion Injury ◽

Transfusion Therapy

Sickle cell disease crises are precipitated by an acute occlusion of microvessels, which can lead to end organ ischaemia reperfusion injury and acute haemolysis. Acute fat emboli syndrome, acute lung injury (the acute chest syndrome), acute pulmonary hypertension, and cor pulmonale, haemorrhagic and occlusive stroke, and systemic infection represent the most common life-threatening complications observed in current ICU practice. General principles of management in all patients admitted to the critical care unit are hydration, antibiotics, pain control, and maintenance of oxygenation and ventilation. Red blood cell transfusion therapy is the treatment of choice for most complications of sickle cell disease requiring intensive care management. Transfusion of sickle negative, leukoreduced red blood cells, phenotypically matched for Rhesus and Kell antigens is the minimum standard of care in sickle cell disease patients as they have a high incidence of red blood cell alloimmunization.

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An Evidence-Based Approach to the Treatment of Adults with Sickle Cell Disease

Hematology ◽

10.1182/asheducation-2005.1.58 ◽

2005 ◽

Vol 2005 (1) ◽

pp. 58-65 ◽

Cited By ~ 50

Author(s):

Richard Lottenberg ◽

Kathryn L. Hassell

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Enzyme Inhibitor ◽

Controlled Trial ◽

Acute Chest Syndrome ◽

Evidence Based ◽

Clinical Expertise ◽

Cell Disease ◽

Transfusion Therapy ◽

Treatment And Prevention

Abstract The application of evidence-based medicine to the management of adults with sickle cell disease (SCD) is currently primarily driven by clinical expertise and patient preference, as there is a paucity of randomized controlled trial (RCT) data to guide decision-making. A summary of SCD management principles in the areas of health care maintenance, transfusion therapy, treatment and prevention of painful episodes, acute chest syndrome, stroke, renal disease, contraception and pregnancy, and priapism is predominantly based on the authors’ interpretation of available observational studies as well as the opinions of experts in SCD. RCTs impacting current practices address use of hydroxyurea to prevent painful episodes and acute chest syndrome, intensity of pre-operative transfusion, transfusion during pregnancy, and angiotensin-converting enzyme inhibitor therapy for proteinuria, but most issues in adult SCD care have not been rigorously studied and management may not be appropriately extrapolated from pediatric data. While challenging clinical problems need to be addressed by RCTs, there is also the need for development of practice guidelines using formal methodological strategies. This brief review is not a substitute for the process but provides a literature-based approach to making treatment decisions when caring for adults with SCD.

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Refining Th Predictive Value of Secretory Phospholipase A2 In Sickle Cell Disease Patients with Acute Chest Syndrome

Blood ◽

10.1182/blood.v116.21.846.846 ◽

2010 ◽

Vol 116 (21) ◽

pp. 846-846 ◽

Cited By ~ 2

Author(s):

Lori Styles ◽

Carrie Greene Wager ◽

Richard J. Labotka ◽

Kim Smith-Whitley ◽

Alexis A. Thompson ◽

...

Keyword(s):

Sickle Cell Disease ◽

Phospholipase A2 ◽

Sickle Cell ◽

Predictive Value ◽

Laboratory Data ◽

Research Network ◽

Acute Chest Syndrome ◽

Secretory Phospholipase A2 ◽

Cell Disease ◽

Secretory Phospholipase

Abstract Abstract 846 Elevation of the serum level of secretory phospholipase A2 (sPLA2) has previously been reported to predict impending acute chest syndrome (ACS) in sickle cell disease (SCD) patients admitted with pain. The Sickle Cell Disease Clinical Research Network initiated the PROACTIVE Feasibility Study to 1) assess the feasibility of screening, randomizing and treating with simple transfusion eligible patients and 2) assess the predictive utility of sPLA2 in screening for imminent ACS, characterize the distribution of sPLA2 values in sickle cell patients hospitalized with pain, and define a cut-off point for predicting ACS to optimize its reliability, sensitivity and specificity in predicting ACS. All SCD patients (hemoglobin SS, SC and SBeta-thalassemia) admitted for pain at a participating center were to be screened for eligibility; patients with a diagnosis of ACS at entry were not eligible. sPLA2 levels were drawn daily on consenting patients for up to three days during the admission. All patients had at least one CXR (mandated at 72 hr if not done for clinical indications) during the course of their hospital stay to determine if they had developed a new infiltrate, considered diagnostic for ACS. Patients who developed T>38°C, a sPLA2 level > 100ng/ml and had a normal CXR were eligible for randomization to observation or simple transfusion; the remaining patients were followed in an Observation arm. Of 421 patients potentially eligible for screening, 238 were enrolled in the study with 10 of these patients randomized (4 to transfusion 6 to standard care). Of these, 203 patients had from one to three sPLA2 levels drawn prior to an ACS diagnosis or did not develop ACS; if transfused, they received blood only after a diagnosis of ACS was made. Twenty-two of these patients (11%) developed ACS. Analysis of the maximum sPLA2 levels prior to ACS diagnosis revealed that a threshold of 45 ng/ml was the most accurate level to predict ACS (accuracy: 73%, sensitivity: 73%, specificity: 73%). The positive predictive value (PPV: 25%) was low due to the relative infrequency of ACS events. When sPLA2 levels were analyzed in children versus adults, sPLA2 was more accurate for adults in predicting ACS with a level of 65ng/ml having accuracy: 88%, sensitivity: 44%, specificity: 95%, PPV: 57%. The addition of a requirement for fever did not improve the accuracy of sPLA2 in either adults or children. Further analysis of sPLA2 levels with various clinical and laboratory data is ongoing to improve the PPV of sPLA2. These results indicate that sPLA2 can predict ACS with good sensitivity, but may require additional parameters to be useful in clinical management of SCD patients admitted with pain and at risk for ACS. Supported by the NHLBI. Disclosures: Labotka: HemaQuest Pharmaceuticals, Inc: Research Funding.

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

Blood ◽

10.1182/blood.v122.21.2249.2249 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2249-2249

Author(s):

Michel Gowhari ◽

Aileen Chu ◽

Julie Golembiewski ◽

Robert E. Molokie

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Pain Control ◽

Low Dose ◽

Conflicts Of Interest ◽

Adult Patients ◽

Cell Disease ◽

Ketamine Infusion ◽

The Past ◽

Painful Episode

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

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Microparticles As Biomarkers Of Osteonecrosis Of The Hip In Sickle Cell Disease

Blood ◽

10.1182/blood.v122.21.2226.2226 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2226-2226

Author(s):

Anne M Marsh ◽

Raymond Schiffelers ◽

Ginny Gildengorin ◽

Frans A Kuypers ◽

Carolyn Hoppe

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Conflicts Of Interest ◽

Vascular Occlusion ◽

Predictive Biomarker ◽

Acute Chest Syndrome ◽

Mobility Limitations ◽

Cell Disease ◽

The Past ◽

D Dimer

Abstract Introduction Sickle cell disease (SCD) is the most common cause of osteonecrosis of the femoral head (ONFH) in children. ONFH is a debilitating condition that is associated with mobility limitations, chronic pain, and an impaired quality of life. While the mechanisms that cause ONFH remain unknown, ischemia from recurrent microvascular occlusion is likely to play a role. Vascular occlusion may result directly from obstruction by sickled cells, or indirectly via complex interdependent pathways characterized by sustained endothelial activation, chronic inflammation, and coagulation. Microparticles (MP) are small, cell membrane-derived vesicles generated in response to cellular activation, injury or apoptosis. MPs have emerged as potential modulators of inflammation and thrombosis and have been found to be elevated in patients with ONFH in the general population. Objective This pilot study examined whether microparticle levels in patients with SCD who have ONFH differ from SCD patients without ONFH, as well as healthy African American (AA) controls. Methods Subjects were recruited at their baseline status and were excluded if they had been transfused within the past 30 days, hospitalized for a vaso-occlusive pain episode, acute chest syndrome, fever or surgery within the past 30 days, or had bony lesions of the femur or hip due to causes unrelated to SCD. For MP analysis, whole blood was collected in sodium citrate tubes and centrifuged for 15 minutes at 1500 x g at 20° C to generate platelet poor plasma. Aliquots of the plasma were immediately frozen and stored at -80° C until the time of MP analysis. 300 μl samples were diluted in PBS and centrifuged at 10000 x g for 1hr and the supernatant was centrifuged at 100,000 x g for 2 hr. The pellet was re-suspended in 1 mL of PBS and subjected to nanoparticle-tracking analysis to determine concentration and size. Additional laboratory biomarkers of inflammation and coagulation, including highly-sensitive C-reactive protein (hs-CRP), von Willebrand factor antigen (vWF Ag), tissue factor (TF), and D-dimer were analyzed for differences between groups. Analysis of variance was used to compare MP and biomarker levels between the three groups. The institutional review board at Children's Hospital & Research Center Oakland approved the study protocol and written informed consent was obtained from all participants. Results Characteristics of the 30 subjects enrolled are shown in Table I. Total microparticle levels in ONFH(+) patients were 2.3-fold higher than in ONFH(-) patients, and 2.5-fold higher than in AA controls (Figure 1). Mean MP levels for ONFH(+) patients, ONFH(-) patients, and AA controls were 4.55 x 1010, 1.99 x 1010, and 1.85 x 1010, respectively. Microparticle levels in ONFH(-) SCD patients did not differ from AA controls. There were no statistically significant differences in hsCRP, vWF Ag, TF, or D-dimer levels between the ONFH(-) and ONFH(+) groups. Conclusions The results of this study demonstrate significantly elevated MP levels in individuals with SCD who have ONFH. Additional studies are needed to better understand the mechanistic effects of MPs on the development of ONFH and to determine whether MP levels may be useful as a predictive biomarker for early disease detection. This publication was supported by NIH/NCRR UCSF-CTSI Grant Number UL1 RR024131. Disclosures: No relevant conflicts of interest to declare.

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