Prevalence and Predictors of Steady-State Hypoxemia in Sickle Cell Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1662-1662
Author(s):  
Charles T. Quinn ◽  
Naveed Ahmad
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Arterial Oxygen ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Chronic Anemia ◽  
Independent Variables ◽  
Hemoglobin C ◽  
Age And Sex

Abstract Individuals with sickle cell disease (SCD) may have arterial oxygen desaturation during the steady-state that is mainly due to a right shift of the oxyhemoglobin dissociation curve. This right shift has both non-specific causes (increased concentration of 2,3-DPG due to chronic anemia) and SCD-related causes (an effect of the intracellular concentration of hemoglobin (Hgb) S and an enhanced Bohr effect). Another possible cause is chronic cardiopulmonary disease that may be related to past acute chest syndrome (ACS). We aimed to describe the distribution of steady-state peripheral oxygen saturation (SpO2) in a large population of children with SCD and to determine whether any simple laboratory or clinical features were predictive of SpO2. We hypothesized that most of the variation in SpO2 was not explained by steady-state Hgb alone, and that a history of ACS could explain some of this variability. Using our center’s comprehensive database we identified all subjects with sickle cell anemia (SS), sickle-hemoglobin C disease (SC), sickle-β+-thalassemia (Sβ+), or sickle-β0-thalassemia (Sβ0) who had been evaluated within the past 5 years for whom steady-state Hgb concentration, reticulocyte count (retic), and SpO2 were available. All steady-state values are rolling averages calculated at routine well clinic visits. SpO2 was determined by pulse oximetry in room air. Individuals receiving chronic transfusions were excluded. Lifetime rates of ACS were known for a subset of subjects with SS and Sβ0. A standard multiple regression analysis was performed between steady-state SpO2 as the dependent variable, and steady-state Hgb and retic, age, and sex as independent variables. 585 subjects were analyzed (390 SS/Sβ0, 195 SC/ Sβ+; 47% female, 53% male). Mean age was 9.4 years (SD 5.6, range 0.2 – 19.7). Mean SpO2 was 96.3% (SD 3.0) for SS/Sβ0 and 98.7% (SD 1.7) for SC/ Sβ+ subjects. The percentage of subjects with SpO2 <96% and <90% was 33.1 and 2.8 for SS/Sβ0 and 3.6 and 0.5 for SC/ Sβ+. Bivariate analyses showed no correlation between Hgb and SpO2 for SC/ Sβ+ subjects (N=195, Pearson R=0.024, P=0.74) and no correlation between ACS rate and SpO2 in those with SS/Sβ0 (N=183, Pearson R=−0.043, P=0.56). Thus, only the 390 subjects with SS/Sβ0 were included in the multivariate analysis, and ACS rate was not included in the model as an idependent variable. All 4 independent variables (Hgb, retic, age, and sex) contributed significantly to prediction of SpO2. Altogether, about 45% (adjusted 44%) of the variability in SpO2 was explained by the model. Multiple correlation coefficient (R = 0.67) showed a significant linear relationship between independent variables and SpO2 (F = 78.07, p < 0.001). The estimated model can be given as: SpO2 = 94.24 + (0.58 * Hgb) − (0.16 * Age in years) + (0.64 * Female sex) − (0.20 * Retic in %). In summary, steady-state hypoxemia is common among individuals with SS and Sβ0, in whom decreased steady-state SpO2 is related to decreased steady-state Hgb, increased steady-state retic, increased age, and male sex. This relationship was not found for individuals with SC and Sβ+. Only 5% of the variation in SpO2 was explained by Hgb while controlling for other variables, and ACS rate was not associated with SpO2. We conclude that most steady-state hypoxemia in individuals with SCD is explained by factors other than chronic anemia, and that hypoxemia appears to be unrelated to prior episodes of ACS.

scholarly journals Beneficial effects of adenotonsillectomy in children with sickle cell disease

2020 ◽  
Vol 6 (4) ◽  
pp. 00071-2020
Author(s):  
Ilaria Liguoro ◽  
Michele Arigliani ◽  
Bethany Singh ◽  
Lisa Van Geyzel ◽  
Subarna Chakravorty ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Arterial Oxygen Saturation ◽  
Arterial Oxygen ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Beneficial Effects ◽  
Admission Rates ◽  
The Mean ◽  
The Impact

Tonsillectomy and adenoidectomy (T&A) is frequently performed in children with sickle cell disease (SCD). Our aim was to evaluate the impact of this surgery on overnight oxygenation and rates of complications in these patients.Children with SCD who underwent T&A between 2008 and 2014 in two tertiary hospitals were retrospectively evaluated. Overnight oximetry and admission rates due to vaso-occlusive pain episodes (VOEs) and acute chest syndrome (ACS) in the year preceding and following the surgery were compared.19 patients (10 males, 53%) with a median age of 6 years (range 3.5–8) were included. A significant increase of mean overnight arterial oxygen saturation measured by pulse oximetry (SpO2) (from 93±3.6% to 95.3±2.8%, p=0.001), nadir SpO2 (from 83.0±7.1% to 88±4.1%, p=0.004) and a reduction of 3% oxygen desaturation index (from a median value of 5.7 to 1.8, p=0.003) were shown. The mean annual rate of ACS decreased from 0.6±1.22 to 0.1±0.2 events per patient-year (p=0.003), while the mean cumulative rate of hospitalisations for all causes and the incidence of VOEs were not affected.T&A improved nocturnal oxygenation and was also associated with a reduction in the incidence of ACS at 1-year follow-up after surgery.

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

Blood ◽  
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.

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) &gt; 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

Splenectomy in Jamaican children with sickle cell disease: Outcome of selective blood transfusion

2020 ◽  
pp. 004947552097461
Author(s):  
Odayne Steele ◽  
Alfred L Duncan ◽  
Larnelle N Simms ◽  
Shani A Duncan ◽  
Simone E. Dundas Byles ◽  
...  
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
Blood Transfusion ◽  
Sickle Cell ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Operative Morbidity ◽  
Open Splenectomy ◽  
Bank Reserves ◽  
Transfusion Protocol

We reviewed the post-operative morbidity and mortality of open splenectomy undertaken in conjunction with selective blood transfusion in Jamaican children with sickle cell disease. Data were collected on 150 splenectomies performed between November 1994 and October 2017. Selective blood transfusion involved raising haemoglobin levels to approximately 100 g/L in patients with admission haemoglobin ≥10 g/L below steady state. There was no mortality. Mean post-operative stay was 3.2 days with a median of three days. Total morbidity was 19/150 cases (12.7%), with acute chest syndrome accounting for 11/19 (57.9%). Among the non-transfused, acute chest syndrome occurred in 10/117 cases (8.5%), while among transfused, acute chest syndrome occurred in 1/33 cases (2.9%). We recommend this selective blood transfusion protocol for patients with sickle cell disease to surgeons who undertake splenectomies in settings where blood bank reserves are perennially low.

scholarly journals Pulse oximetry and factors associated with hemoglobin oxygen desaturation in children with sickle cell disease

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3422-3427 ◽  
Author(s):  
WR Rackoff ◽  
N Kunkel ◽  
JH Silber ◽  
T Asakura ◽  
K Ohene-Frempong
Keyword(s):  
Sickle Cell Disease ◽  
Pulse Oximetry ◽  
Sickle Cell ◽  
Arterial Oxygen Saturation ◽  
Oxygen Desaturation ◽  
Arterial Oxygen ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Factors Associated ◽  
History Of

The observation of low transcutaneous arterial oxygen saturation (SaO2) in otherwise well sickle cell patients has lead to questions about the interpretation of pulse oximetry values in these patients. We undertook a prospective study of children with sickle cell disease to (1) determine the prevalence of, and factors associated with, low transcutaneous SaO2 in clinically well patients, (2) develop an algorithm for the use of pulse oximetry in acutely ill patients, and (3) assess the accuracy of pulse oximetry in these patients. Eighty-six clinically well children with hemoglobin (Hb) SS had a lower mean transcutaneous SaO2 than 22 Hb SC patients and 10 control subjects (95.6% v 99.1% v 99.0%, respectively; p < .001). In Hb SS patients, a history of acute chest syndrome and age greater than 5 years were associated with lower transcutaneous SaO2 (mean 93.8% for those with a history of acute chest syndrome v 97.8% for those without a history of acute chest syndrome, and 94.0% for patients = 5 years old v 97.2% for those < or = 5 years old; P < .001). These associations were not seen in Hb SC patients. During acute illness, Hb SS patients with acute chest syndrome had transcutaneous SaO2 values that were less than 96% and at least 3 points lower than measurements made when they were well. A nomogram was designed to aid in the interpretation of transcutaneous SaO2 in acutely ill Hb SS patients when a comparison value is not available. The accuracy of pulse oximetry was shown by the correlation between SaO2 measured by pulse oximetry and calculated by using the patient's oxygen dissociation curve and PaO2 (r = .97). This study provides evidence that Hb oxygen desaturation is not a universal finding among children with sickle cell disease and identifies factors associated with Hb oxygen desaturation. We conclude that pulse oximetry may be useful to assess whether progressive pulmonary dysfunction begins at an early age in Hb SS patients, and to assess acutely ill patients for the presence of hypoxemia associated with acute chest syndrome.

Report on the International Co-Operative Study of the Effects of L-Selectin Gene Polymorphisms on the Development of Complications in Sickle Cell Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3775-3775
Author(s):  
Iheanyi Okpala ◽  
Cynthia C. Ugochukwu ◽  
Panagiotis Pantelidis ◽  
Baba Inusa ◽  
Obike Ibegbulam ◽  
...  
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Surface Expression ◽  
Control Individual ◽  
Acute Chest Syndrome ◽  
Nucleotide Polymorphisms ◽  
Cell Disease ◽  
Increased Risk ◽  
Significant Difference

Abstract Our previous study showed that patients with sickle cell disease (SCD) and high steady-state expression of the adhesion molecules L-selectin and αMβ2 integrin on leukocytes developed complications [Blood. 2002;100(suppl):11a. Eur J. Haematol. 2002; 69:135–144]. The aim of this study was to find out if L-selectin protein expression by leukocytes and the development of complications in SCD are affected by previously described single nucleotide polymorphisms within the coding regions of the gene. To detect F206L, T49S and P213S polymorphisms we determined the L-selectin genotype in 142 HbSS patients (64M, 78F, age 2 – 62 yr, mean 27 yr ±12); and 102 racially-matched HbAA controls with similar age and sex distribution. The T49S and P213S amino acid changes in L-selectin are respectively associated with increased risk of vasculopathy and nephropathy; important features of SCD. [Hum Genet. 1996; 97:15–20. Am. J. Hum. Genet.2002; 70: 781–786]. All HbSS patients were evaluated for disease complications. Steady-state expression of L-selectin on neutrophils, lymphocytes and monocytes was measured by flow cytometry in 44 HbSS patients. With respect to F206L polymorphism, 100/142 (70%) patients and 73/102 (72%) controls were FF homozygous, 42 patients and 28 controls were heterozygous FL, and 1 control individual was LL homozygous. There was no significant difference in distribution of the polymorphic variants between patients and controls [Chi-squared (X2) = 0.1, p&gt;0.05]. In codon 213, 48 (33.8%) patients and 42 (41.2%) controls were PP homozygous, 91 patients and 55 controls PS heterozygous, 1 patient and 5 controls SS homozygous [X2 =1.9, p&gt;0.05]. With regard to the T49S polymorphism, 100% of the patients and controls were TT homozygous. At least one complication of SCD was observed in 110 SCD patients; 32 had uncomplicated disease. The most common complications observed were avascular joint necrosis (n=39), sickle nephropathy (n=31), stroke (n=25) and acute chest syndrome (n=20). The observed frequencies of FF genotype in codon 206 among patients with complications (74), and without complication (26) were not significantly different from the expected values [X2 = 2.37, p&gt;0.05]. Similarly, none of the other genotypes (FL, PP, PS) was significantly associated with complications of SCD. Of the 44 patients in who leukocyte L-selectin expression was measured, 31 turned out to be FF homozygous in codon 206, and 13 FL. No significant differences were observed between FF and FL patients in the mean levels of L-selectin expression by neutrophils (FF: 4.00+ 4.56 vs FL: 3.24+ 3.4), monocytes (FF: 4.30+ 5.6 vs FL: 2.56+ 3.39) or lymphocytes (FF: 2.61+ 3.02 vs FL: 2.11+ 2.0); p&gt;0.05. Similarly, the P213S polymorphism had no effect on the level of L-selectin expression. The findings suggest that neither F206L nor P213S L-selectin gene polymorphism predisposes to high leukocyte surface expression of this adhesion molecule, or the development of complications in SCD.

Antecedent Transfusion and Primary Hemorrhagic Stroke in Adults with Sickle Cell Disease.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1437-1437
Author(s):  
John J. Strouse ◽  
Joshua Field ◽  
Regina D. Crawford ◽  
Sophie Lanzkron
Keyword(s):  
Risk Factors ◽  
Ischemic Stroke ◽  
Steady State ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Hemorrhagic Stroke ◽  
Neurological Deficits ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Elevated Systolic Blood Pressure

Abstract Primary hemorrhagic stroke is an uncommon but serious complication of sickle cell disease (SCD) with mortality from 20 to 65%. Proposed risk factors include previous ischemic stroke, aneurysms, low steady-state hemoglobin, high steady-state leukocyte count, acute chest syndrome, and transfusion. We performed a retrospective case-control study to evaluate risk factors for primary hemorrhagic stroke in adults (age &gt;18 years) with SCD from Johns Hopkins and Barnes- Jewish Hospitals and Duke University Medical Center from January 1989 to April 2008. Cases had SCD and intraparenchymal (IPH), subarachnoid (SAH), or intraventricular (IVH) hemorrhage confirmed by neuroimaging or analysis of cerebrospinal fluid; traumatic hemorrhages and hemorrhagic conversion of ischemic strokes were excluded. Controls had SCD and ischemic stroke (focal neurological deficits with corresponding cerebral infarcts by neuroimaging). Both were identified by searching the hospital discharge database using ICD-9 codes for acute stroke and SCD and reviewing divisional records. We compared continuous variables by Student’s t-test and calculated odds ratios with exact methods. We identified 19 cases (mean age 29 years, range 18 – 66, 42% male) and 18 controls (mean age 34 years, range 19 – 61, 39% male). Most cases (14/18) had sickle cell anemia (HbSS) and 22% had a prior overt stroke; controls had HbSS (9/17), HbSB0thalassemia (1), or HbSC (7) and 41% had a history of overt stroke. Cases presented with headache (89%) and seizure (37%) and less frequently hemiparesis (27%). Controls presented with hemiparesis (78%), headache (57%), and rarely seizure (11%). Twelve cases had IPH including those with extension to the ventricles (1), subarachnoid (2) or both (2); six had SAH including ventricular extension (1). Potential causes of hemorrhagic stroke included moyamoya (4), aneurysms (3), anticoagulation (1) and ateriovenous malformation (1). Four cases (21%) and no controls died during the initial hospitalization. More cases (82%) than controls (44%, P&lt;0.05) had elevated systolic blood pressure at the time of stroke. At steady-state, cases had lower hemoglobin (mean ± SEM 8.5 ± 0.6 g/dl vs. 9.7 ± 0.6 g/dl), lower blood pressures (systolic 121 ± 4 vs. 127 ± 6 mm Hg, diastolic 71 ± 4 vs. 72 ± 9 mm Hg) and higher platelet counts (399,231 ± 74,024/ul vs. 362,200/ul ± 39,927/ul) than controls, but these differences were not statistically significant. Mean hemoglobin concentration at the time of stroke increased 1.3 g/dl (19%) from steady-state in cases and 0.01 g/dl (2%) in controls (p&lt;0.05). Seven cases had simple transfusions (between 1 and 11 days before their primary hemorrhagic stroke) in preparation for surgery (3), and for aplastic crisis (1), bacteremia (1), acute renal failure (1), or suspected acute chest syndrome (1). Only 1 control was transfused; and 1 with HbSS had a hemoglobin of 14.5 g/dl at the time of stroke (from excessive erythropoietin administration). In this group of adults with SCD, primary hemorrhagic stroke was associated with antecedent transfusion. Identifiable causes include moyamoya from obstructive cerebral vasculopathy, aneurysms and other vascular malformations, and rarely coagulopathy. Mortality was similar to that previously described. The association of recent transfusion and cerebral vasculopathy with hemorrhagic stroke suggests caution in the use of simple transfusion in adults with SCD and moyamoya or cerebral aneurysms. Table 1: Associations with Primary Hemorrhagic Stroke Variable Odds Ratio (95% CI) P-value Genotype (HbSS vs. other) 3 (0.6 – 17) NS Moyamoya 5 (0.4 – 260) NS Transfusion in the last 14 days 13 (1.3 – 630) &lt;0.02 NSAID in the last 14 days 2.9 (0.3 – 36) NS

Acute Chest Syndrome In Transgenic Mouse Models of Sickle Cell Disease Triggered by Free Heme

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 944-944 ◽  
Author(s):  
Samit Ghosh ◽  
Solomon F Ofori-Acquah
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Arterial Oxygen ◽  
Acute Chest Syndrome ◽  
Heme Oxygenase 1 ◽  
Cell Disease ◽  
Cardiopulmonary Function ◽  
Acute Elevation ◽  
Free Heme ◽  
Pulmonary Infiltration

Abstract Abstract 944 Acute chest syndrome (ACS) is the leading cause of death among patients with sickle cell disease (SCD). It is a process of devastating acute lung injury that evolves from multiple exacerbating events including vaso-occlusive pain crises, infection and fat emboli. ACS results in pulmonary infiltration, hypoxemia, and occlusions in the pulmonary microcirculation. Hitherto, experimental models of ACS have been lacking, and molecular targets of therapy remain to be identified. Clinical studies indicate that most patients diagnosed with ACS hemolyse during the acute phase of the syndrome, which highlights a role for circulating heme/hemin in this process. Since the deleterious effects of hemin are defined by increased vascular permeability, we tested the hypothesis that acute elevation of circulating hemin would increase pulmonary microvascular leakage sufficiently to trigger ACS. Adult transgenic mice expressing exclusively human sickle hemoglobin (Hb SS), and control Hb AS and Hb AA mice were intravenously injected with hemin (70 micromoles/kg body weight), and cardiopulmonary function assessed in real-time using a mouse pulse oximeter. Arterial oxygen saturation (SpO2) in the SS mice reduced significantly (p = 0.02) to 84.1 ± 5.6 % from a normal baseline value of 98.6 ± 0.3 %, within 25 minutes of administration of i.v. hemin, while SpO2 in control AS and AA mice remained unchanged. Consistent with changes in cardiopulmonary function, all the SS mice (n=14) succumbed to hemin, within 2 hours, while all control AS and AA mice survived, and remained alive several weeks after the experiment (log-rank survival test, p= <0.0001). We obtained identical results for survival in experiments using the Berkeley mouse model of SCD (Sickle 0/6, hemizygote 5/6, p=0.003). Post-mortem findings of gross pulmonary infiltration, alveolar flooding and microvascular occlusions, in the lungs of SS and Berkeley sickle mice that succumbed to hemin was consistent with respiratory distress associated sudden death. Younger SS mice aged 5–6 weeks were more resistant to i.v. hemin, with a survival rate of 80% (12/15), recapitulating the age-dependant mortality in human ACS. As expected, i.v. hemin raised the total plasma heme concentration to the same level in all mice, regardless of genotype. However, the concentration of protein-free plasma heme (PFPH) was increased by 6-fold in SS compared to AS mice (p = 0.001, n=12). The inability of SS mice to effectively scavenge excess free heme was likely because of very low plasma concentrations of hemopexin (SS: 0.17 ± 0.06 mg/ml, AS: 0.71 ± 0.14 mg/ml, p=0.002, n=8). We found a 10-fold higher concentration of heme oxygenase-1 (HO-1) in the plasma of SS mice, compared to AS mice (p=0.006, n=12), however, this enhanced capacity to degrade circulating heme, failed to protect the SS mice. This study demonstrates that acute elevation of plasma hemin triggers ACS in SCD mice. Infusion of hemopexin may prevent ACS during episodes of hemolytic crises in SCD. Disclosures: Ofori-Acquah: Emory University : Patents & Royalties.

scholarly journals Phospholipase A2 levels in acute chest syndrome of sickle cell disease

Blood ◽  
1996 ◽  
Vol 87 (6) ◽  
pp. 2573-2578 ◽  
Author(s):  
LA Styles ◽  
CG Schalkwijk ◽  
AJ Aarsman ◽  
EP Vichinsky ◽  
BH Lubin ◽  
...  
Keyword(s):  
Steady State ◽  
Sickle Cell Disease ◽  
Phospholipase A2 ◽  
Sickle Cell ◽  
Fat Embolism ◽  
Clinical Severity ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Marrow Fat ◽  
Embolism Syndrome

Acute chest syndrome (ACS) is associated with significant morbidity and is the leading cause of death in patients with sickle cell disease (SCD). Recent reports suggest that bone marrow fat embolism can be detected in many cases of severe ACS. Secretory phospholipase A2 (sPLA2) is an important inflammatory mediator and liberates free fatty acids, which are felt to be responsible for the acute lung injury of the fat embolism syndrome. We measured SPLA2 levels in 35 SCD patients during 20 admissions for ACS, 10 admissions for vaso-occlusive crisis, and during 12 clinic visits when patients were at the steady state. Eleven non-SCD patients with pneumonia were also evaluated. To determine if there was a relationship between sPLA2 and the severity of ACS we correlated SPLA2 levels with the clinical course of the patient. In comparison with normal controls (mean = 3.1 +/- 1.1 ng/mL), the non- SCD patients with pneumonia (mean = 68.6 +/- 82.9 ng/mL) and all three SCD patient groups had an elevation of SPLA2 (steady state mean = 10.0 +/- 8.4 ng/mL; vaso-occlusive crisis mean = 23.7 +/- 40.5 ng/mL; ACS mean = 336 +/- 209 ng/mL). In patients with ACS sPLA2 levels were 100- fold greater than normal control values, 35 times greater than values in SCD patients at baseline, and five times greater than non-SCD patients with pneumonia. The degree of SPLA2 elevation in ACS correlated with three different measures of clinical severity and, in patients followed sequentially, the rise in SPLA2 coincided with the onset of ACS. The dramatic elevation of SPLA2 in patients with ACS but not in patients with vaso-occlusive crisis or non-SCD patients with pneumonia and the correlation between levels of SPLA2 and clinical severity suggest a role for SPLA2 in the diagnosis and, perhaps, in the pathophysiology of patients with ACS.

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