Cage S. Johnson

Outcome of Sickle Cell Anemia: A 4-decade Observational Study of 1056 Patients

Abstract: Based on a prospective cohort study of 1056 patients with sickle cell anemia (Hb SS) initiated in 1959, we investigated the influence of calendar era, age, sex, and prior medical conditions on the subsequent development of irreversible organ damage and survival using the Cox regression model with time-dependent covariates adjusting for all prior occurrences. We studied 30 acute clinical events, and focused on 8 prototypic forms of irreversible organ damage. Childhood survival to age 20 years has improved from 79% for those born before 1975 to 89% for children born in or after 1975. Bone infarction was a significant risk factor for avascular necrosis (p = 0.01), and infantile dactylitis was a significant risk factor for stroke (p = 0.01). Prior hospitalized vaso-occlusive sickle crisis in adults was significantly associated with the increased rate of avascular necrosis (p < 0.001), leg ulcers (p < 0.001), sickle chronic lung disease (p < 0.001), renal failure (p < 0.005), and early death (p < 0.001). The diagnosis of clearly evident clinical conditions such as leg ulcer, osteonecrosis, and retinopathy predicted an increased likelihood of developing a more lethal form of organ damage and earlier death: 77% of patients with chronic lung disease, 75% of those with renal insufficiency, and 51% of those with stroke had a prior chronic condition. Of the 232 patients who died, 73% had 1 or more clinically recognized forms of irreversible organ damage. By the fifth decade, nearly one-half of the surviving patients (48%) had documented irreversible organ damage. End-stage renal disease (glomerulosclerosis), chronic pulmonary disease with pulmonary hypertension, retinopathy, and cerebral microinfarctions are manifestations of arterial and capillary microcirculation obstructive vasculopathy. The current study underscores the need for preventive therapy to ameliorate the progression of the sickle vasculopathy. Abbreviations: CVA = cerebral vascular accident.

Sickle Cell Chronic Lung Disease: Prior Morbidity and the Risk of Pulmonary Failure

Sickle cell chronic lung disease (SCLD) is a prime contributor to mortality in young adult patients with sickle cell disease, especially those with sickle cell anemia (SS). Both perfusion and diffusion defects have been demonstrated, with generalized pulmonary fibrosis and disabling restrictive lung failure. We report 28 cases (25 SS, 1 S beta(0) thalassemia, 1 S beta(+) thalassemia and 1 SO-Arab) which began during the second decade of life and which ended in death by the fourth decade, after an ordered progression to pulmonary failure and cor pulmonale. Myocardial hypoxia with multifocal fibrosis and segmental infarction occurred in more than one-third of the cases and sudden death was a frequent final event. We define 4 stages of SCLD, based on pulmonary function tests, chest roentgenograms, blood gases, and noninvasive cardiac studies; each stage is 2 or 3 years in length, until death ensues in Stage 4. Case-control analysis showed that the significant risk factors associated with SCLD are 1) the total number of acute chest syndrome events in an individual before the onset of SCLD, (p = 0.0001), 2) sickle cell crisis marked by chest pain (p = 0.03) and 3) aseptic necrosis (p = 0.005). Temporal clustering of acute chest syndrome episodes frequently heralds the onset of SCLD. The pulmonary arterial bed, which has low oxygen tension and low pressure in a slow-flow system, is ideally suited to facilitate the polymerization of sickle hemoglobin, causing endothelial damage and culminating in an obstructive arteriolar vasculopathy. Identification of the significant risk factors predictive of SCLD can lead to early diagnosis of the disease; this is the only hope for effective intervention therapy.

Definitions of the phenotypic manifestations of sickle cell disease

Sickle cell disease (SCD) is a pleiotropic genetic disorder of hemoglobin that has profound multiorgan effects. The low prevalence of SCD (∼100,000/US) has limited progress in clinical, basic, and translational research. Lack of a large, readily accessible population for clinical studies has contributed to the absence of standard definitions and diagnostic criteria for the numerous complications of SCD and inadequate understanding of SCD pathophysiology. In 2005, the Comprehensive Sickle Cell Centers initiated a project to establish consensus definitions of the most frequently occurring complications. A group of clinicians and scientists with extensive expertise in research and treatment of SCD gathered to identify and categorize the most common complications. From this group, a formal writing team was formed that further reviewed the literature, sought specialist input, and produced definitions in a standard format. This article provides an overview of the process and describes 12 body system categories and the most prevalent or severe complications within these categories. A detailed Appendix provides standardized definitions for all complications identified within each system. This report proposes use of these definitions for studies of SCD complications, so future studies can be comparably robust and treatment efficacy measured. Use of these definitions will support greater accuracy in genotype–phenotype studies, thereby achieving a better understanding of SCD pathophysiology. This should nevertheless be viewed as a dynamic rather than final document; phenotype descriptions should be reevaluated and revised periodically to provide the most current standard definitions as etiologic factors are better understood, and new diagnostic options are developed. Am. J. Hematol. 2010.

Neuropsychological dysfunction and neuroimaging abnormalities in neurologically intact adults with sickle cell anemia

CONTEXT Sickle cell anemia (SCA) is a chronic illness causing progressive deterioration in quality of life. Brain dysfunction may be the most important and least studied problem affecting individuals with this disease. OBJECTIVE To measure neurocognitive dysfunction in neurologically asymptomatic adults with SCA vs healthy control individuals. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study comparing neuropsychological function and neuroimaging findings in neurologically asymptomatic adults with SCA and controls from 12 SCA centers, conducted between December 2004 and May 2008. Participants were patients with SCA (hemoglobin [Hb] SS and hemoglobin level < or = 10 mg/dL) aged 19 to 55 years and of African descent (n = 149) or community controls (Hb AA and normal hemoglobin level) (n = 47). Participants were stratified on age, sex, and education. MAIN OUTCOME MEASURES The primary outcome measure was nonverbal function assessed by the Wechsler Adult Intelligence Scale, third edition (WAIS-III) Performance IQ Index. Secondary exploratory outcomes included performance on neurocognitive tests of executive function, memory, attention, and language and magnetic resonance imaging measurement of total intracranial and hippocampal volume, cortical gray and white matter, and lacunae. RESULTS The mean WAIS-III Performance IQ score of patients with SCA was significantly lower than that of controls (adjusted mean, 86.69 for patients with SCA vs 95.19 for controls [mean difference, -5.50; 95% confidence interval {CI}, -9.55 to -1.44]; P = .008), with 33% performing more than 1 SD (<85) below the population mean. Among secondary measures, differences were observed in adjusted mean values for global cognitive function (full-scale IQ) (90.47 for patients with SCA vs 95.66 for controls [mean difference, -5.19; 95% CI, -9.24 to -1.13]; P = .01), working memory (90.75 vs 95.25 [mean difference, -4.50; 95% CI, -8.55 to -0.45]; P = .03), processing speed (86.50 vs 97.95 [mean difference, -11.46; 95% CI, -15.51 to -7.40]; P < .001), and measures of executive function. Anemia was associated with poorer neurocognitive function in older patients. No differences in total gray matter or hippocampal volume were observed. Lacunae were more frequent in patients with SCA but not independently related to neurocognitive function. CONCLUSION Compared with healthy controls, adults with SCA had poorer cognitive performance, which was associated with anemia and age.

Failure of Methylene Blue Treatment in Toxic Methemoglobinemia: Association with Glucose-6-Phosphate Dehydrogenase Deficiency

Abstract A patient who ingested an aniline-containing material developed severe methemoglobinemia. The usual beneficial response from administering methylene blue was not obtained, and within 24 ho...

Liver involvement in sickle cell disease.

In an effort to clarify the features of hepatic dysfunction in sickle cell disease, we obtained serial tests of liver function in 100 consecutive patients with sickle cell anemia and in 30 consecutive patients with hemoglobinopathy SC during a five-year period. There were 32 patients with chronic abnormalities in tests of liver function. These abnormal tests were explained by a variety of lesions in 30 cases, and the liver disease remained unexplained in only 2 patients who declined liver biopsy. The diagnoses in these 30 patients included hepatitis, chronic passive congestion, common duct obstruction, alcoholic liver disease, pregnancy, collagen-vascular disease, and sarcoidosis. Evidence for hepatitis B infection was present in 19 of those with sickle cell anemia and in 6 of those with hemoglobinopathy SC. The bilirubin levels in sickle cell anemia appeared to have a trimodal distribution, with six patients exhibiting markedly elevated levels of indirect bilirubin suggesting a difference in bilirubin metabolism. There was no evidence of liver disease in 72 patients with sickle cell anemia, nor in 24 patients with hemoglobinopathy SC, as these patients exhibited only mild elevation of their serum indirect bilirubin levels owing to chronic hemolysis. Intrasinusoidal sickling and Kupffer cell erythrophagocytosis were nearly universal findings at liver biopsy, irrespective of the clinical disorder, and were not related to the degree of liver test abnormalities. Liver and biliary tract dysfunction in sickle cell disease have been attributed to anoxia secondary to sinusoidal obstruction by sickled erythrocytes and Kupffer cell erythrophagocytosis. However, some causes of liver disease in sickle cell patients can be explained by clinical disorders other than the hemoglobinopathy alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathological spectrum of liver diseases in sickle cell disease

Most pathologic studies of liver disease in sickle cell anemia and its variants were performed retrospectively on autopsy specimens, and, because of the prominent histologic features of intrasinusoidal sickling and Kupffer cell erythrophagocytosis, hepatic dysfunction was attributed to the intrahepatic sickling of erythrocytes in this hemoglobinopathy. We compared the liver histology from 19 patients who had liver biopsies to the autopsy specimens from 32 patients who succumbed to the complications of the hemoglobinopathy. In the former, nine patients had histological evidence of viral hepatitis. Four of these patients had both serological and immunohistochemical evidence of hepatitis B surface antigen. The features of biliary tree obstruction were found in two cases and alcoholic cirrhosis and sarcoid granuloma in one case each. Only one patient, who had recovered from septic shock, showed ischemic necrosis. In five patients incidentally biopsied during cholecystectomy, no significant lesions were found. Fourteen of the autopsy specimens showed ischemic necrosis, a result which was significantly different from the biopsy group. Ten cases had no significant morphologic changes other than heavy iron deposits. There were two cases with chronic active hepatitis, two with diffuse fibrosis, and one case each of cirrhosis, acute viral hepatitis, cholestasis, and giant cell hepatitis. Intrahepatic sickling and erythrophagocytosis were seen in almost all specimens and did not correlate with liver disease or transaminase elevation. Other than the patient with septic shock, ischemic necrosis was found only in postmortem material. These histological features may represent red cell destruction rather than the etiology of liver disease in these patients.

Rheologic behavior of sickle and normal red blood cell mixtures in sickle plasma: implications for transfusion therapy.

BACKGROUND:  Guidelines for transfusion in sickle cell disease usually define an upper hematocrit (Hct) limit of 0.30 to 0.35 to avoid blood hyperviscosity. In vitro viscosity studies of normal (AA) and sickle (SS) red blood cell (RBC) mixtures in buffer appear to confirm that this Hct limit is optimal for oxygen delivery to vascular beds as judged by the ratio of Hct to viscosity, with this ratio often termed “oxygen or RBC transport effectiveness.” In the absence of plasma, however, effects due to RBC‐RBC interactions mediated by plasma proteins cannot be assessed.

Multisystem damage associated with tricorporal priapism in sickle cell disease

PURPOSE Priapism is an uncommon but debilitating complication of sickle cell disease (SCD). Recent observations among adult males regarding the abysmal failure of medical and surgical therapy encouraged us to review our 25-year experience identifying the prognostic features that might determine outcome. PATIENTS AND METHODS As part of a prospective 25-year longitudinal demographic and clinical cohort study, a subset of 38 (8.2%) patients with priapism were identified among a cohort of 461 men with SCD. The patients with priapism were compared with the nonaffected men with respect to severity of disease expression, hematologic status, beta s globin gene haplotype, and the incidence of sickle-related major organ failure. The influence of the treatment modalities on outcome was also evaluated. RESULTS Priapism occurred as a single episode in 24 patients, and in 14 as temporally clustered repeat episodes. Eighty-seven percent of those with priapism had sickle cell anemia (SS), an increased risk as compared with other variants of SCD (p = < 0.05). There were two distinct age-related patterns of disease expression. Eight patients were prepubertal; they experienced shorter episodes, involvement of the corpora cavernosa only, few recurrent episodes, and a good prognosis for future erectile function. Non-surgical therapy in children was associated with excellent results. In contrast, the 29 postpubertal adults often had involvement of the corpora cavernosa and corpus spongiosa (tricorporal disease) and half had prolonged episodes that lasted longer than 8 days. One pubescent patient had repeated episodes and became impotent. Prolonged or repeated episodes eventuated in impotence in 56%. Surgical intervention was not beneficial. Sickle cell-related organ failure such as stroke, chronic restrictive lung disease, chronic renal failure, and nonhealing leg ulcers was observed more frequently in men who had priapism. Death occurred in nine adult patients (25%) within 5 years of the first episode of priapism. CONCLUSION Priapism in adult males identifies those at high risk for other sickle cell-related organ failure syndromes and, as such, is another complication indicative of severe disease. The dismal prognosis in SS adults requires better understanding of the precise pathophysiology of low-flow tricorporal priapism. Clarification of the mechanisms inducing the priapic state should lead to specific therapeutic maneuvers and an improved prognosis for this disabling condition.

Cobalt chloride-induced signaling in endothelium leading to the augmented adherence of sickle red blood cells and transendothelial migration of monocyte-like HL-60 cells is blocked by PAF-receptor antagonist

In response to hypoxia, sickle red blood cells (SS RBC) and leukocytes exhibit increased adherence to the vascular endothelium, while diapedesis of leukocytes through the blood vessel increases. However, the cellular signaling pathway(s) caused by hypoxia is poorly understood. We utilized CoCl2 as a mimetic molecule for hypoxia to study cellular signaling pathways. We found that in human umbilical vein endothelial cells (HUVEC), CoCl2 at 2 mM concentration induced the surface expression of a subset of CAMs (VCAM‐1) and activation of transcription factor NF‐kB in the nuclear extracts of HUVEC. Furthermore, CoCl2 also caused time‐dependent tyrosine phosphorylation of mitogen‐activated protein (MAP) kinase isoform ERK2 without significantly affecting ERK1, indicating ERK2 is the preferred substrate for upstream kinase of the MAPK pathway. Inhibitors of MAP kinase (PD98059) or platelet‐activating factor (PAF)– receptor antagonist (CV3988) inhibited the CoCl2‐induced NF‐kB activation and VCAM‐1 expression. Augmented expression of VCAM‐1 led to increased SS RBC adhesion, inhibitable by a VCAM‐1 antibody. Additionally, CoCl2 caused a two‐ to threefold increase in the rate of transendothelial migration of monocyte‐like HL‐60 cells and a twentyfold increase in phosphorylation of platelet endothelial cell adhesion molecules (PECAM‐1). The transendothelial migration of monocytes was inhibited by an antibody to PECAM‐1. Both phosphorylation of PECAM‐1 and transendothelial migration of monocytes in response to CoCl2 were inhibited by protein kinase inhibitor (GF109203X) and augmented by protein phosphatase inhibitor (Calyculin A). Our data suggests that CoCl2‐induced cellular signals directing increased expression of VCAM‐1 in HUVEC involve downstream activation of MAP kinase and NF‐kB, while the phosphorylation of PECAM‐1 occurs as a result of activation of PKC. We conclude that PAF‐receptor antagonist inhibits the CoCl2‐ or hypoxia‐induced increase in the adhesion of SS RBC, PECAM‐1 phosphorylation, and the concomitant transendothelial migration of monocytes. J. Cell. Physiol. 179:67–78, 1999.