Lillian McMahon

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.

A randomized phase II trial of Arginine Butyrate with standard local therapy in refractory sickle cell leg ulcers

Sickle cell leg ulcers are often debilitating, refractory to healing, and prone to recurrence. Healing of leg ulcers was incidentally observed during dose‐ranging trials of Arginine Butyrate in beta haemoglobinopathies. Here, a controlled Phase II trial was performed in sickle cell patients who had lower extremity ulcers refractory to standard care for at least 6 months. Patients were randomized to receive standard local care alone (Control Arm) or standard care with Arginine Butyrate administered 5 d/week (Treatment Arm), for 12 weeks. Ulcers were photographed weekly, traced, and ulcer areas were calculated by computerized planimetry and compared between the two study arms. Twenty‐seven study courses were evaluated. Control Arm subjects had 25 ulcers with a mean area of 25·7 cm2 initially and 23·2 cm2 after 12 weeks; 2/25 (8%) healed completely. Treatment Arm subjects had 37 ulcers with a mean area of 50·6 cm2 initially and 28·3 cm2 at 12 weeks; 11/37 of these (30%) healed completely. After 3 months, proportions of ulcers which healed were 6/25 (24%) and 29/37 (78%), in the Control and Treatment Arms respectively (P < 0·001). These findings strongly suggest that Arginine Butyrate merits further evaluation for the treatment of refractory sickle cell leg ulcers in larger trials.

A potent oral P-selectin blocking agent improves microcirculatory blood flow and a marker of endothelial cell injury in patients with sickle cell disease.

Abnormal blood flow accounts for most of the clinical morbidity of sickle cell disease (SCD) [1,2]. Most notably, occlusion of flow in the microvasculature causes the acute pain crises [3] that are the commonest cause for patients with SCD to seek medical attention [4] and major determinants of their quality of life [5]. Based on evidence that endothelial P-selectin is central to the abnormal blood flow in SCD we provide results from four of our studies that are germane to microvascular blood flow in SCD. A proof-of-principle study established that doses of heparin lower than what are used for anticoagulation but sufficient to block P-selectin improved microvascular blood flow inpatients with SCD. An in vitro study showed that Pentosan Polysulfate Sodium (PPS) had greater P-selectin blocking activity than heparin. A Phase I clinical study demonstrated that a single oral dose of PPS increased microvascular blood flow in patients with SCD. A Phase II clinical study that was not completed documented that daily oral doses of PPS administered for 8 weeks lowered plasma levels of sVCAM-1 and tended to improve microvascular blood flow in patients with SCD. These data support the concept that P-selectin on the microvascular endothelium is critical to both acute vascular occlusion and chronically impaired microvascular blood flow in SCD. They also demonstrate that oral PPS is beneficial to microvascular sickle cell blood flow and has potential as an efficacious agent for long-term prophylactic therapy of SCD.

Refining the value of secretory phospholipase A2 as a predictor of acute chest syndrome in sickle cell disease: results of a feasibility study (PROACTIVE)

Acute chest syndrome (ACS) is defined as fever, respiratory symptoms and a new pulmonary infiltrate in an individual with sickle cell disease (SCD). Nearly half of ACS episodes occur in SCD patients already hospitalized, potentially permitting pre‐emptive therapy in high‐risk patients. Simple transfusion of red blood cells may abort ACS if given to patients hospitalized for pain who develop fever and elevated levels of secretory phospholipase A2 (sPLA2). In a feasibility study (PROACTIVE; ClinicalTrials.gov NCT00951808), patients hospitalized for pain who developed fever and elevated sPLA2 were eligible for randomization to transfusion or observation; all others were enrolled in an observational arm. Of 237 enrolled, only 10 were randomized; one of the four to receive transfusion had delayed treatment. Of 233 subjects receiving standard care, 22 developed ACS. A threshold level of sPLA2 ≥ 48 ng/ml gave optimal sensitivity (73%), specificity (71%) and accuracy (71%), but a positive predictive value of only 24%. The predictive value of sPLA2 was improved in adults and patients with chest or back pain, lower haemoglobin concentration and higher white blood cell counts, and in those receiving less than two‐thirds maintenance fluids. The hurdles identified in PROACTIVE should facilitate design of a larger, definitive, phase 3 randomized controlled trial.

Self-Reported Transition Readiness among Young Adults with Sickle Cell Disease

Background: A growing body of literature addresses the need for transition programs for young adults with sickle cell disease (SCD); however, studies assessing transition readiness are limited and there are few validated instruments to use. Objective: To conduct a pilot study to assess transition readiness of patients with SCD in our transition program and to evaluate a SCD-specific assessment tool that measures 5 knowledge skill sets (medical, educational/vocational, health benefits, social, and independent living), and 3 psychological assessments (feelings, stress, and self-efficacy). Results: Of the 47 SCD patients between the ages of 18 and 22 seen in our facility, 33 completed the assessment tool. The majority of patients reported good medical knowledge of SCD and said they were motivated to pursue a career despite the burden of living with the disease. We identified knowledge gaps in the area of independent living and health benefits skills sets. A majority of patients reported being worried that their SCD would prevent them from doing things in their life; however, few respondents said they were worried or anxious about their transition to adult care. Conclusions: Adolescents beginning a transition intervention program reported a high level of knowledge of their disease and demonstrated a positive attitude toward transition with good self-efficacy.

Sickle cell disease caused by heterozygosity for Hb S and novel LCR deletion: Report of two patients

The b-globin gene LCR is located approximately 6 kb upstream of the embryonic epsilon-globin gene, and is made up of five DNase I hypersensitive sites (HSs), HS 1-5. LCR plays a pivotal role in regulating the expression of downstream epsilon-, (G)gamma-, (A)gamma-, delta-, and beta-globin genes in cis [1]. Deletions removing the LCR and parts of the downstream beta-globin gene cluster in patients have been described [2]. These individuals present with a (gammadeltabeta)0-thalassemia carrier phenotype. We now report two patients with severe sickle cell disease who were compound heterozygous for Hb S mutation and novel LCR deletion. In one case, HS 1-3 were deleted; in the other, HS 1-5 were deleted. In both cases, the b-like globin genes in cis to the LCR deletions were intact. Genotypically, both patients appeared to have sickle cell trait. Coinherited with either LCR deletion, these individuals presented as sickle cell disease patients. The breakpoints of these LCR deletions were defined. These results affirm that HS 2 and 3 are primarily responsible for conferring erythroid specific high-level expression of cis-linked beta-like globin genes. Furthermore, LCR deletions might cause hemolytic disease of newborns.

A novel sickle hemoglobin: hemoglobin S-south end.

Sickle hemoglobin (Hb S; beta Glu6Val) is due to an A<T transversion in codon 6 of the beta-globin gene. Several Hb S variants have both the Hb S mutation plus another mutation in the same beta-globin gene. Some of these variant hemoglobins can lead to sickle cell disease even in the simple heterozygote. Moreover, some variant hemoglobins mimic Hb A, S, or C on one or several clinical laboratory diagnostic tools, thus making their correct identification potentially problematic. The authors report a novel Hb S variant hemoglobin, Hb S-South End (beta Glu6Val, GAG>GTG; beta Lys132Asn, AAA>AAC). When present alone, the beta Lys132Asn mutation has low oxygen affinity. Therefore, this mutation may enhance the polymerization of the Hb S variant. Furthermore, the variant hemoglobin mimics Hb A on high-pressure liquid chromatography, and its identity is not easily diagnosed. A succinct review of variant sickle hemoglobins is also presented.

Keeping it in the family: three relatives with HbSC disease and simultaneous acute pulmonary emboli.

A 30-year-old African American female (Patient #1) with Hemoglobin SC (HbSC) disease presented with a 1 week history of progressive left flank and lower extremity pain with diffuse myalgias. She had a history of multiple prior vasoocclusive episodes requiring simple and exchange transfusions. At the time of admission on physical examination, she was afebrile and hemodynamically stable with an oxygen saturation of 100% in ambient air. The only pertinent finding was mild diffuse abdominal tenderness. Laboratory studies are summarized in Table 1 and were significant for leukocytosis with a left shift, anemia worse than baseline, a depressed reticulocyte count, a normal bilirubin but a mild elevation in transaminases. Chest radiography was normal. HbSC disease is a compound heterozygous condition characterized by inheritance of one gene for ‘‘S’’ hemoglobin (Glu-Val substitution in the 6th position of the b-globin chain) and one gene for ‘‘C’’ hemoglobin (Glu-Lys substitution in the 6th position of the b-globin chain), with subsequent formation of similar levels of HbS and HbC within the erythrocyte. HbCC disease is a non-sickling disorder which results in a mild hemolytic anemia. The combination of HbS and HbC is much more clinically significant suggesting that HbS has major disease modifying effect. Population studies suggest that while patients with HbSC have less frequent complications occurring later in life than those with HbSS disease, when complications occur they can be equally severe. In contrast, there is generally milder anemia and hemolytic complications, including aplastic episodes and cholelithiasis are less severe compared to HbSS disease [1]. In our first patient, the presence of diffuse pain was suggestive of a vasoocclusive episode (VOE). There were no abnormalities on history, physical exam, or chest radiography suggestive of acute chest syndrome (ACS). In terms of anemia, this patient was noted to have approximately a 3.5 g decrease in Hb concentration with an inappropriately low reticulocyte response. This suggested a VOE complicated by an aplastic crisis. Patient #1 was admitted to the medical service and commenced on treatment for a vasoocclusive epsiode with intravenous fluids and analgesics. She was commenced on low molecular weight heparin (LMWH) for deep venous thrombosis (DVT) prophylaxis. A red blood cell transfusion was administered for treatment of symptomatic anemia. The next day, the 24-year-old brother of Patient #1 (Patient #2), was admitted to the medical service. He also had HbSC disease and lived in same household as Patient #1. He had a history of cough productive of green sputum, fever, chills, myalgia and lower back pain for one week prior to admission. On physical examination, he was afebrile and had an oxygen saturation of 100% in ambient air. The rest of his exam was unremarkable other than pain with limb and spine motion. Laboratory studies are summarized in Table 1 and were significant for a leukocytosis with a left shift, worse anemia from baseline, an abnormally reduced reticulocyte response and mild hyperbilirubinemia. Chest radiography was normal. He was treated with intravenous fluids, analgesics and was administered LMWH for DVT prophylaxis. One of the recognized complications of sickle cell disease (SCD) is a reticulocytopenic anemia, referred to as an aplastic crisis or episode. This condition can be associated with a decrease in any peripheral blood cell lines, but most commonly, there are decreased mature erythrocytes and reticulocytes, and this is referred to as transient red cell aplasia (TRCA) [2]. A number of infectious agents have been implicated as either being causative or temporally related to such an episode. The best detailed of these is Parvovirus B19 (HPV B19), the causative agent of fifth disease. This virus is the only member of the Parvoviridae family known to be pathogenic in humans, occurring worldwide endemically [3]. Most infections occur in children and young adults and are highly contagious. The association between parvovirus infection and hypoplastic episodes in sickle cell anemia was first identified in 1981, when sera from 600 children in a London hospital were analyzed for HPV B19. Six children were identified with either the presence of the B19 antigen or its acute phase antibody [4]. All six were originally from Jamaica, had SCD with worsening anemia and evidence of bone marrow erythroid hypoplasia [4]. Other viruses recognized to be associated with red cell aplasia, although not specifically in SCD, include Epstein Barr, mumps, hepatitis, and Human Herpes virus 6 [5,6].