Biomedical subjects

L A Styles

Publications and source records attributed to L A Styles.

8 recordsLinked to original sources

PubMed1998

Whole blood tissue factor procoagulant activity is elevated in patients with sickle cell disease.

We developed a simple assay for the measurement of tissue factor procoagulant activity (TF PCA) in whole blood samples that avoids the need for mononuclear cell isolation. This method combines convenience of sample collection and processing with a high degree of sensitivity and specificity for TF. Using this method, we have determined that TF PCA is detectable in whole blood samples from normal individuals, which is itself a novel observation. Essentially all PCA could be shown to be localized in the mononuclear cell fraction of blood. Compared with controls, whole blood TF levels were significantly (P < .000001) elevated in patients with sickle cell disease (SCD), regardless of the subtype of hemoglobinopathy (SS or SC disease). No significant difference in TF PCA was observed between patients in pain crisis compared with those in steady-state disease. Because TF functions as cofactor in the proteolytic conversion of FVII to FVIIa in vitro, it was expected that an increase in circulating TF PCA would lead to an increased in vivo generation of FVIIa. On the contrary, FVIIa levels were actually decreased in the plasma of patients with SCD. Plasma TF pathway inhibitor (TFPI) antigen levels were normal in SCD patients, suggesting that accelerated clearance of FVIIa by the TFPI pathway was not responsible for the reduced FVIIa levels. We propose that elevated levels of circulating TF PCA may play an important role in triggering the activation of coagulation known to occur in patients with SCD. Because TF is the principal cellular ligand for FVIIa, it is possible that increased binding to TF accounts for the diminished plasma FVIIa levels.

Adolescent↗

PubMed1997

Decrease of very late activation antigen-4 and CD36 on reticulocytes in sickle cell patients treated with hydroxyurea.

Sickle cell disease (SCD) is characterized by repeated vaso-occlusive events, which result in substantial morbidity. Abnormal adhesion of sickle red blood cells (RBC) to the vascular endothelium is postulated to play a role in the pathogenesis of vaso-occlusion. Two adhesion receptors, very late activation antigen-4 (VLA-4) and CD36, are found in unusually high numbers on sickle cell reticulocytes and do mediate adhesion of sickle RBC to endothelium. Hydroxyurea (HU) therapy results in fewer vaso-occlusive episodes, and we postulated that HU-related modulation of VLA-4 and CD36 receptors may contribute to its clinical benefit. Using flow cytometry, eight patients were followed from the onset of HU treatment through a mean treatment length of 200 +/- 49 days. Mean corpuscular volume and percent fetal hemoglobin (Hb F) increased from 87% +/- 6% to 98% +/- 9% and 6.6% +/- 3.9% to 12.7% +/- 5.6%, respectively. The percentage of reticulocytes expressing VLA-4 decreased from 29.0% +/- 5.9% to 14.9% +/- 2.3% (P = .0003). Two thirds of the total decrease in VLA-4 expression occurred after 10 weeks of HU and plateaued by 20 weeks. Changes in VLA-4 expression occurred before substantial increases in Hb F. The percentage of reticulocytes expressing CD36 decreased from 55.3% +/- 6.4% to 42.6% (P = .0046). Changes in adhesion receptor expression were not caused by a decrease in reticulocytosis with HU therapy. This report is the first to associate a decrease in adhesion receptor expression with a therapy known to reduce the clinical severity of SCD.

Adolescent↗

PubMed1997

Acute chest syndrome in sickle cell disease: clinical presentation and course. Cooperative Study of Sickle Cell Disease.

Acute chest syndrome (ACS) is an important cause of morbidity and mortality in sickle cell disease (SCD). Previous studies reported conflicting pictures of ACS making therapeutic interventions difficult. The Cooperative Study of Sickle Cell Disease prospectively followed 3,751 patients enrolled from birth to 66 years of age for ACS. Data on presenting signs and symptoms, laboratory findings, and hospital course were collected. There were 1,722 ACS episodes in 939 patients. Young children (age 2 to 4 years) presented with fever and cough, a negative physical exam, and rarely had pain. Adults were often afebrile and complained of shortness of breath, chills, and severe pain. Upper lobe disease was more common in children; multilobe and lower lobe disease affected adults more often. Severe hypoxia occurred in 18% of adults tested and could not be predicted by examination or laboratory findings. Bacteremia was documented in 3.5% of episodes, but was strongly influenced by age (14% of infants and 1.8% of patients > 10 years). ACS was most common in winter with children having the most striking increase. Transfusion was used less frequently, but earlier in children. Young children were hospitalized for 5.4 days versus 9 days for adults. Fifty percent of adults had a pain event in the 2 weeks preceding ACS and children were more likely to have febrile events. The death rate was four times higher in adults than in children. Fatal cases generally developed rapid pulmonary failure and one third were associated with bacteremia. Age has a striking effect on the clinical picture of ACS. In children, ACS was milder and more likely due to infection, whereas in adults ACS was severe, associated with pain and had a higher mortality rate.

Adolescent↗

PubMed1997

New therapies and approaches to transfusion in sickle cell disease in children.

Until recently, transfusion was the only effective therapy for children with sickle cell disease (SCD). Although transfusion can be used to prevent or treat many of the complications of SCD, it has often been used indiscriminantly and with considerable risk to the patient. Recent studies attempted to define those clinical situations in which transfusion is effective as well as to optimize its delivery while minimizing complications. Other therapies are emerging, and in the future many will likely play an important role in the treatment of children with SCD. These therapies include pharmacologic interventions, such as hydroxyurea; bone marrow and cord blood transplantation; and improvements in supportive and preventive care. The future for new therapies looks promising, but the appropriate role for many of these therapeutic interventions remains to be determined.

Anemia, Sickle Cell↗

PubMed1996

Phospholipase A2 levels in acute chest syndrome of sickle cell disease.

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.

Acute Disease↗

PubMed1996

Core decompression in avascular necrosis of the hip in sickle-cell disease.

Sickle-cell disease (SCD) is the most common cause of avascular necrosis (AVN) of the hip in childhood. It results in significant physical impairment and chronic pain, and often progresses to require hip replacement. Conservative therapy is ineffective. We evaluated whether core decompression can arrest progression of AVN. We performed 13 coring procedures in 10 patients with SCD and AVN. Patients ranged from age 9-21 years at diagnosis (mean, median age, 15 years); five hips were stage I, six hips were stage II, and two hips were stage III. Mean follow-up on these patients was 3.7 years. Efficacy of the procedure was evaluated by clinical improvement in pain, radiographic progression, and need for further surgery. All 5 stage I patients had substantial improvement in pain, and only one showed X-ray progression. Five of the 6 (83%) stage II patients had improvement in pain, and 2 patients progressed on X-ray. Both stage III patients progressed on X-ray, but one was clinically improved. None of the 10 patients has required further surgery. Our results demonstrate that in early AVN, core decompression was beneficial for almost all patients, even with progression on X-ray. Core decompression should be considered in the management of SCD patients with early AVN.

Adolescent↗

PubMed1996

Ototoxicity in hemoglobinopathy patients chelated with desferrioxamine.

PURPOSE: Ototoxicity often limits the dose of desferrioxamine (DFO) tolerated by patients who are transfusion dependent. Current recommendations advise doses of < 50 mg/kg/day after early reports noted higher rates of oxotoxicity with increasing doses. There have been no follow-up studies to determine the effect of this recommendation on oxotoxicity and iron overload. METHODS: We followed 28 patients who were chronically chelated with serial audiograms over a 5-year period. Patients with and without oxotoxicity were compared with respect to age, disease, DFO dose, peak DFO dose, length of DFO therapy, ferritin, and therapeutic index. RESULTS: Eight of the 28 patients (29%) had an abnormal audiogram during threshold testing. Two patients had two separate episodes with hearing deficit. Nine of the 10 episodes were high-frequency losses, with seven being moderate and three mild. All deficits were rapidly reversible with DFO dose reduction. No significant differences were found between the affected and unaffected groups with respect to age, DFO dose or duration, ferritin, or therapeutic index. Numbers of affected patients were small, but patients with SCD differed from patients with thalassemia in that they developed ototoxicity earlier and with lower doses of DFO and lower therapeutic indexes. CONCLUSIONS: Despite DFO doses usually felt to be low risk for ototoxicity, we found a high rate of ototoxicity in our patients who we've chronically chelated. No variables were identified that reliably predicted ototoxicity. We stress the need for regular audiological exams and feel no dose of DFO is "safe" from the development of ototoxicity.

Adolescent↗

PubMed1994

Effects of a long-term transfusion regimen on sickle cell-related illnesses.

The efficacy of a long-term transfusion regimen in preventing sickle cell disease complications is unknown. We examined 17 patients before, during, and after transfusion for cerebral vascular accident and vaso-occlusive crisis. Total hospitalization rate, as well as admissions for vaso-occlusive crisis, cases of acute chest syndrome, and bacterial infections decreased while patients were on a transfusion regimen.

Adolescent↗