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1.
Complement Ther Med ; 49: 102334, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32147052

RESUMO

Pain and vaso-occlusive crises (VOC) are hallmark complications of sickle cell disease (SCD) and result in significant physical and psychosocial impairment. The variability in SCD pain frequency and triggers for the transition from steady state to VOC are not well understood. This paper summarizes the harmful physiological effects of pain and emotional stressors on autonomically-mediated vascular function in individuals with SCD and the effects of a cognitive, neuromodulatory intervention (i.e. hypnosis) on microvascular blood flow. We reviewed recent studies from the authors' vascular physiology laboratory that assessed microvascular responses to laboratory stressors in individuals with SCD. Results indicate that participants with SCD exhibit marked neurally mediated vascular reactivity in response to pain, pain-related fear, and mental stress. Further, pilot study results show that engagement in hypnosis may attenuate harmful microvascular responses to pain. The collective results demonstrate that autonomically-mediated vascular responses to pain and mental stress represent an important SCD intervention target. This ongoing work provides physiological justification for the inclusion of cognitive, neuromodulatory and complementary treatments in SCD disease management and may inform the development of targeted, integrative interventions that prevent the enhancement of autonomic vascular dysfunction in SCD.

4.
Haematologica ; 105(1): 83-90, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30975906

RESUMO

Vaso-occlusive crisis (VOC) is a hallmark of sickle cell disease (SCD) and occurs when deoxygenated sickled red blood cells occlude the microvasculature. Any stimulus, such as mental stress, which decreases microvascular blood flow will increase the likelihood of red cell entrapment resulting in local vaso-occlusion and progression to VOC. Neurally mediated vasoconstriction might be the physiological link between crisis triggers and vaso-occlusion. In this study, we determined the effect of mental stress on microvascular blood flow and autonomic nervous system reactivity. Sickle cell patients and controls performed mentally stressful tasks, including a memory task, conflict test and pain anticipation test. Blood flow was measured using photoplethysmography, autonomic reactivity was derived from electrocardiography and perceived stress was measured by the State-Trait Anxiety Inventory questionnaire. Stress tasks induced a significant decrease in microvascular blood flow, parasympathetic withdrawal and sympathetic activation in all subjects. Of the various tests, pain anticipation caused the highest degree of vasoconstriction. The magnitude of vasoconstriction, sympathetic activation and perceived stress was greater during the Stroop conflict test than during the N-back memory test, indicating the relationship between magnitude of experimental stress and degree of regional vasoconstriction. Baseline anxiety had a significant effect on the vasoconstrictive response in sickle cell subjects but not in controls. In conclusion, mental stress caused vasoconstriction and autonomic nervous system reactivity in all subjects. Although the pattern of responses was not significantly different between the two groups, the consequences of vasoconstriction can be quite significant in SCD because of the resultant entrapment of sickle cells in the microvasculature. This suggests that mental stress can precipitate a VOC in SCD by causing neural-mediated vasoconstriction.

5.
Hematology Am Soc Hematol Educ Program ; 2019(1): 337-344, 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31808901

RESUMO

Before the advent of effective iron chelation, death from iron-induced cardiomyopathy occurred in the second decade in patients with transfusion-dependent chronic anemias. The advances in our understanding of iron metabolism; the ability to monitor iron loading in the liver, heart, pancreas and pituitary; and the availability of several effective iron chelators have dramatically improved survival and reduced morbidity from transfusion-related iron overload. Nevertheless, significantly increased survival brings about new complications such as malignant transformation resulting from prolonged exposure to iron, which need to be considered when developing long-term therapeutic strategies. This review discusses the current biology of iron homeostasis and its close relation to marrow activity in patients with transfusion-dependent anemias, and how biology informs clinical approach to treatment.

6.
J Clin Med ; 8(10)2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31618931

RESUMO

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by polymerization of hemoglobin S upon deoxygenation that results in the formation of rigid sickled-shaped red blood cells that can occlude the microvasculature, which leads to sudden onsets of pain. The severity of vaso-occlusive crises (VOC) is quite variable among patients, which is not fully explained by their genetic and biological profiles. The mechanism that initiates the transition from steady state to VOC remains unknown, as is the role of clinically reported triggers such as stress, cold and pain. The rate of hemoglobin S polymerization after deoxygenation is an important determinant of vaso-occlusion. Similarly, the microvascular blood flow rate plays a critical role as fast-moving red blood cells are better able to escape the microvasculature before polymerization of deoxy-hemoglobin S causes the red cells to become rigid and lodge in small vessels. The role of the autonomic nervous system (ANS) activity in VOC initiation and propagation has been underestimated considering that the ANS is the major regulator of microvascular blood flow and that most triggers of VOC can alter the autonomic balance. Here, we will briefly review the evidence supporting the presence of ANS dysfunction in SCD, its implications in the onset of VOC, and how differences in autonomic vasoreactivity might potentially contribute to variability in VOC severity.

7.
Ann Am Thorac Soc ; 16(9): e17-e32, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31469310

RESUMO

Background: Pulmonary complications of sickle cell disease (SCD) are diverse and encompass acute and chronic disease. The understanding of the natural history of pulmonary complications of SCD is limited, no specific therapies exist, and these complications are a primary cause of morbidity and mortality.Methods: We gathered a multidisciplinary group of pediatric and adult hematologists, pulmonologists, and emergency medicine physicians with expertise in SCD-related lung disease along with an SCD patient advocate for an American Thoracic Society-sponsored workshop to review the literature and identify key unanswered clinical and research questions. Participants were divided into four subcommittees on the basis of expertise: 1) acute chest syndrome, 2) lower airways disease and pulmonary function, 3) sleep-disordered breathing and hypoxia, and 4) pulmonary vascular complications of SCD. Before the workshop, a comprehensive literature review of each subtopic was conducted. Clinically important questions were developed after literature review and were finalized by group discussion and consensus.Results: Current knowledge is based on small, predominantly observational studies, few multicenter longitudinal studies, and even fewer high-quality interventional trials specifically targeting the pulmonary complications of SCD. Each subcommittee identified the three or four most important unanswered questions in their topic area for researchers to direct the next steps of clinical investigation.Conclusions: Important and clinically relevant questions regarding sickle cell lung disease remain unanswered. High-quality, multicenter, longitudinal studies and randomized clinical trials designed and implemented by teams of multidisciplinary clinician-investigators are needed to improve the care of individuals with SCD.

8.
J Clin Med ; 8(8)2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31382365

RESUMO

Adult sickle cell disease (SCD) patients frequently transition from pediatric hematology to adult primary care. We examined healthcare utilization for adult patients with SCD with shared care between hematologists and primary care providers (PCP). We analyzed the OneFlorida Data Trust, a centralized data repository of electronic medical record (EMR) data from eight different health systems in Florida. The number of included adults with SCD was 1147. We examined frequent hospitalizations and emergency department (ED) visits by whether the patient had shared care or single specialty care alone. Most patients were seen by a PCP only (30.4%), followed by both PCP and hematologist (27.5%), neither PCP nor hematologist (23.3%), and hematologist only (18.7%). For patients with shared care versus single specialist care other than hematologist, the shared care group had a lower likelihood of frequent hospitalizations (OR 0.63; 95% CI 0.43-0.90). Similarly, when compared to care from a hematologist only, the shared care group had a lower likelihood of frequent hospitalizations (OR 0.67; 95% CI 0.47-0.95). There was no significant relationship between shared care and ED use. When patients with SCD have both a PCP and hematologist involved in their care there is a benefit in decreased hospitalizations.

9.
Free Radic Biol Med ; 141: 408-415, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31279092

RESUMO

Sickle cell disease (SCD) is a monogenetic disease that results in the formation of hemoglobin S. Due to more rapid oxidation of hemoglobin S due to intracellular heme and adventitious iron in SCD, it has been thought that an inherent property of SCD red cells would be an imbalance in antioxidant defenses and oxidant production. Less deformable and fragile RBC in SCD results in intravascular hemolysis and release of free hemoglobin (PFHb) in the plasma, which might be expected to produce oxidative stress in the plasma. Thus, we aimed to characterize intracellular and vascular oxidative stress in whole blood and plasma samples from adult SCD patients and controls recruited into a large study of SCD at Children's Hospital of Los Angeles. We evaluated the cellular content of metHb and several components of the antioxidant system in RBC as well as oxidation of GSH and Prx-2 oxidation in RBC after challenge with hydroperoxides. Plasma markers included PFHb, low molecular weight protein bound heme (freed heme), hemopexin, isoprostanes, and protein carbonyls. While GSH was slightly lower in SCD RBC, protein carbonyls, NADH, NAD+ and total NADP+ + NADPH were not different. Furthermore, GSH or Prx-2 oxidation was not different after oxidative challenge in SCD vs. Control. Elevated freed heme and PFHb had a significant negative, non-linear association with hemopexin. There appeared to be a threshold effect for hemopexin (200 µg/ml), under which the freed heme rose acutely. Plasma F2-isoprostanes were not significantly elevated in SCD. Despite significant release of Hb and elevation of freed heme in SCD when hemopexin was apparently saturated, there was no clear indication of uncompensated vascular oxidative stress. This somewhat surprising result, suggests that oxidative stress is well compensated in RBCs and plasma during a period of relative health.

10.
Am J Hematol ; 94(10): 1055-1065, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31259431

RESUMO

Severe chronic anemia is an independent predictor of overt stroke, white matter damage, and cognitive dysfunction in the elderly. Severe anemia also predisposes to white matter strokes in young children, independent of the anemia subtype. We previously demonstrated symmetrically decreased white matter (WM) volumes in patients with sickle cell disease (SCD). In the current study, we investigated whether patients with non-sickle anemia also have lower WM volumes and cognitive dysfunction. Magnetic Resonance Imaging was performed on 52 clinically asymptomatic SCD patients (age = 21.4 ± 7.7; F = 27, M = 25; hemoglobin = 9.6 ± 1.6 g/dL), 26 non-sickle anemic patients (age = 23.9 ± 7.9; F = 14, M = 12; hemoglobin = 10.8 ± 2.5 g/dL) and 40 control subjects (age = 27.7 ± 11.3; F = 28, M = 12; hemoglobin = 13.4 ± 1.3 g/dL). Voxel-wise changes in WM brain volumes were compared to hemoglobin levels to identify brain regions that are vulnerable to anemia. White matter volume was diffusely lower in deep, watershed areas proportionally to anemia severity. After controlling for age, sex, and hemoglobin level, brain volumes were independent of disease. WM volume loss was associated with lower Full Scale Intelligence Quotient (FSIQ; P = .0048; r2 = .18) and an abnormal burden of silent cerebral infarctions (P = .029) in males, but not in females. Hemoglobin count and cognitive measures were similar between subjects with and without white-matter hyperintensities. The spatial distribution of volume loss suggests chronic hypoxic cerebrovascular injury, despite compensatory hyperemia. Neurocognitive consequences of WM volume changes and silent cerebral infarction were strongly sexually dimorphic. Understanding the possible neurological consequences of chronic anemia may help inform our current clinical practices.

11.
Front Physiol ; 10: 381, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31031633

RESUMO

In sickle cell disease (SCD), prolonged capillary transit times, resulting from reduced peripheral blood flow, increase the likelihood of rigid red cells entrapment in the microvasculature, predisposing to vaso-occlusive crisis. Since changes in peripheral flow are mediated by the autonomic nervous system (ANS), we tested the hypothesis that the cardiac and peripheral vascular responses to head-up tilt (HUT) are abnormal in SCD. Heart rate, respiration, non-invasive continuous blood pressure and finger photoplethysmogram (PPG) were monitored before, during, and after HUT in SCD, anemic controls and healthy subjects. Percent increase in heart rate from baseline was used to quantify cardiac ANS response, while percent decrease in PPG amplitude represented degree of peripheral vasoconstriction. After employing cluster analysis to determine threshold levels, the HUT responses were classified into four phenotypes: (CP) increased heart rate and peripheral vasoconstriction; (C) increased heart rate only; (P) peripheral vasoconstriction only; and (ST) subthreshold cardiac and peripheral vascular responses. Multinomial logistic regression (MLR) was used to relate these phenotypic responses to various parameters representing blood properties and baseline cardiovascular activity. The most common phenotypic response, CP, was found in 82% of non-SCD subjects, including those with chronic anemia. In contrast, 70% of SCD subjects responded abnormally to HUT: C-phenotype = 22%, P-phenotype = 37%, or ST-phenotype = 11%. MLR revealed that the HUT phenotypes were significantly associated with baseline cardiac parasympathetic activity, baseline peripheral vascular variability, hemoglobin level and SCD diagnosis. Low parasympathetic activity at baseline dramatically increased the probability of belonging to the P-phenotype in SCD subjects, even after adjusting for hemoglobin level, suggesting a characteristic autonomic dysfunction that is independent of anemia. Further analysis using a mathematical model of heart rate variability revealed that the low parasympathetic activity in P-phenotype SCD subjects was due to impaired respiratory-cardiac coupling rather than reduced cardiac baroreflex sensitivity. By having strong peripheral vasoconstriction without compensatory cardiac responses, P-phenotype subjects may be at increased risk for vaso-occlusive crisis. The classification of autonomic phenotypes based on HUT response may have potential use for guiding therapeutic interventions to alleviate the risk of adverse outcomes in SCD.

12.
Haematologica ; 104(10): 1974-1983, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30948484

RESUMO

Quality of response to immunosuppressive therapy and long-term outcomes for pediatric severe aplastic anemia remain incompletely characterized. Contemporary evidence to inform treatment of relapsed or refractory severe aplastic anemia for pediatric patients is also limited. The clinical features and outcomes for 314 children treated from 2002 to 2014 with immunosuppressive therapy for acquired severe aplastic anemia were analyzed retrospectively from 25 institutions in the North American Pediatric Aplastic Anemia Consortium. The majority of subjects (n=264) received horse anti-thymocyte globulin (hATG) plus cyclosporine (CyA) with a median 61 months follow up. Following hATG/CyA, 71.2% (95%CI: 65.3,76.6) achieved an objective response. In contrast to adult studies, the quality of response achieved in pediatric patients was high, with 59.8% (95%CI: 53.7,65.8) complete response and 68.2% (95%CI: 62.2,73.8) achieving at least a very good partial response with a platelet count ≥50×109L. At five years post-hATG/CyA, overall survival was 93% (95%CI: 89,96), but event-free survival without subsequent treatment was only 64% (95%CI: 57,69) without a plateau. Twelve of 171 evaluable patients (7%) acquired clonal abnormalities after diagnosis after a median 25.2 months (range: 4.3-71 months) post treatment. Myelodysplastic syndrome or leukemia developed in 6 of 314 (1.9%). For relapsed/refractory disease, treatment with a hematopoietic stem cell transplant had a superior event-free survival compared to second immunosuppressive therapy treatment in a multivariate analysis (HR=0.19, 95%CI: 0.08,0.47; P=0.0003). This study highlights the need for improved therapies to achieve sustained high-quality remission for children with severe aplastic anemia.

13.
Am J Hematol ; 94(6): 678-688, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30916797

RESUMO

We have previously demonstrated that sickle cell disease (SCD) patients maintain normal global systemic and cerebral oxygen delivery by increasing cardiac output. However, ischemic end-organ injury remains common suggesting that tissue oxygen delivery may be impaired by microvascular dysregulation or damage. To test this hypothesis, we performed fingertip laser Doppler flowmetry measurements at the base of the nailbed and regional oxygen saturation (rSO2 ) on the dorsal surface of the same hand. This was done during flow mediated dilation (FMD) studies in 26 chronically transfused SCD, 75 non-transfused SCD, and 18 control subjects. Chronically transfused SCD patients were studied prior to and following a single transfusion and there was no acute change in rSO2 or perfusion. Laser Doppler estimates of resting perfusion were 76% higher in non-transfused and 110% higher in transfused SCD patients, compared to control subjects. In contrast, rSO2 was 12 saturation points lower in non-transfused SCD patients, but normal in the transfused SCD patients. During cuff occlusion, rSO2 declined at the same rate in all subjects suggesting similar intrinsic oxygen consumption rates. Upon cuff release, laser doppler post occlusive hyperemia was blunted in SCD patients in proportion to their resting perfusion values. Transfusion therapy did not improve the hyperemia response. FMD was impaired in SCD subjects but partially ameliorated in transfused SCD subjects. Taken together, non-transfused SCD subjects demonstrate impaired conduit artery FMD, impaired microcirculatory post-occlusive hyperemia, and resting hypoxia in the hand despite compensated oxygen delivery, suggesting impaired oxygen supply-demand matching. Transfusion improves FMD and oxygen supply-demand matching but not microcirculation hyperemic response.


Assuntos
Anemia Falciforme , Transfusão de Sangue , Fluxometria por Laser-Doppler , Microcirculação , Consumo de Oxigênio , Oxigênio/sangue , Adolescente , Adulto , Anemia Falciforme/sangue , Anemia Falciforme/fisiopatologia , Anemia Falciforme/terapia , Velocidade do Fluxo Sanguíneo , Feminino , Humanos , Masculino
15.
Am J Hematol ; 94(4): 467-474, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30697803

RESUMO

Although modern medical management has lowered overt stroke occurrence in patients with sickle cell disease (SCD), progressive white matter (WM) damage remains common. It is known that cerebral blood flow (CBF) increases to compensate for anemia, but sufficiency of cerebral oxygen delivery, especially in the WM, has not been systematically investigated. Cerebral perfusion was measured by arterial spin labeling in 32 SCD patients (age range: 10-42 years old, 14 males, 7 with HbSC, 25 HbSS) and 25 age and race-matched healthy controls (age range: 15-45 years old, 10 males, 12 with HbAS, 13 HbAA); 8/24 SCD patients were receiving regular blood transfusions and 14/24 non-transfused SCD patients were taking hydroxyurea. Imaging data from control subjects were used to calculate maps for CBF and oxygen delivery in SCD patients and their T-score maps. Whole brain CBF was increased in SCD patients with a mean T-score of 0.5 and correlated with lactate dehydrogenase (r2 = 0.58, P < 0.0001). When corrected for oxygen content and arterial saturation, whole brain and gray matter (GM) oxygen delivery were normal in SCD, but WM oxygen delivery was 35% lower than in controls. Age and hematocrit were the strongest predictors for WM CBF and oxygen delivery in patients with SCD. There was spatial co-localization between regions of low oxygen delivery and WM hyperintensities on T2 FLAIR imaging. To conclude, oxygen delivery is preserved in the GM of SCD patients, but is decreased throughout the WM, particularly in areas prone to WM silent strokes.


Assuntos
Anemia Falciforme , Circulação Cerebrovascular , Angiografia por Ressonância Magnética , Oxigênio/metabolismo , Substância Branca , Adolescente , Adulto , Anemia Falciforme/diagnóstico por imagem , Anemia Falciforme/metabolismo , Anemia Falciforme/fisiopatologia , Feminino , Hematócrito , Humanos , Masculino , Pessoa de Meia-Idade , Substância Branca/irrigação sanguínea , Substância Branca/diagnóstico por imagem , Substância Branca/metabolismo , Substância Branca/fisiopatologia
17.
J Pain Res ; 11: 2207-2219, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30323655

RESUMO

Purpose: The purpose of this work was to noninvasively detect and quantify microvascular blood flow changes in response to externally applied pain in humans. The responsiveness of the microvasculature to pain stimulation might serve as an objective biomarker in diseases associated with altered pain perception and dysregulated vascular functions. The availability of such a biomarker may be useful as a tool for predicting outcome and response to treatments, particularly in diseases like sickle cell anemia where clinical manifestations are directly linked to microvascular perfusion. We, therefore, developed a method to distinguish the blood flow response due to the test stimulus from the blood flow measurement that also includes concurrent flow changes from unknown origins. Subjects and methods: We measured the microvascular blood flow response in 24 healthy subjects in response to a train of randomly spaced and scaled heat pulses on the anterior forearm. The fingertip microvascular perfusion was measured using laser Doppler flowmetry. The cross-correlation between the heat pulses and the blood flow response was computed and tested for significance against the null distribution obtained from the baseline recording using bootstrapping method. Results: We estimated correlation coefficients, response time, response significance, and the magnitude of vasoreactivity from microvascular blood flow responses. Based on these pain response indices, we identified strong responders and subjects who did not show significant responses. Conclusion: The cross-correlation of a random pattern of painful stimuli with directly measured microvascular flow can detect vasoconstriction responses in a noisy blood flow signal, determine the time between stimulus and response, and quantify the magnitude of this response. This approach provided an objective measurement of vascular response to pain that may be an inherent characteristic of individual human subjects, and may also be related to the severity of vascular disorders.

18.
Proc IEEE Int Symp Biomed Imaging ; 2018: 889-892, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30344893

RESUMO

White matter (WM) lesion identification and segmentation has proved of clinical importance for diagnosis, treatment and neurological outcomes. Convolutional neural networks (CNN) have demonstrated their success for large lesion load segmentation, but are not sensitive to small deep WM and sub-cortical lesion segmentation. We propose to use multi-scale and supervised fully convolutional networks (FCN) to segment small WM lesions in 22 anemic patients. The multiple scales enable us to identify the small lesions while reducing many false alarms, and the multi-supervised scheme allows a better management of the unbalanced data. Compared to a single FCN (Dice score ~0.31), the performance on the testing dataset of our proposed networks achieved a Dice score of 0.78.

19.
J Am Board Fam Med ; 31(5): 812-816, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30201679

RESUMO

INTRODUCTION: Although most patients with rare diseases like sickle cell disease (SCD) are treated in the primary care setting, primary care physicians may find it challenging to keep abreast of medication improvements and complications associated with treatment for rare and complex diseases. The purpose of this study was to evaluate the effectiveness of a clinical decision support (CDS) -based intervention system for transfusional iron overload in adults with SCD to improve management in primary care. METHODS: An electronic medical record based clinical decision support system for potential transfusional iron overload in SCD patients in primary care was evaluated. The intervention was implemented in 3 family medicine clinics with a control group of 3 general internal medicine clinics. Data were collected in the 6 months before the intervention and 6 months after the intervention. There were 47 patients in the family medicine group and 24 in the general internal medicine group. RESULTS: There was no management change in the control group while the intervention group improved primary care management from 0% to 44% (P < .001). CONCLUSION: A CDS tool can improve management of SCD patients in primary care.


Assuntos
Anemia Falciforme/terapia , Sistemas de Apoio a Decisões Clínicas , Sobrecarga de Ferro/diagnóstico , Adolescente , Adulto , Transfusão de Sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
20.
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