Catherine Seamon

Hemodynamic Predictors of Mortality in Adults with Sickle Cell Disease

BACKGROUND Pulmonary hypertension (PH) in adults with sickle cell disease (SCD) is associated with early mortality, but no prior studies have evaluated quantitative relationships of mortality to physiological measures of pre- and postcapillary PH. OBJECTIVES To identify risk factors associated with mortality and to estimate the expected survival in a cohort of patients with SCD with PH documented by right heart catheterization. METHODS Nine-year follow-up data (median, 4.7 yr) from the National Institutes of Health SCD PH screening study are reported. A total of 529 adults with SCD were screened by echocardiography between 2001 and 2010 with no exclusion criteria. Hemodynamic data were collected from 84 patients. PH was defined as mean pulmonary artery pressure (PAP) ≥ 25 mm Hg. Survival rates were estimated by the Kaplan-Meier method, and mortality risk factors were analyzed by the Cox proportional hazards regression. MEASUREMENTS AND MAIN RESULTS Specific hemodynamic variables were independently related to mortality: mean PAP (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.05-2.45 per 10 mm Hg increase; P = 0.027), diastolic PAP (HR, 1.83; 95% CI, 1.09-3.08 per 10 mm Hg increase; P = 0.022), diastolic PAP - pulmonary capillary wedge pressure (HR, 2.19; 95% CI, 1.23-3.89 per 10 mm Hg increase; P = 0.008), transpulmonary gradient (HR, 1.78; 95% CI, 1.14-2.79 per 10 mm Hg increase; P = 0.011), and pulmonary vascular resistance (HR, 1.44; 95% CI, 1.09-1.89 per Wood unit increase; P = 0.009) as risk factors for mortality. CONCLUSIONS Mortality in adults with SCD and PH is proportional to the physiological severity of precapillary PH, demonstrating its prognostic and clinical relevance despite anemia-induced high cardiac output and less severely elevated pulmonary vascular resistance.

Severe painful vaso-occlusive crises and mortality in a contemporary adult sickle cell anemia cohort study.

Background Frequent painful vaso-occlusive crises (VOCs) were associated with mortality in the Cooperative Study of Sickle Cell Disease (CSSCD) over twenty years ago. Modern therapies for sickle cell anemia (SCA) like hydroxyurea are believed to have improved overall patient survival. The current study sought to determine the relevance of the association between more frequent VOCs and death and its relative impact upon overall mortality compared to other known risk factors in a contemporary adult SCA cohort. Methods Two hundred sixty four SCA adults were assigned into two groups based on patient reported outcomes for emergency department (ED) visits or hospitalizations for painful VOC treatment during the 12 months prior to evaluation. Results Higher baseline hematocrit (p = 0.0008), ferritin (p = 0.005), and HDL cholesterol (p = 0.01) were independently associated with 1 or more painful VOCs requiring an ED visit or hospitalization for acute pain. During a median follow-up of 5 years, mortality was higher in the ED visit/hospitalization group (relative risk [RR] 2.68, 95% CI 1.1-6.5, p = 0.03). Higher tricuspid regurgitatant jet velocity (TRV) (RR 2.41, 95% CI 1.5-3.9, p < 0.0001), elevated ferritin (RR 4.00, 95% CI 1.8-9.0, p = 0.001) and lower glomerular filtration rate (RR=2.73, 95% CI 1.6-4.6, p < 0.0001) were also independent risk factors for mortality. Conclusions Severe painful VOCs remain a marker for SCA disease severity and premature mortality in a modern cohort along with other known risk factors for death including high TRV, high ferritin and lower renal function. The number of patient reported pain crises requiring healthcare utilization is an easily obtained outcome that could help to identify high risk patients for disease modifying therapies. Trial Registration ClinicalTrials.gov NCT00011648 http://clinicaltrials.gov/

Leg Ulcers in Sickle Cell Disease: Current Patterns and Practices

Leg ulcers are a debilitating complication of patients with sickle cell disease, and their frequency in North America was reported to be 2.5% by the Cooperative Study of Sickle Cell Disease more than 20 years ago. We sought to determine if the frequency of leg ulcers in sickle cell patients in the United States had declined and to assess which treatments providers use most commonly. We sent an e-mail survey to health professionals belonging to the national Sickle Cell Adult Provider Network. Responses were obtained from 31 of them (26.0%). Most of them (96.0%) reported having some patients with leg ulcers. Providers reported a total of 185 patients with active leg ulcers and 224 in the previous 5 years, for a total of 409 patients. Hb SS (homozygous sickle cell anemia) was the most common genotype of affected individuals, followed by Hb SC (double heterozygote for Hb S [β6(A3)Glu→Val, GAG>GTG; HBB: c.20A>T] and Hb C [β6(A3)Glu→Lys, GAG>AAG; HBB: c.19G>A]). Males showed a 2:1 predominance. Two-thirds of patients were treated with either hydroxyurea (HU) or transfusion therapy and most used compression stockings and topical therapies as directed by wound care services. We conclude that leg ulcers continue to be a debilitating complication of young adults with sickle cell disease, despite improved supportive care and the widespread use of disease modifying agents such HU and transfusion. While some providers offer office-based ulcer care, the majority prefer specialty consultation including podiatry, plastic surgery and dermatology. Despite their frequency, there is no clear consensus among providers as to the best treatment.

Imaging flow cytometry for morphologic and phenotypic characterization of rare circulating endothelial cells

Endothelial cells in the peripheral circulation are rare events that require technically rigorous approaches for detection by flow cytometry. Visualization of these cells has been even more demanding, as this has historically required extensive enrichment and processing prior to attempting imaging. As a result, few, if any, examples exist on images of peripheral blood circulating endothelial cells (CECs) that include verification of the cell lineage both phenotypically and genomically. In this study, we have devised a method whereby CECs can be directly visualized after lysis of red blood cells and staining, without pre‐enrichment or additional processing. Peripheral blood is stained with CD45, CD146, CD3, Hoechst, and DAPI to permit identification of CD146 positive, nonleukocyte, nucleated, and live cells that fit the description of CECs. These cells are imaged using the Amnis ImageStreamX, an imaging flow cytometer. Genomic verification of the endothelial nature of these cells is accomplished by using an aliquot of the same stained samples for sorting CECs using similar gating strategies. This proof of principle of direct imaging of CECs by imaging flow cytometry will permit studies to be conducted heretofore not possible, as the ImageStreamX has the capability of detecting additional fluorochromes other than those used to identify the CECs. Such potential investigations include antigen colocalization or capping, autophagy and apoptosis, morphologic changes in response to therapy, and others. Thus, this method will enable a broad range of novel studies to be conducted using CECs as surrogates of the endothelium. Published 2013 Wiley‐Periodicals, Inc.†

Infrared imaging of nitric oxide-mediated blood flow in human sickle cell disease

Vascular dysfunction is an important pathophysiologic manifestation of sickle cell disease (SCD), a condition that increases risk of pulmonary hypertension and stroke. We hypothesized that infrared (IR) imaging would detect changes in cutaneous bloodflow reflective of vascular function. We performed IR imaging and conventional strain gauge plethysmography in twenty-five adults with SCD at baseline and during intra-arterial infusions of an endothelium-dependent vasodilator acetylcholine (ACh), an endothelium-independent vasodilator sodium nitroprusside (SNP), and a NOS inhibitor L-NMMA. Skin temperature measured by IR imaging increased in a dose-dependent manner to graded infusions of ACh (+1.1°C, p<0.0001) and SNP (+0.9°C, p<0.0001), and correlated with dose-dependent increases in forearm blood flow (ACh: +19.9 mL/min/100 mL, p<0.0001; r(s)=0.57, p=0.003; SNP: +8.6 mL/min/100 mL, p<0.0001; r=0.70, p=0.0002). Although IR measurement of skin temperature accurately reflected agonist-induced increases in blood flow, it was less sensitive to decreases in blood flow caused by NOS inhibition. Baseline forearm skin temperature measured by IR imaging correlated significantly with baseline forearm blood flow (31.8±0.2°C, 6.0±0.4 mL/min/100 mL; r=0.58, p=0.003), and appeared to represent a novel biomarker of vascular function. It predicted a blunted blood flow response to SNP (r=-0.61, p=0.002), and was independently associated with a marker of pulmonary artery pressure, as well as hemoglobin level, diastolic blood pressure, homocysteine, and cholesterol (R(2)=0.84, p<0.0001 for the model). IR imaging of agonist-stimulated cutaneous blood flow represents a less cumbersome alternative to plethysmography methodology. Measurement of baseline skin temperature by IR imaging may be a useful new marker of vascular risk in adults with SCD.

Liver stiffness increases acutely during sickle cell vaso-occlusive crisis

Acute vaso‐occlusive crisis (VOC) in sickle cell disease (SCD) is an important cause of end‐organ damage. It is estimated that 10–39% of VOC occurs with hepatic involvement. Current assessments of hepatic involvement during VOC are unsatisfactory. We investigated transient elastography (TE) as a marker of hepatic involvement, its relationship with histology, and biochemical markers during VOC. SCD patients were evaluated with biochemical markers and TE at steady‐state and during VOC. Change in TE and biochemical markers were correlated with length of hospital stay. When available, liver biopsy and tricuspid regurgitation velocity (TRV) at steady‐state were correlated with TE. Twenty‐three patients were evaluated (mean age = 34.3 years, standard deviation = 7.96). In 15 patients with liver biopsies, TE correlated with fibrosis (P = 0.01) and TRV (P = 0.0063), but not hepatic iron. Hemolysis biomarkers changed during VOC (P < 0.022), but not alanine aminotransferase (ALT). Paired comparison of TE at steady‐state and during VOC showed an increased from 6.2 to 12.3 kPa (P = 0.0029). Increasing TE during VOC associated with increasing ALT and alkaline phosphatase (P = 0.0088 and 0.0099, respectively). At steady‐state, increasing inflammation on biopsy (P = 0.0037) and TRV (P = 0.0075) correlated with increasing TE during VOC. Increased hospital stay was associated with higher ALT (P = 0.041), lower albumin (P = 0.046), hemoglobin/hematocrit (P < 0.0021) but not TE. TE may identify patients with hepatic involvement during VOC independent of biochemical measures. Increase in TE may reflect both hepatic passive congestion and hepatic involvement during VOC. TE may serve as a physiological biomarker for hepatic features of VOC. Am. J. Heamtol. 88:E250–E254, 2013.

Effect of extended-release niacin on serum lipids and on endothelial function in adults with sickle cell anemia and low high-density lipoprotein cholesterol levels.

Through bound apolipoprotein A-I (apoA-I), high-density lipoprotein cholesterol (HDL-C) activates endothelial nitric oxide synthase, inducing vasodilation. Because patients with sickle cell disease (SCD) have low apoA-I and endothelial dysfunction, we conducted a randomized, double-blinded, placebo-controlled trial to test whether extended-release niacin (niacin-ER) increases apoA-I-containing HDL-C and improves vascular function in SCD. Twenty-seven patients with SCD with levels of HDL-C <39 mg/dl or apoA-I <99 mg/dl were randomized to 12 weeks of niacin-ER, increased in 500-mg increments to a maximum of 1,500 mg/day, or placebo. The primary outcome was the absolute change in HDL-C level after 12 weeks, with endothelial function assessed before and at the end of treatment. Niacin-ER-treated patients trended to greater increase in HDL-C level compared with placebo treatment at 12 weeks (5.1 ± 7.7 vs 0.9 ± 3.8 mg/dl, 1-tailed p = 0.07), associated with significantly greater improvements in the ratios of low-density lipoprotein to HDL-C levels (1.24 vs 1.95, p = 0.003) and apolipoprotein B to apoA-I levels (0.46 vs 0.58, p = 0.03) compared with placebo-treated patients. No improvements were detected in 3 independent vascular physiology assays of endothelial function. Thus, the relatively small changes in HDL-C levels achieved by the dose of niacin-ER used in our study are not associated with improved vascular function in patients with SCD with initially low levels of apoA-I or HDL-C.

Microvascular oxygen consumption during sickle cell pain crisis

Sickle cell disease is an inherited blood disorder characterized by chronic hemolytic anemia and episodic vaso-occlusive pain crises. Vaso-occlusion occurs when deoxygenated hemoglobin S polymerizes and erythrocytes sickle and adhere in the microvasculature, a process dependent on the concentration of hemoglobin S and the rate of deoxygenation, among other factors. We measured oxygen consumption in the thenar eminence during brachial artery occlusion in sickle cell patients and healthy individuals. Microvascular oxygen consumption was greater in sickle cell patients than in healthy individuals (median [interquartile range]; sickle cell: 0.91 [0.75-1.07] vs healthy: 0.75 [0.62-0.94] -ΔHbO2/min, P < .05) and was elevated further during acute pain crisis (crisis: 1.10 [0.78-1.30] vs recovered: 0.88 [0.76-1.03] -ΔHbO2/min, P < .05). Increased microvascular oxygen consumption during pain crisis could affect the local oxygen saturation of hemoglobin when oxygen delivery is limiting. Identifying the mechanisms of elevated oxygen consumption during pain crisis might lead to the development of new therapeutic interventions. This trial was registered at www.clinicaltrials.gov as #NCT01568710.

Elevated Transpulmonary Gradient and Cardiac Magnetic Resonance-Derived Right Ventricular Remodeling Predict Poor Outcomes in Sickle Cell Disease

Adults with sickle cell disease have a high prevalence of pulmonary hypertension. This picture is often complicated by concurrent left ventricular diastolic dysfunction and anemia-related changes in hemodynamics. The change in pressure across the pulmonary circulation reflected by the transpulmonary gradient is less clouded by anemia-related adaptations. We characterized the association of elevated transpulmonary gradient with right ventricular structure and function, exercise capacity and mortality. Data from 84 patients (age 41+/-13 years, 55% female [n=46], 82% hemoglobin SS [n=69]) with right heart catheterization from the Bethesda Sickle Cell Cohort were analyzed. Of the 84 patients, forty-one underwent cardiac magnetic resonance imaging within two days of right heart catheterization. Patients with a catheterization-derived transpulmonary gradient ≥12mmHg had more severe symptoms (p=0.013), shorter 6-minute walk distance (p=0.006), lower cardiac index (p<0.001), reduced right ventricular ejection fraction (p=0.002) and cardiac magnetic resonance imaging markers of adverse morphologic adaptation. An RVEF <32% derived from cardiac magnetic resonance predicted decreased survival (HR 3.70, 95% CI 1.04-13.12, p=0.030) and higher New York Heart Association classification (OR 9.29, p=0.018). In a multivariate model controlling for age and phenotype, transpulmonary gradient ≥12mmHg and right ventricular ejection fraction <32% were independently predictive of increased mortality (HR 5.47, 95% CI 1.13-26.42, p=0.035 and HR 5.11, 95% CI 1.13-23.13, p=0.034). Patients with sickle cell disease and elevated transpulmonary gradient have findings of maladaptive RV remodeling on cardiac magnetic resonance imaging. Elevated transpulmonary gradient and cardiac magnetic resonance-derived RV dysfunction independently predict higher mortality in sickle cell disease. Cardiac magnetic resonance may have a useful role in the clinical evaluation and non-invasive prognostication of adults with sickle cell disease and suspected pulmonary hypertension. This clinical trial was registered at clinicaltrials.gov identifier: [NCT00011648][1] NCT00081523, [NCT00023296][2], and [NCT00352430][3]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00011648&atom=%2Fhaematol%2Fearly%2F2015%2F11%2F13%2Fhaematol.2015.125229.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00023296&atom=%2Fhaematol%2Fearly%2F2015%2F11%2F13%2Fhaematol.2015.125229.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00352430&atom=%2Fhaematol%2Fearly%2F2015%2F11%2F13%2Fhaematol.2015.125229.atom

Haem augments and iron chelation decreases toll-like receptor 4 mediated inflammation in monocytes from sickle cell patients

normalization prior to transplant is of independent prognostic significance in multiple myeloma: a BMT CTN 0102 correlative study. British Journal of Haematology, 178, 816. Durie, B.G., Harousseau, J.L., Miguel, J.S., Blad e, J., Barlogie, B., Anderson, K., Gertz, M., Dimopoulos, M., Westin, J., Sonneveld, P., Ludwig, H., Gahrton, G., Beksac, M., Crowley, J., Belch, A., Boccadaro, M., Cavo, M., Turesson, I., Joshua, D., Vesole, D., Kyle, R., Alexanian, R., Tricot, G., Attal, M., Merlini, G., Powles, R., Richardson, P., Shimizu, K., Tosi, P., Morgan, G. & Rajkumar, S.V.; for the International Myeloma Working Group. (2006) International uniform response criteria for multiple myeloma. Leukemia, 20, 1467–1473. Kumar, S., Paiva, B., Anderson, K.C., Durie, B., Landgren, O., Moreau, P., Munshi, N., Lonial, S., Blad e, J., Mateos, M.V., Dimopoulos, M., Kastritis, E., Boccadoro, M., Orlowski, R., Goldschmidt, H., Spencer, A., Hou, J., Chng, W.J., Usmani, S.Z., Zamagni, E., Shimizu, K., Jagannath, S., Johnsen, H.E., Terpos, E., Reiman, A., Kyle, R.A., Sonneveld, P., Richardson, P.G., McCarthy, P., Ludwig, H., Chen, W., Cavo, M., Harousseau, J.L., Lentzsch, S., Hillengass, J., Palumbo, A., Orfao, A., Rajkumar, S.V., San Miguel, J. & Avet-Loiseau, H. (2016) International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. The Lancet Oncology, 17, e328–e346. Ludwig, H., Milosavljevic, D., Zojer, N., Zojer, N., Faint, J.M., Bradwell, A.R., H€ ubl, W. & Harding, S.J. (2013) Immunoglobulin heavy/light chain ratios improve paraprotein detection and monitoring, identify residual disease and correlate with survival in multiple myeloma patients. Leukemia, 27, 213–219. Mart ınez-L opez, J., Paiva, B., L opez-Anglada, L., Mateos, M.V., Cedena, T., Vidr ıales, M.B., S aezG omez, M.A., Contreras, T., Oriol, A., Rapado, I., Teruel, A.I., Cord on, L., Blanchard, M.J., Bengoechea, E., Palomera, L., de Arriba, F., Cueto-Felgueroso, C., Orfao, A., Blad e, J., San Miguel, J.F. & Lahuerta, J.J.; Spanish Multiple Myeloma Group/Program for the Study of Malignant Blood Diseases Therapeutics (GEM/ PETHEMA) Cooperative Study Group. (2015) Critical analysis of the stringent complete response in multiple myeloma: contribution of sFLC and bone marrow clonality. Blood, 126, 858–862. Paolini, L., Di Noto, G., Maffina, F., Martellosio, G., Radeghieri, A., Luigi, C. & Ricotta, D. (2015) Comparison of Hevylite IgA and IgG assay with conventional techniques for the diagnosis and follow-up of plasma cell dyscrasia. Annals of Clinical Biochemistry, 52, 337–345. Suehara, Y., Takamatsu, H., Fukumoto, K., Fujisawa, M., Narita, K., Usui, Y., Takeuchi, M., Endean, K. & Matsue, K. (2017) Abnormal heavy/light chain ratio after treatment is associated with shorter survival in patients with IgA myeloma. Cancer Science, 108, 187–192. Tacchetti, P., Pezzi, A., Zamagni, E., Pantani, L., Rocchi, S., Zannetti, B.A., Mancuso, K., Rizzello, I. & Cavo, M. (2017) Role of serum free light chain assay in the detection of early relapse and prediction of prognosis after relapse in multiple myeloma patients treated upfront with novel agents. Haematologica, 102, e104–e107.