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      Men with Sickle Cell Anemia and Priapism Exhibit Increased Hemolytic Rate, Decreased Red Blood Cell Deformability and Increased Red Blood Cell Aggregate Strength

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          Abstract

          Objectives

          To investigate the association between priapism in men with sickle cell anemia (SCA) and hemorheological and hemolytical parameters.

          Materials and Methods

          Fifty-eight men with SCA (median age: 38 years) were included; 28 who had experienced priapism at least once during their life (priapism group) and 30 who never experienced this complication (control group). Twenty-two patients were treated with hydroxycarbamide, 11 in each group. All patients were at steady state at the time of inclusion. Hematological and biochemical parameters were obtained through routine procedures. The Laser-assisted Optical Rotational Cell Analyzer was used to measure red blood cell (RBC) deformability at 30 Pa (ektacytometry) and RBC aggregation properties (laser backscatter versus time). Blood viscosity was measured at a shear rate of 225 s -1 using a cone/plate viscometer. A principal component analysis was performed on 4 hemolytic markers (i.e., lactate dehydrogenase (LDH), aspartate aminotransferase (ASAT), total bilirubin (BIL) levels and reticulocyte (RET) percentage) to calculate a hemolytic index.

          Results

          Compared to the control group, patients with priapism exhibited higher ASAT ( p = 0.01), LDH ( p = 0.03), RET ( p = 0.03) levels and hemolytic indices ( p = 0.02). Higher RBC aggregates strength ( p = 0.01) and lower RBC deformability ( p = 0.005) were observed in patients with priapism compared to controls. After removing the hydroxycarbamide-treated patients, RBC deformability ( p = 0.01) and RBC aggregate strength ( p = 0.03) were still different between the two groups, and patients with priapism exhibited significantly higher hemolytic indices ( p = 0.01) than controls.

          Conclusion

          Our results confirm that priapism in SCA is associated with higher hemolytic rates and show for the first time that this complication is also associated with higher RBC aggregate strength and lower RBC deformability.

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          Most cited references38

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          Blood rheology and hemodynamics.

          Blood is a two-phase suspension of formed elements (i.e., red blood cells [RBCs], white blood cells [WBCs], platelets) suspended in an aqueous solution of organic molecules, proteins, and salts called plasma. The apparent viscosity of blood depends on the existing shear forces (i.e., blood behaves as a non-Newtonian fluid) and is determined by hematocrit, plasma viscosity, RBC aggregation, and the mechanical properties of RBCs. RBCs are highly deformable, and this physical property significantly contributes to aiding blood flow both under bulk flow conditions and in the microcirculation. The tendency of RBCs to undergo reversible aggregation is an important determinant of apparent viscosity because the size of RBC aggregates is inversely proportional to the magnitude of shear forces; the aggregates are dispersed with increasing shear forces, then reform under low-flow or static conditions. RBC aggregation also affects the in vivo fluidity of blood, especially in the low-shear regions of the circulatory system. Blood rheology has been reported to be altered in various physiopathological processes: (1) Alterations of hematocrit significantly contribute to hemorheological variations in diseases and in certain extreme physiological conditions; (2) RBC deformability is sensitive to local and general homeostasis, with RBC deformability affected by alterations of the properties and associations of membrane skeletal proteins, the ratio of RBC membrane surface area to cell volume, cell morphology, and cytoplasmic viscosity. Such alterations may result from genetic disorders or may be induced by such factors as abnormal local tissue metabolism, oxidant stress, and activated leukocytes; and (3) RBC aggregation is mainly determined by plasma protein composition and surface properties of RBCs, with increased plasma concentrations of acute phase reactants in inflammatory disorders a common cause of increased RBC aggregation. In addition, RBC aggregation tendency can be modified by alterations of RBC surface properties because of RBC in vivo aging, oxygen-free radicals, or proteolytic enzymes. Impairment of blood fluidity may significantly affect tissue perfusion and result in functional deteriorations, especially if disease processes also disturb vascular properties.
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            Pulmonary hypertension as a risk factor for death in patients with sickle cell disease.

            The prevalence of pulmonary hypertension in adults with sickle cell disease, the mechanism of its development, and its prospective prognostic significance are unknown. We performed Doppler echocardiographic assessments of pulmonary-artery systolic pressure in 195 consecutive patients (82 men and 113 women; mean [+/-SD] age, 36+/-12 years). Pulmonary hypertension was prospectively defined as a tricuspid regurgitant jet velocity of at least 2.5 m per second. Patients were followed for a mean of 18 months, and data were censored at the time of death or loss to follow-up. Doppler-defined pulmonary hypertension occurred in 32 percent of patients. Multiple logistic-regression analysis, with the use of the dichotomous variable of a tricuspid regurgitant jet velocity of less than 2.5 m per second or 2.5 m per second or more, identified a self-reported history of cardiovascular or renal complications, increased systolic blood pressure, high lactate dehydrogenase levels (a marker of hemolysis), high levels of alkaline phosphatase, and low transferrin levels as significant independent correlates of pulmonary hypertension. The fetal hemoglobin level, white-cell count, and platelet count and the use of hydroxyurea therapy were unrelated to pulmonary hypertension. A tricuspid regurgitant jet velocity of at least 2.5 m per second, as compared with a velocity of less than 2.5 m per second, was strongly associated with an increased risk of death (rate ratio, 10.1; 95 percent confidence interval, 2.2 to 47.0; P<0.001) and remained so after adjustment for other possible risk factors in a proportional-hazards regression model. Pulmonary hypertension, diagnosed by Doppler echocardiography, is common in adults with sickle cell disease. It appears to be a complication of chronic hemolysis, is resistant to hydroxyurea therapy, and confers a high risk of death. Therapeutic trials targeting this population of patients are indicated. Copyright 2004 Massachusetts Medical Society
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              Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes.

              Hemolysis, long discounted as a critical measure of sickle cell disease severity when compared with sickle vaso-occlusion, may be the proximate cause of some disease complications. New mechanistic information about hemolysis and its effects on nitric oxide (NO) biology and further examination of the subphenotypes of disease requires a reappraisal and deconstruction of the clinical features of sickle cell disease. The biology underlying clinical phenotypes linked to hemolysis may increase our understanding of the pathogenesis of other chronic hemolytic diseases while providing new insights into treating sickle cell disease. The pathophysiological roles of dysregulated NO homeostasis and sickle reticulocyte adherence have linked hemolysis and hemolytic rate to sickle vasculopathy. Nitric oxide binds soluble guanylate cyclase which converts GTP to cGMP, relaxing vascular smooth muscle and causing vasodilatation. When plasma hemoglobin liberated from intravascularly hemolyzed sickle erythrocytes consumes NO, the normal balance of vasoconstriction:vasodilation is skewed toward vasoconstriction. Pulmonary hypertension, priapism, leg ulceration and stroke, all subphenotypes of sickle cell disease, can be linked to the intensity of hemolysis. Hemolysis plays less of a role in the vaso-occlusive-viscosity complications of disease like the acute painful episode, osteonecrosis of bone and the acute chest syndrome. Agents that decrease hemolysis or restore NO bioavailability or responsiveness may have potential to reduce the incidence and severity of the hemolytic subphenotypes of sickle cell disease. Some of these drugs are now being studied in clinical trials.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                4 May 2016
                2016
                : 11
                : 5
                : e0154866
                Affiliations
                [1 ]Inserm UMR 1134, Université des Antilles, Pointe à Pitre, Guadeloupe
                [2 ]Laboratoire d’Excellence du Globule Rouge (LABEX GR-Ex), COMUE Sorbonne Paris Cité, Paris, France
                [3 ]CHU de Pointe-à-Pitre, Service d’Urologie, Pointe-à-Pitre, Guadeloupe
                [4 ]Inserm, U1085—IRSET, Pointe-à-Pitre, Guadeloupe, France
                [5 ]CHU de Pointe-à-Pitre, Unité Transversale de la Drépanocytose, Centre de référence maladies rares de la drépanocytose aux Antilles-Guyane, Pointe-à-Pitre, Guadeloupe
                [6 ]Institut Universitaire de France, Paris, France
                [7 ]Université Claude Bernard Lyon 1, COMUE Lyon, Laboratoire LIBM EA 7424, Team “Vascular Biology and red blood cell”, Lyon, France
                [8 ]Inserm, CHU de Pointe-à-Pitre, Centre d’Investigation Clinique Antilles Guyane CIC 14–24, Guadeloupe, France
                [9 ]Inserm U 1134, Paris, France
                Emory University/Georgia Insititute of Technology, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: JE MR PC. Performed the experiments: KCC SF. Analyzed the data: KCC MR VT SF. Contributed reagents/materials/analysis tools: PB LB NL MB VT MEJ. Wrote the paper: JE MR SF KCC PC.

                Article
                PONE-D-16-08174
                10.1371/journal.pone.0154866
                4856257
                27145183
                9026db2e-002c-41d4-a415-7a7edb30a391
                © 2016 Cita et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 25 February 2016
                : 20 April 2016
                Page count
                Figures: 0, Tables: 1, Pages: 10
                Funding
                This study was supported in part by the Region Guadeloupe (grant N°: J-2-1-J210002).
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                The Commission Nationale de l’Informatique et des Libertés strictly forbids the provision of a full database with individual data. However, stratified data on the patients studied is available upon request to the corresponding author: Dr. Marc Romana, marc.romana@ 123456wanadoo.fr .

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