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Vasculopathy in Sickle Cell Disease: From Red Blood Cell Sickling to Vascular Dysfunction

Elie Nader, Nicola Conran, Marc Romana, Philippe Connes

10.1002/cphy.c200024

Source: Volume 11, Issue 2, April 2021

Published online: April 2021

Full Article on Wiley Online Library



Abstract

Sickle cell disease (SCD) is a hereditary disorder that leads to the production of an abnormal hemoglobin, hemoglobin S (HbS). HbS polymerizes in deoxygenated conditions, which can prompt red blood cell (RBC) sickling and leaves the RBCs more rigid, fragile, and prone to hemolysis. SCD patients suffer from a plethora of complications, ranging from acute complications, such as characteristic, frequent, and debilitating vaso‐occlusive episodes to chronic organ damage. While RBC sickling is the primary event at the origin of vaso‐occlusive processes, other factors that can further increase RBC transit times in the microcirculation may also be required to precipitate vaso‐occlusive processes. The adhesion of RBC and leukocytes to activated endothelium and the formation of heterocellular aggregates, as well as increased blood viscosity, are among the mechanisms involved in slowing the progress of RBCs in deoxygenated vascular areas, favoring RBC sickling and promoting vascular occlusion. Chronic inflammatory processes and oxidative stress, which are perpetuated by hemolytic events and ischemia‐reperfusion injury, result in this pan cellular activation and some acute events, such as stroke and acute chest syndrome, as well as chronic end‐organ damage. Furthermore, impaired vasodilation and vasomotor hyperresponsiveness in SCD also contribute to vaso‐occlusive processes. Treating SCD as a vascular disease in addition to its hematological perspective, the present article looks at the interplay between abnormal RBC physiology/integrity, vascular dysfunction and clinical severity in SCD, and discusses existing therapies and novel drugs in development that may ameliorate vascular complications in the disease. © 2021 American Physiological Society. Compr Physiol 11:1785‐1803, 2021.

Figure 1. Figure 1. Intravascular hemolysis in SCD is responsible for a decrease in NO bioavailability, which contributes to endothelial dysfunction notably in the arterioles and arteries, promoting several vascular complications. Hemolysis leads to the release of free hemoglobin, which reacts with NO to form nitrate and methemoglobin. Arginase released from RBCs consumes the NO precursor, l‐arginine. ADMA promotes the uncoupling of endothelial nitric oxide synthase. Free heme and free hemoglobin increase the production of reactive oxygen species, which react with NO to form peroxynitrite, a harmful nitrosative agent. Repeated ischemia/reperfusion events increase Xanthine Oxidase activity and increase NADPH oxidase activity which promote the production of ROS. The resulting decreased NO bioavailability impairs arteriole and artery vasodilation and leads to a progressive endothelial dysfunction. Hb, hemoglobin; NO, nitric oxide; eNOS, endothelial nitric oxide synthase; ADMA, asymmetric dimethylarginine; ROS, reactive oxygen species; XO, xanthine oxidase; I/R, ischemia/reperfusion.
Figure 2. Figure 2. Oxidative stress and inflammation play a major role in the vascular dysfunction in SCD. Intravascular hemolysis leads to the release of heme and iron (Fe) that increase the production of ROS. Erythrocyte NADPH Oxidase activity is enhanced in SCD RBCs, due to chronic inflammation, and produces ROS. ROS can damage the endothelium through the activation of NF‐κB, leading to the expression of adhesion molecules and eventually to apoptosis. Repeated episodes of vaso‐occlusion and reperfusion lead to ischemia‐reperfusion injury (I/R), which increases the activity of the pro‐oxidant enzyme, Xanthine Oxidase. It also promotes the expression of adhesion molecules by endothelial cells, eventually leading to the activation of NF‐κB and cell apoptosis. I/R injuries participate in pulmonary injury, cerebrovascular disease, and ACS. Activated endothelial cells also produce ET‐1, a potent pro‐inflammatory, and vasoconstrictive agent, that have been linked to glomerulopathy, cardiopathy, and pulmonary vascular congestion. ROS and inflammation also activate circulating cells, which release microvesicles. Extracellular vesicles (EVs), notably originating from RBCs alter the endothelium and impair vascular function. RBC‐medium/large (m/l) EVs can scavenge NO leading to vasoconstriction. They can also transfer their toxic heme to the endothelium which promotes endothelial inflammation by activating TLR4 signaling and by producing ROS. Phosphatidylserine exposure at the surface of m/lEVs can also promote the expression of adhesion molecules, such as VCAM‐1 and ICAM‐1. RBC‐m/lEVs cause endothelial dysfunction, increase arterial stiffness and would be able to trigger the onset of VOC in SCA. Free heme also plays a key role in the chronic inflammation and endothelial dysfunction in SCD. Heme may stimulate the production of several pro‐inflammatory cytokines through the activation of NF‐kb and TLR4/NLRP3 inflammasome pathways. Some of these cytokines, such as IL‐1b and IL‐6, would be involved in stroke and pulmonary hypertension, respectively. Heme also induces the expression of endothelial adhesion molecules such as ICAM‐1, VCAM‐1, E‐Selectin, and P‐Selectin that promote cell‐cell interactions and the onset of VOC in post‐capillary venules. Heme induces the release of Neutrophil Extracellular Traps that promote immune system activation, inflammation, oxidative stress, and the adhesion of RBCs and platelets which also contribute to VOC process. The alternative complement pathway is also activated by heme. C3b and C5b9 alter endothelial cells and may contribute to vascular dysfunction in SCD, leading to nephropathy. In SCD, free hemoglobin and free heme are not neutralized because of the overwhelming consumption of haptoglobin and hemopexin, respectively. Hb, hemoglobin; Fe, iron; ROS, reactive oxygen species; XO, xanthine oxidase; NO, nitric oxide; TLR4, toll‐like receptor 4; NF‐κB, nuclear factor‐kappa B; PS, phosphatidylserine; ET‐1, endothelin 1; NO, nitric oxide; I/R, ischemia/reperfusion; PLT, platelets; RBC, red blood cells; WBC, leukocytes; Hpx, hemopexin; Hpt, haptoglobin; RBC‐m/lEVs, red blood cell medium/large extracellular vesicles; NETs, neutrophil extracellular traps; NLRP3, NOD‐like receptor family 3; ICAM‐1, interCellular adhesion molecule 1; VCAM‐1, vascular cell adhesion molecule‐1; ACS, acute chest syndrome; VOC, vaso‐occlusive crisis.


Figure 1. Intravascular hemolysis in SCD is responsible for a decrease in NO bioavailability, which contributes to endothelial dysfunction notably in the arterioles and arteries, promoting several vascular complications. Hemolysis leads to the release of free hemoglobin, which reacts with NO to form nitrate and methemoglobin. Arginase released from RBCs consumes the NO precursor, l‐arginine. ADMA promotes the uncoupling of endothelial nitric oxide synthase. Free heme and free hemoglobin increase the production of reactive oxygen species, which react with NO to form peroxynitrite, a harmful nitrosative agent. Repeated ischemia/reperfusion events increase Xanthine Oxidase activity and increase NADPH oxidase activity which promote the production of ROS. The resulting decreased NO bioavailability impairs arteriole and artery vasodilation and leads to a progressive endothelial dysfunction. Hb, hemoglobin; NO, nitric oxide; eNOS, endothelial nitric oxide synthase; ADMA, asymmetric dimethylarginine; ROS, reactive oxygen species; XO, xanthine oxidase; I/R, ischemia/reperfusion.


Figure 2. Oxidative stress and inflammation play a major role in the vascular dysfunction in SCD. Intravascular hemolysis leads to the release of heme and iron (Fe) that increase the production of ROS. Erythrocyte NADPH Oxidase activity is enhanced in SCD RBCs, due to chronic inflammation, and produces ROS. ROS can damage the endothelium through the activation of NF‐κB, leading to the expression of adhesion molecules and eventually to apoptosis. Repeated episodes of vaso‐occlusion and reperfusion lead to ischemia‐reperfusion injury (I/R), which increases the activity of the pro‐oxidant enzyme, Xanthine Oxidase. It also promotes the expression of adhesion molecules by endothelial cells, eventually leading to the activation of NF‐κB and cell apoptosis. I/R injuries participate in pulmonary injury, cerebrovascular disease, and ACS. Activated endothelial cells also produce ET‐1, a potent pro‐inflammatory, and vasoconstrictive agent, that have been linked to glomerulopathy, cardiopathy, and pulmonary vascular congestion. ROS and inflammation also activate circulating cells, which release microvesicles. Extracellular vesicles (EVs), notably originating from RBCs alter the endothelium and impair vascular function. RBC‐medium/large (m/l) EVs can scavenge NO leading to vasoconstriction. They can also transfer their toxic heme to the endothelium which promotes endothelial inflammation by activating TLR4 signaling and by producing ROS. Phosphatidylserine exposure at the surface of m/lEVs can also promote the expression of adhesion molecules, such as VCAM‐1 and ICAM‐1. RBC‐m/lEVs cause endothelial dysfunction, increase arterial stiffness and would be able to trigger the onset of VOC in SCA. Free heme also plays a key role in the chronic inflammation and endothelial dysfunction in SCD. Heme may stimulate the production of several pro‐inflammatory cytokines through the activation of NF‐kb and TLR4/NLRP3 inflammasome pathways. Some of these cytokines, such as IL‐1b and IL‐6, would be involved in stroke and pulmonary hypertension, respectively. Heme also induces the expression of endothelial adhesion molecules such as ICAM‐1, VCAM‐1, E‐Selectin, and P‐Selectin that promote cell‐cell interactions and the onset of VOC in post‐capillary venules. Heme induces the release of Neutrophil Extracellular Traps that promote immune system activation, inflammation, oxidative stress, and the adhesion of RBCs and platelets which also contribute to VOC process. The alternative complement pathway is also activated by heme. C3b and C5b9 alter endothelial cells and may contribute to vascular dysfunction in SCD, leading to nephropathy. In SCD, free hemoglobin and free heme are not neutralized because of the overwhelming consumption of haptoglobin and hemopexin, respectively. Hb, hemoglobin; Fe, iron; ROS, reactive oxygen species; XO, xanthine oxidase; NO, nitric oxide; TLR4, toll‐like receptor 4; NF‐κB, nuclear factor‐kappa B; PS, phosphatidylserine; ET‐1, endothelin 1; NO, nitric oxide; I/R, ischemia/reperfusion; PLT, platelets; RBC, red blood cells; WBC, leukocytes; Hpx, hemopexin; Hpt, haptoglobin; RBC‐m/lEVs, red blood cell medium/large extracellular vesicles; NETs, neutrophil extracellular traps; NLRP3, NOD‐like receptor family 3; ICAM‐1, interCellular adhesion molecule 1; VCAM‐1, vascular cell adhesion molecule‐1; ACS, acute chest syndrome; VOC, vaso‐occlusive crisis.
References
 1.Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, Abboud M, Gallagher D, Kutlar A, Nichols FT, Bonds DR, Brambilla D. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 339: 5‐11, 1998.
 2.Adewoye AH, Klings ES, Farber HW, Palaima E, Bausero MA, McMahon L, Odhiambo A, Surinder S, Yoder M, Steinberg MH, Asea A. Sickle cell vaso‐occlusive crisis induces the release of circulating serum heat shock protein‐70. Am J Hematol 78: 240‐242, 2005.
 3.Adisa OA, Hu Y, Ghosh S, Aryee D, Osunkwo I, Ofori‐Acquah SF. Association between plasma free haem and incidence of vaso‐occlusive episodes and acute chest syndrome in children with sickle cell disease. Br J Haematol 162: 702‐705, 2013.
 4.Ait Abdallah N, Connes P, Di Liberto G, Offredo L, Beaumont JL, Menouche D, Debbache K, Jebali A, Habibi A, Pirenne F, Galacteros F, Ranque B, Bartolucci P. Automated RBC exchange has a greater effect on whole blood viscosity than manual whole blood exchange in adult patients with sickle cell disease. Vox Sang 115 (8): 722‐728, 2020.
 5.Aessopos A, Farmakis D, Tsironi M, Diamanti‐Kandarakis E, Matzourani M, Fragodimiri C, Hatziliami A, Karagiorga M. Endothelial function and arterial stiffness in sickle‐thalassemia patients. Atherosclerosis 191: 427–432. 2007.
 6.Al Balushi H, Hannemann A, Rees D, Brewin J, Gibson JS. The effect of antioxidants on the properties of red blood cells from patients with sickle cell anemia. Front Physiol 10: 976, 2019.
 7.Al‐Janabi H, Hamdan F, Al Tameemi W. Statins for endothelial dysfunction in sickle cell disease: A cohort study. J Appl Hema 9: 16‐21, 2018.
 8.Almeida CB, Souza LE, Leonardo FC, Costa FT, Werneck CC, Covas DT, Costa FF, Conran N. Acute hemolytic vascular inflammatory processes are prevented by nitric oxide replacement or a single dose of hydroxyurea. Blood 126: 711‐720, 2015.
 9.Antoniades C, Shirodaria C, Leeson P, Antonopoulos A, Warrick N, Van‐Assche T, Cunnington C, Tousoulis D, Pillai R, Ratnatunga C, Stefanadis C, Channon KM. Association of plasma asymmetrical dimethylarginine (ADMA) with elevated vascular superoxide production and endothelial nitric oxide synthase uncoupling: Implications for endothelial function in human atherosclerosis. Eur Heart J 30: 1142‐1150, 2009.
 10.Aslan M, Ryan TM, Adler B, Townes TM, Parks DA, Thompson JA, Tousson A, Gladwin MT, Patel RP, Tarpey MM, Batinic‐Haberle I, White CR, Freeman BA. Oxygen radical inhibition of nitric oxide‐dependent vascular function in sickle cell disease. Proc Natl Acad Sci USA 98: 15215‐15220, 2001.
 11.Ataga KI, Derebail VK, Caughey M, Elsherif L, Shen JH, Jones SK, Maitra P, Pollock DM, Cai J, Archer DR, Hinderliter AL, Albuminuria I. Associated with endothelial dysfunction and elevated plasma endothelin‐1 in sickle cell anemia. PLoS One 11: e0162652, 2016.
 12.Ataga KI, Kutlar A, Kanter J, Liles D, Cancado R, Friedrisch J, Guthrie TH, Knight‐Madden J, Alvarez OA, Gordeuk VR, Gualandro S, Colella MP, Smith WR, Rollins SA, Stocker JW, Rother RP. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med 376: 429‐439, 2017.
 13.Ataga KI, Reid M, Ballas SK, Yasin Z, Bigelow C, James LS, Smith WR, Galacteros F, Kutlar A, Hull JH, Stocker JW, Investigators ICAS. Improvements in haemolysis and indicators of erythrocyte survival do not correlate with acute vaso‐occlusive crises in patients with sickle cell disease: A phase III randomized, placebo‐controlled, double‐blind study of the Gardos channel blocker senicapoc (ICA‐17043). Br J Haematol 153: 92‐104, 2011.
 14.Ataga KI, Wichlan D, Elsherif L, Derebail VK, Wogu AF, Maitra P, Cai J, Caughey MC, Pollock DM, Pollock JS, Archer DR, Hinderliter AL. A pilot study of the effect of atorvastatin on endothelial function and albuminuria in sickle cell disease. Am J Hematol 94: E299‐E301, 2019.
 15.Ayoola OO, Bolarinwa RA, Onakpoya OH, Onigbinde SO, Asaleye CM, Odedeyi AA. Intima‐media thickness of the common carotid arteries as a marker of retinopathy and nephropathy in sickle cell disease. Ultrasonography 39: 79‐84, 2020.
 16.Baskurt O, Meiselman HJ. In vivo hemorheology. In: Baskurt OK, Hardeman MR, Rampling MW, Meiselman HJ, editors. Handbook of Hemorheology and Hemodynamics. Amsterdam, Berlin, Oxford, Tokyo, Washington,DC: IOS Press, 2007, p. 322‐338.
 17.Belcher JD, Chen C, Nguyen J, Abdulla F, Nguyen P, Nguyen M, Okeley NM, Benjamin DR, Senter PD, Vercellotti GM. The fucosylation inhibitor, 2‐fluorofucose, inhibits vaso‐occlusion, leukocyte‐endothelium interactions and NF‐kB activation in transgenic sickle mice. PLoS One 10: e0117772, 2015.
 18.Belcher JD, Chen C, Nguyen J, Abdulla F, Zhang P, Nguyen H, Nguyen P, Killeen T, Miescher SM, Brinkman N, Nath KA, Steer CJ, Vercellotti GM. Haptoglobin and hemopexin inhibit vaso‐occlusion and inflammation in murine sickle cell disease: Role of heme oxygenase‐1 induction. PLoS One 13: e0196455, 2018.
 19.Belcher JD, Chen C, Nguyen J, Milbauer L, Abdulla F, Alayash AI, Smith A, Nath KA, Hebbel RP, Vercellotti GM. Heme triggers TLR4 signaling leading to endothelial cell activation and vaso‐occlusion in murine sickle cell disease. Blood 123: 377‐390, 2014.
 20.Belcher JD, Mahaseth H, Welch TE, Vilback AE, Sonbol KM, Kalambur VS, Bowlin PR, Bischof JC, Hebbel RP, Vercellotti GM. Critical role of endothelial cell activation in hypoxia‐induced vasoocclusion in transgenic sickle mice. Am J Physiol Heart Circ Physiol 288: H2715‐H2725, 2005.
 21.Belcher JD, Young M, Chen C, Nguyen J, Burhop K, Tran P, Vercellotti GM. MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO‐1, inflammation, and vaso‐occlusion in transgenic sickle mice. Blood 122: 2757‐2764, 2013.
 22.Belcher JD, Zhang P, Nguyen J, Kiser ZM, Nath KA, Hu J, Trent JO, Vercellotti GM. Identification of a heme activation site on the MD‐2/TLR4 complex. Front Immunol 11: 1370, 2020.
 23.Belhassen L, Pelle G, Sediame S, Bachir D, Carville C, Bucherer C, Lacombe C, Galacteros F, Adnot S. Endothelial dysfunction in patients with sickle cell disease is related to selective impairment of shear stress‐mediated vasodilation. Blood 97: 1584‐1589, 2001.
 24.Blum A, Yeganeh S, Peleg A, Vigder F, Kryuger K, Khatib A, Khazim K, Dauerman H. Endothelial function in patients with sickle cell anemia during and after sickle cell crises. J Thromb Thrombolysis 19: 83‐86, 2005.
 25.Brousse V, Connes P. Vasomotor hyper‐responsiveness in sickle cell disease. Blood 136: 1120‐1121, 2020.
 26.Camus SM, De Moraes JA, Bonnin P, Abbyad P, Le Jeune S, Lionnet F, Loufrani L, Grimaud L, Lambry JC, Charue D, Kiger L, Renard JM, Larroque C, Le Clesiau H, Tedgui A, Bruneval P, Barja‐Fidalgo C, Alexandrou A, Tharaux PL, Boulanger CM, Blanc‐Brude OP. Circulating cell membrane microparticles transfer heme to endothelial cells and trigger vasoocclusions in sickle cell disease. Blood 125: 3805‐3814, 2015.
 27.Camus SM, Gausseres B, Bonnin P, Loufrani L, Grimaud L, Charue D, De Moraes JA, Renard JM, Tedgui A, Boulanger CM, Tharaux PL, Blanc‐Brude OP. Erythrocyte microparticles can induce kidney vaso‐occlusions in a murine model of sickle cell disease. Blood 120: 5050‐5058, 2012.
 28.Carden MA, Little J. Emerging disease‐modifying therapies for sickle cell disease. Haematologica 104: 1710‐1719, 2019.
 29.Chaar V, Laurance S, Lapoumeroulie C, Cochet S, De Grandis M, Colin Y, Elion J, Le Van Kim C, El Nemer W. Hydroxycarbamide decreases sickle reticulocyte adhesion to resting endothelium by inhibiting endothelial lutheran/basal cell adhesion molecule (Lu/BCAM) through phosphodiesterase 4A activation. J Biol Chem 289: 11512‐11521, 2014.
 30.Chang J, Patton JT, Sarkar A, Ernst B, Magnani JL, Frenette PS. GMI‐1070, a novel pan‐selectin antagonist, reverses acute vascular occlusions in sickle cell mice. Blood 116: 1779‐1786, 2010.
 31.Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, Bonds DR. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the multicenter study of hydroxyurea in sickle cell anemia. N Engl J Med 332: 1317‐1322, 1995.
 32.Charlot K, Romana M, Moeckesch B, Jumet S, Waltz X, Divialle‐Doumdo L, Hardy‐Dessources MD, Petras M, Tressieres B, Tarer V, Hue O, Etienne‐Julan M, Antoine‐Jonville S, Connes P. Which side of the balance determines the frequency of vaso‐occlusive crises in children with sickle cell anemia: Blood viscosity or microvascular dysfunction? Blood Cells Mol Dis 56: 41‐45, 2016.
 33.Charlot K, Waltz X, Hedreville M, Sinnapah S, Lemonne N, Etienne‐Julan M, Soter V, Hue O, Hardy‐Dessources MD, Connes P. Impaired oxygen uptake efficiency slope and off‐transient kinetics of pulmonary oxygen uptake in sickle cell anemia are associated with hemorheological abnormalities. Clin Hemorheol Microcirc 60: 413‐421, 2015.
 34.Chen G, Zhang D, Fuchs TA, Manwani D, Wagner DD, Frenette PS. Heme‐induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease. Blood 123: 3818‐3827, 2014.
 35.Cheung AT, Miller JW, Craig SM, To PL, Lin X, Samarron SL, Chen PC, Zwerdling T, Wun T, Li CS, Green R. Comparison of real‐time microvascular abnormalities in pediatric and adult sickle cell anemia patients. Am J Hematol 85: 899‐901, 2010.
 36.Cita KC, Brureau L, Lemonne N, Billaud M, Connes P, Ferdinand S, Tressieres B, Tarer V, Etienne‐Julan M, Blanchet P, Elion J, Romana M. Men with sickle cell anemia and priapism exhibit increased hemolytic rate, decreased red blood cell deformability and increased red blood cell aggregate strength. PLoS One 11: e0154866, 2016.
 37.Cokic VP, Smith RD, Beleslin‐Cokic BB, Njoroge JM, Miller JL, Gladwin MT, Schechter AN. Hydroxyurea induces fetal hemoglobin by the nitric oxide‐dependent activation of soluble guanylyl cyclase. J Clin Invest 111: 231‐239, 2003.
 38.Colombo M, Raposo G, Thery C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol 30: 255‐289, 2014.
 39.Connes P, Alexy T, Detterich J, Romana M, Hardy‐Dessources MD, Ballas SK. The role of blood rheology in sickle cell disease. Blood Rev 30: 111‐118, 2016.
 40.Connes P, Lamarre Y, Hardy‐Dessources MD, Lemonne N, Waltz X, Mougenel D, Mukisi‐Mukaza M, Lalanne‐Mistrih ML, Tarer V, Tressieres B, Etienne‐Julan M, Romana M. Decreased hematocrit‐to‐viscosity ratio and increased lactate dehydrogenase level in patients with sickle cell anemia and recurrent leg ulcers. PLoS One 8: e79680, 2013.
 41.Connes P, Lamarre Y, Waltz X, Ballas SK, Lemonne N, Etienne‐Julan M, Hue O, Hardy‐Dessources MD, Romana M. Haemolysis and abnormal haemorheology in sickle cell anaemia. Br J Haematol 165: 564‐572, 2014.
 42.Conran N, Belcher JD. Inflammation in sickle cell disease. Clin Hemorheol Microcirc 68: 263‐299, 2018.
 43.Da Q, Teruya M, Guchhait P, Teruya J, Olson JS, Cruz MA. Free hemoglobin increases von Willebrand factor‐mediated platelet adhesion in vitro: Implications for circulatory devices. Blood 126: 2338‐2341, 2015.
 44.Dampier CD, Telen MJ, Wun T, Smith WR, Clark Brown R, Desai P, El Rassi FA, Kanter J, Fuh BR, Pastore YD, Rothman JA, Taylor JG, Readett D, Lozier JN, Magnani JL, Thackray HM, and Hassell KL. Early initiation of treatment with rivipansel for acute vaso‐occlusive crisis in sickle cell disease (SCD) achieves earlier discontinuation of IV opioids and shorter hospital stay: Reset clinical trial analysis Blood, 136: 18–19, 2020.
 45.De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MA Jr, Shin WS, Liao JK. Nitric oxide decreases cytokine‐induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 96: 60‐68, 1995.
 46.de Montalembert M, Aggoun Y, Niakate A, Szezepanski I, Bonnet D. Endothelial‐dependent vasodilation is impaired in children with sickle cell disease. Haematologica 92: 1709‐1710, 2007.
 47.de Montalembert M, Tshilolo L, Allali S. Sickle cell disease: A comprehensive program of care from birth. Hematology Am Soc Hematol Educ Program 2019: 490‐495, 2019.
 48.de Souza GR, Hounkpe BW, Fiusa MML, Colella MP, Annichino‐Bizzacchi JM, Traina F, Costa FF, De Paula EV. Tissue factor‐dependent coagulation activation by heme: A thromboelastometry study. PLoS One 12: e0176505, 2017.
 49.Detterich JA, Kato RM, Rabai M, Meiselman HJ, Coates TD, Wood JC. Chronic transfusion therapy improves but does not normalize systemic and pulmonary vasculopathy in sickle cell disease. Blood 126: 703‐710, 2015.
 50.Donadee C, Raat NJ, Kanias T, Tejero J, Lee JS, Kelley EE, Zhao X, Liu C, Reynolds H, Azarov I, Frizzell S, Meyer EM, Donnenberg AD, Qu L, Triulzi D, Kim‐Shapiro DB, Gladwin MT. Nitric oxide scavenging by red blood cell microparticles and cell‐free hemoglobin as a mechanism for the red cell storage lesion. Circulation 124: 465‐476, 2011.
 51.Dutra FF, Alves LS, Rodrigues D, Fernandez PL, de Oliveira RB, Golenbock DT, Zamboni DS, Bozza MT. Hemolysis‐induced lethality involves inflammasome activation by heme. Proc Natl Acad Sci USA 111: E4110‐E4118, 2014.
 52.Eaton WA. Hemoglobin S polymerization and sickle cell disease: A retrospective on the occasion of the 70th anniversary of Pauling's Science paper. Am J Hematol 95: 205‐211, 2020.
 53.Eleftheriadis T, Pissas G, Antoniadi G, Liakopoulos V, Stefanidis I. Damage‐associated molecular patterns derived from mitochondria may contribute to the hemodialysis‐associated inflammation. Int Urol Nephrol 46: 107‐112, 2014.
 54.Eltzschig HK, Eckle T. Ischemia and reperfusion‐‐from mechanism to translation. Nat Med 17: 1391‐1401, 2011.
 55.Faes C, Sparkenbaugh EM, Pawlinski R. Hypercoagulable state in sickle cell disease. Clin Hemorheol Microcirc 68: 301‐318, 2018.
 56.Fantasia HC, Morse BL. Voxelotor for the treatment of sickle cell disease. Nurs Womens Health 24: 233‐237, 2020.
 57.Ferreira WA Jr, Chweih H, Lanaro C, Almeida CB, Brito PL, Gotardo EMF, Torres L, Miguel LI, Franco‐Penteado CF, Leonardo FC, Garcia F, Saad STO, Frenette PS, Brockschnieder D, Costa FF, Stasch JP, Sandner P, Conran N. Beneficial effects of soluble guanylyl cyclase stimulation and activation in sickle cell disease are amplified by hydroxyurea: In vitro and In vivo studies. J Pharmacol Exp Ther 374: 469‐478, 2020.
 58.Ferrone FA. The delay time in sickle cell disease after 40 years: A paradigm assessed. Am J Hematol 90: 438‐445, 2015.
 59.Folco EJ, Mawson TL, Vromman A, Bernardes‐Souza B, Franck G, Persson O, Nakamura M, Newton G, Luscinskas FW, Libby P. Neutrophil extracellular traps induce endothelial cell activation and tissue factor production through interleukin‐1alpha and cathepsin G. Arterioscler Thromb Vasc Biol 38: 1901‐1912, 2018.
 60.Frimat M, Tabarin F, Dimitrov JD, Poitou C, Halbwachs‐Mecarelli L, Fremeaux‐Bacchi V, Roumenina LT. Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome. Blood 122: 282‐292, 2013.
 61.Garcia‐Cardena G, Fan R, Shah V, Sorrentino R, Cirino G, Papapetropoulos A, Sessa WC. Dynamic activation of endothelial nitric oxide synthase by Hsp90. Nature 392: 821‐824, 1998.
 62.Garnier Y, Ferdinand S, Garnier M, Cita KC, Hierso R, Claes A, Connes P, Hardy‐Dessources MD, Lapoumeroulie C, Lemonne N, Etienne‐Julan M, El Nemer W, Romana M. Plasma microparticles of sickle patients during crisis or taking hydroxyurea modify endothelium inflammatory properties. Blood 136: 247‐256, 2020.
 63.Gavriilaki E, Mainou M, Christodoulou I, Koravou EE, Paleta A, Touloumenidou T, Papalexandri A, Athanasiadou A, Apostolou C, Klonizakis P, Anagnostopoulos A, Vlachaki E. In vitro evidence of complement activation in patients with sickle cell disease. Haematologica 102: e481‐e482, 2017.
 64.George A, Pushkaran S, Konstantinidis DG, Koochaki S, Malik P, Mohandas N, Zheng Y, Joiner CH, Kalfa TA. Erythrocyte NADPH oxidase activity modulated by Rac GTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease. Blood 121: 2099‐2107, 2013.
 65.Ghosh S, Adisa OA, Chappa P, Tan F, Jackson KA, Archer DR, Ofori‐Acquah SF. Extracellular hemin crisis triggers acute chest syndrome in sickle mice. J Clin Invest 123: 4809‐4820, 2013.
 66.Gladwin MT. Deconstructing endothelial dysfunction: Soluble guanylyl cyclase oxidation and the NO resistance syndrome. J Clin Invest 116: 2330‐2332, 2006.
 67.Gladwin MT, Kato GJ, Weiner D, Onyekwere OC, Dampier C, Hsu L, Hagar RW, Howard T, Nuss R, Okam MM, Tremonti CK, Berman B, Villella A, Krishnamurti L, Lanzkron S, Castro O, Gordeuk VR, Coles WA, Peters‐Lawrence M, Nichols J, Hall MK, Hildesheim M, Blackwelder WC, Baldassarre J, Casella JF, De NI. Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: A randomized controlled trial. JAMA 305: 893‐902, 2011.
 68.Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, Brown B, Coles WA, Nichols JS, Ernst I, Hunter LA, Blackwelder WC, Schechter AN, Rodgers GP, Castro O, Ognibene FP. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med 350: 886‐895, 2004.
 69.Gladwin MT, Schechter AN, Ognibene FP, Coles WA, Reiter CD, Schenke WH, Csako G, Waclawiw MA, Panza JA, Cannon RO 3rd. Divergent nitric oxide bioavailability in men and women with sickle cell disease. Circulation 107: 271‐278, 2003.
 70.Gladwin MT, Shelhamer JH, Ognibene FP, Pease‐Fye ME, Nichols JS, Link B, Patel DB, Jankowski MA, Pannell LK, Schechter AN, Rodgers GP. Nitric oxide donor properties of hydroxyurea in patients with sickle cell disease. Br J Haematol 116: 436‐444, 2002.
 71.Gondelaud F, Connes P, Nader E, Renoux C, Fort R, Gauthier A, Joly P, Ricard‐Blum S. Sialic acids rather than glycosaminoglycans affect normal and sickle red blood cell rheology by binding to four major sites on fibrinogen. Am J Hematol, 2020. DOI: 10.1002/ajh.25718.
 72.Graido‐Gonzalez E, Doherty JC, Bergreen EW, Organ G, Telfer M, McMillen MA. Plasma endothelin‐1, cytokine, and prostaglandin E2 levels in sickle cell disease and acute vaso‐occlusive sickle crisis. Blood 92: 2551‐2555, 1998.
 73.Greenwalt TJ. The how and why of exocytic vesicles. Transfusion 46: 143‐152, 2006.
 74.Hebbel RP, Belcher JD, Vercellotti GM. The multifaceted role of ischemia/reperfusion in sickle cell anemia. J Clin Invest 130: 1062‐1072, 2020.
 75.Hierso R, Lemonne N, Villaescusa R, Lalanne‐Mistrih ML, Charlot K, Etienne‐Julan M, Tressieres B, Lamarre Y, Tarer V, Garnier Y, Hernandez AA, Ferracci S, Connes P, Romana M, Hardy‐Dessources MD. Exacerbation of oxidative stress during sickle vaso‐occlusive crisis is associated with decreased anti‐band 3 autoantibodies rate and increased red blood cell‐derived microparticle level: A prospective study. Br J Haematol 176: 805‐813, 2017.
 76.Hoppe C, Jacob E, Styles L, Kuypers F, Larkin S, Vichinsky E. Simvastatin reduces vaso‐occlusive pain in sickle cell anaemia: A pilot efficacy trial. Br J Haematol 177: 620‐629, 2017.
 77.Howard J. Sickle cell disease: When and how to transfuse. Hematology Am Soc Hematol Educ Program 2016: 625‐631, 2016.
 78.Hsu L, Diwan B, Ward JM, Noguchi CT. Pathology of “Berkeley” sickle‐cell mice includes gallstones and priapism. Blood 107: 3414‐3415, 2006.
 79.Hsu LL, Champion HC, Campbell‐Lee SA, Bivalacqua TJ, Manci EA, Diwan BA, Schimel DM, Cochard AE, Wang X, Schechter AN, Noguchi CT, Gladwin MT. Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability. Blood 109: 3088‐3098, 2007.
 80.Hyacinth HI, Adams RJ, Greenberg CS, Voeks JH, Hill A, Hibbert JM, Gee BE. Effect of chronic blood transfusion on biomarkers of coagulation activation and thrombin generation in sickle cell patients at risk for stroke. PLoS One 10: e0134193, 2015.
 81.Hyacinth HI, Adams RJ, Voeks JH, Hibbert JM, Gee BE. Frequent red cell transfusions reduced vascular endothelial activation and thrombogenicity in children with sickle cell anemia and high stroke risk. Am J Hematol 89: 47‐51, 2014.
 82.Jane‐wit D, Surovtseva YV, Qin L, Li G, Liu R, Clark P, Manes TD, Wang C, Kashgarian M, Kirkiles‐Smith NC, Tellides G, Pober JS. Complement membrane attack complexes activate noncanonical NF‐kappaB by forming an Akt+ NIK+ signalosome on Rab5+ endosomes. Proc Natl Acad Sci USA 112: 9686‐9691, 2015.
 83.Johnson C, Telen MJ. Adhesion molecules and hydroxyurea in the pathophysiology of sickle cell disease. Haematologica 93: 481‐485, 2008.
 84.Jorch SK, Kubes P. An emerging role for neutrophil extracellular traps in noninfectious disease. Nat Med 23: 279‐287, 2017.
 85.Kato GJ, Gladwin MT, Steinberg MH. Deconstructing sickle cell disease: Reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev 21: 37‐47, 2007.
 86.Kato GJ, McGowan V, Machado RF, Little JA, Taylor Jt, Morris CR, Nichols JS, Wang X, Poljakovic M, Morris SM Jr, Gladwin MT. Lactate dehydrogenase as a biomarker of hemolysis‐associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. Blood 107: 2279‐2285, 2006.
 87.Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene‐Frempong K, Krishnamurti L, Smith WR, Panepinto JA, Weatherall DJ, Costa FF, Vichinsky EP. Sickle cell disease. Nat Rev Dis Primers 4: 18010, 2018.
 88.Kato GJ, Steinberg MH, Gladwin MT. Intravascular hemolysis and the pathophysiology of sickle cell disease. J Clin Invest 127: 750‐760, 2017.
 89.Kaul DK, Hebbel RP. Hypoxia/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice. J Clin Invest 106: 411‐420, 2000.
 90.Kaul DK, Liu XD, Fabry ME, Nagel RL. Impaired nitric oxide‐mediated vasodilation in transgenic sickle mouse. Am J Physiol Heart Circ Physiol 278: H1799‐H1806, 2000.
 91.Keikhaei B, Mohseni AR, Norouzirad R, Alinejadi M, Ghanbari S, Shiravi F, Solgi G. Altered levels of pro‐inflammatory cytokines in sickle cell disease patients during vaso‐occlusive crises and the steady state condition. Eur Cytokine Netw 24: 45‐52, 2013.
 92.Keipert PE, Investigators MC‐S‐S. Clinical evaluation of MP4CO: A phase 1b escalating‐dose, safety and tolerability study in stable adult patients with sickle cell disease. Adv Exp Med Biol 923: 23‐29, 2016.
 93.Khalyfa A, Khalyfa AA, Akbarpour M, Connes P, Romana M, Lapping‐Carr G, Zhang C, Andrade J, Gozal D. Extracellular microvesicle microRNAs in children with sickle cell anaemia with divergent clinical phenotypes. Br J Haematol 174: 786‐798, 2016.
 94.King SB. A role for nitric oxide in hydroxyurea‐mediated fetal hemoglobin induction. J Clin Invest 111: 171‐172, 2003.
 95.Knepler JL Jr, Taher LN, Gupta MP, Patterson C, Pavalko F, Ober MD, Hart CM. Peroxynitrite causes endothelial cell monolayer barrier dysfunction. Am J Physiol Cell Physiol 281: C1064‐C1075, 2001.
 96.Krysko DV, Agostinis P, Krysko O, Garg AD, Bachert C, Lambrecht BN, Vandenabeele P. Emerging role of damage‐associated molecular patterns derived from mitochondria in inflammation. Trends Immunol 32: 157‐164, 2011.
 97.Lamarre Y, Hardy‐Dessources MD, Romana M, Lalanne‐Mistrih ML, Waltz X, Petras M, Doumdo L, Blanchet‐Deverly A, Martino J, Tressieres B, Maillard F, Tarer V, Etienne‐Julan M, Connes P. Relationships between systemic vascular resistance, blood rheology and nitric oxide in children with sickle cell anemia or sickle cell‐hemoglobin C disease. Clin Hemorheol Microcirc 58: 307‐316, 2014.
 98.Lamarre Y, Romana M, Lemonne N, Hardy‐Dessources MD, Tarer V, Mougenel D, Waltz X, Tressieres B, Lalanne‐Mistrih ML, Etienne‐Julan M, Connes P. Alpha thalassemia protects sickle cell anemia patients from macro‐albuminuria through its effects on red blood cell rheological properties. Clin Hemorheol Microcirc 57: 63‐72, 2014.
 99.Lamarre Y, Romana M, Waltz X, Lalanne‐Mistrih ML, Tressieres B, Divialle‐Doumdo L, Hardy‐Dessources MD, Vent‐Schmidt J, Petras M, Broquere C, Maillard F, Tarer V, Etienne‐Julan M, Connes P. Hemorheological risk factors of acute chest syndrome and painful vaso‐occlusive crisis in children with sickle cell disease. Haematologica 97: 1641‐1647, 2012.
 100.Landburg PP, Teerlink T, Biemond BJ, Brandjes DP, Muskiet FA, Duits AJ, Schnog JB, CURAMA study group. Plasma asymmetric dimethylarginine concentrations in sickle cell disease are related to the hemolytic phenotype. Blood Cells Mol Dis 44: 229‐232, 2010.
 101.Lapoumeroulie C, Connes P, El Hoss S, Hierso R, Charlot K, Lemonne N, Elion J, Le Van Kim C, Romana M, Hardy‐Dessources MD. New insights into red cell rheology and adhesion in patients with sickle cell anaemia during vaso‐occlusive crises. Br J Haematol 185: 991‐994, 2019.
 102.Lavrovsky Y, Chatterjee B, Clark RA, Roy AK. Role of redox‐regulated transcription factors in inflammation, aging and age‐related diseases. Exp Gerontol 35: 521‐532, 2000.
 103.Lemonne N, Charlot K, Waltz X, Ballas SK, Lamarre Y, Lee K, Hierso R, Connes C, Etienne‐Julan M, Romana M, Connes P. Hydroxyurea treatment does not increase blood viscosity and improves red blood cell rheology in sickle cell anemia. Haematologica 100: e383‐e386, 2015.
 104.Lemonne N, Lamarre Y, Romana M, Mukisi‐Mukaza M, Hardy‐Dessources MD, Tarer V, Mougenel D, Waltz X, Tressieres B, Lalanne‐Mistrih ML, Etienne‐Julan M, Connes P. Does increased red blood cell deformability raise the risk for osteonecrosis in sickle cell anemia? Blood 121: 3054‐3056, 2013.
 105.Lemonne N, Romana M, Lamarre Y, Hardy‐Dessources MD, Lionnet F, Waltz X, Tarer V, Mougenel D, Tressieres B, Lalanne‐Mistrih ML, Etienne‐Julan M, Connes P. Association between relative systemic hypertension and otologic disorders in patients with sickle cell‐hemoglobin C disorder. Am J Hematol 89: 667, 2014.
 106.Liu D, Yang P, Gao M, Yu T, Shi Y, Zhang M, Yao M, Liu Y, Zhang X. NLRP3 activation induced by neutrophil extracellular traps sustains inflammatory response in the diabetic wound. Clin Sci (Lond) 133: 565‐582, 2019.
 107.Lombardi E, Matte A, Risitano AM, Ricklin D, Lambris JD, De Zanet D, Jokiranta ST, Martinelli N, Scambi C, Salvagno G, Bisoffi Z, Colato C, Siciliano A, Bortolami O, Mazzuccato M, Zorzi F, De Marco L, De Franceschi L. Factor H interferes with the adhesion of sickle red cells to vascular endothelium: A novel disease‐modulating molecule. Haematologica 104: 919‐928, 2019.
 108.Manci EA, Hillery CA, Bodian CA, Zhang ZG, Lutty GA, Coller BS. Pathology of Berkeley sickle cell mice: Similarities and differences with human sickle cell disease. Blood 107: 1651‐1658, 2006.
 109.Mendonca R, Silveira AA, Conran N. Red cell DAMPs and inflammation. Inflamm Res 65: 665‐678, 2016.
 110.Meng F, Kaul D, Thangaswamy S, Bhutoria S, Gerfen G, Branch C, Intaglietta M, Acharya SA. Semisynthetic supra plasma expanders: A new class of therapeutics to improve microcircualtion in sickle cell anaemia. Artif Cells Nanomed Biotechnol 47: 73‐82, 2019.
 111.Merle NS, Grunenwald A, Rajaratnam H, Gnemmi V, Frimat M, Figueres ML, Knockaert S, Bouzekri S, Charue D, Noe R, Robe‐Rybkine T, Le‐Hoang M, Brinkman N, Gentinetta T, Edler M, Petrillo S, Tolosano E, Miescher S, Le Jeune S, Houillier P, Chauvet S, Rabant M, Dimitrov JD, Fremeaux‐Bacchi V, Blanc‐Brude OP, Roumenina LT. Intravascular hemolysis activates complement via cell‐free heme and heme‐loaded microvesicles. JCI Insight 3: e96910, 2018.
 112.Minniti CP, Gorbach AM, Xu D, Hon YY, Delaney KM, Seidel M, Malik N, Peters‐Lawrence M, Cantilena C, Nichols JS, Mendelsohn L, Conrey A, Grimes G, Kato GJ. Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia: A phase 1 dose‐finding safety and tolerability trial. Lancet Haematol 1: e95‐e103, 2014.
 113.Möckesch B, Charlot K, Jumet S, Romana M, Divialle‐Doumdo L, Hardy‐Dessources MD, Petras M, Tressieres B, Tarer V, Hue O, Etienne‐Julan M, Connes P, Antoine‐Jonville S. Micro‐ and macrovascular function in children with sickle cell anaemia and sickle cell haemoglobin C disease. Blood Cells Mol Dis 64: 23‐29, 2017.
 114.Mohan JS, Lip GY, Blann AD, Bareford D, Marshall JM. Endothelium‐dependent and endothelium‐independent vasodilatation of the cutaneous circulation in sickle cell disease. Eur J Clin Invest 41: 546‐551, 2011.
 115.Muller‐Eberhard U, Javid J, Liem HH, Hanstein A, Hanna M. Plasma concentrations of hemopexin, haptoglobin and heme in patients with various hemolytic diseases. Blood 32: 811‐815, 1968.
 116.Murad F, Rapoport RM, Fiscus R. Role of cyclic‐GMP in relaxations of vascular smooth muscle. J Cardiovasc Pharmacol 7 (Suppl 3): S111‐S118, 1985.
 117.Nader E, Connes P, Lamarre Y, Renoux C, Joly P, Hardy‐Dessources MD, Cannas G, Lemonne N, Ballas SK. Plasmapheresis may improve clinical condition in sickle cell disease through its effects on red blood cell rheology. Am J Hematol 92: E629‐E630, 2017.
 118.Nader E, Grau M, Fort R, Collins B, Cannas G, Gauthier A, Walpurgis K, Martin C, Bloch W, Poutrel S, Hot A, Renoux C, Thevis M, Joly P, Romana M, Guillot N, Connes P. Hydroxyurea therapy modulates sickle cell anemia red blood cell physiology: Impact on RBC deformability, oxidative stress, nitrite levels and nitric oxide synthase signalling pathway. Nitric Oxide 81: 28‐35, 2018.
 119.Nader E, Romana M, Guillot N, Fort R, Stauffer E, Lemonne N, Garnier Y, Skinner SC, Etienne‐Julan M, Robert M, Gauthier A, Cannas G, Antoine‐Jonville S, Tressieres B, Hardy‐Dessources MD, Bertrand Y, Martin C, Renoux C, Joly P, Grau M, Connes P. Association between nitric oxide, oxidative stress, eryptosis, red blood cell microparticles, and vascular function in sickle cell anemia. Front Immunol 11: 551441, 2020.
 120.Nader E, Skinner S, Romana M, Fort R, Lemonne N, Guillot N, Gauthier A, Antoine‐Jonville S, Renoux C, Hardy‐Dessources MD, Stauffer E, Joly P, Bertrand Y, Connes P. Blood rheology: Key parameters, impact on blood flow, role in sickle cell disease and effects of exercise. Front Physiol 10: 1329, 2019.
 121.Naik RP, Streiff MB, Haywood C Jr, Segal JB, Lanzkron S. Venous thromboembolism incidence in the cooperative study of sickle cell disease. J Thromb Haemost 12: 2010‐2016, 2014.
 122.Nebor D, Bowers A, Connes P, Hardy‐Dessources MD, Knight‐Madden J, Cumming V, Reid M, Romana M. Plasma concentration of platelet‐derived microparticles is related to painful vaso‐occlusive phenotype severity in sickle cell anemia. PLoS One 9: e87243, 2014.
 123.Nebor D, Bowers A, Hardy‐Dessources MD, Knight‐Madden J, Romana M, Reid H, Barthelemy JC, Cumming V, Hue O, Elion J, Reid M, Connes P, Group CS. Frequency of pain crises in sickle cell anemia and its relationship with the sympatho‐vagal balance, blood viscosity and inflammation. Haematologica 96: 1589‐1594, 2011.
 124.Nebor D, Romana M, Santiago R, Vachiery N, Picot J, Broquere C, Chaar V, Doumdo L, Odievre MH, Benkerrou M, Elion J. Fetal hemoglobin and hydroxycarbamide moduate both plasma concentration and cellular origin of circulating microparticles in sickle cell anemia children. Haematologica 98: 862‐867, 2013.
 125.Niihara Y, Smith WR, Stark CW. A phase 3 trial of l‐glutamine in sickle cell disease. N Engl J Med 379: 1880, 2018.
 126.Niu X, Nouraie M, Campbell A, Rana S, Minniti CP, Sable C, Darbari D, Dham N, Reading NS, Prchal JT, Kato GJ, Gladwin MT, Castro OL, Gordeuk VR. Angiogenic and inflammatory markers of cardiopulmonary changes in children and adolescents with sickle cell disease. PLoS One 4: e7956, 2009.
 127.Noubouossie D, Key NS, Ataga KI. Coagulation abnormalities of sickle cell disease: Relationship with clinical outcomes and the effect of disease modifying therapies. Blood Rev 30: 245‐256, 2016.
 128.Nouraie M, Lee JS, Zhang Y, Kanias T, Zhao X, Xiong Z, Oriss TB, Zeng Q, Kato GJ, Gibbs JS, Hildesheim ME, Sachdev V, Barst RJ, Machado RF, Hassell KL, Little JA, Schraufnagel DE, Krishnamurti L, Novelli E, Girgis RE, Morris CR, Rosenzweig EB, Badesch DB, Lanzkron S, Castro OL, Goldsmith JC, Gordeuk VR, Gladwin MT, Walk PI, Patients. The relationship between the severity of hemolysis, clinical manifestations and risk of death in 415 patients with sickle cell anemia in the US and Europe. Haematologica 98: 464‐472, 2013.
 129.Nur E, Brandjes DP, Teerlink T, Otten HM, Oude Elferink RP, Muskiet F, Evers LM, ten Cate H, Biemond BJ, Duits AJ, Schnog JJ, CURAMA study group. N‐acetylcysteine reduces oxidative stress in sickle cell patients. Ann Hematol 91: 1097‐1105, 2012.
 130.Olatunya OS, Lanaro C, Longhini AL, Penteado CFF, Fertrin KY, Adekile A, Saad STO, Costa FF. Red blood cells microparticles are associated with hemolysis markers and may contribute to clinical events among sickle cell disease patients. Ann Hematol 98: 2507‐2521, 2019.
 131.Pitanga TN, Oliveira RR, Zanette DL, Guarda CC, Santiago RP, Santana SS, Nascimento VML, Lima JB, Carvalho GQ, Maffili VV, Carvalho MOS, Alcantara LCJ, Borges VM, Goncalves MS. Sickle red cells as danger signals on proinflammatory gene expression, leukotriene B4 and interleukin‐1 beta production in peripheral blood mononuclear cell. Cytokine 83: 75‐84, 2016.
 132.Pohlman TH, Harlan JM. Adaptive responses of the endothelium to stress. J Surg Res 89: 85‐119, 2000.
 133.Poludasu S, Ramkissoon K, Salciccioli L, Kamran H, Lazar JM. Left ventricular systolic function in sickle cell anemia: A meta‐analysis. J Card Fail 19: 333‐341, 2013.
 134.Potoka KP, Gladwin MT. Vasculopathy and pulmonary hypertension in sickle cell disease. Am J Physiol Lung Cell Mol Physiol 308: L314‐L324, 2015.
 135.Potoka KP, Wood KC, Baust JJ, Bueno M, Hahn SA, Vanderpool RR, Bachman T, Mallampalli GM, Osei‐Hwedieh DO, Schrott V, Sun B, Bullock GC, Becker‐Pelster EM, Wittwer M, Stampfuss J, Mathar I, Stasch JP, Truebel H, Sandner P, Mora AL, Straub AC, Gladwin MT. Nitric oxide‐independent soluble guanylate cyclase activation improves vascular function and cardiac remodeling in sickle cell disease. Am J Respir Cell Mol Biol 58: 636‐647, 2018.
 136.Pritchard KA Jr, Ou J, Ou Z, Shi Y, Franciosi JP, Signorino P, Kaul S, Ackland‐Berglund C, Witte K, Holzhauer S, Mohandas N, Guice KS, Oldham KT, Hillery CA. Hypoxia‐induced acute lung injury in murine models of sickle cell disease. Am J Physiol Lung Cell Mol Physiol 286: L705‐L714, 2004.
 137.Quinn CT. l‐Glutamine for sickle cell anemia: More questions than answers. Blood 132: 689‐693, 2018.
 138.Radomski MW, Moncada S. The biological and pharmacological role of nitric oxide in platelet function. Adv Exp Med Biol 344: 251‐264, 1993.
 139.Ranque B, Menet A, Boutouyrie P, Diop IB, Kingue S, Diarra M, N'Guetta R, Diallo D, Diop S, Diagne I, Sanogo I, Tolo A, Chelo D, Wamba G, Gonzalez JP, Abough'elie C, Diakite CO, Traore Y, Legueun G, Deme‐Ly I, Faye BF, Seck M, Kouakou B, Kamara I, Le Jeune S, Jouven X. Arterial stiffness impairment in sickle cell disease associated with chronic vascular complications: The multinational african CADRE study. Circulation 134: 923‐933, 2016.
 140.Ravelojaona M, Feasson L, Oyono‐Enguelle S, Vincent L, Djoubairou B, Ewa'Sama Essoue C, Messonnier LA. Evidence for a profound remodeling of skeletal muscle and its microvasculature in sickle cell anemia. Am J Pathol 185: 1448‐1456, 2015.
 141.Rees DC, Williams TN, Gladwin MT. Sickle‐cell disease. Lancet 376: 2018‐2031, 2010.
 142.Reiter CD, Wang X, Tanus‐Santos JE, Hogg N, Cannon RO 3rd, Schechter AN, Gladwin MT. Cell‐free hemoglobin limits nitric oxide bioavailability in sickle‐cell disease. Nat Med 8: 1383‐1389, 2002.
 143.Renoux C, Connes P, Nader E, Skinner S, Faes C, Petras M, Bertrand Y, Garnier N, Cuzzubbo D, Divialle‐Doumdo L, Kebaili K, Renard C, Gauthier A, Etienne‐Julan M, Cannas G, Martin C, Hardy‐Dessources M‐D, Pialoux V, Romana M, Joly P. Alpha‐thalassaemia promotes frequent vaso‐occlusive crises in children with sickle cell anaemia through haemorheological changes. Pediatr Blood Cancer 64: e26455, 2017.
 144.Riddell DR, Owen JS. Nitric oxide and platelet aggregation. Vitam Horm 57: 25‐48, 1999.
 145.Rybicki AC, Benjamin LJ. Increased levels of endothelin‐1 in plasma of sickle cell anemia patients. Blood 92: 2594‐2596, 1998.
 146.Sabaa N, de Franceschi L, Bonnin P, Castier Y, Malpeli G, Debbabi H, Galaup A, Maier‐Redelsperger M, Vandermeersch S, Scarpa A, Janin A, Levy B, Girot R, Beuzard Y, Leboeuf C, Henri A, Germain S, Dussaule JC, Tharaux PL. Endothelin receptor antagonism prevents hypoxia‐induced mortality and morbidity in a mouse model of sickle‐cell disease. J Clin Invest 118: 1924‐1933, 2008.
 147.Saleh AW, Hillen HF, Duits AJ. Levels of endothelial, neutrophil and platelet‐specific factors in sickle cell anemia patients during hydroxyurea therapy. Acta Haematol 102: 31‐37, 1999.
 148.Santiago RP, Guarda CC, Figueiredo CVB, Fiuza LM, Aleluia MM, Adanho CSA, Carvalho MOS, Pitanga TN, Zanette DL, Lyra IM, Nascimento VML, Vercellotti GM, Belcher JD, Goncalves MS. Serum haptoglobin and hemopexin levels are depleted in pediatric sickle cell disease patients. Blood Cells Mol Dis 72: 34‐36, 2018.
 149.Saraf SL, Zhang X, Kanias T, Lash JP, Molokie RE, Oza B, Lai C, Rowe JH, Gowhari M, Hassan J, Desimone J, Machado RF, Gladwin MT, Little JA, Gordeuk VR. Haemoglobinuria is associated with chronic kidney disease and its progression in patients with sickle cell anaemia. Br J Haematol 164: 729‐739, 2014.
 150.Schechter AN, Gladwin MT. Hemoglobin and the paracrine and endocrine functions of nitric oxide. N Engl J Med 348: 1483‐1485, 2003.
 151.Schimmel M, Nur E, Biemond BJ, van Mierlo GJ, Solati S, Brandjes DP, Otten HM, Schnog JJ, Zeerleder S, Curama Study Group. Nucleosomes and neutrophil activation in sickle cell disease painful crisis. Haematologica 98: 1797‐1803, 2013.
 152.Schmidt HM, Kelley EE, Straub AC. The impact of xanthine oxidase (XO) on hemolytic diseases. Redox Biol 21: 101072, 2019.
 153.Setty BN, Stuart MJ. Vascular cell adhesion molecule‐1 is involved in mediating hypoxia‐induced sickle red blood cell adherence to endothelium: Potential role in sickle cell disease. Blood 88: 2311‐2320, 1996.
 154.Shet AS, Aras O, Gupta K, Hass MJ, Rausch DJ, Saba N, Koopmeiners L, Key NS, Hebbel RP. Sickle blood contains tissue factor‐positive microparticles derived from endothelial cells and monocytes. Blood 102: 2678‐2683, 2003.
 155.Sins JWR, Fijnvandraat K, Rijneveld AW, Boom MB, Kerkhoffs JH, van Meurs AH, de Groot MR, Heijboer H, Dresse MF, Le PQ, Hermans P, Vanderfaeillie A, Van Den Neste EW, Benghiat FS, Kesse‐Adu R, Delannoy A, Efira A, Azerad MA, de Borgie CA, Biemond BJ. Effect of N‐acetylcysteine on pain in daily life in patients with sickle cell disease: A randomised clinical trial. Br J Haematol 182: 444‐448, 2018.
 156.Sivamurthy KM, Dampier C, MacDermott M, Maureen M, Cahill M, Hsu LL. Peripheral arterial tonometry in assessing endothelial dysfunction in pediatric sickle cell disease. Pediatr Hematol Oncol 26: 589–596, 2009.
 157.Smith TP, Schlenz AM, Schatz JC, Maitra R, Sweitzer SM. Modulation of pain in pediatric sickle cell disease: Understanding the balance between endothelin mediated vasoconstriction and apelin mediated vasodilation. Blood Cells Mol Dis 54: 155‐159, 2015.
 158.Sriram K, Salazar Vazquez BY, Tsai AG, Cabrales P, Intaglietta M, Tartakovsky DM. Autoregulation and mechanotransduction control the arteriolar response to small changes in hematocrit. Am J Physiol Heart Circ Physiol 303: H1096‐H1106, 2012.
 159.Tantawy AA, Adly AA, Ismail EA, Habeeb NM, Farouk A. Circulating platelet and erythrocyte microparticles in young children and adolescents with sickle cell disease: Relation to cardiovascular complications. Platelets 24: 605‐614, 2013.
 160.Teixeira RS, Terse‐Ramos R, Ferreira TA, Machado VR, Perdiz MI, Lyra IM, Nascimento VL, Boa‐Sorte N, Andrade BB, Ladeia AM. Associations between endothelial dysfunction and clinical and laboratory parameters in children and adolescents with sickle cell anemia. PLoS One 12: e0184076, 2017.
 161.Telen MJ. Beyond hydroxyurea: New and old drugs in the pipeline for sickle cell disease. Blood 127: 810‐819, 2016.
 162.Telen MJ, Wun T, McCavit TL, De Castro LM, Krishnamurti L, Lanzkron S, Hsu LL, Smith WR, Rhee S, Magnani JL, Thackray H. Randomized phase 2 study of GMI‐1070 in SCD: Reduction in time to resolution of vaso‐occlusive events and decreased opioid use. Blood 125: 2656‐2664, 2015.
 163.Thalin C, Hisada Y, Lundstrom S, Mackman N, Wallen H. Neutrophil extracellular traps: Villains and targets in arterial, venous, and cancer‐associated thrombosis. Arterioscler Thromb Vasc Biol 39: 1724‐1738, 2019.
 164.Thamilarasan M, Fogler WE, Magnani JL, and Zennadi R. Restoration of normal blood flow in mouse models of sickle cell vaso‐occlusion following intravenous or subcutaneous administration of a highly potent E‐selectin specific inhibitor. Blood 136: 17, 2020.
 165.Tharaux PL, Girot R, Kanfer A, Dussaule JC, Gaitz JP, Tribout L, Baudot N, Vayssairat M. Cutaneous microvascular blood flow and reactivity in patients with homozygous sickle cell anaemia. Eur J Haematol 68: 327‐331, 2002.
 166.Thery C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, Antoniou A, Arab T, Archer F, Atkin‐Smith GK, Ayre DC, Bach JM, Bachurski D, Baharvand H, Balaj L, Baldacchino S, Bauer NN, Baxter AA, Bebawy M, Beckham C, Bedina Zavec A, Benmoussa A, Berardi AC, Bergese P, Bielska E, Blenkiron C, Bobis‐Wozowicz S, Boilard E, Boireau W, Bongiovanni A, Borras FE, Bosch S, Boulanger CM, Breakefield X, Breglio AM, Brennan MA, Brigstock DR, Brisson A, Broekman ML, Bromberg JF, Bryl‐Gorecka P, Buch S, Buck AH, Burger D, Busatto S, Buschmann D, Bussolati B, Buzas EI, Byrd JB, Camussi G, Carter DR, Caruso S, Chamley LW, Chang YT, Chen C, Chen S, Cheng L, Chin AR, Clayton A, Clerici SP, Cocks A, Cocucci E, Coffey RJ, Cordeiro‐da‐Silva A, Couch Y, Coumans FA, Coyle B, Crescitelli R, Criado MF, D'Souza‐Schorey C, Das S, Datta Chaudhuri A, de Candia P, De Santana EF, De Wever O, Del Portillo HA, Demaret T, Deville S, Devitt A, Dhondt B, Di Vizio D, Dieterich LC, Dolo V, Dominguez Rubio AP, Dominici M, Dourado MR, Driedonks TA, Duarte FV, Duncan HM, Eichenberger RM, Ekstrom K, El Andaloussi S, Elie‐Caille C, Erdbrugger U, Falcon‐Perez JM, Fatima F, Fish JE, Flores‐Bellver M, Forsonits A, Frelet‐Barrand A, Fricke F, Fuhrmann G, Gabrielsson S, Gamez‐Valero A, Gardiner C, Gartner K, Gaudin R, Gho YS, Giebel B, Gilbert C, Gimona M, Giusti I, Goberdhan DC, Gorgens A, Gorski SM, Greening DW, Gross JC, Gualerzi A, Gupta GN, Gustafson D, Handberg A, Haraszti RA, Harrison P, Hegyesi H, Hendrix A, Hill AF, Hochberg FH, Hoffmann KF, Holder B, Holthofer H, Hosseinkhani B, Hu G, Huang Y, Huber V, Hunt S, Ibrahim AG, Ikezu T, Inal JM, Isin M, Ivanova A, Jackson HK, Jacobsen S, Jay SM, Jayachandran M, Jenster G, Jiang L, Johnson SM, Jones JC, Jong A, Jovanovic‐Talisman T, Jung S, Kalluri R, Kano SI, Kaur S, Kawamura Y, Keller ET, Khamari D, Khomyakova E, Khvorova A, Kierulf P, Kim KP, Kislinger T, Klingeborn M, Klinke DJ 2nd, Kornek M, Kosanovic MM, Kovacs AF, Kramer‐Albers EM, Krasemann S, Krause M, Kurochkin IV, Kusuma GD, Kuypers S, Laitinen S, Langevin SM, Languino LR, Lannigan J, Lasser C, Laurent LC, Lavieu G, Lazaro‐Ibanez E, Le Lay S, Lee MS, Lee YXF, Lemos DS, Lenassi M, Leszczynska A, Li IT, Liao K, Libregts SF, Ligeti E, Lim R, Lim SK, Line A, Linnemannstons K, Llorente A, Lombard CA, Lorenowicz MJ, Lorincz AM, Lotvall J, Lovett J, Lowry MC, Loyer X, Lu Q, Lukomska B, Lunavat TR, Maas SL, Malhi H, Marcilla A, Mariani J, Mariscal J, Martens‐Uzunova ES, Martin‐Jaular L, Martinez MC, Martins VR, Mathieu M, Mathivanan S, Maugeri M, McGinnis LK, McVey MJ, Meckes DG Jr, Meehan KL, Mertens I, Minciacchi VR, Moller A, Moller Jorgensen M, Morales‐Kastresana A, Morhayim J, Mullier F, Muraca M, Musante L, Mussack V, Muth DC, Myburgh KH, Najrana T, Nawaz M, Nazarenko I, Nejsum P, Neri C, Neri T, Nieuwland R, Nimrichter L, Nolan JP, Nolte‐'t Hoen EN, Noren Hooten N, O'Driscoll L, O'Grady T, O'Loghlen A, Ochiya T, Olivier M, Ortiz A, Ortiz LA, Osteikoetxea X, Ostergaard O, Ostrowski M, Park J, Pegtel DM, Peinado H, Perut F, Pfaffl MW, Phinney DG, Pieters BC, Pink RC, Pisetsky DS, Pogge von Strandmann E, Polakovicova I, Poon IK, Powell BH, Prada I, Pulliam L, Quesenberry P, Radeghieri A, Raffai RL, Raimondo S, Rak J, Ramirez MI, Raposo G, Rayyan MS, Regev‐Rudzki N, Ricklefs FL, Robbins PD, Roberts DD, Rodrigues SC, Rohde E, Rome S, Rouschop KM, Rughetti A, Russell AE, Saa P, Sahoo S, Salas‐Huenuleo E, Sanchez C, Saugstad JA, Saul MJ, Schiffelers RM, Schneider R, Schoyen TH, Scott A, Shahaj E, Sharma S, Shatnyeva O, Shekari F, Shelke GV, Shetty AK, Shiba K, Siljander PR, Silva AM, Skowronek A, Snyder OL 2nd, Soares RP, Sodar BW, Soekmadji C, Sotillo J, Stahl PD, Stoorvogel W, Stott SL, Strasser EF, Swift S, Tahara H, Tewari M, Timms K, Tiwari S, Tixeira R, Tkach M, Toh WS, Tomasini R, Torrecilhas AC, Tosar JP, Toxavidis V, Urbanelli L, Vader P, van Balkom BW, van der Grein SG, Van Deun J, van Herwijnen MJ, Van Keuren‐Jensen K, van Niel G, van Royen ME, van Wijnen AJ, Vasconcelos MH, Vechetti IJ Jr, Veit TD, Vella LJ, Velot E, Verweij FJ, Vestad B, Vinas JL, Visnovitz T, Vukman KV, Wahlgren J, Watson DC, Wauben MH, Weaver A, Webber JP, Weber V, Wehman AM, Weiss DJ, Welsh JA, Wendt S, Wheelock AM, Wiener Z, Witte L, Wolfram J, Xagorari A, Xander P, Xu J, Yan X, Yanez‐Mo M, Yin H, Yuana Y, Zappulli V, Zarubova J, Zekas V, Zhang JY, Zhao Z, Zheng L, Zheutlin AR, Zickler AM, Zimmermann P, Zivkovic AM, Zocco D, Zuba‐Surma EK. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): A position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles 7: 1535750, 2018.
 167.Tripette J, Alexy T, Hardy‐Dessources MD, Mougenel D, Beltan E, Chalabi T, Chout R, Etienne‐Julan M, Hue O, Meiselman HJ, Connes P. Red blood cell aggregation, aggregate strength and oxygen transport potential of blood are abnormal in both homozygous sickle cell anemia and sickle‐hemoglobin C disease. Haematologica 94: 1060‐1065, 2009.
 168.van Beers EJ, Schaap MC, Berckmans RJ, Nieuwland R, Sturk A, van Doormaal FF, Meijers JC, Biemond BJ, CURAMA study group. Circulating erythrocyte‐derived microparticles are associated with coagulation activation in sickle cell disease. Haematologica 94: 1513‐1519, 2009.
 169.VanWijk MJ, VanBavel E, Sturk A, Nieuwland R. Microparticles in cardiovascular diseases. Cardiovasc Res 59: 277‐287, 2003.
 170.Veluswamy S, Shah P, Khaleel M, Thuptimdang W, Chalacheva P, Sunwoo J, Denton CC, Kato RM, Detterich JA, Wood JC, Sposto R, Khoo MC, Zeltzer L, Coates TD. Progressive vasoconstriction with sequential thermal stimulation indicates vascular dysautonomia in sickle cell disease. Blood 136: 1191‐1200, 2020.
 171.Vichinsky E, Gordeuk VR, Telfer P, Inati A, Tonda M, Gray S, Agodoa I, and Ataga KI. Higher hemoglobin levels achieved with voxelotor are associated with lower vaso‐occlusive crisis incidence: 72‐Week analysis from the HOPE study. Blood, 136: 31–32, 2020.
 172.Vichinsky E, Hoppe CC, Ataga KI, Ware RE, Nduba V, El‐Beshlawy A, Hassab H, Achebe MM, Alkindi S, Brown RC, Diuguid DL, Telfer P, Tsitsikas DA, Elghandour A, Gordeuk VR, Kanter J, Abboud MR, Lehrer‐Graiwer J, Tonda M, Intondi A, Tong B, Howard J, Investigators HTA. Phase 3 randomized trial of voxelotor in sickle cell disease. N Engl J Med 381: 509‐519, 2019.
 173.Villagra J, Shiva S, Hunter LA, Machado RF, Gladwin MT, Kato GJ. Platelet activation in patients with sickle disease, hemolysis‐associated pulmonary hypertension, and nitric oxide scavenging by cell‐free hemoglobin. Blood 110: 2166‐2172, 2007.
 174.Voskou S, Aslan M, Fanis P, Phylactides M, Kleanthous M. Oxidative stress in beta‐thalassaemia and sickle cell disease. Redox Biol 6: 226‐239, 2015.
 175.Wagener FA, Eggert A, Boerman OC, Oyen WJ, Verhofstad A, Abraham NG, Adema G, van Kooyk Y, de Witte T, Figdor CG. Heme is a potent inducer of inflammation in mice and is counteracted by heme oxygenase. Blood 98: 1802‐1811, 2001.
 176.Wagener FA, Feldman E, de Witte T, Abraham NG. Heme induces the expression of adhesion molecules ICAM‐1, VCAM‐1, and E selectin in vascular endothelial cells. Proc Soc Exp Biol Med 216: 456‐463, 1997.
 177.Ware RE, de Montalembert M, Tshilolo L, Abboud MR. Sickle cell disease. Lancet 390: 311‐323, 2017.
 178.Ware RE, Helms RW, Investigators SW. Stroke with transfusions changing to hydroxyurea (SWiTCH). Blood 119: 3925‐3932, 2012.
 179.Warnatsch A, Ioannou M, Wang Q, Papayannopoulos V. Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science 349: 316‐320, 2015.
 180.Werdehoff SG, Moore RB, Hoff CJ, Fillingim E, Hackman AM. Elevated plasma endothelin‐1 levels in sickle cell anemia: Relationships to oxygen saturation and left ventricular hypertrophy. Am J Hematol 58: 195‐199, 1998.
 181.Wood KC, Hebbel RP, Granger DN. Endothelial cell NADPH oxidase mediates the cerebral microvascular dysfunction in sickle cell transgenic mice. FASEB J 19: 989‐991, 2005.
 182.Xu H, Wandersee NJ, Guo Y, Jones DW, Holzhauer SL, Hanson MS, Machogu E, Brousseau DC, Hogg N, Densmore JC, Kaul S, Hillery CA, Pritchard KA Jr. Sickle cell disease increases high mobility group box 1: A novel mechanism of inflammation. Blood 124: 3978‐3981, 2014.
 183.Zhang D, Xu C, Manwani D, Frenette PS. Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology. Blood 127: 801‐809, 2016.
 184.Zhang L, Levy A, Rifkind JM. Autoxidation of hemoglobin enhanced by dissociation into dimers. J Biol Chem 266: 24698‐24701, 1991.
 185.Zimmer DP, Shea CM, Tobin JV, Tchernychev B, Germano P, Sykes K, Banijamali AR, Jacobson S, Bernier SG, Sarno R, Carvalho A, Chien YT, Graul R, Buys ES, Jones JE, Wakefield JD, Price GM, Chickering JG, Milne GT, Currie MG, Masferrer JL. Olinciguat, an oral sGC stimulator, exhibits diverse pharmacology across preclinical models of cardiovascular, metabolic, renal, and inflammatory disease. Front Pharmacol 11: 419, 2020.

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Article Title: Vasculopathy in Sickle Cell Disease: From Red Blood Cell Sickling to Vascular Dysfunction
 

How to Cite

Elie Nader, Nicola Conran, Marc Romana, Philippe Connes. Vasculopathy in Sickle Cell Disease: From Red Blood Cell Sickling to Vascular Dysfunction. Compr Physiol 2021, 11: 1785-1803. doi: 10.1002/cphy.c200024