Sevuparin binds to multiple adhesive ligands and reduces sickle red blood cell-induced vaso-occlusion

British Journal of Haematology

Volumn 175, Issue 5, 2016, Pages 935-948

  Telen, Marilyn J ^a   Batchvarova, Milena ^a   Shan, Siqing ^a   Bovee Geurts, Petra H ^b   Zennadi, Rahima ^a   Leitgeb, Anna ^c   Brock, Roland ^b   Lindgren, Maria ^c  

^a DUKE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b RADBOUD UNIVERSITY MEDICAL CENTER   (Netherlands)

^c Dilaforette Ab   (Sweden)

Author keywords

adhesion receptors; cell adhesion; heparinoids; sickle cell disease; vaso occlusion

Indexed keywords

FIBRONECTIN; L SELECTIN; PADGEM PROTEIN; SEVUPARIN; THROMBOSPONDIN; TINZAPARIN; VON WILLEBRAND FACTOR; HEPARIN; LOW MOLECULAR WEIGHT HEPARIN; PROTEIN BINDING;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BLOOD FLOW; BLOOD VESSEL OCCLUSION; CONTROLLED STUDY; DISSOCIATION CONSTANT; DOSE RESPONSE; DRUG DOSE COMPARISON; DRUG STRUCTURE; ERYTHROCYTE ADHESIVENESS; FLUORESCENCE CORRELATION SPECTROSCOPY; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NONHUMAN; PRIORITY JOURNAL; SICKLE CELL ANEMIA; SURFACE PLASMON RESONANCE; UMBILICAL VEIN ENDOTHELIAL CELL; ANALOGS AND DERIVATIVES; ANEMIA, SICKLE CELL; ANIMAL; ARTERIAL OCCLUSIVE DISEASES; CELL ADHESION; CELL CULTURE; COMPLICATION; DRUG EFFECTS; ENDOTHELIUM CELL; ERYTHROCYTE; METABOLISM; PATHOLOGY;

ANEMIA, SICKLE CELL; ANIMALS; ARTERIAL OCCLUSIVE DISEASES; CELL ADHESION; CELLS, CULTURED; ENDOTHELIAL CELLS; ERYTHROCYTES; HEPARIN; HEPARIN, LOW-MOLECULAR-WEIGHT; HUMANS; MICE; PROTEIN BINDING;

EID: 84983474446     PISSN: 00071048     EISSN: 13652141     Source Type: Journal    
DOI: 10.1111/bjh.14303     Document Type: Article

References (83)

1. Ahmed, S., Siddiqui, A.K., Iqbal, U., Sison, C.P., Shahid, R.K., Sheth, M., Patel, D.V. & Russo, L.A. (2004) Effect of low-dose warfarin on D-dimer levels during sickle cell vaso-occlusive crisis: a brief report. European Journal of Haematology, 72, 213–216.
2. Ataga, K.I., Brittain, J.E., Desai, P., May, R., Jones, S., Delaney, J., Strayhorn, D., Hinderliter, A. & Key, N.S. (2012) Association of coagulation activation with clinical complications in sickle cell disease. PLoS ONE, 7, e29786.
3. Ballas, S.K. & Darbari, D.S. (2013) Neuropathy, neuropathic pain, and sickle cell disease. American Journal of Hematology, 88, 927–929.
4. Barabino, G.A., Liu, X.D., Ewenstein, B.M. & Kaul, D.K. (1999) Anionic polysaccharides inhibit adhesion of sickle erythrocytes to the vascular endothelium and result in improved hemodynamic behavior. Blood, 93, 1422–1429.
5. Bartolucci, P., Chaar, V., Picot, J., Bachir, D., Habibi, A., Fauroux, C., Galacteros, F., Colin, Y., Le Van Kim, C. & El Nemer, W. (2010) Decreased sickle red blood cell adhesion to laminin by hydroxyurea is associated with inhibition of Lu/BCAM protein phosphorylation. Blood, 116, 2152–2159.
6. Brittain, H.A., Eckman, J.R., Swerlick, R.A., Howard, R.J. & Wick, T.M. (1993) Thrombospondin from activated platelets promotes sickle erythrocyte adherence to human microvascular endothelium under physiologic flow: a potential role for platelet activation in sickle cell vaso-occlusion. Blood, 81, 2137–2143.
7. Brittain, J.E., Mlinar, K.J., Anderson, C.S., Orringer, E.P. & Parise, L.V. (2001a) Activation of sickle red blood cell adhesion via integrin-associated protein/CD47-induced signal transduction. The Journal of Clinical Investigation, 107, 1555–1562.
8. Brittain, J.E., Mlinar, K.J., Anderson, C.S., Orringer, E.P. & Parise, L.V. (2001b) Integrin-associated protein is an adhesion receptor on sickle red blood cells for immobilized thrombospondin. Blood, 97, 2159–2164.
9. Brittain, J.E., Han, J., Ataga, K.I., Orringer, E.P. & Parise, L.V. (2004) Mechanism of CD47-induced alpha4beta1 integrin activation and adhesion in sickle reticulocytes. Journal of Biological Chemistry, 279, 42393–42402.
10. Brown, M.D., Wick, T.M. & Eckman, J.R. (2001) Activation of vascular endothelial cell adhesion molecule expression by sickle blood cells. Pediatric Pathology & Molecular Medicine, 20, 47–72.
11. Burnette, A.D., Nimjee, S.M., Batchvarova, M., Zennadi, R., Telen, M.J., Nishimura, J. & Sullenger, B.A. (2011) RNA aptamer therapy for vaso-occlusion in sickle cell disease. Nucleic Acid Therapeutics, 21, 275–283.
12. Chaar, V., Laurance, S., Lapoumeroulie, C., Cochet, S., De Grandis, M., Colin, Y., Elion, J., Le Van Kim, C. & El Nemer, W. (2014) Hydroxycarbamide decreases sickle reticulocyte adhesion to resting endothelium by inhibiting endothelial lutheran/basal cell adhesion molecule (Lu/BCAM) through phosphodiesterase 4A activation. Journal of Biological Chemistry, 289, 11512–11521.
13. Chang, J., Shi, P.A., Chiang, E.Y. & Frenette, P.S. (2008) Intravenous immunoglobulins reverse acute vaso-occlusive crises in sickle cell mice through rapid inhibition of neutrophil adhesion. Blood, 111, 915–923.
14. Chang, J., Patton, J.T., Sarkar, A., Ernst, B., Magnani, J.L. & Frenette, P.S. (2010) GMI-1070, a novel pan-selectin antagonist, reverses acute vascular occlusions in sickle cell mice. Blood, 116, 1779–1786.
15. Chaplin, H. Jr, Monroe, M.C., Malecek, A.C., Morgan, L.K., Michael, J. & Murphy, W.A. (1989) Preliminary trial of minidose heparin prophylaxis for painful sickle cell crises. East African Medical Journal, 66, 574–584.
16. Chen, J., Hobbs, W.E., Le, J., Lenting, P.J., de Groot, P.G. & Lopez, J.A. (2011) The rate of hemolysis in sickle cell disease correlates with the quantity of active von Willebrand factor in the plasma. Blood, 117, 3680–3683.
17. De Castro, L.M., Zennadi, R., Jonassaint, J.C., Batchvarova, M. & Telen, M.J. (2012) Effect of propranolol as antiadhesive therapy in sickle cell disease. Clinical and Translational Science, 5, 437–444.
18. Dworkis, D.A., Klings, E.S., Solovieff, N., Li, G., Milton, J.N., Hartley, S.W., Melista, E., Parente, J., Sebastiani, P., Steinberg, M.H. & Baldwin, C.T. (2011) Severe sickle cell anemia is associated with increased plasma levels of TNF-R1 and VCAM-1. American Journal of Hematology, 86, 220–223.
19. Ebnet, K. & Vestweber, D. (1999) Molecular mechanisms that control leukocyte extravasation: the selectins and the chemokines. Histochemistry and Cell Biology, 112, 1–23.
20. Embury, S.H., Matsui, N.M., Ramanujam, S., Mayadas, T.N., Noguchi, C.T., Diwan, B.A., Mohandas, N. & Cheung, A.T.W. (2004) The contribution of endothelial cell P-selectin to the microvascular flow of mouse sickle erythrocytes in vivo. Blood, 104, 3378–3385.
21. Faulcon, L.M., Fu, Z., Dulloor, P., Barron-Casella, E., Savage, W., Jennings, J.M., Van Eyk, J.E., Debaun, M., Casella, J.F. & Everett, A. (2013) Thrombospondin-1 and L-selectin are associated with silent cerebral infarct in children with sickle cell anaemia. British Journal of Haematology, 162, 421–424.
22. Finnegan, E.M., Barabino, G.A., Liu, X.D., Chang, H.Y., Jonczyk, A. & Kaul, D.K. (2007a) Small-molecule cyclic alpha V beta 3 antagonists inhibit sickle red cell adhesion to vascular endothelium and vasoocclusion. American Journal of Physiology. Heart and Circulatory Physiology, 293, H1038–H1045.
23. Finnegan, E.M., Turhan, A., Golan, D.E. & Barabino, G.A. (2007b) Adherent leukocytes capture sickle erythrocytes in an in vitro flow model of vaso-occlusion. American Journal of Hematology, 82, 266–275.
24. Frenette, P.S. (2002) Sickle cell vaso-occlusion: multistep and multicellular paradigm. Current Opinion in Hematology, 9, 101–106.
25. Gambero, S., Canalli, A.A., Traina, F., Albuquerque, D.M., Saad, S.T., Costa, F.F. & Conran, N. (2007) Therapy with hydroxyurea is associated with reduced adhesion molecule gene and protein expression in sickle red cells with a concomitant reduction in adhesive properties. European Journal of Haematology, 78, 144–151.
26. Gayen Betal, S. & Setty, B.N. (2008) Phosphatidylserine-positive erythrocytes bind to immobilized and soluble thrombospondin-1 via its heparin-binding domain. Translational Research, 152, 165–177.
27. Gupta, K., Gupta, P., Solovey, A. & Hebbel, R.P. (1999) Mechanism of interaction of thrombospondin with human endothelium and inhibition of sickle erythrocyte adhesion to human endothelial cells by heparin. Biochimica et Biophysica Acta, 1453, 63–73.
28. Gutsaeva, D.R., Parkerson, J.B., Yerigenahally, S.D., Kurz, J.C., Schaub, R.G., Ikuta, T. & Head, C.A. (2011) Inhibition of cell adhesion by anti–P-selectin aptamer: a new potential therapeutic agent for sickle cell disease. Blood, 117, 727–735.
29. Hebbel, R.P., Yamada, O., Moldow, C.F., Jacob, H.S., White, J.G. & Eaton, J.W. (1980a) Abnormal adherence of sickle erythrocytes to cultured vascular endothelium: possible mechanism for microvascular occlusion in sickle cell disease. The Journal of Clinical Investigation, 65, 154–160.
30. Hebbel, R.P., Boogaerts, M.A., Koresawa, S., Jacob, H.S., Eaton, J.W. & Steinberg, M.H. (1980b) Erythrocyte adherence to endothelium as a determinant of vasocclusive severity in sickle cell disease. Transactions of the Association of American Physicians, 93, 94–99.
31. Hidalgo, A., Chang, J., Jang, J.E., Peired, A.J., Chiang, E.Y. & Frenette, P.S. (2009) Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury. Nature Medicine, 15, 384–391.
32. Kaul, D.K. & Hebbel, R.P. (2000) Hypoxia/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice. The Journal of Clinical Investigation, 106, 411–420.
33. Kaul, D.K., Tsai, H.M., Liu, X.D., Nakada, M.T., Nagel, R.L. & Coller, B.S. (2000) Monoclonal antibodies to alphaVbeta3 (7E3 and LM609) inhibit sickle red blood cell-endothelium interactions induced by platelet-activating factor. Blood, 95, 368–374.
34. Kaul, D.K., Liu, X.D., Zhang, X., Mankelow, T., Parsons, S., Spring, F., An, X., Mohandas, N., Anstee, D. & Chasis, J.A. (2006) Peptides based on alphaV-binding domains of erythrocyte ICAM-4 inhibit sickle red cell-endothelial interactions and vaso-occlusion in the microcirculation. American Journal of Physiology. Cell Physiology, 291, C922–C930.
35. Kinney, T.R., Sleeper, L.A., Wang, W.C., Zimmerman, R.A., Pegelow, C.H., Ohene-Frempong, K., Wethers, D.L., Bello, J.A., Vichinsky, E.P., Moser, F.G., Gallagher, D.M., DeBaun, M.R., Platt, O.S. & Miller, S.T. (1999) Silent cerebral infarcts in sickle cell anemia: a risk factor analysis. The Cooperative Study of Sickle Cell Disease. Pediatrics, 103, 640–645.
36. Koenig, A., Norgard-Sumnicht, K., Linhardt, R. & Varki, A. (1998) Differential interactions of heparin and heparan sulfate glycosaminoglycans with the selectins. Implications for the use of unfractionated and low molecular weight heparins as therapeutic agents. The Journal of Clinical Investigation, 101, 877–889.
37. Koppel, D.E. (1974) Statistical accuracy in fluorescence correlation spectroscopy. Physical Review, 10, 1938–1945.
38. Krishnan, S., Siegel, J., Pullen, G. Jr, Hevelow, M., Dampier, C. & Stuart, M. (2008) Increased von Willebrand factor antigen and high molecular weight multimers in sickle cell disease associated with nocturnal hypoxemia. Thrombosis Research, 122, 455–458.
39. Kutlar, A., Ataga, K.I., McMahon, L., Howard, J., Galacteros, F., Hagar, W., Vichinsky, E., Cheung, A.T., Matsui, N. & Embury, S.H. (2012) A potent oral P-selectin blocking agent improves microcirculatory blood flow and a marker of endothelial cell injury in patients with sickle cell disease. American Journal of Hematology, 87, 536–539.
40. Langer, H.F. & Chavakis, T. (2009) Leukocyte-endothelial interactions in inflammation. Journal of Cellular and Molecular Medicine, 13, 1211–1220.
41. Lever, R. & Page, C.P. (2002) Novel drug development opportunities for heparin. Nature Reviews. Drug Discovery, 1, 140–148.
42. Lindgren, M., Meijers, J.C.M., Biemond, B.J., Ramstrom, S., Lindahl, T.L., Eriksson, P.-O., Leitgeb, A.M., Wahlgren, M., Hogwood, J., Gray, E. & Holmer, E. (2015) Sevuparin; effects on hemostasis of a novel polysaccharide drug derived from heparin. Journal of Thrombosis and Haemostasis, 13, 369.
43. Mader, O., Reiner, K., Egelhaaf, H.-J., Fischer, R. & Brock, R. (2004) Structure property analysis of pentamethine indocyanine dyes: identification of a new dye for life science applications. Bioconjugate Chemistry, 15, 70–78.
44. Manwani, D. & Frenette, P.S. (2013) Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. Blood, 122, 3892–3898.
45. Manwani, D., Chen, G., Carullo, V., Serban, S., Olowokure, O., Jang, J., Huggins, M., Cohen, H.W., Billett, H., Atweh, G.F., Frenette, P.S. & Shi, P.A. (2015) Single-dose intravenous gammaglobulin can stabilize neutrophil Mac-1 activation in sickle cell pain crisis. American Journal of Hematology, 90, 381–385.
46. Matsui, N.M., Borsig, L., Rosen, S.D., Yaghmai, M., Varki, A. & Embury, S.H. (2001) P-selectin mediates the adhesion of sickle erythrocytes to the endothelium. Blood, 98, 1955–1962.
47. Matsui, N.M., Varki, A. & Embury, S.H. (2002) Heparin inhibits the flow adhesion of sickle red blood cells to P-selectin. Blood, 100, 3790–3796.
48. de Montalembert, M. (2008) Management of sickle cell disease. BMJ, 337, a1397.
49. Moulson, C.L., Li, C. & Miner, J.H. (2001) Localization of Lutheran, a novel laminin receptor, in normal, knockout, and transgenic mice suggests an interaction with laminin alpha5 in vivo. Developmental Dynamics, 222, 101–114.
50. Mulloy, B., Hogwood, J., Gray, E., Lever, R. & Page, C.P. (2016) Pharmacology of Heparin and Related Drugs. Pharmacological Reviews, 68, 76–141.
51. Novelli, E.M., Kato, G.J., Ragni, M.V., Zhang, Y., Hildesheim, M.E., Nouraie, M., Barge, S., Meyer, M.P., Hassett, A.C., Gordeuk, V.R., Gladwin, M.T. & Isenberg, J.S. (2012) Plasma thrombospondin-1 is increased during acute sickle cell vaso-occlusive events and associated with acute chest syndrome, hydroxyurea therapy, and lower hemolytic rates. American Journal of Hematology, 87, 326–330.
52. Odievre, M.H., Bony, V., Benkerrou, M., Lapoumeroulie, C., Alberti, C., Ducrocq, R., Jacqz-Aigrain, E., Elion, J. & Cartron, J.P. (2008) Modulation of erythroid adhesion receptor expression by hydroxyurea in children with sickle cell disease. Haematologica, 93, 502–510.
53. Parent, C. & Eichacker, P.Q. (1999) Neutrophil and endothelial cell interactions in sepsis. The role of adhesion molecules. Infectious Disease Clinics of North America, 13, 427–447, x.
54. Pathare, A., Kindi, S.A., Daar, S. & Dennison, D. (2003) Cytokines in sickle cell disease. Hematology, 8, 329–337.
55. Polanowska-Grabowska, R., Wallace, K., Field, J.J., Chen, L., Marshall, M.A., Figler, R., Gear, A.R. & Linden, J. (2010) P-selectin-mediated platelet-neutrophil aggregate formation activates neutrophils in mouse and human sickle cell disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 30, 2392–2399.
56. Qari, M.H., Aljaouni, S.K., Alardawi, M.S., Fatani, H., Alsayes, F.M., Zografos, P., Alsaigh, M., Alalfi, A., Alamin, M., Gadi, A. & Mousa, S.A. (2007) Reduction of painful vaso-occlusive crisis of sickle cell anaemia by tinzaparin in a double-blind randomized trial. Thrombosis and Haemostasis, 98, 392–396.
57. Salvaggio, J.E., Arnold, C.A. & Banov, C.H. (1963) Long-term anti-coagulation in sickle-cell disease. A clinical study. New England Journal of Medicine, 269, 182–186.
58. Scheffler, K., Ernst, B., Katopodis, A., Magnani, J.L., Wang, W.T., Weisemann, R. & Peters, T. (1995) Determination of the bioactive conformation of the carbohydrate ligand in the E-selectin/sialyl LewisX complex. Angewandte Chemie (International ed. in English), 34, 1841–1844.
59. Setty, B.N. & Stuart, M.J. (1996) 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.
60. Shah, N., Willen, S., Telen, M.J. & Ortel, T.L. (2013) Prophylactic dose low molecular weight heparin (dalteparin) for treatment of vaso-occlusive pain crisis in patients with sickle cell disease. Blood, 122, 2241.
61. Simonis, D., Christ, K., Alban, S. & Bendas, G. (2007) Affinity and kinetics of different heparins binding to P- and L-selectin. Seminars in Thrombosis and Hemostasis, 33, 534–539.
62. Sparkenbaugh, E. & Pawlinski, R. (2013) Interplay between coagulation and vascular inflammation in sickle cell disease. British Journal of Haematology, 162, 3–14.
63. Steinberg, M.H. (2011) In the clinic. Sickle cell disease. Annals of Internal Medicine, 155, ITC31–15; quiz ITC316.
64. Sugimoto, K., Tsurumaki, Y., Hoshi, H., Kadowaki, S., LeBousse-Kerdiles, M.C., Smadja-Joffe, F. & Mori, K.J. (1994) Effects of anti-CD44 monoclonal antibody on adhesion of erythroid leukemic cells (ELM-I-1) to hematopoietic supportive cells (MS-5): CD44, but not hyaluronate-mediated, cell-cell adhesion. Experimental Hematology, 22, 488–494.
65. Tan, F.L. & Ginsburg, D. (2008) What a polyclonal antibody sees in von Willebrand factor. Thrombosis Research, 121, 519–526.
66. Telen, M.J., Wun, T., McCavit, T.L., De Castro, L.M., Krishnamurti, L., Lanzkron, S., Hsu, L.L., Smith, W.R., Rhee, S., Magnani, J.L. & Thackray, H. (2015) 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.
67. Trinh-Trang-Tan, M.M., Vilela-Lamego, C., Picot, J., Wautier, M.P. & Cartron, J.P. (2010) Intercellular adhesion molecule-4 and CD36 are implicated in the abnormal adhesiveness of sickle cell SAD mouse erythrocytes to endothelium. Haematologica, 95, 730–737.
68. Turhan, A., Weiss, L.A., Mohandas, N., Coller, B.S. & Frenette, P.S. (2002) Primary role for adherent leukocytes in sickle cell vascular occlusion: a new paradigm. Proceedings of the National Academy of Sciences of the United States of America, 99, 3047–3051.
69. Udani, M., Zen, Q., Cottman, M., Leonard, N., Jefferson, S., Daymont, C., Truskey, G. & Telen, M.J. (1998) Basal cell adhesion molecule/lutheran protein. The receptor critical for sickle cell adhesion to laminin. The Journal of Clinical Investigation, 101, 2550–2558.
70. Verfaillie, C.M., Benis, A., Iida, J., McGlave, P.B. & McCarthy, J.B. (1994) Adhesion of committed human hematopoietic progenitors to synthetic peptides from the C-terminal heparin-binding domain of fibronectin: cooperation between the integrin alpha 4 beta 1 and the CD44 adhesion receptor. Blood, 84, 1802–1811.
71. Wang, J.G. & Geng, J.G. (2003) Affinity and kinetics of P-selectin binding to heparin. Thrombosis and Haemostasis, 90, 309–316.
72. Wang, L., Brown, J.R., Varki, A. & Esko, J.D. (2002) Heparin's anti-inflammatory effects require glucosamine 6-O-sulfation and are mediated by blockade of L- and P-selectins. The Journal of Clinical Investigation, 110, 127–136.
73. Weatherall, D.J. (2010) The inherited diseases of hemoglobin are an emerging global health burden. Blood, 115, 4331–4336.
74. Weller, A., Isenmann, S. & Vestweber, D. (1992) Cloning of the mouse endothelial selectins. Expression of both E- and P-selectin is inducible by tumor necrosis factor alpha. Journal of Biological Chemistry, 267, 15176–15183.
75. Zen, Q., Cottman, M., Truskey, G., Fraser, R. & Telen, M.J. (1999) Critical factors in basal cell adhesion molecule/lutheran-mediated adhesion to laminin. Journal of Biological Chemistry, 274, 728–734.
76. Zen, Q., Batchvarova, M., Twyman, C.A., Eyler, C.E., Qiu, H., De Castro, L.M. & Telen, M.J. (2004) B-CAM/LU expression and the role of B-CAM/LU activation in binding of low- and high-density red cells to laminin in sickle cell disease. American Journal of Hematology, 75, 63–72.
77. Zennadi, R. (2014) MEK inhibitors, novel anti-adhesive molecules, reduce sickle red blood cell adhesion in vitro and in vivo, and vasoocclusion in vivo. PLoS ONE, 9, e110306.
78. Zennadi, R., Hines, P.C., De Castro, L.M., Cartron, J.P., Parise, L.V. & Telen, M.J. (2004) Epinephrine acts through erythroid signaling pathways to activate sickle cell adhesion to endothelium via LW-alphavbeta3 interactions. Blood, 104, 3774–3781.
79. Zennadi, R., Moeller, B.J., Whalen, E.J., Batchvarova, M., Xu, K., Shan, S., Delahunty, M., Dewhirst, M.W. & Telen, M.J. (2007) Epinephrine-induced activation of LW-mediated sickle cell adhesion and vaso-occlusion in vivo. Blood, 110, 2708–2717.
80. Zennadi, R., Chien, A., Xu, K., Batchvarova, M. & Telen, M.J. (2008) Sickle red cells induce adhesion of lymphocytes and monocytes to endothelium. Blood, 112, 3474–3483.
81. Zennadi, R., Whalen, E.J., Soderblom, E.J., Alexander, S.C., Thompson, J.W., Dubois, L.G., Moseley, M.A. & Telen, M.J. (2012) Erythrocyte plasma membrane-bound ERK1/2 activation promotes ICAM-4-mediated sickle red cell adhesion to endothelium. Blood, 119, 1217–1227.
82. Zhao, Y., Schwartz, E.A., Palmer, G.M. & Zennadi, R. (2016) MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease. FASEB Journal, 30, 1171–1186.
83. Zhou, Z., Han, H., Cruz, M.A., Lopez, J.A., Dong, J.F. & Guchhait, P. (2009) Haemoglobin blocks von Willebrand factor proteolysis by ADAMTS-13: a mechanism associated with sickle cell disease. Thrombosis and Haemostasis, 101, 1070–1077.