New Insights into the Role of Erythrocytes in Thrombus Formation

Vivian X. Du; Dana Huskens; Coen Maas; Raed Al Dieri; Philip G. de Groot; Bas de Laat

doi:10.1055/s-0033-1363470

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2014; 40(01): 072-080
DOI: 10.1055/s-0033-1363470

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

New Insights into the Role of Erythrocytes in Thrombus Formation

Vivian X. Du

¹Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands

²Sanquin Research, Amsterdam, The Netherlands

,

Dana Huskens

³Cardiovascular Research Institute Maastricht, University of Maastricht, The Netherlands

⁴Synapse BV, Maastricht, The Netherlands

,

Coen Maas

¹Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands

,

Raed Al Dieri

³Cardiovascular Research Institute Maastricht, University of Maastricht, The Netherlands

⁴Synapse BV, Maastricht, The Netherlands

,

Philip G. de Groot

¹Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands

,

Bas de Laat

¹Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands

²Sanquin Research, Amsterdam, The Netherlands

³Cardiovascular Research Institute Maastricht, University of Maastricht, The Netherlands

⁴Synapse BV, Maastricht, The Netherlands

› Author Affiliations

Abstract

The role of erythrocytes in thrombus formation has previously been regarded as passive by their influence on rheology. Erythrocytes are known, due to their abundance and size, to push platelets to the vascular wall (laminar shearing). This results in an increased platelet delivery at the vascular wall enabling platelets to seal off a vascular damage preventing excessive blood loss. Recently, there is new evidence for erythrocytes to influence thrombus formation in multiple ways besides their effect on rheology. Several groups have shown that besides platelets, erythrocytes are the main suppliers of phosphatidylserine-exposing membranes needed for coagulation resulting in fibrin formation. In addition, our group has found that the intercellular adhesion molecule 4–α_IIbβ₃ interaction mediates erythrocyte–platelet interaction in flowing blood. By inhibiting this interaction, we found decreased thrombin formation and decreased incorporation of erythrocytes into a thrombus. This review will provide more in-detail information of existing and new hypotheses regarding the role of erythrocytes in thrombus formation.

Keywords

erythrocyte - thrombosis - hemostasis - coagulation - thrombin

Full Text

References

References
1 Ruggeri ZM. Von Willebrand factor, platelets and endothelial cell interactions. J Thromb Haemost 2003; 1 (7) 1335-1342
2 Schafer AI. Bleeding and thrombosis in the myeloproliferative disorders. Blood 1984; 64 (1) 1-12
3 Randi ML, Stocco F, Rossi C, Tison T, Girolami A. Thrombosis and hemorrhage in thrombocytosis: evaluation of a large cohort of patients (357 cases). J Med 1991; 22 (4-5) 213-223
4 Stewart GW, Amess JA, Eber SW , et al. Thrombo-embolic disease after splenectomy for hereditary stomatocytosis. Br J Haematol 1996; 93 (2) 303-310
5 Michaeli J, Mittelman M, Grisaru D, Rachmilewitz EA. Thromboembolic complications in beta thalassemia major. Acta Haematol 1992; 87 (1-2) 71-74
6 Wong V, Yu YL, Liang RH, Tso WK, Li AM, Chan TK. Cerebral thrombosis in beta-thalassemia/hemoglobin E disease. Stroke 1990; 21 (5) 812-816
7 Koshy M, Thomas C, Goodwin J. Vascular lesions in the central nervous system in sickle cell disease (neuropathology). J Assoc Acad Minor Phys 1990; 1 (3) 71-78
8 Rossi C, Randi ML, Zerbinati P, Rinaldi V, Girolami A. Acute coronary disease in essential thrombocythemia and polycythemia vera. J Intern Med 1998; 244 (1) 49-53
9 Zimmermann J, Schramm L, Wanner C , et al. Hemorheology, plasma protein composition and von Willebrand factor in type I diabetic nephropathy. Clin Nephrol 1996; 46 (4) 230-236
10 Kwaan HC, Levin M, Sakurai S , et al. Digital ischemia and gangrene due to red blood cell aggregation induced by acquired dysfibrinogenemia. J Vasc Surg 1997; 26 (6) 1061-1068
11 Andrews DA, Low PS. Role of red blood cells in thrombosis. Curr Opin Hematol 1999; 6 (2) 76-82
12 Gao C, Xie R, Yu C , et al. Procoagulant activity of erythrocytes and platelets through phosphatidylserine exposure and microparticles release in patients with nephrotic syndrome. Thromb Haemost 2012; 107 (4) 681-689
13 Tokarev AA, Butylin AA, Ataullakhanov FI. Platelet adhesion from shear blood flow is controlled by near-wall rebounding collisions with erythrocytes. Biophys J 2011; 100 (4) 799-808
14 Schreijer AJ, Reitsma PH, Cannegieter SC. High hematocrit as a risk factor for venous thrombosis. Cause or innocent bystander?. Haematologica 2010; 95 (2) 182-184
15 Tannheimer M, Fusch C, Böning D, Thomas A, Engelhardt M, Schmidt R. Changes of hematocrit and hemoglobin concentration in the cold Himalayan environment in dependence on total body fluid. Sleep Breath 2010; 14 (3) 193-199
16 Schmid-Schönbein H, Wells R, Goldstone J. Influence of deformability of human red cells upon blood viscosity. Circ Res 1969; 25 (2) 131-143
17 Vayá A, Suescun M. Hemorheological parameters as independent predictors of venous thromboembolism. Clin Hemorheol Microcirc 2013; 53 (1-2) 131-141
18 Meiselman HJ. Red blood cell aggregation: 45 years being curious. Biorheology 2009; 46 (1) 1-19
19 Baskurt OK, Meiselman HJ. Erythrocyte aggregation: basic aspects and clinical importance. Clin Hemorheol Microcirc 2013; 53 (1-2) 23-37
20 Baskurt OK, Meiselman HJ. Iatrogenic hyperviscosity and thrombosis. Semin Thromb Hemost 2012; 38 (8) 854-864
21 Baskurt OK, Neu B, Meiselman HJ. Red Blood Cell Aggregation. Boca Raton: CRC Press; 2011: 1-304
22 Knox RJ, Nordt FJ, Seaman GV, Brooks DE. Rheology of erythrocyte suspensions: dextran-mediated aggregation of deformable and nondeformable erythrocytes. Biorheology 1977; 14 (2-3) 75-84
23 Brooks DE, Goodwin JW, Seaman GV. Interactions among erythrocytes under shear. J Appl Physiol 1970; 28 (2) 172-177
24 Chien S, Sung LA, Kim S, Burke AM, Usami S. Determination of aggregation force in rouleaux by fluid mechanical technique. Microvasc Res 1977; 13 (3) 327-333
25 Chien S, Feng SS, Vayo M, Sung LA, Usami S, Skalak R. The dynamics of shear disaggregation of red blood cells in a flow channel. Biorheology 1990; 27 (2) 135-147
26 Bäumler H, Donath E, Krabi A, Knippel W, Budde A, Kiesewetter H. Electrophoresis of human red blood cells and platelets. Evidence for depletion of dextran. Biorheology 1996; 33 (4-5) 333-351
27 Bäumler H, Neu B, Mitlöhner R, Georgieva R, Meiselman HJ, Kiesewetter H. Electrophoretic and aggregation behavior of bovine, horse and human red blood cells in plasma and in polymer solutions. Biorheology 2001; 38 (1) 39-51
28 Neu B, Meiselman HJ. The role of macromolecules in stabilization and de-stabilization of biofluids. In: Artmann G, Chien S, , eds. Bioengineering in cell and tissue research. New York: Springer; 2008: 387-408
29 Neu B, Meiselman HJ. Depletion interactions in polymer solutions promote red blood cell adhesion to albumin-coated surfaces. Biochim Biophys Acta 2006; 1760 (12) 1772-1779
30 Neu B, Wenby R, Meiselman HJ. Effects of dextran molecular weight on red blood cell aggregation. Biophys J 2008; 95 (6) 3059-3065
31 Meiselman HJ, Neu B, Rampling MW, Baskurt OK. RBC aggregation: laboratory data and models. Indian J Exp Biol 2007; 45 (1) 9-17
32 Baskurt OK, Meiselman HJ. Hemodynamic effects of red blood cell aggregation. Indian J Exp Biol 2007; 45 (1) 25-31
33 Cokelet GR, Goldsmith HL. Decreased hydrodynamic resistance in the two-phase flow of blood through small vertical tubes at low flow rates. Circ Res 1991; 68 (1) 1-17
34 Fahraeus R. The influence of the rouleau formation of the erythrocytes on the rheology of the blood. Acta Med Scand 1958; 161 (2) 151-165
35 Pries AR, Ley K, Claassen M, Gaehtgens P. Red cell distribution at microvascular bifurcations. Microvasc Res 1989; 38 (1) 81-101
36 Pries AR, Secomb TW, Gaehtgens P. Biophysical aspects of blood flow in the microvasculature. Cardiovasc Res 1996; 32 (4) 654-667
37 Baskurt OK, Yalcin O, Ozdem S, Armstrong JK, Meiselman HJ. Modulation of endothelial nitric oxide synthase expression by red blood cell aggregation. Am J Physiol Heart Circ Physiol 2004; 286 (1) H222-H229
38 Yalcin O, Ulker P, Yavuzer U, Meiselman HJ, Baskurt OK. Nitric oxide generation by endothelial cells exposed to shear stress in glass tubes perfused with red blood cell suspensions: role of aggregation. Am J Physiol Heart Circ Physiol 2008; 294 (5) H2098-H2105
39 James SH, Meyers AM. Microangiopathic hemolytic anemia as a complication of diabetes mellitus. Am J Med Sci 1998; 315 (3) 211-215
40 Hebbel RP. Beyond hemoglobin polymerization: the red blood cell membrane and sickle disease pathophysiology. Blood 1991; 77 (2) 214-237
41 Aarts PA, Banga JD, van Houwelingen HC, Heethaar RM, Sixma JJ. Increased red blood cell deformability due to isoxsuprine administration decreases platelet adherence in a perfusion chamber: a double-blind cross-over study in patients with intermittent claudication. Blood 1986; 67 (5) 1474-1481
42 Chien S. Red cell deformability and its relevance to blood flow. Annu Rev Physiol 1987; 49: 177-192
43 Lux SE. Dissecting the red cell membrane skeleton. Nature 1979; 281 (5731) 426-429
44 Mohandas N, Shohet SB. The role of membrane-associated enzymes in regulation of erythrocyte shape and deformability. Clin Haematol 1981; 10 (1) 223-237
45 Mohandas N, Chasis JA. Red blood cell deformability, membrane material properties and shape: regulation by transmembrane, skeletal and cytosolic proteins and lipids. Semin Hematol 1993; 30 (3) 171-192
46 Friederichs E, Meiselman HJ. Effects of calcium permeabilization on RBC rheologic behavior. Biorheology 1994; 31 (2) 207-215
47 Shiga T, Maeda N, Kon K. Erythrocyte rheology. Crit Rev Oncol Hematol 1990; 10 (1) 9-48
48 Davie EW, Fujikawa K, Kisiel W. The coagulation cascade: initiation, maintenance, and regulation. Biochemistry 1991; 30 (43) 10363-10370
49 Renné T, Schmaier AH, Nickel KF, Blombäck M, Maas C. In vivo roles of factor XII. Blood 2012; 120 (22) 4296-4303
50 Rosing J, Tans G, Govers-Riemslag JW, Zwaal RF, Hemker HC. The role of phospholipids and factor Va in the prothrombinase complex. J Biol Chem 1980; 255 (1) 274-283
51 Hemker HC, Esnouf MP, Hemker PW, Swart AC, Macfarlane RG. Formation of prothrombin converting activity. Nature 1967; 215 (5098) 248-251
52 van Dieijen G, Tans G, Rosing J, Hemker HC. The role of phospholipid and factor VIIIa in the activation of bovine factor X. J Biol Chem 1981; 256 (7) 3433-3442
53 Gailani D, Broze Jr GJ. Factor XI activation in a revised model of blood coagulation. Science 1991; 253 (5022) 909-912
54 Maas C, Meijers JC, Marquart JA , et al. Activated factor V is a cofactor for the activation of factor XI by thrombin in plasma. Proc Natl Acad Sci U S A 2010; 107 (20) 9083-9087
55 Bevers EM, Comfurius P, van Rijn JL, Hemker HC, Zwaal RF. Generation of prothrombin-converting activity and the exposure of phosphatidylserine at the outer surface of platelets. Eur J Biochem 1982; 122 (2) 429-436
56 Zwaal RF, Bevers EM, Comfurius P, Rosing J, Tilly RH, Verhallen PF. Loss of membrane phospholipid asymmetry during activation of blood platelets and sickled red cells; mechanisms and physiological significance. Mol Cell Biochem 1989; 91 (1-2) 23-31
57 Leventis PA, Grinstein S. The distribution and function of phosphatidylserine in cellular membranes. Annu Rev Biophys 2010; 39: 407-427
58 Yeung T, Gilbert GE, Shi J, Silvius J, Kapus A, Grinstein S. Membrane phosphatidylserine regulates surface charge and protein localization. Science 2008; 319 (5860) 210-213
59 Woon LA, Holland JW, Kable EP, Roufogalis BD. Ca2+ sensitivity of phospholipid scrambling in human red cell ghosts. Cell Calcium 1999; 25 (4) 313-320
60 Dekkers DW, Comfurius P, Bevers EM, Zwaal RF. Comparison between Ca2+-induced scrambling of various fluorescently labelled lipid analogues in red blood cells. Biochem J 2002; 362 (Pt 3) 741-747
61 Shi J, Shi Y, Waehrens LN, Rasmussen JT, Heegaard CW, Gilbert GE. Lactadherin detects early phosphatidylserine exposure on immortalized leukemia cells undergoing programmed cell death. Cytometry A 2006; 69 (12) 1193-1201
62 Morel O, Jesel L, Freyssinet JM, Toti F. Cellular mechanisms underlying the formation of circulating microparticles. Arterioscler Thromb Vasc Biol 2011; 31 (1) 15-26
63 van Beers EJ, Schaap MC, Berckmans RJ , et al; CURAMA study group. Circulating erythrocyte-derived microparticles are associated with coagulation activation in sickle cell disease. Haematologica 2009; 94 (11) 1513-1519
64 Horne III MK, Cullinane AM, Merryman PK, Hoddeson EK. The effect of red blood cells on thrombin generation. Br J Haematol 2006; 133 (4) 403-408
65 Van Der Meijden PE, Van Schilfgaarde M, Van Oerle R, Renné T, ten Cate H, Spronk HM. Platelet- and erythrocyte-derived microparticles trigger thrombin generation via factor XIIa. J Thromb Haemost 2012; 10 (7) 1355-1362
66 Setty BN, Rao AK, Stuart MJ. Thrombophilia in sickle cell disease: the red cell connection. Blood 2001; 98 (12) 3228-3233
67 Bonomini M, Sirolli V, Settefrati N, Dottori S, Di Liberato L, Arduini A. Increased erythrocyte phosphatidylserine exposure in chronic renal failure. J Am Soc Nephrol 1999; 10 (9) 1982-1990
68 Bonomini M, Sirolli V, Gizzi F, Di Stante S, Grilli A, Felaco M. Enhanced adherence of human uremic erythrocytes to vascular endothelium: role of phosphatidylserine exposure. Kidney Int 2002; 62 (4) 1358-1363
69 Setty BN, Betal SG. Microvascular endothelial cells express a phosphatidylserine receptor: a functionally active receptor for phosphatidylserine-positive erythrocytes. Blood 2008; 111 (2) 905-914
70 Solá E, Vayá A, Martínez M , et al. Erythrocyte membrane phosphatidylserine exposure in obesity. Obesity (Silver Spring) 2009; 17 (2) 318-322
71 Ninivaggi M, Apitz-Castro R, Dargaud Y, de Laat B, Hemker HC, Lindhout T. Whole-blood thrombin generation monitored with a calibrated automated thrombogram-based assay. Clin Chem 2012; 58 (8) 1252-1259
72 Peyrou V, Lormeau JC, Hérault JP, Gaich C, Pfliegger AM, Herbert JM. Contribution of erythrocytes to thrombin generation in whole blood. Thromb Haemost 1999; 81 (3) 400-406
73 Whelihan MF, Zachary V, Orfeo T, Mann KG. Prothrombin activation in blood coagulation: the erythrocyte contribution to thrombin generation. Blood 2012; 120 (18) 3837-3845
74 Ruf A, Pick M, Deutsch V , et al. In-vivo platelet activation correlates with red cell anionic phospholipid exposure in patients with beta-thalassaemia major. Br J Haematol 1997; 98 (1) 51-56
75 Wood BL, Gibson DF, Tait JF. Increased erythrocyte phosphatidylserine exposure in sickle cell disease: flow-cytometric measurement and clinical associations. Blood 1996; 88 (5) 1873-1880
76 Whelihan MF, Mann KG. The role of the red cell membrane in thrombin generation. Thromb Res 2013; 131 (5) 377-382
77 Kawakami S, Kaibara M, Kawamoto Y, Yamanaka K. Rheological approach to the analysis of blood coagulation in endothelial cell-coated tubes: activation of the intrinsic reaction on the erythrocyte surface. Biorheology 1995; 32 (5) 521-536
78 Kaibara M, Iwata H, Ujiie H, Himeno R, Kaibara M. Rheological analyses of coagulation of blood from different individuals with special reference to procoagulant activity of erythrocytes. Blood Coagul Fibrinolysis 2005; 16 (5) 355-363
79 Kawakami S, Kaibara M, Kawamoto Y, Yamanaka K. Rheological approach to the analysis of blood coagulation in endothelial cell-coated tubes: activation of the intrinsic reaction on the erythrocyte surface. Biorheology 1995; 32 (5) 521-536
80 Wautier JL, Wautier MP. Molecular basis of erythrocyte adhesion to endothelial cells in diseases. Clin Hemorheol Microcirc 2013; 53 (1-2) 11-21
81 El Nemer W, Gauthier E, Wautier MP , et al. Role of Lu/BCAM in abnormal adhesion of sickle red blood cells to vascular endothelium. Transfus Clin Biol 2008; 15 (1-2) 29-33
82 Hermand P, Gane P, Huet M , et al. Red cell ICAM-4 is a novel ligand for platelet-activated alpha IIbbeta 3 integrin. J Biol Chem 2003; 278 (7) 4892-4898
83 Hermand P, Gane P, Callebaut I, Kieffer N, Cartron JP, Bailly P. Integrin receptor specificity for human red cell ICAM-4 ligand. Critical residues for alphaIIbeta3 binding. Eur J Biochem 2004; 271 (18) 3729-3740
84 Joneckis CC, Ackley RL, Orringer EP, Wayner EA, Parise LV. Integrin alpha 4 beta 1 and glycoprotein IV (CD36) are expressed on circulating reticulocytes in sickle cell anemia. Blood 1993; 82 (12) 3548-3555
85 Sugihara K, Sugihara T, Mohandas N, Hebbel RP. Thrombospondin mediates adherence of CD36+ sickle reticulocytes to endothelial cells. Blood 1992; 80 (10) 2634-2642
86 Swerlick RA, Eckman JR, Kumar A, Jeitler M, Wick TM. Alpha 4 beta 1-integrin expression on sickle reticulocytes: vascular cell adhesion molecule-1-dependent binding to endothelium. Blood 1993; 82 (6) 1891-1899
87 van Schravendijk MR, Handunnetti SM, Barnwell JW, Howard RJ. Normal human erythrocytes express CD36, an adhesion molecule of monocytes, platelets, and endothelial cells. Blood 1992; 80 (8) 2105-2114
88 Wautier JL, Wautier MP. Erythrocytes and platelet adhesion to endothelium are mediated by specialized molecules. Clin Hemorheol Microcirc 2004; 30 (3-4) 181-184
89 Zen Q, Cottman M, Truskey G, Fraser R, Telen MJ. Critical factors in basal cell adhesion molecule/lutheran-mediated adhesion to laminin. J Biol Chem 1999; 274 (2) 728-734
90 Hughes KR, Biagini GA, Craig AG. Continued cytoadherence of Plasmodium falciparum infected red blood cells after antimalarial treatment. Mol Biochem Parasitol 2010; 169 (2) 71-78
91 Miller LH, Good MF, Milon G. Malaria pathogenesis. Science 1994; 264 (5167) 1878-1883
92 Grossin N, Wautier MP, Picot J, Stern DM, Wautier JL. Differential effect of plasma or erythrocyte AGE-ligands of RAGE on expression of transcripts for receptor isoforms. Diabetes Metab 2009; 35 (5) 410-417
93 Wautier JL, Zoukourian C, Chappey O , et al. Receptor-mediated endothelial cell dysfunction in diabetic vasculopathy. Soluble receptor for advanced glycation end products blocks hyperpermeability in diabetic rats. J Clin Invest 1996; 97 (1) 238-243
94 Ihanus E, Uotila LM, Toivanen A, Varis M, Gahmberg CG. Red-cell ICAM-4 is a ligand for the monocyte/macrophage integrin CD11c/CD18: characterization of the binding sites on ICAM-4. Blood 2007; 109 (2) 802-810
95 Sistonen P. Linkage of the LW blood group locus with the complement C3 and Lutheran blood group loci. Ann Hum Genet 1984; 48 (Pt 3) 239-242
96 Sistonen P, Green CA, Lomas CG, Tippett P. Genetic polymorphism of the LW blood group system. Ann Hum Genet 1983; 47 (Pt 4) 277-284
97 Bailly P, Tontti E, Hermand P, Cartron JP, Gahmberg CG. The red cell LW blood group protein is an intercellular adhesion molecule which binds to CD11/CD18 leukocyte integrins. Eur J Immunol 1995; 25 (12) 3316-3320
98 Ihanus E, Uotila LM, Toivanen A, Varis M, Gahmberg CG. Red-cell ICAM-4 is a ligand for the monocyte/macrophage integrin CD11c/CD18: characterization of the binding sites on ICAM-4. Blood 2007; 109 (2) 802-810
99 Hermand P, Gane P, Huet M , et al. Red cell ICAM-4 is a novel ligand for platelet-activated alpha IIbbeta 3 integrin. J Biol Chem 2003; 278 (7) 4892-4898
100 Toivanen A, Ihanus E, Mattila M, Lutz HU, Gahmberg CG. Importance of molecular studies on major blood groups—intercellular adhesion molecule-4, a blood group antigen involved in multiple cellular interactions. Biochim Biophys Acta 2008; 1780 (3) 456-466
101 Zennadi R, Hines PC, De Castro LM, Cartron JP, Parise LV, Telen MJ. Epinephrine acts through erythroid signaling pathways to activate sickle cell adhesion to endothelium via LW-alphavbeta3 interactions. Blood 2004; 104 (12) 3774-3781
102 Lee G, Lo A, Short SA , et al. Targeted gene deletion demonstrates that the cell adhesion molecule ICAM-4 is critical for erythroblastic island formation. Blood 2006; 108 (6) 2064-2071
103 Du VX, de Groot PG, van Wijk R, Ruggeri ZM, de Laat B. Binding of erythrocyte ICAM–4 to the platelet activated integrin αIIbβ3 leads to a direct erythrocyte-platelet adhesion under venous flow shear rate. Paper presented at: Annual Meeting of the American Society of Hematology; December 9,. 2012 ; Atlanta, GA
104 Valles J, Santos MT, Aznar J , et al. Erythrocytes metabolically enhance collagen-induced platelet responsiveness via increased thromboxane production, adenosine diphosphate release, and recruitment. Blood 1991; 78 (1) 154-162
105 Vallés J, Santos MT, Aznar J , et al. Platelet-erythrocyte interactions enhance alpha(IIb)beta(3) integrin receptor activation and P-selectin expression during platelet recruitment: down-regulation by aspirin ex vivo. Blood 2002; 99 (11) 3978-3984
106 Santos MT, Valles J, Marcus AJ , et al. Enhancement of platelet reactivity and modulation of eicosanoid production by intact erythrocytes. A new approach to platelet activation and recruitment. J Clin Invest 1991; 87 (2) 571-580