Thrombosis and Sickle Cell Disease

Lucia De Franceschi; Maria Domenica Cappellini; Oliviero Olivieri

doi:10.1055/s-0031-1273087

Subscribe to RSS

Please copy the URL and add it into your RSS Feed Reader.

https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00000077.xml

Share / Bookmark

Facebook Twitter Linkedin Weibo

Download PDF

Semin Thromb Hemost 2011; 37(3): 226-236
DOI: 10.1055/s-0031-1273087

Thrombosis and Sickle Cell Disease

Lucia De Franceschi¹ , Maria Domenica Cappellini² , Oliviero Olivieri¹

¹Department of Medicine, University of Verona, Verona, Italy
²Policlinico Foundation, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), University of Milan, Milan, Italy

Further Information

Publication History

Publication Date:
31 March 2011 (online)

Abstract
Full Text
References

Permissions and Reprints

ABSTRACT

Sickle cell disease (SCD) is characterized by the presence of sickle hemoglobin, which has the unique property of polymerizing when deoxygenated. The pathophysiology of acute and chronic clinical manifestations of SCD have shown the central role of dense, dehydrated red cells in acute and chronic clinical manifestations of this pathology. Recent studies have indicated that SCD is characterized by a hypercoagulable state that contributes to the vaso-occlusive events in microcirculation, leading to acute and chronic sickle cell–related organ damage. This review discusses, in the context of SCD, (1) abnormalities in the coagulation system, (2) perturbation of platelet activation and aggregation, (3) vascular endothelial dysfunction, (4) the contribution of cell inflammatory responses, and (5) the connection with nitric oxide metabolism. We also review the available studies on the therapeutic approaches in clinical management of hypercoagulability in SCD.

KEYWORDS

Hypercoagulability - vascular endothelial dysfunction - inflammation - neutrophils - dense red cells

REFERENCES

1 Modell B, Darlison M. Global epidemiology of haemoglobin disorders and derived service indicators. Bull World Health Organ. 2008; 86 (6) 480-487
2 Modell B, Darlison M, Birgens H et al.. Epidemiology of haemoglobin disorders in Europe: an overview. Scand J Clin Lab Invest. 2007; 67 (1) 39-69
3 Weatherall D J. The global problem of genetic disease. Ann Hum Biol. 2005; 32 (2) 117-122
4 Weatherall D J, Clegg J B. Inherited haemoglobin disorders: an increasing global health problem. Bull World Health Organ. 2001; 79 (8) 704-712
5 Eaton W A, Hofrichter J. Sickle cell hemoglobin polymerization. Adv Protein Chem. 1990; 40 63-279
6 Steinberg M H. Management of sickle cell disease. N Engl J Med. 1999; 340 (13) 1021-1030
7 Ballas S K, Smith E D. Red blood cell changes during the evolution of the sickle cell painful crisis. Blood. 1992; 79 (8) 2154-2163
8 Solovey A A, Solovey A N, Harkness J, Hebbel R P. Modulation of endothelial cell activation in sickle cell disease: a pilot study. Blood. 2001; 97 (7) 1937-1941
9 Gayen Betal S, Setty B N. Phosphatidylserine-positive erythrocytes bind to immobilized and soluble thrombospondin-1 via its heparin-binding domain. Transl Res. 2008; 152 (4) 165-177
10 Setty B N, Betal S G, Zhang J, Stuart M J. Heme induces endothelial tissue factor expression: potential role in hemostatic activation in patients with hemolytic anemia. J Thromb Haemost. 2008; 6 (12) 2202-2209
11 Setty B N, Rao A K, Stuart M J. Thrombophilia in sickle cell disease: the red cell connection. Blood. 2001; 98 (12) 3228-3233
12 Rosenbaum C, Peace D, Rich E, Van Besien K. Granulocyte colony-stimulating factor-based stem cell mobilization in patients with sickle cell disease. Biol Blood Marrow Transplant. 2008; 14 (6) 719-723
13 Ataga K I, Cappellini M D, Rachmilewitz E A. Beta-thalassaemia and sickle cell anaemia as paradigms of hypercoagulability. Br J Haematol. 2007; 139 (1) 3-13
14 Ataga K I, Orringer E P. Hypercoagulability in sickle cell disease: a curious paradox. Am J Med. 2003; 115 (9) 721-728
15 Cappellini M D. Coagulation in the pathophysiology of hemolytic anemias [review]. Hematology Am Soc Hematol Educ Program. 2007; 74-78
16 Morris C R. Mechanisms of vasculopathy in sickle cell disease and thalassemia. Hematology Am Soc Hematol Educ Program. 2008; 177-185
17 Adam S S, Key N S, Greenberg C S. D-dimer antigen: current concepts and future prospects. Blood. 2009; 113 (13) 2878-2887
18 Archer D R, Stiles J K, Newman G W et al.. C-reactive protein and interleukin-6 are decreased in transgenic sickle cell mice fed a high protein diet. J Nutr. 2008; 138 (6) 1148-1152
19 Ou J, Ou Z, Jones D W et al.. L-4F, an apolipoprotein A-1 mimetic, dramatically improves vasodilation in hypercholesterolemia and sickle cell disease. Circulation. 2003; 107 (18) 2337-2341
20 Lanaro C, Franco-Penteado C F, Albuqueque D M, Saad S T, Conran N, Costa F F. Altered levels of cytokines and inflammatory mediators in plasma and leukocytes of sickle cell anemia patients and effects of hydroxyurea therapy. J Leukoc Biol. 2009; 85 (2) 235-242
21 Austin H, Key N S, Benson J M et al.. Sickle cell trait and the risk of venous thromboembolism among blacks. Blood. 2007; 110 (3) 908-912
22 Stein P D, Beemath A, Meyers F A, Skaf E, Olson R E. Deep venous thrombosis and pulmonary embolism in hospitalized patients with sickle cell disease. Am J Med. 2006; 119 (10) 897 e7-e11
23 Verduzco L A, Nathan D G. Sickle cell disease and stroke. Blood. 2009; 114 (25) 5117-5125
24 James A H, Jamison M G, Brancazio L R, Myers E R. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol. 2006; 194 (5) 1311-1315
25 Prengler M, Pavlakis S G, Prohovnik I, Adams R J. Sickle cell disease: the neurological complications. Ann Neurol. 2002; 51 (5) 543-552
26 Adedeji M O, Cespedes J, Allen K, Subramony C, Hughson M D. Pulmonary thrombotic arteriopathy in patients with sickle cell disease. Arch Pathol Lab Med. 2001; 125 (11) 1436-1441
27 Haque A K, Gokhale S, Rampy B A, Adegboyega P, Duarte A, Saldana M J. Pulmonary hypertension in sickle cell hemoglobinopathy: a clinicopathologic study of 20 cases. Hum Pathol. 2002; 33 (10) 1037-1043
28 Peters M, Plaat B E, ten Cate H, Wolters H J, Weening R S, Brandjes D P. Enhanced thrombin generation in children with sickle cell disease. Thromb Haemost. 1994; 71 (2) 169-172
29 Tomer A, Kasey S, Connor W E, Clark S, Harker L A, Eckman J R. Reduction of pain episodes and prothrombotic activity in sickle cell disease by dietary n-3 fatty acids. Thromb Haemost. 2001; 85 (6) 966-974
30 Leslie J, Langler D, Serjeant G R, Serjeant B E, Desai P, Gordon Y B. Coagulation changes during the steady state in homozygous sickle-cell disease in Jamaica. Br J Haematol. 1975; 30 (2) 159-166
31 Rickles F R, O'Leary D S. Role of coagulation system in pathophysiology of sickle cell disease. Arch Intern Med. 1974; 133 (4) 635-641
32 Stuart M J, Setty B N. Hemostatic alterations in sickle cell disease: relationships to disease pathophysiology. Pediatr Pathol Mol Med. 2001; 20 (1) 27-46
33 Green D, Scott J P. Is sickle cell crisis a thrombotic event?. Am J Hematol. 1986; 23 (4) 317-321
34 Francis Jr R B. Elevated fibrin D-dimer fragment in sickle cell anemia: evidence for activation of coagulation during the steady state as well as in painful crisis. Haemostasis. 1989; 19 (2) 105-111
35 Richardson S G, Matthews K B, Stuart J, Geddes A M, Wilcox R M. Serial changes in coagulation and viscosity during sickle-cell crisis. Br J Haematol. 1979; 41 (1) 95-103
36 Tomer A, Harker L A, Kasey S, Eckman J R. Thrombogenesis in sickle cell disease. J Lab Clin Med. 2001; 137 (6) 398-407
37 Kurantsin-Mills J, Ofosu F A, Safa T K, Siegel R S, Lessin L S. Plasma factor VII and thrombin-antithrombin III levels indicate increased tissue factor activity in sickle cell patients. Br J Haematol. 1992; 81 (4) 539-544
38 Westerman M P, Green D, Gilman-Sachs A et al.. Antiphospholipid antibodies, proteins C and S, and coagulation changes in sickle cell disease. J Lab Clin Med. 1999; 134 (4) 352-362
39 Hagger D, Wolff S, Owen J, Samson D. Changes in coagulation and fibrinolysis in patients with sickle cell disease compared with healthy black controls. Blood Coagul Fibrinolysis. 1995; 6 (2) 93-99
40 Branch D W, Rodgers G M. Induction of endothelial cell tissue factor activity by sera from patients with antiphospholipid syndrome: a possible mechanism of thrombosis. Am J Obstet Gynecol. 1993; 168 (1 Pt 1) 206-210
41 Ataga K I, Moore C G, Hillery C A et al.. Coagulation activation and inflammation in sickle cell disease-associated pulmonary hypertension. Haematologica. 2008; 93 (1) 20-26
42 van Beers E J, Spronk H M, Ten Cate H CURAMA study Group et al. No association of the hypercoagulable state with sickle cell disease related pulmonary hypertension. Haematologica. 2008; 93 (5) e42-e44
43 Shet A S, Aras O, Gupta K et al.. Sickle blood contains tissue factor-positive microparticles derived from endothelial cells and monocytes. Blood. 2003; 102 (7) 2678-2683
44 van Beers E J, Schaap M C, Berckmans R J CURAMA study group et al. Circulating erythrocyte-derived microparticles are associated with coagulation activation in sickle cell disease. Haematologica. 2009; 94 (11) 1513-1519
45 Tam D A. Protein C and protein S activity in sickle cell disease and stroke. J Child Neurol. 1997; 12 (1) 19-21
46 el-Hazmi M A, Warsy A S, Bahakim H. Blood proteins C and S in sickle cell disease. Acta Haematol. 1993; 90 (3) 114-119
47 Karayalcin G, Lanzkowsky P. Plasma protein C levels in children with sickle cell disease. Am J Pediatr Hematol Oncol. 1989; 11 (3) 320-323
48 Kuypers F A, Larkin S K, Emeis J J, Allison A C. Interaction of an annexin V homodimer (Diannexin) with phosphatidylserine on cell surfaces and consequent antithrombotic activity. Thromb Haemost. 2007; 97 (3) 478-486
49 Lane P A, O'Connell J L, Marlar R A. Erythrocyte membrane vesicles and irreversibly sickled cells bind protein S. Am J Hematol. 1994; 47 (4) 295-300
50 Nsiri B, Gritli N, Bayoudh F, Messaoud T, Fattoum S, Machghoul S. Abnormalities of coagulation and fibrinolysis in homozygous sickle cell disease. Hematol Cell Ther. 1996; 38 (3) 279-284
51 Nsiri B, Gritli N, Mazigh C, Ghazouani E, Fattoum S, Machghoul S. Fibrinolytic response to venous occlusion in patients with homozygous sickle cell disease. Hematol Cell Ther. 1997; 39 (5) 229-232
52 Yamamoto K, Saito H. A pathological role of increased expression of plasminogen activator inhibitor-1 in human or animal disorders. Int J Hematol. 1998; 68 (4) 371-385
53 Key N S, Slungaard A, Dandelet L et al.. Whole blood tissue factor procoagulant activity is elevated in patients with sickle cell disease. Blood. 1998; 91 (11) 4216-4223
54 Solovey A, Gui L, Key N S, Hebbel R P. Tissue factor expression by endothelial cells in sickle cell anemia. J Clin Invest. 1998; 101 (9) 1899-1904
55 Andrade F L, Annichino-Bizzacchi J M, Saad S T, Costa F F, Arruda V R. Prothrombin mutant, factor V Leiden, and thermolabile variant of methylenetetrahydrofolate reductase among patients with sickle cell disease in Brazil. Am J Hematol. 1998; 59 (1) 46-50
56 Kahn M J, Scher C, Rozans M, Michaels R K, Leissinger C, Krause J. Factor V Leiden is not responsible for stroke in patients with sickling disorders and is uncommon in African Americans with sickle cell disease. Am J Hematol. 1997; 54 (1) 12-15
57 Cumming A M, Olujohungbe A, Keeney S, Singh H, Hay C R, Serjeant G R. The methylenetetrahydrofolate reductase gene C677T polymorphism in patients with homozygous sickle cell disease and stroke. Br J Haematol. 1999; 107 (3) 569-571
58 Rees D C, Chapman N H, Webster M T, Guerreiro J F, Rochette J, Clegg J B. Born to clot: the European burden. Br J Haematol. 1999; 105 (2) 564-566
59 Rahimi Z, Vaisi-Raygani A, Nagel R L, Muniz A. Thrombophilic mutations among Southern Iranian patients with sickle cell disease: high prevalence of factor V Leiden. J Thromb Thrombolysis. 2008; 25 (3) 288-292
60 Isma'eel H, Arnaout M S, Shamseddeen W et al.. Screening for inherited thrombophilia might be warranted among Eastern Mediterranean sickle-beta-0 thalassemia patients. J Thromb Thrombolysis. 2006; 22 (2) 121-123
61 Fawaz N A, Bashawery L, Al-Sheikh I, Qatari A, Al-Othman S S, Almawi W Y. Factor V-Leiden, prothrombin G20210A, and MTHFR C677T mutations among patients with sickle cell disease in Eastern Saudi Arabia. Am J Hematol. 2004; 76 (3) 307-309
62 Zimmerman S A, Ware R E. Inherited DNA mutations contributing to thrombotic complications in patients with sickle cell disease. Am J Hematol. 1998; 59 (4) 267-272
63 Adekile A D, Kutlar F, Haider M Z, Kutlar A. Frequency of the 677 C—> T mutation of the methylenetetrahydrofolate reductase gene among Kuwaiti sickle cell disease patients. Am J Hematol. 2001; 66 (4) 263-266
64 Foulon I, Bachir D, Galacteros F, Maclouf J. Increased in vivo production of thromboxane in patients with sickle cell disease is accompanied by an impairment of platelet functions to the thromboxane A2 agonist U46619. Arterioscler Thromb. 1993; 13 (3) 421-426
65 Browne P V, Mosher D F, Steinberg M H, Hebbel R P. Disturbance of plasma and platelet thrombospondin levels in sickle cell disease. Am J Hematol. 1996; 51 (4) 296-301
66 Kenny M W, George A J, Stuart J. Platelet hyperactivity in sickle-cell disease: a consequence of hyposplenism. J Clin Pathol. 1980; 33 (7) 622-625
67 Westwick J, Watson-Williams E J, Krishnamurthi S et al.. Platelet activation during steady state sickle cell disease. J Med. 1983; 14 (1) 17-36
68 Winichagoon P, Fucharoen S, Wasi P. Increased circulating platelet aggregates in thalassaemia. Southeast Asian J Trop Med Public Health. 1981; 12 (4) 556-560
69 Wun T, Paglieroni T, Rangaswami A et al.. Platelet activation in patients with sickle cell disease. Br J Haematol. 1998; 100 (4) 741-749
70 Famodu A A, Oduwa D. Platelet count and platelet factor 3 (PF-3) availability in sickle cell disease. Br J Biomed Sci. 1995; 52 (4) 323-324
71 Lee S P, Ataga K I, Orringer E P, Phillips D R, Parise L V. Biologically active CD40 ligand is elevated in sickle cell anemia: potential role for platelet-mediated inflammation. Arterioscler Thromb Vasc Biol. 2006; 26 (7) 1626-1631
72 Villagra J, Shiva S, Hunter L A, Machado R F, Gladwin M T, Kato G J. Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin. Blood. 2007; 110 (6) 2166-2172
73 Proença-Ferreira R, Franco-Penteado C F, Traina F, Saad S T, Costa F F, Conran N. Increased adhesive properties of platelets in sickle cell disease: roles for alphaIIb beta3-mediated ligand binding, diminished cAMP signalling and increased phosphodiesterase 3A activity. Br J Haematol. 2010; 149 (2) 280-288
74 Mehta P, Mehta J. Abnormalities of platelet aggregation in sickle cell disease. J Pediatr. 1980; 96 (2) 209-213
75 Haut M J, Cowan D H, Harris J W. Platelet function and survival in sickle cell disease. J Lab Clin Med. 1973; 82 (1) 44-53
76 Buchanan G R, Holtkamp C A. Evidence against enhanced platelet activity in sickle cell anaemia. Br J Haematol. 1983; 54 (4) 595-603
77 Kunicki T J. The influence of platelet collagen receptor polymorphisms in hemostasis and thrombotic disease. Arterioscler Thromb Vasc Biol. 2002; 22 (1) 14-20
78 Deckmyn H, Ulrichts H, Van De Walle G, Vanhoorelbeke K. Platelet antigens and their function. Vox Sang. 2004; 87 (Suppl 2) 105-111
79 Bray P F. Platelet glycoprotein polymorphisms as risk factors for thrombosis. Curr Opin Hematol. 2000; 7 (5) 284-289
80 Castro V, Alberto F L, Costa R N et al.. Polymorphism of the human platelet antigen-5 system is a risk factor for occlusive vascular complications in patients with sickle cell anemia. Vox Sang. 2004; 87 (2) 118-123
81 Al-Subaie A M, Fawaz N A, Mahdi N et al.. Human platelet alloantigens (HPA) 1, HPA2, HPA3, HPA4, and HPA5 polymorphisms in sickle cell anemia patients with vaso-occlusive crisis. Eur J Haematol. 2009; 83 (6) 579-585
82 Solovey A, Gui L, Ramakrishnan S, Steinberg M H, Hebbel R P. Sickle cell anemia as a possible state of enhanced anti-apoptotic tone: survival effect of vascular endothelial growth factor on circulating and unanchored endothelial cells. Blood. 1999; 93 (11) 3824-3830
83 Ortiz A. Circulating endothelial cells in sickle cell anemia. N Engl J Med. 1998; 338 (16) 1162 author reply 1162-1163
84 Parise L V, Telen M J. Erythrocyte adhesion in sickle cell disease. Curr Hematol Rep. 2003; 2 (2) 102-108
85 De Franceschi L, Corrocher R. Established and experimental treatments for sickle cell disease. Haematologica. 2004; 89 (3) 348-356
86 Kaul D K, Tsai H M, Liu X D, Nakada M T, Nagel R L, Coller B S. Monoclonal antibodies to alphaVbeta3 (7E3 and LM609) inhibit sickle red blood cell-endothelium interactions induced by platelet-activating factor. Blood. 2000; 95 (2) 368-374
87 Barabino G A, Liu X D, Ewenstein B M, Kaul D K. Anionic polysaccharides inhibit adhesion of sickle erythrocytes to the vascular endothelium and result in improved hemodynamic behavior. Blood. 1999; 93 (4) 1422-1429
88 Hines P C, Zen Q, Burney S N et al.. Novel epinephrine and cyclic AMP-mediated activation of BCAM/Lu-dependent sickle (SS) RBC adhesion. Blood. 2003; 101 (8) 3281-3287
89 Murphy M M, Zayed M A, Evans A et al.. Role of Rap1 in promoting sickle red blood cell adhesion to laminin via BCAM/LU. Blood. 2005; 105 (8) 3322-3329
90 Zennadi R, Hines P C, De Castro L M, Cartron J P, Parise L V, Telen M J. Epinephrine acts through erythroid signaling pathways to activate sickle cell adhesion to endothelium via LW-alphavbeta3 interactions. Blood. 2004; 104 (12) 3774-3781
91 Zennadi R, De Castro L, Eyler C, Xu K, Ko M, Telen M J. Role and regulation of sickle red cell interactions with other cells: ICAM-4 and other adhesion receptors. Transfus Clin Biol. 2008; 15 (1-2) 23-28
92 Kaul D K, Liu X D, Zhang X et al.. Peptides based on alphaV-binding domains of erythrocyte ICAM-4 inhibit sickle red cell-endothelial interactions and vaso-occlusion in the microcirculation. Am J Physiol Cell Physiol. 2006; 291 (5) C922-C930
93 Mankelow T J, Spring F A, Parsons S F et al.. Identification of critical amino-acid residues on the erythroid intercellular adhesion molecule-4 (ICAM-4) mediating adhesion to alpha V integrins. Blood. 2004; 103 (4) 1503-1508
94 Sabina R L, Wandersee N J, Hillery C A. Ca2 + -CaM activation of AMP deaminase contributes to adenine nucleotide dysregulation and phosphatidylserine externalization in human sickle erythrocytes. Br J Haematol. 2009; 144 (3) 434-445
95 Hebbel R P. Adhesion of sickle red cells to endothelium: myths and future directions. Transfus Clin Biol. 2008; 15 (1-2) 14-18
96 Kuypers F A, Styles L A. The role of secretory phospholipase A2 in acute chest syndrome. Cell Mol Biol (Noisy-le-grand). 2004; 50 (1) 87-94
97 Kuypers F A, de Jong K. The role of phosphatidylserine in recognition and removal of erythrocytes. Cell Mol Biol (Noisy-le-grand). 2004; 50 (2) 147-158
98 Schnog J J, Hovinga J A, Krieg S CURAMA Study Group et al. ADAMTS13 activity in sickle cell disease. Am J Hematol. 2006; 81 (7) 492-498
99 Krishnan S, Siegel J, Pullen Jr G, Hevelow M, Dampier C, Stuart M. Increased von Willebrand factor antigen and high molecular weight multimers in sickle cell disease associated with nocturnal hypoxemia. Thromb Res. 2008; 122 (4) 455-458
100 Roberts D D, Williams S B, Gralnick H R, Ginsburg V. von Willebrand factor binds specifically to sulfated glycolipids. J Biol Chem. 1986; 261 (7) 3306-3309
101 Kaul D K, Nagel R L, Chen D, Tsai H M. Sickle erythrocyte-endothelial interactions in microcirculation: the role of von Willebrand factor and implications for vasoocclusion. Blood. 1993; 81 (9) 2429-2438
102 Tsai H M. Current concepts in thrombotic thrombocytopenic purpura. Annu Rev Med. 2006; 57 419-436
103 Sadler J E. A new name in thrombosis, ADAMTS13. Proc Natl Acad Sci U S A. 2002; 99 (18) 11552-11554
104 Feys H B, Anderson P J, Vanhoorelbeke K, Majerus E M, Sadler J E. Multi-step binding of ADAMTS-13 to von Willebrand factor. J Thromb Haemost. 2009; 7 (12) 2088-2095
105 Turner N A, Nolasco L, Ruggeri Z M, Moake J L. Endothelial cell ADAMTS-13 and VWF: production, release, and VWF string cleavage. Blood. 2009; 114 (24) 5102-5111
106 Studt J D, Hovinga J A, Antoine G et al.. Fatal congenital thrombotic thrombocytopenic purpura with apparent ADAMTS13 inhibitor: in vitro inhibition of ADAMTS13 activity by hemoglobin. Blood. 2005; 105 (2) 542-544
107 Zhou Z, Han H, Cruz M A, López J A, Dong J F, Guchhait P. Haemoglobin blocks von Willebrand factor proteolysis by ADAMTS-13: a mechanism associated with sickle cell disease. Thromb Haemost. 2009; 101 (6) 1070-1077
108 Taylor VI J G, Tang D C, Savage S A et al.. Variants in the VCAM1 gene and risk for symptomatic stroke in sickle cell disease. Blood. 2002; 100 (13) 4303-4309
109 Hoppe C, Klitz W, D'Harlingue K Stroke Prevention Trial in Sickle Cell Anemia (STOP) Investigators et al. Confirmation of an association between the TNF(-308) promoter polymorphism and stroke risk in children with sickle cell anemia. Stroke. 2007; 38 (8) 2241-2246
110 Chaar V, Tarer V, Etienne-Julan M, Diara J P, Elion J, Romana M. ET-1 and ecNOS gene polymorphisms and susceptibility to acute chest syndrome and painful vaso-occlusive crises in children with sickle cell anemia. Haematologica. 2006; 91 (9) 1277-1278
111 Sharan K, Surrey S, Ballas S et al.. Association of T-786C eNOS gene polymorphism with increased susceptibility to acute chest syndrome in females with sickle cell disease. Br J Haematol. 2004; 124 (2) 240-243
112 Baldwin C, Nolan V G, Wyszynski D F et al.. Association of klotho, bone morphogenic protein 6, and annexin A2 polymorphisms with sickle cell osteonecrosis. Blood. 2005; 106 (1) 372-375
113 Sebastiani P, Ramoni M F, Nolan V, Baldwin C T, Steinberg M H. Genetic dissection and prognostic modeling of overt stroke in sickle cell anemia. Nat Genet. 2005; 37 (4) 435-440
114 Nolan V G, Baldwin C, Ma Q et al.. Association of single nucleotide polymorphisms in klotho with priapism in sickle cell anaemia. Br J Haematol. 2005; 128 (2) 266-272
115 Nolan V G, Adewoye A, Baldwin C et al.. Sickle cell leg ulcers: associations with haemolysis and SNPs in Klotho, TEK and genes of the TGF-beta/BMP pathway. Br J Haematol. 2006; 133 (5) 570-578
116 Elliott L, Ashley-Koch A E, De Castro L et al.. Genetic polymorphisms associated with priapism in sickle cell disease. Br J Haematol. 2007; 137 (3) 262-267
117 Graido-Gonzalez E, Doherty J C, Bergreen E W, Organ G, Telfer M, McMillen M A. Plasma endothelin-1, cytokine, and prostaglandin E2 levels in sickle cell disease and acute vaso-occlusive sickle crisis. Blood. 1998; 92 (7) 2551-2555
118 Natarajan M, Udden M M, McIntire L V. Adhesion of sickle red blood cells and damage to interleukin-1 beta stimulated endothelial cells under flow in vitro. Blood. 1996; 87 (11) 4845-4852
119 Croizat H. Circulating cytokines in sickle cell patients during steady state. Br J Haematol. 1994; 87 (3) 592-597
120 Francis Jr R B, Haywood L J. Elevated immunoreactive tumor necrosis factor and interleukin-1 in sickle cell disease. J Natl Med Assoc. 1992; 84 (7) 611-615
121 Hibbert J M, Hsu L L, Bhathena S J et al.. Proinflammatory cytokines and the hypermetabolism of children with sickle cell disease. Exp Biol Med (Maywood). 2005; 230 (1) 68-74
122 Conran N, Costa F F. Hemoglobin disorders and endothelial cell interactions. Clin Biochem. 2009; 42 (18) 1824-1838
123 Enenstein J, Milbauer L, Domingo E et al.. Proinflammatory phenotype with imbalance of KLF2 and RelA: risk of childhood stroke with sickle cell anemia. Am J Hematol. 2010; 85 (1) 18-23
124 Fadlon E, Vordermeier S, Pearson T C et al.. Blood polymorphonuclear leukocytes from the majority of sickle cell patients in the crisis phase of the disease show enhanced adhesion to vascular endothelium and increased expression of CD64. Blood. 1998; 91 (1) 266-274
125 Canalli A A, Franco-Penteado C F, Saad S T, Conran N, Costa F F. Increased adhesive properties of neutrophils in sickle cell disease may be reversed by pharmacological nitric oxide donation. Haematologica. 2008; 93 (4) 605-609
126 Lum A F, Wun T, Staunton D, Simon S I. Inflammatory potential of neutrophils detected in sickle cell disease. Am J Hematol. 2004; 76 (2) 126-133
127 Assis A, Conran N, Canalli A A, Lorand-Metze I, Saad S T, Costa F F. Effect of cytokines and chemokines on sickle neutrophil adhesion to fibronectin. Acta Haematol. 2005; 113 (2) 130-136
128 Hidalgo A, Chang J, Jang J E, Peired A J, Chiang E Y, Frenette P S. Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury. Nat Med. 2009; 15 (4) 384-391
129 Wallace K L, Marshall M A, Ramos S I et al.. NKT cells mediate pulmonary inflammation and dysfunction in murine sickle cell disease through production of IFN-gamma and CXCR3 chemokines. Blood. 2009; 114 (3) 667-676
130 de Franceschi L, Baron A, Scarpa A et al.. Inhaled nitric oxide protects transgenic SAD mice from sickle cell disease-specific lung injury induced by hypoxia/reoxygenation. Blood. 2003; 102 (3) 1087-1096
131 Yang Y, Loscalzo J. Regulation of tissue factor expression in human microvascular endothelial cells by nitric oxide. Circulation. 2000; 101 (18) 2144-2148
132 Kato G J, Martyr S, Blackwelder W C et al.. Levels of soluble endothelium-derived adhesion molecules in patients with sickle cell disease are associated with pulmonary hypertension, organ dysfunction, and mortality. Br J Haematol. 2005; 130 (6) 943-953
133 Chaplin Jr H, Alkjaersig N, Fletcher A P, Michael J M, Joist J H. Aspirin-dipyridamole prophylaxis of sickle cell disease pain crises. Thromb Haemost. 1980; 43 (3) 218-221
134 Osamo N O, Photiades D P, Famodu A A. Therapeutic effect of aspirin in sickle cell anaemia. Acta Haematol. 1981; 66 (2) 102-107
135 Greenberg J, Ohene-Frempong K, Halus J, Way C, Schwartz E. Trial of low doses of aspirin as prophylaxis in sickle cell disease. J Pediatr. 1983; 102 (5) 781-784
136 Semple M J, Al-Hasani S F, Kioy P, Savidge G F. A double-blind trial of ticlopidine in sickle cell disease. Thromb Haemost. 1984; 51 (3) 303-306
137 Cabannes R, Lonsdorfer J, Castaigne J P, Ondo A, Plassard A, Zohoun I. Clinical and biological double-blind-study of ticlopidine in preventive treatment of sickle-cell disease crises. Agents Actions Suppl. 1984; 15 199-212
138 Zago M A, Costa F F, Ismael S J, Tone L G, Bottura C. Treatment of sickle cell diseases with aspirin. Acta Haematol. 1984; 72 (1) 61-64
139 Mohan J S, Lip G Y, Wright J, Bareford D, Blann A D. Plasma levels of tissue factor and soluble E-selectin in sickle cell disease: relationship to genotype and to inflammation. Blood Coagul Fibrinolysis. 2005; 16 (3) 209-214
140 Wood K, Russell J, Hebbel R P, Granger D N. Differential expression of E- and P-selectin in the microvasculature of sickle cell transgenic mice. Microcirculation. 2004; 11 (4) 377-385
141 Blum A, Yeganeh S, Peleg A et al.. Endothelial function in patients with sickle cell anemia during and after sickle cell crises. J Thromb Thrombolysis. 2005; 19 (2) 83-86
142 Qari M H, Aljaouni S K, Alardawi M S et al.. Reduction of painful vaso-occlusive crisis of sickle cell anaemia by tinzaparin in a double-blind randomized trial. Thromb Haemost. 2007; 98 (2) 392-396
143 Ahmed S, Siddiqui A K, Iqbal U et al.. Effect of low-dose warfarin on D-dimer levels during sickle cell vaso-occlusive crisis: a brief report. Eur J Haematol. 2004; 72 (3) 213-216
144 Salvaggio J E, Arnold C A, Banov C H. Long-term anti-coagulation in sickle-cell disease. A clinical study. N Engl J Med. 1963; 269 182-186
145 Dobson S R, Holden K R, Nietert P J et al.. Moyamoya syndrome in childhood sickle cell disease: a predictive factor for recurrent cerebrovascular events. Blood. 2002; 99 (9) 3144-3150
146 Aessopos A, Farmakis D, Loukopoulos D. Elastic tissue abnormalities resembling pseudoxanthoma elasticum in beta thalassemia and the sickling syndromes. Blood. 2002; 99 (1) 30-35

Lucia De FranceschiM.D.

Department of Medicine, University of Verona, Policlinico GB Res8i

P.le L Scuro, 10, 37134 Verona, Italy

Email: lucia.defranceschi@univr.it

>