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

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)

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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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 3 Weatherall D J. The global problem of genetic disease.  Ann Hum Biol. 2005;  32 (2) 117-122
    CrossrefPubMedGoogle Scholar
  • 4 Weatherall D J, Clegg J B. Inherited haemoglobin disorders: an increasing global health problem.  Bull World Health Organ. 2001;  79 (8) 704-712
    PubMedGoogle Scholar
  • 5 Eaton W A, Hofrichter J. Sickle cell hemoglobin polymerization.  Adv Protein Chem. 1990;  40 63-279
    PubMedGoogle Scholar
  • 6 Steinberg M H. Management of sickle cell disease.  N Engl J Med. 1999;  340 (13) 1021-1030
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 14 Ataga K I, Orringer E P. Hypercoagulability in sickle cell disease: a curious paradox.  Am J Med. 2003;  115 (9) 721-728
    CrossrefPubMedGoogle Scholar
  • 15 Cappellini M D. Coagulation in the pathophysiology of hemolytic anemias [review].  Hematology Am Soc Hematol Educ Program. 2007;  74-78
    PubMedGoogle Scholar
  • 16 Morris C R. Mechanisms of vasculopathy in sickle cell disease and thalassemia.  Hematology Am Soc Hematol Educ Program. 2008;  177-185
    PubMedGoogle Scholar
  • 17 Adam S S, Key N S, Greenberg C S. D-dimer antigen: current concepts and future prospects.  Blood. 2009;  113 (13) 2878-2887
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 23 Verduzco L A, Nathan D G. Sickle cell disease and stroke.  Blood. 2009;  114 (25) 5117-5125
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 25 Prengler M, Pavlakis S G, Prohovnik I, Adams R J. Sickle cell disease: the neurological complications.  Ann Neurol. 2002;  51 (5) 543-552
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 33 Green D, Scott J P. Is sickle cell crisis a thrombotic event?.  Am J Hematol. 1986;  23 (4) 317-321
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 45 Tam D A. Protein C and protein S activity in sickle cell disease and stroke.  J Child Neurol. 1997;  12 (1) 19-21
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 74 Mehta P, Mehta J. Abnormalities of platelet aggregation in sickle cell disease.  J Pediatr. 1980;  96 (2) 209-213
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 76 Buchanan G R, Holtkamp C A. Evidence against enhanced platelet activity in sickle cell anaemia.  Br J Haematol. 1983;  54 (4) 595-603
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 78 Deckmyn H, Ulrichts H, Van De Walle G, Vanhoorelbeke K. Platelet antigens and their function.  Vox Sang. 2004;  87 (Suppl 2) 105-111
    PubMedGoogle Scholar
  • 79 Bray P F. Platelet glycoprotein polymorphisms as risk factors for thrombosis.  Curr Opin Hematol. 2000;  7 (5) 284-289
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 83 Ortiz A. Circulating endothelial cells in sickle cell anemia.  N Engl J Med. 1998;  338 (16) 1162 author reply 1162-1163
    CrossrefPubMedGoogle Scholar
  • 84 Parise L V, Telen M J. Erythrocyte adhesion in sickle cell disease.  Curr Hematol Rep. 2003;  2 (2) 102-108
    PubMedGoogle Scholar
  • 85 De Franceschi L, Corrocher R. Established and experimental treatments for sickle cell disease.  Haematologica. 2004;  89 (3) 348-356
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 95 Hebbel R P. Adhesion of sickle red cells to endothelium: myths and future directions.  Transfus Clin Biol. 2008;  15 (1-2) 14-18
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 102 Tsai H M. Current concepts in thrombotic thrombocytopenic purpura.  Annu Rev Med. 2006;  57 419-436
    CrossrefPubMedGoogle Scholar
  • 103 Sadler J E. A new name in thrombosis, ADAMTS13.  Proc Natl Acad Sci U S A. 2002;  99 (18) 11552-11554
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 119 Croizat H. Circulating cytokines in sickle cell patients during steady state.  Br J Haematol. 1994;  87 (3) 592-597
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 122 Conran N, Costa F F. Hemoglobin disorders and endothelial cell interactions.  Clin Biochem. 2009;  42 (18) 1824-1838
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 131 Yang Y, Loscalzo J. Regulation of tissue factor expression in human microvascular endothelial cells by nitric oxide.  Circulation. 2000;  101 (18) 2144-2148
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar
  • 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
    CrossrefPubMedGoogle Scholar

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

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