The risk for thromboembolic disease in lupus anticoagulant patients due to pathways involving P-selectin and CD154

Peter Bugert; Ingrid Pabinger; Kathrin Stamer; Rainer Vormittag; Robert C. Skeate; Monika M. Wahi; Simon Panzer

doi:10.1160/TH06-12-0730

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 97(04): 573-580
DOI: 10.1160/TH06-12-0730

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

The risk for thromboembolic disease in lupus anticoagulant patients due to pathways involving P-selectin and CD154

Peter Bugert^*

¹Institute of Transfusion Medicine and Immunology, German Red Cross Blood Service of Baden-Württemberg – Hessen, University of Heidelberg, Faculty of Clinical Medicine, Mannheim, Germany

,

Ingrid Pabinger^*

²Division of Haematology and Haemostaseology, Department of Internal Medicine

,

Kathrin Stamer

¹Institute of Transfusion Medicine and Immunology, German Red Cross Blood Service of Baden-Württemberg – Hessen, University of Heidelberg, Faculty of Clinical Medicine, Mannheim, Germany

,

Rainer Vormittag

²Division of Haematology and Haemostaseology, Department of Internal Medicine

,

Robert C. Skeate

⁴Division of Health Informatics, Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA

,

Monika M. Wahi

⁵Department of Epidemiology and Biostatistics, University of South Florida College of Public Health, and Johnnie B. Byrd, Sr. Alzheimer’s Center and Research Institute, Tampa, Florida, USA

,

Simon Panzer

³Clinic for Blood Group Serology, Medical University Vienna, Austria

› Author Affiliations

Abstract

Summary

Individuals with lupus anticoagulants (LA) are at risk for thromboembolism(TE). Chronic inflammation is an important characteristicin LA patients which may dispose for TE. Platelets play akey role in inflammation and TE. We therefore investigated genepolymorphisms as well as plasma levels of platelet receptors aspredictors of TE in 107 LA patients. We compared 74 patientswith a history of thromboembolic disease (TE+),56 with venousthrombosis (VT), 12 with arterial thrombosis (AT), and six patientswho had both, with 33 LA patients without previousthrombosis (TE-).The P-selectin Pro715 allele was slightly morefrequent inVT (OR=3.167,95 % CI 0.955–10.503;p=0.0594),butno patient with AT had this allele (OR=0.099, 95 % CI0.001–0.790; p=0.0238) which therefore may protect from AT. Plasma levels of P-selectin, collected a median of 35 months(range 2–329 months) after the last thrombotic event, werehigher in patients withVT (p=0.0096) than inTE-,but not withAT(p=0.4713).These high P-selectin levels were not explained bythe P-selectin polymorphism. The CA repeat polymorphism inthe 3’-noncoding region of CD154 was significantly associatedwith the development of AT (OR=4.035, 95 % CI 1.329–12.249;p=0.0138). Plasma levels of CD154 were not significantly differentamong the subgroups. Thus, theThr715Pro polymorphism ofP-selectin and CA repeats of CD154 are differentiating betweenthe risk for VT and AT. Further, soluble P-selectin is elevated inLA patients with previousVT, but its role to predictVT needs to be evaluated in prospective studies.

Keywords

Lupus anticoagulant - thromboembolism - P-selectin - CD154

Full Text

References

References
1 Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Prevalence and clinical significance. Ann Intern Med 1990; 112: 682-698.
2 Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002; 346: 752-763.
3 Campbell AL, Pierangeli SS, Wellhausen S. et al. Comparison of the effects of anticardiolipin antibodies from patients with the antiphospholipid syndrome and with syphilis on platelet activation and aggregation. Thromb Haemost 1995; 73: 529-534.
4 Escolar G, Font J, Reverter JC. et al. Plasma from systemic lupus erythematosus patients with antiphospholipid antibodies promotes platelet aggregation. Studies in a perfusion system. Arterioscler Thromb 1992; 12: 196-200.
5 Galli M, Bevers EM, Comfurius P. et al. Effect of antiphospholipid antibodies on procoagulant activity of activated platelets and platelet-derived microvesicles. Br J Haematol 1993; 83: 466-472.
6 Joseph JE, Harrison P, Mackie IJ. et al. Increased circulating platelet-leucocyte complexes and platelet activation in patients with antiphospholipid syndrome, systemic lupus erythematosus and rheumatoid arthritis. Br J Haematol 2001; 115: 451-459.
7 Martinuzzo ME, Maclouf J, Carreras LO. et al. Antiphospholipid antibodies enhance thrombin-induced platelet activation and thromboxane formation. Thromb Haemost 1993; 70: 667-671.
8 Panzer S, Gschwandtner ME, Hutter D. et al. Specificities of platelet autoantibodies in patients with lupus anticoagulants in primary antiphospholipid syndrome. Ann Hematol 1997; 74: 239-242.
9 Sailer T, Vormittag R, Pabinger I. et al. Inflammation in patients with lupus anticoagulant and implications for thrombosis. J Rheumatol 2005; 32: 462-468.
10 Clemetson KJ. . Platelet receptors .In. Platelets: Academic Press; 2002: 65-84.
11 Michelson AD, Barnard MR, Krueger LA. et al. Circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin. Circulation 2001; 104: 1533-1537.
12 Zeller JA, Lenz A, Eschenfelder CC. et al. Plateletleukocyte interaction and platelet activation in acute stroke with and without preceding infection. Arterioscler Thromb Vasc Biol 2005; 25: 1519-1523.
13 Danese S, Fiocchi C. Platelet activation and the CD40/CD40 ligand pathway: mechanisms and implications for human disease. Crit Rev Immunol 2005; 25: 103-121.
14 Weyrich AS, Lindemann S, Zimmerman GA. The evolving role of platelets in inflammation. J Thromb Haemost 2003; 1: 1897-1905.
15 Ikeda H, Nakayama H, Oda T. et al. Soluble form of P-selectin in patients with acute myocardial infarction. Coron Artery Dis 1994; 5: 515-518.
16 Ikeda H, Takajo Y, Ichiki K. et al. Increased soluble form of P-selectin in patients with unstable angina. Circulation 1995; 92: 1693-1696.
17 Serebruany VL, Gurbel PA, Shustov AR. et al. Heterogeneity of platelet aggregation and major surface receptor expression in patients presenting with acute myocardial infarction. Am Heart J 1998; 136: 398-405.
18 Lee Y, Lee WH, Lee SC. et al. CD40L activation in circulating platelets in patients with acute coronary syndrome. Cardiology 1999; 92: 11-16.
19 Garlichs CD, Eskafi S, Raaz D. et al. Patients with acute coronary syndromes express enhanced CD40 ligand/ CD154 on platelets. Heart 2001; 86: 649-655.
20 Garlichs CD, Kozina S, Fateh-Moghadam S. et al. Upregulation of CD40-CD40 ligand (CD154) in patients with acute cerebral ischemia. Stroke 2003; 34: 1412-1418.
21 Cha JK, Jeong MH, Jang JY. et al. Serial measurement of surface expression of CD63, P-selectin and CD40 ligand on platelets in atherosclerotic ischemic stroke. A possible role of CD40 ligand on platelets in atherosclerotic ischemic stroke. Cerebrvasc Dis 2003; 16: 376-382.
22 Afshar-Kharghan V, Bray PF, Jeong MH, Jang JY. Platelet polymorphisms. In:. Platelets: Academic Press; 2002: 157-180.
23 Meisel C, Lopez JA, Stangl K. Role of platelet glycoprotein polymorphisms in cardiovascular diseases. Naunyn-Schmiedberg’s Arch Pharmacol 2004; 369: 38-54.
24 Deckmyn H, Ulrichts H, van de Walle G. et al. Platelet antigens and their function. Vox Sang 2004; 87 (Suppl. 02) Suppl 105-111.
25 Blankenberg S, Barbaux S, Tiret L. Adhesion molecules and atherosclerosis. Atherosclerosis 2003; 170: 191-203.
26 Herrmann SM, Ricard S, Nicaud V. et al. The P-selectin gene is highly polymorphic: reduced frequency of the Pro715 allele carriers in patients with myocardial infarction. Hum Mol Genet 1998; 7: 1277-1284.
27 Barbaux SC, Blankenberg S, Rupprecht HJ. et al. Association between P-selectin gene polymorphisms and soluble P-selectin levels and their relation to coronary artery disease. Arterioscl Thromb Vasc Biol 2001; 21: 1668-1673.
28 Afshar-Kharghan V, Diz-Kucükkaya R, Ludwig EH. et al. Human polymorphism of P-selectin glycoprotein ligand-1 (PSGL-1) attributable to variable number of tandem decameric repeats in the mucin like region. Blood 2001; 97: 3306-3307.
29 Lozano ML, Gonzales-Conejero R, Corral J. et al. Polymorphisms of P-selectin glycoprotein ligand-1 are associated with neutrophil-platelet adhesion and with ischaemic cerebrovasculer disease. Br J Haematol 2001; 115: 969-976.
30 Roldan V, Gonzalez-Conejero R, Marin F. et al. Short alleles of P-selectin glycoprotein ligand-1 protect against premature myocardial infarction. Am Heart J 2004; 148: 602-605.
31 Bugert P, Hoffmann MM, Winkelmann BR. et al. The variable number of tandem repeat polymorphism in the P-selectin glycoprotein ligand-1 (PSGL-1) gene is not associated with coronary heart disease. J Mol Med 2003; 81: 495-501.
32 Citores MJ, Rua-Figueroa I, Rodriguez-Gallego C. et al. The dinucleotide repeat polymorphism in the 3’UTR of the CD154 gene has a functional role on protein expression and is associated with systemic lupus erythematosus. Ann Rheum Dis 2004; 63: 310-317.
33 Brandt JT, Triplett DA, Alving B. et al. Criteria for the diagnosis of lupus anitcoagulants: an update. On behalf of the Subcommitte on Lupus Anticoagulant/ Antiphospholipid Antibody of the Scientific and Standardisation Committe of the ISTH. Thromb Haemost 1995; 74: 1185-1190.
34 Wenzel C, Stoiser B, Locker GJ. et al. Frequent development of lupus anticoagulants in critically ill patients treated under intensive care conditions. Crit Care Med 2002; 30: 763-770.
35 Bugert P, Vosberg M, Entelmann M. et al. Polymorphisms in the P-selectin (CD62P) and P-selectin glycoprotein ligand-1 (PSGL-1) genes and coronary heart disease. Clin Chem Lab Med 2004; 42: 997-1004.
36 Tan EM, Cohen AS, Fries JF. et al. The 1982 revised criteria for the clssification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271-1277.
37 Kee F, Morrison C, Evans AE. et al. Polymorphisms of the P-selectin gene and risk of myocardial infarction in men and women in the ECTIM extension study. Etude cas-temoin de l'infarctus myocarde. Heart 2000; 84: 548-552.
38 Blann AD, Lip GY. Hypothesis: is soluble P-selectin a new marker of platelet activation?. Atherosclerosis 1997; 128: 135-138.
39 Blann AD, Noteboom WM, Rosendaal FR. Increased soluble P-selectin levels following deep venous thrombosis: cause or effect?. Br J Haematol 2000; 108: 191-193.
40 Ay C, Jungbauer LV, Sailer T. et al. High Levels of Soluble P-Selectin Are Associated with the Risk of Venous Thromboembolism and the P-Selectin Thr715 Variant. Blood 2006; 108: 384 Abstract
41 Myers Jr DD, Schaub R, Wrobleski SK. et al. P-selectin antagonism causes dose-dependent venous thrombosis inhibition. Thromb Haemost 2001; 85: 423-429.
42 Zoghlami-Rintelen C, Vormittag R, Sailer T. et al. The presence of IgG antibodies against b2-glycoprotein I predicts the risk of thrombosis in patients with the lupus anticoagulant. J Thromb Haemost 2005; 3: 1160-1165.
43 de Groot PG, Dirksen RHWM. Pathophysiology of the antiphospholipid syndrome. J Thromb Haemost 2005; 3: 1854-1860.
44 Vakkalanka RK, Woo C, Kirou KA. et al. Elevated levels and functional capacity of soluble CD40 ligand in systemic lupus erythematosus sera. Arthritis Rheum 1999; 42: 871-881.
45 Kato K, Santana-Sahagun E, Rassenti LZ. et al. The soluble CD40 ligand sCD154 in systemic lupus erythematosus. J Clin Invest 1999; 104: 947-955.
46 Harigai M, Hara M, Fukasawa C. et al. Responsiveness of peripheral blood B cells to recombinant CD40 ligand in patients with systemic lupus erythematosus. Lupus 1999; 8: 227-233.
47 Aukrust P, Muller F, Ueland T. et al. Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina. Possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes. Circulation 1999; 100: 614-620.
48 Heeschen C, Dimmeler S, Hamm CW. et al. CAPTURE Study Investigators. Soluble CD40 ligand in acute coronary syndromes. N Engl J Med 2003; 348: 1104-1111.
49 Schallmoser K, Rosin C, Knittelfelder R. et al. The FcampγRIIa polymorphism R/H131, autoantibodies against the platelet receptors GPIbα and Fcγ; RIIa and a risk for thromboembolism in lupus anticoagulant patients. Thromb Haemost 2005; 93: 544-548.