Thrombosis in Autoimmune Diseases: A Role for Immunosuppressive Treatments?

Elena Silvestri; Antonella Scalera; Giacomo Emmi; Danilo Squatrito; Lucia Ciucciarelli; Caterina Cenci; Carlo Tamburini; Lorenzo Emmi; Giovanni Di Minno; Domenico Prisco

doi:10.1055/s-0036-1579642

Seminars in Thrombosis and Hemostasis, Inhaltsverzeichnis

Semin Thromb Hemost 2016; 42(06): 650-661
DOI: 10.1055/s-0036-1579642

Review Article

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

Thrombosis in Autoimmune Diseases: A Role for Immunosuppressive Treatments?

Authors

Elena Silvestri

¹Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

²SOD Interdisciplinary Internal Medicine, Center for Autoimmune Systemic Diseases–Behçet Center and Lupus Clinic–AOU Careggi Hospital of Florence, Florence, Italy
Antonella Scalera

³Department of Clinical Medicine and Surgery, Federico II University Medical School of Naples, Naples, Italy
Giacomo Emmi

¹Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

²SOD Interdisciplinary Internal Medicine, Center for Autoimmune Systemic Diseases–Behçet Center and Lupus Clinic–AOU Careggi Hospital of Florence, Florence, Italy
Danilo Squatrito

¹Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

²SOD Interdisciplinary Internal Medicine, Center for Autoimmune Systemic Diseases–Behçet Center and Lupus Clinic–AOU Careggi Hospital of Florence, Florence, Italy
Lucia Ciucciarelli

¹Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
Caterina Cenci

²SOD Interdisciplinary Internal Medicine, Center for Autoimmune Systemic Diseases–Behçet Center and Lupus Clinic–AOU Careggi Hospital of Florence, Florence, Italy
Carlo Tamburini

²SOD Interdisciplinary Internal Medicine, Center for Autoimmune Systemic Diseases–Behçet Center and Lupus Clinic–AOU Careggi Hospital of Florence, Florence, Italy
Lorenzo Emmi

²SOD Interdisciplinary Internal Medicine, Center for Autoimmune Systemic Diseases–Behçet Center and Lupus Clinic–AOU Careggi Hospital of Florence, Florence, Italy
Giovanni Di Minno

³Department of Clinical Medicine and Surgery, Federico II University Medical School of Naples, Naples, Italy
Domenico Prisco

¹Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

²SOD Interdisciplinary Internal Medicine, Center for Autoimmune Systemic Diseases–Behçet Center and Lupus Clinic–AOU Careggi Hospital of Florence, Florence, Italy

Abstract

Autoimmune diseases are not infrequently associated with arterial or venous thrombotic events. Chronic inflammation and immune system impairment are considered the main pathogenetic mechanisms. Some of the drugs used in the treatment of such diseases have been associated with an increased risk of thrombosis. On the contrary, their anti-inflammatory and immune modulator activity could correct some mechanisms leading to thrombosis. In this review, recent evidence available on this topic is examined. There is a lack of adequate studies, but available evidence suggests that glucocorticoids and high-dose immunoglobulins are associated with an increased incidence of venous thromboembolism. Although available data do not allow drawing definite conclusions and more data are needed from future studies and registries, physicians should be aware of these associations.

Keywords

thrombosis - immunosuppressive drugs - autoimmune disease

Volltext

Referenzen

References
1 Zöller B, Li X, Sundquist J, Sundquist K. Autoimmune diseases and venous thromboembolism: a review of the literature. Am J Cardiovasc Dis 2012; 2 (3) 171-183
2 Becatti M, Emmi G, Silvestri E , et al. Neutrophil activation promotes fibrinogen oxidation and thrombus formation in Behçet's disease. Circulation 2016; 133 (3) 302-311
3 Katz OB, Brenner B, Horowitz NA. Thrombosis in vasculitic disorders-clinical manifestations, pathogenesis and management. Thromb Res 2015; 136 (3) 504-512
4 Margetic S. Inflammation and haemostasis. Biochem Med (Zagreb) 2012; 22 (1) 49-62
5 Zinger H, Sherer Y, Shoenfeld Y. Atherosclerosis in autoimmune rheumatic diseases-mechanisms and clinical findings. Clin Rev Allergy Immunol 2009; 37 (1) 20-28
6 Teixeira PC, Ferber P, Vuilleumier N, Cutler P. Biomarkers for cardiovascular risk assessment in autoimmune diseases. Proteomics Clin Appl 2015; 9 (1–2) 48-57
7 Choy E, Ganeshalingam K, Semb AG, Szekanecz Z, Nurmohamed M. Cardiovascular risk in rheumatoid arthritis: recent advances in the understanding of the pivotal role of inflammation, risk predictors and the impact of treatment. Rheumatology (Oxford) 2014; 53 (12) 2143-2154
8 Stojan G, Petri M. Atherosclerosis in systemic lupus erythematosus. J Cardiovasc Pharmacol 2013; 62 (3) 255-262
9 Meesters EW, Hansen H, Spronk HM , et al. The inflammation and coagulation cross-talk in patients with systemic lupus erythematosus. Blood Coagul Fibrinolysis 2007; 18 (1) 21-28
10 Urowitz MB, Bookman AA, Koehler BE, Gordon DA, Smythe HA, Ogryzlo MA. The bimodal mortality pattern of systemic lupus erythematosus. Am J Med 1976; 60 (2) 221-225
11 Schoenfeld SR, Kasturi S, Costenbader KH. The epidemiology of atherosclerotic cardiovascular disease among patients with SLE: a systematic review. Semin Arthritis Rheum 2013; 43 (1) 77-95
12 Skeoch S, Haque S, Pemberton P, Bruce IN. Cell adhesion molecules as potential biomarkers of nephritis, damage and accelerated atherosclerosis in patients with SLE. Lupus 2014; 23 (8) 819-824
13 Deng XL, Li XX, Liu XY, Sun L, Liu R. Comparative study on circulating endothelial progenitor cells in systemic lupus erythematosus patients at active stage. Rheumatol Int 2010; 30 (11) 1429-1436
14 Frieri M. Accelerated atherosclerosis in systemic lupus erythematosus: role of proinflammatory cytokines and therapeutic approaches. Curr Allergy Asthma Rep 2012; 12 (1) 25-32
15 Skaggs BJ, Hahn BH, McMahon M. Accelerated atherosclerosis in patients with SLE—mechanisms and management. Nat Rev Rheumatol 2012; 8 (4) 214-223
16 Soltész P, Kerekes G, Dér H , et al. Comparative assessment of vascular function in autoimmune rheumatic diseases: considerations of prevention and treatment. Autoimmun Rev 2011; 10 (7) 416-425
17 Emmi G, Silvestri E, Squatrito D , et al. Thrombosis in vasculitis: from pathogenesis to treatment. Thromb J 2015; 13: 15
18 International Team for the Revision of the International Criteria for Behçet's Disease (ITR-ICBD). The International Criteria for Behçet's Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria. J Eur Acad Dermatol Venereol 2014; 28 (3) 338-347
19 Springer J, Villa-Forte A. Thrombosis in vasculitis. Curr Opin Rheumatol 2013; 25 (1) 19-25
20 Niccolai E, Emmi G, Squatrito D , et al. Microparticles: bridging the gap between autoimmunity and thrombosis. Semin Thromb Hemost 2015; 41 (4) 413-422
21 Peters MJ, Symmons DP, McCarey D , et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis 2010; 69 (2) 325-331
22 Prisco D. Behçet's Syndrome: From Pathogenesis to Treatment. Series-Rare Diseases of the Immune System. Springer; 2014
23 Danish Medicines Agency. Sales of Medicinal Products within the Different ATC Groups in the Primary Healthcare Sector. Medicinal Product Statistics 2006–2010. Copenhagen: Danish Medicines Agency; 2011: 80
24 Overman RA, Yeh JY, Deal CL. Prevalence of oral glucocorticoid usage in the United States: a general population perspective. Arthritis Care Res (Hoboken) 2013; 65 (2) 294-298
25 Miljic P, Miljic D, Cain JW, Korbonits M, Popovic V. Pathogenesis of vascular complications in Cushing's syndrome. Hormones (Athens) 2012; 11 (1) 21-30
26 Zakarija A, Kwaan HC. Adverse effects on hemostatic function of drugs used in hematologic malignancies. Semin Thromb Hemost 2007; 33 (4) 355-364
27 Stuijver DJ, van Zaane B, Feelders RA , et al. Incidence of venous thromboembolism in patients with Cushing's syndrome: a multicenter cohort study. J Clin Endocrinol Metab 2011; 96 (11) 3525-3532
28 Johannesdottir SA, Horváth-Puhó E, Dekkers OM , et al. Use of glucocorticoids and risk of venous thromboembolism: a nationwide population-based case-control study. JAMA Intern Med 2013; 173 (9) 743-752
29 Majoor CJ, Kamphuisen PW, Zwinderman AH , et al. Risk of deep vein thrombosis and pulmonary embolism in asthma. Eur Respir J 2013; 42 (3) 655-661
30 Wun T, White RH. Venous thromboembolism in patients with acute leukemia, lymphoma, and multiple myeloma. Thromb Res 2010; 125 (Suppl. 02) S96-S102
31 Weber DM, Chen C, Niesvizky R , et al. Multiple Myeloma (009) Study Investigators. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 2007; 357 (21) 2133-2142
32 Katodritou E, Vadikolia C, Lalagianni C , et al. “Real-world” data on the efficacy and safety of lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma who were treated according to the standard clinical practice: a study of the Greek Myeloma Study Group. Ann Hematol 2014; 93 (1) 129-139
33 Nguyen GC, Elnahas A, Jackson TD. The impact of preoperative steroid use on short-term outcomes following surgery for inflammatory bowel disease. J Crohn's Colitis 2014; 8 (12) 1661-1667
34 Kappelman MD, Horvath-Puho E, Sandler RS , et al. Thromboembolic risk among Danish children and adults with inflammatory bowel diseases: a population-based nationwide study. Gut 2011; 60 (7) 937-943
35 Giannotta M, Tapete G, Emmi G, Silvestri E, Milla M. Thrombosis in inflammatory bowel diseases: what's the link?. Thromb J 2015; 13: 14
36 Higgins PD, Skup M, Mulani PM, Lin J, Chao J. Increased risk of venous thromboembolic events with corticosteroid vs biologic therapy for inflammatory bowel disease. Clin Gastroenterol Hepatol 2015; 13 (2) 316-321
37 Sáez-Giménez B, Berastegui C, Loor K , et al. Deep vein thrombosis and pulmonary embolism after solid organ transplantation: an unresolved problem. Transplant Rev (Orlando) 2015; 29 (2) 85-92
38 Patrassi GM, Sartori MT, Rigotti P , et al. Reduced fibrinolytic potential one year after kidney transplantation. Relationship to long-term steroid treatment. Transplantation 1995; 59 (10) 1416-1420
39 Sartori MT, Patrassi GM, Rigotti P , et al. Improved fibrinolytic capacity after withdrawal of steroid immunosuppression in renal transplant recipients. Transplantation 2000; 69 (10) 2116-2121
40 Peeters PJ, Bazelier MT, Uitdehaag BM, Leufkens HG, De Bruin ML, de Vries F. The risk of venous thromboembolism in patients with multiple sclerosis: the Clinical Practice Research Datalink. J Thromb Haemost 2014; 12 (4) 444-451
41 Stassen PM, Derks RP, Kallenberg CG, Stegeman CA. Venous thromboembolism in ANCA-associated vasculitis—incidence and risk factors. Rheumatology (Oxford) 2008; 47 (4) 530-534
42 Al Sawah S, Zhang X, Zhu B , et al. Effect of corticosteroid use by dose on the risk of developing organ damage over time in systemic lupus erythematosus-the Hopkins Lupus Cohort. Lupus Sci Med 2015; 2 (1) e000066
43 Calvo-Alén J, Toloza SM, Fernández M , et al; LUMINA Study Group. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXV. Smoking, older age, disease activity, lupus anticoagulant, and glucocorticoid dose as risk factors for the occurrence of venous thrombosis in lupus patients. Arthritis Rheum 2005; 52 (7) 2060-2068
44 Karp I, Abrahamowicz M, Fortin PR , et al. Recent corticosteroid use and recent disease activity: independent determinants of coronary heart disease risk factors in systemic lupus erythematosus?. Arthritis Rheum 2008; 59 (2) 169-175
45 Jacoby RC, Owings JT, Ortega T, Gosselin R, Feldman EC. Biochemical basis for the hypercoagulable state seen in Cushing syndrome; discussion 1006-7. Arch Surg 2001; 136 (9) 1003-1006
46 Fatti LM, Bottasso B, Invitti C, Coppola R, Cavagnini F, Mannucci PM. Markers of activation of coagulation and fibrinolysis in patients with Cushing's syndrome. J Endocrinol Invest 2000; 23 (3) 145-150
47 Patrassi GM, Sartori MT, Viero ML, Scarano L, Boscaro M, Girolami A. The fibrinolytic potential in patients with Cushing's disease: a clue to their hypercoagulable state. Blood Coagul Fibrinolysis 1992; 3 (6) 789-793
48 Laug WE. Glucocorticoids inhibit plasminogen activator production by endothelial cells. Thromb Haemost 1983; 50 (4) 888-892
49 Barouski-Miller PA, Gelehrter TD. Paradoxical effects of glucocorticoids on regulation of plasminogen activator activity of rat hepatoma cells. Proc Natl Acad Sci U S A 1982; 79 (7) 2319-2322
50 Franchini M, Lippi G, Manzato F, Vescovi PP, Targher G. Hemostatic abnormalities in endocrine and metabolic disorders. Eur J Endocrinol 2010; 162 (3) 439-451
51 Kastelan D, Dusek T, Kraljevic I , et al. Hypercoagulability in Cushing's syndrome: the role of specific haemostatic and fibrinolytic markers. Endocrine 2009; 36 (1) 70-74
52 Casonato A, Pontara E, Boscaro M , et al. Abnormalities of von Willebrand factor are also part of the prothrombotic state of Cushing's syndrome. Blood Coagul Fibrinolysis 1999; 10 (3) 145-151
53 Erem C, Nuhoglu I, Yilmaz M , et al. Blood coagulation and fibrinolysis in patients with Cushing's syndrome: increased plasminogen activator inhibitor-1, decreased tissue factor pathway inhibitor, and unchanged thrombin-activatable fibrinolysis inhibitor levels. J Endocrinol Invest 2009; 32 (2) 169-174
54 Peppa M, Krania M, Raptis SA. Hypertension and other morbidities with Cushing's syndrome associated with corticosteroids: a review. Integr Blood Press Control 2011; 4: 7-16
55 Roubert P, Viossat I, Lonchampt MO , et al. Endothelin receptor regulation by endothelin synthesis in vascular smooth muscle cells: effects of dexamethasone and phosphoramidon. J Vasc Res 1993; 30 (3) 139-144
56 Börcsök I, Schairer HU, Sommer U , et al. Glucocorticoids regulate the expression of the human osteoblastic endothelin A receptor gene. J Exp Med 1998; 188 (9) 1563-1573
57 Magiakou MA, Smyrnaki P, Chrousos GP. Hypertension in Cushing's syndrome. Best Pract Res Clin Endocrinol Metab 2006; 20 (3) 467-482
58 Kennedy B, Ziegler MG. Cardiac epinephrine synthesis. Regulation by a glucocorticoid. Circulation 1991; 84 (2) 891-895
59 Edvinsson L, Ekblad E, Håkanson R, Wahlestedt C. Neuropeptide Y potentiates the effect of various vasoconstrictor agents on rabbit blood vessels. Br J Pharmacol 1984; 83 (2) 519-525
60 Yang S, Zhang L. Glucocorticoids and vascular reactivity. Curr Vasc Pharmacol 2004; 2 (1) 1-12
61 Koutroumpi S, Spiezia L, Albiger N , et al. Thrombin generation in Cushing's syndrome: do the conventional clotting indices tell the whole truth?. Pituitary 2014; 17 (1) 68-75
62 Woodruff RK, Grigg AP, Firkin FC, Smith IL. Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients. Lancet 1986; 2 (8500) 217-218
63 Misbah S, Sturzenegger MH, Borte M , et al. Subcutaneous immunoglobulin: opportunities and outlook. Clin Exp Immunol 2009; 158 (Suppl. 01) 51-59
64 Paran D, Herishanu Y, Elkayam O, Shopin L, Ben-Ami R. Venous and arterial thrombosis following administration of intravenous immunoglobulins. Blood Coagul Fibrinolysis 2005; 16 (5) 313-318
65 Marie I, Maurey G, Hervé F, Hellot MF, Levesque H. Intravenous immunoglobulin-associated arterial and venous thrombosis; report of a series and review of the literature. Br J Dermatol 2006; 155 (4) 714-721
66 Caress JB, Hobson-Webb L, Passmore LV, Finkbiner AP, Cartwright MS. Case-control study of thromboembolic events associated with IV immunoglobulin. J Neurol 2009; 256 (3) 339-342
67 Rajabally YA, Kearney DA. Thromboembolic complications of intravenous immunoglobulin therapy in patients with neuropathy: a two-year study. J Neurol Sci 2011; 308 (1–2) 124-127
68 Huang L, Kanellis J, Mulley W. Slow and steady. Reducing thrombotic events in renal transplant recipients treated with IVIg for antibody-mediated rejection. Nephrology (Carlton) 2011; 16 (2) 239-242
69 Daniel GW, Menis M, Sridhar G , et al. Immune globulins and thrombotic adverse events as recorded in a large administrative database in 2008 through 2010. Transfusion 2012; 52 (10) 2113-2121
70 Funk MB, Gross N, Gross S , et al. Thromboembolic events associated with immunoglobulin treatment. Vox Sang 2013; 105 (1) 54-64
71 Menis M, Sridhar G, Selvam N , et al. Hyperimmune globulins and same-day thrombotic adverse events as recorded in a large healthcare database during 2008-2011. Am J Hematol 2013; 88 (12) 1035-1040
72 Ramírez E, Romero-Garrido JA, López-Granados E , et al. Symptomatic thromboembolic events in patients treated with intravenous-immunoglobulins: results from a retrospective cohort study. Thromb Res 2014; 133 (6) 1045-1051
73 Sridhar G, Ekezue BF, Izurieta HS , et al. Immune globulins and same-day thrombotic events as recorded in a large health care database during 2008 to 2012. Transfusion 2014; 54 (10) 2553-2565
74 Benadiba J, Robitaille N, Lambert G, Itaj NK, Pastore Y. Intravenous immunoglobulin-associated thrombosis: is it such a rare event? Report of a pediatric case and of the Quebec Hemovigilance System. Transfusion 2015; 55 (3) 571-575
75 Dear Manufacturer: Immune Globulin Intravenous (Human) (IGIV); Required Updates to Product Labeling. Silver Spring, MD: U.S. Food and Drug Administration; 2003. Available online at: http://www.fda.gov/biologicsbloodvaccines/safetyavailability/ucm093491.htm
76 Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 1994; 44 (2) 223-226
77 Caress JB, Cartwright MS, Donofrio PD, Peacock Jr JE. The clinical features of 16 cases of stroke associated with administration of IVIg. Neurology 2003; 60 (11) 1822-1824
78 Flannery MT, Humphrey D. Deep venous thrombosis with pulmonary embolism related to IVIg treatment: a case report and literature review. Case Rep Med 2015; 2015: 971321
79 Basta M. Intravenous immunoglobulin-related thromboembolic events - an accusation that proves the opposite. Clin Exp Immunol 2014; 178 (Suppl. 01) 153-155
80 Emmi G, Silvestri E, Squatrito D , et al. An approach to differential diagnosis of antiphospholipid antibody syndrome and related conditions. ScientificWorldJournal 2014; 2014: 341342
81 Bayry J, Negi VS, Kaveri SV. Intravenous immunoglobulin therapy in rheumatic diseases. Nat Rev Rheumatol 2011; 7 (6) 349-359
82 Duhem C, Dicato MA, Ries F. Side-effects of intravenous immune globulins. Clin Exp Immunol 1994; 97 (Suppl. 01) 79-83
83 Salge-Bartels U, Heiden M, Groß N, Seitz R. Significance of platelet and monocyte activation for therapeutic immunoglobulin-induced thromboembolism. Thromb Res 2014; 133 (2) 244-253
84 Bentley P, Rosso M, Sadnicka A, Israeli-Korn S, Laffan M, Sharma P. Intravenous immunoglobulin increases plasma viscosity without parallel rise in blood pressure. J Clin Pharm Ther 2012; 37 (3) 286-290
85 Reinhart WH, Berchtold PE. Effect of high-dose intravenous immunoglobulin therapy on blood rheology. Lancet 1992; 339 (8794) 662-664
86 Sztajzel R, Le Floch-Rohr J, Eggimann P. High-dose intravenous immunoglobulin treatment and cerebral vasospasm: A possible mechanism of ischemic encephalopathy?. Eur Neurol 1999; 41 (3) 153-158
87 Sakurai Y, Takatsuka H, Onaka M, Takada M, Nishino M. Persistent endothelial damage after intravenous immunoglobulin therapy in Kawasaki disease. Int Arch Allergy Immunol 2014; 165 (2) 111-118
88 Wolberg AS, Kon RH, Monroe DM, Hoffman M. Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol 2000; 65 (1) 30-34
89 Etscheid M, Breitner-Ruddock S, Gross S, Hunfeld A, Seitz R, Dodt J. Identification of kallikrein and FXIa as impurities in therapeutic immunoglobulins: implications for the safety and control of intravenous blood products. Vox Sang 2012; 102 (1) 40-46
90 Roemisch JR, Kaar W, Zoechling A, Kannicht C, Putz M, Kohla G. Identification of activated FXI as the major biochemical root cause in IVIG batches associated with thromboembolic events. Analytical and experimental approaches resulting in corrective and preventive measures implemented into the Octagam® manufacturing process. WebmedCentral Immunotherapy 2011; 2 (6) WMC002002
91 Kim SC, Solomon DH, Liu J, Franklin JM, Glynn RJ, Schneeweiss S. Risk of venous thromboembolism in patients with rheumatoid arthritis: initiating disease-modifying antirheumatic drugs. Am J Med 2015; 128 (5) 539.e7-539.e17
92 Mato A, Feldman T, Zielonka T , et al. Rituximab, cyclophosphamide-fractionated, vincristine, doxorubicin and dexamethasone alternating with rituximab, methotrexate and cytarabine overcomes risk features associated with inferior outcomes in treatment of newly diagnosed, high-risk diffuse large B-cell lymphoma. Leuk Lymphoma 2013; 54 (12) 2606-2612
93 Iaccarino L, Bartoloni E, Carli L , et al. Efficacy and safety of off-label use of rituximab in refractory lupus: data from the Italian Multicentre Registry. Clin Exp Rheumatol 2015; 33 (4) 449-456
94 Roy A, Khanna N, Senguttuvan NB. Rituximab-vincristine chemotherapy-induced acute anterior wall myocardial infarction with cardiogenic shock. Tex Heart Inst J 2014; 41 (1) 80-82
95 Ke C, Khosla A, Davis MK, Hague C, Toma M. A case of coronary vasospasm after repeat rituximab infusion. Case Rep Cardiol 2015; 2015: 523149
96 van Sijl AM, van der Weele W, Nurmohamed MT. Myocardial infarction after rituximab treatment for rheumatoid arthritis: is there a link?. Curr Pharm Des 2014; 20 (4) 496-499
97 Shetty S, Ahmed AR. Preliminary analysis of mortality associated with rituximab use in autoimmune diseases. Autoimmunity 2013; 46 (8) 487-496
98 van Vollenhoven RF, Fleischmann RM, Furst DE, Lacey S, Lehane PB. Longterm safety of rituximab: final report of the Rheumatoid Arthritis Global Clinical Trial Program over 11 years. J Rheumatol 2015; 42 (10) 1761-1766
99 Navarro-Millán I, Singh JA, Curtis JR. Systematic review of tocilizumab for rheumatoid arthritis: a new biologic agent targeting the interleukin-6 receptor. Clin Ther 2012; 34 (4) 788-802.e3
100 Ridker PM, Lüscher TF. Anti-inflammatory therapies for cardiovascular disease. Eur Heart J 2014; 35 (27) 1782-1791
101 Sarwar N, Butterworth AS, Freitag DF , et al; IL6R Genetics Consortium Emerging Risk Factors Collaboration. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet 2012; 379 (9822) 1205-1213
102 Ringelstein M, Ayzenberg I, Harmel J , et al. Long-term therapy with interleukin 6 receptor blockade in highly active neuromyelitis optica spectrum disorder. JAMA Neurol 2015; 72 (7) 756-763
103 Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther 2008; 117 (2) 244-279
104 Bacon PA. Endothelial cell dysfunction in systemic vasculitis: new developments and therapeutic prospects. Curr Opin Rheumatol 2005; 17 (1) 49-55
105 Danese S, Sans M, Scaldaferri F , et al. TNF-alpha blockade down-regulates the CD40/CD40L pathway in the mucosal microcirculation: a novel anti-inflammatory mechanism of infliximab in Crohn's disease. J Immunol 2006; 176 (4) 2617-2624
106 Ingegnoli F, Fantini F, Favalli EG , et al. Inflammatory and prothrombotic biomarkers in patients with rheumatoid arthritis: effects of tumor necrosis factor-alpha blockade. J Autoimmun 2008; 31 (2) 175-179
107 Ingegnoli F, Fantini F, Griffini S, Soldi A, Meroni PL, Cugno M. Anti-tumor necrosis factor alpha therapy normalizes fibrinolysis impairment in patients with active rheumatoid arthritis. Clin Exp Rheumatol 2010; 28 (2) 254-257
108 Agirbasli M, Inanc N, Baykan OA, Direskeneli H. The effects of TNF alpha inhibition on plasma fibrinolytic balance in patients with chronic inflammatory rheumatical disorders. Clin Exp Rheumatol 2006; 24 (5) 580-583
109 Bollen L, Vande Casteele N, Peeters M , et al. Short-term effect of infliximab is reflected in the clot lysis profile of patients with inflammatory bowel disease: a prospective study. Inflamm Bowel Dis 2015; 21 (3) 570-578
110 Davies R, Galloway JB, Watson KD, Lunt M, Symmons DP, Hyrich KL ; BSRBR Control Centre Consortium, British Society for Rheumatology Biologics Register. Venous thrombotic events are not increased in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis 2011; 70 (10) 1831-1834
111 Di Minno MN, Iervolino S, Peluso R, Di Minno A, Ambrosino P, Scarpa R ; CaRRDs Study Group. Hemostatic and fibrinolytic changes are related to inflammatory conditions in patients with psoriatic arthritis—effect of different treatments. J Rheumatol 2014; 41 (4) 714-722
112 Yoshida S, Takeuchi T, Yoshikawa A , et al. Good response to infliximab in a patient with deep vein thrombosis associated with Behçet disease. Mod Rheumatol 2012; 22 (5) 791-795
113 Adler S, Baumgartner I, Villiger PM. Behçet's disease: successful treatment with infliximab in 7 patients with severe vascular manifestations. A retrospective analysis. Arthritis Care Res (Hoboken) 2012; 64 (4) 607-611
114 Silvestri E, Emmi G, Prisco D. Vascular Behçet's disease: new insights in the management of thrombosis. Expert Rev Cardiovasc Ther 2013; 11 (12) 1583-1585
115 Ferraccioli G, Gremese E. Thrombogenicity of TNF alpha in rheumatoid arthritis defined through biological probes: TNF alpha blockers. Autoimmun Rev 2004; 3 (4) 261-266
116 van Oosten BW, Barkhof F, Truyen L , et al. Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology 1996; 47 (6) 1531-1534
117 Nosbaum A, Goujon C, Fleury B, Guillot I, Nicolas JF, Bérard F. Arterial thrombosis with anti-phospholipid antibodies induced by infliximab. Eur J Dermatol 2007; 17 (6) 546-547
118 Vereckei E, Kriván G, Réti M, Szodoray P, Poór G, Kiss E. Anti-TNF-alpha-induced anti-phospholipid syndrome manifested as necrotizing vasculitis. Scand J Rheumatol 2010; 39 (2) 175-177
119 Puli SR, Benage DD. Retinal vein thrombosis after infliximab (Remicade) treatment for Crohn's disease. Am J Gastroenterol 2003; 98 (4) 939-940
120 Virupannavar S, Brandau A, Guggenheim C, Laird-Fick H. Possible association of etanercept, venous thrombosis, and induction of antiphospholipid syndrome. Case Rep Rheumatol 2014; 2014: 801072
121 Hemmati I, Kur J. Adalimumab-associated antiphospholipid syndrome: a case report and review of the literature. Clin Rheumatol 2013; 32 (7) 1095-1098
122 Yamashita T, Sasaki N, Kasahara K, Hirata K. Anti-inflammatory and immune-modulatory therapies for preventing atherosclerotic cardiovascular disease. J Cardiol 2015; 66 (1) 1-8
123 Belizna C. Hydroxychloroquine as an anti-thrombotic in antiphospholipid syndrome. Autoimmun Rev 2015; 14 (4) 358-362
124 Petri M. Use of hydroxychloroquine to prevent thrombosis in systemic lupus erythematosus and in antiphospholipid antibody-positive patients. Curr Rheumatol Rep 2011; 13 (1) 77-80
125 Erkan D, Aguiar CL, Andrade D , et al. 14th International Congress on Antiphospholipid Antibodies: task force report on antiphospholipid syndrome treatment trends. Autoimmun Rev 2014; 13 (6) 685-696
126 Review: could Azathioprine cause Dvt (Deep venous thrombosis)? Available online at: http://www.ehealthme.com/print/ds14570451 . Accessed December 3, 2015
127 Vazquez SR, Rondina MT, Pendleton RC. Azathioprine-induced warfarin resistance. Ann Pharmacother 2008; 42 (7) 1118-1123
128 Pushpakom SP, Gambhir N, Latif A, Hadfield KD, Campbell S, Newman WG. Exacerbation of hereditary warfarin resistance by azathioprine. Clin Appl Thromb Hemost 2011; 17 (3) 293-296
129 Ödek Ç, Kendirli T, Yaman A, Ileri T, Kuloğlu Z, Ince E. Cyclosporine-associated thrombotic microangiopathy and thrombocytopenia-associated multiple organ failure: a case successfully treated with therapeutic plasma exchange. J Pediatr Hematol Oncol 2014; 36 (2) e88-e90
130 Elliott MA, Nichols Jr WL, Plumhoff EA , et al. Posttransplantation thrombotic thrombocytopenic purpura: a single-center experience and a contemporary review. Mayo Clin Proc 2003; 78 (4) 421-430
131 Andersohn F, Bronder E, Klimpel A, Garbe E. Proportion of drug-related serious rare blood dyscrasias: estimates from the Berlin Case-Control Surveillance Study. Am J Hematol 2004; 77 (3) 316-318
132 Medina PJ, Sipols JM, George JN. Drug-associated thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Curr Opin Hematol 2001; 8 (5) 286-293
133 Zarifian A, Meleg-Smith S, O'donovan R, Tesi RJ, Batuman V. Cyclosporine-associated thrombotic microangiopathy in renal allografts. Kidney Int 1999; 55 (6) 2457-2466
134 Poli D, Zanazzi M, Antonucci E , et al. Renal transplant recipients are at high risk for both symptomatic and asymptomatic deep vein thrombosis. J Thromb Haemost 2006; 4 (5) 988-992
135 Poli D, Zanazzi M, Antonucci E , et al. High rate of recurrence in renal transplant recipients after a first episode of venous thromboembolism. Transplantation 2005; 80 (6) 789-793
136 Zanazzi M, Poli D, Antonucci E , et al. Venous thromboembolism in renal transplant recipients: high rate of recurrence. Transplant Proc 2005; 37 (6) 2493-2494
137 Steurer W, Malaise J, Mark W, Koenigsrainer A, Margreiter R ; Euro-SPK Study Group. Spectrum of surgical complications after simultaneous pancreas-kidney transplantation in a prospectively randomized study of two immunosuppressive protocols. Nephrol Dial Transplant 2005; 20 (Suppl. 02) ii54-ii62
138 Vanrenterghem Y, Roels L, Lerut T , et al. Thromboembolic complications and haemostatic changes in cyclosporin-treated cadaveric kidney allograft recipients. Lancet 1985; 1 (8436) 999-1002
139 Bombeli T, Müller M, Straub PW, Haeberli A. Cyclosporine-induced detachment of vascular endothelial cells initiates the intrinsic coagulation system in plasma and whole blood. J Lab Clin Med 1996; 127 (6) 621-634
140 Püschel A, Lindenblatt N, Katzfuss J, Vollmar B, Klar E. Immunosuppressants accelerate microvascular thrombus formation in vivo: role of endothelial cell activation. Surgery 2012; 151 (1) 26-36
141 Kedzierska K, Sporniak-Tutak K, Bober J , et al. Oxidative stress indices in rats under immunosuppression. Transplant Proc 2011; 43 (10) 3939-3945
142 Grace AA, Barradas MA, Mikhailidis DP , et al. Cyclosporine A enhances platelet aggregation. Kidney Int 1987; 32 (6) 889-895
143 Naik UP, Markell M, Ehrlich YH, Kornecki E. Cyclosporine A enhances agonist-induced aggregation of human platelets by stimulating protein phosphorylation. Cell Mol Biol Res 1993; 39 (3) 257-264
144 Haddad TC, Greeno EW. Chemotherapy-induced thrombosis. Thromb Res 2006; 118 (5) 555-568
145 Kansu E. Thrombosis in stem cell transplantation. Hematology 2012; 17 (Suppl. 01) S159-S162
146 Mukherjee SD, Swystun LL, Mackman N , et al. Impact of chemotherapy on thrombin generation and on the protein C pathway in breast cancer patients. Pathophysiol Haemost Thromb 2010; 37 (2–4) 88-97
147 Kessler P, Pour L, Gregora E , et al; Czech Myeloma Group. Low molecular weight heparins for thromboprophylaxis during induction chemotherapy in patients with multiple myeloma. Klin Onkol 2011; 24 (4) 281-286
148 Ganjoo K, Hong F, Horning SJ , et al. Bevacizumab and cyclosphosphamide, doxorubicin, vincristine and prednisone in combination for patients with peripheral T-cell or natural killer cell neoplasms: an Eastern Cooperative Oncology Group study (E2404). Leuk Lymphoma 2014; 55 (4) 768-772
149 Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer 2007; 110 (10) 2339-2346
150 Swystun LL, Mukherjee S, Levine M, Liaw PC. The chemotherapy metabolite acrolein upregulates thrombin generation and impairs the protein C anticoagulant pathway in animal-based and cell-based models. J Thromb Haemost 2011; 9 (4) 767-775
151 Zeng L, Yan Z, Ding S, Xu K, Wang L. Endothelial injury, an intriguing effect of methotrexate and cyclophosphamide during hematopoietic stem cell transplantation in mice. Transplant Proc 2008; 40 (8) 2670-2673
152 Nepomnyashchikh LM, Molodykh OP, Lushnikova EL, Sorokina YA. Morphogenesis and histostereological analysis of hepatopathy induced by cyclophosphamide. Bull Exp Biol Med 2010; 149 (1) 104-112
153 Rella C, Coviello M, Giotta F , et al. A prothrombotic state in breast cancer patients treated with adjuvant chemotherapy. Breast Cancer Res Treat 1996; 40 (2) 151-159
154 Ajmani S, Misra DP, Raja DC, Mohindra N, Agarwal V. Behcet's disease with intracardiac thrombus presenting with fever of unknown etiology. Case Reports Immunol 2015; 2015: 149359
155 Tascilar NF, Akman-Demir G, Demiryurek BE, Tokgoz O, Akgun N, Ozen Barut B. An unusual case of neuro-Behçet's disease presenting with co-occurence of cerebral venous sinus thrombosis with basilar artery occlusion. Neurol Sci 2013; 34 (5) 785-788
156 Düzgün N, Küçükşahin O, Atasoy KÇ , et al. Behçet's disease and intracardiac thrombosis: a report of three cases. Case Rep Rheumatol 2013; 2013: 637015
157 Tseng ST, Tseng MH, Huang JL. Concurrent pulmonary hemorrhage and deep vein thrombosis in a child with ANCA-associated vasculitis: case report and review of literature. Pediatr Rheumatol Online J 2015; 13: 20
158 Emmungil H, Yaşar Bilge NŞ, Küçükşahin O , et al. A rare but serious manifestation of Behçet's disease: intracardiac thrombus in 22 patients. Clin Exp Rheumatol 2014; 32 (4) (Suppl. 84) S87-S92
159 Desbois AC, Wechsler B, Resche-Rigon M , et al. Immunosuppressants reduce venous thrombosis relapse in Behçet's disease. Arthritis Rheum 2012; 64 (8) 2753-2760