Anti-TNFα agents curb platelet activation in patients with rheumatoid arthritis

Angelo A. Manfredi, Mattia Baldini, Marina Camera, Elena Baldissera, Marta Brambilla, Giuseppe Peretti, Attilio Maseri, Patrizia Rovere-Querini, Elena Tremoli, Maria Grazia Sabbadini, Norma Maugeri

Research output: Contribution to journalArticle

Abstract

Background Cardiovascular disease is important in rheumatoid arthritis (RA). Tissue factor (TF) is expressed upon platelet activation and initiates coagulation. Antitumour necrosis factor-a (TNFa) agents seem to decrease RA-associated cardiovascular events. We investigated whether (1) TNFa activates human platelets and (2) TNFa pharmacological blockade modulates the platelet-leucocyte reciprocal activation in RA. Design The expression of platelet TNFa receptors has been assessed by flow cytometry and immunogold electron microscopy. Platelet and leucocyte activation has been assessed also in the presence of antibodies against the TNFa receptors 1 and 2 and of infliximab. TF expression, binding to fibrinogen and phosphatidylserine exposure, has been assessed by flow cytometry, TF activity by coagulation time and by endogenous thrombin generation. Markers of platelet and leucocyte activation have been assessed in 161 subjects: 42 patients with RA, 12 with osteoarthritis, 37 agematched and sex-matched patients with chronic stable angina and 70 age-matched and sex-matched healthy subjects. Results TNFa elicited the platelet activation and the expression of TF, which in turn prompted thrombin generation and clot formation. Inhibition of the TNFa- induced activation restricted platelet ability to activate leucocytes and to induce leucocyte TF. TNFa inhibition did not influence platelet activation induced by collagen, ADP or thrombin receptor activating peptide-6. Platelets of patients with RA were more activated than those of controls. Activation was reduced in patients treated with TNFa inhibitors. Conclusions TNFa-dependent pathways control platelet activation and TF expression in RA. Further studies will verify whether the protective effect of TNFa inhibitors on cardiovascular events involves their ability to modulate platelet function.

Original languageEnglish
JournalAnnals of the Rheumatic Diseases
DOIs
Publication statusAccepted/In press - Jan 27 2016

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Curbs
Platelet Activation
Platelets
Thromboplastin
Rheumatoid Arthritis
Chemical activation
Leukocytes
Blood Platelets
Flow Cytometry
Collagen Receptors
Flow cytometry
Purinergic P2 Receptors
Thrombin Time
Coagulation
Stable Angina
Phosphatidylserines
Thrombin
Osteoarthritis
Fibrinogen
Electron Microscopy

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Allergy

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Anti-TNFα agents curb platelet activation in patients with rheumatoid arthritis. / Manfredi, Angelo A.; Baldini, Mattia; Camera, Marina; Baldissera, Elena; Brambilla, Marta; Peretti, Giuseppe; Maseri, Attilio; Rovere-Querini, Patrizia; Tremoli, Elena; Sabbadini, Maria Grazia; Maugeri, Norma.

In: Annals of the Rheumatic Diseases, 27.01.2016.

Research output: Contribution to journalArticle

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abstract = "Background Cardiovascular disease is important in rheumatoid arthritis (RA). Tissue factor (TF) is expressed upon platelet activation and initiates coagulation. Antitumour necrosis factor-a (TNFa) agents seem to decrease RA-associated cardiovascular events. We investigated whether (1) TNFa activates human platelets and (2) TNFa pharmacological blockade modulates the platelet-leucocyte reciprocal activation in RA. Design The expression of platelet TNFa receptors has been assessed by flow cytometry and immunogold electron microscopy. Platelet and leucocyte activation has been assessed also in the presence of antibodies against the TNFa receptors 1 and 2 and of infliximab. TF expression, binding to fibrinogen and phosphatidylserine exposure, has been assessed by flow cytometry, TF activity by coagulation time and by endogenous thrombin generation. Markers of platelet and leucocyte activation have been assessed in 161 subjects: 42 patients with RA, 12 with osteoarthritis, 37 agematched and sex-matched patients with chronic stable angina and 70 age-matched and sex-matched healthy subjects. Results TNFa elicited the platelet activation and the expression of TF, which in turn prompted thrombin generation and clot formation. Inhibition of the TNFa- induced activation restricted platelet ability to activate leucocytes and to induce leucocyte TF. TNFa inhibition did not influence platelet activation induced by collagen, ADP or thrombin receptor activating peptide-6. Platelets of patients with RA were more activated than those of controls. Activation was reduced in patients treated with TNFa inhibitors. Conclusions TNFa-dependent pathways control platelet activation and TF expression in RA. Further studies will verify whether the protective effect of TNFa inhibitors on cardiovascular events involves their ability to modulate platelet function.",
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AU - Manfredi, Angelo A.

AU - Baldini, Mattia

AU - Camera, Marina

AU - Baldissera, Elena

AU - Brambilla, Marta

AU - Peretti, Giuseppe

AU - Maseri, Attilio

AU - Rovere-Querini, Patrizia

AU - Tremoli, Elena

AU - Sabbadini, Maria Grazia

AU - Maugeri, Norma

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N2 - Background Cardiovascular disease is important in rheumatoid arthritis (RA). Tissue factor (TF) is expressed upon platelet activation and initiates coagulation. Antitumour necrosis factor-a (TNFa) agents seem to decrease RA-associated cardiovascular events. We investigated whether (1) TNFa activates human platelets and (2) TNFa pharmacological blockade modulates the platelet-leucocyte reciprocal activation in RA. Design The expression of platelet TNFa receptors has been assessed by flow cytometry and immunogold electron microscopy. Platelet and leucocyte activation has been assessed also in the presence of antibodies against the TNFa receptors 1 and 2 and of infliximab. TF expression, binding to fibrinogen and phosphatidylserine exposure, has been assessed by flow cytometry, TF activity by coagulation time and by endogenous thrombin generation. Markers of platelet and leucocyte activation have been assessed in 161 subjects: 42 patients with RA, 12 with osteoarthritis, 37 agematched and sex-matched patients with chronic stable angina and 70 age-matched and sex-matched healthy subjects. Results TNFa elicited the platelet activation and the expression of TF, which in turn prompted thrombin generation and clot formation. Inhibition of the TNFa- induced activation restricted platelet ability to activate leucocytes and to induce leucocyte TF. TNFa inhibition did not influence platelet activation induced by collagen, ADP or thrombin receptor activating peptide-6. Platelets of patients with RA were more activated than those of controls. Activation was reduced in patients treated with TNFa inhibitors. Conclusions TNFa-dependent pathways control platelet activation and TF expression in RA. Further studies will verify whether the protective effect of TNFa inhibitors on cardiovascular events involves their ability to modulate platelet function.

AB - Background Cardiovascular disease is important in rheumatoid arthritis (RA). Tissue factor (TF) is expressed upon platelet activation and initiates coagulation. Antitumour necrosis factor-a (TNFa) agents seem to decrease RA-associated cardiovascular events. We investigated whether (1) TNFa activates human platelets and (2) TNFa pharmacological blockade modulates the platelet-leucocyte reciprocal activation in RA. Design The expression of platelet TNFa receptors has been assessed by flow cytometry and immunogold electron microscopy. Platelet and leucocyte activation has been assessed also in the presence of antibodies against the TNFa receptors 1 and 2 and of infliximab. TF expression, binding to fibrinogen and phosphatidylserine exposure, has been assessed by flow cytometry, TF activity by coagulation time and by endogenous thrombin generation. Markers of platelet and leucocyte activation have been assessed in 161 subjects: 42 patients with RA, 12 with osteoarthritis, 37 agematched and sex-matched patients with chronic stable angina and 70 age-matched and sex-matched healthy subjects. Results TNFa elicited the platelet activation and the expression of TF, which in turn prompted thrombin generation and clot formation. Inhibition of the TNFa- induced activation restricted platelet ability to activate leucocytes and to induce leucocyte TF. TNFa inhibition did not influence platelet activation induced by collagen, ADP or thrombin receptor activating peptide-6. Platelets of patients with RA were more activated than those of controls. Activation was reduced in patients treated with TNFa inhibitors. Conclusions TNFa-dependent pathways control platelet activation and TF expression in RA. Further studies will verify whether the protective effect of TNFa inhibitors on cardiovascular events involves their ability to modulate platelet function.

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