Abstract
The prothrombotic fibrin clot phenotype has been reported in patients with thrombotic antiphospholipid syndrome (APS) and venous thromboembolism (VTE). Protein composition of plasma fibrin clots in APS has not been studied. We evaluated 23 patients with thrombotic APS, 19 with VTE alone, and 20 well-matched controls. A proteomic analysis of fibrin clots generated from citrated plasma was based on liquid chromatography-mass spectrometry. Plasma levels of thrombospondin-1 (TSP1), apolipoprotein(a), A-I, and B-100, complement components (C)3a, C5b-C9, histidine-rich glycoprotein (HRG), and prothrombin were evaluated using immunoenzymatic tests. In plasma fibrin clots of APS patients, compared with VTE subjects and controls, we identified decreased amounts of (pro)thrombin, antithrombin-III, apolipoprotein A-I, and HRG with no differences in plasma levels of antithrombin, prothrombin, along with lower plasma HRG and apolipoprotein A-I. In APS patients, plasma HRG positively correlated with amounts of clot-bound HRG, while apolipoprotein A-I was inversely associated with clot-bound levels of this protein. The most predominant proteins within the clots of APS patients were bone marrow proteoglycan, C5-C9, immunoglobulins, apolipoprotein B-100, platelet-derived proteins, and TSP1. Our study is the first to demonstrate differences in the protein composition of fibrin clots generated from plasma of thrombotic APS patients versus those with VTE alone.
Highlights
Antiphospholipid syndrome (APS) is an autoimmune disease characterized by a hypercoagulable state associated with vascular thrombosis and/or pregnancy morbidity in the presence of circulating antiphospholipid antibodies including immunoglobulin (Ig)G and IgM antibodies to β-2Glycoprotein I (β2GpI) and anticardiolipin antibodies1. aPL are observed in up to 10% of patients with deep vein thrombosis (DVT) with or without pulmonary embolism (PE)[2]
We have shown that a multiple enzyme digestion filter aided sample preparation (MED-FASP) method combined with a label-free quantification on Q Exactive HF is an excellent proteomic approach for the analysis of fibrin clots prepared ex vivo from citrate plasma of 4 venous thromboembolism (VTE) patients[6]
This study provides insights into specific changes within fibrin clot composition in thrombotic antiphospholipid syndrome (APS), suggesting that a number of proteins, including those beyond blood coagulation components, such as inflammatory proteins, might be involved in thrombus formation and affect its properties
Summary
Antiphospholipid syndrome (APS) is an autoimmune disease characterized by a hypercoagulable state associated with vascular thrombosis and/or pregnancy morbidity in the presence of circulating antiphospholipid antibodies (aPL) including immunoglobulin (Ig)G and IgM antibodies to β-2Glycoprotein I (β2GpI) and anticardiolipin antibodies (aCL)1. aPL are observed in up to 10% of patients with deep vein thrombosis (DVT) with or without pulmonary embolism (PE)[2]. Multiple prothrombotic mechanisms associated with the presence of aPL have been demonstrated including enhanced blood coagulation and impaired fibrinolysis[3]. Proteomics of fibrin clots generated from plasma of patients with acute myocardial infarction (AMI) using shotgun method (2DLC-MS/MS) identified 62 proteins belonging to several distinct functional clusters (e.g. cholesterol transporter activity, immunoglobulin binding and peptidase regulatory activity)[7]. Our previous study revealed 476 proteins repeatedly identified in the plasma fibrin clots from 4 patients with VTE including extracellular vesicle-derived proteins, lipoproteins, fibrinolysis inhibitors, and proteins involved in immune responses[6]. Employing label-free quantitative proteomics we aimed to investigate the protein composition of plasma clots prepared ex vivo from patients with APS-associated VTE versus those with VTE unrelated to APS and age- and sex-matched healthy controls
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