title: Beta2-glycoprotein I is proteolytically cleaved in vivo upon activation of fibrinolysis.
abstract: Beta2-glycoprotein I (beta2GPI) is a plasma glycoprotein with unknown physiological function(s). In in vitro experiments it has been demonstrated that beta2GPI has both anticoagulant properties, such as the inhibition of factor X and prothrombin activation and procoagulant properties, such as the inhibition of the anticoagulant activity of activated protein C. Besides this, beta2GPI bound to cardiolipin is recognized by antiphospholipid antibodies (aPL). In this study we demonstrate that beta2GPI is very sensitive for cleavage between Lys317 and Thr318 by plasmin, resulting in two immunologically different cleaved forms. In vitro experiments show that these plasmin cleaved forms of beta2GPI bind to negatively charged phospholipids with much lower affinity compared to intact beta2GPI. Similar to plasmin, trypsin and elastase can also induce this proteolytical cleavage in beta2GPI, whereas thrombin and factor Xa do not cleave beta2GPI. The in vivo occurrence of the proteolytical cleavage was demonstrated by the finding that in plasmas of patients with disseminated intravascular coagulation (DIC) and in plasmas of patients treated with streptokinase, significant amounts of cleaved beta2GPI (up to 12 microg/ml) are present. During the development of DIC, the increase in levels of cleaved beta2GPI is accompanied by a 70% decrease in the levels of intact beta2GPI, whereas in streptokinase treated patients levels of intact beta2GPI stay within the normal range. This study demonstrates for the first time that during in vivo activation of fibrinolysis beta2GPI is cleaved. which results in the formation of a form of beta2GPI with much lower affinity for negatively charged phospholipids. Plasmin is most likely responsible for this modification.
authors.affiliation: Department of Haematology, University Hospital Utrecht, Institute of Biomembranes, Utrecht University, The Netherlands.
authors.forename: D A
authors.initials: DA
authors.lastname: Horbach
authors.forename: E
authors.initials: E
authors.lastname: van Oort
authors.forename: T
authors.initials: T
authors.lastname: Lisman
authors.forename: J C
authors.initials: JC
authors.lastname: Meijers
authors.forename: R H
authors.initials: RH
authors.lastname: Derksen
authors.forename: P G
authors.initials: PG
authors.lastname: de Groot
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000276:immunology; D004211:Disseminated Intravascular Coagulation / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000378:metabolism; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis; D006023:Glycoproteins / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010196:Pancreatic Elastase / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism; D053482:beta 2-Glycoprotein I
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D006023:Glycoproteins; D053482:beta 2-Glycoprotein I; D010196:Pancreatic Elastase; D014357:Trypsin; D005341:Fibrinolysin