title: The lectin complement pathway serine proteases (MASPs) represent a possible crossroad between the coagulation and complement systems in thromboinflammation.
abstract: ESSENTIALS: The lectin pathway's MASP-1/2 activates coagulation factors but the trigger of the activation is unknown. MASP-1/2 activation was assessed by quantifying complexes between MASPs and antithrombin/C1-inhibitor. Activated platelets and fibrin were demonstrated to activate MASP-1 and MASP-2 both in vitro and in vivo. These findings may represent a crossroad between the complement and the coagulation systems.
  
  
  CONCLUSIONS
  
  
  
  BACKGROUND
  The activated forms of the complement lectin pathway (LP) proteases MASP-1 and MASP-2 are able to cleave the coagulation factors prothrombin, fibrinogen, factor XIII and thrombin-activatable fibrinolysis inhibitor in vitro. In vivo studies also show that MASP-1 is involved in thrombogenesis.
  
  
  OBJECTIVE
  To clarify the not yet identified mechanisms involved in triggering activation of the LP during thrombotic reactions.
  
  
  METHODS
  Novel sandwich-ELISAs for detection of complexes between MASP-1 or MASP-2 and the serpins C1 inhibitor (C1-INH) or antithrombin (AT), were used to specifically detect and quantify the activated forms of MASP-1 and MASP-2.
  
  
  RESULTS
  Activated platelets were shown by flow cytometry to bind Ficolin-1, -2 and -3 but not MBL, which was associated with activation of MASP-1 and MASP-2. We also demonstrated that fibrin and the plasmin-generated fibrin fragment DD in plasma, bind and activate MASP-1 and MASP-2. As demonstrated by the ELISA and SDS-PAGE/Western blotting, the fibrin-associated activation was reflected in a specific inactivation by AT during clotting without the assistance of heparin. In all other cases the MASPs were, as previously reported, inactivated by C1-INH. In systemic lupus erythematosus patients with thrombotic disease and in polytrauma patients, the levels of activated MASP-1 and MASP-2 in complex with both AT and C1-INH were associated with markers of thrombotic disease and contact/coagulation system activation.
  
  
  CONCLUSIONS
  MASP-1 and MASP-2 are activated during blood clotting. This activation is triggered by activated platelets and by the generation of fibrin during thrombotic reactions in vitro and in vivo, and may represent a novel activation/amplification mechanism in thromboinflammation.
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Kozarcanin
authors.affiliation: Section of Rheumatology, Department of Clinical Sciences Lund, Skåne University Hospital and Lund University, Lund, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Lood
authors.affiliation: Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: L
authors.initials: L
authors.lastname: Munthe-Fog
authors.affiliation: Linnaeus Center for Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Sandholm
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden.
authors.forename: O A
authors.initials: OA
authors.lastname: Hamad
authors.affiliation: Section of Rheumatology, Department of Clinical Sciences Lund, Skåne University Hospital and Lund University, Lund, Sweden.
authors.forename: A A
authors.initials: AA
authors.lastname: Bengtsson
authors.affiliation: Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: M-O
authors.initials: MO
authors.lastname: Skjoedt
authors.affiliation: Department of Traumatology, Hand, Plastic, Reconstructive Surgery, University Hospital of Ulm, Ulm, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Huber-Lang
authors.affiliation: Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Rigshospitalet, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: P
authors.initials: P
authors.lastname: Garred
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden.|Linnaeus Center for Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden.
authors.forename: K N
authors.initials: KN
authors.lastname: Ekdahl
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Nilsson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058833:Antithrombin Proteins / Q000378:metabolism; D001777:Blood Coagulation; D001792:Blood Platelets / Q000201:enzymology* / Q000276:immunology; D016022:Case-Control Studies; D050718:Complement C1 Inhibitor Protein / Q000378:metabolism; D037582:Complement Pathway, Mannose-Binding Lectin; D004789:Enzyme Activation; D005260:Female; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000201:enzymology* / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000201:enzymology / Q000276:immunology; D008297:Male; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000276:immunology / Q000378:metabolism*; D008875:Middle Aged; D009104:Multiple Trauma / Q000097:blood / Q000201:enzymology / Q000276:immunology; D015539:Platelet Activation; D011485:Protein Binding; D015398:Signal Transduction; D013927:Thrombosis / Q000097:blood / Q000201:enzymology* / Q000276:immunology; D013997:Time Factors; D055815:Young Adult
chemical_list: D058833:Antithrombin Proteins; D050718:Complement C1 Inhibitor Protein; D005337:Fibrin; C084067:MASP1 protein, human; C105296:MASP2 protein, human; D050606:Mannose-Binding Protein-Associated Serine Proteases
keywords: blood coagulation; complement pathway; fibrin; mannose-binding lectin; mannose-binding protein-associated serine proteases; platelet activation