The lectin complement pathway serine proteases (MASPs) represent a possible crossroad between the coagulation and complement systems in thromboinflammation

Abstract

EssentialsThe 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.Summary. 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. Objectives: 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.

A journey through the lectin pathway of complement—MBL and beyond

“…However, MASP‐1 is activated in a completely different fashion than thrombin and the two proteases likely promote complementary effects on coagulation. As mentioned, activated platelets and fibrin have been suggested as novel mediators of MASP‐1‐driven coagulation and clot formation may thereby augment even more MASP‐1‐catalyzed coagulation. Moreover, fibrin clots generated by MASP‐1 have different physical properties than thrombin‐generated clots.…”

“…Alternative routes of MASP‐1‐mediated blood clotting involving platelets and fibrin have recently been proposed as a part of the thrombo‐inflammatory response. Reportedly, MASP‐1 can amplify coagulation through recruitment of ficolin/MASP complexes to activated platelets and moreover via MASP/fibrin complexes …”

The Complement System and Preeclampsia

“…Platelets express most complement regulatory components and more recent studies demonstrate that complement may activate the coagulation cascade as well. Specifically, complement MASP-2 activates prothrombin to create thrombin [34] and C5a binding of C5aR1 activates tissue factor and the extrinsic coagulation pathway [35]. In pregnancy, placental development requires tissue factor while formation of pseudoendothelial cells within the placenta inhibits thrombin activation [36, 37].…”

Distinct contributions of complement factors to platelet activation and fibrin formation in venous thrombus development

“…Deletions of the complement lectin pathway components, mannose-binding lectin and mannosebinding lectin-associated serine protease-1/-3 but not C2/factor B, prevent ferric chloride-induced arterial thrombosis, 59 and triggering platelets leads to activation of mannose-binding lectin-associated serine protease-1 and -3. 60 Hemostasis and thrombus formation in a photochemical thrombosis model were also impaired in C3 2/2 mice. Time (h) analyzed by Mann-Whitney U test.…”