title: Mannose-binding lectin-associated serine protease-1 is a significant contributor to coagulation in a murine model of occlusive thrombosis.
abstract: Bleeding disorders and thrombotic complications constitute a major cause of death and disability worldwide. Although it is known that the complement and coagulation systems interact, no studies have investigated the specific role or mechanisms of lectin-mediated coagulation in vivo. FeCl(3) treatment resulted in intra-arterial occlusive thrombogenesis within 10 min in wild-type (WT) and C2/factor B-null mice. In contrast, mannose-binding lectin (MBL)-null and MBL-associated serine protease (MASP)-1/-3 knockout (KO) mice had significantly decreased FeCl(3)-induced thrombogenesis. Reconstitution with recombinant human (rh) MBL restored FeCl(3)-induced thrombogenesis in MBL-null mice to levels comparable to WT mice, suggesting a significant role of the MBL/MASP complex for in vivo coagulation. Additionally, whole blood aggregation demonstrated increased MBL/MASP complex-dependent platelet aggregation. In vitro, MBL/MASP complexes were captured on mannan-coated plates, and cleavage of a chromogenic thrombin substrate (S2238) was measured. We observed no significant differences in S2238 cleavage between WT, C2/factor B-null, MBL-A(-/-), or MBL-C(-/-) sera; however, MBL-null or MASP-1/-3 KO mouse sera demonstrated significantly decreased S2238 cleavage. rhMBL alone failed to cleave S2238, but cleavage was restored when rMASP-1 was added to either MASP-1/-3 KO sera or rhMBL. Taken together, these findings indicate that MBL/MASP complexes, and specifically MASP-1, play a key role in thrombus formation in vitro and in vivo.
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Laura R
authors.initials: LR
authors.lastname: La Bonte
authors.forename: Vasile I
authors.initials: VI
authors.lastname: Pavlov
authors.forename: Ying S
authors.initials: YS
authors.lastname: Tan
authors.forename: Kazue
authors.initials: K
authors.lastname: Takahashi
authors.forename: Minoru
authors.initials: M
authors.lastname: Takahashi
authors.forename: Nirmal K
authors.initials: NK
authors.lastname: Banda
authors.forename: Chenhui
authors.initials: C
authors.lastname: Zou
authors.forename: Teizo
authors.initials: T
authors.lastname: Fujita
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Stahl
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000276:immunology; D002341:Carotid Artery Thrombosis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D002712:Chlorides / Q000633:toxicity; D037582:Complement Pathway, Mannose-Binding Lectin / Q000235:genetics; D004195:Disease Models, Animal; D005290:Ferric Compounds / Q000633:toxicity; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D037241:Mannose-Binding Lectins / Q000172:deficiency / Q000235:genetics; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000009:adverse effects / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D013917:Thrombin / Q000502:physiology
chemical_list: D002712:Chlorides; D005290:Ferric Compounds; D037241:Mannose-Binding Lectins; C491340:MASP-2 protein, mouse; C468572:MASP-3 protein, mouse; D050606:Mannose-Binding Protein-Associated Serine Proteases; D013917:Thrombin; C024555:ferric chloride