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: Laura R La Bonte, Vasile I Pavlov, Ying S Tan, Kazue Takahashi, Minoru Takahashi, Nirmal K Banda, Chenhui Zou, Teizo Fujita, Gregory L Stahl
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 188 Issue 2 Pg. 885-91 (Jan 15 2012) ISSN: 1550-6606 [Electronic] United States
• PMID: 22156595 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Chlorides
• Ferric Compounds
• Mannose-Binding Lectins
• MASP-2 protein, mouse
• MASP-3 protein, mouse
• Mannose-Binding Protein-Associated Serine Proteases
• Thrombin
• ferric chloride

Topics

• Animals
• Blood Coagulation (immunology)
• Carotid Artery Thrombosis (chemically induced, enzymology, genetics)
• Chlorides (toxicity)
• Complement Pathway, Mannose-Binding Lectin (genetics)
• Disease Models, Animal
• Ferric Compounds (toxicity)
• Humans
• Immunity, Innate (genetics)
• Mannose-Binding Lectins (deficiency, genetics)
• Mannose-Binding Protein-Associated Serine Proteases (adverse effects, deficiency, genetics, physiology)
• Mice
• Thrombin (physiology)