Michael W. Mosesson, M.D.

Senior Investigator
Blood Research Institute
BloodCenter of Wisconsin

Clinical Professor of Hematology

Department of Medicine
Medical College of Wisconsin

Selected Publications
Grant Support
Contact Information

Research Interests

Fibrinogen is the circulating precursor of fibrin, the latter forming as the result of thrombin cleavage of fibrinogen. Fibrinogen and fibrin play critically important roles in numerous biological events, and these include clot formation, cellular and matrix interactions, fibrinolysis, and wound healing. Molecules of fibrinogen are elongated structures comprised of two outer D domains, each connected by a coiled-coil segment to a central E domain (see diagram). Each molecule is composed of two sets of polypeptide chains termed Aa, Bb, and g, and their amino-terminal regions are located in the central domain (see diagram). Fibrinogen or fibrin undergoes intermolecular covalent cross-linking of its g chains that is mediated through a plasma transglutaminase termed factor XIII. The positioning of g chains (purple) for cross-linking in fibrin places them ‘transversely’ between fibril strands, a location that accounts for their contribution to the viscoelastic properties of cross-linked fibrin. The question of their location in fibrin has been controversial, and this issue has generated a vigorous debate on the subject (see ‘debate’ reference).

We have several coordinated interests concerned with the biology of fibrin(ogen) among which includes thrombin binding to thrombin (‘Antithrombin I’). One involves the exact mechanism by which thrombin binds to fibrinogen and fibrin. We are also studying the crystal structures of thrombin molecules that have been co-crystallized with the fibrin E domain.

Another major interest involves the mechanism and consequences of thrombin binding to fibrin after its conversion from fibrinogen. This interaction between fibrin and thrombin has one major physiological effect: It sequesters thrombin in the forming fibrin clot, removing it from the fluid-phase clotting reaction, and also down-regulates its catalytic potential. Such events markedly reduce thrombin generation. On the other hand, thrombin that is bound to fibrin is resistant to inhibition by potent thrombin inhibitors like ‘antithrombin III’, an effect that would promote the clot forming activity of bound thrombin. Our experimental approach to this problem includes in vitro assessments of the kinetics and stoichiometry of thrombin binding to fibrin, and preparation of a transgenic mouse whose fibrinogen molecules have been endowed with the thrombin-binding features displayed by human fibrin. We also are measuring the levels of thrombin binding structures in fibrin (i.e., g’ chains) in healthy subjects and in a variety of disease states, in order to determine their pathophysiological roles. Finally, we conduct clinical and basic studies on patients and families with congenital fibrinogen abnormalities (dysfibrinogenemias), particularly those families with a history of bleeding or thromboembolism.

Selected Publications

• The Covalent Structure of Factor XIIIa-crosslinked Fibrinogen Fibrils. Mosesson MW, KR Siebenlist, JF Hainfeld, JS Wall. J Structural Biol 115:88-101,1995
• The Role of Fibrinogen D Domain Intermolecular Association Sites in the Polymerization of Fibrin and Fibrinogen Tokyo II (g275 ARG®CYS). Mosesson MW, KR Siebenlist, JP DiOrio, M Matsuda, JF Hainfeld, JS Wall. J Clin Invest 96:1053-1058, 1995
• The Relationship Between the Fibrinogen D Domain Self-association/crosslinking Site (γXL) and the Fibrinogen Dusart Abnormality (Aα R554C-Albumin) – Clues to Thrombophilia in the ‘Dusart Syndrome’. Mosesson MW, KR Siebenlist, JF Hainfeld, JS Wall, J Soria, C Soria, JP Caen. J Clin Invest 97:2342-2350, 1996
• Identification and Characterization of the Thrombin Binding Sites on Fibrin. Meh DA, KR Siebenlist, MW Mosesson. J Biol Chem 271:23121-23125, 1996
• The Location of the Carboxy-terminal Region of γ Chains in Fibrinogen and Fibrin D Domains. Mosesson MW, KR Siebenlist, DA Meh, JS Wall, JF Hainfeld. Proc Natl Acad Sci (USA) 95:10511-10516, 1998
• The Amino Acid Sequence in Fibrin Responsible for High Affinity Thrombin Binding. Meh DA, Siebenlist KR, Brennan SO, Holyst T, Mosesson MW. Thromb Haemostas 85:470-474, 2001
• Protransglutaminase (Factor XIII) Mediated Crosslinking of Fibrinogen and Fibrin. Siebenlist KR, Meh DA, Mosesson MW. Thromb Haemostas 86:1221-1228, 2001
• Fibrinogen Naples I (Bβ A68T) Non-substrate Thrombin Binding Capacities. Meh DA, Mosesson MW, Siebenlist KR, Simpson-Haidaris PJ, Brennan SO, DiOrio JP, Thompson K, Di Minno G. Thromb Res 102:1-11, 2001
• Disintegration and Reorganization of Fibrin Networks During tPA-induced Clot Lysis. Meh DA, Mosesson MW, Diorio, JP, Siebenlist KR, Hernandez I, Amrani DL, Stojanovic L. Blood Coag Fibrinol 12:627-637, 2001
• Fibrinogen Assembly and Crosslinking on a Fibrin Fragment E Template. Mosesson MW, Siebenlist KR, Hernandez I, Wall JS, Hainfeld JF. Thromb Haemostas 87:651-658, 2002
• Antithrombin I. Inhibition of Thrombin Generation in Plasma by Fibrin Formation. Mosesson, MW. Thromb Haemostas.89:9-12, 2003
• Crystal Structure of the Complex Between Thrombin and the Central ‘E’ Region of Fibrin. Pechik I, Madrazo J, Mosesson MW, Hernandez I, Gilliland GL, Medved L. Proc Natl Acad Sci (USA) 101:2718-2723, 2004.
• Regulation of Transglutaminase Activity in Articular Chondrocytes through Thrombin Receptor-mediated Factor XIII Synthesis. Rosenthal AK, Mosesson MW, Gohr CM, Masuda I, Heinkel D, Siebenlist KR. Thromb Haemostas 91:558-568, 2004
• The Fibrin Cross-linking Debate: Cross-linked g-chains in Fibrin Fibrils Bridge ‘Transversely’ Between Strands: Yes. Mosesson MW. J Thromb Haemost 2:388-393, 2004.
• Evidence that Catalytically-inactivated Thrombin Forms Non-covalently Linked Dimers that Bridge Between Fibrin/fibrinogen Fibers and Enhance Fibrin Polymerization. Mosesson MW, Hernandez I, Siebenlist KR Biophysical Chemistry 110:93-100. 2004
• John D Ferry-Special Issue (Mosesson MW, E Di Cera, eds). Biophysical Chemistry 112 (2/3):89-302, 2004 (Festschrift)
• Fibrinogen Saint-Germain II: Hypofibrinogenemia Due To Heterozygous N345SS Mutation. De Raucort E, de Mazancourt P, Maghzal GJ, Brennan SO, Mosesson MW. Thromb Haemostas 94:965-968, 2005
• Studies on the Basis for the Properties of Fibrin Produced from Fibrinogen Containing g’ Chains. Siebenlist KR, Mosesson MW, Hernandez I Bush LA, Di Cera E, Shainoff JR, DiOrio JP, Stojanovic L. Blood 106:2730-2736, 2005 

Grant Support

HL 70627 Physiological Role of Fibrin Anti-Thrombin I Activities (2002-2006) 

Employment Opportunities

If opportunities are available, they will be listed on the Employment page.

Contact Information
Phone: (414) 937-3811
Fax: (414) 937-6284
E-mail: michael.mosesson@bcw.edu