Abnormal fibrinogens are detected in clinical assays as prolonged thrombin clotting times, a result typically associated with bleeding symptoms. Nevertheless, abnormal fibrinogens have been identified in patients with thrombotic disease. Work in our laboratory has established the genetic defect in several abnormal fibrinogens linked to thrombosis. Biochemical analyses of these abnormal fibrinogens demonstrated that the fibrin matrix formed from these molecules is abnormal. We conclude that the patients' thrombotic symptoms correlate with an abnormal clot structure, which delays clot dissolution.

• g -chain Dysfibrinogenemias: Molecular structure-function relationships of naturally occurring mutations in the g chain of human fibrinogen. Cote, HCF, Lord, ST, and Pratt, KP. Review Article, BLOOD 92:2195, 1998.

• Severe hypodysfibrinogenemia in compound heterozygotes of the fibrinogen AαIVS4+1 G>T mutation and an AαGln328 truncation (Fibrinogen Keokuk ). Lefebvre, P., Velasco, P.T., Dear, A., Lounes, K.C., Lord, S.T., Brennan, S.O., Green, D. and Lorand, L., Blood, 103:2571-6, 2004.

The correlation between fibrinogen structure and function has been examined using abnormal fibrinogens synthesized in cultured cells. We have identified residues that are critical for recognition by thrombin, the enzyme that initiates the conversion of fibrinogen to fibrin. We have identified domains that are critical for normal fibrin matrix structure and subsequent fibrinolysis. Recently we have been able to correlate biochemical properties with high-resolution crystallographic structures of these variants. These data provide insight into the molecular mechanisms that control fibrin polymerization.

• Decreased lateral aggregation of a variant recombinant fibrinogen provides insight into the polymerization mechanism. Mullin, J.L., Gorkun, O.V. and Lord, S.T., Biochemistry 39:9843-9849, 2000. (See the electron microscopy photo in Recent Results.)

• Recombinant fibrinogen studies reveal that thrombin specificity dictates order of fibrinopeptide release. Mullin, J.L., Gorkun, O.V. and Lord, S.T., J. Biol. Chem. 275:25239-25246, 2000.

• Calcium-binding site ß2, adjacent to the "b" polymerization site, modulates lateral aggregation of protofibrils during fibrin polymerization. Kostelansky, M.S., Lounes, K.C., Ping, L.F., Dickerson, S.K., Gorkun, O.V., and Lord, S.T. Biochemistry, 43:2475-83, 2004.

• BßGlu397 and BßAsp398, but not BßAsp432, are required for "B:b" interactions. Kostelansky, M.S., Bolliger-Stucki, B., Betts, L., Gorkun, O.V., and Lord, S.T., Biochemistry, 43:2465-74, 2004.

To examine the correlation between elevated plasma fibrinogen and risk of cardiovascular disease, we have generated transgenic mice with elevated levels of mouse fibrinogen. With these mice we have examined the development of lesions in the aorta in animals fed either a normal diet or a high fat/high cholesterol diet. We found no difference in the development of lesions when normal mice were compared to transgenic mice whose fibrinogen levels were twice normal. We conclude that elevated fibrinogen did not contribute either to the initiation or the development of diet-induced lesions. Recent studies show elevated fibrinogen causes changes in vascular responses to injury. We have also generated mice with fibrinogen analogous to the human Vlissingen/Frankfurt IV variant.

• Effects of hyperfibrinogenemia on vasculature of C57BL/6 mice with and without atherogenic diet, Gulledge, A.A., McShea, C., Schwartz, T., Koch, G., and Lord, S.T., Arterioscler Thromb Vasc Biol., 23:130-135, 2003.

• Cause-effect relation between hyperfibrinogenemia and vascular disease. Kerlin, B.A., Cooley, B.C., Isermann, B.H., Hernandez, I., Sood, R., Zogg, M., Hendrickson, S.B., Mosesson, M.W., Lord, S. and Weiler, H., Blood, 103:1728-34, 2004.

• Neonatal bleeding and decreased plasma fibrinogen levels in mice modeled after the dysfibrinogen Vlissingen/Frankfurt IV. Hogan, KA, Merenbloom BK, Kim HS and Lord, ST.
  J Thromb Haemost. 2:1484-7, 2004.