The blood coagulation system is a delicately balanced homeostatic mechanism. When it functions as it should, clots form at sites of injury while the rest of the blood circulates in a fluid state.Inappropriate clotting results in strokes, heart attacks, thrombophlebitis and pulmonary embolism.While we know a great deal about the biochemistry of coagulation proteins, much remains to be learned about how they interact with cell surfaces and how inflammatory mediators and other cardiovascular risk factors influence normal and pathologic coagulation.
My laboratory studies the role of cells in regulating coagulation and how inflammation can alter coagulation. Studies are ongoing at the protein, cellular, and clinical (human patient) levels, using biochemical, immunological, and microscopic techniques. We have developed an in vitro model of normal and abnormal coagulation. The model system includes purified human blood monocytes and platelets as well as human coagulation proteins. The monocytes are treated to express tissue factor. Tissue factor, in complex with the coagulation protein factor VIIa, is primarily responsible for initiating coagulation in vivo. Platelets do not express tissue factor but provide a necessary surface for the coagulation proteins to assemble into functional complexes. Our model system has allowed us to study coagulation by varying the amount of each component, varying the time that cells are in contact with one another, or treating the leukocytes with inflammatory cytokines. We can measure the effect of these maneuvers on the activation of coagulation enzymes and compare the results to known disease states. Using this model we have evolved a conceptual model of coagulation that better explains the physiology of some clotting and bleeding disorders than does the previous coagulation cascade model. We now understand why hemophiliacs, which lack coagulation factor VIII or IX, have such a severe bleeding disorder.Our model has also helped us understand why high levels of coagulation factor VIIa can bypass the need for the deficient factor. This has led to a conceptual underpinning for factor VIIa treatment protocols in hemophilia.
We are now also studying the mechanism by which elevated plasma homocysteine leads to accelerated atherosclerosis and thrombosis.This is a problem of great importance from a public health point of view.We are using biochemical, biophysical, cellular and mass spectroscopy techniques to examine the effects of homocysteine on key clotting protein in humans and a rabbit model.We believe these studies will lead to a better way of testing which patients have the highest risk of cardiovascular events and might benefit from homocysteine-lowering therapy.
Selected Publications:
Review articles
Monroe DM, Hoffman M, Roberts HR:Platelets and Thrombin Generation. Atherosclerosis, Thrombosis and Vascular Biol 22:1381-1389, 2002.
Hoffman M, Monroe DM:A Cell-Based Model of Hemostasis.Thromb Haemostas, 85:958-65, 2001.
Roubey, RAS, Hoffman, M:From Antiphospholipid Syndrome to Antibody-Mediated Thrombosis. The Lancet 350 (9090):1491-3, 1997.
Interaction of cells and proteins in a model of coagulation:
Wolberg AS , Monroe DM, Roberts HR, Hoffman M: Effect of varied procoagulant concentration on thrombin generation and fibrin clot structure in a model system. BLOOD, In Press for 2003.
Oliver JA, Monroe DM, Roberts HR, Church FC, Hoffman M: Activated Protein C Cleaves Factor Va more Efficiently on Endothelium than on Platelets. BLOOD, 100(2):539-546, 2002
Oliver JA, Monroe DM, Roberts HR, Hoffman MR: Feedback Activation of Factor XI on Platelets in the Absence of Factor XII. Atherosclerosis, Thrombosis and Vascular Biol 19:170-77, 1999.
Monroe, DM, Hoffman, MR, Oliver, JA, Roberts, HR:Platelet Activity of High Dose Factor VIIa is Independent of Tissue Factor.Br J Haematol 99:542-7, 1997.
Hoffman M, Monroe DM, Oliver JA, Roberts HR. Factor IXa and factor Xa play distinct roles in tissue factor-dependent initiation of coagulation. BLOOD86:1794-801, 1995.
Hoffman M, Monroe DM, Roberts HR. Human monocytes support factor X activation by factor VIIa independent of tissue factor: implications for the therapeutic mechanism of high dose factor VIIa in hemophilia. BLOOD83:38-42, 1994.
Gui T, Lin HF, Hoffman M, Straight DL, Stafford DW:Circulation and Binding Characteristics of Wild-Type Factor IX and Certain Gla Domain Mutants in Coagulation Factor IX-Deficient Mice, BLOOD, 100:153-158, 2002.
Effect of Hyperhomocysteinemia on Coagulation
Sauls DL, Wolberg AS , Hoffman M:Hyperhomocysteinemia induces alterations in fibrinogen function and fibrin clot structure in a rabbit model. J of Thromb Haemostas, In Press for 2003.