Durham, NC 27710
Blood coagulation; apheresis; blood transfusion
The blood coagulation system is a delicately balanced homeostatic mechanism. When it functions as it should, blood clots at sites of injury while the rest of the blood circulates in a fluid state. Inappropriate clotting is a major cause of morbidity and mortality, resulting in strokes, heart attacks, thrombophlebitis and pulmonary embolism.
My research is directed toward understanding basic mechanisms in hemostasis, and the connections between inflammation/immune and coagulation responses to injury. Recent work in this laboratory has shown that thrombin (the ultimate protease produced during blood clotting) can play an important role in regulating monocyte/macrophage chemotaxis and cytokine release, as well as the effectiveness of healing after an injury.
We have developed a cell-based model of tissue factor-initiated coagulation. This model is proving to be a powerful tool for studying basic mechanisms in hemostasis. It has taught us that the cellular LOCATION of activation of the clotting factors is critically important in determining their ability to initiate and support formation of a clot. Using this model system we have been able to explain why factors VIII and IX (the factors that are deficient in hemophilia A and B, respectively) are essential for hemostasis in vivo, and also how high dose FVIIa can bypass the need for FVIII or FIX and restore hemostasis in hemophiliacs. We have also modeled the hemostatic defects in dilutional coagulopathy, liver disease and coumadin treatment. These models are helping us understand why the common clinical coagulation tests do not predict the risk of bleeding well in these conditions.
We have demonstrated that factor XI is activated by thrombin on the platelet surface, rather than requiring FXII as in the traditional "coagulation cascade", thus explaining why patients deficient in FXII do not have a bleeding tendency. Our data suggest that coagulation on the platelet surface is not terminated by proteins C and S, but rather these factors act primarily on the endothelial surface in protecting against thrombosis. Work in our model system has led to a revised understanding of the hemostatic process in vivo in normal and pathologic states as detailed in our chapter in Williams Hematology text (see citation below).
We have recently begun to expand our studies into the role of thrombin in directly the wound healing response. Clinicians have long felt that wound healing is delayed in hemophiliacs. We have now developed a wound healing model in hemophilia B mice and ascertained that these mice do indeed have delayed wound healing. They have poor influx of phagocytic cells into the wound area and delayed clearance of debris and iron from hemorrhage. Surprisingly, the mice with defective hemostasis have greater angiogenesis during the healing process. We think this is a result of the toxic and inflammatory effects of iron in the tissues. The excess angiogenesis may be one reason why hemophiliacs often have recurrent bleeding into their joints - the healing process produces a large number of fragile vessels.
Finally, we are exploring the mechanisms by which elevated plasma homocysteine levels lead to a pro-thrombotic state. We have found that hyperhomocysteinemic rabbits develop an acquired dysfibrinogenemia. This is characterized by the formation of clots that are highly resistant to normal lysis. We have used mass spec to demonstrate the specific structural changes in fibrinogen when a metaobilite of homocysteine reacts with fibrinogen, and have shown that these changes result in functional changes similar to what we have observed in hyperhomocysteinemic rabbits.
This faculty member has no reported relationships with industry.
Hoffman, M; Monroe, DM. The multiple roles of tissue factor in wound healing. Frontiers in Bioscience (Scholar edition). 2012;4:713-721. (2012) Abstract
Hoffman, M. Hypothesis: hyperhomocysteinemia is an indicator of oxidant stress. Medical Hypotheses. 2011;77:1088-1093. (2011) Abstract
Hoffman, M; Volovyk, Z; Persson, E; Gabriel, DA; Ezban, M; Monroe, DM. Platelet binding and activity of a factor VIIa variant with enhanced tissue factor independent activity. Journal of Thrombosis and Haemostasis. 2011;9:759-766. (2011) Abstract
West, KL; Adamson, C; Hoffman, M. Prophylactic correction of the international normalized ratio in neurosurgery: a brief review of a brief literature. Journal of Neurosurgery. 2011;114:9-18. (2011) Abstract
Hoffman, M; Monroe, DM. Wound healing in haemophilia--breaking the vicious cycle. Haemophilia. 2010;16 Suppl 3:13-18. (2010) Abstract
Hoffman, M; Monroe, DM. Tissue factor in brain is not saturated with factor VIIa: implications for factor VIIa dosing in intracerebral hemorrhage. Stroke. 2009;40:2882-2884. (2009) Abstract
Monroe, DM; Hoffman, M. The coagulation cascade in cirrhosis. Clinics in Liver Disease. 2009;13:1-9. (2009) Abstract
Nimjee, SM; Oney, S; Volovyk, Z; Bompiani, KM; Long, SB; Hoffman, M; Sullenger, BA. Synergistic effect of aptamers that inhibit exosites 1 and 2 on thrombin. RNA. 2009;15:2105-2111. (2009) Abstract
Volovyk, Z; Monroe, DM; Qi, Y; Becker, R; Hoffman, M. A rationally designed heparin, M118, has anticoagulant activity similar to unfractionated heparin and different from Lovenox in a cell-based model of thrombin generation. Journal of Thrombosis and Thrombolysis. 2009;28:132-139. (2009) Abstract
Hoffman, M. Alterations of fibrinogen structure in human disease. Cardiovascular and Hematological Agents in Medicinal Chemistry. 2008;6:206-211. (2008) Abstract
McDonald, AG; Yang, K; Roberts, HR; Monroe, DM; Hoffman, M. Perivascular tissue factor is down-regulated following cutaneous wounding: implications for bleeding in hemophilia. Blood. 2008;111:2046-2048. (2008) Abstract
Hoffman, M; Colina, CM; McDonald, AG; Arepally, GM; Pedersen, L; Monroe, DM. Tissue factor around dermal vessels has bound factor VII in the absence of injury. Journal of Thrombosis and Haemostasis. 2007;5:1403-1408. (2007) Abstract
Sauls, DL; Banini, AE; Boyd, LC; Hoffman, M. Elevated prothrombin level and shortened clotting times in subjects with type 2 diabetes. Journal of Thrombosis and Haemostasis. 2007;5:638-639. (2007) Abstract
Hoffman, M; Harger, A; Lenkowski, A; Hedner, U; Roberts, HR; Monroe, DM. Cutaneous wound healing is impaired in hemophilia B. Blood. 2006;108:3053-3060. (2006) Abstract
Hoffman, M; Whinna, HC; Monroe, DM. Circulating tissue factor accumulates in thrombi, but not in hemostatic plugs. Journal of Thrombosis and Haemostasis. 2006;4:2092-2093. (2006) Abstract
Monroe, DM; Hoffman, M. What does it take to make the perfect clot?. Arteriosclerosis, Thrombosis and Vascular Biology. 2006;26:41-48. (2006) Abstract
Sauls, DL; Lockhart, E; Warren, ME; Lenkowski, A; Wilhelm, SE; Hoffman, M. Modification of fibrinogen by homocysteine thiolactone increases resistance to fibrinolysis: a potential mechanism of the thrombotic tendency in hyperhomocysteinemia. Biochemistry. 2006;45:2480-2487. (2006) Abstract
Wolberg, AS; Meng, ZH; Monroe, DM; Hoffman, M. A systematic evaluation of the effect of temperature on coagulation enzyme activity and platelet function. Journal of Trauma: Injury Infection and Critical Care. 2004;56:1221-1228. (2004) Abstract
Meng, ZH; Wolberg, AS; Monroe, DM; Hoffman, M. The effect of temperature and pH on the activity of factor VIIa: implications for the efficacy of high-dose factor VIIa in hypothermic and acidotic patients. Journal of Trauma: Injury Infection and Critical Care. 2003;55:886-891. (2003) Abstract
Sauls, DL; Wolberg, AS; Hoffman, M. Elevated plasma homocysteine leads to alterations in fibrin clot structure and stability: implications for the mechanism of thrombosis in hyperhomocysteinemia. Journal of Thrombosis and Haemostasis. 2003;1:300-306. (2003) Abstract
Hoffman, M; Monroe, DM. A cell-based model of hemostasis. Thrombosis and Haemostasis. 2001;85:958-965. (2001) Abstract
Oliver, JA; Monroe, DM; Roberts, HR; Hoffman, M. Thrombin activates factor XI on activated platelets in the absence of factor XII. Arteriosclerosis, Thrombosis and Vascular Biology. 1999;19:170-177. (1999) Abstract
Hoffman, M; Monroe, DM; Roberts, HR. Activated factor VII activates factors IX and X on the surface of activated platelets: thoughts on the mechanism of action of high-dose activated factor VII. Blood Coagulation and Fibrinolysis: international journal in haemostasis and thrombosis. 1998;9 Suppl 1:S61-S65. (1998) Abstract
Monroe, DM; Hoffman, M; Oliver, JA; Roberts, HR. Platelet activity of high-dose factor VIIa is independent of tissue factor. British Journal of Haematology. 1997;99:542-547. (1997) Abstract
Roubey, RA; Hoffman, M. From antiphospholipid syndrome to antibody-mediated thrombosis. Lancet. 1997;350:1491-1493. (1997) Abstract
Hoffman, M. Antibody-coated erythrocytes induce secretion of tumor necrosis factor by human monocytes: a mechanism for the production of fever by incompatible transfusions. Vox Sanguinis: international journal of transfusion medicine. 1991;60:184-187. (1991) Abstract
Hoffman, M; Fuchs, HE; Pizzo, SV. The macrophage-mediated regulation of hepatocyte synthesis of antithrombin III and alpha 1-proteinase inhibitor. Thrombosis Research: vascular obstruction, hemorrhage and hemostasis. 1986;41:707-715. (1986) Abstract