Physicians

Departments / Divisions

• Pathology / Pathology - General
• Immunology

Address
DUMC 3712
Durham, NC 27710

Office Telephone
919-286-6925

Fax Telephone
919-286-6818

Training

• MD, University of Iowa Roy J. and Lucille A. Carver College of Medicine, 1982

Residency

• Pathology, Duke University Medical Center, 1982-1985

Other Training

• PhD, Pharmacology/Toxicology, University of Iowa, 1982

Clinical Interests
Blood coagulation, apheresis, blood transfusion

Research Interests
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.

Industry Relationships and Collaborations (What's this?)

This physician (or a member of their immediate family) has a working relationship (i.e. consulting, research, and/or educational services) with the companies listed below. These relations have been reported to the health system leadership and, when appropriate, management plans are in place to address potential conflicts.

• Inspiration Biopharmaceuticals
• Medical Mutual Insurance Company
• Novo Nordisk
• The Doctors Company
• University of North Carolina at Chapel Hill

Representative Publications
Hoffman M, Monroe DM. The multiple roles of tissue factor in wound healing. Front Biosci (Schol Ed). 2012;4:713.-721. (2012) 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. J Thromb Haemost. 2011 Apr;9(4):759-66. (2011) Abstract

Hoffman M. Hypothesis: hyperhomocysteinemia is an indicator of oxidant stress. Med Hypotheses. 2011 Dec;77(6):1088-93. (2011) Abstract

Hoffman M, Monroe DM. Wound healing in haemophilia--breaking the vicious cycle. Haemophilia. 2010 May;16 Suppl 3:13-8. (2010) Abstract

West KL, Adamson C, Hoffman M. Prophylactic correction of the international normalized ratio in neurosurgery: a brief review of a brief literature. J Neurosurg. 2010 Sep 3. (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 Aug;40(8):2882-4. (2009) Abstract

Monroe DM, Hoffman M. The coagulation cascade in cirrhosis. Clin Liver Dis. 2009 Feb;13(1):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 Dec;15(12):2105-11. (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. J Thromb Thrombolysis. 2009 Aug;28(2):132-9. (2009) Abstract

Hoffman M. Alterations of fibrinogen structure in human disease. Cardiovasc Hematol Agents Med Chem. 2008 Jul;6(3):206-11. (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 Feb 15;111(4):2046-8. (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. J Thromb Haemost. 2007 Jul;5(7):1403-8. (2007) Abstract

Sauls DL, Banini AE, Boyd LC, Hoffman M. Elevated prothrombin level and shortened clotting times in subjects with type 2 diabetes. J Thromb Haemost. 2007 Mar;5(3):638-9. (2007) Abstract

Hoffman M, Harger A, Lenkowski A, Hedner U, Roberts HR, Monroe DM. Cutaneous wound healing is impaired in hemophilia B. Blood. 2006 Jul 6. (2006) Abstract

Hoffman M, Whinna HC, Monroe DM. Circulating tissue factor accumulates in thrombi, but not in hemostatic plugs. J Thromb Haemost. 2006 Sep;4(9):2092-3. (2006) Abstract

Monroe DM, Hoffman M. What does it take to make the perfect clot? Arterioscler Thromb Vasc Biol. 2006 Jan;26(1):41-8. (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 Feb 28;45(8):2480-7. (2006) Abstract

Wolberg AS, Meng ZH, Monroe DM 3rd, Hoffman M. A systematic evaluation of the effect of temperature on coagulation enzyme activity and platelet function. J Trauma. 2004 Jun;56(6):1221-8. (2004) Abstract

Meng ZH, Wolberg AS, Monroe DM 3rd, 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. J Trauma. 2003 Nov;55(5):886-91. (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. J Thromb Haemost. 2003 Feb;1(2):300-6. (2003) Abstract

Hoffman M, Monroe DM 3rd. A cell-based model of hemostasis. Thromb Haemost. 2001 Jun;85(6):958-65. (2001) Abstract

Roberts HR, Monroe DM, Hoffman M: Molecular biology and biochemistry of the coagulation factors, and pathways of blood coagulation. In William's Hematology sixth edition, Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U, eds. McGraw-Hill Publishing, New York, 2000. (2000)

Oliver JA, Monroe DM, Roberts HR, Hoffman M. Thrombin activates factor XI on activated platelets in the absence of factor XII. Arterioscler Thromb Vasc Biol. 1999 Jan;19(1):170-7. (1999) Abstract

Hoffman M, Monroe DM 3rd, 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 Coagul Fibrinolysis. 1998 Mar;9 Suppl 1:S61-5. (1998) Abstract

Monroe DM, Hoffman M, Oliver JA, Roberts HR. Platelet activity of high-dose factor VIIa is independent of tissue factor. Br J Haematol. 1997 Dec;99(3):542-7. (1997) Abstract

Roubey RA, Hoffman M. From antiphospholipid syndrome to antibody-mediated thrombosis. Lancet. 1997 Nov 22;350(9090):1491-3. (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 Sang. 1991;60(3):184-7. (1991) Abstract

Hoffman M, Fuchs HE, Pizzo SV. The macrophage-mediated regulation of hepatocyte synthesis of antithrombin III and alpha 1-proteinase inhibitor. Thromb Res. 1986 Mar 1;41(5):707-15. (1986) Abstract