Maureane R. Hoffman, MD, PhD

Department / Division:
Pathology / Pathology

Address:
DUMC 3712
Durham, NC 27710

Office Telephone:
919-286-6925

Fax Telephone:
919-286-6818

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

• Pathology, Duke University Medical Center, 1982-1985

• 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 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.

Representative Publications:
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

Roberts HR, Hoffman M, Monroe DM. A cell-based model of thrombin generation. Semin Thromb Hemost. 2006 Apr;32 Suppl 1:32-8. (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

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

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

Caldwell SH, Hoffman M, Lisman T, Macik BG, Northup PG, Reddy KR, Tripodi A, Sanyal AJ. Coagulation disorders and hemostasis in liver disease: Pathophysiology and critical assessment of current management. Hepatology. 2006 Oct;44(4):1039-46. (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

Wolberg AS, Monroe DM, Roberts HR, Hoffman M. Elevated prothrombin results in clots with an altered fiber structure: a possible mechanism of the increased thrombotic risk. Blood. 2003 Apr 15;101(8):3008-13. (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

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

Hoffman M, Loh KL, Bond VK, Palmieri D, Ryan JL, Church FC. Localization of heparin cofactor II in injured human skin: a potential role in wound healing. Exp Mol Pathol. 2003 Oct;75(2):109-18. (2003) Abstract

Monroe DM, Hoffman M. Coagulation factor interaction with platelets. Thromb Haemost. 2002 Aug;88(2):179. (2002) Abstract

Hoffman M, Monroe DM, Roberts HR. Platelet-dependent action of high-dose factor VIIa. Blood. 2002 Jul 1;100(1):364-5; discussion 365. (2002) 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)

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

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

Hoffman M, Monroe DM, Oliver JA, Roberts HR. Factors IXa and Xa play distinct roles in tissue factor-dependent initiation of coagulation. Blood. 1995 Sep 1;86(5):1794-801. (1995) Abstract

Church FC, Hoffman M: Heparin Cofactor II and Thrombin: Heparin-binding proteins linking hemostasis and inflammation. Trends in Cardiovascular Medicine 4(3): 140-146, 1994. (1994)