International normalized ratio Response

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2011-01-01

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Scholars@Duke

Hoffman

Maureane Hoffman

Professor of Pathology

The blood coagulation system is a delicately balanced homeostatic mechanism. 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/immunity and coagulation responses to injury.  We are also committed to translating our basic finding into clinical practice.

We have developed a cell-based model of tissue factor-initiated coagulation. This model is a powerful tool for understanding and 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 hemostatic 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) 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 anticoagulant 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 also examined the role of the coagulation process in wound healing. Clinicians have long felt that wound healing is delayed in hemophiliacs. We have now ascertained that hemophilia B 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. This is a result of the 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.

Anticoagulation also impairs wound healing.  Patients are often anti coagulated after surgery to prevent deep vein thrombosis and pulmonary embolism. However, the impact of this therapy on tissue repair is not well understood.  Our aim is to define the extent and time frame of hemostatic function that is needed for optimal healing, thereby setting the stage for scientifically based strategies for anticoagulation.


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