An activated factor VII variant with enhanced tissue factor-independent activity speeds wound healing in a mouse hemophilia B model.

Loading...
Thumbnail Image

Date

2016-06

Journal Title

Journal ISSN

Volume Title

Repository Usage Stats

100
views
222
downloads

Citation Stats

Abstract

UNLABELLED: Essentials Disorders of hemostasis can lead to delayed and defective wound healing. In hemophilia B (HB) mice, 7 days of Factor (F)IX or VIIa are needed to normalize wound healing. One dose of a highly active FVIIa variant (DVQ) restored normal wound closure time in HB mice. Coagulation factors with enhanced activity may acquire biological effects not due to hemostasis. SUMMARY: Introduction We have previously reported that hemophilia B (HB) mice have delayed healing of cutaneous wounds and alterations in wound histology. Administration of a single dose of either factor IX or recombinant activated FVII (rFVIIa) (NovoSeven) prior to wounding did not improve wound closure time or histology. The FVIIa analog DVQ (V158D, E296V and M298Q mutations) was designed to have higher tissue factor-independent activity than rVIIa. We hypothesized that a single dose of DVQ would be more effective in restoring wound healing in HB mice. Methods Cutaneous punch wounds were made on the backs of HB and wild-type mice, and the time to wound closure was monitored. HB mice were treated with a dose of rFVIIa (10 mg kg(-1) ) or DVQ (1 mg kg(-1) ) that corrected the tail bleeding time. Skin samples were taken at various time points after wounding, fixed, and stained, and the histology was examined. Results As previously reported, wound closure times in HB mice given one dose of rFVIIa were not improved over those in untreated HB mice. Surprisingly, healing times in HB mice treated with an equally hemostatic dose of DVQ were normalized to that in wild-type mice. However, DVQ did not correct all histologic abnormalities in HB mice. Conclusions As the doses of DVQ and rFVIIa were chosen to support comparable levels of hemostasis, our data suggest that the improved healing seen with DVQ is not solely attributable to its hemostatic activity. It is possible that the improved wound healing arises through the effect of DVQ on cell signaling mechanisms.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1111/jth.13311

Publication Info

Hoffman, M, J-Y Chang, M Ezban and DM Monroe (2016). An activated factor VII variant with enhanced tissue factor-independent activity speeds wound healing in a mouse hemophilia B model. J Thromb Haemost, 14(6). pp. 1249–1254. 10.1111/jth.13311 Retrieved from https://hdl.handle.net/10161/15926.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.

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.


Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.