Research Summary

The focus of the Henke laboratory is to determine the basic mechanisms of deep vein thrombosis resolution as well as the effect of the vein wall. The clinical relevance of this is that DVT is a major, and until recently, neglected health problem. The acute sequlae may be pulmonary embolism which can be fatal and more commonly, post thrombotic syndrome with its significant morbidity. Using state of the art physiological, immunological and molecular biological techniques, mouse and rat models are used to define the process of venous thrombus resolution. Over the last 5 years, much has been learned. First, the thrombus is biologically active with leukocytes directing the adjacent vein wall response. Secondly, the thrombi undergo neovascularization as a normal process to allow return of prograde blood flow. Third, the leukocyte is essential for thrombus resolution, and is directed by a class of signaling molecules termed chemokines. More specifically, neutrophils are essential for early DVT resolution while monocytes are critical for the later processes. Forth, matrix metalloproteinases play an integral role in both vein wall injury and remodeling as well as DVT resolution. Our current National Institutes of Health R-01 grant specifically applies to this. Lastly, the mechanism of how a thrombus forms directs the vein wall response. For example, stasis derived DVT is more damaging to the vein wall than endothelial injury or an inert stretch injury. This latter data is clinically applicable because it suggests that methods to actively remove thrombus in a timely fashion, rather than passive anticoagulation, may decrease the long term risk of fibrotic injury.

Relevant References

1. Varma M, Varga AJ, Knipp BS, Sukheepod P, Upchurch GR, Kunkel SL, Wakefield TW, Henke PK. Neutropenia impairs venous thrombosis resolution in the rat. J Vasc Surg 2003;38:1090-8.
2. Henke PK, Varga A, De S, Arenberg DA, Sukheepod P, Thanaporn P, Kunkel SL, Upchurch GR Jr., Wakefield TW. Deep vein thrombosis resolution is dependent on CXCR2 but not neutrophil mediated activity in a mouse model. Aterioscler Thromb Vasc Biol 2004;24:1130-1137.
3. Varma M, Moaveni DM, Dewyer NA, Varga AJ, Deatrick KB, Kunkel SL, Upchurch GR, Wakefield TW, Henke PK. Deep vein thrombosis resolution is not accelerated with increased neovascularization. J Vasc Surg 2004;40:536-42
4. Henke PK, Varma MR, Deatrick KB, Lynch EM, Moore AJ, Dubay DA, Sukheepod P, Pearce CG, Dewyer NA, Upchurch GR, Kunkel SL, Franz MG, Wakefield TW. Neutrophils modulate post- thrombotic vein wall fibrosis but not thrombus neovascularization. Thromb Haemost 2006;95:272-81.
5. Henke PK, Pearce CG, Moaveni DM, Moore AJ, Lynch EM, Longo CM, Varma M, Dewyer NA, Deatrick KB, Upchurch, Jr. GR,Wakefield TW, Hogaboam C, Kunkel SL. Targeted deletion of CCR2 impairs DVT resolution in a mouse model. J Immunol 2006;177:3388-97.
6. Myers DD, Henke PK, Bedard PW, Wrobleski SK, Kaila N, Shaw G, Meier TR, Hawley AE, Schaub RG, Wakefield TW. Treatment with an oral small molecule inhibitor of P-selectin (PSI-697) decreases vein wall injury in a rat stenosis model of venous thrombosis. J Vasc Surg 2006;44:625-32.
7. Thanaporn P, Myers DD, Wrobleski SK, Hawley AE, Farris DM, Wakefield TW, Henke PK. P-selectin inhibition decreases post thrombotic vein wall fibrosis in a rat model. Surgery 2003;134:365-71.
8. Henke PK, Varma MR, Moaveni DK, Dewyer NA, Moore AJ, Lynch EM, Longo C, Deatrick CB, Kunkel SL, Upchurch GR, Wakefield TW. Fibrotic injury after experimental deep vein thrombosis is determined by the mechanism of thrombogenesis. Thromb Haemost 2007 (in press).

Related Websites

• JOBST