Deep Vein Thrombosis (DVT) Pathophysiology

Prepared by Peter Henke, MD
Corresponding chapter in Handbook of Venous Disorders: Chapter 8

Wakefield TW, Myers DD, Henke PK. Mechanisms of venous thrombosis and resolution. Venous thromboembolism is a significant health care problem in the US. Arterioscler Thromb Vasc Biol 2008;28:387-91.

PMID: 18296594
Comment: This is an up to date and concise summary of experimental venous thrombosis inflammation and resolution.

Henke PK, Varma MR, Moaveni DK, Dewyer NA, Moore AJ, Lynch EM, Longo C, Deatrick CB, Kunkel SL, Upchurch GR Jr, Wakefield TW. Fibrotic injury after experimental deep vein thrombosis is determined by the mechanism of thrombogenesis. Thromb Haemost 2007;98:1045-55.

PMID: 18000610
Comment: This experimental study sheds light on why prolonged thombosis-vein wall contact possibly leads to worse PTS. Fibrosis and inflammation are increased, but this is not dependent on DVT size or mechanical stretch.

Henke PK, Pearce CG, Moaveni DM, Moore AJ, Lynch EM, LongoC, Varma M, Dewyer NA, Deatrick KB, Upchurch GR Jr, Wakefield TW, Hogaboam C, Kunkel SL. Targeted deletion of CCR2 impairs deep vein thrombosis resolution in a mouse model. J Immunol 2006;177:3388-97.

PMID: 16920980
Comment: This experimental report highlights the role of chemokines, monocytes, and MMP's in DVT resolution.

Singh I, Burnand KG, Collins M, Luttun A, Collen D, Boelhouwer B, Smith A. Failure of thrombus to resolve in urokinase-type plasminogen activator gene-knockout mice: rescue by normal bone marrow-derived cells. Circulation 2003;107:869-75.

PMID: 12591758
Comment: This experimental study showed the importance of uPA in DVT resolution, and that this effect is later in the time course and cell dependent.

Humphries J, Gossage JA, Modarai B, Burnand KG, Sisson TH, Murdoch C, Smith A. Monocyte urokinase-type plasminogen activator up-regulation reduces thrombus size in a model of venous thrombosis. J Vasc Surg 2009;50:1127-34.

PMID: 19703758
Comment: This experimental study shows that transfection with uPA, the plasminogen activator, can accelerate thrombus resolution.

Modarai B, Burnand KG, Sawyer B, Smith A. Endothelial progenitor cells are recruited into resolving venous thrombi. Circulation 2005;111:2645-53.

PMID: 15883207
Comment: This experimental study shows the thrombus is an active cellular tissue, and bone marrow derived progenitor cells partake in the process of resolution.

Wakefield TW, Strieter RM, Wilke CA, Kadell AM, Wrobleski SK, Burdick MD, Schmidt R, Kunkel SL, Greenfield LJ. Venous thrombosis-associated inflammation and attenuation with neutralizing antibodiesto cytokines and adhesion molecules. Arterioscler Thromb Vasc Biol 1995;15:258-68.

PMID: 7749835
Comment: This was the first experimental study to characterize the cytokine based inflammatory process of the DVT resolution.

Esmon CT. Inflammation and thrombosis. J Thromb Haemost 2003;1:1343-8.

PMID: 12871267
Comment: This manuscript defines that thrombosis and inflammation are inter-related. For example, inflammation increases tissue factor, platelet reactivity, fibrinogen, and leads to exposure of increased levels of phosphotidyl serine, while decreasing thrombomodulin and inhibiting fibrinolysis (by increasing PAI-1).

Myers DD, Hawley AE, Farris DM, Wrobleski SK, Thanaporn P, Schaub RG, Wagner DD, Kumar A, Wakefield TW. P-selectin and leukocyte microparticles are associated with venous thrombogenesis. J Vasc Surg 2003;38:1075-89.

PMID: 14603220
Comment: In this manuscript, venous stasis experimentally results in the up-regulation of P-selectin which localizes pro-thrombotic microparticles to the area of stasis and promotes DVT formation.

Hrachovinová I, Cambien B, Hafezi-Moghadam A, KappelmayerJ, Camphausen RT, Widom A, Xia L, Kazazian HH Jr, Schaub RG, McEver RP, WagnerDD. Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A. Nat Med 2003;9:1020-5.

PMID: 12858167
Comment: In this article chimeras of P-selectin and immunoglobulin induce microparticle formation, and how the P-seectin-Ig chimera may be useful in treating hemophelia A.

André P, Hartwell D, Hrachovinová I, Saffaripour S, WagnerDD. Pro-coagulant state resulting from high levels of soluble P-selectin in blood. Proc Natl Acad Sci U S A 2000;97:13835-40.

PMID: 11095738
Comment: In this and the previous manuscripts, it is demonstrated that P-selectin: PSGL-1 interactions stimulate the production of thrombogenic microparticles from leukocytes, particularly monocytes along with platelets and endothelial cells.