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Home > Medical Professionals > Research > Index > Inflammation and Thrombosis a 30-Year Perspective Schaub

Inflammation and Thrombosis - A 30-Year Perspective 

Robert G. Schaub
Cardiovascular and Metabolic Diseases Research,
Wyeth Research, Cambridge, MA

In 1974, Stewart and colleagues reported that surgical exposure of canine jugular veins, combined with transient occlusion resulted in a massive sticking and emigration of leukocytes (1).  This observation led Stewart to hypothesize that leukocytes have a significant role in the initiation and propagation of venous thrombosis.  She suggested that surgery produced a variety of inflammatory and vasoactive factors that produced increased venous permeability, generation of local chemotactic factors, local accumulation of leukocytes, leukocyte derived protease mediated endothelial injury, basement membrane exposure and subsequent thrombosis.  Research in her laboratory and that of others evaluated leukocyte adhesion and thrombosis as a result of various levels of surgical severity, infusion of vasoactive agents, changes in venous permeability and veno-dilation (2-7).

The effect of reducing leukocyte activation through leukocyte cytoskeleton disruption (lidocaine and lidocaine mimetics) or inhibition of arachidonic acid derived mediators of inflammation (lipoxygenase inhibition) was also studied. Both approaches were shown to be effective in reducing leukocyte accumulation associated with surgical trauma and stasis (8,9).  The use of lidocaine for DVT prevention was even evaluated in a small clinical trial in elective total hip surgery.  Infusion of lidocaine for the first 6 post-operative days reduced the incidence of DVT from 78% in 14 control patients compared to 6 calf vein thrombi in 28 lidocaine treated patients.  After lidocaine was stopped on Day 6 the incidence of DVT increased to 53% with a 21% incidence of thigh vein thrombi between Days 7-14 suggesting the inflammatory response was long-lasting (10).

The culture of human endothelial cells reported in the 1970’s, followed a decade later by the discovery of specific adhesion molecules that were expressed on normal, activated and diseased endothelium resulted in a focus on the endothelium as an active component of the thrombotic process (11,12).  By the 1990’s a family of adhesion molecules known as selectins and their ligands were identified and a large number of coagulation, inflammatory and vasoactive substances were identified that induced selectin expression and leukocyte adhesion  (13).  P-selectin is particularly important because it is stored in platelet granules and in endothelial cell Weibel-Palade bodies and can be rapidly translocated to the cell surface after stimulation with agonists similar to those studied by Stewart and colleagues (13).  This up regulation of P-selectin results in an immediate increase in leukocyte rolling on the activated endothelium, increased binding of activated platelets to leukocytes, activation of the bound cells and generation of amplification pathways for inflammation and thrombosis (13).  Of greater interest, is the recent observation that soluble P-selectin or P-selectin mediated binding of platelets to neutrophils and monocytes can promote surface tissue factor expression and release of PSGL-1 positive tissue factor rich micro particles.  These micro particles can promote clot initiation and propagation by localizing to vascular surfaces expressing P-selectin on endothelial cell surfaces or on the surface of adherent platelets.

These observations suggest that targeting inhibition of the P-selectin/P-selectin ligand  (PSGL-1) interaction may be an approach to reduce the leukocyte component associated with development of deep vein thrombosis.  In rat models of DVT the inhibition of P-selectin reduced the leukocyte infiltrate related to venous thrombosis and subsequent vein wall fibrosis, while in murine models of stasis induced DVT, the P/E and the P knock-out mice had the most effective limitation of inflammation after venous thrombosis (14,15).  Most importantly, in a baboon stasis model of inferior vena cava thrombosis, either an antibody to P-selectin or a soluble form of the P-selectin ligand PSGL-1, known as rPSGL-Ig and acting as a competitive inhibitor, significantly decreased thrombosis. (16-18).  Subsequent studies have demonstrated a significant benefit in venous thrombosis treatment in the baboon model suggesting that inhibition of the leukocytes can, without anticoagulation, influence the dissolution of a formed clot days after formation.  More importantly, treatment resulted in an improved vein valve function at 3 months after treatment (19).  Of interest is the fact that in many of these studies the number of infiltrating leukocytes into the vessel wall were not decreased, suggesting some separation between reduced thrombosis by selectin inhibition and the influx of leukocytes into the vessel wall.

Taken together, these data support a major role for leukocytes in the pathology of venous thrombosis and its sequelae.  The up regulation of P-selectin on the endothelial cell surface by factors induced by surgical intervention or trauma provide for the initial interaction between the leukocyte and the vessel wall.   The subsequent leukocyte activation and accumulation are an important part of the developing thrombus and venous injury that results from venous thrombosis.  The inhibition of the P-selectin/PSGL-1 interaction may have an important role in reducing incidence and severity of venous thrombosis.

References

1. Stewart GJ, Ritchie WG, Lynch PR.  Venous endothelial damage produced by massive sticking and emigration of leukocytes.  Am J Path 74:507-532, 1974.

2. Schaub RG, Lynch PR, Stewart GJ.  The response of canine veins to three type of abdominal surgery: a scanning and transmission electron microscopic study.  Surgery 83:411-424, 1978.

3. Stewart GJ, Stern HR, Schaub RG.  Endothelial alterations, deposition of blood elements and increased accumulation of  131I-albumin in canine jugular veins following abdominal surgery.  Thromb Res 12:555-563, 1978.

4. Stewart GJ, Schaub RG, Niewiarowski S.  Products of tissue injury.  Their induction of venous endothelial damage and blood cell adhesion in the dog.  Arch Path Lab Med 104:409-413, 1980.

5. Stewart GJ, Stern HS, Lynch PR, Malmud LS, Schaub RG.  Responses of canine jugular veins and carotid arteries to hysterectomy: increased permeability and leukocyte adhesion and invasion.  Thromb Res 20:473-489, 1980.

6. Stewart GJ, Alburger PD Jr, Stone EA, Soszka TW.  Total hip replacement induces injury to remote veins in a canine model.  J Bone and Joint Surg 65:97-102, 1983.

7. Schaub RG, Simmons CA, Koets MH, Romano PJ, Stewart GJ.  Early events in the formation of a venous thrombus following local trauma and stasis.  Lab Invest 51:218-224, 1984.

8. Stewart GJ, Knight LC, Arbogast BW, Stern HS.  Inhibition of leukocyte locomotion by tocainide, a primary amine analog of lidocaine: a study with 111-indium-labelled leukocytes and scanning electron microscopy.  Lab Invest 42:302-309, 1980.

9. Schaub RG and Yamashita A.  Leukocyte mediated vein injury and thrombosis is reduced by a lipoxygenase inhibitor.  Exp Mol Pathol 45:343-353, 1986.

10. Cooke ED, Bowcock SA, Lloyd MJ, Pilcher MF.  Intravenous lignocaine in prevention of deep venous thrombosis after elective hip surgery.  Lancet 2:797-799, 1977.

11. Gimbrone MA, Cotran RS, Folkman J.  Human vascular endothelial cells in culture.  Growth and DNA synthesis.  J Cell Biol 60:673-694, 1974.

12. Bevilacqua MP, Pober JS, Mendrick DL, Cotran RS, Gimbrone MA.  Identification of an inducible endothelial-leukocyte adhesion molecule.  PNAS USA 84:9238-9242, 1987.

13. McEver RP.  P-selectin and PSGL-1: Exploiting connections between inflammation and venous thrombosis.  Thromb Haemost 87:364-365, 2002.

14. Wakefield TW, Strieter RM, Downing LJ, Kadell AM, Wilke CA, Burdick MD, Wrobleski SK, Phillips L, Paulson JC, Anderson DC. Greenfield L.  P selectin and TNF inhibition reduce venous thrombosis inflammation J Surg Res 64:26-31, 1996

15. Myers DD, Henki PK, Wrobleski SK, Hawley AE, Farris DM, Chapman AM, Knipp BS, Thanaporn P, Schaub RG, Greenfield LJ, Wakefield TW.  P-selectin inhibition enhances thrombus resolution and decreases vein wall fibrosis in a rat model.  J Vasc Surg 36:928-938, 2002.

16. Downing LJ, Wakefield TW, Strieter RM, Prince MR, Londy FJ, Fowlkes JB, Hulin MS, Kadell AM, Wilke CA, Brown SL, Wrobleski SK, Burdick MD, Anderson DC, Greenfield LJ.   Anti-p-selectin antibody decreases inflammation and thrombus formation in venous thrombosis.  J Vasc Surg 25:816-828, 1997.

17. Wakefield TW, Strieter RM, Schaub RG, Myers DD, Prince MR, Wrobleski SK, Long FJ, Kadell AM, Brown SL, Henki PK, Greenfield LJ.  Venous thrombosis prophylaxis by inflammatory inhibition without anticoagulation therapy.  J Vasc Surg 31:309-324, 2000.

18. Myers DD Jr, Schaub R, Wrobleski SK, Londy FJ, Fex BA, Chapman AM, Greenfield LJ, Wakefield TW.  P-selectin antagonism causes dose-dependent venous thrombosis inhibition.  Thromb Haemost 85:423-429, 2001.

19. Myers D, Wrobleski S, Londy F, Fex B, Hawley A, Schaub R, Greenfield L, Wakefield T.  New and effective treatment of experimentally induced venous thrombosis with anti-inflammatory rPSGL-Ig.  Thromb Haemost 87:374-382, 2002.