Pathophysiology of Acute Venous Thrombosis



Pathophysiology of Acute Venous Thrombosis



Daniel D. Myers, Jr., Evelyn M. Shea and Thomas W. Wakefield


Venous thromboembolism (VTE) is a significant national health problem, with approximately 900,000 individuals affected annually. When compared with whites, African Americans have a 40% higher incidence of VTE. Despite improvements in prophylaxis and treatment of VTE, the incidence of this disease has not changed significantly over the past 25 years. Deep vein thrombosis (DVT) affects around 380,000 patients annually, and pulmonary embolism (PE) is diagnosed yearly in at least 520,000 patients. Treatment costs to the U.S. health care system reach billions of dollars per year just for the acute treatment of venous thrombosis. The national importance of venous thromboembolism to our health care system has been documented in the Surgeon General’s Call to Action to Prevent Deep Venous Thrombosis and Pulmonary Embolism. This Call to Action specifically requested a multiagency approach to developing evidence-based practice guidelines to combat this disease.



Risk Factors for Acute Venous Thromboembolism


The factors that could lead to or interact with one another to lead to VTE include blood stasis, endothelial injury, and blood hypercoagulability. Of these three factors, vein wall endothelial injury triggers a local inflammatory response, which promotes a prothrombotic state driven by tissue factor, adhesion molecules, hemostatic factors, and proinflammatory cytokines that support acute VTE. In 1974, it was first hypothesized that vascular inflammation and thrombosis are interrelated. The original hypothesis suggested that prothrombotic factors lead to the activation of leukocytes and platelets. This process promotes thrombus amplification via adherence and layering of the activated platelets and leukocytes. Risk factors for acute VTE include increasing age, pregnancy, prolonged periods of immobility, estrogen therapy, surgery and trauma, malignancies, hypercoagulable states, cardiovascular disease (myocardial infarction, congestive heart failure), inflammatory diseases, obesity, and for VTE recurrence male gender (Figure 1).


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FIGURE 1 Risk factors for acute venous thromboembolism as it relates to Virchow’s triad.

The aging process is an important common denominator in the development of VTE. The incidence of DVT is 2 to 7 times higher in those older than 55 years as compared to younger age groups, and the incidence increases 74% per decade of age over 45 years. With aging, the anatomy of the venous vessel wall is adversely modified. Thickening of venous valve cusps caused by increases in valve collagen and intimal thickening with age has been documented.



Pathophysiology of Acute Venous Thromboembolism


The vascular inflammatory response is initially protective by nature; its role is to promote the recruitment of inflammatory cells for the removal of microorganisms and endotoxins. However, local and systemic inflammation can produce a prothrombotic environment driven by platelet activation, tissue factor, prothrombotic microparticles (MPs), adhesion molecules, hemostatic factors, and proinflammatory cytokines.



Selectins


Inflammation and thrombosis have been shown to interact and share common mechanisms. P-selectin and E-selectin are cell adhesion molecules with critical roles in thrombogenesis, as shown in numerous animal studies. Investigations using rat and mouse thrombosis models demonstrated up-regulation of P-selectin and E-selectin in the vein wall 6 hours and 6 days after thrombus induction, respectively. The increase in the number of P-selectin molecules present on the endothelial cell surface is caused by their release from the Weibel–Palade body (WPB). WPBs are the endothelial-specific storage organelles for regulated secretion of von Willebrand factor (vWF) and P-selectin onto the endothelial cell membrane. Thus the exocytosis of WPBs initiates a rapid translocation of P-selectin to the endothelial surface, resulting in augmented endothelial binding of leukocytes and platelets.


The therapeutic benefits of P-selectin inhibition of acute venous thrombosis has been well documented. Using rodent and nonhuman primate animal models, the relationship between selectins and thrombosis has been defined. In animal models, P-selectin inhibition, with either an antibody, small molecule inhibitor, or aptamer administered prophylactically or after DVT, significantly decreased thrombogenesis, decreased vein wall fibrosis, and increased venous thrombus resolution in these animal models.


Previous studies have demonstrated the beneficial effects of combined P- and E-selectin inhibition in decreasing DVT in a mouse model of stasis thrombosis. E-selectin is expressed on activated vascular endothelium; the receptor for E-selectin is E-selectin ligand-1 (ESL-1) in the mouse. Published work shows that mice gene-deleted for both E- and P-selectin had significantly smaller venous thrombi versus control animals in a stasis model of VT. Mice lacking the E-selectin gene had the lowest thrombus burden, evaluated 2 and 6 days after thrombosis.


In a pilot study, a continuous dosing strategy was used to give mice a consistent level of a novel Pan-selectin inhibitor that primarily targets E-selectin. A significant decrease in both thrombus burden and soluble E-selectin activity in mice 2 and 6 days after venous thrombosis versus saline controls in a flow electrolytic inferior vena cava model (EIM) was noted. This suggested that targeting E-selectin could be an effective therapeutic strategy to modulate venous thrombosis.

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Aug 25, 2016 | Posted by in CARDIOLOGY | Comments Off on Pathophysiology of Acute Venous Thrombosis

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