Inflammation And Venous Thrombosis


Venous thromboembolic disease represents an ideal opportunity for advancing our understanding of inflammation within the vascular system. A great deal of progress has been made in the interdependent fields of selectin, micropar-ticle, phospholipid, and platelet biology in recent years. Much of this knowledge has been acquired through the utilization of models of venous thrombosis and the compilation of data from patients with deep vein thrombosis. Present therapy directed at venous thromboembolic disease (VTE) relies on anticoagulation strategies with their associated risk of severe bleeding complications. Our work is directed toward developing and testing new, targeted therapies for VTE that will be safer and more effective. These therapies will exploit new knowledge of the inflammatory mechanisms leading to venous thrombosis.


Deep vein thrombosis (DVT) and its acute and chronic sequelae are a significant source of morbidity, mortality, and cost to the American public. American Heart Association statistics document two million cases of DVT each year with the incidence of DVT increasing as the population ages.1 Pulmonary embolus (PE) accounts for 200,000 deaths each year, and the annual cost of the treatment of VTE is measured in billions of dollars.2 We have found that VTE is noted in one percent of all medicare inpatient discharges.3

Chronic venous insufficiency (CVI) is a late complication of DVT suffered by nearly seven million Americans. The

20-year incidence of CVI is 28% following deep vein thrombosis, although some have suggested the incidence is higher. The symptoms include swelling, discomfort, and skin changes ranging from stasis pigmentation to frank ulceration requiring chronic wound care.4 Chronic thromboembolic pulmonary hypertension (CTPH) has a two-year incidence of 3.8% following PE, leading to severe debilitation and high mortality.5

Anticoagulation is the keystone of contemporary therapy for VTE but carries a significant risk of severe bleeding. Ten percent of patients suffer minor to moderate hemorrhagic complications each year, and the annual incidence of life-threatening hemorrhage is 2%.6,7 The risk of bleeding complications on heparin therapy is dose dependent, with a 7% increase in risk for each 10-second increase in the aPTT value.8 Data from early studies revealed a lower incidence of bleeding complications with low molecular weight heparin versus unfractionated heparin, but recent studies have demonstrated no significant difference.9 The risk of a major bleeding complication in the first three months of treatment with heparin initially followed by coumadin is 3%, with a significantly higher incidence in cancer patients.10 The incidence of major bleeding complications in patients on cou-madin maintained with an INR of 2.0-3.0 is half that of someone maintained with an INR of more than 3.0. Couma-din can be difficult to dose, and variability in the INR is independently associated with an increased frequency of hemorrhage.11

Patients managed with present optimal therapy have a 20% incidence of thrombus extension or recurrence.12 Heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) can complicate both unfractionated and low molecular weight heparin therapy resulting in arterial and venous thrombotic complications.13 Heparin-based therapies also raise valid concerns regarding side effects such as the loss of bone mineral density and alopecia.1415

Systemic thrombolytic therapy has not demonstrated consistent efficacy due to difficulties in patient selection and an unacceptable risk of catastrophic bleeding complications.1617 Catheter-directed thrombolysis in the first week following ileofemoral DVT formation has a lower incidence of bleeding complications and has demonstrated benefit in terms of venous patency and a decreased incidence of CVI.18

The development of new therapies for the treatment of VTE and the prevention of its sequelae will require a more thorough understanding of venous thrombosis, propagation, and resolution. The goals of any new therapy should be a reduction in hemorrhagic complications and increased efficacy.

Inflammation and Thrombosis

In the 1850s, Ludwig Rudolf Karl Virchow postulated what came to be known as Virchow's Triad of risk factors for DVT formation: blood stasis, vessel wall injury, and changes in the constituents of blood (hypercoagulability). A contemporary view still benefits from this framework but is informed by knowledge of genetics and molecular biology. Mammalian physiology strikes a fine balance among coagulation factors, inhibitors of coagulation, and fibrinolytic factors to optimize hemostasis while maintaining fluidity and end-organ oxygen delivery. There are many described perturbations in this balance leading to hemophilic and thrombophilic disorders. These perturbations are discussed in detail in other chapters of this text.

A significant advance from the time of Virchow occurred with the work of Stewart et al. in 1974, who suggested a link between vascular inflammation and thrombosis.19 Stewart's original hypothesis stated that the initiating factors that promote thrombosis cause the activation of leukocytes and platelets. She proposed that this activation leads to the localization of leukocytes and platelets to the area of injury, resulting in amplification of the thrombus. Advances in molecular biology since 1974 have allowed the elucidation of the relationship between inflammatory mediators and pathways with the coagulation cascade. Inflammatory mediators upregulate procoagulant factors and downregulate natural anticoagulants while inhibiting fibrinolysis (see Table 37.1).20 These may be systemic mediators of inflammation such as the pro-inflammatory cytokine TNFa, cytokines released locally from the area of injury such as IL-6 and IL-8, or factors localized within the growing thrombus such as thrombin. Our research has focused on strategies to treat venous thrombosis and prevent vein wall fibrosis via inhibition of selectin signaling.

TABLE 37.1 Impact of Inflammation on Coagulation (Adapted from Esrnon20)


Tissue factor

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