Beyond Virchow's Triad: does cardiovascular inflammation explain the recurrent nature of venous thromboembolism?

Abstract

Venous thromboembolism (VTE) has been traditionally considered a transient acute disorder requiring a limited duration of anticoagulant therapy. Patients who suffer deep vein thrombosis (DVT) or pulmonary embolism (PE) following major surgery, major trauma, or periods of immobility are generally treated with anticoagulation for 3–6 months. After completion of anticoagulation for the initial event, the risk of VTE recurrence is believed to return to that of the general population. However, epidemiological studies suggest that VTE may be better characterized as a chronic disorder with periodic relapses. While patients who suffer unprovoked (idiopathic) VTE bear the highest risk of recurrent events, exceeding 50% over 10 years if not treated with extended duration anticoagulation, those who suffer VTE in the setting of identifiable provoking factors have an enduring risk of recurrence that exceeds 20% over 10 years. 1 Randomized controlled trials of extended duration anticoagulation for prevention of recurrent unprovoked VTE have demonstrated that the rate of recurrence increases abruptly if anticoagulation is discontinued. 2 An analysis of the Danish National Registry of Patients demonstrated that patients with VTE have increased mortality over 30 years of follow-up and that recurrent PE is an important cause of death throughout this period. 3 The efficacy of extended duration anticoagulation for prevention of recurrent events after an initial unprovoked DVT or PE further supports the classification of VTE as a chronic relapsing disease. Prolonged anticoagulation with a low- (international normalized ratio (INR) target 1.5–2.0) 4 or conventional-intensity (INR target 2.0–3.0) 5 or a non-vitamin K-dependent oral anticoagulant such as rivaroxaban, 6 dabigatran, 2 or apixaban 7 provides a 60–90% reduction in recurrent events in patients who suffer an initial unprovoked VTE. Evidence-based practice guidelines recognize the increased risk of recurrence among patients with idiopathic VTE and recommend extended duration anticoagulation in those with a low bleeding risk. Virchow’s Triad of stasis, hypercoagulability, and endothelial dysfunction and injury does not fully explain the increased risk of recurrent VTE and the need for extended duration anticoagulation. Immobility resulting in stasis is only a transient risk factor in the majority of patients with VTE. Although frequently sought as an explanation for VTE, thrombophilia is detected in only a minority of patients. 8 Furthermore, common thrombophilias such as the factor V Leiden and prothrombin gene mutations do not appear to increase the risk of recurrence. 8 Endothelial dysfunction and injury may play an important role in a subset of patients with VTE, but the underlying mechanism leading to recurrence remains unclear. Advances in our understanding of the pathophysiology of atherothrombosis may shed light on critical mechanisms for VTE recurrence. Traditionally, the burden of recurrent atherothrombotic events has been largely ascribed to dyslipidemia. However, even with intensive lipid-lowering therapy for secondary prevention, a significant burden of recurrent atherothrombotic events remains. A growing body of literature suggests that cardiovascular inflammation is a key pathophysiologic factor in recurrent atherothrombotic events. 9,10 Traditionally considered distinct and unrelated disorders, atherothrombosis and VTE are linked both epidemiologically and pathophysiologically. In fact, a reciprocal relationship exists: patients with VTE have an increased risk of myocardial infarction and stroke, and vice versa. Proven cardiovascular risk factors such as obesity, tobacco use, diabetes, stress, and diet increase the risk of atherothrombotic events and VTE. These particular risk factors share a common pathophysiological mechanism of promoting cardiovascular inflammation. In epidemiologic studies, systemic inflammation has been closely associated with an increased risk of VTE. The increased frequency of DVT and PE in patients with chronic inflammatory disorders such as inflammatory bowel disease and systemic vasculitis highlights the role of inflammation in VTE. Furthermore, increased levels of the inflammatory biomarker C-reactive protein (CRP) are associated with an increased risk of VTE. In an analysis of 10,505 participants in