Beyond Virchow’s Triad: Does cardiovascular inflammation explain the recurrent nature of venous thromboembolism?

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 endothe-lial 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 the Atherosclerosis Risk In Communities (ARIC) Study, followed for incident DVT or PE over 8.3 years, CRP above the 90th percentile was associated with a 76% increase in the risk of VTE versus lower percentiles. ¹¹ Activation of the innate immunity, marked by increased levels of tumor necrosis factor-α, interleukin-1β, interleukin-6, and interleukin-8, increases the risk of VTE even after adjustment for CRP. ¹² Polymorphisms in genes encoding factor VII, interleukin-1β, and interleukin-10 have been shown to modulate the risk of idiopathic VTE. ¹³ A recent analysis from the Copenhagen City Heart Study and the Copenhagen General Population Study demonstrated that rheumatoid factor in patients without overt autoimmune disease was strongly associated with DVT, even after adjustment for additional variables such as CRP and thrombophilia. ¹⁴

Key components of the systemic inflammatory response, platelets and neutrophils, have been shown to play a mechanistic role in the pathophysiology of VTE. Staining of human acute PE specimens for CD42b, a platelet surface membrane glycoprotein, has demonstrated a high concentration of platelets in venous thrombus. ¹⁵ This observation challenges a long-held belief that platelets play little role in the pathogenesis of VTE.

In the animal model, neutrophils play an important role in the pathophysiology of venous thrombosis. Neutrophil extracellular traps (NETs) consist of released nuclear DNA containing histones and neutrophil granular proteins, such as elastase, myeloperoxidase, and cathepsin G. In sepsis, NETs serve a critical role in the host immune response by trapping circulating bacteria. NETs also provide a scaffolding for thrombus formation by binding circulating erythrocytes and platelets. Recent data confirming the presence of neutrophils and NETs in the organizing stage of human venous thrombus further highlight the importance of inflammation to the development of VTE. ¹⁵

Based on the growing body of literature supporting inflammation as a key component to the pathogenesis of VTE, anti-inflammatory therapies may play a vital role in prevention of recurrent VTE. In two randomized placebo-controlled trials, the Aspirin for Prevention of Recurrent Venous Thromboembolism (the Warfarin and Aspirin [WARFASA]) study ¹⁶ and the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) trial, ¹⁷ extended-duration low-dose aspirin (100 mg daily) was evaluated for prevention of recurrent DVT and PE in patients with initial unprovoked VTE who had completed anticoagulation for the acute treatment phase. A meta-analysis of these trials demonstrated a 35% reduction in the risk of recurrent VTE and a 37% reduction in major vascular events. ¹⁸ Low-dose aspirin resulted in an overall net clinical benefit without any increased risk of major bleeding compared with placebo.

Further evidence for the anti-inflammatory hypothesis for VTE prevention comes from the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial. ¹⁹ JUPITER randomized 17,802 patients without hyperlipidemia but with increased systemic inflammation, defined as a high-sensitivity CRP level of 2.0 mg/L or higher, to rosuvastatin 20 mg daily or placebo. In this primary prevention study, rosuvastatin reduced the risk of symptomatic VTE by 43%.

Two large ongoing randomized controlled trials are designed to assess the impact of anti-inflammatory therapy on prevention of thrombotic events. The Canakinu-mab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) (NCT01327846) is a randomized placebo-controlled trial of a subcutaneously administered human monoclonal antibody to interleukin-1β in 10,000 stable patients following myocardial infarction who have persistent elevation of high-sensitivity CRP. ²⁰ Designed to test the hypothesis that interleukin-1β inhibition will reduce the primary outcome of myocardial infarction, stroke, and cardiovascular death, CANTOS will also specifically evaluate the impact of inflammatory modulation on incident VTE. Patient enrollment for CANTOS has been completed.

The Cardiovascular Inflammation Reduction Trial (CIRT) (NCT01594333) is a randomized placebo-controlled trial of low-dose methotrexate in 7000 patients with either stable myocardial infarction or multivessel coronary artery disease and either type 2 diabetes mellitus or the metabolic syndrome to test the hypothesis that a commonly used anti-inflammatory regimen can prevent atherothrombotic complications of myocardial infarction, stroke, and cardiovascular death. ²¹ CIRT will also assess the impact of anti-inflammatory therapy on incident VTE. Enrollment in CIRT is ongoing.

Positive findings in either of these large randomized controlled trials of anti-inflammatory therapy for prevention of atherothrombosis and VTE will force us to extend our understanding of the pathophysiology of thrombosis beyond Virchow’s Triad and abandon the concept of VTE as a time-limited disease treated with only a few short months of anticoagulation. Rather, we will need to renounce decades of clinical practice and adopt a new paradigm in which VTE is a chronic disease and in which anti-inflammatory therapy is as important as anticoagulation for prevention of recurrent events.