Since the prospective controlled trial that demonstrated the importance of anticoagulant therapy in the treatment of patients with pulmonary embolism (PE) was published in 1960,1 there has been a steady advance in our management of patients with venous thromboembolism (VTE). Early clinical studies investigating the role of thrombolysis, initially using urokinase and streptokinase, appeared in the 1970s. Low-molecular-weight heparins (LMWHs) were first studied as therapeutic alternatives to unfractionated heparin in patients with VTE in the early 1990s,2 which eventually facilitated studies investigating the treatment of patients with deep vein thrombosis (DVT) at home. The currently available direct oral anticoagulants were first studied as therapeutic options for patients with VTE beginning ∼10 years ago, and these agents are now recommended as the preferred anticoagulants for the treatment of VTE.3
This review series includes 6 articles that address the treatment of patients with venous thromboembolic disease. The topics focus on the treatment of VTE in the adult and pediatric patient populations, management issues of VTE developing in unusual locations and in the setting of thrombophilia, and new targets and antithrombotic therapies that are in development.
“Acute treatment of venous thromboembolism” by Cecilia Becattini and Giancarlo Agnelli
“Long-term treatment of venous thromboembolism” by Clive Kearon and Susan R. Kahn
“Treatment of unusual thrombotic manifestations” by Maria Abbattista, Marco Capecchi, and Ida Martinelli
“Treatment of venous thromboembolism in pediatric patients” by Char Witmer and Leslie Raffini
“Managing thromboembolic risk in patients with hereditary and acquired thrombophilias” by Jason Moran and Kenneth A. Bauer
“Novel antithrombotic strategies for treatment of venous thromboembolism” by Jeffrey I. Weitz and Noel C. Chan
Becattini and Agnelli open the series with a discussion of the early management of patients presenting with an acute VTE. All patients with VTE should be started on anticoagulant therapy as soon as possible, in the absence of an absolute contraindication. For patients with an absolute contraindication to anticoagulation, an inferior vena cava filter may reduce the risk of PE until anticoagulant therapy can be initiated. Patients with an acute PE and hemodynamic instability should be considered for reperfusion with fibrinolytic therapy. For patients with acute DVT, catheter-directed thrombolysis may be considered if patients have limb-threatening disease, although the majority of patients with DVT are effectively treated with anticoagulant therapy alone. The direct oral anticoagulants are the treatment of choice for most patients with VTE, although certain patients may benefit from therapy with a vitamin K antagonist or LMWH. Most patients with DVT as well as selected patients with PE who are hemodynamically stable can be safely treated in the outpatient setting.
Kearon and Kahn then address the issue of long-term treatment of VTE. Patients with VTE provoked by a reversible risk factor (eg, following major surgery) should be treated with anticoagulant therapy for 3 months, after which it can be discontinued. In contrast, patients with VTE provoked by a chronic or progressive risk factor and those with unprovoked proximal DVT or PE, especially if recurrent, should be considered for indefinite anticoagulant therapy. The choice of anticoagulant therapy for patients who will be treated indefinitely should take into consideration whether or not the patient has cancer, has renal insufficiency, or is taking medications that may strongly inhibit or induce the CYP 3A4 pathway. As many as 20% to 50% of patients with DVT may develop postthrombotic syndrome, which may be severe in 5% to 10%. Elastic compression stockings may benefit patients with persistent leg swelling, but are not recommended for routine use in all patients with DVT. Long-term complications related to PE may occur in ∼25% of patients, with chronic thromboembolic pulmonary hypertension developing in ∼3% of patients within 2 years of a symptomatic PE.
Although the majority of patients with VTE present with PE and/or DVT affecting the lower extremities, as many as 10% of all thrombotic events may occur in other vascular beds. These unusual thrombotic manifestations, which include cerebral sinus venous thrombosis, splanchnic vein thrombosis, and upper extremity thrombosis, among others, are discussed in the review by Abbattista, Capecchi, and Martinelli. Thrombotic events at certain sites may be associated with specific clinical conditions, such as splanchnic vein thrombosis, in patients with myeloproliferative syndromes or paroxysmal nocturnal hemoglobinuria. In contrast, retinal vein thrombosis is frequently associated with systemic risk factors for arterial rather than venous thrombosis (eg, arterial hypertension, hyperlipidemia, or diabetes). Anticoagulant therapy is recommended for most patients with these uncommon thrombotic events, with the exception of retinal vein thrombosis complicated by macular edema, which is treated with intravitreal antivascular endothelial growth factors. For those patients treated with anticoagulant therapy, there are few studies to help guide optimal management, including duration of therapy.
Witmer and Raffini address the treatment of VTE in pediatric patients. These patients represent a highly heterogeneous population that varies in age, thrombosis location, and associated comorbidities. Unique aspects of pediatric VTE include the impact of developmental hemostasis and the major role of central venous access devices, particularly in neonatal patients. Unfortunately, limited data are available to guide treatment of VTE in pediatric patients, resulting in recommendations that are frequently extrapolated from clinical trials with adult patients and expert opinion. Prospective studies investigating the role of direct oral anticoagulants in pediatric VTE are beginning to appear in the literature, however, which will lead to changes in the management of these patients.4,5 Thrombotic complications may also occur in unusual locations, as observed in the adult population, and efforts to study these rare subgroups will require international collaborative registries.
Moran and Bauer review the management of thromboembolic risk in patients with documented hereditary and acquired thrombophilias. For the majority of patients with VTE, the presence, or absence, of transient provoking risk factors is more important for assessing an individual patient’s risk for recurrent events than the presence of an inherited thrombophilia. Although efforts have been made to decrease inappropriate thrombophilia testing by physicians,6 patients are able to independently obtain thrombophilia test results through commercially available genetic screening platforms. Through several case scenarios, the authors illustrate the nuances of how thrombophilia test results may impact clinical management of individual patients. For example, the presence of antiphospholipid antibodies, particularly if multiple types of antibodies are detected, identifies a subset of individuals with VTE who manifest an increased risk for recurrent events7 and for whom warfarin would be the preferred anticoagulant over the direct oral anticoagulant rivaroxaban.8
Although the introduction of the direct oral anticoagulants has transformed the management of patients with VTE, hemorrhagic complications still occur, particularly in patients with cancer-associated VTE, and a subset of patients develop long-term complications following DVT or PE, as noted above. Weitz and Chan close this series by looking into the future, with a discussion of novel antithrombotic strategies for the prevention and treatment of VTE. Focus has recently shifted toward factors XI and XII as targets for anticoagulant therapy, given the evidence that suggests that these upstream factors are involved in thrombus stabilization and growth, but are less important for hemostasis. Approaches to inhibit factor XI include the use of antisense oligonucleotides, monoclonal antibodies, aptamers, and small molecule inhibitors. An approach to the treatment of acute PE that involves enhancing endogenous fibrinolysis may be achieved with inhibitors that target thrombin-activatable fibrinolysis inhibitor or α2-antiplasmin. Disrupting the interaction between leukocytes and endothelial cell surfaces may decrease prothrombotic and inflammatory responses associated with the development of PTS.
This review series summarizes recent advances in the treatment of VTE, identifies areas where additional research is needed, and provides a guide to developments that may appear in the near future.