Recent Pathophysiological Insights Are Advancing the Treatment of Venous Thromboembolism

Abstract

Venous thromboembolism, defined as deep vein thrombosis and pulmonary embolism, is the third leading cause of cardiovascular deaths globally. Long-term complications of unresolved venous thrombi include post-thrombotic syndrome in the legs and chronic thromboembolic pulmonary hypertension. As the venous thrombus ages, the acute, fibrin, and red blood cell-rich composition changes to a chronic cellular, fibrotic mass that does not respond to presently available therapeutic approaches. Standard anticoagulation treatment does not fully prevent recurrent thrombosis and may cause serious bleeding. Thrombolytic therapy may resolve thrombi but it has unacceptable bleeding risks. Recent drug discovery for acute venous thromboembolism has focused on novel targets that may provide enhanced safety and efficacy. Additional therapeutic strategies have focused on the transition phase of acute-to-chronic venous thromboembolism with anti-inflammatory agents, statins, and vasodilator drugs. In this review, we discuss the mechanisms of venous thrombus aging, its clinical implications, and the latest developments in pharmacotherapeutic approaches for venous thromboembolism.

Keywords: CTEPH; Factor XI; PTS; fibrinolysis inhibitors; thrombus composition; venous thromboembolism; venous thrombosis.

Graphical abstract

Figure 1

Natural History of Venous Thromboembolism The diagram represents the current understanding of the mechanisms of the acute-to-chronic transition of venous thrombi. (A) Acute fibrin and red blood cell (RBC)–rich thrombi (B) propagate and (C) remodel to collagen-rich fibrotic thrombi with cellular infiltration (smooth muscle cells, fibroblasts, endothelial cells, and macrophages) that are (D) increasingly fibrotic with the formation of neovascular channels. Accumulation of cellular and fibrous tissue in the venous wall and within the thrombus leads to venous wall stiffness, reduced blood flow, and hypertension. Anticoagulation therapy prevents thrombus propagation (B), but it is unclear if affects remodeling (C) or fibrosis (D). Thrombolytic therapy (E) prevents thrombus propagation and (F) dissolves existing thrombi leading to resolution which appears to reduce remodeling (C) and fibrosis (D). Still, limited clinical data is available for the effectiveness of these approaches for chronic complications of VTE. Parts of the figure were drawn by using pictures from Servier Medical Art (https://creativecommons.org/Licenses/by/3.0/).

Figure 2

Clinical and Preclinical Evidence of Acute and Chronic Venous Thromboembolism The figure shows clinical and preclinical evidence of acute-to-chronic transition of venous thrombi. (A and B) Stained sections of lungs after 4 hours of experimentally induced pulmonary embolism in mice. (A) FITC-fibrin labeled (green) plasma clots in lungs (with DAPI stained nuclei) and its magnified image. (B) Martius Scarlet Blue stained fibrin (red) clot in the lungs. (C and D) Acute-to-chronic IVC thrombi in mice. (C) The thrombi harvested after IVC ligation in mice at different time points, i.e., 1 day (acute), 7 days (subacute or early chronic), and 14 days (chronic), which turn from red to white over time. (D) Immunostained (type IV collagen, red color) sections of IVC thrombi represent fibrosis from acute (minimum collagen) to subacute and chronic stages (increasing collagen), (Guy Reed’s laboratory, unpublished data, December 15, 2017). (E) Red clots removed from the pulmonary artery of a patient by thrombectomy, an example of an acutely formed extensive venous thrombus. The image is reused with permission under a Creative Commons license (https://creativecommons.org/Licenses/by/4.0/) and public domain dedication waiver ((http://creativecommons.org/publicdomain/zero/1.0/). (F) The image shows chronic fibrous thrombi from a patient removed by pulmonary endarterectomy; reused in modified form (cropped) from a case study under a Creative Commons license (https://creativecommons.org/Licenses/by/4.0/).

Figure 3

Timeline for the U.S. FDA-Approved Anticoagulants and Thrombolytics (A) The light green boxes represent the timeline for U.S. Food and Drug Administration (FDA) approval of direct oral anticoagulants (DOACs), and the red box (within the light green box) represents the timeline for the promising agents in clinical trials internationally specifically for venous thromboembolism. The DOACs timeline represents the approval year for specific brand names such as dabigatran (a thrombin inhibitor, Pradaxa, Boehringer Ingelheim Pharmaceuticals), and the inhibitors of factor X including Rivaroxaban (Xarelto, Janssen Pharmaceuticals, Inc), Apixaban (Eliquis, Bristol-Myers Squibb and Pfizer, Inc) and Edoxaban (Savaysa, Daiichi Sankyo Inc) specifically for VTE (e.g., based on the results of clinical trials in hip or knee arthroplasty patients or acutely ill medical patients). Factor XI inhibition is a novel anticoagulation strategy in advanced clinical trials (B) Thrombolytic agents including streptokinase, urokinase, and r-tPA were first approved by the FDA several decades ago. r-tPA remains the preferred thrombolytic agent for clinical use in VTE management. The limited use of streptokinase, a thrombolytic agent of bacterial origin, is still reported in developing countries. Monoclonal antibodies inhibiting the antifibrinolytic function of alpha2-antiplasmin (α2AP) are currently in phase 2 trials for submassive acute pulmonary embolism and proximal deep vein thrombosis patients.

Central Illustration

Emerging Therapeutic Approaches for Venous Thromboembolism Emerging therapeutic approaches (white boxes) in anticoagulation and thrombolytics are inhibitors of factor XI and antagonists of fibrinolysis inhibitors respectively. Additional therapeutic approaches include statins, micronized purified flavonoid fraction (MPFF), and the use of pulmonary artery hypertension drugs for chronic thromboembolic pulmonary hypertension (CTEPH). The list contains the promising approaches in clinical trials for different conditions of venous thromboembolism (VTE). DVT = deep vein thrombosis; PAH = pulmonary artery hypertension; PE = pulmonary embolism; PTS = post-thrombotic syndrome.