A novel swine model of chronic deep vein thrombosis (DVT) suitable for endovascular device assessment

This is an invited commentary on Parchment et al. ¹⁰ Variation in compressive mechanical properties between subacute and chronic venous thrombosis in a novel unilateral iliac thrombosis model. Vasc Med. 2025; 30: 124-135.

Postthrombotic syndrome (PTS) is a common sequelae of lower-extremity deep vein thrombosis (DVT), producing a range of symptoms and signs including limb pain, edema, hyperpigmentation, venous claudication, and skin ulceration.^1,2 Although compression therapy, weight management, exercise, lifestyle modifications, medications, wound care, and endovascular interventions may mitigate PTS symptoms in some patients, these measures are not curative, and many patients still experience ongoing debilitating symptoms, functional limitations, and suboptimal health-related quality of life.^1,2 Therefore, prevention of PTS is a crucial and desired goal in DVT treatment.

Despite therapeutic anticoagulation, up to 50% of patients with proximal DVT will develop symptomatic PTS, and approximately 5–10% of proximal DVT cases will develop severe PTS that sometimes involves venous ulceration.^1,3 The persistently high prevalence of PTS and lack of medical therapies beyond anticoagulation have motivated efforts to restore vein patency, stated as the ‘open vein hypothesis’ via catheter-directed interventions (CDIs) utilizing thrombolysis and/or thrombectomy.^4,5 However, at present, the current state of CDI remains indicated for selective use in patients with symptomatic acute iliofemoral DVT (IFDVT) and low bleeding risk, given the lack of efficacy for the broader population with less extensive DVT.^4,6,7 Of note, to date, endovascular devices are designed for acute or subacute thrombus recanalization; however, such devices cannot efficiently and safely remove collagen-rich thrombus at the chronic phase that firmly adheres to the adjacent vein wall. Therefore, for patients with a chronic DVT who remain symptomatic due to persistent thrombus obstruction, CDI could help reduce PTS symptoms by restoring vein patency. The ongoing NIH-sponsored randomized trial ‘Chronic Venous Thrombosis: Relief with Adjunctive Catheter-Directed Therapy (C-TRACT)’ is testing this hypothesis. ⁸ Accordingly, there is thus a need to develop new large animal models that will permit evaluation of endovascular devices specifically designed to recanalize chronic DVT. ⁹

To address this unmet need, this issue of Vascular Medicine includes a study by Parchment and colleagues who establish an innovative swine model that reliably and efficiently produces subacute and chronic unilateral iliac DVT. ¹⁰ The new DVT model utilizes a fully endovascular approach and leverages Virchow’s triad (endothelial injury, stasis, and hypercoagulability) in a four-step process. First, the authors occluded large side branches (hypogastric, high profunda veins) identified by venography and intravascular ultrasound using microvascular plugs. Second, animals underwent iliac venous endothelial injury via four pullbacks of a partially deployed/flared 12-mm self-expanding vascular stent, which was then recaptured and removed. Third, an iliac venous pouch was created between proximal and distal iliac vein segments using 11.5-mm diameter occlusive balloon catheters. Fourth, thrombin (400 units in 4 mL) was injected into the pouch via the central lumen of the balloons. After approximately 2 hours, as guided by duplex ultrasound to identify new thrombus, the balloon catheters were deflated and removed. At timepoints from day 0 to day 14, the authors then performed duplex ultrasound and venography, followed by ex vivo histopathological analysis (for erythrocytes, collagen, recanalization channels) and measurement of thrombus biomechanical properties (e.g., stiffness, resistance to deformation, and shearing). To understand how the new DVT model recapitulated human DVT stage, swine DVT specimens were compared with resected human IFDVT specimens at the acute, subacute, or chronic phases. ¹⁰

Duplex ultrasound revealed a 100% success rate of producing unilateral, acute, long-segment iliac DVT in female swine (n = 7) at day 0. ¹⁰ No animals developed main branch pulmonary embolism identified at the day of sacrifice. In this new model, acute DVT showed neither collagen nor chronic inflammatory cells at day 0 (n = 1). Subacute DVT exhibited organizing thrombus and inflammation at the thrombus-wall interface, as well as robust collateral formation on venography at day 7 (n = 3). In contrast, chronic DVT (day 14, n = 3) exhibited greater organization with diffuse myointimal thickening and collagen matrix formation, and fewer red blood cells, but with evident hemosiderin deposition in both the thrombus and vein wall. Chronic thrombi further demonstrated a higher secant modulus (resistance to deformation, 276.0 vs 153.8 kPa) and average shear constant (resistance to shearing, 2.85 vs 1.85 kPa) compared to day 7 subacute thrombi. In comparison to human DVT based on histopathological analysis, swine DVT at days 0, 7, and 14 matched approximately to clinical IFDVT aged 1.5 weeks (acute), 2 months (subacute), and 3 years (chronic), respectively. ¹⁰

Although there were a number of limitations of this study, including small sample size, lack of a demonstration of device-based DVT recanalization, spontaneous vein recanalization of the day-21 DVT animal suggesting a limited time period for future device evaluation, and the absence of PTS signs and symptoms in quadrupedal pigs, the authors are to be commended for validating a new model for chronic DVT. There are several strengths of this work, including: (1) induction of a reproducible unilateral, long-segment, in situ iliac DVT model via fully endovascular procedures, avoiding open surgery and residual foreign material, and applicable to female and male swine; (2) efficient generation of acute, subacute, and chronic DVT within 2 weeks that recapitulates many features of human DVT; (3) development of a chronic DVT preclinical model in clinically relevant veins suitable for evaluating next-generation devices for chronic DVT recanalization; and (4) the applicability of this model to study acute and subacute DVT pathophysiology with respect to development of the PTS (e.g., timing of restoration of blood flow, thrombus persistence, vein wall fibrosis, and valvular reflux).^11,12

Future studies will likely focus on creating a model of more durable chronic DVT (e.g., > 14 days to months) and evaluation of the performance of clinically available devices for recanalizing chronic-equivalent DVT (e.g., day 14 or older). It will be impactful to assess features of currently available DVT devices in this new chronic DVT model, including crossing profile, thrombus extraction capability, residual vein wall compliance and recoil, and final venous patency after catheter-based thrombus extraction, with or without adjunctive ballooning or stenting, and to compare these features with current clinical experience. In addition, the model developed by Parchment and colleagues is expected to facilitate testing and refinement of next-generation targeted chronic DVT recanalization devices, and thus help address the clinical burden of symptomatic PTS due to persistent DVT obstruction.