In Vivo Porcine Model of Acute Iliocaval Deep Vein Thrombosis

doi:10.21203/rs.3.rs-2608370/v1

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In Vivo Porcine Model of Acute Iliocaval Deep Vein Thrombosis

https://doi.org/10.21203/rs.3.rs-2608370/v1

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Acute deep vein thrombosis (DVT) is a potentially life-threatening condition in which blood clots form in the venous system. Recently, a number of endovascular thrombectomy devices have been commercialized for the treatment of acute DVT. With variable efficacy and safety profiles, the current state-of-the-art has identified potential areas for further device innovation and opportunities for improvement. However, a major limitation in the testing, verification, and validation of new thrombectomy is a clinically representative large animal model of acute DVT. Unfortunately, existing approaches to creating DVT in porcine models are time consuming, technically challenging, and provide inconsistent results. We therefore developed a rapid and more reproducible protocol for induction of large-volume iliocaval DVTs in a living porcine host. This approach involves sequestering the iliocaval with standard balloon occlusion catheters, and a controlled and limited infusion of a 25% ethanol solution within the sequestered segment. We observed that this method was safe, technically straightforward, and reproducible in creating large-volume acute DVTs. We believe this model can be utilized in a standardized approach for the future testing of future endovascular venous thrombectomy devices.

Cardiac & Cardiovascular Systems

Deep venous thrombosis

large animal model

vena cava

large-volume thrombus

Deep vein thrombosis (DVT) remains a major health concern, with an annual incidence of over 900,000 in the United States, and as high as 10 million globally [1]. While DVT in the distal veins can be successfully treated with anticoagulation therapy alone, large-volume DVTs occurring in the iliocaval system are less likely to recanalize with anticoagulation, and may require further intervention to prevent pulmonary emboli (PE) [2]. PE can lead to elevated pulmonary arterial pressures, right heart strain, myocardial dysfunction, and even death [1, 3–7]. In the acute setting, approximately 10–25% of patients with large-volume DVT will develop PE and major hemodynamic complications [8, 9]. Over the longer term, patients who sustain large-volume DVT are at high risk of developing post thrombotic syndrome (PTS), which is a condition characterized by chronic leg pain, edema, discoloration, and skin ulceration [10]. PTS results from valvular incompetence or residual chronic venous outflow obstructions, and is associated with significant morbidity and disability [11]. As such, DVT can be life-threatening in the acute setting, and debilitating in the chronic setting.

Over the past decade there has been a rapid increase in endovascular device options for the treatment of acute DVT as reflected by the number of relevant active and completed clinical trials [12–22]. These include mechanical thrombolysis catheters that aim to de-bulk and fragment intraluminal thrombus, mechanical suction thrombectomy devices that use vacuums to suction out a thrombus, and thrombolysis catheters that use pharmacological thrombolytic agents to chemically fragment and dissolve thrombus. Although each of these devices are effective in thrombus dissolution, clinical human studies have revealed that each device type also has important limitations (Table 1). Therefore, despite recent progress, endovascular treatment of DVTs still represents an area of continued innovation and need for improvement in device functionality, efficacy, and safety profiles.

Table 1

Current Interventions for DVT
Intervention	Mechanism	Limitations
PMT	Mechanical fragmentation of thrombus	Risk of damage to veins wall/valves and passive microembolization
ST	Physical removal of thrombus	Vein wall collapse and blood loss with suction
CDT	Chemical lysis of thrombus	Increased risk of perioperative bleeding, need for multiple sessions
PCDT	Combined chemical lysis and mechanical fragmentation of thrombus	Red blood cell lysis, increased risk of perioperative bleeding, passive microembolization

One of the major limitations in DVT device iteration is the lack of clinically representative, large animal models of acute DVT that can be used in the verification and validation testing of newly designed devices. A porcine model for DVT is ideal due to the similarities between human and porcine anatomy and blood clotting cascades [23]. Previously reported acute DVT models suffer from technically challenging and time-consuming procedures, that require a high level of technical expertise, and suffer from inconsistent outcomes. As such, there is a pressing need to develop a standardized, large animal, acute DVT model that can be utilized in ongoing research and development efforts for testing of next generation devices tailored for the treatment of large-volume DVT. Here we report, a low-cost, straightforward protocol, for reproducibly creating a large-volume DVT in an adult pig.

Animals

All animal procedures were approved by the Washington University in St. Louis School of Medicine Animal Studies Committee. Procedures were performed using adult male Yorkshire pigs from Oak Hill Farm (Apple River, Illinois), weighing 100–109 kg. Pigs were housed one pig per pen and allowed to acclimate for 72 hours prior to the procedure. Pigs were given a normal chow diet and underwent an overnight fast prior to the procedure.

Surgical procedure preparation

Intravenous access of obtained in the ear pinna of an adult pig. Anesthetic cocktail of telazol 4mg/kg, ketamine 2mg/kg, and xylazine 2mg/kg was administered to sedate the animal, place in a supine position, secure limbs to operating room table, and induce general anesthesia using isoflurane 1–3% in 100% oxygen. Animals underwent endotracheal intubation and were maintained on ventilator support. Hemodynamics including blood pressure and heart rate were monitored following induction of anesthesia. Oxygen saturation was also monitored using a pulse oximeter attached to the ear pinna. Respiratory rate and end-tidal CO₂ were monitored using the respirator. Continuous electrocardiography was utilized throughout the procedure to monitor heart rate and rhythm.

Porcine endovascular balloon stasis and infusion of intraluminal ethanol

A longitudinal 5cm incision was made in the left neck. Alternating blunt and sharp dissection was used to expose the left external jugular vein. The vein was cannulated by direct puncture using an 18-gauge needle. An 0.035” J-tip wire was then advanced through the needle and into the external jugular vein. The needle was then exchanged for a 7Fr 11cm Cordis Brite Tip sheath (Cordis, Miami Lakes, FL). A 5Fr 65cm angled-tip catheter and 0.035” 150cm Amplatz wire were advanced into the distal inferior vena cava (IVC). A 12Fr 90cm sheath was advanced over the wire, and a venogram through the sheath confirmed IVC, its bifurcation, and the level of the renal veins.

Using ultrasound guidance, the bilateral femoral veins were percutaneously cannulated using 18 guage needle, and 0.035” J-tip wires. Over wires, 10Fr 11cm Cordis Brite Tip sheaths (Cordis, Miami Lakes, FL) were advanced over the wires and into the bilateral femoral veins. Similarly, the right femoral artery was percutaneously cannulated using ultrasound guidance and a 7Fr 11cm Cordis Brite Tip sheath (Cordis, Miami Lakes, FL) was placed in the vessel. The side port of the sheath was attached to a saline pressure line for arterial hemodynamic monitoring.

A 32mm Coda Balloon Catheter (Cook Medical, Bloomington, IN) was introduced over the wire through the left external jugular vein sheath, advanced under fluoroscopy, and inflated in the IVC directly below the level of the oigins of the renal veins. Similarly, 16mm balloon catheters (Atlas Gold, Becton Dickinson and Company, Franklin Lakese, NJ) were advanced the bilateral femoral sheaths and inflated in the proximal common iliac veins. A venogram was then performed through the Coda Balloon Catheter wire lumen and into the sequestered segment to confirm stasis in the IVC between the inflated balloon catheters. Through the Coda Balloon Catheter wire lumen 20mL of 25% ethanol and 75% normal saline solution was slowly manually infused into the sequestered IVC segment. A depiction of the operative setup can be seen in Fig. 1. Animal vital signs were monitored throughout the procedure. Serial venograms of the sequestered segment were obtained through the Coda Balloon Catheter (Fig. 2).

Intra-procedural venography and image analysis

With all three balloons inflated, thrombus formation was assessed in real-time with serial venograms at the time of ethanol injection, 30 minutes post-infusion, and 60 minutes post-infusion. Digital subtraction venography (DSV) was utilized with each contrast injection to visualize residual venous flow in the sequestered segment. The DSV image with peak contrast intensity was imported into ImageJ and a region of interest (ROI) was manually drawn to include the entire sequestered iliocaval segment. The minimum and maximum thresholds were set at 0 and 103, respectively, and the percent area of contrast enhancement within the sequestered segment was measured. The percent area of contrast enhancement was subtracted from the area of the sequestered segment to give the percent area of thrombosis. Threshold analysis revealed sequestered segments were on average 80.8% ± 22.3% thrombosed at 60 minutes post-infusion.

Euthanasia and iliocaval tissue harvest

At 60 minutes following ethanol infusion, a midline laparotomy was performed followed by a left visceral rotation. Next, a left retroperitoneal dissection was performed to expose the infrarenal IVC and proximal common iliac veins 2 − 0 silk ties were used to tie off the sequestered segment just distal to the CODA balloon and just proximal to the bilateral Atlas balloons (Fig. 1D). 88mg/mL KCl was administered, all three balloons were deflated, and the sequestered segment was immediately removed en bloc with the intraluminal thrombus in place. Death was confirmed with asystole and apnea. The silk ties were immediately removed and the clot was expressed from the iliocaval segment intact (Fig. 1E).

Tissue and thrombus histology

Harvested porcine IVC and thrombus were then fixed in 10% formalin and embedded in paraffin. Paraffin blocks were sectioned at 5µm in preparation for staining. Cross sections of both IVC and thrombus were stained for hematoxylin and eosin. Paraffin sections were dewaxed with xylene for 10 minutes x2 and rehydrated with a series of washes: 100% ethanol for 1 minute x2, 50% ethanol for 1 minute x2, deionized water for 5 min x1. Hematoxylin was applied to samples for 1 minute and subsequently washed with deionized water and 70% ethanol. Eosin was applied to samples for 1 minute, followed by three washes with 95% ethanol. The slides were dehydrated with xylene for 2 minutes x2. Finally, a coverslip was applied and slides were imaged using the C13220-01 MD NanoZoomer S360MD slide scanner system (Hamamatsu, Shizuoka, Japan).

IVC cross sections were also stained for collagen and elastin content using Verhoeff-Van Gieson (VVG). Paraffin sections were dewaxed with xylene for 5 minutes x3 and rehydrated witht a series of washes: 95% ethanol for 5 minutes, 70% ethanol for 5 minutes, 50% ethanol for 5 minutes, and deionized water for 5 minutes. A working elastin solution was prepared with 100 mL hematoxylin, 15mL ferric chloride, 40 mL iodine, and 25 mL deionized water. The working elastin solution was applied to the tissue sections for 10 minutes. Sections were subsequently washed with deionized water, ferric chloride, a second wash of deionized water, 95% ethanol, and a third was of deionized water. Van Geisen solution was then applied to sections for 1 minute. Sections were dehydrated with 95% ethanol for 20 seconds, 100% ethanol for 2 minutes, and xylene for 5 minutes. A coverslip was applied and slides were imaged using the C13220-01 MD NanoZoomer S360MD slide scanner system (Hamamatsu, Shizuoka, Japan).

VVG stained IVC segments within the sequestered zone were evaluated for microtrauma, elastin fiber breaks, and collagen fiber breaks using NDPviewer (Hamamatsu, Shizuoka, Japan). Quantification method for assessment of collagen and elastin fiber breaks was performed as follow: Perpendicular lines were drawn across the vessel wall and across collagen fibers in the media. Three random regions of interest (ROIs) were selected in the IVC wall. The number of fiber breaks along each line was recorded and divided by the length of the line to generate a normalized value.

Cross sections of thrombus were stained for platelets, red blood cells, and fibrin using a modified Carstairs stain [24]. Sections were deparaffinized using xylene and an ethanol gradient, followed by incubation in 5% ferric ammonium sulfate for 5 min then washed with distilled water. The slides were stained with hematoxylin for 5 min, washed in distilled water, and transferred to a Picric Acid-Orange G solution for 1 hour. Slides were then transferred to Biebrich scarlet-acid fuchin solution for 20 sec, rinsed in distilled water, and incubated in 1% phosphotungstic acid for 1 min. After rinsing, they were dipped in Anilin blue solution for 5 sec, rinsed, and dehydrated. All reagents were purchased from Sigma-Aldrich (St. Louis, Missouri). A coverslip was applied and slides were imaged using the C13220-01 MD NanoZoomer S360MD slide scanner system (Hamamatsu, Shizuoka, Japan).

Thrombus samples were evaluated in ImageJ and quantified as a percentage of total area [25, 26]. Fibrin, platelets, collagen and red blood cells were quantified by using a hue and brightness threshold in ImageJ, and the pixel number for each feature was reported as a percentage of the total area.

Statistics

A paired t test was used to compare differences in pig vital signs pre- and post-formation of DVTs. P < 0.05 was chosen as the threshold for statistical significance. All statistical analysis were performed using STATA software (StataCorp LLC, College Station, TX).

Pig survival and hemodynamics

We evaluated our described protocol in 11 male adult Yorkshire pigs. All 11 pigs (100%) survived and tolerated the entire DVT formation procedure. Throughout the procedure there was no evidence of hemodynamic instability, or incidence of arrhythmias, or major complications. Placement of proximal and distal IVC occlusion balloons was uncomplicated and tolerated with no hemodynamic changes in all pigs. Upon infusion of 25% ethanol solution in the sequestered segments between the occlusion balloons, no significant changes in vital signs were also observed (Table 2).

Table 2

Comparison of Key Vital Signs Pre and Post Sclerosant Infusion.
Vital Sign	Pre-Ethanol	Post-Ethanol	P-value
Heart Rate	87 ± 15	80 ± 10	0.24
Respiratory Rate	12 ± 2	13 ± 2	0.38
Oxygen Saturation	100 ± 1	98 ± 5	0.33
End-Tidal Carbon Dioxide	38.8 ± 1.6	39.7 ± 1.6	0.21
A) Fluoroscopic confirmation of balloon placement with a 32mm CODA balloon (red arrow) occluding the IVC and 16mm Atlas balloons (yellow arrows) occluding the bilateral iliac veins. B) Venogram demonstrating occlusion of the iliocaval segment. C) Venogram demonstrating developing thrombus (green arrow) within the occluded iliocaval segment after 25% ethanol infusion. All scale bars are 2cm in length.

Venography analysis and DVT formation

Serial venograms in the sequestered venous segment demonstrated thrombus formation as early as10 minutes. Thrombus volume increased over time, and reached maximal capacity 98.9% thrombosis at 60 minutes. There was no incidence of vena cava perforation, retroperitoneal bleeding, or gross PE with hemodynamic change (Fig. 1D, Table 2).

Vena cava and thrombus histopathology

IVC wall from the sequestered segment demonstrated minimal micro-trauma, and minimal collagen and elastin fiber breaks (0.696 ± 0.545 breaks per 100um of collagen fiber, and 0.543 ± 0.349 breaks per 100um of elastin fiber, respectively) (Figure A-C). Thrombus histopathology revealed an acute, platelet-rich thrombus, with an average composition of 11.95% platelets and 2.5% fibrin segments (Fig. 3D-F).

This study presents a safe, effective, and reproducible method for creating large-volume iliocaval DVTs in an adult pig that is clinically representative of human acute DVT. Thrombus was successfully formed in the sequestered venous segment in all 11 pigs tested within 60 minutes without incidence of hemodynamic instability or major complications. All animals survived the DVT formation procedure until euthanization. The DVT formation process did not cause trauma or damage to the vena cava or its surrounding tissue, further demonstrating the safety, stability, and reproducibility of the model. Histologic assessment of the IVC wall demonstrated minimal microtrauma. Thrombi were also found to contain a significant fraction of platelets consistent with acute DVT formation.

Current acute DVT treatment includes anticoagulation with or without adjunct endovascular venous recanalization techniques. While current CHEST guidelines only contain a weak recommendation for interventional therapy in patients with very severe, limb-threatening DVT, endovascular interventions are being performed with increased frequency in patients with extensive iliocaval DVT to reduce the rates of PTS [27]. To reduce the DVT-associated risk of PE and PTS, various endovascular techniques have been developed to facilitate dissolving, fragmenting, debulking, and suctioning of intraluminal acute large-volume DVTs [28–35]. Recently, a variety of endovascular devices have arrived on the market to facilitate these treatment strategies [10, 14, 21, 22, 28, 36]. Unfortunately, several recent studies have demonstrated endovascular treatment of acute DVT is associated with non-negligible risks such as bleeding, hemoglobinuria, venous wall trauma, recurrent DVT formation, thrombus distal embolization, intraprocedural PE, and death [37–39]. For example, the CaVenT study randomized 209 patients with acute iliofemoral DVT to anticoagulation or catheter directed thrombolysis, and observed significant bleeding complications in 20 of the enrolled patients [40]. A recent meta-analysis comparing thrombolysis versus mechanical thrombectomy revealed similar rates of thrombus removal (95% vs. 96%, respectively) but thrombolysis alone was thrombectomy was associated with higher DVT recurrence at 6 months and major bleeding complications [41]. The RAPID registry and CLOUT registry, which are industry-sponsored prospective clinical trials evaluating different thrombectomy devices (AngioVac suction thrombectomy device manufactured by AngioDynamics, Inc, and ClotTriever mechanical thrombectomy device manufactured by Inari Medical, Inc.) similarly reported complications related to distal thrombus embolization, and intraoperative blood loss [37, 42, 43].

Recent thrombectomy devices have reached the market based on substantial equivalence to a predicate device [44, 45]. However, in vivo animal testing has not been a routine requirement in the regulatory approval process, since no standardized and widely applied DVT models have been applied in commercial research and development efforts [46]. Therefore, there is a critical need for a simple and reproducible large animal DVT model to facilitate in vivo testing for next generation thrombectomy devices. A porcine model is ideal due to clinical relevance and similarities to the human vascular anatomy. The porcine host also has a similar coagulation cascade, therefore serving as a good model for acute thrombosis [47, 48]. However, prior porcine DVT have demonstrated several shortcomings. Some models simulate DVT by using stents to create an in-stent thrombosis in the desired vessel [49, 50], which limits its correlation to human pathology and limits post-mortem tissue histologic analysis. Another model, described an IVC stasis and thrombosis model via implantation of an intraluminal suture netting [51]. This model yields a relatively slow forming thrombus over 7 to 14 days, and is associated with notable technical challenges and a high level of expertise for implantation of the netting. Finally, other models have employed distal intravascular infusion of thrombin with a proximally occlusive balloon catheter or proximal and distal occlusion with surgical ligatures [52–55]. However, these processes involve utilization of expensive reagents that may be relatively difficult to source on a routine basis.

The advantages of our described model include its simplicity, efficiency, and reproducibility. This method employs relatively simple endovascular techniques that can be performed without extensive surgical training or sophisticated endovascular expertise. Ethanol is an attractive primary thrombus stimulant, as it is an inexpensive and readily available laboratory reagent. Ethanol has been used clinically as a sclerosant in the treatment of peripheral venous malformations for decades [56]. Absolute ethanol induces thrombosis by denaturing blood proteins, denuding endothelial cells and precipitating their protoplasm, and segmentally fracturing the vascular wall to the level of the elastic lamina [57]. We hypothesized that a short-course exposure to 25% ethanol solution would efficiently and effectively incite thrombosis in a sequestered segment of the porcine iliocaval system. This method is also highly reproducible, with all procedures performed in this study yielding successful thrombus without significant changes in hemodynamics or major complications (Table 2). Further, this model does not involve placement of retained foreign material and forms thrombus relatively quickly. This important advantage allows for subsequent evaluation of therapeutic interventions within the same operative setting.

Our study demonstrates that our acute IVC model is also grossly and histologically tolerated by the porcine host. We observed no gross and very minimal microscopic trauma to the IVC wall. On average, the thrombus composition was also consistent with other acute models with > 10% platelet content (Fig. 4). Alkarithi et al. found that STEMI thrombi are on average 11% platelets by composition [58]. The platelet and fibrin content are expected to rise in subacute model, with DVT thrombi removed by suction thrombectomy after 1 to 3 days displaying an average composition of 18.5% platelets and 28.3% fibrin [59].

Previous reports indicate that intravascular infusion of ethanol can be caustic to vascular tissue and lead to severe hemodynamic perturbations. A rat model for endovascular treatment of venous malformations revealed that intravascular injection of 50% and 75% ethanol damaged vessel walls. However, no damage to the vessel wall was observed with injection of 25% ethanol [60]. In our study, we did not observe any hemodynamic changes with infusion of a small volume of 25% ethanol in the sequestered IVC. We also observed no gross or histologic changes to the IVC that can be attributed to the ethanol infusion. Perhaps the combination of robust sequestration and venous stasis within the IVC helped prevent systemic dispersal of the ethanol solution, thereby circumventing any hemodynamic complications. It is also unknown whether the porcine host would develop be at risk of hemodynamic instability if a higher concertation of larger volumes of ethanol were used during the infusion process.

We acknowledge that our model has some limitations. First, the model is only representative of acute DVT, and not sub-acute or chronic DVT processes. Notably, the longer-term effects of the ethanol on the vessel wall are unknown at this time. Nevertheless, under the defined procedural parameters, our model provides a potentially highly useful and reproducible model for assessment of endovascular devices in the setting of DVT. Second, the stasis model suggests that upon removal of the balloon occlusion catheters, the intraluminal thrombus may quickly embolize. Therefore, testing procedures of future thrombectomy devices may need to consider maintaining distal balloon occlusion to prevent immediate loss of intraluminal IVC thrombus.

In conclusion, the proposed in vivo porcine model utilizes venous stasis and 25% ethanol solution to create acute iliocaval DVT in a safe and reproducible manner. This clinically relevant large animal model may be used for future verification and validation testing of next generation endovascular thrombectomy devices.

Conflicts of Interest

Dr. Zayed and Dr. Genin declare that they are co-founders of Caeli Vascular, Inc.. This medical device company was developed to support NIH STTR grant funding for developing novel and effective venous thrombectomy devices.

Beckman, M.G., et al., Venous thromboembolism: a public health concern. Am J Prev Med, 2010. 38(4 Suppl): p. S495-501.
Kahn, S.R., et al., Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med, 2008. 149(10): p. 698–707.
Furie, B. and B.C. Furie, Mechanisms of thrombus formation. N Engl J Med, 2008. 359(9): p. 938–49.
Mahan, C.E., et al., Venous thromboembolism: annualised United States models for total, hospital-acquired and preventable costs utilising long-term attack rates. Thromb Haemost, 2012. 108(2): p. 291–302.
Middeldorp, S., et al., Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost, 2020. 18(8): p. 1995–2002.
Stone, J., et al., Deep vein thrombosis: pathogenesis, diagnosis, and medical management. Cardiovasc Diagn Ther, 2017. 7(Suppl 3): p. S276-S284.
Winter, M.P., G.H. Schernthaner, and I.M. Lang, Chronic complications of venous thromboembolism. J Thromb Haemost, 2017. 15(8): p. 1531–1540.
Huynh, N., et al., Risk factors for presence and severity of pulmonary embolism in patients with deep venous thrombosis. J Vasc Surg Venous Lymphat Disord, 2018. 6(1): p. 7–12.
Meissner, M.H., et al., Acute venous disease: venous thrombosis and venous trauma. J Vasc Surg, 2007. 46 Suppl S: p. 25S-53S.
Hansrani, V., M. Khanbhai, and C. McCollum, The Diagnosis and Management of Early Deep Vein Thrombosis. Adv Exp Med Biol, 2017. 906: p. 23–31.
Zayed, M.A., et al., Management of Cavoatrial Deep Venous Thrombosis: Incorporating New Strategies. Semin Intervent Radiol, 2017. 34(1): p. 25–34.
ClinicalTrials.gov. DEFIANCE: RCT of ClotTriever System Versus Anticoagulation in Deep Vein Thrombosis (DEFIANCE). https://beta.clinicaltrials.gov/study/NCT05701917. Accessed February 16, 2023.
ClinicalTrials.gov. Treatment of Chronic Deep Vein Thrombosis (DVT) and Post-Thrombotic Syndrome (PTS) With the EkoSonic® Endovascular System (ACCESS PTS). https://beta.clinicaltrials.gov/study/NCT02159521. Accessed February 16, 2023.
ClinicalTrials.gov. Safety and Efficacy Study of OmniWave Endovascular System to Treat Deep Vein Thrombosis (SONIC I). https://beta.clinicaltrials.gov/study/NCT00640731. Accessed February 16, 2023.
ClinicalTrials.gov. DUTCH CAVA-trial: Catheter Versus Anticoagulation Alone for Acute Primary (Ilio)Femoral DVT. (NL28394). https://beta.clinicaltrials.gov/study/NCT00970619. Accessed February 16, 2023.
ClinicalTrials.gov. Safety and Efficacy of Thrombolysis in Combination With Endhole Aspiration in the Treatment of Acute DVT (INDIGO). https://beta.clinicaltrials.gov/study/NCT04297787. Accessed on February 16, 2023.
ClinicalTrials.gov. Preservation of Venous Valvular Function After PMT for Acute DVT (PREFER). https://beta.clinicaltrials.gov/study/NCT05588284. Accessed on February 16, 2023.
ClinicalTrials.gov. Rheolytic Thrombectomy For Acute Deep Vein Thrombosis Of Whole Lower Limb. https://beta.clinicaltrials.gov/study/NCT05286710. Accessed on February 16, 2023.
ClinicalTrials.gov. Safety and Efficacy Study of OmniWave Endovascular System to Treat Deep Vein Thrombosis (SONIC I). https://beta.clinicaltrials.gov/study/NCT00640731. Accessed on February 16, 2023.
ClinicalTrials.gov. Single Session Percutaneous Mechanical Thrombectomy for the Treatment of Ilio-femoral Deep Vein Thrombosis: A Preliminary Evaluation (SPADE). https://beta.clinicaltrials.gov/study/NCT02066597. Accessed on February 16, 2023.
ClinicalTrials.gov. The Venous Thrombus Extraction (VETEX) Clinical Study: A Preliminary Investigation (VETEX). https://beta.clinicaltrials.gov/study/NCT03489135. Accessed on February 16, 2023.
ClinicalTrials.gov. ClotTriever Outcomes (CLOUT) Registry (CLOUT). https://beta.clinicaltrials.gov/study/NCT03575364. Accessed on February 16, 2023.
Albadawi, H., et al., Animal models of venous thrombosis. Cardiovasc Diagn Ther, 2017. 7(Suppl 3): p. S197-S206.
Carstairs, K.C., The identification of platelets and platelet antigens in histological sections. J Pathol Bacteriol, 1965. 90(1): p. 225–31.
Schindelin, J., et al., Fiji: an open-source platform for biological-image analysis. Nat Methods, 2012. 9(7): p. 676–82.
Schneider, C.A., W.S. Rasband, and K.W. Eliceiri, NIH Image to ImageJ: 25 years of image analysis. Nat Methods, 2012. 9(7): p. 671–5.
Stevens, S.M., et al., Executive Summary: Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report. Chest, 2021. 160(6): p. 2247–2259.
ClinicalTrials.gov. Bolt: study of the Indigo® aspiration system when used in patients with deep vein thrombosis. https://clinicaltrials.gov/ct2/show/NCT05003843. Accessed February 16, 2023. Available from: https://clinicaltrials.gov/ct2/show/NCT05003843..
Cakir, V., et al., Use of percutaneous aspiration thrombectomy vs. anticoagulation therapy to treat acute iliofemoral venous thrombosis: 1-year follow-up results of a randomised, clinical trial. Cardiovasc Intervent Radiol, 2014. 37(4): p. 969–76.
Garcia, M.J., et al., Endovascular Management of Deep Vein Thrombosis with Rheolytic Thrombectomy: Final Report of the Prospective Multicenter PEARL (Peripheral Use of AngioJet Rheolytic Thrombectomy with a Variety of Catheter Lengths) Registry. J Vasc Interv Radiol, 2015. 26(6): p. 777 – 85; quiz 786.
Kakkos, S.K., et al., Editor's Choice - European Society for Vascular Surgery (ESVS) 2021 Clinical Practice Guidelines on the Management of Venous Thrombosis. Eur J Vasc Endovasc Surg, 2021. 61(1): p. 9–82.
Kohi, M.P., et al., Catheter directed interventions for acute deep vein thrombosis. Cardiovasc Diagn Ther, 2016. 6(6): p. 599–611.
Lopez, R., et al., Aspiration thrombectomy for acute iliofemoral or central deep venous thrombosis. J Vasc Surg Venous Lymphat Disord, 2019. 7(2): p. 162–168.
Rao, A.S., et al., Pharmacomechanical thrombectomy for iliofemoral deep vein thrombosis: an alternative in patients with contraindications to thrombolysis. J Vasc Surg, 2009. 50(5): p. 1092–8.
Zheng, X., et al., Effectiveness of pigtail catheter crushing combined with AngioJet mechanical aspiration for treatment of acute left iliofemoral vein thrombosis. Asian J Surg, 2022. 45(1): p. 226–231.
Robertson, B., et al., Technical success and short-term results from mechanical thrombectomy for lower extremity iliofemoral deep vein thrombosis using a computer aided mechanical aspiration thrombectomy device. J Vasc Surg Venous Lymphat Disord, 2022. 10(3): p. 594–601.
Moriarty, J.M., et al., Procedural outcomes associated with use of the AngioVac System for right heart thrombi: A safety report from RAPID registry data. Vasc Med, 2022. 27(3): p. 277–282.
Pouncey, A.L., et al., AngioJet Pharmacomechanical Thrombectomy and Catheter Directed Thrombolysis vs. Catheter Directed Thrombolysis Alone for the Treatment of Iliofemoral Deep Vein Thrombosis: A Single Centre Retrospective Cohort Study. Eur J Vasc Endovasc Surg, 2020. 60(4): p. 578–585.
Xu, Y., et al., Outcome of AngioJet mechanical thrombus aspiration in the treatment of acute lower extremities deep venous thrombosis. Vascular, 2021. 29(3): p. 415–423.
Enden, T., et al., Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet, 2012. 379(9810): p. 31–8.
Lichtenberg, M.K.W., et al., Endovascular mechanical thrombectomy versus thrombolysis in patients with iliofemoral deep vein thrombosis - a systematic review and meta-analysis. Vasa, 2021. 50(1): p. 59–67.
Dexter, D.J., et al., Interim outcomes of mechanical thrombectomy for deep vein thrombosis from the All-Comer CLOUT Registry. J Vasc Surg Venous Lymphat Disord, 2022. 10(4): p. 832–840 e2.
Maldonado, T.S., et al., Outcomes from the ClotTriever Outcomes Registry show symptom duration may underestimate deep vein thrombus chronicity. J Vasc Surg Venous Lymphat Disord, 2022. 10(6): p. 1251–1259.
Shah, N.G., et al., Management of inferior vena cava thrombosis with the FlowTriever and ClotTriever systems. J Vasc Surg Venous Lymphat Disord, 2021. 9(3): p. 615–620.
Weissler, E.H., et al., Restoring Venous Patency with the ClotTriever Following Deep Vein Thrombosis. Ann Vasc Surg, 2022.
Administration, U.S.F.a.D. Summary of Safety and Effectiveness Data, AngioJet Rheolytic Thrombectomy System. 1999 [cited 2022 October 25]; Available from: https://www.accessdata.fda.gov/scripts/cdrh/devicesatfda/index.cfm?db=pma&id=319870.
Kashiwakura, Y., et al., Porcine model of hemophilia A. PLoS One, 2012. 7(11): p. e49450.
Kobayashi, E., et al., The pig as a model for translational research: overview of porcine animal models at Jichi Medical University. Transplant Res, 2012. 1(1): p. 8.
Lin, P.H., et al., Evaluation of thrombolysis in a porcine model of chronic deep venous thrombosis: an endovascular model. J Vasc Surg, 2001. 33(3): p. 621–7.
Weinberg, R.J., et al., Comparison of ASPIRE Mechanical Thrombectomy Versus AngioJet Thrombectomy System in a Porcine Iliac Vein Thrombosis Model. Ann Vasc Surg, 2017. 42: p. 254–262.
Shi, W.Y., et al., Swine Model of Thrombotic Caval Occlusion Created by Autologous Thrombus Injection with Assistance of Intra-caval Net Knitting. Sci Rep, 2015. 5: p. 18546.
Gromadzinski, L., et al., A New Experimental Porcine Model of Venous Thromboembolism. J Clin Med, 2021. 10(9).
Robinson, V.J., et al., Latex D-dimer signal in in situ femoral vein thrombus in swine and effect of minidose exogenous tissue plasminogen activator bolus. Chest, 2005. 127(2): p. 622–9.
Roy, S., et al., Animal model of acute deep vein thrombosis. Cardiovasc Intervent Radiol, 1998. 21(4): p. 329–33.
Stocker, G.E., et al., In Vivo Porcine Aged Deep Vein Thrombosis Model for Testing Ultrasound-based Thrombolysis Techniques. Ultrasound Med Biol, 2021. 47(12): p. 3447–3457.
Rimon, U., et al., Ethanol sclerotherapy of peripheral venous malformations. Eur J Radiol, 2004. 52(3): p. 283–7.
Hammer, F.D., et al., Ethanol sclerotherapy of venous malformations: evaluation of systemic ethanol contamination. J Vasc Interv Radiol, 2001. 12(5): p. 595–600.
Alkarithi, G., et al., Thrombus Structural Composition in Cardiovascular Disease. Arterioscler Thromb Vasc Biol, 2021. 41(9): p. 2370–2383.
Silver, M.J., et al., Histopathologic analysis of extracted thrombi from deep venous thrombosis and pulmonary embolism: Mechanisms and timing. Catheter Cardiovasc Interv, 2021. 97(7): p. 1422–1429.
Wu, Q., et al., [Endovascular treatment for venous malformations with three-point anhydrous ethanol injection]. Zhong Nan Da Xue Xue Bao Yi Xue Ban, 2015. 40(8): p. 907–11.

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In Vivo Porcine Model of Acute Iliocaval Deep Vein Thrombosis

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Abstract

Figures

Introduction

Materials And Methods

Animals

Surgical procedure preparation

Porcine endovascular balloon stasis and infusion of intraluminal ethanol

Intra-procedural venography and image analysis

Euthanasia and iliocaval tissue harvest

Tissue and thrombus histology

Statistics

Results

Pig survival and hemodynamics

Venography analysis and DVT formation

Vena cava and thrombus histopathology

Discussion

Declarations

References

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