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. Author manuscript; available in PMC: 2012 Oct 1.
Published in final edited form as: J Vasc Interv Radiol. 2011 Jul 28;22(10):1471–1477. doi: 10.1016/j.jvir.2011.06.011

An Experimental Model of Large Pulmonary Embolism Employing Controlled Release of Subacute Caval Thrombus in Swine

Israel M Barbash 1, William H Schenke 1, Majdi Halabi 1, Kanishka Ratnayaka 1,2, Anthony Z Faranesh 1, Ozgur Kocaturk 1, Robert J Lederman 1
PMCID: PMC3185124  NIHMSID: NIHMS307910  PMID: 21802315

Abstract

Purpose

We aimed to develop a catheter based model of large pulmonary embolism in swine based on in situ venous thrombus formation.

Materials and Methods

Ten Yorkshire swine underwent transjugular implantation of a retrievable inferior vena cava (IVC) filter. A thrombin and collagen mixture was injected into a confined space created by two inflated balloons proximal and distal to the IVC filter. Animals were survived for 7±3 days to allow the thrombus to organize in situ. The caval thrombus was released upon transcatheter retrieval of the IVC filter and embolized into the main and branch pulmonary arteries. The severity of pulmonary embolism was scored by digital subtraction angiography (Miller index). At necropsy thrombi were recovered and analyzed by histopathology.

Results

Large pulmonary embolism was induced in all animals (average Miller index score of 15±5). Two animals developed saddle embolus with bilateral pulmonary artery occlusion and five developed proximal occlusion of either the left or right pulmonary arteries. Nevertheless no animal exhibited significant hemodynamic compromise. Large tubular thrombi were explanted in the size range of 5–10 cm long and .5–1 cm wide. Histology indicated an organized thrombus with infiltration of white blood cells and fibrin deposition.

Conclusions

Large caval thrombi can be formed in vivo and released at a predetermined time to induce large pulmonary embolism in a large animal model. This may help developing and testing new therapeutic approaches for pulmonary embolism.

INTRODUCTION

Submassive and massive pulmonary embolism (PE) is associated with high mortality (1–3). Pharmacologic and mechanical treatments are underutilized, controversial and associated with morbidity (1–6). Clinical development of new treatments for massive PE is hindered by heterogeneity of clinical presentation, by significant comorbidity, and by significant clinical instability when it arises. A relevant and appropriate large animal model of PE would be invaluable for development and evaluation of percutaneous thrombectomy approaches and devices (7, 8).

Previous animal models for PE use injection of few or multiple fresh or two day old ex vivo formed blood clots into the venous circulation (9–13) or ex vivo models (14). While sufficient for studying diagnostic imaging approaches (15, 16) and long term outcome of PE (10, 12), these models may be insufficient for evaluating acute therapeutic approaches (7), especially for massive PE with high thrombus burden. We sought to create a model of large PE by generating subacute organized thrombus in situ and to induce PE following the controlled release of the preformed thrombus. This model will enable proper preclinical evaluation of various therapeutic approaches for treatment of various degrees of PE.

METHODS

Animals

Animal procedures were approved by the institutional animal care and use committee and conducted according to contemporary National Institutes of Health guidelines. Eleven Yorkshire swine (60±8 Kg) were used to develop the model. Anesthesia was induced with ketamine, midazolam, and glycopyrrolate, and maintained with inhaled isoflurane and mechanical ventilation with room air.

In situ inferior vena cava thrombus creation

A thrombus was created using intravascular thrombin and collagen injected between occlusive caval balloons, and held in place using a retrievable inferior vena cava (IVC) filter (Figure 1A). A transjugular retrievable IVC filter (Günther Tulip, Cook Medical, Bloomington IN) was placed below the renal veins. Two occlusion balloons (Coda Balloon Catheter, 10Fr, 120 cm, 34 mL, Cook Medical) were inserted into the IVC via transjugular and transfemoral 14Fr × 12cm vein introducer sheaths (Fast-Cath, St. Jude Medical, St Paul, MN). The occlusion balloons were inflated as closely together as allowed by the interposed IVC filter, to “isolate” the space and create a thrombus. A large lumen angled guiding catheter (7Fr Veripath, inner diameter 0.078”, Abbott Vascular) was positioned via a second femoral vein introducer (Pinnacle 7Fr, Terumo, Somerset, NJ) to deliver a viscous prothrombotic mixture into this isolated space. The prothrombotic mixture consisted of thrombin 10,000 international units and collagen 400 mg (packaged together as D-stat Flowable Hemostat, Vascular Solutions, Minneapolis, MN) and iopamidol 1–2mL (Isovue 300, Bracco Therapeutics, Princeton, NJ) in a total volume of ~6mL. The mixture was injected slowly and flushed with saline to clear the catheter dead space. The balloons were kept inflated for 90 minutes and then deflated and removed.

Figure 1.

Figure 1

Figure 1

Figure 1

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Figure 1A. Coda balloon catheter was positioned just below the IVC filter but above the level of the iliac veins bifurcation (Double asterisks). A second coda balloon catheter was positioned proximally to the IVC filter (Single asterisks). Both balloons were inflated to achieve complete flow occlusion in IVC. The prothrombotic mixture was injected through 7Fr Veripath catheter (Arrow head) into the confined spaces between the two balloons and was readily visible (Arrow) under fluoroscopy.

Figure 1B. The use of two inflated balloons was important for prevention of thrombin leakage proximally to the IVC filter (Arrow). A marked pigtail catheter was used for determining the level of IVC filter deployment inferior to the renal veins.

Figure 1C. Caval thrombus was evident immediately after deflation of the two occlusive balloons. Of note, “negative contrast” from renal venous return (Arrow).

All animals received a single dose of cefazolin 500 mg intramuscularly and a single dose of ketoprofen 1mg/kg intramuscularly. After sheath removal and manual hemostasis, animals were allowed to recover and returned to their regular diet with water ad libitum.

Release of in situ thrombus for pulmonary embolism

At 7±3 days following IVC filter positioning and thrombus induction, the IVC filter was retrieved via trans jugular approach using a Günther Tulip Retrieval Set (Cook Medical) through an 11Fr introducer sheath (10 cm, Pinnacle, Terumo). In cases that the thrombus did not embolize spontaneously, it was dislodged manually using an inflated Coda balloon catheter (10Fr, 120 cm, 34 mL, Cook Medical) advanced from below. No antithrombin was administered.

Pulmonary embolism severity assessment

Pulmonary angiograms were performed at baseline, immediately after a 90 minute thrombus incubation period and immediately after IVC filter retrieval and thrombus release. PE extent and severity was assessed by digital subtraction pulmonary angiography on supine animals in two projections; 30° LAO, caudal 20° (for right pulmonary artery) and 30° RAO, caudal 20° (for left pulmonary artery) using 30 ml iodinated contrast at a rate of 30 ml/sec. The Miller angiographic index of severity was calculated from angiograms (17) (Figure 2). A Miller score of 15 or higher was considered a large PE as it indicated a reduction of > 50% of the swine pulmonary vascular bed (18). Proximal, mid or distal PE was defined as angiographic involvement of branch numbers 1, 2–5 or 6–9 respectively (Figure 2).

Figure 2.

Figure 2

Figure 2

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Classification system for swine pulmonary artery branches. Pulmonary embolism severity was graded according to Miller angiographic index as described in (17). Brief the rightly, pulmonary artery was regarded as having nine major segmental branches (A) R1-9. The left pulmonary artery was regarded as having seven major branches (B) L1-7. The presence of a filling defect in any the 16 branches scored 1 point, i.e. maximum of 9 and 7 points in the right and left pulmonary arteries respectively. Angiographic filling defect proximal to segmental branches scored a value equal to the number of segmental branches arising distally; i.e. maximum of 9 and 7 points in the right and left pulmonary arteries respectively. For scoring of reduction of flow each lung was divided into three zones (upper, mid and lower) and scoring was 0–3 per zone according to the severity of flow reduction. Summing up the three categories creates a severity score of 0–34.

Right heart hemodynamics were evaluated at baseline and after induction of PE using a Berman Angiography Balloon Catheter (Arrow, Belgium) positioned in the main pulmonary artery. Cardiac function was assessed before and after PE using MRI at 1.5T (Espree, Siemens Medical Solutions, Erlangen, Germany) (n=4). Scans used ECG-gated, segmented, breath-held, balanced steady state free precession and parallel imaging with an acceleration factor of two. Scan parameters were: repetition time/echo time, 34/1.4 ms; flip angle, 65°; field of view, 300 × 281 mm; matrix, 256 × 127 pixels; slice thickness, 8 mm; bandwidth, 930 Hz/pixel. Argus Function software (Siemens) was used to calculate ventricular volumes (LV) and area (RV).

Pathology examination

Animals were euthanized following the procedural studies and the thrombus was extracted from the pulmonary arteries for macroscopic (assessment of size and consistency) and histological studies. Clots were fixed in formalin 10%, slides stained with hematoxylin & eosin, and examined by one of the authors (IMB). In one additional animal, the IVC filter was excised surgically at day 14 following thrombus induction in order to evaluate the thrombus within the filter device.

Data analysis

Statistical analysis used InStat (Version 3, GraphPad Software, La Jolla, CA). Numerical parameters with normal Gaussian distribution (According to Kolmogorov-Smirnov test) are reported as mean ± 1 standard deviation, other parameters are reported as median (minimum-maximum range). We tested whether there was a change in continuous parameters from baseline to after IVC occlusion and from IVC thrombus release (i.e. prior to IVC filter retrieval) to after PE induction using paired Student t-test. Recorded parameters included heart rate, systolic arterial blood pressure, LV ejection fraction, right ventricular area and pulmonary artery pressure. We considered a p value <0.05 significant.

RESULTS

In situ IVC thrombus creation and release

IVC occlusion by the double balloons caused acute decrease in venous return that resulted in transient tachycardia (96±7 versus 122±25 beats per minute (BPM) respectively, p = 0.08) and hypotension (systolic arterial pressure of 76±8 versus 60±10 mmHg respectively, p=0.01) at baseline as compared to after IVC occlusion. This was effectively treated by supplemental isotonic saline fluid administration.

The prothrombotic mixture of thrombin, collagen and iodinated contrast formed a viscous solution evident under fluoroscopy during delivery (Figure 1A). The addition of iodinated contrast proved useful to identify leakage proximal to the IVC filter (Figure 1B). After 90 minute balloon inflation, the thrombi were sufficiently stable to remain in place below the IVC filter after balloon deflation (Figure 1C). Thrombus was effectively created in all animals. Small vessel (distal) PE were evident immediately during this encounter in 3/10 animals (Miller index score of 2±3) without hemodynamic significance. All animals recovered uneventfully from the procedure.

At 7±3 days after IVC filter implantation and thrombus formation, follow-up IVC angiography consistently showed a large thrombus extending beyond (proximal to) the IVC filter in all animals (Figure 3). IVC filters were retrieved via a transjugular approach, which embolized the caval thrombus into the pulmonary arteries in 7/10 animals. When thrombi did not embolize immediately, they were easily released by advancing a partially inflated Coda balloon catheter from below, cephalad along the IVC. Eventually, all the thrombus material dislodged from the IVC, evident from caval angiography after release.

Figure 3.

Figure 3

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Iodinated contrast injection into the IVC (Arrow) demonstrating in situ thrombus (Double head arrow) at the IVC filter prior to filter retrieval at days 7±3.

In one animal (1 of 11), which was survived 14 days with the IVC filter and thrombus in situ, we failed to retrieve the IVC filter. Pathologic examination of the excised IVC indicated that adhesions between the filter’s retrieval hook, organized thrombus and the IVC wall prevented retrieval with thrombus dislodgement. This animal was excluded from further analysis but was used for histology evaluation.

In all cases, the resulting PE involved at least one first-order branch pulmonary artery (Table 1, Figure 4). The Miller index was 15±5, and corresponded to large PE (Miller index≥15) in 6/10. Heart rate increased from 100±15 BPM at baseline to 113±14 BPM post PE (p=0.0004), and systolic arterial pressure fell from 85±13 to 81±9 mmHg respectively (p=0.5). All animals stabilized with fluid administration. Pulmonary artery pressures increased significantly from 23 mmHg (21–24) at baseline to 32 mmHg (29–38) after PE induction (p=0.013). Cardiac MRI (n=4) did not show any significant change in right ventricle size (14 (18–22) to 17 (16–27) cm2 respectively, p=0.2) or left ventricular ejection fraction (0.43 (0.32–0.46) to 0.44 (0.39–0.51) respectively, p=0.4) from baseline to after PE.

Table 1.

Pulmonary embolism vessel involvement. N=10

Animal # PE location Thrombus incubation period (Day)
1 Saddle
LPA – proximal
RPA - Middle		 6
2 Saddle
LPA - Distal
RPA – Middle		 8
3 LPA – Middle
RPA - Distal		 8
4 LPA – Proximal
RPA - Distal		 7
5 LPA – Distal
RPA - Proximal		 4
6 RPA - Proximal 6
7 LPA – Middle
RPA - Distal		 7
8 LPA – Proximal
RPA - Middle		 5
9 LPA - Middle 7
10 RPA - Middle 5
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LPA – Left pulmonary artery; RPA – Right pulmonary artery; PE – Pulmonary embolism

Figure 4.

Figure 4

Figure 4

Figure 4

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Figure 4A. Baseline pulmonary artery angiogram.

Figure 4B. Extensive pulmonary embolism involving main pulmonary artery bifurcation, the right and left pulmonary arteries (Arrows) as compared to baseline in 4A.

Figure 4C. Baseline pulmonary artery angiogram.

Figure 4D. Extensive pulmonary embolism involving main pulmonary artery bifurcation, the right and left pulmonary arteries (Arrows) as compared to baseline in 4A.

Pathology

Typically, the clot formed initially just below the IVC filter (Figure 5A), however in most cases the clot propagated proximally and reached several cm length inside the IVC (Figure 3). Macroscopic evaluation of retrieved clots from excised lung tissues (Figure 5B, C) demonstrated long, organized clots in the size range of 5 – 10 cm length and diameter of .5 – 1 cm. Histological analysis showed fibrin and platelet layers intertwined with erythrocytes and white blood cells, typical for premortem, organized intravascular clot (19) (Figure 5D).

Figure 5.

Figure 5

Figure 5

Figure 5

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Figure 5A. Surgical retrieval of the IVC filter (IVC wall dissected indicated by asterisks) demonstrated the position of the preformed clot (Arrow) just below the filter.

Figure 5B. Pathology image of pulmonary thrombus in situ in the right pulmonary artery (Arrow). Notice the right bronchus (asterisks) adjacent to the pulmonary artery.

Figure 5C. Pulmonary thrombus following complete extraction from main pulmonary artery bifurcation.

Figure 5D. Histologic evaluation of 6 days old thrombus extracted from the pulmonary arteries stained by hematoxylin & eosin, demonstrating presence of inflammatory cells (arrows) and fibrin depositions (arrow heads).

DISCUSSION

The present study describes a reproducible animal model for large PE. The in situ thrombus formation in this model mimics the pathophysiology of PE, and allows both large thrombi and controlled thromboembolism. This model may serve as a platform to develop new nonsurgical therapies for PE.

Nearly 5% of patients with PE are hemodynamically unstable on admission. These patients suffer mortality rates of up to 58% (1, 20). Catheter thrombectomy is typically considered a second-tier therapy after intravenous thrombolysis (21–23) despite the high morbidity associated with thrombolysis (1). No percutaneous pulmonary thrombectomy devices are approved for marketing in the United States (4, 5). An appropriate animal model would support suitable preclinical research to understand concepts of pulmonary thrombectomy and thereafter robust device development of potentially lifesaving technology (7).

Previously reported PE models used various methods to occlude pulmonary vasculature for evaluating diagnostic approaches for PE or pulmonary hypertension, and to evaluate various treatment approaches for PE. These models used either fresh (9) or ex vivo incubated clots (11, 12, 14) injected via the jugular vein. Neither creates organized thrombi (7) that model clinical PE, and therefore is suitable to test percutaneous mechanical therapies. The presented model creates an organized thrombus as evidenced by presence of inflammatory cells and fibrin deposits which do not occur in thrombi formed ex vivo. Furthermore, such thrombus would be too large to inject through a vascular catheter.

Most clinically significant pulmonary artery thrombi originate from the iliofemoral veins (24). Iliofemoral thrombosis typically forms in areas with slow flow, are usually occlusive and evolve into mature thrombi with infiltration of fibroblasts and smooth muscle cells into a fibrin rich clot (25). This process leads to the formation of a complex structure with different mechanical properties than fresh thrombus (7, 26). Accordingly, mechanical thrombectomy devices might be expected to perform differently in organized compared with fresh thrombus (27). Thus, the proposed model aimed to create a more “real life” thromboembolism.

There are several limitations to this model of PE. There is no effective method to control the size of thrombus, its final location after embolism, and magnitude of acute pulmonary vascular obstruction. Our attempt to further increase thrombus size by prolonging in vivo incubation to two weeks in a single animal failed because the organized thrombus adhered to the cava and prevented retrieval of the IVC filter.

It is noteworthy that despite large PE in these healthy juvenile animals (average Miller index score of 15), there was no significant hemodynamic deterioration. This is fortuitous in allowing less urgent testing of novel therapeutic approaches on large thrombus mass without the need to manage acute hemodynamic collapse.

Subacute clot can be formed in vivo and released at a predetermined time to induce large PE in a large animal model. This model may help in the development and testing of new therapeutic approaches for PE.

Acknowledgments

Sources of Funding:

Supported by the Division of Intramural Research, NHLBI, NIH (1ZIAHL005062-08, Z01-HL006041-01).

The authors are grateful to Katherine Lucas and Joni Taylor for assistance with animal experiments and to Victor Wright for assistance with MRI scans.

Footnotes

Financial disclosures: None.

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