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(Circulation. 1995;92:1697-1700.)
© 1995 American Heart Association, Inc.

Articles

Inhibition of Platelet-Dependent Thrombosis by Local Delivery of Heparin With a Hydrogel-Coated Balloon

Gilberto L. Nunes, MD; Clifford N. Thomas, MD; Stephen R. Hanson, PhD; James J. Barry, PhD; Spencer B. King, III, MD; Neal A. Scott, MD, PhD

From the Andreas R. Gruentzig Cardiovascular Center (G.L.N., C.N.T., S.B.K. III, N.A.S.) and the Division of Hematology-Oncology (S.R.H.), Emory University Hospital, Atlanta, Ga; and Boston Scientific Corp (J.J.B.), Watertown, Mass.

Correspondence to Neal A. Scott, MD, PhD, Andreas R. Gruentzig Cardiovascular Center, Emory University Hospital, F-606, 1364 Clifton Rd, Atlanta, GA 30322.

	Abstract

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Background Systemic administration of heparin can decrease mortality and morbidity of acute ischemic coronary syndromes such as unstable angina and myocardial infarction. Hemorrhage is the major limiting factor in the clinical use of systemic heparin. The objective of the present study was to determine whether local delivery of heparin could inhibit platelet-dependent thrombosis without altering systemic bleeding parameters.

Methods and Results Hydrogel-coated angioplasty balloon catheters were dipped in a heparin solution, dried, and applied to a platelet-rich mural thrombus in a chronic ex vivo porcine arteriovenous shunt. ¹¹¹In-labeled platelet deposition was quantified by gamma camera imaging. In a separate series of experiments, ³H-heparin was used to estimate the amount of heparin delivered to the thrombus with the coated balloon. Systemic heparin administration produced a dose-dependent decrease in platelet-dependent thrombus formation that was maximal at 200 units/kg. Bleeding times and activated partial thromboplastin times were prolonged at this dose. An equal inhibition of thrombus formation was achieved after the coated balloon was dipped in a heparin solution (10 000 units/mL) and deployed at the mural thrombus. In contrast to systemic heparin administration, there was no alteration in bleeding parameters associated with local heparin delivery. The estimated amount of heparin delivered with the coated balloon was 40 units.

Conclusions Local delivery of heparin in amounts sufficient to inhibit platelet-dependent thrombosis can be accomplished with a hydrogel-coated coronary angioplasty balloon catheter. Local heparin delivery can inhibit thrombus formation in amounts that are several orders of magnitude lower than the required systemic dose. Local delivery of heparin was not associated with prolongation of bleeding parameters.

Key Words: thrombosis • heparin

	Introduction

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Pathological,¹ angiographic,^{2 3} and angioscopic⁴ studies have identified intracoronary thrombus formation as the major etiological factor in the acute coronary syndromes such as unstable angina and myocardial infarction. Systemic heparin administration, when used in the treatment of unstable angina, causes a reduction in the frequency and duration of anginal episodes and in the incidence of subsequent myocardial infarction.^{5 6} However, bleeding complications are associated with systemic heparin administration and commonly limit its use.⁷

Prior studies with a hydrogel-coated percutaneous transluminal coronary angioplasty (PTCA) catheter demonstrated the effectiveness of local drug delivery with a synthetic thrombin antagonist in the inhibition of platelet-dependent thrombus formation.⁸ Local delivery of heparin has been shown to successfully inhibit thrombus formation without altering systemic bleeding parameters in a microvascular injury model.^{9 10} Because hydrogel-coated catheters are available for clinical use, this study was performed to test the hypothesis that a clinically available formulation of heparin could be locally delivered with a hydrogel-coated PTCA balloon catheter to inhibit thrombus formation in an experimental model of arterial thrombosis.

	Methods

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Surgical Procedures
Normal domestic swine were used in these studies. The animals weighed 25 to 35 kg and were observed to be disease free for at least 1 week before use. All procedures were approved by the Emory University Institutional Animal Care and Use Committee in accordance with federal guidelines.¹¹ All animals had a chronic, ex vivo arteriovenous shunt surgically implanted between the common carotid artery and external jugular vein. Construction of the shunts, platelet labeling, imaging, and quantification of deposited platelets were performed in an identical manner as described previously.⁸ All shunt studies were performed in conscious animals that were sedated with diazepam and ketamine.

Systemic Heparin Administration
Porcine heparin (ESI Pharmaceuticals) was administered as an intravenous bolus just before the beginning of the experiment. Monitoring of platelet deposition was continued for a 2-hour period.

Local Delivery Protocol
Extension tubing containing the thrombogenic Dacron graft was connected to the animal for 15 minutes. Prior studies have shown that this period of time is sufficient for the formation of a nonocclusive mural thrombus on the Dacron graft. The tubing was then disconnected from the animal and gently flushed with 0.9% NaCl. The extension tubing was designed so that a coupling point occurred just before the Dacron graft. This coupling point was opened, and the balloon was inserted directly at the site of the Dacron graft. The balloon was inflated for 15 minutes. The balloon was then deflated and gently withdrawn. The extension tubing was reconnected, gently flushed with 0.9% NaCl, and reconnected to the animal. Gamma camera imaging was performed throughout the entire 2-hour study.

Hydrogel Coating
The hydrogel coating for the balloon catheters was made from a high-molecular-weight, medical-grade, soluble polyacrylic acid polymer.¹² The polymer was covalently bound to the polyethylene balloon by a chemical reaction that used a cross-linker. The coating, when placed in contact with water, swelled to approximately twofold to fivefold its initial thickness. The polymer coating was buffered to maintain a neutral charge at pH 7.0. The hydrogel-coated balloons were supplied by Boston Scientific Corp. To ensure that an adequate amount of drug could be delivered with this coating, special balloons were designed with which the thickness was controlled to achieve a total thickness of 5 to 10 µm. In a separate series of experiments, a group of commercially available balloons that contain a thin hydrogel coating (2 to 5 µm) (Hydroplus Slider) were used to evaluate their ability to inhibit thrombosis by local delivery of heparin. Dip coating was performed by inflating the balloon to its nominal pressure (6 atm), immersing it in the heparin solution for approximately 10 seconds, and air drying the balloon for approximately 1 minute. This procedure was repeated for a total of three times for each balloon. The balloon was then deflated and placed onto a dry surface until use. All balloons were used on the same day on which they were coated. Each balloon used in the study had an inflated diameter of 4.0 mm and was 2.0 cm long. The balloons were inflated with a Boston Scientific inflation device filled with 0.9% NaCl.

Estimation of Heparin Deployed With the Coated Balloon
In an attempt to estimate the maximum amount of heparin delivered to the thrombus during the balloon inflation, 12 hydrogel-coated balloons were dipped in a solution of ³H-heparin (New England Nuclear) (specific activity, 0.57 mCi/mg; heparin activity, 133.9 units/mg) and 0.9% NaCl (0.175 mg/mL). The balloons were then air dried. Six balloons were cut off of their catheters, placed into a scintillation vial, and counted in a well counter. An additional six balloons were placed at the site of a mural thrombus on a Dacron graft that had been exposed to blood flowing in an arteriovenous shunt for 15 minutes. The balloon was expanded for 15 minutes, deflated, and withdrawn in a manner identical to that described above. The balloons were cut from the catheters, placed into scintillation vials, and counted. The maximum amount of heparin that could be delivered to the thrombus was calculated by subtracting the counts per minute of the deployed balloons from the undeployed balloons and dividing by the specific activity (cpm/µL) of the ³H-heparin solution.

Bleeding Time Measurements
Bleeding time measurements were performed in duplicate on the shaved dorsal surface of the ear with a commercially available kit (Organon Teknika).

Statistical Analysis
All data are given as mean±SEM. All statistical analyses were done with statistical analysis software for an IBM personal computer (SIGMASTAT). Statistical comparisons for more than two groups were made with ANOVA, followed by Dunnett's test.

	Results

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Intravenous Heparin Administration
Heparin in a dose of 100 units/kg produced a small decrease in platelet-dependent thrombus formation early after the bolus administration (Fig 1). A heparin dose of 200 units/kg produced a near-complete inhibition of thrombus formation. A dose of heparin 1000 units/kg completely inhibited platelet deposition. There was no significant difference in platelet deposition between the 200 and 1000 units/kg doses. Intravenous heparin administration in doses of 100 and 1000 units/kg were associated with a significant elevation of both bleeding time and activated partial thromboplastin time (aPTT) (Table).

View larger version (27K): [in this window] [in a new window]   Figure 1. Plot of the effect of intravenous heparin on platelet deposition. Animals received a bolus of heparin 5 minutes before the shunt containing the thrombogenic segment was connected. Platelet deposition was monitored for 2 hours after connection of the shunt to the animal.

View this table: [in this window] [in a new window]   Table 1. Effects of Systemic Heparin Administration on Bleeding Parameters

Local Delivery of Heparin
When heparin was delivered with a coated balloon with a 5- to 10-µm-thick coating, there was a marked inhibition of thrombus formation that persisted for at least 90 minutes after exposure of the mural thrombus to the balloon (Fig 2). There was no difference in the response in platelet deposition between an uncoated balloon dipped in heparin and a coated or uncoated balloon dipped in saline. When balloons with a thin coating of the hydrogel (2- to 5-µm-thick) were dipped in a 10 000-units/mL heparin solution and deployed (Fig 3), there was no significant difference in the inhibition of thrombus formation when compared with the thickly coated balloons. When balloons with a thin coating were dipped in a heparin solution of 5000 units/mL, platelet deposition was inhibited at an intermediate level between the 10 000-units/mL group and control. There was no change in bleeding time or aPTT associated with any local delivery group.

View larger version (26K): [in this window] [in a new window]   Figure 2. Plot of the effect of local heparin delivery with a hydrogel-coated balloon (5- to 10-µm thickness) on platelet deposition. The coated balloon was applied to a mural thrombus for 15 minutes (t=15 until t=30) and then removed. Platelet deposition in the coated balloon plus heparin (10 000 units/mL) group was significantly lower than the other controls for the remainder of the experiment.

View larger version (24K): [in this window] [in a new window]   Figure 3. Plot of the effect of local heparin delivery with a thin hydrogel coating (2- to 5-µm thickness) on platelet deposition. The experiment was performed in an identical manner as described in Fig 2.

To estimate the amount of heparin deployed onto the thrombus with the coated balloon, a solution containing ³H-heparin was used to coat two groups of balloons. Both groups of balloons were dipped in the ³H-heparin solution and dried. One group was counted in a well counter, and the other group was deployed in a shunt at the site of the mural thrombus for 15 minutes and then counted. The average number of counts on the six balloons that were only dip-coated was 4.1±1.0x10⁵ cpm. The specific activity of the heparin solution used was 1.1x10⁵ cpm for 1 µL and 10.7x10⁵ cpm for 10 µL. Interpolating between these values, approximately 4 µL of the heparin solution was adsorbed onto the balloon. The average number of counts remaining on the six balloons that were dip-coated and deployed in the shunt was 1.5±0.4x10⁴ cpm. Therefore, approximately 96% of the heparin adsorbed onto the balloon was lost from the balloon either before or during deployment.

	Discussion

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The experiments described in this report demonstrate that heparin can inhibit platelet-dependent thrombus formation in this model of arterial thrombosis. However, very high heparin doses were necessary when the heparin was administered systemically. In contrast, local delivery enabled the inhibition of thrombus formation exceedingly small amounts of heparin.

The model used in the present study involves the placement of a thrombogenic graft segment into an ex vivo shunt. This model closely mimics the geometry and flow conditions observed in medium-sized arteries. The thrombogenic segment, when used in this model system, has been demonstrated to initiate, anchor, and localize the growing thrombus.¹³ This shunt system is "ex vivo" in the sense that it is extracorporeal but simulates in vivo thrombus formation because blood is continuously recirculated in the animal and therefore is subject to all normal filtration, dilution, and inactivation mechanisms within the host animal. This model closely simulates in vivo thrombus formation and has been widely accepted for studies in both pigs¹⁴ and primates¹⁵ for the evaluation of thrombotic mechanisms and pharmacological interventions. Although results obtained from this model may not necessarily extrapolate directly to humans, this model is generally viewed as a valid approach for developing hypotheses and therapeutic strategies that may ultimately find applications in humans.

Heparin inhibits the clotting of whole blood and plasma, an action that has been attributed to its ability to catalyze the inhibition by antithrombin of the intrinsic coagulation pathway proteases (thrombin; factors Xa, IXa, and XIIa; and kallikrein)^{16 17} and, to a lesser extent, to catalyze the inhibition of thrombin by heparin cofactor II.¹⁸ Previous studies with a similar arteriovenous shunt model of arterial thrombosis in nonhuman primates demonstrated that heparin, when administered in doses similar to those used clinically, was ineffective in preventing the deposition of platelets on thrombogenic surfaces, including coronary stents.^{19 20} Possible mechanisms for the ineffectiveness of heparin in this model are the release of specific heparin-binding proteins, including platelet factor IV and ß-thromboglobulin by activated platelets, the inability of the heparin–antithrombin III complex to inactivate meizothrombin during thrombin generation,²¹ and the possible steric or ionic exclusion of heparin from the thrombin formed within the thrombus.²² In contrast, the results from the present study demonstrate that heparin, when administered in either very high systemic doses or locally, can inhibit platelet-dependent thrombus formation. A possible mechanism of action may be via the direct inhibition of clot-bound thrombin by the very high doses of heparin, an action that has not been attributed to heparin when it was administered in doses that approximated blood levels after conventional clinical dosing (ie, 2 units/mL).²²

Locally delivered heparin has been proven to be effective in preventing thrombus formation in a microvascular injury model.^{9 10} A major advantage of local heparin delivery is the ability to anticoagulate the target site without the prolongation of systemic bleeding parameters. Local heparin delivery was successfully achieved with the use of a hydrogel coating that was chemically bonded to a PTCA balloon catheter. Hydrogel coatings have been applied to PTCA balloons to increase their lubricity during coronary deployment.²³ These hydrogels, when placed in aqueous solutions, absorb the solution and swell.²⁴ If the hydrogel-coated balloon is then removed from the aqueous solution, the water evaporates and the solute precipitates in the interstices of the polymer. When the balloon is then deployed, the interstices of the polymer become filled with aqueous solution and the solute dissolves and is delivered to the adjacent tissue (or thrombus) down a concentration gradient. Prior studies have demonstrated the usefulness of this concept with the successful local delivery of a synthetic antithrombin to inhibit thrombus formation.⁸ In addition, Azrin et al²⁵ demonstrated that heparin, when delivered with a hydrogel-coated balloon, can inhibit platelet deposition in balloon-injured porcine arteries. The present study confirmed the experiments of Azrin et al and demonstrated that the inhibition of thrombus formation persisted for at least 90 minutes after the heparin-treated balloon was removed from the system. This study also demonstrated that as little as 40 units heparin, when delivered locally, could provide a profound inhibitory effect on platelet-dependent thrombus formation. A possible mechanism for the action of the locally delivered heparin is the application of high concentrations of heparin directly to the thrombus. Another possible contributing mechanism could be the mechanical disruption of the thrombus by the inflated PTCA balloon. This disruption of the thrombus by the PTCA balloon could have enabled more thrombin-binding sites within the thrombus to be accessible to the heparin in the hydrogel. Mechanical disruption of the thrombus by the balloon could also explain the lesser amount of platelets deposited on the thrombogenic surface in the PTCA balloon experiments. Other possible mechanisms for the action of high-dose heparin include the anticoagulant actions of heparin that are independent of antithrombin. Recent data have suggested that heparin may directly inhibit the activation of the factor VIII–von Willebrand factor complex by thrombin in a concentration-dependent manner.²⁶ In addition to its effect on thrombin-induced activation of factor VIII, heparin is a potent inhibitor of intrinsic fXase.²⁷

In summary, these studies demonstrate that in this experimental model of arterial thrombosis, systemically administered heparin can inhibit platelet-dependent thrombus formation when given in very high doses. Also, heparin delivered locally with a hydrogel-coated PTCA balloon can inhibit platelet deposition to the same extent with no change in bleeding parameters. The results obtained in this model system suggest that additional studies are warranted to further characterize the effects and potential clinical applications of local delivery in the treatment of arterial thrombosis.

	Acknowledgments

 
This work was supported by National Heart, Lung, and Blood Institute grant HL-31469, by Boston Scientific Corporation, and by Gruentzig Cardiovascular Center. N.A.S. was supported in part by the Robert Wood Johnson Funding for Minority Faculty Development.

Received December 27, 1994; revision received July 27, 1995; accepted August 7, 1995.

	References

Top Abstract Introduction Methods Results Discussion References

 
1. Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Circulation. 1985;71:669-708. [Abstract/Free Full Text]

2. Wilensky RL, Bourdillon PD, Vix VA, Zeller JA. Intracoronary artery thrombus formation in unstable angina: a clinical, biochemical and angiographic correlation. J Am Coll Cardiol. 1993;21:692-994021.[Abstract]

3. Rehr R, Disciascio G, Vetrovec G, Cowley M. Angiographic morphology of coronary artery stenoses in prolonged rest angina: evidence of intracoronary thrombosis. J Am Coll Cardiol. 1989;14:1429-1437. [Abstract]

4. Mizuno K, Satomura K, Miyamoto A, Arakawa K, Shibuya T, Arai T, Kurita A, Nakamura H, Ambrose JA. Angioscopic evaluation of coronary-artery thrombi in acute coronary syndromes. N Engl J Med. 1992;326:287-291. [Abstract]

5. Serneri GGN, Gensini GF, Poggesi L, Trotta F, Modesti PA, Boddi M, Ieri A, Margheri M, Casolo GC, Bini M, Rostagno C, Carnovali M, Abbate R. Effect of heparin, aspirin, or alteplase in reduction of myocardial ischemia in refractory unstable angina. Lancet. 1990;335:615-618. [Medline] [Order article via Infotrieve]

6. Theroux P, Ouimet H, McCans J, Latour JC, Joly P, Levy G, Pelletier E, Juneau M, Stasiak J, deGuise P, Pelletier GB, Rinzler D, Waters DD. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med. 1988;319:1105-1110. [Abstract]

7. Landefeld CS, Beyth RJ. Anticoagulant-related bleeding: clinical epidemiology, prediction, and prevention. Am J Med. 1993;95:315-328. [Medline] [Order article via Infotrieve]

8. Nunes GL, Hanson SR, King SB III, Sahatjian RA, Scott NA. Local delivery of an antithrombin via a hydrogel-coated PTCA balloon catheter inhibits platelet-dependent thrombosis. J Am Coll Cardiol. 1994;23:1578-1583. [Abstract]

9. Jones NS, Glenn MG, Orloff LA, Mayberg MR. Prevention of microvascular thrombosis with controlled-release transmural heparin. Arch Otolaryngol Head Neck Surg. 1990;116:779-785.

10. Okada T, Bark DH, Mayberg MR. Local anticoagulation without systemic effect using a polymer heparin delivery system. Stroke. 1988;19:1470-1476. [Abstract/Free Full Text]

11. Committee on Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources Commission on Life Sciences. Guide for the Care and Use of Laboratory Animals. Bethesda, Md: National Institutes of Health; Publication No. 85-23, 1985:1-83.

12. Fan YL. Hydrophilic lubricious coating. US Patent No. 5,091,205:1990.

13. Hanson SR, Kotze HF, Savage B, Harker LA. Platelet interactions with Dacron vascular grafts: a model of acute thrombosis in baboons. Arteriosclerosis. 1985;5:595-603. [Abstract/Free Full Text]

14. Scott NA, Nunes GL, King SBI, Harker LA, Hanson SR. Local delivery of an antithrombin prevents platelet-dependent thrombosis. Circulation. 1994;90:1951-1955. [Abstract/Free Full Text]

15. Harker LA, Kelly AB, Hanson SR. Experimental arterial thrombosis in nonhuman primates. Circulation. 1991;83(suppl IV):IV-41-IV-55.

16. Brinkhous KM, Smith HP, Warner ED, Seegers WH. Am J Physiol. 1939;125:683-687.

17. Rosenberg RD, Damus PS. The purification and mechanism of action of human antithrombin-heparin cofactor. J Biol Chem. 1973;248:6490-6505. [Abstract/Free Full Text]

18. Tollefson DM, Lane DA, Lindahl U, eds. Heparin: Clinical and Biological Properties, Clinical Indications. Boca Raton, Fla: CRC Press; 1989:257-273.

19. Hanson SR, Harker LA. Interruption of acute platelet-dependent thrombosis by the synthetic antithrombin D-phenylalanyl-L-prolyl-L-arginyl chloromethyl ketone. Proc Natl Acad Sci U S A. 1988;85:3184-3188. [Abstract/Free Full Text]

20. Krupski WC, Bass A, Kelly AB, Marzec UM, Hanson SR, Harker LA. Heparin-resistant thrombus formation by endovascular stents in baboons: interruption with a synthetic antithrombin. Circulation. 1990;81:570-577.

21. Lindout T, Baruch D, Schoen P, Franssen J, Hemker HC. Thrombin generation and inactivation in the presence of antithrombin III and heparin. Biochemistry. 1986;25:5962-5969. [Medline] [Order article via Infotrieve]

22. Weitz JI, Huboda M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest. 1990;86:385-391.

23. Gravier D, Durall RL, Okada T. Surface morphology and friction coefficient of various types of Foley catheter. Biomaterials. 1993;14:465-469.[Medline] [Order article via Infotrieve]

24. Kim SW, Bae YH, Okano T. Hydrogels: swelling, drug loading, and release. Pharm Res. 1992;9:283-290. [Medline] [Order article via Infotrieve]

25. Azrin MA, Mitchel JF, Fram DB, Pedersen CA, Cartun RW, Barry JJ, Bow LM, Waters DD, McKay RG. Decreased platelet deposition and smooth muscle cell proliferation after intramural heparin delivery with hydrogel-coated balloons. Circulation. 1994;90:433-441. [Abstract/Free Full Text]

26. Barow RT, Healey JF, Lollar P. Inhibition by heparin of thrombin-catalyzed activation of the factor VIII-von Willebrand factor complex. J Biol Chem. 1994;269:593-598. [Abstract/Free Full Text]

27. Barrow RT, Parker ET, Krishnaswamy S, Lollar P. Inhibition by heparin of the blood coagulation intrinsic pathway factor X activator. J Biol Chem. 1994;269:26796-26800.[Abstract/Free Full Text]

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nunes, G. L. Articles by Scott, N. A. Search for Related Content PubMed PubMed Citation Articles by Nunes, G. L. Articles by Scott, N. A. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Angioplasty Blood Thinners Hazardous Substances DB HEPARIN TRITIUM