Heparin coatings for improving blood compatibility of medical devices

    Heparin coatings for improving blood compatibility of medical devices Roy Biran, Daniel Pond PII: DOI: Reference:

S0169-409X(16)30321-0 doi:10.1016/j.addr.2016.12.002 ADR 13079

To appear in:

Advanced Drug Delivery Reviews

Received date: Revised date: Accepted date:

8 April 2016 29 October 2016 25 December 2016

Please cite this article as: Roy Biran, Daniel Pond, Heparin coatings for improving blood compatibility of medical devices, Advanced Drug Delivery Reviews (2016), doi:10.1016/j.addr.2016.12.002

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ACCEPTED MANUSCRIPT Title: HEPARIN COATINGS FOR IMPROVING BLOOD COMPATIBILITY OF MEDICAL DEVICES

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Authors: Roy Biran*

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Daniel Pond

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* Corresponding author

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[email protected]

Affiliation:

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W.L. Gore & Associates, Inc. 3650 W Kiltie Lane

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Flagstaff, AZ 86005

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Journal:

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Advanced Drug Delivery Reviews

Submission Deadline:

March 31, 2016

Target Publication Date: Fall 2016

ACCEPTED MANUSCRIPT HEPARIN COATINGS FOR IMPROVING BLOOD COMPATIBILITY OF MEDICAL DEVICES Abstract

Blood contact with biomaterials triggers activation of multiple reactive mechanisms that can impair the

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performance of implantable medical devices and potentially cause serious adverse clinical events. This

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includes thrombosis and thromboembolic complications due to activation of platelets and the

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coagulation cascade, activation of the complement system, and inflammation. Numerous surface coatings have been developed to improve blood compatibility of biomaterials. For more than thirty

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years, the anticoagulant drug heparin has been employed as a covalently immobilized surface coating on a variety of medical devices. This review describes the fundamental principles of non-eluting heparin

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coatings, mechanisms of action, and clinical applications with focus on those technologies which have been commercialized. Because of its extensive publication history, there is emphasis on the Carmeda®

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bonding of heparin.

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Bioactive Surface (CBAS® Heparin Surface), a widely used commercialized technology for the covalent

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CONTENTS 1. INTRODUCTION

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2. COAGULATION AND HEPARIN MECHANISM OF ACTION 3. APPROACHES TO HEPARIN IMMOBILIZATION FOR THROMBORESISTANCE

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4. COMMERCIAL HEPARIN COATING TECHNOLOGIES

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5. MECHANISM AND PROPERTIES OF COVALENT HEPARIN SURFACES

7. PROTEIN BINDING TO HEPARIN SURFACES

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8. PRODUCT CONSIDERATIONS

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6. IMPORTANCE OF PRESERVING AT BINDING

9. PERFORMANCE OF CBAS® HEPARIN SURFACES IN VIVO

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10. POTENTIAL ADVERSE REACTIONS TO HEPARIN: EVIDENCE ON HEPARIN INDUCED

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11. CONCLUSIONS

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THROMBOCYTOPENIA (HIT) ASSOCIATED WITH HEPARIN-CONTAINING MEDICAL DEVICES

12. REFERENCES

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1.0 INTRODUCTION The activation of blood defense mechanisms upon exposure to biomaterials poses a challenge to the

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design and performance of blood contacting medical devices. Activation of the coagulation cascade,

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complement system, cellular inflammatory mechanisms, and platelets are among the key adverse

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reactions of blood that may compromise the performance of medical devices [1-2]. This may manifest clinically as thrombotic occlusion and embolization across a spectrum of cardiovascular medical devices,

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including vascular stents, grafts, and catheters, as well as cardiopulmonary bypass and oxygenation equipment, prosthetic valves, and ventricular assist devices. In some cases, for example in patients with

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coronary stents, mechanical heart valves, and left ventricular assist devices, chronic pharmacological inhibition with antiplatelet or anticoagulant drugs is required to protect against thrombotic

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complications.

Modification of medical device surfaces to improve blood compatibility has been sought to reduce

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device-related thrombus formation and inflammatory reactions. Surface modification technologies can be assigned into two broad categories: passivation of material surfaces and bioactive surface treatments and coatings [3]. Passive approaches are aimed at reducing the inherent thrombogenicity of the material surface through modification of surface chemistry (e.g. hydrophilicity) or material physical structure (e.g. topography). Bioactive strategies employ direct pharmacologic inhibition of the coagulation response by local drug delivery or permanent immobilization of an active agent. A precipitating event in the modern field of blood compatible surface modifications was the serendipitous discovery of the thromboresistant properties of a heparin coated surface by Gott and colleagues in 1963 [4]. It was observed that by temporarily immobilizing the anticoagulant drug heparin at the device surface, there was marked reduction in thrombus formation on materials implanted into

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the vena cava. Numerous approaches to hemocompatible surface modifications have been described since [1][3][2], including a number of heparin-based surface modifications [5-8].

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The focus of this review is on a specific subset of commercialized non-eluting heparin coating

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technologies which were developed for use in the medical device industry. Of the various heparin-based

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technologies, the Carmeda® Bioactive Surface (CBAS® Heparin Surface; Carmeda AB, Upplands Väsby, Sweden), has the most extensive publication history describing both basic biochemical mechanisms and

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clinical applications. Hence, this review will focus on the immobilization of the anticoagulant drug

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heparin with emphasis on the CBAS® Heparin Surface.

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2.0 COAGULATION AND HEPARIN MECHANISM OF ACTION

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Thrombus formation is the result of two interdependent mechanisms, platelets and circulating protein

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clotting factors. Platelets, small anuclear cells that circulate in blood in ranges from 150 x 106/mL to 400 x 106/mL are a critical component of hemostasis. Activation of platelets by a variety of stimuli triggers complex pathways that result in platelet aggregation and the release of potent pro-thrombotic molecules. It is well known that blood contact with artificial surfaces can elicit platelet activation by a variety of mechanisms[1], including device related alteration in blood flow that trigger shear-related platelet activation [9], and due to direct platelet adherence to the deposited protein layer on synthetic surfaces of the device, an event largely attributed to adsorption of fibrinogen [1-2]. Activated platelets undergo dramatic shape changes which promote aggregation with other platelets, and release platelet and pro-coagulant agonists (such as thromboxane A2, ADP, and FVa) [10]. The phospholipids of the platelet membrane also serve as the substrate for activated clotting factors, resulting in local amplification of the coagulation cascade. Aggregation of platelets, together with explosive activation of protein clotting factors, may result in significant thrombus accumulation on the device surface, 4

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embolization of thrombus particles into the bloodstream, and may cause detectable reductions in circulating platelet count (consumption of platelets).

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The protein clotting factors are a set of structurally similar serine proteases that circulate in the plasma

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as inactive proenzymes. After vascular injury, or through the introduction of foreign materials into the

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circulatory system, clotting factors are triggered and undergo activation in a sequential cascade-like fashion that culminates in the formation of a fibrin clot. This cascade consists of two pathways, the

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intrinsic and extrinsic, each of which is triggered by different mechanisms. Tissue factor that is released due to vascular injury is the primary initiator of extrinsic pathway [11]. The intrinsic pathway is

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considered the more critical pathway in biomaterial-associated thrombosis [1]. Contact activation of FXII, together with kallikrein and high molecular weight kininogen (HMWK), initiates the intrinsic

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pathway leading to activation of FX, and consequently conversion of prothrombin into thrombin.

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Thrombin converts soluble fibrinogen into insoluble fibrin, which polymerizes into an insoluble fibrous

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network. Clotting factor activation is typically accompanied by and promoted by platelet activation, and the resultant thrombus often contains both platelets, fibrin, and other entrapped cells (Figure 1). A key inhibitor of the clotting factors is the plasma serine protease inhibitor antithrombin (AT). AT binds and irreversibly inhibits the active forms of several clotting factors, including thrombin, FXa, FIXa, FXIa, and FXIIa [12]. AT-mediated inhibition of the clotting factors occurs at relatively slow rate, but is accelerated by binding to the polysaccharides heparan sulfate and heparin [13]. Heparin is a naturally occurring linear polysaccharide that shares chemical and structural similarity to heparan sulfate, a cell surface proteoglycan that provides the natural anticoagulant surface activity of the vascular endothelium [14]. Unlike heparan sulfate, heparin is largely intracellular, within the granules of mast cells. Heparin consists primarily of two highly sulfated sugar monomers, which occur as repeating disaccharide units. The anticoagulant function of heparin is dependent on a specific sequence of five sugars (the so-called pentasaccharide sequence), which are required for efficient binding of AT 5

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[15]. This sequence is only found in approximately one-third of the molecules in a commercial heparin preparation [16, 17][18]. Binding of AT to the heparin pentasaccharide sequence causes a

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conformational change in the AT molecule and greatly accelerates the rate of AT-mediated inhibition of the various serine protease clotting factors by a factor of 100-1000. Importantly, heparin is not

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consumed in the reaction and is capable of continuously catalyzing inhibition of activated clotting

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factors. However, heparin in the blood stream is quickly cleared from circulation through a combination

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of saturable cell-based binding and non-saturable renal clearance [19-23], with an average half-life of approximately 60 minutes for unfractionated heparin (UFH) and longer a longer half-life for low

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molecular weight heparins (LMWH).

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3.0 APPROACHES TO HEPARIN IMMOBILIZATION FOR THROMBORESISTANCE

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Heparin-coated blood contacting medical devices have been in clinical application for more than three decades. A comprehensive description and comparison of the various commercial technologies has not been possible due to the lack of published detailed technical information on all the technologies. A partial list of commercial heparin coating technologies used in the medical device industry is provided in Table 1.

Heparin immobilization technologies can be divided into two broad categories: eluting technologies that release heparin from the device and non-eluting technologies intended for permanent covalent immobilization of heparin to the device surface. Release-based approaches are essentially drug delivery systems that can prevent local device-related thrombus acutely. The release rate of heparin from the surface may be tailored through physical entrapment or ionic binding of heparin to the surface. For example, complexes of heparin with branched surfactants bearing quaternary ammonium groups can be deposited on a material surface. Blood contact causes release of the ionic complex from the surface, but 6

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the presence of the surfactant slows the rate of heparin release. Other elution-based technologies have been described in previous reviews [3,6].

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The alternative approach intended to confer long-term surface thromboresistance is to permanently

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immobilize heparin to the device surface. By virtue of its strong net negative charge, low pKa due to the

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abundance of caroboxyl and sulfo groups, and variety of chemically active functional groups, heparin can be readily immobilized by different surface conjugation chemistries [7]. Each repeating disaccharide

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unit offers at least one carboxyl and hydroxyl functional group which may be activated and subsequently attached to a compatible functional group on the target surface. This may be achieved by direct

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chemical activation of the surface to introduce complementary functional groups for immobilization of heparin, or through application of an intermediary priming matrix to which the heparin can be

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covalently linked. For example, the carbodiimide crosslinker EDC has been used to activate carboxyl

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groups along the heparin chain and then conjugate to amines incorporated into the target surface [24-

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25] . Periodate oxidation of vicinal diols introduces aldehydes along the heparin chain, which may also be linked to an aminated surface by reductive amination [26]. It is important to recognize that covalent immobilization of heparin to a material is not a guarantee that the immobilized heparin will retain its anticoagulant activity. Chemical modification or obstruction of the critical pentasaccharide sequence will reduce or eliminate the ability of heparin to bind AT. Thus simply achieving covalent bonding of heparin to a surface may not be sufficient to produce active thromboresistance on the surface [25] . In this context, it is relevant to recognize that the standard metric of injectable heparin potency, expressed as International Units (IU) of heparin, is not a useful means of assessing the activity of covalently bonded heparin because the reaction kinetics of bound heparin are drastically different from freely soluble heparin. For this reason it is appropriate to assess the functional activity of covalently bonded heparin by measuring the capacity of the surface to specifically uptake AT from solution [27]. An immobilization method that is durable and retains the 7

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catalytic function of heparin has the potential to confer thromboresistance to a surface for extended periods of time. These non-eluting commercialized technologies are the focus of the remainder of this

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review.

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4.0 COMMERCIAL HEPARIN COATING TECHNOLOGIES

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While there exist numerous means to immobilize heparin to a substrate, only a relative few technologies have been successfully employed in marketed medical devices, with only a subset designed as non-

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eluting surfaces. Of those commercial covalent chemistries, even fewer have demonstrable evidence of surface heparin bioactivity. The amount of available published information, particularly of a technical

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nature, differs widely between the commercial technologies and as a result, a comprehensive

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comparison among them is not entirely possible. The following provides an overview of several relevant

4.1

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commercial non-eluting heparin coatings.

BioInteractions ASTUTE® Advanced Heparin Coating / Medtronic Trillium® Biosurface

The ASTUTE® Advanced Heparin Coating was developed by BioInteractions Ltd. and is licensed to Medtronic as the Trillium® Biosurface. The coating consists of a hydrophilic priming layer (a modified polyethyleneimine) that enables adsorption to a variety of surfaces. Sulfonate bearing groups, PEG chains, and heparin molecules are covalently attached to the priming layer [28]. The coating is described as non-eluting, and data published by the manufacturer describes functional activity of the surface as measured by specific uptake of AT [29]. This technology has been used for coating blood contacting equipment used in cardiopulmonary bypass (CPB) and on hemodialysis catheters. 4.2 8

Maquet BIOLINE® Coating

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The BIOLINE® heparin coating is was originally developed by Jostra AG and is now a technology owned by Maquet Medical (Getinge Group) and incorporated into CPB equipment and vascular grafts. The

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technology consists of a recombinant human albumin coating to which heparin is covalently attached [30-31]. Detailed technical data on the coating chemistry and demonstration of surface heparin

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functionality by uptake of AT has not been published. In a previous review it was noted that heparin

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used is of high molecular weight and that the bonding approach preserves the active sequence of the

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heparin [5], however no supporting information was provided.

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4.3 CORLINE® Heparin Surface (CHS™)

The CORLINE® Heparin Surface (CHS™), developed by the Swedish company Corline Systems, AB, has

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been in clinic use since 1997. One major commercial application of the technology was in coronary

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stents. The CHS™ surface is composed of macromolecular complexes of unfractionated heparin covalently attached via a heterobifunctional crosslinker to a polyamine carrier chain [32]. The ratio of

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heparin to polyamine carrier is approximately 70 molecules of heparin coupled to a polyamine carrier chain. The coating process involves first preconditioning the surface with a layer of cationic polyamine and then attaching the pre-formed heparin complexes to the polyamine through ionic interactions [33]. The result is a non-leaching surface, and published reports have demonstrated detectable heparin density and AT uptake on the CHS™surface [34-35]. Since 2005, Corline began to expand the application of their heparin technology beyond medical devices. The technology is being investigated to treat biologic products, including cells, to improve therapies in regenerative medicine by shielding transplanted organs and cells from adverse immune reactions and reducing the inflammatory reaction to implanted collagen matrices.

4.4 Flowline BIPORE® Heparin surface 9

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The Flowline BIPORE® Heparin surface (Jotec GmbH) is described as heparin that is bonded through covalent and ionic interactions to the substrate. This presumably involves an intermediate adhesive

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layer between the device surface and the heparin, but the nature of this layer has not been published. Additionally, no published data providing biochemical evidence of surface heparin functionality could be

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found. This heparin surface is marketed by Jotec as the FlowLine Bipore® Heparin ePTFE vascular graft

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with heparin coating.

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4.5 Surmodics Photolink® Heparin Coating

Surmodics, Inc. developed a photolinking technology that serves as a platform for covalent

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immobilization of a variety of coatings. The process involves application of a photoreagent to the

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substrate followed by UV illumination under wet or dry conditions [36]. This approach has been used by

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Surmodics to produce a covalently immobilized heparin surface. Surmodics coatings have been used on commercial medical devices throughout the world, although specific information on which devices use the Surmodics technology are not disclosed.

4.6 Perouse POLYMAILLE® Flow Plus Heparin The PM® Flow Plus Heparin Surface used by the French company Perouse Medical (acquired by the Vygon Group in 2015) is a covalent heparin surface used on ePTFE vascular grafts. Technical information on the properties of the surface, including biochemical evidence of surface heparin functionality, have not been found in the published literature.

4.7 Medtronic Hepamed™ Heparin Coating 10

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The Hepamed™ coating developed by Medtronic was a covalent heparin coating applied to coronary stents. The coating consists of a poly(vinylsiloxane) that is first covalently attached to the stent surface.

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This is followed by grafting a copolymer to the poly(vinylsiloxane) followed by a third layer consisting of polyethyleneimine which is covalently attached to the copolymer. Finally heparin is covalently coupled

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to the polyethyleneimine [37]. The heparin used was not depolymerized or enriched for the high affinity

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fraction of heparin molecules. Published data have demonstrated functional activity of the heparin

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surface by specific uptake of AT [37-38].

CARMEDA® Bioactive Surface (CBAS® HEPARIN SURFACE)

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This heparin bonding technology was developed by Carmeda AB, a wholly owned subsidiary of W.L.

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Gore & Associates, Inc. The technology has been used in a variety of applications including CPB

grafts.

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equipment, hemodialysis catheters, ventricular assist devices, vascular stents, stent grafts, and vascular

The Carmeda heparin binding approach employs a single covalent bond between the reducing end of the heparin molecule and the material substrate [39]. Unfractionated heparin is first partially depolymerized by nitrous acid deamination. The process yields heparin molecules of a reduced molecular weight that contain single reactive aldehyde groups at their reducing terminus. The depolymerized heparin is subsequently covalently bonded by reductive amination to a substrate that contains amine functional groups. The amines are introduced onto the surface by application of base matrix that consists of alternating layers of the anionic polysaccharide dextran sulfate and the cationic polymer polyethyleneimine (Figure 2). The base matrix can be deposited on a diverse types of materials (polymers, metals, glass). The end result is a permanently immobilized, stable, non-leaching coating that is a few hundred nanometers thick [40]. 11

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The Carmeda approach of end-point attachment is predicated on the availability of relatively high affinity AT-binding preparations of heparin and the principle of preserving the ability of heparin to bind

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AT. Its development was spurred by a combination of events: the early and discouraging attempts to permanently bind heparin to surfaces, which often failed to preserve heparin’s anticoagulant function,

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as well as increased understanding of heparin’s mechanism of action, including the discovery of the

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critical pentasaccharide sequence [15]. Biochemical evidence of surface heparin functionality as

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measured by the specific uptake of AT has been demonstrated in multiple studies [41-44].

5.0 MECHANISM AND PROPERTIES OF COVALENT HEPARIN SURFACES

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The following sections review In vitro studies of the end-point attached (EPA) heparin of the CBAS®

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Heparin Surface which elucidated the basic mechanisms by which EPA-heparin acts in blood, including

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additional features not associated with freely soluble heparin that is administered systemically. An illustrative comparison and summary of basic mechanisms of freely soluble heparin, the natural heparan sulfate of the endothelium, and EPA-heparin is shown in Figure 3.

5.1

Reaction Kinetics

The reaction kinetics for an immobilized heparin surface are distinctly different from those of systemically administered heparin in solution. Functional non-eluting heparin surfaces would not be expected to impact clotting in the bulk, and hence have no systemic anticoagulant effects. Studies of EPA-heparin under controlled conditions in vitro have demonstrated that the inhibitory capacity of EPAheparin toward activated clotting factors is limited by convective transport of reactants [45] and flow rate has a strong influence on the uptake of AT on the surface [46] . This has implications on the

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relationship between surface AT uptake capacity and performance measures of the surface in blood

Inhibition of Activated Clotting Factors

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5.2

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(discussed further in Section 6.0).

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Experiments conducted using recirculating in vitro blood and plasma contact models have demonstrated

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that materials coated with EPA-heparin reduce the formation of activated thrombin [25,27,47-48] and FXa [27, 41]. In similar models it was also identified that the intrinsic clotting cascade, in which FXII

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activation is a key upstream trigger, is an important target of EPA-heparin [35,49]. Contact with negatively charged surfaces by key initiators of the intrinsic pathway (high molecular weight kininogen,

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prekallikrein, and FXII) is required for activation [50]. In a whole human blood in vitro model examining

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the CBAS® Heparin Surface, Gore et al. [25] also noted the absence of thrombin-antithrombin (TAT)

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complexes and low levels of fluid phase thrombin activation markers in blood that had recirculated over end-point attached heparin for a period of an hour. This was consistent with efficient inhibition of the clotting cascade upstream of thrombin, likely through the intrinsic pathway. An important lesson from the studies of contact activation is that functionally inactive immobilized heparin may actually accelerate activation of the intrinsic pathway by virtue of the strong net negative charge imparted on the surface. Surfaces produced with high heparin density but low AT uptake were efficient in the uptake of FXII, but failed to promote its inhibition [35]. This raises the possibility that an inactive heparin surface that retains heparin’s net negative charge may have the unintended consequence of promoting coagulation rather than preventing it.

5.3

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Reduced Complement Activation and Inflammation

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The earliest clinical applications of heparin surfaces was on materials used in extracorporeal circulation, where the high surface area exposure to the polymeric materials of the circuits was known to trigger

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systemic inflammation due to complement activation and cellular inflammatory reactions [51]. Using in vitro models, EPA-heparin has been shown to reduce complement activation (C3 activation products, C5

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activation products, terminal complement complex) [52-59] as well as cellular markers of inflammation

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[60-61]. The heparin-based mechanism for this effect is believed to be an indirect result of inhibition of

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the contact activation pathway, which can trigger activation of the complement cascade [5] as well direct inhibition of complement proteins by other serine protease inhibitors enriched on the EPA-

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heparin surface, such as C1-Inhibitor [58]. This may also have downstream effects on cellular elements

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of inflammation, as inhibition of complement reduces adhesion of granulocytes to surfaces [6].

Reduced Platelet Adherence and Activation

An additional feature of immobilized heparin is the reported resistance to platelet adhesion and activation. In vitro recirculatory models, in which platelets are counted before and after exposure and biomarkers of platelet activation (e.g. beta-thromboglobulin and platelet factor 4) were measured in plasma, demonstrated that EPA-heparin surfaces result in reduced platelet adhesion and activation compared with control materials [25,48,57-58,62-66]. Reduced platelet adhesion is attributed to reduction of fibrinogen deposition produced from a functionally active heparin surface, and the extent of reduction is correlated with the extent of AT uptake [5]. Reduced activation can be attributed to the overall considerable reduction of platelet adherence, as well as to the inhibition of platelet stimulating factors such as thrombin. It is however interesting that in its freely soluble state, heparin has mild platelet stimulating properties [67]. 14

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6.0 IMPORTANCE OF PRESERVING AT BINDING The ability of heparin to inhibit the clotting cascade as well as reduce platelet attachment is dependent

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on the specific uptake of AT by the immobilized heparin [25,41-24,44,68]. Gore et al. [25] conducted a

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controlled evaluation comparing AT uptake and performance of various heparin surfaces using the same base matrix and material. Only end-point attached heparin conferred thromboresistance in a sensitive

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recirculating blood loop model using freshly collected non-anticoagulated human blood. Heparin

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attached by multiple covalent bonds using the common carboxylic reactive linker EDC failed to preserve thromboresistance, as did periodate oxidized heparin, which creates multiple aldehyde functionality

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within heparin molecules. Further evaluation of the surfaces after blood contact revealed that

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antithrombin uptake from blood was only detectable on the end-point attached heparin surface, further indicating that loss of heparin functionality is possible with some linking chemistries (Figure 4). It is

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important to note that these chemistries may still be viable approaches to retaining some functional activity of the heparin molecules, but the reaction conditions may need to be carefully manipulated so as to minimize interference with the AT binding site. Resistance to platelet adhesion has also been shown to be dependent on AT uptake of EPA-heparin [25,44] as well several other heparin coatings which have demonstrated AT uptake [34,37]. The resistance to platelet binding may thus be the indirect result of the action of heparin on the coagulation cascade, not solely due to the negative charge imparted by heparin.

In an in vitro recirculatory model, Sanchez et al. examined the relationship between the amount of AT uptake on the surface and FXII activation and plasma clotting time. Based on the process used for the CBAS® Heparin Surface, the data pointed to preserved functional activity in the low single pmol of AT 15

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uptake per cm2 surface area of material [42]. Above the threshold value of AT uptake, no additional inhibition of FXIIa could be detected, and plasma clotting times were not further increased. This

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suggests that beyond a certain density of functional activity on the surface, effective thromboresistance is achieved and there may be little additional benefit gained from greater surface concentration of AT.

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Similar plateau-like effects were also identified when studying other heparin coatings for which AT

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uptake data was available [34,37]. It was proposed that steric hindrance as result of heparin interaction

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with plasma proteins, including AT, may have been a contributing mechanism [42]. This may also be explained by kinetic modeling of covalently bonded heparin surfaces, which demonstrated that above a

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specific surface concentration of AT, reactant flux to the surface was rate limiting [45], and hence increasingly higher levels of AT uptake would not necessarily contribute to any further biological effect.

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It is important to recognize that the relationship between specific AT uptake values and certain

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performance attributes attributed to one type of heparin surface bonding technology may not be

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universal and should not be assumed to be the same for other heparin technologies. While AT uptake is a key measure of surface functionality, heparin is not the only entity exposed on a heparin coated surface. Other chemical groups, surface charge, surface coverage, and specific flow dynamics associated with a specific coating technology may also influence the reactivity of the surface with blood components. The level of AT binding required to mitigate against these effects will thus likely vary between technologies.

7.0 PROTEIN BINDING TO HEPARIN SURFACES Heparin is known to bind to many proteins, including protease inhibitors other than AT, enzymes, growth factors, chemokines, and a variety of pathogen proteins [69]. Heparin-protein interactions occur through non-specific ionic interactions (because of heparin’s strong anionic character) [70] and through 16

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sequence-specific high affinity interactions (as with AT) [71] . Indeed because of the recognized relatively high affinity binding (KD < 10-6 M) of certain types of proteins, heparin has been used as a

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vehicle for drug delivery, most notably of growth factors [8].

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While it is recognized that selective AT uptake is required for a functionally active thromboresistant heparin surface, it has also been proposed that other protein interactions may contribute to the

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observed hemocompatibility of functional surfaces. Weber et al. [58] proposed that binding (or notable

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absence) of certain plasma proteins may also contribute to the mechanism of action, most notably the absence or reduced binding of platelet adhesive proteins such as fibrinogen and complement protein C3

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[57]. Previous studies have demonstrated differences in the uptake of these proteins between various

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heparin technologies, with lowest binding of fibrinogen and C3 on the CBAS® Heparin Surface [57]. In a study of EPA-heparin Gore et al. [25] observed that AT constituted 40% of the total protein uptake from

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blood after acute contact, but in separate studies also noted the presence of other protease inhibitors such as heparin cofactor II and the absence of fibrinogen, cell adhesive proteins such as fibronectin and vitronectin, and complement proteins [72]. The net result of these acute protein interactions may contribute to the long-term remodeling that takes place chronically on blood contacting surfaces coated with the CBAS® Heparin Surface. In the same model described by Begovac et al. [43], which demonstrated improved patency at 6 months and sustained AT uptake on vascular grafts for at least 3 months in vivo, there was significantly reduced protein deposition compared to uncoated controls [73] (Figure 5).

8.0 PRODUCT CONSIDERATIONS

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The ability to preserve AT uptake under physiological conditions is a key attribute required for creating a functionally active heparin coated surface. While robust in vitro data in model systems are important,

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there are other important considerations for development of a heparin coating to be used as part of an implantable device in the clinic. Many of these requirements are part of international and regional

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standards required by regulatory bodies. Specific considerations for a heparin coating include

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demonstration that the coating is sufficiently durable to survive downstream product processing and

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shelf life, including mechanical manipulation, sterilization, and packaging. Here multiple mechanisms may be involved in the deterioration of heparin activity: chemical degradation, chemical modification or

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reduced availability of the active site, and mechanical damage to the coating (ie. loss of integrity). Hence it is not only important to demonstrate AT uptake initially, but to ensure that sufficient levels are

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maintained throughout processing and shelf life of the product. In addition, functionally active heparin

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must be sufficiently uniform across the surface area of the material so that the thromboresistant

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performance of the surface is not compromised by uncoated regions or by exposure of any other component of the surface. For this reason, biochemical activity must also be verified by performance testing in blood and other appropriate preclinical models.

Because it is not consumed in the AT-mediated inhibition of clotting factors, immobilized functionally active heparin should in theory render a surface thromboresistant over extended periods of time if the heparin is not otherwise degraded. This catalytic activity of heparin is the key feature of its attractiveness for permanent covalent immobilization. In a series of chronic implant studies, it was shown that AT-uptake was retained on the CBAS® Heparin Surface of ePTFE vascular grafts after 3 months in vivo [43] and after at least 1 year in ventricular assist devices (VADs) [74-75]. Durability of the surface is further supported by anecdotal reports of retained functionally active AT uptake by CBAS® Heparin Surfaces in explants of the GORE® PROPATEN® Vascular Graft after implant periods of up to 8 18

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years [76]. Published data on long-term in vivo durability of other covalent heparin coating technologies

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could not be found.

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9.0 PERFORMANCE OF CBAS® HEPARIN SURFACES IN VIVO

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The CBAS® Heparin Surface has been successfully used on a number of blood contacting medical devices

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and substrates for both acute and chronic settings. This includes hemodialysis catheters, peripheral and

Extracorporeal Circulation Equipment

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coronary vascular stents, stent grafts, and ventricular assist devices.

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Blood exposure to a high surface area of polymeric materials of extracorporeal circuits is known to

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trigger systemic inflammation due in part to complement activation [51]. In addition, longer term circulation on extracorporeal membrane oxygenation (ECMO) is also complicated by bleeding complications due to chronic pharmacologic anticoagulation required to prevent circuit thrombosis. Application of the CBAS® Heparin Surface to blood contacting equipment of extracorporeal circuits resulted in significant reductions in clotting factor, complement activation, cellular inflammatory markers, and platelet activation in animal models [59,77-78] and in human clinical studies [54, 79-82] . In addition, it was demonstrated that systemic heparin dosing could be reduced or eliminated without adverse coagulation or inflammatory responses [83-85] and resulted in a lower rate of blood loss requiring transfusion, shorter hospitalization periods, and improvement in treatment cost [86].

Despite a wealth of strong in vitro data demonstrating reductions in adverse blood reaction to various heparin coated circuits, widespread and consistent clinical benefit in the hands of different research 19

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groups has not been as clear, and there is a lack of studies that directly compare the performance attributes of different heparin coated circuits [87]. However, meta-analyses of numerous studies,

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including both heparin eluting and covalently bonded heparin circuits have demonstrated improved outcomes with heparin-coated circuits compared to uncoated circuits [88]. In a more contemporary

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review of the subject, there continue to be improved outcomes associated with heparin coated surfaces

SC

[89]. In a meta-analysis that compared the CBAS® Heparin Surface with the an ionically bonded heparin

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surface (DURAFLO II®) and uncoated circuits, there was a clear benefit associated with the heparin coated circuits, and a greater magnitude and significance associated with the CBAS® Heparin coated

Ventricular Assist Devices

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circuits [90].

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Ventricular assist devices (VADs) are used to bridge patients for heart transplantation. Systemic treatment with anticoagulants is required to mitigate against clot formation in the equipment. However, serious thromboembolic events still occur. Application of the CBAS® Heparin Surface to VADs developed by Berlin Heart GmbH reduced clot deposition within the pump and lengthened the duration that patients could be effectively maintained on the VAD [91].

9.3

Vascular Stents

Device-related thrombosis is a potentially life threatening adverse outcome associated with the use of coronary stents. What were initially high acute thrombosis (SAT) rates with the first generations of metallic stents was reduced due to improvements in stent placement techniques, product design enhancements, and effective dual antiplatelet therapy [92-95]. Even with these improvements, acute

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thrombosis rates were still between 1% and 3% [96]. Before the full emergence of drug eluting coronary stents (DES), the CBAS® Heparin Surface and other heparin technologies were evaluated as a surface

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treatments for metallic coronary stents. Studies on a number of different stents indicated coating with the CBAS® Heparin surface resulted in improvement in thrombosis, reduced platelet deposition, and

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reduced intimal hyperplasia in animal models [44, 97-102]. In a large single center retrospective study

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significant reductions thrombosis rates were observed for the stents coated with the CBAS® Heparin

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Surface compared with bare metal stents [96], however registry data from a larger patient population did not demonstrate significant differences between coronary stents coated with the CBAS® Heparin

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Surface and uncoated bare metal stents [103]. This was due in part to difficulty in effectively powering studies because of the overall low rates of acute thrombosis. Two other covalent heparin coatings with

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established surface heparin activity were used on coronary stents and had a similar clinical experience

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[38, 104-107].

Vascular Grafts

Synthetic vascular grafts have a long history of use as “off the shelf” alternatives to autologous vein for peripheral bypass of diseased vessels. Synthetic grafts composed of ePTFE provided favorable outcomes in peripheral bypass, but nevertheless produced lower patency rates than autologous vein. As a result ePTFE grafts are considered a suitable prosthetic when autologous saphenous vein is not available. As diameter decreases below 6mm, patency of synthetic vascular grafts is generally viewed as suboptimal, particularly in bypass applications below the knee. Primary modes of failure include occlusion of the graft lumen by thrombus or intimal hyperplasia, both of which contribute to reduced patency. Early studies of ePTFE vascular grafts coated with the CBAS® Heparin Surface demonstrated dramatic reduction in occlusive thrombus (Figure 6) and significant improvement in patency compared with

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uncoated control grafts for at least 6 months in vivo [43, 108]. Animal models also demonstrated that the CBAS® Heparin Surface reduced platelet attachment and peri-anastomotic intimal hyperplasia on

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ePTFE vascular grafts [109-110]. Extensive clinical evaluation of ePTFE vascular grafts coated with the CBAS® Heparin Surface have shown improved patency relative to uncoated grafts [40]. A prospective

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randomized trial across 11 centers in Scandinavia demonstrated significantly improved patency of the

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GORE® PROPATEN® Vascular Graft compared with uncoated control in patients with critical limb

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ischemia [111]. Retrospective multicenter analyses of the GORE® PROPATEN® Vascular Graft have also

POTENTIAL ADVERSE REACTIONS TO HEPARINIZED SURFACES: EVIDENCE ON HEPARIN

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demonstrated patency rates comparable to autologous vein [112].

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DEVICES

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INDUCED THROMBOCYTOPENIA (HIT) ASSOCIATED WITH HEPARIN-CONTAINING MEDICAL

There are risks associated with the use of heparin, including the rare but potentially life threatening complication of Heparin Induced Thrombocytopenia (HIT). HIT is a transient, antibody-mediated hypercoagulability state that can be life-threatening with an incidence rate of <1-5% in surgical patients [113]. It is caused by antibodies that form in response to complexes of heparin and platelet factor 4 (PF4). It is observed clinically as a severe decline in circulating platelets sometimes accompanied by thrombosis that follows a well described timeline [114-116], with typical onset of thrombocytopenia occurring between 5 and 10 days following heparin exposure. The immunological features of HIT are somewhat unique. Anti-PF4/heparin antibodies persist only briefly, disappearing from circulation between 50 and 85 days. The immune response is also not anamnestic. If circulating antibodies have disappeared, history of HIT does not predict formation of antibodies upon re-exposure to heparin [115].

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However if antibodies are already in circulation, as a result of recent heparin administration, reexposure to heparin accelerates thrombocytopenia [115].

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For devices incorporating heparin, there is a paucity of published studies on whether covalently

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immobilized heparin may cause or contribute to the condition. Available data have not demonstrated a

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causal relationship between covalently immobilized heparin and either the initial immunizing event or exacerbation of ongoing HIT. Definitive conclusions are difficult to draw because interpretation is

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confounded by the near ubiquitous use of relatively large doses of injectable heparin prior to, during,

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and after implantation of heparin coated devices [117].

Serology studies on the occurrence of anti-PF4/heparin antibodies over time in patients with devices

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coated with the CBAS® Heparin Surface have provided insight as to whether the presence of the CBAS®

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Heparin Surface affects the rate of anti-PF4/heparin antibody seroconversion. Two separate studies examining a total of 87 patients who received ventricular assist devices (VAD) showed no difference in

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the occurrence of anti-PF4/heparin antibodies in groups who received the devices with the CBAS® Heparin Surface compared with those who received uncoated devices [118-119]. Furthermore, in both the CBAS® Heparin Surface group and the uncoated group, approximately 66% of the patients who were initially positive for anti-PF4/heparin antibodies became seronegative after systemic heparin was discontinued [118].

Several case reports on the GORE® PROPATEN® Vascular Graft, which contains the CBAS® Heparin Surface, suggested that the presence of the covalently bonded heparin on the graft contributed to HIT [120-122]. These cases involved the use of systemic heparin perioperatively and/or postoperatively. In all but one of the cases, the timing of events and assay results were suggestive of delayed-onset HIT [117]. Delayed onset HIT is characterized by the presence of antibodies that are capable of heparinindependent platelet activation [123].It is frequently observed that patients with this condition

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experience declining platelet count and ongoing hypercoagulability even after heparin is discontinued. In one reported case of HIT associated with the GORE® PROPATEN® Vascular Graft, a follow-up

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investigation of the patient’s serum confirmed a serological profile consistent with delayed onset HIT, again calling into question the role of the graft in contributing to the event [117]. Numerous cases of

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delayed onset HIT have been reported in patients for which heparin has been discontinued and no

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heparin coated devices have been implanted. Analysis of the suspected delayed onset HIT cases

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associated with the presence of devices coated with the CBAS® Heparin Surface called into question

CONCLUSIONS

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whether the devices contributed to the condition or their presence was simply coincidental [117].

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Decades of investigation and clinical experience with covalently bonded heparin coatings have

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demonstrated the basic mechanisms and clinical benefits of this technology in a number medical device applications. Because it is not a drug releasing technology, the mechanisms of a permanently bonded heparin surface are different from those of device-based drug releasing systems, and it follows that design considerations also differ. Numerous studies have demonstrated that retaining the anticoagulant activity of heparin, by preserving the ability to bind antithrombin and catalyze the inhibition of clotting factors, is central to the design of a functional heparin surface. Not all approaches to heparin bonding achieve the prerequisite of preserving antithrombin binding, and it is thus important to recognize that not all heparin coatings are equivalent. Although there continue to be development and advances in new and novel coating technologies for blood-contacting medical devices, functionally active noneluting heparin bonding remains a viable and effective approach for enhancing the hemocompatibility of medical devices.

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CARMEDA® and CBAS® are registered trademarks of Carmeda AB GORE® and PROPATEN® are registered trademarks of W.L. Gore & Associates, Inc.

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ASTUTE™ is a trademark of Biointeractions Ltd.

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TRILLIUM® is a registered trademark of Medtronic, Inc.

AMC THROMBOSHIELD® is a registered trademark of Edwards Lifesciences, LLC.

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HYDRAGLIDE® is a registered trademark of Atrium Medical (Maquet Getinge Group) BIOLINE® is a registered trademark of Maquet Cardiovascular, LLC (Maquet Getinge Group)

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CORLINE® is a registered trademark of Corline Systems AB CHS™ is a trademark of Corline Systems AB

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Flowline BIPORE® Heparin is a registered trademark of Jotec, GmbH PHOTOLINK® is a registered trademark of Surmodics, Inc.

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PM® is a registered trademark of Perouse Medical

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DURAFLO® II is a registered trademark of Edwards Lifesciences, LLC

Acknowledgements:

The authors acknowledge Dr. Johan Riesenfeld, Dr. Jonas Andersson, and Dr. Jennifer Recknor for expert review of the manuscript.

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12.0

REFERENCES

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[22] J. Mahadoo, L. Heibert, L.B. Jaques, Vascular sequestration of heparin, Thromb Res, 12 (1978) 7990. [23] J. Dawes, D.S. Papper, Catabolism of low-dose heparin in man, Thromb Res, 14 (1979) 845-860. [24] J.N. Lindon, E.W. Salzman, E.W. Merrill, A.K. Dincer, D. Labarre, K.A. Bauer, R.R. Rosenberg, Catalytic activity and platelet reactivity of heparin covalently bonded to surfaces, J Lab Clin Med, 105 (1985) 219226. [25] S. Gore, J. Andersson, R. Biran, C. Underwood, J. Riesenfeld, Heparin surfaces: Impact of immobilization chemistry on hemocompatibility and protein adsorption, J Biomed Mater Res B Appl Biomater, 102 (2014) 1817-1824. [26] T. Islam, M. Butler, S.A. Sikkander, T. Toida, R.J. Linhardt, Further evidence that periodate cleavage of heparin occurs primarily through the antithrombin binding site, Carbohydr Res, 337 (2002) 22392243. [27] G. Elgue, M. Blomback, P. Olsson, J. Riesenfeld, On the mechanism of coagulation inhibition on surfaces with end point immobilized heparin, Thromb Haemost, 70 (1993) 289-293. [28] S. Sandhu, A. Luthra, New biointeracting materials, Medical device technology, 13 (2002) 10-14, 16. [29] Astute advanced heparin coating overview, Biointeractions Ltd., 2016. [30] E. Tayama, N. Hayashida, K. Akasu, T. Kosuga, S. Fukunaga, H. Akashi, T. Kawara, S. Aoyagi, Biocompatibility of heparin-coated extracorporeal bypass circuits: new heparin bonded bioline system, Artificial organs, 24 (2000) 618-623. [31] BIOLINE coating, Maquet, 2016. [32] E.M. Kristensen, H. Rensmo, R. Larsson, H. Siegbahn, Characterization of heparin surfaces using photoelectron spectroscopy and quartz crystal microbalance, Biomaterials, 24 (2003) 4153-4159. [33] M. Johnell, G. Elgue, R. Larsson, A. Larsson, S. Thelin, A. Siegbahn, Coagulation, fibrinolysis, and cell activation in patients and shed mediastinal blood during coronary artery bypass grafting with a new heparin-coated surface, The Journal of thoracic and cardiovascular surgery, 124 (2002) 321-332. [34] J. Andersson, J. Sanchez, K.N. Ekdahl, G. Elgue, B. Nilsson, R. Larsson, Optimal heparin surface concentration and antithrombin binding capacity as evaluated with human non-anticoagulated blood in vitro, J Biomed Mater Res A, 67 (2003) 458-466. [35] R.M. Cornelius, J. Sanchez, P. Olsson, J.L. Brash, Interactions of antithrombin and proteins in the plasma contact activation system with immobilized functional heparin, J Biomed Mater Res A, 67 (2003) 475-483. [36] M. Lohdi, G. Opperman, J. Wall, A. Anderson, Surface modification chemistries and their utilization in microarrays, diagnostics and drug delivery, NSTI nanotechnology conference and trade show, 2005, pp. 389-392. [37] R. Blezer, L. Cahalan, P.T. Cahalan, T. Lindhout, Heparin coating of tantalum coronary stents reduces surface thrombin generation but not factor IXa generation, Blood Coagul Fibrinolysis, 9 (1998) 435-440. [38] W.J. van Der Giessen, H.M. van Beusekom, R. Larsson, P. Serruys, Heparin-Coated Coronary Stents, Current interventional cardiology reports, 1 (1999) 234-240. [39] O. Larm, R. Larsson, P. Olsson, A new non-thrombogenic surface prepared by selective covalent binding of heparin via a modified reducing terminal residue, Biomater Med Devices Artif Organs, 11 (1983) 161-173. [40] P.C. Begovac, D. Pond, J. Recknor, E. Scholander, Thromboresistant vascular graft, in: R. Siegel, S. Lyu (Eds.) Drug-device Combinations for Chronic Diseases, John Wiley and Sons, Inc., Hoboken, 2016, pp. 142-181. [41] K. Kodama, B. Pasche, P. Olsson, J. Swedenborg, L. Adolfsson, O. Larm, J. Riesenfeld, Antithrombin III binding to surface immobilized heparin and its relation to F Xa inhibition, Thromb Haemost, 58 (1987) 1064-1067.

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[42] J. Sanchez, G. Elgue, J. Riesenfeld, P. Olsson, Inhibition of the plasma contact activation system of immobilized heparin: relation to surface density of functional antithrombin binding sites, J Biomed Mater Res, 37 (1997) 37-42. [43] P.C. Begovac, R.C. Thomson, J.L. Fisher, A. Hughson, A. Gallhagen, Improvements in GORE-TEX vascular graft performance by Carmeda BioActive surface heparin immobilization, Eur J Vasc Endovasc Surg, 25 (2003) 432-437. [44] J.F. Kocsis, G. Llanos, E. Holmer, Heparin-coated stents, J Long Term Eff Med Implants, 10 (2000) 1945. [45] T. Lindhout, R. Blezer, P. Schoen, G.M. Willems, B. Fouache, M. Verhoeven, M. Hendriks, L. Cahalan, P.T. Cahalan, Antithrombin activity of surface-bound heparin studied under flow conditions, J Biomed Mater Res, 29 (1995) 1255-1266. [46] B. Pasche, G. Elgue, P. Olsson, J. Riesenfeld, A. Rasmuson, Binding of antithrombin to immobilized heparin under varying flow conditions, Artificial organs, 15 (1991) 481-491. [47] B. Pasche, K. Kodama, O. Larm, P. Olsson, J. Swedenborg, Thrombin inactivation on surfaces with covalently bonded heparin, Thromb Res, 44 (1986) 739-748. [48] H.P. Wendel, A.M. Scheule, F.S. Eckstein, G. Ziemer, Haemocompatibility of paediatric membrane oxygenators with heparin-coated surfaces, Perfusion, 14 (1999) 21-28. [49] J. Sanchez, G. Elgue, J. Riesenfeld, P. Olsson, Studies of adsorption, activation, and inhibition of factor XII on immobilized heparin, Thromb Res, 89 (1998) 41-50. [50] A.H. Schmaier, Contact activation: a revision, Thromb Haemost, 78 (1997) 101-107. [51] B. Nilsson, K.N. Ekdahl, T.E. Mollnes, J.D. Lambris, The role of complement in biomaterial-induced inflammation, Mol Immunol, 44 (2007) 82-94. [52] V. Videm, T.E. Mollnes, P. Garred, J.L. Svennevig, Biocompatibility of extracorporeal circulation. In vitro comparison of heparin-coated and uncoated oxygenator circuits, The Journal of thoracic and cardiovascular surgery, 101 (1991) 654-660. [53] U.R. Nilsson, O. Larm, B. Nilsson, K.E. Storm, H. Elwing, K. Nilsson Ekdahl, Modification of the complement binding properties of polystyrene: effects of end-point heparin attachment, Scand J Immunol, 37 (1993) 349-354. [54] T.E. Mollnes, V. Videm, O. Gotze, M. Harboe, M. Oppermann, Formation of C5a during cardiopulmonary bypass: inhibition by precoating with heparin, The Annals of thoracic surgery, 52 (1991) 92-97. [55] T.E. Mollnes, J. Riesenfeld, P. Garred, E. Nordstrom, K. Hogasen, E. Fosse, O. Gotze, M. Harboe, A new model for evaluation of biocompatibility: combined determination of neoepitopes in blood and on artificial surfaces demonstrates reduced complement activation by immobilization of heparin, Artificial organs, 19 (1995) 909-917. [56] M. Kirschfink, B. Kovacs, K. Mottaghy, Extracorporeal circulation: in vivo and in vitro analysis of complement activation by heparin-bonded surfaces, Circulatory shock, 40 (1993) 221-226. [57] N. Weber, H.P. Wendel, G. Ziemer, Quality assessment of heparin coatings by their binding capacities of coagulation and complement enzymes, J Biomater Appl, 15 (2000) 8-22. [58] N. Weber, H.P. Wendel, G. Ziemer, Hemocompatibility of heparin-coated surfaces and the role of selective plasma protein adsorption, Biomaterials, 23 (2002) 429-439. [59] R. Kopp, K. Mottaghy, M. Kirschfink, Mechanism of complement activation during extracorporeal blood-biomaterial interaction: effects of heparin coated and uncoated surfaces, ASAIO journal (American Society for Artificial Internal Organs : 1992), 48 (2002) 598-605. [60] P. Garred, T.E. Mollnes, Immobilized heparin inhibits the increase in leukocyte surface expression of adhesion molecules, Artificial organs, 21 (1997) 293-299.

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antiplatelet therapy. 30-day clinical outcome of the French Multicenter Registry, Circulation, 94 (1996) 1519-1527. [95] A. Schomig, F.J. Neumann, A. Kastrati, H. Schuhlen, R. Blasini, M. Hadamitzky, H. Walter, E.M. Zitzmann-Roth, G. Richardt, E. Alt, C. Schmitt, K. Ulm, A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents, N Engl J Med, 334 (1996) 10841089. [96] V. Gupta, B.R. Aravamuthan, S. Baskerville, S.K. Smith, M.A. Lauer, T.A. Fischell, Reduction of subacute stent thrombosis (SAT) using heparin-coated stents in a large-scale, real world registry, The Journal of invasive cardiology, 16 (2004) 304-310. [97] P.A. Hardhammar, H.M. van Beusekom, H.U. Emanuelsson, S.H. Hofma, P.A. Albertsson, P.D. Verdouw, E. Boersma, P.W. Serruys, W.J. van der Giessen, Reduction in thrombotic events with heparincoated Palmaz-Schatz stents in normal porcine coronary arteries, Circulation, 93 (1996) 423-430. [98] N.A. Chronos, K.A. Robinson, S.B. King, A. Lunn, D. White, A.B. Kelly, L.A. Harker, Heparin coated Palmaz-Schatz™ stents are highly thrombo-resistant: A baboon AV shunt study, Journal of the American College of Cardiology, 27 (1996) 84-85. [99] N.A. Chronos, K.A. Robinson, D. White, S.B. King, J. Koscis, A. Kelly, L. Harker, Heparin coating dramatically reduces platelet deposition on incompletely deployed Palmaz-Schatz™ in the baboon AV shunt, Journal of the American College of Cardiology, 27 (1996) 84. [100] E. Holmer, S. Hanson, N. Chronos, G. Llanos, J.F. Kocsis, On the mechanism for the nonthrombogenic properties of the Carmeda BioActive Surface on coronary stents; results from a baboon AV-shunt study, Holmer E, Hanson S, Chronos N, Llanos G, Kocsis JF, (1999) Abstract presented at Surfaces in Biomaterials '99; September 92-94, 1999; Scottsdale, AZ. [101] P.H. Lin, N.A. Chronos, M.M. Marijianowski, C. Chen, R.L. Bush, B. Conklin, A.B. Lumsden, S.R. Hanson, Heparin-coated balloon-expandable stent reduces intimal hyperplasia in the iliac artery in baboons, Journal of vascular and interventional radiology : JVIR, 14 (2003) 603-611. [102] P.H. Lin, N.A. Chronos, M.M. Marijianowski, C. Chen, B. Conklin, R.L. Bush, A.B. Lumsden, S.R. Hanson, Carotid stenting using heparin-coated balloon-expandable stent reduces intimal hyperplasia in a baboon model, The Journal of surgical research, 112 (2003) 84-90. [103] R. Mehran, E. Nikolsky, E. Camenzind, M. Zelizko, I. Kranjec, R. Seabra-Gomes, M. Negoita, S. Slack, C. Lotan, An Internet-based registry examining the efficacy of heparin coating in patients undergoing coronary stent implantation, American heart journal, 150 (2005) 1171-1176. [104] J. Wohrle, E. Al-Khayer, U. Grotzinger, C. Schindler, M. Kochs, V. Hombach, M. Hoher, Comparison of the heparin coated vs the uncoated Jostent--no influence on restenosis or clinical outcome, European heart journal, 22 (2001) 1808-1816. [105] M.C. Vrolix, V.M. Legrand, J.H. Reiber, G. Grollier, M.J. Schalij, P. Brunel, L. Martinez-Elbal, M. Gomez-Recio, F.W. Bar, M.E. Bertrand, A. Colombo, J. Brachman, Heparin-coated Wiktor stents in human coronary arteries (MENTOR trial). MENTOR Trial Investigators, The American journal of cardiology, 86 (2000) 385-389. [106] E. Semiz, C. Ermis, S. Yalcinkaya, O. Sancaktar, N. Deger, Comparison of initial efficacy and longterm follow-up of heparin-coated Jostent with conventional NIR stent, Japanese heart journal, 44 (2003) 889-898. [107] O.F. Bertrand, R. Sipehia, R. Mongrain, J. Rodes, J.C. Tardif, L. Bilodeau, G. Cote, M.G. Bourassa, Biocompatibility aspects of new stent technology, Journal of the American College of Cardiology, 32 (1998) 562-571. [108] P.C. Begovac, S. Frazer, A. Hughson, A. Holmqvist, Improved performance of a heparin-coated GORE-TEX® Vascular Graft, Begovac PC, Frazer S, Hughson A, Holmqvist A, Improved performance of a heparin-coated GORE-TEX® Vascular Graft (1999) Pages 123-125.

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[109] P.H. Lin, R.L. Bush, Q. Yao, A.B. Lumsden, C. Chen, Evaluation of platelet deposition and neointimal hyperplasia of heparin-coated small-caliber ePTFE grafts in a canine femoral artery bypass model, J Surg Res, 118 (2004) 45-52. [110] P.H. Lin, C. Chen, R.L. Bush, Q. Yao, A.B. Lumsden, S.R. Hanson, Small-caliber heparin-coated ePTFE grafts reduce platelet deposition and neointimal hyperplasia in a baboon model, Journal of vascular surgery, 39 (2004) 1322-1328. [111] J.S. Lindholt, B. Gottschalksen, N. Johannesen, D. Dueholm, H. Ravn, E.D. Christensen, B. Viddal, T. Florenes, G. Pedersen, M. Rasmussen, M. Carstensen, N. Grondal, H. Fasting, The Scandinavian Propaten((R)) trial - 1-year patency of PTFE vascular prostheses with heparin-bonded luminal surfaces compared to ordinary pure PTFE vascular prostheses - a randomised clinical controlled multi-centre trial, Eur J Vasc Endovasc Surg, 41 (2011) 668-673. [112] K. Daenens, S. Schepers, I. Fourneau, S. Houthoofd, A. Nevelsteen, Heparin-bonded ePTFE grafts compared with vein grafts in femoropopliteal and femorocrural bypasses: 1- and 2-year results, Journal of vascular surgery, 49 (2009) 1210-1216. [113] L.-A. Linkins, D.H. Lee, Frequency of heparin-induced thrombocytopenia, in: T.E. Warkentin, A. Greinacher (Eds.) Heparin-Induced Thrombocytopenia, CRC Press, Boca Raton, 2013. [114] A. Greinacher, T. Kohlmann, U. Strobel, J.A. Sheppard, T.E. Warkentin, The temporal profile of the anti-PF4/heparin immune response, Blood, 113 (2009) 4970-4976. [115] T.E. Warkentin, J.G. Kelton, Temporal aspects of heparin-induced thrombocytopenia, N Engl J Med, 344 (2001) 1286-1292. [116] N. Lubenow, R. Kempf, A. Eichner, P. Eichler, L.E. Carlsson, A. Greinacher, Heparin-induced thrombocytopenia: temporal pattern of thrombocytopenia in relation to initial use or reexposure to heparin, Chest, 122 (2002) 37-42. [117] T.E. Warkentin, Heparin coated intravascular devices and heparin-induced thrombocytopenia, in: T.E. Warkentin, A. Greinacher (Eds.) Heparin-Induced Thrombocytopenia, CRC Press, Boca Raton, 2013, pp. 573-590. [118] A. Koster, M. Loebe, R. Sodian, E.V. Potapov, R. Hansen, J. Muller, F. Mertzlufft, G.J. Crystal, H. Kuppe, R. Hetzer, Heparin antibodies and thromboembolism in heparin-coated and noncoated ventricular assist devices, The Journal of thoracic and cardiovascular surgery, 121 (2001) 331-335. [119] A. Koster, S. Sanger, R. Hansen, R. Sodian, F. Mertzlufft, C. Harke, H. Kuppe, R. Hetzer, M. Loebe, Prevalence and persistence of heparin/platelet factor 4 antibodies in patients with heparin coated and noncoated ventricular assist devices, Asaio J, 46 (2000) 319-322. [120] S. Thakur, J.P. Pigott, A.J. Comerota, Heparin-induced thrombocytopenia after implantation of a heparin-bonded polytetrafluoroethylene lower extremity bypass graft: A case report and plan for management, Journal of vascular surgery, 49 (2009) 1037-1040. [121] R. Gabrielli, A. Siani, M.S. Rosati, R. Antonelli, F. Accrocca, G.A. Giordano, G. Marcucci, Heparininduced thrombocytopenia type II because of heparin-coated polytetrafluoroethylene graft used to bypass, Ann Vasc Surg, 25 (2011) 840 e849-812. [122] M.D. Wheatcroft, E. Greco, L. Tse, G. Roche-Nagle, Heparin-induced thrombocytopenia in the presence of a heparin-bonded bypass graft, Vascular, 19 (2011) 338-341. [123] T.E. Warkentin, J.G. Kelton, Delayed-onset heparin-induced thrombocytopenia and thrombosis, Ann Intern Med, 135 (2001) 502-506. [124] I. W.L. Gore & Associates, The combination that lasts, W.L. Gore & Associates, Inc., 2012.

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Figure 1. Simplified illustration depicting activation of the coagulation cascade and platelets after contact with a material surface. Contact activation of the intrinsic pathway (via FXII activation) is triggered by the material surface. This culminates in production of thrombin and the conversion of fibrinogen into an insoluble fibrin network. Activation of the complement system, and downstream inflammatory responses, is also triggered by the intrinsic pathway. Platelet adhesion to the adsorbed protein layer (most notably fibrinogen) results in platelet activation and aggregation. Activated platelets release a number of bioactive factors (e.g. ADP, thromboxane A2, FV) that promote production of thrombin and further platelet activation. Fibrin and platelet aggregates form a thrombus on the device surface.

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Figure 2. Schematic of the CBAS® Heparin Surface. Alternating layers of positively charged polyethyleneimine (PEI) and negatively charged dextran sulfate (DS) polymers comprise the base matrix. Heparin molecules are end-point attached by covalent bonding to amines in the base matrix. The heparin active sequence (orange curved sections of the linear heparin chains at top) is not present in every attached heparin molecule. Image reproduced with permission from Carmeda AB.

Figure 3. Illustration of the anticoagulant effects of freely soluble heparin in solution (A), end-point attached heparin on a biomaterial substrate (B), and the heparan sulfate of the native endothelium (C). A) Heparin in solution catalyzes inhibition of activated clotting factors by AT. The reaction rate is practically limited by heparin concentration, and heparin is cleared from circulation with a half-life of between 1 hour and 4 hours depending on heparin molecular weight. Heparin dosing is made on the basis of potency (expressed in International Units) and in surgical settings its effect on coagulation is monitored by measuring blood clotting time. B) End-point attached heparin also catalyzes the inhibition of activated clotting factors by AT, but only at the material interface. The reaction rate is limited by reactant flux to the surface, which is dependent on flow conditions. Heparin is retained at the interface over time. The ability of the end-point attached heparin to confer thromboresistance to the surface is related to the specific AT uptake, which is expressed as pmol of AT uptake per unit area. C) The heparan sulfate of endothelial cells also binds AT and is capable of catalyzing inhibition of activated clotting factors. FIGURE 4 Figure 4. Western blot analysis for AT and thrombin in protein recovered from different heparin bonded surfaces after acute blood contact with whole human non-anticoagulated blood. A). AT, observed as a band of ~54 KDa was most intense on the end-point attached heparin surface (EPA-Heparin). Alternative multi-point covalent bonding schemes using periodate (PO-heparin) and the crosslinker EDC (EDCHeparin) yielded less AT binding not recognizably different from end-point attached heparin with low 33

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affinity for AT (LA EPA-Heparin). The higher molecular weight band was determined to be thrombinantithrombin complex (TAT). B) Western blot for thrombin showed active free thrombin ~35 KDa band on all surfaces except end-point attached heparin. The higher molecular weight band at ~80 kDa was identified as TAT. Figure reproduced with permission from Gore et al. [25].

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Figure 5. Analysis of total protein mass recovered from explants of ePTFE vascular grafts coated with the CBAS® Heparin Surface and control uncoated ePTFE vascular after various implant durations in a canine bypass model. Significantly less protein mass was deposited on vascular grafts coated with the CBAS® Heparin Surface compared with control. Deposition of protein on the uncoated grafts was highly variable. Data from Fisher et al. [73] . FIGURE 6

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Figure 6. Representative image of the lumen of an ePTFE vascular graft coated with the CBAS® Heparin Surface compared with an uncoated control ePTFE vascular graft after 2 hours in a challenging nonanticoagulated canine carotid interpositional model. The CBAS® Heparin surface eliminated thrombotic occlusion of the graft, which was evident in the uncoated control graft. Figure adapted with permission from W.L. Gore & Associates, Inc. [124].

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Table 1. List of Commercial Heparin Coating Technologies Company

Technical Description

Products

ASTUTE™ Advanced Heparin Coating (licensed to Medtronic plc as the TRILLIUM® Biopassive Surface)

Biointeractions Ltd

Cardiopulmonary bypass devices, hemodialysis catheters

AMC THROMBOSHIELD® Treatment

Edwards Lifesciences, LLC Atrium Medical (Maquet Getinge Group) Maquet Cardiovascular, LLC (Maquet Getinge Group) Carmeda AB (Carmeda AB is a wholly owned subsidiary of W.L. Gore & Associates, Inc.)

Heparin, polyethylene oxide chains, and sulfonate groups covalently bonded to a hydrophilic priming layer Heparin ionically bonded with benalkonium chloride Covalently bonded heparin complex

Heparin ionically and covalently bonded to an albumin priming layer

Extracorporeal circulation devices, vascular grafts

Heparin covalently bonded by endpoint attachment to a base matrix

Extracorporeal circulation devices (Medtronic, Inc.), ventricular assist devices (Berlin Heart GmbH), vascular grafts, stent-grafts, vascular stents (W.L. Gore & Associates, Inc.) Coronary stents, heparin coating kit Extracorporeal circulation devices Vascular grafts

FlowLine BIPORE® Heparin

Corline Systems AB Edwards Lifesciences, LLC Jotec GmbH

Hepamed™ Heparin Coating

Medtronic plc

PHOTOLINK® heparin coating

Surmodics, Inc.

PM® Flow Plus Heparin

Perouse Medical

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Macromolecular complex of heparin with polyamines Heparin ionically bonded with benzalkonium chloride Heparin covalently and ionically bonded Heparin covalently bonded to a matrix Heparin covalently bonded by light activated chemistry Heparin covalently bonded

Catheters Catheters

Coronary stents Various medical devices Vascular grafts

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Graphical abstract

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