Coatings that Stop Blood Clots Cold

Author: 
Bob Michaels
Coatings with antithrombogenic properties prevent the risk of blood clotting in stents, catheters, and other implantable devices

Medical disciplines ranging from cardiovascular medicine and oncology to orthopedics and ophthalmology rely increasingly on the implantation of medical devices into coronary arteries, jugular and femoral veins, joints, and many other parts of the body. However, the use of implantable devices can be hazardous. While the risk of bacterial infection associated with such devices as stents, catheters, heart valves, assist devices, guidewires, and artificial joints makes headlines, equally problematic is implant-induced thrombogenesis, or blood clotting.

Because implantable devices are as common today as the diseases they are designed to treat, medical device manufacturers are striving to prevent thrombogenesis by developing new drug-eluting and non-drug-eluting coatings. Based on these efforts, the industry is making headway in its effort to reduce the risk of blood clots caused by the use of implantable devices. Furthermore, signs of progress are beginning to emerge in the battle against late stent thrombosis, a particularly intractable form of blood clotting that afflicts many patients that undergo stenting to treat coronary artery disease.

Blocking Clots
Blood clotting resulting from the use of implantable medical devices has a variety of causes, including the action of shear forces, the body’s physiological reaction to foreign bodies, and the surface roughness, surface energy, geometry, and hydrophobicity of the implantable device. “Blood is what we call a smart fluid,” says Ron Sahatjian, president and CEO of Medi-Solve Coatings LLC (Natick, MA). “It’s shear-sensitive, and because of that, it responds to high-shear areas by clotting to stop the body from bleeding to death. A simple example is a cut. It’s easier for a jagged cut to clot and heal than for a paper cut.” When blood-clotting proteins such as thrombin receive a signal that the blood is being sheared, a cascade of events starts to cause clotting in an effort to stop the bleeding.

A guidewire before and after being coated with the Vertellus phosphorylcholine polymer coating shows reduced thrombogenicity.

Similar to jagged wounds, invasive medical devices act as shear forces in the blood stream, Sahatjian explains. When present, they signal thrombin and prothrombin to form clots. “For example, when blood traverses over the coiled configuration of a guidewire, it’s not a smooth laminar flow,” Sahatjian says. “The blood gets caught between the coils, causing shear stress. This causes clotting.”

Explaining the implant-body interaction that causes blood to clot, William Lee, director of R&D at AST Products Inc. (Billerica, MA), remarks that when a medical device is implanted into the human body and is detected by blood cells, the cells react because they detect a foreign surface. This interaction provokes an immune response in which cells try to adhere to the implant surface. “The result is clotting,” Lee says. “This physiological mechanism is a common reaction to the use of medical implantables.”

To counteract the effects of these clotting mechanisms, medical device manufacturers have developed a variety of coatings to protect patients and lower treatment costs. However, while antithrombogenic coatings come in many forms, the classic variant elutes heparin, or heparin sulfate, Sahatjian notes. For example, this naturally occurring drug is the active antithrombogenic agent in Medi-Solve’s AquaCoat coatings, which are employed in a range of medical devices such as guidewires and catheters. “Lubricious and water soluble, these coatings are abrasion resistant and particulate free, making them a suitable matrix for heparin,” Sahatjian adds.

While antithrombogenic coatings used on dialysis, central venous, and peripherally inserted central catheters impede clotting, their operable lifespan is extremely limited, Sahatjian notes. “Such catheters clot after about two to three weeks, and then they have to be replaced.” To overcome this limitation, the company is working with a manufacturer of dialysis catheters to extend protection to six weeks. “However, the success or failure of this endeavor will depend on how persistent the heparin is,” Sahatjian notes.

Prolonging heparin’s active lifetime, however, is easier said than done because the drug cannot simply be bonded to a catheter, Sahatjian explains. It must untangle its molecules so that it can react with molecules in the blood. “In other words, it has to be released slowly in order to work, but this is a function of how it is electrostatically connected with the catheter’s hydrophilic polymer substrate.”

While some thrombogenic issues have not been considered enough of a clinical problem to justify using antithrombogenic coatings, dialysis catheters are a real problem, Sahatjian says. “If you could extend the ability of antithrombogenic agents to last from two weeks to six, that would save money on healthcare costs and increase patient comfort.”

Heparin Alternatives
Like Medi-Solve’s AquaCoat, AST Products also offers an assortment of coatings that rely on the use of heparin to prevent thrombogenesis. Based on the company’s LubriLast water- and polymer-based coating platform, heparin-eluting HemoLast coatings are employed on a variety of implantable devices, including catheters, guidewires, intraocular lenses, insulin pumps, and orthopedic implants such as artificial hips. How much heparin loading a coating undergoes, according to Lee, depends on how long the device will remain in the body.

While heparin is used widely in antithrombogenic applications, it is not right for every application, Lee comments. For example, because it is usually made from animal products, the drug can cause reactions in patients that have allergies to certain animal-based reagents. However, while universities are exploring alternatives to heparin, the drug is currently the only antithrombogenic substance approved by FDA for use in the United States.

An alternative to heparin, however, is a synthetic chemical antithrombogenic agent known as hirudin. Currently available in Australia, hirudin features a smaller molecular weight than heparin, does not contain animal products, and functions much like heparin. “Some of our customers are requesting that we use drugs other than heparin, such as hirudin,” Lee says. “We are trying to determine whether we can mix it into our solutions and coat it on implants.”

In addition to using heparin-based coatings, Medi-Solve, for example, coats certain implantable devices with a nonthrombogenic polymer called phosphorylcholine. Manufactured by Vertellus, this material differs from drug-eluting coatings in that the polymer itself acts to prevent platelets from depositing on the device surface, thereby arresting blood-clot formation.

After the implantation of a stent coated with Allvivo’s ProteoGuard, a pig coronary artery shows a thin neointima and a well-healed endothelial cell lining.

A different approach to preventing medical device–induced thrombogenesis is being pursued by Allvivo Vascular Inc. (Lake Forest, CA). “We develop two types of nonthrombogenic coatings for medical device applications,” notes Jennifer Neff, the company’s CEO and CTO. “One works through a passive mechanism by incorporating a high density of polyethylene-oxide chains at the device surface. The other combines our nonthrombogenic polymer coating with an active biologic, whose primary function is to prevent activation of the complement cascade.”

Known as ProteoGuard, Allvivo’s coating technology contains a protein called factor H, Neff explains. Factor H’s role is not to inhibit the coagulation cascade directly but to function as a regulator of complement activation. Interrelated with the coagulation cascade, the complement system helps or ‘complements’ the ability of antibodies and phagocytic cells to remove pathogens from an organism, lysing cells and upregulating the inflammatory response in the presence of a foreign object. If the object cannot be removed, however, prolonged inflammation results. Present in the cells, Factor H provides the signal to prevent the complement from attacking them. By attaching factor H to the device, the foreign-body response is essentially turned off, allowing healthy healing to occur. “This technology,” according to Neff,  “has also been found to be highly nonthrombogenic.”

Late Stent Thrombosis
In addition to shear forces and the presence of foreign bodies, inflammation is another cause of clotting. “That’s what people think happens in the case of late stent thrombosis,” Sahatjian states. “It is believed that this condition has to do with prolonged inflammation caused by the stent, the polymer coating of which may prevent healing.”

Combating late stent thrombosis depends on the kinds of stents that doctors implant, Lee explains. The drug-eluting coatings deposited on bare-metal stents become degraded over time, exposing the metal at various locations. Thus, even biocompatible materials can cause a thrombogenic reaction to occur once the coating is consumed. To prevent such occurrences, OEMs are starting to use bioresorbable materials that enable the stent to degrade by itself.

The risk of late stent thrombosis is thought to increase with the lack of endothelial cell coverage and exposed stent struts, Neff adds. Drug-eluting stents incorporate antiproliferative drugs that may delay or prevent healing of the endothelial lining and increase the likelihood of exposed struts. Exposed struts may also occur because of stent malapposition, which results when one or more struts may not be in full contact with the artery wall, causing blood to flow around the strut and creating turbulence.

Allvivo Vascular’s approach to combating restenosis involves inhibiting the process at an early stage, according to Neff. “Our coating prevents device-induced inflammation and thrombus, which are early triggers of the restenosis process. An advantage of this approach is that it does not impair healing and provides a favorable surface for regeneration of the endothelial layer, which provides long-term protection against late stent thrombosis.”