Heparin Coatings

(by J.J.G. Bos)

Heparin is commonly used as antithrombogenic agent. Its main purpose is to prevent blood from clotting. It helps antithrombin III (AT3) to inhibit thrombin, an enzyme that induces blood coagulation. Heparin is known to interfere with other parts of the blood coagulation cascade as well.

The so-called intrinsic pathway of the blood coagulation sequence (cascade) is always triggered when a medical device comes into contact with the blood. Clots are rapidly formed on and around the device unless the sequence is interrupted. This is where the heparin comes in.

A blood-contacting medical device coated with (active) heparin will trigger the intrinsic pathway of blood coagulation, but the heparin interrupts the cascade before clot formation can occur. This keeps the heparin-coated medical device free from blood-clots (thrombi). Patient safety is greatly enhanced, and functionality of the device is not degraded by blood coagulation.

The illustration below demonstrates the thrombin inhibition caused by heparin. Thrombin is generated in the blood as part of the coagulation cascade. Increased thrombin levels are usually associated with increased blood coagulation. Thrombin is inhibited by anti-thrombin III (AT3). Inhibition is greatly accelerated in the presence of heparin.

A mono-molecular layer of heparin was applied to tubing made of nylon-12, and the coated tubing was successively tested with a thrombin generation assay in compliance with ISO 10993-4 (haemocompatibility). The results show how the nylon-12 surface itself generated close to 1000 mU/ml/min/cm2 of thrombin, whereas the heparinized nylon 12 surface induced a net decrease of thrombin in the blood, scoring some -400 mU/ml/min/cm2 typically. The decrease is associated with the anti-thrombogenic action that is so typical for the heparin.

It must be noted that the thrombin results reflect the net effect, i.e. thrombin generation minus thrombin inhibition. In this case, the heparin coating induces more thrombin inhibition than thrombin generation. Experiments described in literature show however that heparin not only induces (increased) inhibition of thrombin but also decreases thrombin generation in the blood. Less is made, and what is made is inhibited. Truly antithrombogenic!

Thrombin inhibition still prevails over thrombin generation after extraction of this particular coating in phosphate-buffered saline (pH7.3) at body temperature for some 40 minutes. This is generally longer than a standard catheterization procedure lasts. Animal tests (porcine model) revealed at least 4 hours of sustained antithrombogenic action of this particular coating. The clinical test lasted this long - unfortunately no longer tests could be conducted with these samples, in order to determine the actual limit of the coating's operating window.

Two barriers are commonly encountered when it comes to application of heparin coatings:

1. The heparin coating is too expensive
2. Registration seems impossible (heparin is a drug)

Cetry is specialized in breaking down both barriers by optimizing coating economy and assisting in generating the proper documentation for purpose of registration.


Here follows a list of some heparin-coating applications, just to get the idea:

1. Endovascular Catheters
   Heparinized endovascular catheters cause less generation of thrombi than the uncoated versions. This in turn reduces thrombi-related risks such as distal embolization. Unofficial data indicated a reduction from 7 out of 2000 downto 1 out of 2000 patients with major cerebral complications (i.e. blood clots blocking blood vessels feeding the brain) as caused by routine cardiovascular procedures. In other words: Induced near the heart, clots caused trouble in the brain. Not all devices involved in these procedures - such as the guide wires and the catheter sheath introducers - were heparinized, just the diagnostic catheters. And still the effect was very significant! Typical base materials involved during these procedures were: nylon, polyurethane (linear chains), polyethylene. Typical exposure times: 10 - 20 minutes.
   
   
2. Sets for Blood Transfusion
   Sets for blood transfusion are generally made with use of PVC tubing. By coating the inside of the tubing (or the entire set) with heparin, it becomes possible to significantly reduce blood coagulation. It may also be profitable to coat the outer surface at the parts that are inserted into the veins.
   
   
3. Intraocular Lenses
   Intraocular lenses with heparin coating are commercially available nowadays. The heparin helps reduce inflammatory response. Typical base material: polycarbonate.
   
   
4. Draining sets for Hydrocephalus Treatment
   It may be advantageous to coat both the inner and outer surface of tubing (and valve) of hydrocephalus drains, in order to reduce inflammatory response.
   
   

I have some photographs included on the web page about heparin in tubing. The pictures show heparin coatings applied to nylon, silicone, polyethylene and PVC, but application to many other materials is well possible such as PU and FEP.

Below is a picture of covalently bound heparin on nylon-12 strips. The coating is stained with toluidine blue O, thus explaining the purple color.

Patients are usually injected with heparin as part of the endovascular procedure. This is done in order to increase blood coagulation times, so that the chance of complications due to (ongoing) clotting is significantly reduced. This helps, because now there is more time for fresh blood to dilute the activated blood that comes from the area of intervention. There is thus more time and chance for the blood to restore its original biochemical balance.

It may be argued that no heparin coating is required on the endovascular devices, since heparin is already injected (typically a dose of 5000 - 10,000 IU). This is not correct. Experience from animal studies (porcine) showed that coagulation onto standard diagnostic catheters occurred just as fast with or without the systemic heparin injection. Effectiveness of the systemic injection was monitored by a coagulation test (partial thromboplastin time - PTT) on blood samples taken at regular intervals. Coagulation time significantly increased immediately after the injection, and then it gradually decreased over time. However, clot formation on the catheters occurred just as fast every time, unless the catheter was heparin-coated. It must be noted that most physicians clear catheter lumens from coagulating blood by gently flushing with saline, often enhanced by dissolved heparin. This is done at approximately 5-minute intervals, in order to prevent massive coagulation inside the catheter. The mentioned porcine model was run without preventive flushing, and still no coagulation occurred inside the heparinized catheters! However, catheters without heparin coating were blocked by thrombi within 10 minutes after exposure to the blood, when no preventive flushing was applied.

The main difference between a heparin coating and an heparin injection is found in the fact that blood cannot reach the medical device without bumping into a wall of heparin in the former case, whereas the latter still allows full contact and thus full (but very localized) activation of the coagulation cascade. Listed below are some very distinctive differences between the two.

Blocking of Contact

Heparin coating forms an active anticoagulant barrier between the blood and the medical device, thus blocking contact.
Injected heparin does not. It cannot prevent coagulation on and near the medical device.

Localized Effect

Heparin coating only operates locally, i.e. where the coated medical device is and nowhere else.
Injected heparin works throughout the body.
Both effects have their merits, but they are different (complementary).

Duration of Action

Heparin coating is removed with the medical device.
Injected heparin stays in the body until removed by the blood itself (heparinase).
Again, both effects have their almost complementary merits, but they are very different from each other.

A heparin coating with activity of 0.1 IU per square cm and an impact range into the blood of e.g. 5 microns shows a very localized impact, equivalent to 200,000 IU per liter blood. Safe systemic injections, however, involve doses of 5,000 - 10,000 IU heparin for adult persons. This relates to some 1,000 - 2,000 IU heparin per liter blood. For blood localized within the 5-micron zone around an uncoated medical device, this is a hundred times less than that of the heparin-coated device. It illustrates how the coating works as a barrier. The closer to the device, the greater the effect. Do note that the blood outside the action range of the heparin coating is not affected by clotting, due to absence of contact activation.

It may be concluded from the presented considerations, that systemic injection of heparin and a heparin coating are two different things. One cannot replace the other. The systemic heparin dose is for repression of "bulk" coagulation and operates throughout the body, but it cannot prevent clot formation on and especially inside medical devices (think of catheter lumens). Heparin coating represses local device-induced coagulation (with emphasis on the intrinsic pathway).
The systemic injection and the coating work in different areas of enhancing patient safety, and they are quite complementary.

Heparin is a hydrophilic molecule, i.e. it attracts water, but most heparin coatings are not slippery as is the case for some hydrogels. The coefficient of friction of heparin in water is close to that of for instance nylon or (linear) polyurethane, thus in now way close to that of polytetrafluoroethylene (PTFE-teflon). However, the coefficient of friction experienced between uncoated nylon surfaces (or PE, PU, etc.) may increase when in contact with living blood due to thrombus formation, whereas friction between heparin-coated surfaces tends to remain constant. Cetry has successfully developed a low-friction heparin coating, with a coefficient of friction comparable to that of PTFE and HDPE. Information regarding Cetry's own low-friction heparin coating can be found HERE.

More information regarding in-vitro and in-vivo friction can be found under: Note concerning In-Vivo versus In-Vitro Friction