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Ann Thorac Surg 1996;61:374-375
© 1996 The Society of Thoracic Surgeons
University of Pennsylvania, Temple University Hospital, Philadelphia, Pennsylvania
I will provide what insights I can. Most of what I will be presenting relates to analytic work that began in 1976 and has continued to the present. Much of the analytic work was generated by many people who have crossed the paths of the cardiothoracic laboratories at two universities in Philadelphia, the University of Pennsylvania and Temple, and there would be too many names to really thank all.
I will concentrate on both thrombosis and bleeding. For someone who is interested in coagulation, bleeding and thrombosis are two different sides of the same coin. If there is rapid consumption of coagulant proteins, then a coagulopathy develops and excessive bleeding is measured. If, on the other hand, activation of these elements remains localized, a thrombus can form, which can embolize. Thus, although the stimulus is similar, the clinical outcome may be very different, and the strategies for dealing with the situation may also be very different.
The competitor of the synthetic surface is the endothelial surface. It is important to return to the endothelial surface because it serves as a logical foundation and frame of reference for assessing the biocompatibility of synthetic surfaces. Endothelial surfaces remain metabolically active in their ability to maintain the fluidity of blood. It is interesting that when I first became interested in hemostasis and thrombosis, the emphasis was on coagulation and thrombus formation and now it is on how to maintain the fluidity of blood.
However, the contribution of intact endothelium to the maintenance of fluidity of blood is still incompletely understood, but clearly is complex and involves a number of mechanisms, including the synthesis and release of prostaglandins, such as prostacyclin, which inhibits platelets, which, in turn, release protein elements that can interfere with the coagulation cascade. Endothelial cells also release tissue plasminogen activator, which can maintain the fluidity of blood by removing any generated fibrin.
Endothelial cells, of course, also have a procoagulant role. They can release a number of elements such as tissue factor that can serve to activate coagulation by the extrinsic pathway and are the main source of the von Willebrand's protein, so they have both a procoagulant/anticoagulant role; again, I am using endothelium to serve as a frame of reference for our future understanding of synthetic surfaces.
For the cellular elements, of course, we have platelets, which are 2-µm-diameter anuclear fragments of protoplasm with a very complex subcellular architecture and complex synthetic machinery, but basically can participate in all facets of thrombus formation. On the platelet surface can occur binding of all the coagulant proteins, and they can serve as a lipid micelle that permits the further propagation of thrombus formation. They are the source of some of the most potent vasoconstrictors known, the thomboxanes, and can mediate some of the inflammatory reactions that one notices when a circulating thrombotic process is underway, such as an increase in vascular permeability.
Finally, there are the circulating protein elements, which comprise the contact, intrinsic, and extrinsic phases of coagulation. It is important to keep this in mind because, for situations where the thrombotic stimulus is pronounced, a more imaginative antithrombotic regimen than is currently present will be required.
Available antithrombotic drugs are conventional antiplatelet agents such as aspirin, which are minimally effective in situations in which we would desire platelet inhibition most, and heparin or warfarin with which to inhibit the protein systems. The big advantage of heparin, of course, is the fact that protamine allows heparin to be rapidly reversed. Heparin is a polydispersed molecule that can inhibit all serum proteases in both the intrinsic and extrinsic pathway.
For alternatives to current antithrombolytic therapy, we remain limited. We are just now beginning to understand the contact phase and ways we might intervene to inhibit this pathway, the earliest phase of coagulation. Conceivably, if we could create antithrombin at a specific site, we would reduce the risk of a bleeding diathesis.
Just as the intact endothelium maintains blood fluidity via synthesis and release of prostacyclin or tissue plasminogen activator, these agents can be added to devices or extracorporeal circuits, but use of these agents as antithrombolitic agents to prevent blood-synthetic surface interactions has remained confined to isolated situations, eg, heparin-induced thrombocytopenia.
Can we ever extrapolate from what is known about hemostasis, as it occurs in a test tube, or as it occurs on the surface of a damaged endothelium or subendothelium, to what occurs when blood is exposed to a synthetic surface? If we are going to intervene pharmacologically to prevent thrombosis when blood is exposed to a synthetic surface, we are naturally going to use agents that were first tested to prevent thrombosis in vitro. It turns out that you can extrapolate to a certain extent but not completely. There are both differences and similarities between damaged endothelium and the synthetic surfaces of a complex device.
When the synthetic surface is exposed to blood you have first a rearrangement of ions at the synthetic surface interface, then adsorption of proteins, which extends to about 200 µm. These proteins serve as the real interface between the cellular elements of the circulating blood, such as platelets, which adhere singly, and the synthetic surface itself. It has been believed that most synthetic surfaces behave in a stereotypic pattern when it comes to the absorption of proteins on the surface.
So when we talk about strategies to reduce the thrombogenicity of synthetic surfaces, we will be limited to a certain extent, because the protein adsorbates remain largely similar. The thrombogenic components are largely fibrinogen, and the contact phase coagulant proteins; platelets then adhere, first singly, but recruit other platelets by degranulation. Large aggregates can form. Thus, if there is rapid consumption of coagulant proteins and cellular elements locally, a thrombus will form, which can embolize; as is often forgotten, this is a dynamic process. Thus, to take a synthetic surface, explant it, and conclude that the absence of thromboli indicates the synthetic surface is nonthrombogenic may not be correct.
Leukocytes are also involved in this thrombotic process, although their role is less well characterized. Once activated, they can invade the subendothelium. In any case, as found in our laboratory, leukocytes' ability to activate coagulation is via the extrinsic pathway of coagulation and occurs by shed membranes.
Synthetic surfaces, particularly in devices, do activate leukocytes. Similarly, the pathway shared by activated leukocytes and coagulation is probably the extrinsic pathway of coagulation. Further, it is extremely difficult to prevent this activation of coagulation because it is very difficult to inhibit leukocytes.
To summarize, if blood is exposed to synthetic surfaces, for instance during cardiopulmonary bypass, there are certain predictable events that occur and that can serve as a frame of reference for other devices. Then you have loss of cellular elements from adhesion and then subsequent release of nonhemostatically effective cells, prolonged bleeding times that can be measured, and decreased responsiveness of cellular elements because they have shed membrane at the synthetic surface interface, which can in turn set up a coagulopathic state or a nidus for thrombosis.
On the platelet's surface, there is a decrease in fibrinogen and 
-adrenergic receptors. The synthetic surface can function as a strong agonist that causes release not just of dense granules but lysosomes as well.
There is synthesis of thromboxane A2, so we know that this is a biochemical event. There is a true activation process and not just cell lysis, which suggests that we could intervene pharmacologically to reduce thrombogenesis. Thus, many of these changes in cellular elements can in fact be prevented by providing for synthetic surfaces what normal endothelium provides in vivo.
In conclusion, it is hoped that even for complex devices the adsorption of proteins can be altered, passivation of surfaces produced, and thrombogenicity thus reduced. However, each device must be compared as a separate entity. You can rarely extrapolate from one device to another regardless of the components of the device. Nevertheless, the best devices, the least thrombogenic devices, will be the ones that preserve lamina blood flow and prevent the development of secondary currents.
Footnotes
Presented at The Third International Conference on Circulatory Support Devices for Severe Cardiac Failure, Pittsburgh, PA, Oct 28-30, 1994.
Address reprint requests to Dr Addonizio, Temple University Hospital, 3401 N Broad St, 3rd Floor Parkinson Pavilion, Rm 300, Philadelphia, PA 19140.
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