Anticoagulation is an important consideration for cardiothoracic surgeons. We are all aware of the nature of flowing blood of forming clots whenever it encounters a foreign material. Prosthetic valves present a unique situation where all the individual components of a prosthetic valve like the housing, the leaflets, and even the exposed sewing cloth are thrombogenic. Anti-coagulants prevent new clot formation and thus act to wash away any impediment to unobstructed prosthetic valvular disc (leaflet) motion.
Heparin was the first anticoagulant discovered. The discovery was credited to a 2nd-year medical student, Jay McLean, who was working in William Howell's laboratory. The original research was an investigation of a pro-coagulant effect of the neuro-cephalins and its comparison with other phosphatides. McLean accidentally found out that a product he had isolated from a dog liver prevented clot formation both in vivo and vitro, i.e., rather than having a pro-coagulant action the agent was acting as an anticoagulant. The name was given by Howell by the organ of origin, i.e., the liver or hepar in Latin and hepatis in Greek. The anticoagulant effect of heparin was announced in 1916.
The discovery, that Heparin, a complex glycoso-aminoglycan with a pentasaccharide moiety and numerous sulphonations, binds and potentiates the action of anti-thrombin III, happened later. This protein moiety is naturally present in the blood, Antithrombin III together with heparin is responsible for maintaining the fine balance between coagulation and anticoagulation. It is said that this heparin-antithrombin III interaction is the most unique system in Nature. The size of the polysaccharide substrate and sulphonations of heparin determine the character and affinity towards antithrombin III. With thrombin and antithrombin III heparin forms a temporary ternary complex, which is responsible for the anticoagulant effect. This molecule, in its part, inactivates several factors involved in coagulation, viz., factors IIa, Xa, IXa, XIa, and XIIa, by binding and forming a complex with them. Covalent bonding and conformational molecular changes are involved, and a strong temporary complex is formed which prevents clotting.
Heparin is present in different forms in several animals. We are still in the process of finding out the right source for human pharmacological use and it has been a difficult exercise. In fact, the industrial process differs from unit to unit, and extrapolation of this for pharmaceutical production has many pitfalls. Of late prion transmitted diseases like the bovine spongiform encephalopathy or the scrapie disease in sheep must be borne in mind. Porcine heparin is good in efficacy, but both bovine and porcine products have religious implications. Both require a clear explanation and consent before use.
At one period, before the era of open-heart procedures, heparin was so costly that a fortune was required for production, and shipment was needed out of America to the European continent for an operation requiring heparin use.
Heparin, as an anticoagulant, is increasingly used now in cardiac and vascular cases. With an exponential rise in interventions and minimally invasive procedures, the use of heparin has become very common. However, though there has been an effort, agents with similar effects and desired properties have not been developed since their discovery by McLean in 1916. Heparin remains the only choice with all its failings.
The route of administration can be i/v, i/m, or deep s/c and this has a bearing on the time heparin takes to work. Obviously, with the intravenous route, immediate action starts. Still, it is prudent to wait for some time, three minutes at least, or till the activated clotting time is more than 480 seconds if diatomaceous earth (or kaolin clay) and the agitator machine are available. Three minutes is the arbitrary time chosen, taking a minute for one complete cardiac cycle to complete. Thus, there is a total of three cardiac cycles finished and heparin properly admixed in the blood of the recipient before the introduction of foreign agents starts. With i/m or s/c administration, at least 60 minutes are required before the desired effect is expected. Hence the latter route is suitable in long-term maintenance therapy or in conditions where the immediate effect is not wanted.
As heparin involves the actual clotting process and affects the factors of the extrinsic system mainly, it will prolong the time required to form a clot. A clot activator will have to be added and the prolonged partial thromboplastin time (PTT) measured. The common surveillance test of prothrombin time (PT) done for vitamin K antagonists has no role.
When a prosthetic valve is implanted, one must remember that all the blood
stream exposed components like the housing, the discs and even the suturing cloth are foreign. Anticoagulation is important so that no intravascular thrombus forms and impedes leaflet or disc motion. immediate anticoagulation is done with heparin, but oral anticoagulation with a vitamin K antagonist is necessary and practical for maintenance. Dicoumarol agents like warfarin or acenocoumarol are commonly used and indandiones are not preferred. The preference is mainly evidence-based and personal or institutional preference plays an important role. The recent guidelines suggest:
Maintenance of an international normalized ratio (INR) of 2.5 when a single leaflet or bi-leaflet valve is used.
Maintenance of an INR of around 2 when the all-carbon On-X valve has been used.
An INR of 3 must be maintained when there are inherent risks of intravascular clotting or atrial fibrillation.
Mitral prosthesis implantation always merits maintenance of an INR of 3.
A higher INR is always justified in hypercoagulable conditions, and a personal physician preference is necessary.
A prosthetic valve in the tricuspid position warrants an INR of 3.
When there has been a double valve replacement, INR values for a mitral valve prosthetic replacement is accepted.
A low dose of aspirin is recommended nowadays along with the vitamin K antagonist as evidence, especially observational studies showing that the addition of a low dose of aspirin lowers the thrombotic risk.
The risk of thrombo-embolic events and cerebrovascular accidents are always there. The addition of aspirin reduces such events even though the complications related to these vitamin K antagonists will be there.
There has been a flooding of the market with the direct or newer non-vitamin K oral anticoagulants (DOAC/NOAC) and the direct thrombin inhibitor dabigatran has no role in mechanical valve prosthesis implantation scenarios. Though the ACCP guidelines suggest the use of unfractionated or d-polymerized low molecular weight heparins (LMWH) during early bridging to vitamin K antagonists only, long-term anticoagulation with these agents is never recommended.
Unfractionated heparin is a heterogeneous molecule with an average molecular weight of 15,000 Dalton. As said before chemically these are glycosaminoglycan with a pentasaccharide moiety and numerous o-sulphonations. They are found as granules in mast cells and normally are not active unless there is degranulation and liberation of mast cells. Heparin molecule has the maximal number of anions and is the strongest acid in the body. A wide variation is seen with unfractionated heparin. The effective half-life is 30 minutes when given i/v and it becomes 1.5 hours when the deep s/c route is preferred. Again, there is an extensive variety of activities among individuals. Though an INR of 2-3 in prosthetic valve replaced cases is the goal, the measurement of the activity of heparin requires an aPTT. A prothrombin time (PT) with an international normalized ratio (INR) will be fallacious. The variability in pharmacokinetics makes it unreliable for long-term maintenance. Though it does not lyse a formed clot, heparin is given the minute a thrombo-embolic event happens. However, heparin has a role in bridging to and from vitamin K antagonists.
One must remember that, even as it sounds innocuous, bio-prosthetic valves are composite structures with several thrombogenic components. Anticoagulation with vitamin K and aspirin (an anti-platelet dose) is necessary after implantation, during the early post-implantation period, and a period to cover the neo-endothelization of the exposed foreign cloth suturing areas and commissural posts. The risk of thrombo-embolic events is highest during this early post-operative period. Anti-coagulation cover is always a must during this time. There are guidelines to these but in addition, some personal preferences modify anti-coagulation methods. Almost everyone accepts no anti-coagulants are required after 3 months and this is universally followed. This makes the patient happy also as they do not have to encumber themselves in remembering the necessity of taking an essentially required medicine every day.
Maintenance with vitamin K antagonists in prosthetic valve replacement patients needing other surgeries is a different issue. Vitamin K antagonists mainly stop the liver from the utilization of factors II, VII, IX, and X in the clotting cascade. Prevention of gamma-carboxylation of the epoxide reductase reaction, where vitamin K is the co-factor, inhibits interconversion. Factors II, VII, IX, and X are mainly involved in prothrombinase activity, and this interference does not allow a clot to form. Whenever these patients require surgery on a different organ or system, the first advice is that the anti-coagulants will have to be stopped for at least 5-7 days before surgery and they are referred back to the cardiothoracic surgeon for advice. This is ethically wrong and may even cause sudden death due to stuck leaflets. When a patient is on anti-platelet agents for a stent or surgical revascularization, the simplest solution is to initiate with un-fractionated heparin stopping the vitamin K antagonist or the anti-platelet agent. A careful bridging should be done by withdrawing the vitamin k antagonist and starting heparin. It should be remembered that this is a period similar to bridging after valve replacement surgery and has the maximum thrombo-embolic risk. The last dose of heparin should be 6 hours before surgery. Either a similar bridging to vitamin K antagonists may be done or vitamin K antagonists directly started 6-8 hours after the procedure with a settled clinical feature and other findings not suggesting any further bleeding.
Cataracts and dental procedures are common surgical procedures that may be needed in the future in such patients. Cataracts need a small incision in the cornea near the sclero-corneal junction. The cornea is an avascular structure and hence stopping the maintenance of anticoagulants is not justified. For other surgeries, heparin bridging from vitamin K antagonists and short-term maintenance with heparin is the chosen method keeping in mind that the risk of spontaneous intravascular and prosthesis-related thrombo-embolism is again high in this period. A dental extraction may require prolonged pressure and add one or two stitches.
The cardiac surgeons of recent training do not stop antiplatelet agents before surgery honoring the patency of stents or with the idea of maintaining whatever blood flow is therein coronary artery disease patients with compromised blood flow on medical management. bleeding is never excessive unless a vessel is breached.
Nowadays it may so happen that a prosthetic valve-replaced case suddenly needs a heart transplant. Platelet infusion may benefit those patients taking antiplatelet agents. For patients on vitamin K antagonists, the following measures are adopted:
Immediate intravenous vitamin K administration.
Meticulous hemostasis while dissection.
Careful hemostasis while closure.
Infusion of blood products as recommended by thromboelastography.
Immediate infusion of 2000-3000 units of prothrombin complex prior to the procedure.
Personal experience showed that there never has been vision-obscuring hemorrhage unless a major vessel is breached, and modern diathermies can control a difficult ooze with elan. For pacemaker implantation and similar surgeries where the chance of intra-cavitary bleeding is not there, stopping these drugs is not mandated. Even nowadays every cardiac surgeon does a coronary artery bypass graft in acute or unstable angina patients not having the chance of omitting antiplatelet agents. The caution in prosthetic valve replacement patients on vitamin K antagonists is justified and measures are taken accordingly in major elective surgeries. Operating on avascular structures like the cornea does not necessitate a stoppage of anticoagulation. As such a small incision is made for cataract surgery within the sclero-corneal junction. At best one has to be careful, know the structures and their blood supply, and be patient about the hemostasis.