PRO: Cardiac surgery without use of CPB does not require 'full' dose heparinization

Bruce D. Spiess, MD, FAHA
Professor and Vice Chair
Department of Anesthesiology
Director, VCURES Shock Center
Virginia Commonwealth Univ. Med. Center
Richmond, Virginia

Cardiopulmonary bypass (CPB) is over 50 years old. Off-pump heart surgery is older. The last 5 years have seen a growth and development of off-pump CABG that is exciting and revolutionary. Debate continues as to outcome data from CPB CABG versus off-pump CABG.1-3 Blood utilization is decreased in off-pump CABG and there could be some data to suggest that neurologic outcome is different.3-5 However, data on perioperative MI rate and graft patency are as yet either unstudied or unable to demonstrate differences. Kaplan-Meier curves for survival are also not yet available and randomized controlled trials are either just now being conducted or what is available is retrospective with largely uncomparable groups.

Unfractionated heparin (UFH) has gone hand in hand with the development of CPB and for those 50 plus years. UFH has been the only viable anticoagulant for use. The "best" heparin dose or activated clotting time (ACT) for conduct of CPB is still in debate. What is the standard of practice in one institution would be considered a violation of protocol in another. This little discussion will therefore not settle the question of safety for any given dose of UFH in off-pump CABG when for 50 years we cannot agree on the science of what is "best" for on pump CABG. That being said, there are some points to be made that might provide assurance for the practitioner that something less than "full dose" heparin is acceptable for off-pump surgery.

UFH is an imperfect or bad drug that actually contributes to or sets up many of the coagulopathies and inflammatory side effects of CPB.6-10 To date, we have never been able to understand the extent of that statement because CPB could not be conducted with any other agent. UFH anticoagulation function is dependent upon the concentration and activity of antithrombin-III (AT-III). AT-III is a circulating zymogen that when bound to UFH changes its binding coefficient for plasma thrombin by 10-100 fold. The triple complex of AT-III, UFH and thrombin then deactivates plasma thrombin.6 Unfortunately, for the line of CPB thinking, thrombin almost never exists in plasma. Contemporary understanding of coagulation holds that thrombin is generated on the surface of endothelial cells (from tissue factor release), on the surface of platelets and on leukocytes.11 It is the thrombin burst present in the neo-tissue of a platelet plug that leads to local critical thrombin concentration, allowing fibrin generation and stabilization of a clot. It therefore is the reactivity of platelets to endothelial cells that secondarily leads to thrombin burst. UFH does not attach to thrombin held at the active sites on cells and UFH does not inactivate clot bound thrombin. Once a clot has begun to form, the ACT has been triggered or the aPTT has signaled clot generation, 96% of thrombin generation is yet to still occur, and UFH does not block all of that thrombin activity. So, UFH is critically ineffective at eliminating thrombin's action in the body. Only with supra-pharmacologic dosages of UFH can one even begin to see UFH attaching to clot bound thrombin. Interestingly, even though UFH does not inactivate clot bound thrombin it actually forms a linkage from the "backside" of thrombin to fibrin making the clot bound thrombin held tighter in the clot matrix.

UFH drives down AT-III concentrations and AT-III is a natural buffer to complement, bradykinin, and all of the serine protease cascade proteins. For some patients AT-III levels on CPB rival those found in severe septic shock, eclampsia and DIC.6 UFH partially activates platelets and actually makes platelets stickier.7-11 Even in very low concentrations it leads to the externalization of platelet ligands: GP-Ib, Gp-IIb/IIIa and PF-4.7-10,12,13 The platelet does not dump its granules with this level of stimulation but it is now vulnerable to attack and in patients with already hyperactive platelets (patients with vascular/cardiovascular disease, diabetes etc) the use of UFH may further potentiate the ability of platelets to find areas of dysfunctional or thrombotic vasculature. UFH attacks the surface of endothelial cells, liberates some heparan and releases tissue factor pathway inhibitor, held within the glycocalyx. UFH changes the selectin responses, sticking, rolling and diapedesis of leukocytes. It appears from some studies that sticking and rolling of leukocytes may be decreased, especially at very high concentrations but the diapedesis is increased.14 The sum totals of all these "side effects" of UFH are unknown but there is significant suggestion that the use of UFH alone increases the risk for thrombosis.

UFH causes heparin-PF-4 antibodies to be formed and heparin induced thrombocytopenia (HITT) is a major problem.15 Type I-HIT occurs with an acute but modest drop in platelet count, probably due to the expression of platelet ligands. Type II-HITT, caused by immunoglobulin activation leads to full blown HITT in 1-3% of CPB patients but antibodies can be found in 30-50% of CPB patients by day 2-4 after CPB. The time when early graft thrombosis is most likely is 2-4 days after CABG. Interestingly, the patients with the highest HITT-II antibodies after CPB have the highest rate of graft thrombosis in a single prospective study.16 We simply have accepted UFH as part of CPB, and these events of thrombosis are just now being investigated. The big fear has historically been bleeding, not thrombosis.

Off-pump CABG could be more analogous to percutaneous coronary intervention (PCI) than to CPB. In PCI the levels of thrombin as well as the "platelet stickiness" have been shown to correlate with early graft thrombosis.17, 18 In on-pump CABG, the biggest surge of thrombin comes after protamine administration and persists for a number of hours.19 It is actually a larger surge than what occurs during the pump run itself. In off-pump CABG it might be appropriate to ask, should we give protamine at all and therefore risk the surge of thrombin? That could be a more appropriate question than whether approximately 30-50% more UFH provides the "sweet spot" for anticoagulation.

The ACT utilized for PCI ranges from about 250-350 seconds. By selection of their disease, patients for off-pump CABG are more pro-thrombotic than the general population. The risk, to be feared, after off-pump CABG is early coronary graft thrombosis, not a major bleeding diathesis. Little prospective data exists in a randomized fashion examining this issue either from on pump or off-pump CABG. From PCI, we know that UFH anticoagulation combined with a platelet ligand inhibitor (abciximab or others) was far superior to simply UFH alone in terms of early and even later graft closure. From the McSPI database, recent work has shown that early platelet inhibition with aspirin decreased major myocardial events after on-pump CABG.20 Are these anti-platelet agents in part countering the pro-thrombotic or partial activation of the platelets by UFH itself? There was nothing to suggest that more UFH improves outcome.

UFH is an imperfect drug. It requires protamine, another very imperfect drug to reverse its action. The SCA audience does not need more instruction on the evils of protamine. UFH-protamine complexes particularly are bad and can cause a 10- 90% acute drop in platelet count. If you increase UFH dose, then the protamine dose will need to be increased. If a particular amount of a bad drug (albeit time tested) is required for surgery there is no reason to make the philosophical jump that more of that bad drug would be somehow better. There is simply nothing scientifically sound about either what constitutes "full dose" UFH, nor whether that dose actually decreases the risk of graft dysfunction.

Today some other fascinating agents are coming on the scene- the direct thrombin inhibitors. These agents block thrombin directly at both of its active sites and actually attack it on cell surfaces as well as in clot bound forms. These agents do not need the other bad drug-protamine. Argatroban, lepirudin and bivalirudin have been used in HITT-II.15 Bivalirudin has been extensively tested in PCI, and therein has been shown to provide improved outcome in patients as compared to UFH alone or UFH plus abciximab.21 A recent study of 100 off-pump CABG patients in New Zealand used bivalirudin versus UFH with protamine reversal.22 The beauty of the New Zealand study was that the patients underwent re-catheterization at 3 months after their off-pump CABG. Those who had bivalirudin, and avoided UFH had a significantly fewer graft flow reductions. So, the questions and directions for the future, are not, is more UFH better but, rather is there a way to replace or modify our use of UFH completely.

There are no studies that definitively can tell us what is best or correct. For on-pump CABG there are no large prospective studies that show an ACT of 450 versus 600 or higher are better for graft thrombosis. Studies examining using the automated "Hepcon" system versus routine ACT for off-pump surgery, and not surprisingly, the automated system called for more UFH and protamine. In 8 patients nothing could be concluded about what is "best".23 Others have trialed whether to reverse the UFH with whole, half or no protamine.24 As stated above, we know that the largest surge in thrombin production is immediately after protamine. However, if we give more UFH and also do not give protamine will we see off-pump CABG bleeding increase to the levels seen for on-pump cases? The study with whole, half and no protamine was inconclusive except to say that the group with low and no protamine had fewer protamine side effects- no big surprise. One study of 76 off-pump patients per group did examine whether those anticoagulated with 300 IU/kg or 150 IU/kg UFH and ultimately an ACT of >400 or >300 had more thrombosis events.25 There were more revised grafts in the patients with a lower ACT and UFH dosage but the assessment was subjective by the surgeons at the time of operation and not blinded. There are no large series wherein patients have been re-catheterized at 3 or 6 months to assess graft patency with blinded examiners scoring the perfusion. The science has not been performed, hence this academic debate. Is that study worth doing simply to decide whether a bit more of UFH is good? Perhaps it is better to think outside the box, understand the biology of the systems involved and ask the critical question, is not 50 years of a bad drug long enough? We should further develop testing that examines hypercoagulability such as the thromboelastograph (which has been shown to correlate to early thrombosis risks), the Hemodyne platelet contractile force or others, so that we know which patients are at risk. Anti-platelet agents during and early after surgery, perhaps even in conjunction with aprotinin added to UFH. Fear of graft thrombosis with aprotinin exists but where is the science? There is science to suggest decreased thrombin generation and serine protease activity with its use. If it were combined with a short acting anti-platelet agent, the three actions in combination could be useful. Perhaps we should very actively work to investigate and replace UFH itself. Off-pump CABG is just the perfect place to replace UFH and that is being investigated at this time. We have been arguing for close to 50 years about what is the right ACT for CPB and we are no closer to any agreement. Probably few patients in the United States would volunteer for the properly organized prospective randomized study of off-pump CABG and UFH dosing to solve the issue. But changing a dose of a bad drug, UFH, by 30-50%, is probably not a secret key to the biologic events that lead to graft thrombosis.


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