HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Stephen Westaby Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Westaby, S. Search for Related Content PubMed PubMed Citation Articles by Westaby, S.

Ann Thorac Surg 1999;67:1983-1985
© 1999 The Society of Thoracic Surgeons

Anti-fibrinolytic therapy in thoracic aortic surgery

^a Oxford Heart Centre, John Radcliffe Hospital, Oxford, England, UNITED KINGDOM

Address reprint requests to Dr Westaby, Department of Cardiac Surgery, Oxford Heart Centre, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, England

Presented at the Aortic Surgery Symposium VI, April 30–May 1, 1998, New York, NY.

	Abstract

Top Abstract Introduction Cardiopulmonary bypass,... Role of anti-fibrinolytic agents... References

 
Background. Bleeding is an important cause of morbidity in thoracic aortic surgery.

Methods. We reviewed the mechanisms for fibrinolysis in aortic surgery and the propensity for intervention. Several studies have addressed the safety and efficacy of aprotinin.

Results. The endothelium regulates the balance between thrombosis and fibrinolysis. During hypothermic circulatory arrest, thrombin generation stimulates protein C production and tissue plasminogen activator release to promote fibrinolysis. Hypothermia also adversely affects platelet function and coagulation. Controversy exists regarding the effectiveness and dangers of antifibrinolytic agents after circulatory arrest.

Conclusions. Fibrinolysis remains problematic during thoracic aortic aneurysm surgery. Heparin management is complicated by aprotinin and insufficient heparin may result in thrombotic events. Aprotinin is safe during rewarming or postoperatively.

	Introduction

Top Abstract Introduction Cardiopulmonary bypass,... Role of anti-fibrinolytic agents... References

 
Problematic bleeding is a common source of morbidity and mortality in thoracic aortic surgery [1]. Bleeding stems from extensive surgical dissection and the friable nature of pathological aortic tissues. Infusions for hypovolemia inevitably result in coagulopathy.

Hemostasis has 3 phases. In the first, platelets exposed to collagen and plasma clotting factors are activated by tissue thromboplastin and pro-coagulant phospholipids. Activation generates the potent vasoconstrictors serotonin and thromboxane A2. Thrombin stimulates platelets to form a plug in the injured vessel. Subsequently, the clotting cascade generates thrombin, which interacts with the endothelial cell, producing a pro-coagulant surface. Finally, thrombin converts fibrinogen into fibrin and stabilizes the platelet plug. Fibrinolysis occurs when plasminogen binds to fibrin. Plasmin then dissolves the fibrin strands and restores patency within the vessel.

The endothelial cell preserves capillary patency through 3 mechanisms (Fig 1 ) [2]. Synthesis of prostacyclin inhibits platelet activation. The cell surface glycoprotein thrombomodulin then binds thrombin, which loses its pro-coagulant property and acquires the capacity to activate protein C. Protein C is a powerful anticoagulant which destroys factors Va and VIIIa and inactivates the plasminogen activator inhibitors PAI/I and PAI/III, thereby promoting fibrinolysis [3]. In turn, protein C activity is regulated by protein C inhibitor and alpha 1 anti-trypsin. The endothelial cell plasma membrane also contains heparan sulphate, which binds anti- thrombin III and enhances its capacity to inactivate thrombin.

View larger version (38K): [in this window] [in a new window]   Fig 1. Anticoagulant function of the endothelial cell. TPA = tissue plasminogen activator.

	Cardiopulmonary bypass, hypothermia and circulatory arrest

Top Abstract Introduction Cardiopulmonary bypass,... Role of anti-fibrinolytic agents... References

 
In contact with the negatively charged perfusion circuit, factor XII undergoes a conformational change and binds to high molecular weight kininogen. This complex interacts with the bypass circuit, releasing kallikrein and bradykinin. These trigger the fibrinolysis system and stimulate TPA release from the endothelium [7]. Thrombin generation increases with duration of CPB, probably through a decrease in anti-thrombin III effect. With fibrinolysis, the platelet binds fibrin degradation products (as distinct from fibrinogen) to the GpIIb/IIIa receptor: binding of an inert clotting fragment causes defective platelet aggregate growth, and the tendency to bleed [8]. The change in platelet function occurs during the first few minutes of CPB and reverses with time [9]. This suggests that only a small proportion of platelets reach the stage of irreversible aggregation.

Hypothermia (even without CPB) causes altered platelet morphology, depressed enzyme function, and arachidonic acid metabolism and sequestration in the hepatic sinusoids. Decreased platelet aggregability during hypothermia occurs through reduced thromboxane release and plasmin-related degradation of GpIb receptors. Rewarming reverses the hypothermic changes, but not those due to CPB or fibrinolysis. The influence of hypothermia on the coagulation cascade is complex [1]. There is kinetic slowing of enzyme activity during cooling, and although clotting factor levels remain stable, clotting times are prolonged. Because laboratory clotting studies are performed at 37°C (although the patient is hypothermic) clotting factors may be normal during an observed coagulopathy.

Whilst blood and foreign surface interaction is generally regarded as the perpetrator of coagulopathy in cardiac surgery, the adverse effects of hypothermia, ischemia, reperfusion and thrombin generation in a static vascular bed are also important [10]. During CPB, complement activation and cytokine release cause endothelial cell activation. During hypothermia and circulatory arrest (HCA), the endothelial cell also produces substantial amounts of TPA, leading to fibrinolysis, which prevents vascular occlusion by fibrin. Thrombin generation during stagnation stimulates the protein C system to inhibit activated factor Va and VIIIa and minimize coagulation. In addition, the potent endothelial anticoagulant factors plasmin and protein C inhibit clotting in the stagnant vessels. Nevertheless, the overall tendency during prolonged HCA is towards endothelial cell ischemia and microvascular thrombus formation. Therefore, basic scientific principles would appear to contraindicate the use of agents that inhibit plasmin or protein C during HCA.

	Role of anti-fibrinolytic agents in aortic surgery

Top Abstract Introduction Cardiopulmonary bypass,... Role of anti-fibrinolytic agents... References

 
Whilst there is an established role for anti-fibrinolytics in preventing down-regulation of the GpIIb/IIIa receptor by fibrin degradation products during continuous CPB, their use in HCA is controversial and unproven. Despite initial enthusiasm for the GpIb receptor theory, the pharmacology of aprotinin is misunderstood [10]. Aprotinin may interfere with contact activation of intrinsic coagulation, as suggested by preservation of platelet function and inhibition of fibrinolysis. Alternatively, inhibition of kallikrein, (which promotes factor XII activation) may decelerate the intrinsic clotting cascade. The assumption that intrinsic coagulation occurs through foreign surface contact is debated. Information from molecular markers now suggests that clotting occurs via the extrinsic pathway, and aprotinin is known to inhibit extrinsic coagulation through an effect on the tissue factor/factor VIIa complex. Improved platelet function could be related to preservation of the platelet membrane GpIb receptor and the ability of the GpIIb/IIIa receptor to bind fibrinogen. Aprotinin may also reduce fibrinolysis by inhibition of plasmin and activated protein C¹⁰.

Few reports directly address the use of aprotinin in aortic surgery, and none consider tranexamic acid or epsilon amino-caproic acid. Interest began in 1993 when Kouchoukos and colleagues reported an increased risk of renal failure, myocardial infarction and death in aprotinin-treated patients undergoing HCA [11]. At autopsy, platelet/fibrin thrombi were found throughout the microcirculation of the kidneys, heart, lungs and brain. Similar findings were reported by Westaby and colleagues [12]. In a study of 80 consecutive acute type A dissection patients, the authors noted increased blood loss in those treated with aprotinin during HCA for the open distal anastomosis, and suggested that aprotinin interfered with production of the proteases endothelial protein C and TPA, which prevent intravascular coagulation. Insufficient heparinization may also have caused the coagulopathic state. The recommended activated clotting time (ACT) with aprotinin has been changed to > 700 seconds because aprotinin prolongs the celite-activated ACT. Since hypothermia also increases ACT, this creates the potential for aprotinin-treated patients to receive less heparan than controls.

In 1995, Goldstein and colleagues questioned the hazards of aprotinin during HCA, and claimed benefit [13]. These authors found an increased incidence of renal dysfunction with aprotinin use, but did not observe multisystem failure from platelet fibrin thrombi in the microvasculature. In their nonrandomized study, however, aprotinin-treated patients had received considerably more heparin than untreated patients, and had ACT values > 1000 seconds, versus 700 seconds for patients without aprotinin. While aprotinin appeared safe, there was no difference in chest tube drainage or transfusion requirement between the groups, and aprotinin was withheld from patients thought to be at risk of thromboembolism or nephrotoxicity.

Currently, there are only 2 ongoing trials of aprotinin use in HCA patients. The difficulties in heparin management were addressed by Okita, who concluded that a policy of repeated heparin administration was necessary irrespective of ACT measurements [14]. Ehrlich and associates (1998) used a low dose regimen and placebo in 50 randomized patients, and documented a difference in blood loss of 200 ml (p = 0.04), without any adverse effects of aprotinin [15]. ACT was kept > 800 seconds.

There is also the option of using aprotinin after HCA. Doctor Hans Borst (personal communication) arbitrarily uses aprotinin during rewarming after CPB, and the Oxford group use a postoperative infusion for abnormal bleeding, and intrapericardial application to counter oozing from dissected tissues.

The synthetic antifibrinolytic tranexamic acid is a potent inhibitor of plasminogen, and is only slightly less effective than aprotinin in coronary bypass studies. Epsilon amino-caproic acid (Amicar) and desmopressin have also been used as antifibrinolytics during continuous CPB, but there are no reports in thoracic aortic operations with or without HCA.

	References

Top Abstract Introduction Cardiopulmonary bypass,... Role of anti-fibrinolytic agents... References

 

1. Westaby S. Coagulation disturbances in profound hypothermia. Sem Thorac Cardiovasc Surg 1997;9:246-256.[Medline]
2. Stern D.M., Kaiser E., Naworth P.P. Regulation of the coagulation system by vascular endothelial cells. Hemostasis 1988;18:202-214.
3. Mackie I.J., Bull H.A. Normal hemostasis and its regulation. Blood Rev 1989;3:237-250.[Medline]
4. Fisher D.F., Yawn D.H., Crawford E.S. Reoperative disseminated intravascular coagulation associated with aortic aneurysms. A prospective study of 76 cases. Arch Surg 1983;118:1252-1255.[Abstract/Free Full Text]
5. Heimark R.L., Kurachi K., Fujikawa K., Davie E.W. Surface activation of blood coagulation, fibrinolysis and kinin formulation. Nature 1980;286:456-460.[Medline]
6. Tice D.A., Reed G.E., Clauss R.H., et al. Hemorrhage due to fibrinolysis occurring in open heart operations. J Thorac Cardiovasc Surg 1963;46:673-676.
7. Stibbe J., Kluft C., Brommer E.J. Enhanced fibrinolytic activity during cardiopulmonary bypass in open heart surgery in main caused by (tissue type) plasminogen activator. Eur J Clin Invest 1984;49:549-556.
8. Wenger R.H.L., Mikuta B., Niewiarowski S.L.H. Loss of platelet fibrinogen receptors during clinical cardiopulmonary bypass. J Thorac Cardiovasc Surg 1989;97:235-243.[Abstract]
9. Menys V.C., Belcher P.R., Nobel M.I.M., et al. Macroaggregation of platelets in plasma as distinct from microaggregation in whole blood as determined using optical aggregometry and platelet counting respectively, is specifically impaired following cardiopulmonary bypass in man. Thromb Haemostas 1994;72:511-518.[Medline]
10. Westaby S. Aprotinin in perspective. Ann Thorac Surg 1993;55:1033-1041.[Abstract]
11. Sundt T.M., Saffitz J.E., Stahl D.J., et al. Renal dysfunction and intravascular coagulation after use of aprotinin in thoracic aortic operation employing hypothermic circulatory arrest. Ann Thorac Surg 1993;55:1418-1424.[Abstract]
12. Westaby S., Forni A., Dunning J., et al. Aprotinin and bleeding in profoundly hypothermic perfusion. Eur J Cardiothorac Surg 1994;8:82-86.[Abstract]
13. Goldstein D.J., DeRosa C.M., Mongero L.B., et al. Safety and efficacy of aprotinin under deep hypothermia and circulatory arrest. J Thorac Cardiovasc Surg 1995;110:1615-1621.[Abstract/Free Full Text]
14. Okita Y., Takamoto S., Ando M., et al. Coagulation and fibrinolysis system in aortic surgery under deep hypothermic circulatory arrest with aprotinin. Circulation 1997;96(Suppl 11):376-381.
15. Ehrlich M., Grabenwöger M., Cartes-Zumelzu F., et al. Operations on the thoracic aorta and hypothermic circulatory arrest: is aprotinin safe?. J Thorac Cardiovasc Surg 1998;115:220-225.[Abstract/Free Full Text]

This article has been cited by other articles:

				V. Casati, L. Sandrelli, G. Speziali, G. Calori, M. A. Grasso, and S. Spagnolo Hemostatic effects of tranexamic acid in elective thoracic aortic surgery: A prospective, randomized, double-blind, placebo-controlled study J. Thorac. Cardiovasc. Surg., June 1, 2002; 123(6): 1084 - 1091. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Stephen Westaby Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Westaby, S. Search for Related Content PubMed PubMed Citation Articles by Westaby, S.