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Ann Thorac Surg 2001;72:S1808-S1813
© 2001 The Society of Thoracic Surgeons

Supplement: Mechanisms and attenuation of abnormalities in hemostasis/inflammation and neurologic injury: implications for patient outcomes

New antiinflammatory and platelet-preserving effects of aprotinin

R. Clive Landis, PhD*a, Dorian O. Haskard, FRCPa, Kenneth M. Taylor, FRCSb

a British Heart Foundation Unit of Cardiovascular Medicine, Hammersmith Hospital, National Heart and Lung Institute, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, England, United Kingdom
b British Heart Foundation Unit of Cardiac Surgery, Hammersmith Hospital, National Heart and Lung Institute, Faculty of Medicine, Imperial College of Science, Technology and Medicine, London, England, United Kingdom

* Address reprint requests to Dr Landis, National Heart and Lung Institute, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Du Cane Rd, London, England W12 0NN, United Kingdom
e-mail: r.landis{at}ic.ac.uk

Presented at Mechanisms and Attenutation of Abnormalities in Hemostasis/Inflammation and Neurologic Injury: Implications for Patient Outcomes, Vancouver, BC, Canada, May 6, 2001.


   Abstract
Top
 Abstract
Introduction
 Selective blockade of the...
 A new mechanism for...
 New antiinflammatory targets for...
 References
 
The clinical benefit of aprotinin with respect to improved hemostasis, platelet function, and inflammatory response to cardiopulmonary bypass (CPB) surgery has been well documented, but these benefits have been overshadowed by the concern that such a potently hemostatic agent might also be prothrombotic. In this article, we discuss recent advances in the understanding of the basic mechanism of aprotinin that have led to the identification of new antiinflammatory targets and the discovery that aprotinin is, in fact, antithrombotic with respect to platelets. Its antithrombotic action is mediated by the selective blocking of the major thrombin receptor, the protease-activated receptor 1 (PAR1), but not other receptors of platelet activation (ie, collagen, adenosine diphosphate [ADP], or epinephrine receptors). The selective targeting of PAR1 enables aprotinin to protect platelets from unwanted activation by thrombin generated during CPB surgery (consistent with a role in platelet-preservation), while permitting the participation of platelets in the formation of hemostatic plugs at wound and suture sites, where collagen, ADP, and epinephrine are most likely to be expressed. Aprotinin therefore exerts a subtle hemostatic yet antithrombotic mechanism of action, which, when allied with its multitiered antiinflammatory effect, makes this drug a valuable companion to cardiac surgery.


   Introduction
Top
 Abstract
 Introduction
Selective blockade of the...
 A new mechanism for...
 New antiinflammatory targets for...
 References
 
Aprotinin is a broad-spectrum serine protease inhibitor that has been in clinical use since the late 1980s to reduce blood loss and preserve platelet function during CPB surgery [1–4]. However, since its clinical introduction to cardiothoracic surgery there has been lingering concern that such a powerfully hemostatic agent might also be prothrombotic, particularly when given to coronary artery surgery patients.

Despite the publication of numerous graft patency trials, this issue has remained controversial and unresolved. Although the studies of Bidstrup and colleagues [5], Havel and colleagues [6], Lass and associates [7], Hayashida and coworkers [8], and Rich [9] revealed no link between aprotinin use and loss of coronary graft patency, the studies of Cosgrove and associates [10], Van der Meer and coworkers [11], and Alderman and colleagues [12] did suggest such an association. In trying to understand these divergent outcomes, it must be remembered that the trials concerned varied with respect to aprotinin dosage, heparin dosage, use of aspirin, quality of distal vessels, time of graft assessment, and imaging modes used to assess graft patency [13, 14]. The clinical evidence has therefore remained ultimately inconclusive, and the debate based on these trials appears to have reached a stalemate.

One of the reasons why the thrombosis debate has reached such an impasse is that the clinical efficacy of aprotinin has outstripped its known mechanism of action. Only with respect to its hemostatic mechanism of action is there general agreement on how it works: because of its potent inhibition of plasmin (relative to other targets in the coagulation cascade), the hemostatic effect of aprotinin has been assumed to be mediated predominantly by means of an inhibition of the fibrinolytic system [15, 16]. The true picture is likely to be more complicated, because of the wide spectrum of antiprotease activity exhibited by aprotinin, but the majority of its hemostatic action (particularly at low-dose regimens) is likely to be accounted for by its effect on plasmin. In contrast, there remains less consensus agreement on how aprotinin mediates platelet protection or how it may influence the participation of platelets in the coagulation cascade.

To better understand the basic mechanism of action of aprotinin with respect to the platelet and to stimulate the thrombosis debate, we have postulated a controversial hypothesis (based on the cloning of the major thrombin receptor): namely, that aprotinin might exert an antithrombotic effect on platelets.


   Selective blockade of the thrombin receptor PAR1
Top
 Abstract
 Introduction
 Selective blockade of the...
A new mechanism for...
 New antiinflammatory targets for...
 References
 
Cloning of the major thrombin receptor on platelets revealed a receptor that, uniquely, required proteolytic cleavage to transmit an intracellular activating signal [17]. Proteolytic cleavage is mediated by the serine protease activity of thrombin or other serine proteases localized to the platelet membrane [18, 19]. We therefore postulated that aprotinin, as a serine protease inhibitor, might inhibit proteolytic activation of the thrombin receptor, thereby preventing thrombin-induced platelet activation.

Because of its proteolytic mechanism of activation, the thrombin receptor has been renamed the protease-activated receptor (PAR)–1 and is now recognized as the prototype member of a family of four related thrombin receptors, namely, PARs 1 to 4 [20]. Platelets express only PAR1 and PAR4, and of these only PAR1 is activated at low concentrations of thrombin (<1 U/mL).

Using low concentrations of thrombin (0.1 U/mL) and washed platelets, we examined the ability of aprotinin to block proteolytic (ie, PAR1-mediated) versus nonproteolytic pathways of platelet activation (ie, those mediated by collagen, ADP, or epinephrine receptors). These experiments revealed that aprotinin, even at the equivalent of "low dose" (50 KIU/mL), significantly inhibited platelet aggregation induced by thrombin, but had no effect on aggregation induced by collagen, ADP, or epinephrine [21] (Fig 1). Inhibition of thrombin-induced aggregation was 42.6% ± 21.6% (mean ± SD) at 50 KIU/mL aprotinin (p = 0.0047), 61.0% ± 25.2% at 100 KIU/mL (p = 0.0001), and 86.6% ± 8.9% at 160 KIU/mL (p < 0.0001).



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  		Fig 1. Aprotinin specifically inhibits thrombin-induced platelet aggregation. Aprotinin specifically inhibits protease-sensitive aggregation induced by thrombin (A), but has no effect on nonproteolytic methods of platelet aggregation induced by collagen (B), adenosine diphosphate (ADP) (C), or epinephrine (D). (Reproduced from Poullis et al, J Thorac Cardiovasc Surg 2000;120:370–8, with permission.)

 
Similar results were obtained using intracellular Ca2+ fluxes as a measure of platelet activation, which placed the effect of aprotinin upstream of the signaling event in PAR1 activation [21]. When the proteolytic requirement for PAR1 was bypassed, using an exogenously added PAR1 agonist-peptide (SFLLRN), aprotinin lost its inhibitory effect. This demonstrated that the antithrombotic effect of aprotinin was targeted to the proteolytic cleavage event in PAR1 activation. Because proteolysis of PAR1 was blocked at a concentration approximately 60X lower than that predicted to inhibit the serine protease activity of thrombin directly [22], this suggested that aprotinin must have targeted a serine protease(s) distinct from thrombin. PAR1 has recently been shown to function as part of a larger signaling complex, which includes other serine proteases such as the membrane type serine protease-1, the coagulation factors VIIa and Xa (themselves presented in association with their own cofactors), and other PARs [19, 23, 24]. Further work will be required to clarify which serine-proteases are directly targeted by aprotinin at the platelet surface.

A further observation of clinical relevance was that platelets, in which aggregation to thrombin had been prevented by aprotinin, still aggregated in response to collagen or epinephrine [21] (Fig 2). This observation revealed an antithrombotic yet hemostatic mode of action for aprotinin, which may have bearing to its use in CPB surgery. Such an inhibitory profile would be predicted to protect platelets from activation by thrombin generated in the bypass circuit while maintaining the hemostatic activity of platelets in surgical wounds, where collagen, ADP, and epinephrine are most likely to be expressed [25].



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  		Fig 2. Evidence for a simultaneous antithrombotic but hemostatic mechanism of action on platelets. The blockade of thrombin-induced aggregation by aprotinin does not prevent subsequent aggregation by collagen (arrowhead) (A) or epinephrine (arrow) (B). This indicates that aprotinin exerts a simultaneous antithrombotic yet hemostatic mechanism of action on platelets in vitro. (Reproduced from Poullis et al, J Thorac Cardiovasc Surg 2000;120:370–8, with permission.)

 

   A new mechanism for platelet preservation
Top
 Abstract
 Introduction
 Selective blockade of the...
 A new mechanism for...
New antiinflammatory targets for...
 References
 
Cardiopulmonary bypass is associated with a loss of platelet function that can result clinically in prolonged bleeding times and the need for platelet transfusions. The platelet deficiency is most probably caused by exposure to thrombin generated in the bypass circuit, after activation of the intrinsic pathway of coagulation [26, 27]. Although an actual drop in platelet numbers is not always measurable, progressive platelet activation within the bypass circuit leads to degranulation and reentry of "exhausted" platelets into the circulation, resulting in a nonfunctional platelet response and excessive bleeding in surgical wounds [28–30].

Aprotinin has been shown by a variety of measures to confer platelet protection when administered to CPB patients. It prevents platelet activation as assessed by shape change [31], formation of platelet microparticles [32], and expression of activation markers [32]. It prevents loss of fibrinogen [33] and von Willebrand binding sites [33, 34] and maintains the ability of platelets to be activated by platelet agonists ex vivo [31, 32, 35, 36]. It also reduces blood loss and the need for blood products—effects that are noticeable from the beginning of bypass, before detectable fibrinolysis has begun [33, 34]. This observation, in combination with the fact that aprotinin is effective when added to the pump-prime only [31–35], suggests that its platelet preservation properties are distinct from its antifibrinolytic properties.

Our finding that aprotinin blocks thrombin-induced platelet activation fits nicely with an early time-scale of intervention. Thus aprotinin administered systemically or in the pump-prime would be expected to protect platelets from unwanted activation by thrombin in the bypass circuit, while permitting their participation in the formation of hemostatic plugs in the chest cavity [25]. This proposed mechanism of action (Fig 3), is consistent with the observation that, when administered directly to the pericardium, aprotinin fails to inhibit platelet activation in the pericardial cavity [37]. As we have argued previously, it is important to maintain adequate anticoagulation in aprotinin-treated patients throughout the perioperative period, at which point aprotinin levels begin to decline but thrombin generation may continue. Because aprotinin can also inhibit thrombin formation and platelet/neutrophil activation through its effect on kallikrein (particularly at high doses) [38], it is likely that the platelet protective mechanism described above represents but one component of a more complex overall mechanism of platelet preservation.



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  		Fig 3. A new "platelet preservation" mechanism during CPB surgery. This schematic summarizes how the selective targeting of the protease-activated receptor 1 (PAR1) may protect platelets from activation by thrombin in the bypass circuit, while leaving activation by collagen, adenosine diphosphate (ADP), or epinephrine in the pericardial cavity untouched. Such a pharmacological profile of action is potentially ideal for a drug used in cardiac surgery.

 

   New antiinflammatory targets for aprotinin
Top
 Abstract
 Introduction
 Selective blockade of the...
 A new mechanism for...
 New antiinflammatory targets for...
References
 
Direct effects on endothelium
The systemic inflammatory response to CPB surgery is due in part to the stress of surgery and in part to the activation of plasma components, platelets and leukocytes within the bypass circuit [39–41]. The clinical consequences of the inflammatory response to bypass vary from increased duration of hospital stay, to neurocognitive disorders, stroke, acute lung injury, multiple organ failure, and death. A leading cause of organ injury, particularly in the ischemic lung, is the accumulation of massive numbers of leukocytes and the discharge of their histotoxic contents within the tissues. Because localized endothelial cell activation is a necessary step in the recruitment of leukocytes to sites of inflammation, there has been much interest in the possibility of targeting vascular endothelium as a means of limiting the inflammatory response to bypass.

Despite the interest in targeting endothelium, endothelium-specific actions of aprotinin have been difficult to pinpoint, particularly in vivo, because of the relative inaccessibility of the vascular endothelial compartment. However, indirect in vivo evidence has suggested that aprotinin can target vascular endothelium. These studies have shown that aprotinin can inhibit trypsin-induced vascular permeability in the lung [42] and limit bronchoalveolar neutrophil accumulation after CPB [43].

To identify direct endothelial effects, we examined the ability of aprotinin to target cultured endothelial cells in vitro in models of acute and chronic inflammation. We asked whether aprotinin could influence adhesion molecule expression and the capacity of endothelial monolayers to support neutrophil transmigration. In these experiments we used human umbilical vein endothelial cells activated over a period of 4 hours by tumor necrosis factor–{alpha}, a key cytokine in the vascular inflammatory response.

Exposure to tumor necrosis factor–{alpha} led to upregulation of three adhesion molecules tested: namely, intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin. Pretreatment with aprotinin significantly inhibited the expression of ICAM-1 and VCAM-1 but not E-selectin [44]. Because ICAM-1 is also a key molecule involved in the extravasation of neutrophils, we examined the effect of aprotinin on neutrophil transmigration. These experiments showed that pretreatment of endothelial cells with aprotinin significantly reduced their capacity to support neutrophil transendothelial migration [44], suggesting that aprotinin might exert a direct effect on endothelium by preventing the expression of adhesion molecule required for leukocyte attachment and extravasation.

Using a model of acute inflammation, we demonstrated further effects on neutrophil transmigration in response to the chemoattractants N-formyl L-methyl L-leucyl L-phenylalanine (fMLP), platelet-activating factor, and interleukin-8 [45]. In this system, aprotinin was shown to target both neutrophils and endothelial cells independently, with maximal effects observed when both cell types were targeted together. Research is now underway to examine the exact proteins recognized by aprotinin on endothelial cells. Strong candidates are the PAR receptors, which are represented on endothelial cells by PAR1, PAR2, and PAR3 [46].

Effects on the leukocyte–endothelial cell adhesion cascade in vivo
Although in vitro studies have been useful in identifying potential new antiinflammatory targets, they do not always indicate whether this can be achieved at clinically relevant doses of aprotinin. Concentrations of inhibitor required to block in vitro responses are often higher than those required to block in vivo responses, as the inflammatory mediators employed in in vitro models are themselves often present at supraphysiological levels. We therefore infused aprotinin into living rats at a dose equivalent to the high dose regime used in CPB and examined the trafficking of leukocytes in the mesenteric microcirculation by the technique of intravital microscopy [45]. This technique allows the interaction of leukocytes within venular endothelium to be visualized directly through the transparent mesenteric tissue.

Intravital microscopy has been instrumental in defining the three steps of the leukocyte–endothelial adhesion cascade: (1) leukocyte rolling on endothelium, (2) firm attachment, and (3) transendothelial migration [47]. Intravital microscopy experiments using infused aprotinin demonstrated that aprotinin did not inhibit the first two steps of the adhesion cascade but did significantly reduce the extravasation step in response to a topically applied chemoattractant [45]. A representative video clip of this study can be viewed on the BHF cardiovascular Medicine Imperial College Website [48]. In conclusion, intravital microscopy in rats demonstrated that aprotinin, infused at a concentration equivalent to "high dose" used in CPB surgery, significantly inhibited the leukocyte extravasation step (72% inhibition, p < 0.04), thereby confirming effects previously noted in vitro.

Taken in conjunction with other reports showing that neutrophil activation and degranulation is diminished in the presence of aprotinin [38, 45, 49–52], these studies suggested that aprotinin may be exerting a potent combined effect during CPB surgery: first, by limiting the extent neutrophil activation within the bypass circuit; second, by limiting extravasation at inflammatory sites; and finally, by preventing degranulation of neutrophils within the tissues. The antiinflammatory properties thus defined should prompt further investigations into the potential clinical benefits of aprotinin used in CPB, with suitable target organs for such studies being the brain, lungs, and heart.

Inflammation is targeted at multiple levels
The distribution of serine proteases and PAR receptors throughout the vasculature and the key role they play in inflammation [53] may explain how aprotinin, as a nonspecific protease inhibitor, can exert such a multitiered antiinflammatory mechanism of action. The results discussed above, together with many others published previously, suggest a complex antiinflammatory mechanism of action. The schematic in Figure 4 summarizes the main points of intervention, both within the bypass circuit and at sites of vascular inflammation: Initially, kallikrein and the contact system is targeted within the bypass circuit, thereby limiting the quantity of thrombin generated and its capacity to activate platelets by means of PAR1. Diminished contact activation of platelets and neutrophils leads to reduced proinflammatory cytokine secretion, which in turn leads to reduced systemic endothelial cell activation. Endothelial responses such as increased vascular permeability and adhesion molecule expression are also curbed. Finally, leukocyte extravasation and degranulation within the tissues is inhibited by aprotinin.



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  		Fig 4. Antiinflammatory targets of aprotinin ({perp}) within the bypass circuit (A) and at sites of vascular inflammation (B). This schematic summarizes the known molecular and cellular targets recognized by aprotinin in the inflammatory response to bypass. ICAM-1 = intercellular adhesion molecule 1; PAR1 = protease-activated receptor 1.

 
The multitiered antiinflammatory mechanism discussed above suggests that aprotinin should provide a significant clinical benefit in the prevention of the systemic inflammatory response to bypass. This expectation has been borne out in clinical practice, particularly in the case of high-risk patients, in whom the length of hospital stay after CPB is significantly reduced with aprotinin compared with other state-of-the-art antiinflammatory strategies (use of methylprednisolone, leukocyte filtration, and heparin-bonded circuitry), more than offsetting the initial cost of the drug used during surgery [54].


   References
Top
 Abstract
 Introduction
 Selective blockade of the...
 A new mechanism for...
 New antiinflammatory targets for...
 References
 

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A. M. Mengistu, K. D. Rohm, J. Boldt, J. Mayer, S. W. Suttner, and S. N. Piper
The Influence of Aprotinin and Tranexamic Acid on Platelet Function and Postoperative Blood Loss in Cardiac Surgery
Anesth. Analg., August 1, 2008; 107(2): 391 - 397.
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Y. Iwata, O. Nicole, T. Okamura, D. Zurakowski, and R. A. Jonas
Aprotinin confers neuroprotection by reducing excitotoxic cell death
J. Thorac. Cardiovasc. Surg., March 1, 2008; 135(3): 573 - 578.
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N. A. Guzzetta, T. Bajaj, T. Fazlollah, F. Szlam, E. Wilson, A. Kaiser, S. R. Tosone, and B. E. Miller
A Comparison of Heparin Management Strategies in Infants Undergoing Cardiopulmonary Bypass
Anesth. Analg., February 1, 2008; 106(2): 419 - 425.
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A. F. Corno
Systemic venous drainage: can we help Newton?
Eur. J. Cardiothorac. Surg., June 1, 2007; 31(6): 1044 - 1051.
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E. B. Mossad, S. Machado, and J. Apostolakis
Bleeding following deep hypothermia and circulatory arrest in children.
Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 2007; 11(1): 34 - 46.
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L. H. Edmunds Jr and R. W. Colman
Thrombin During Cardiopulmonary Bypass
Ann. Thorac. Surg., December 1, 2006; 82(6): 2315 - 2322.
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A. Sedrakyan, A. Wu, G. Sedrakyan, M. Diener-West, M. Tranquilli, and J. Elefteriades
Aprotinin use in thoracic aortic surgery: Safety and outcomes
J. Thorac. Cardiovasc. Surg., October 1, 2006; 132(4): 909 - 917.
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E. Akowuah, V. Shrivastava, B. Jamnadas, D. Hopkinson, P. Sarkar, R. Storey, P. Braidley, and G. Cooper
Comparison of Two Strategies for the Management of Antiplatelet Therapy During Urgent Surgery
Ann. Thorac. Surg., July 1, 2005; 80(1): 149 - 152.
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A. Kokoszka, P. Kuflik, F. Bitan, A. Casden, and M. Neuwirth
Evidence-Based Review of the Role of Aprotinin in Blood Conservation During Orthopaedic Surgery
J. Bone Joint Surg. Am., May 1, 2005; 87(5): 1129 - 1136.
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A. J. Chong, C. R. Hampton, and E. D. Verrier
Microvascular Inflammatory Response in Cardiac Surgery
Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2003; 7(3): 333 - 354.
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R. C. Landis
Aprotinin: Antithrombotic and Vasoactive Mechanisms of Action
Seminars in Cardiothoracic and Vascular Anesthesia, December 1, 2002; 6(4): 307 - 312.
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