Procoagulant activity during coronary interventions and coronary artery patency

International Journal of Cardiology 68 (Suppl. 1) (1999) S23–S27

Procoagulant activity during coronary interventions and coronary artery patency Luigi Oltrona Visconti*, Antonio Pezzano Jr., Giuseppina Quattrocchi, Antonio Pezzano II8 Divisione, Cardiologica De Gasperis, Ospedale Niguarda, Milano, Italy Accepted 18 September 1998

The introduction in the clinical practice of percutaneous coronary angioplasty (PTCA) and other procedures of revascularization in patients with coronary artery disease has changed the history of cardiology. Almost 900 000 interventions were performed worldwide in 1995 [1]. However, despite the implantation of coronary stents or conjunctive treatment with new antithrombotic drugs like blockers of platelet glycoprotein IIb / IIIa receptors, these procedures are associated with death or nonfatal myocardial infarction in about 5% of patients [2] and with 6 months restenosis in about 30% [3]. In particular, the results of aggressive treatment of acute ischemic episodes with interventions of revascularization is less satisfactory: in patients with unstable angina the initial success rate is slightly lower than in those with stable angina [4] and the incidence of abrupt occlusion [5] and restenosis [6] is higher. Moreover, restenosis and reocclusion rates are very high in patients treated with PTCA in the first month after acute transmural myocardial infarction (51% and 13%, respectively) [7]. Abrupt coronary closure accounts for most acute complications of coronary interventions. It occurs in 2–8% of procedures, in 75% of patients within minutes after PTCA, when they are still in the catheterization laboratory, in the other 25% within 24 h after the procedure [8]. Extensive dissection is the *Corresponding author.

principal process that contributes to the occurrence of abrupt closure after PTCA [8]; however, acute thrombus formation accounts for nearly 50% of abrupt occlusions, most likely in patients with extensive dissection, residual stenosis after the procedure, or previous intracoronary thrombus. Moreover, thrombus plays a pivotal role in the long-term process of restenosis after a successful intervention.

1. Role of thrombus formation in acute complications PTCA is highly effective in increasing the size of the arterial lumen and improving vessel patency but is also highly thrombogenic. The presence of thrombus as an early event after PTCA has been demonstrated by a variety of techniques, including angiography [9] and angioscopy [10]. In addition, atherectomy specimens have shown organized thrombus in 25% of lesions [11]. Balloon inflation determines tears, fractures and cracks in the stenotic plaque, dissection through the intima into the media, and it produces stretches of the media or adventitia of the vessel. The depth or extent of vascular injury as well as hemorheologic factors determine the degree of thrombus formation and persistence of such thrombi [12]. When deep intimal and medial damage occurs, highly thrombogenic components of median layer like collagen and tissue factor are exposed to the

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blood circulation resulting in platelet aggregation and mural thrombosis. Elevated shear stress significantly increases the number of platelets deposed; the apex of stenosis is the segment where the greatest platelet accumulation occurs. Therefore, thrombus formation is associated with the presence of a deep injury, even in the absence of a residual stenosis; however, if the initial hemodynamic result of PTCA is suboptimal and a significant residual lesion remains, platelet deposition is augmented because of the presence of elevated wall shear stress at the site of lesion. The contact between circulating blood and tissue thromboplastin, the initiator of coagulation cascade contained in the media, determines the activation of the hemostatic system that has been shown to play a central role in the process of thrombus formation. The result of this activation is thrombin generation mediated by factor Xa activity on prothrombin. Thrombin converts fibrinogen to fibrin and activates platelets. In the effort to reduce the incidence of acute ischemic events during coronary interventions, antithrombotic therapy is currently used during procedures and includes agents inhibiting platelet aggregation or thrombin activity. However, despite aggressive anticoagulation, abrupt coronary occlusion still occurs.

1.1. In vivo characterization of procoagulant activity during coronary interventions Thrombus-associated thrombin activity has been demonstrated to promote platelet aggregation and thrombosis in experimental animal models [13]. In humans, characterization of procoagulant activity during coronary interventions has been investigated measuring plasma levels of markers of activation of the hemostatic system. Marmur et al. through direct sampling across the coronary lesion after PTCA found increased plasma levels of prothrombin fragment 112, a marker of thrombin generation [14]. Oltrona et al. showed increased plasma levels of fibrinopeptide A, a marker of thrombin activity, in the coronary sinus of patients during and immediately after coronary interventions, despite maximal anticoagulation with heparin [15]. In addition, the evidence in the same study of the association between increased plasma levels of fibrinopeptide A and increased incidence of procedural complications or

ischemic events suggests that heparin-resistant thrombin activity plays a role in the failure of coronary interventions [15]. Other in vivo studies have demonstrated a significant platelet activation in the coronary sinus of patients undergoing PTCA [16]. These data confirm the results of previous works showing an increase in the responsiveness of platelet aggregation in animal models after vascular injury secondary to balloon dilation [17–19].

2. The process of restenosis

2.1. Role of vascular injury The mechanism of restenosis after PTCA involves the development of fibrocellular hyperplasia, with smooth muscle cell proliferation [12,20]. In animal models, complete endothelial denudation, marked platelet deposition and macroscopic thrombosis result after a medial tear of the vessel due to the balloon dilation. Mural thrombi organize and persist incorporated into the vascular wall. Within 48 h smooth muscle cell proliferate in the media and migrate to the intima at around 4 days. In the 8 weeks after vascular injury intimal proliferation is observed as a result of synthesis of connective tissue matrix and cellular hyperplasia and hypertrophy. All the animal models demonstrate a striking correlation between the degree of intimal denudation and medial injury and the extent of myointimal thickening.

2.2. Role of thrombin In addition to the direct effect of vascular trauma, stimulation of platelet-derived growth-factors and hemodynamic shear stress, the organization and incorporation of thrombus into the atherosclerotic lesion after PTCA play a significant role in the complex and multifactorial process of restenosis, as suggested by pathological studies and analysis of atherectomy specimens. Thrombin has a central role in the regulation of the hemostatic mechanism and is tightly bound to thrombus where it remains actively thrombotic with a long half-life and where is protected from the inhibitory effects of antithrombin III and heparin. Thrombin has been shown to stimulate platelet aggregation and to have mitogenic

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activity for smooth muscle cells [21], fibroblasts [22] and other cells. Moreover, thrombin is a potent activator of growth factors (PDGF, FGF) [23,24]. The consideration of the multiple functions of this enzyme is the rationale for experiments aimed to inhibit thrombin activity in the context of PTCA. In animal models of vascular injury the antithrombotic effect of new specific and potent thrombin inhibitors was promising [25–28]. However, hirudin did not show apparent benefit compared with heparin in reducing the long term incidence of ischemic events in two large studies in patients undergoing PTCA [29,30]. Although the results of these studies may have been flawed by methodological problems, i.e. the dosage of the drug and the duration of treatment, at present there is a lack of evidence that antithrombin agents may inhibit the process of restenosis in humans.

2.3. Role of tissue factor A growing body of scientific demonstrations highlight the role of tissue factor in enhancing the mechanism of thrombus formation. Tissue-factor is a membrane-bound glycoprotein expressed by cells primarily in the vascular adventitia [31], in the subendothelium [32], in atherosclerotic plaques [33], and is expressed by monocytes / macrophages and endothelial cells after their activation by various agonists [34–37]. When exposed to blood by vessel injury [38] tissue factor binds factor VII and VIIa, resulting in assembly of the functional tissue factorVIIa complex, which in turns activates factors IX and X. Factor Xa and its cofactor Va convert prothrombin to thrombin. It has been shown that the upregulation of tissue factor in the injured vessel wall leads to a bimodal pattern of prolonged procoagulant activity on the luminal surface over 24 h after injury [39]. TFPI (Tissue Factor Pathway Inhibitor) is a glycoprotein produced by endothelium that is the natural inhibitor of tissue factor / VIIa as well as Xa. Oltrona et al. demonstrated that inhibition of tissue factor-mediated coagulation with rTFPI, administered over the first 24 h after vessel injury in carotids of minipigs, was effective for attenuating neointimal formation and stenosis [40]. Another mechanism that may account, in part, for reduced stenosis secondary to rTFPI treatment is the inhibition of Xa that has been shown

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to enhance mitogenesis of smooth muscle cells [41]. The same results were obtained in injured carotid arteries of rabbits with an anti-tissue factor monoclonal antibody [42]. The therapeutic antithrombotic potential of the inhibitors of tissue factor in humans has still to be determined.

2.4. Inhibition of the final pathway of platelet aggregation After vascular injury, adhesion and aggregation of platelets to the vascular wall with release of mitogens and chemoattractants for smooth muscle cells may be sufficient to initiate intimal hyperplasia. The failure of direct thrombin inhibitors to show a striking advantage over heparin during angioplasty is now attributed to their inability to inhibit the multiplicity of pathways for platelet activation. Aspirin has a relatively weak antiplatelet effect and blocks only the thromboxane A2-mediated platelet activation. The final step of platelet activation involves the expression of functional glycoprotein IIb / IIIa receptors on their surface. These receptors permit the recruitment of local platelets by forming fibrinogen bridges between platelets. Moreover, IIb / IIIa integrins bind with other circulating adhesives molecules like von Willebrand’s factor, fibronectin, vitronectin and thrombospondin. The blockade of glycoprotein IIb / IIIa-dependent platelet recruitment appears as an appealing therapeutic strategy because IIb / IIIa are the most abundant platelet membrane proteins and because it inhibits the final phase of platelet activation. Some specific agents directed against IIb / IIIa receptors have been recently developed; monoclonal antibodies directed against glycoprotein IIb / IIIa have resulted in a significant inhibition of thrombosis in the baboon vascular graft model [43] and experimental canine coronary angioplasty [44]. In the EPIC study 2099 patients undergoing PTCA were treated with abciximab, a monoclonal antibody that significantly reduced the combined end-point of death, myocardial infarction, or repeated revascularization at 30 days [45]. These results, obtained in a population at high-risk for complications during the procedure, were confirmed in the EPILOG trial that included 2792 patients of all risk strata. In this study a highly significant 56% relative reduction of death, myocardial infarction and urgent / repeated revascularization

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was observed at 30 days in patients treated with abciximab compared with patients treated with only heparin [46]. Encouraging short-term results arose from two trials that evaluated integrelin and tirofiban, a peptidic and a non-peptidic compound, respectively [47,48]. Beyond the 30 days benefit observed in these trials in patients treated with abciximab, from the EPIC study comes also the evidence for durability and incremental late benefit of this treatment. The reduction of composite end-point of death, acute MI and need of revascularization was sustained at 6 months for the overall cohort of patients [49]. At 3-year follow-up in the subgroup of patients with acute coronary syndromes patients treated with abciximab had a 60% reduction in mortality compared with those treated with placebo [50]. This delayed and sustained effect over time of abciximab raises the hypothesis that arterial passivation was achieved, such that this drug was capable of transforming the vessel wall surface from one that is the target of platelet-thrombus deposition to one that is not.

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