Published online before print December 1, 2003, doi: 10.1161/01.CIR.0000105900.21445.3D
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(Circulation. 2003;108:2864.)
© 2003 American Heart Association, Inc.
Clinical Investigation and Reports |
Involvement of Tissue Factor Pathway Inhibitor in the Coronary Circulation of Patients With Acute Coronary Syndromes
From the Department of Internal Medicine and Cardiovascular Sciences, Division of Cardiology, University of Naples Federico II, Naples, Italy. Dr Golino is currently at the Division of Cardiology, Second University of Naples, Italy.
Correspondence to Paolo Golino, MD, PhD, Division of Cardiology, Second University of Naples, Piazza Luigi Miraglia, 2, 80123 Naples, Italy. E-mail paolo.golino{at}unina2.it
Received February 18, 2003; de novo received July 3, 2003; revision received September 11, 2003; accepted September 12, 2003.
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Abstract |
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Background— Tissue factor pathway inhibitor (TFPI) is the endogenous inhibitor of the extrinsic coagulation pathway; however, its involvement during thrombus formation in patients with acute coronary syndromes (ACS) is still unknown.
Methods and Results— Transcardiac (aorta/coronary sinus) free and total TFPI (free + lipoprotein-bound form) levels, as well as TFPI/factor Xa (FXa) complex levels, were measured in plasma samples obtained from patients with acute myocardial infarction undergoing primary PTCA and patients with unstable angina undergoing urgent PTCA. Patients with stable angina undergoing elective PTCA served as controls. In addition, prothrombin fragment 1+2 and fibrinopeptide A plasma levels were measured. Samples were collected at baseline, after PTCA, and after stent deployment. In patients with ACS, both total and free TFPI plasma levels in the coronary sinus were significantly lower than the corresponding levels measured in the aorta at any time point of the study; conversely, a significant increase in TFPI/FXa complex plasma levels was observed in the coronary sinus as compared with the aorta. In contrast, in patients with stable angina, no differences were observed in TFPI and TFPI/FXa levels at baseline in the coronary sinus as compared with the aorta.
Conclusions— TFPI is involved in the process of thrombus formation in vivo in patients with ACS, which suggests a potential role for TFPI in modulating coronary thrombosis.
Key Words: inhibitors, tissue factor pathway • tissue factor • acute coronary syndromes
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Introduction |
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Coronary thrombosis generally occurs at the site of a preexisting atherosclerotic plaque, usually triggered by fissuring or ulceration of the plaque.1 It is currently believed that a major initiator of intracoronary thrombus formation is tissue factor (TF), a cell-surface protein abundantly expressed by cells residing within the plaque.2 Several studies have identified both TF antigen and activity within human atherosclerotic plaques and suggested that TF might represent an important determinant of thrombogenicity after plaque rupture.3–5 Furthermore, experimental studies have demonstrated that blocking TF activity inhibits intravascular thrombus formation in different animal models.6–9
Tissue factor pathway inhibitor (TFPI) is an important regulator of TF-mediated coagulation.10,11 Although TFPI biochemistry and physiology have been extensively studied during the past decade, its pathophysiological role in thrombotic disorders has only recently started to be unraveled. At the moment, however, the pathophysiological role of TFPI in human atherothrombotic disorders such as acute coronary syndromes (ACS) is still largely unknown. Thus, the aim of the present study was to investigate the role of endogenous TFPI in modulating intracoronary thrombosis in patients with ACS—namely, acute myocardial infarction (AMI) and unstable angina (UA). To test this, transcardiac (aorta/coronary sinus) TFPI plasma levels were measured in patients with AMI undergoing primary PTCA, patients with UA undergoing urgent PTCA, and patients with stable effort angina (SA) undergoing elective PTCA.
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Methods |
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Patient Population
Forty patients, divided into 3 groups, entered the study. Group I included patients with AMI (n=15) undergoing primary PTCA, group II comprised patients with UA (n=13) undergoing urgent PTCA, and group III included patients with SA (n=12) undergoing elective PTCA. Only patients with a culprit lesion located in either the left anterior descending or the circumflex coronary artery, both of which drain into the coronary sinus,12 were included. Patients who received thrombolytics or heparin were excluded from the study. The local ethics committee approved the protocol, and all patients gave written informed consent to participate in the study.
Experimental Protocol
After obtaining vascular access, aspirin (250 mg IV) was given to all patients, whereas abciximab (0.25 mg/kg bolus + 0.125 µg/kg IV per minute for 12 hours) was administered only to patients with ACS. Heparin administration was at this time postponed to avoid a possibly confounding effect of this drug on the release of TFPI from the endothelial pool.13 A 6F multipurpose catheter was positioned in the coronary sinus. A 6F guiding catheter was positioned in the left coronary ostium, and a baseline angiography was obtained. For group I patients, only those showing TIMI flow grade 0 to 1 in the infarct-related artery entered the study.
Immediately after angiography, blood samples (4.5 mL) were obtained from the coronary sinus and the ascending aorta and placed in chilled Vacutainer tubes containing 0.5 mL of 3.8% sodium citrate. PTCA was then performed using a standard technique with a balloon of appropriate size. Immediately after PTCA, a second set of samples (coronary sinus and aorta) was obtained. Heparin was at this time administered (50 IU/kg IV), and a third set of samples was obtained. Finally, an intracoronary stent of the appropriate size was implanted at high pressure (10 to 16 atm) in all patients, and a final set of samples was obtained.
Blood samples were centrifuged at 1000g at 4°C for 20 minutes, and the plasma was stored in aliquots at -80°C.
Measurement of Molecular Markers of Coagulation Activity
Intravascular TFPI consists of a carrier-free and a lipoprotein-bound form.14–16 The free form includes 2 subfractions—ie, a circulating free TFPI fraction without carrier in preheparin plasma and a heparin-releasable fraction from endothelial cells.13 Free and total TFPI plasma levels (Diagnostica Stago),17 the complex TFPI/factor Xa (FXa) (American Diagnostica),18 prothrombin fragment 1+2 (F1+2) (Behringer AG), and fibrinopeptide A (FPA) (Diagnostica Stago) were measured by using commercially available ELISA kits.
Statistical Analysis
Free and total TFPI plasma levels and complex TFPI/FXa plasma levels are expressed as mean±SD. A 2-way ANOVA with a design for repeated measures was used; if an F value was found to be significant, a 2-tailed Student’s t test for paired or unpaired observations with Bonferroni’s correction was used to test differences within groups at different time points or among groups at the same time point, respectively. Because F1+2 and FPA plasma levels are not normally distributed, values are expressed as median and 25th and 75th percentiles. Repeated measures were compared by means of Friedman’s test, and subsequent pairwise comparisons with baseline were made with Wilcoxon’s signed-rank test. The Mann-Whitney U test was used to test the difference among groups. A probability value <0.05 was considered statistically significant.
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Results |
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The demographic, clinical, and angiographic characteristics of the patients are summarized in Table 1.
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Total TFPI plasma levels
At baseline, in patients with AMI and UA, total TFPI plasma levels were significantly lower in the coronary sinus than in the ascending aorta (74.8±8.5 versus 101.6±12.8 ng/mL and 75.5±12.1 versus 97.8±11.4 ng/mL, respectively [P<0.05 for both groups, Figure 1]), which indicates an active involvement (consumption) of TFPI at the level of the culprit lesion. In contrast, in patients with SA, no difference was observed in total TFPI plasma levels in the coronary sinus as compared with the aorta (85.3±11.9 versus 83.7±9.4 ng/mL, respectively; P=NS). Of note is the observation that baseline total TFPI levels in the aorta of patients with SA were significantly lower than the corresponding values measured in patients with AMI or UA (P<0.05; Figure 1). The aorta/coronary sinus difference in total TFPI levels persisted after PTCA before heparin administration in patients with AMI and UA, whereas a nonsignificant trend was observed in patients with SA (Figure 1). After heparin administration, total TFPI plasma levels increased significantly in both the ascending aorta and the coronary sinus in patients from all groups, in accordance with the notion that heparin induces release of TFPI from the endothelially bound pool.13,14 However, the plasma TFPI levels in the coronary sinus remained significantly lower than those in the aorta in patients with MI and UA but not in patients with SA (Figure 1), which indicates a continuous activation of the TF-dependent coagulation and an involvement of TFPI in the culprit coronary artery even after administration of heparin. These differences persisted after stent deployment (Figure 1). Percent changes in the aorta/coronary sinus ratio for total TFPI levels for all groups are shown in Figure 2A.
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Free TFPI Plasma Levels
At baseline, free TFPI plasma levels in the aorta averaged 25.2±3.4, 23.0±4.1, and 11.3±2.1 ng/mL in patients with AMI, UA, and SA, respectively, which represented about 25% of the total TFPI. In patients with AMI and UA, but not in patients with SA, free TFPI levels in the coronary sinus decreased significantly by about 60% compared with the aorta (Figure 2B and Figure 3). After PTCA, a significant decrease was also observed in the coronary sinus of patients with SA, although to a lesser extent than that observed in patients in the other groups (Figure 2B and Figure 3). A major difference was also observed in the magnitude of free TFPI release after heparin administration compared with total TFPI levels. In fact, in postheparin samples, free TFPI plasma levels showed a 6-fold increase, which accounted almost entirely for the increase in total TFPI observed in all patients (Figures 1 and 3
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TFPI/FXa Complex Plasma Levels
The complex TFPI/FXa forms when FXa is generated by the action of the catalytic complex TF/FVIIa and therefore represents an index of activation of the TF-dependent coagulation cascade.18 Thus, any increase in TFPI/FXa complex plasma levels represents active FXa formation consequent to activation of the TF-dependent coagulation cascade.
At baseline, total plasma TFPI/FXa complex levels were significantly higher in samples obtained from the coronary sinus (that is, distal to the site of thrombus formation) than in the samples obtained from the ascending aorta, in only the patients with AMI and UA (8.2±2.1 versus 2.8±1.1 ng/mL and 8.1±2.5 versus 2.5±1.0 ng/mL, respectively) (Figure 4). This difference represented active formation of FXa within the coronary circulation and persisted after PTCA of the culprit lesion and stent implantation (Figure 4). In patients with SA, a certain degree of FXa generation could be observed after PTCA and stent implantation (Figure 4) but to a lesser extent than in patients with AMI or UA (Figure 2C).
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F1+2 and FPA Plasma Levels
Table 2 summarizes F1+2 and FPA plasma levels at the different time points of the study. F1+2, which reflects generation of thrombin, and FPA, which represents thrombin activity, were significantly higher in the systemic circulation (ie, in the aorta) and coronary sinus of patients with ACS as compared with patients with SA, as previously described.19 In contrast to patients with SA, patients with ACS showed higher plasma levels of both F1+2 and FPA in the coronary sinus than in the aorta, indicating activation of the coagulation across the coronary circulation, which persisted throughout the study despite the administration of heparin. In particular, FPA levels (an index of thrombin activity) were significantly decreased in the coronary sinus after heparin administration, but they were still significantly higher than the corresponding values measured in the aorta, indicating a partial inability of heparin to antagonize thrombus-associated thrombin activity.20
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Discussion |
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The major finding of the present study is that in patients with ACS (namely, AMI and UA), both total and free TFPI plasma levels decreased significantly across the coronary circulation at the site of the culprit lesion, indicating an active involvement of TFPI during thrombus formation. Simultaneously, plasma levels of TFPI/FXa complex, which reflect activation of the TF-dependent coagulation pathway, were significantly increased in the samples obtained from the coronary sinus compared with those obtained from the aorta. Furthermore, F1+2, an index of thrombin activity, and FPA, an index of thrombin activity, were also significantly increased in the coronary sinus of patients with ACS, indicating activation of the coagulation across the coronary circulation. As expected, baseline plasma levels of F1+2 and FPA in the ascending aorta were significantly increased in patients with ACS compared with patients with SA. This finding is in agreement with previously published studies.19
Taken together, our data demonstrate that circulating TFPI is involved in the pathophysiology of ACS and that it may modulate the process of thrombus formation in vivo. In addition, our data also demonstrate that the carrier-free form of TFPI is predominantly involved in this pathophysiological process, as indicated by the larger aorta/coronary sinus ratio variation in free TFPI as compared with the changes observed in the total TFPI form, and that most of the increase in TFPI observed after heparin administration is accounted for by release of the free form from the endothelial pool. Although lipoprotein-bound TFPI constituted most of the circulating TFPI before heparin infusion, free TFPI represented the greatest pool in our patients in postheparin plasma. Because some data suggest that the free form of TFPI inhibits TF-induced coagulation more effectively than the lipoprotein-bound form,21 one can speculate that the heparin-releasable TFPI might represent the most important pool, mediating the majority of the antithrombotic activity of the total TFPI pool in postheparin plasma in patients with ACS.
TFPI is a potent inhibitor of the TF/FVIIa complex, particularly in the presence of FXa.22 Much of the circulating TFPI is bound to lipoproteins15,16; this form represents about 50% to 60% of the total circulating TFPI, whereas carrier-free TFPI represents about 20% of the total. A third pool of TFPI is confined to platelets, which carry approximately 10% of the total TFPI.23 The in vivo infusion of heparin increases the circulating levels of TFPI in plasma 2- to 4-fold.13,14 The source of this additional TFPI is thought to be the endothelium, at the surface of which TFPI is bound. The TFPI released by heparin in vivo represents the carrier-free molecule, which might be biologically most active.21
Despite the extensive study of TFPI biochemistry and physiology during the past decade, little is known about the in vivo contribution of TFPI to the regulation of TF-dependent coagulation during atherothrombotic disorders in patients. Indirect evidence for TFPI as a natural anticoagulant in vivo is offered by the finding that depletion of circulating TFPI sensitizes rabbits to TF or endotoxin-induced intravascular coagulation24 and that, in an in vivo rabbit model of recurrent arterial thrombosis, plasma TFPI activity distal to the site of thrombus formation was significantly lower than in plasma obtained at a proximal site.25 Furthermore, exogenous administration of recombinant TFPI5,26 or local overexpression of this protein in the arterial wall is associated with inhibition of thrombosis,27 and in apolipoprotein E–deficient mice, TFPI may protect against atherosclerosis and thrombosis.28 In healthy vessels, TFPI protein and mRNA are present in luminal and microvascular endothelial cells and in smooth muscle cells,29 whereas in atherosclerotic vessels, TFPI protein and mRNA frequently colocalize with TF within the plaque.30,31 More direct evidence suggesting a role for TFPI in modulating coronary thrombosis in patients with ACS is provided by a recent study in which TFPI levels in peripheral blood of patients with UA were significantly higher than in patients with SA.32 An inverse relation between TFPI levels and a poor prognosis was noted, probably related to the well-known release of TFPI by vascular endothelium in response to thrombin.33
Potential Limitations of the Present Study
Two possible limitations should be taken into account in evaluating the results of the present study. First, we did not measure the circulating levels of soluble TF in our patients, and it is known that the balance between TF and TFPI is important in intravascular thrombosis.30 Furthermore, other studies seem to indicate that circulating, TF-containing microparticles might be important in sustaining intravascular thrombosis.34 However, although we agree that not measuring circulating TF in our patients represents a potential limitation, we also believe that the most important determinant of plaque thrombogenicity is represented by the plaque content of TF.2–5
Second, coronary blood flow was not measured in our patients. Thus, it was impossible to quantify the absolute amount of TFPI or TFPI/FXa complex that was extracted from or released into the coronary circulation. This is particularly important immediately after PTCA or stenting, when large modifications in coronary flow were likely to occur. However, simultaneous sampling from the coronary sinus and the ascending aorta can give us qualitative information about the parameters measured, which are important from a pathophysiological point of view.
Conclusion
Up to now, the data on the pathophysiological role of TFPI in patients with ACS were scanty. In this regard, our study represents the first demonstration of a direct involvement of TFPI at the site of thrombus formation in this clinical setting. Because depletion of circulating TFPI has been associated with a prothrombotic state in rabbits,25 and because TFPI knockout mice die prematurely in utero of thrombotic disorders,35 the present study indicates a role for TFPI as a key regulatory element of the degree of activation of the TF-dependent coagulation in humans.
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