Association of Heparin-Resistant Thrombin Activity With Acute Ischemic Complications of Coronary Interventions
Background Acute thrombosis is thought to contribute to abrupt coronary occlusion during percutaneous coronary revascularization despite the administration of heparin and aspirin. This study was designed to detect the presence of heparin-resistant thrombin activity and to define its relationship to the acute ischemic complications of coronary interventions.
Methods and Results Plasma levels of fibrinopeptide A (FPA) and prothrombin fragment 1.2 (F1.2), markers of thrombin and factor Xa activity, respectively, were measured in the coronary sinus with heparin-bonded catheters in 58 patients undergoing coronary interventions. Activated coagulation times were maintained >300 seconds by the Hemochron method. Mean FPA levels decreased significantly, from 7.0±0.9 nmol/L before the procedure to 5.2±0.5 nmol/L after the heparin bolus and to 2.9±0.2 nmol/L after the procedure (P=.0001). In 26 patients (45%), FPA levels remained above the threshold for suppression of thrombin activity determined during angiography in 7 patients without coronary artery disease (>3.0 nmol/L). FPA concentrations after coronary interventions were increased in patients with intracoronary thrombus (P=.01), abrupt coronary occlusion (P=.06), postprocedural non–Q-wave myocardial infarction (P=.04), and clinically unsuccessful procedures (P=.04). F1.2 levels were relatively low before the procedures and did not change significantly.
Conclusions Heparin administration suppresses thrombin activity in most but not all patients undergoing coronary interventions. Heparin-resistant thrombin activity is associated with angiographic evidence of intracoronary thrombus and ischemic complications of coronary interventions.
Abrupt coronary occlusion occurs in an average of 4% to 8% of patients during percutaneous revascularization procedures and accounts for the majority of complications, including death, nonfatal MI, and the need for emergency CABG.1 2 Progression of intracoronary thrombosis despite anticoagulation with heparin is thought to contribute to abrupt occlusion in 20% to 50% of patients.3 4 Persistent intravascular thrombus also plays a role in promoting restenosis after coronary interventions.5
Although the importance of antithrombotic therapy during coronary interventions is widely accepted, the optimal strategy for inhibiting thrombosis is not well defined. Current antithrombotic regimens include the administration of aspirin and intravenous heparin to inhibit platelet function and thrombin activity, respectively.6 Results of previous clinical studies suggest that the incidence of complications immediately after angioplasty may be reduced by administration of heparin in doses sufficient to prolong the whole-blood ACT to >300 seconds.7 8 9 However, despite aggressive anticoagulation, abrupt coronary occlusions still occur, especially in patients with preexisting intracoronary thrombus.10 11
Dosages of heparin have, in general, been chosen on the basis of their ability to reduce the incidence of clinical end points and to prolong the whole-blood ACT. However, since undetected thrombus-associated thrombin activity may promote platelet aggregation and thrombosis,12 and given the unpredictable relationship of the ACT with clinical events, direct characterization of the suppression of thrombin activity in the coronary circulation in response to anticoagulation during coronary interventions may be of more value in defining appropriate doses of anticoagulants.
FPA and F1.2 levels in plasma obtained from peripheral venous blood samples have been demonstrated to be sensitive and specific markers of increases in thrombin and factor Xa activity, respectively, in patients with acute ischemic syndromes.13 14 15 However, concentrations of these plasma markers in the peripheral circulation may not reflect the extent of thrombin activity in the coronary circulation in patients undergoing percutaneous coronary revascularization because increased levels may result from catheter-induced rather than coronary artery–associated procoagulant activity.16 We hypothesized that blood sampling for concentrations of FPA and F1.2 in the coronary sinus by use of heparin-bonded catheters would yield more information in such patients. Accordingly, in this study we validated methods for sampling blood from the coronary sinus to determine concentrations of FPA and F1.2. We then characterized the extent of procoagulant activity during coronary procedures, the degree of suppression of thrombosis by non–weight-adjusted heparin administration,17 and the relationship of heparin-resistant thrombotic activity to ischemic complications of coronary interventions.
Blood samples were obtained from the coronary sinus in 58 patients undergoing PTCA, directional atherectomy, rotational atherectomy, or excimer laser angioplasty between March 1993 and April 1995 at Barnes-Jewish Hospital, Washington University Medical Center, St Louis, Mo. Patients included in the study had a ≥70% diameter stenosis by visual estimate and a clinical indication for revascularization, including stable angina, unstable angina, or recent MI. Patients with conditions known to be associated with elevation of plasma markers of coagulation were excluded, including patients with large groin hematomas after diagnostic angiography and those who had undergone previous CABG or peripheral vascular surgery. Coronary sinus blood samples were also obtained from 7 patients who were referred for diagnostic coronary angiography for evaluation of chest pain but who were found not to have significant coronary disease. Informed consent was obtained from all patients before blood samples were collected. The protocol was approved by the Human Studies Committee (IRB) of the Washington University School of Medicine.
In selected patients with adequate peripheral venous access before catheterization, a blood sample to be analyzed for plasma concentrations of FPA and F1.2 was obtained by antecubital venipuncture with a 19-gauge butterfly needle. A 7F femoral venous sheath was inserted, and a 6F heparin-bonded Simmons catheter (Cook Inc) was advanced into the right atrium over a hydrophilic wire (Terumo Medical Co) and was subsequently placed in the coronary sinus under fluoroscopic guidance.16 18 After coronary sinus cannulation, an 8F femoral arterial sheath was inserted; a bolus of 9077±292 U (range, 5000 to 15 000 U) heparin IV was then given, and a heparin infusion was started at 1000 U/h. The initial heparin bolus was 10 000 U in 70% of patients.
Coronary interventions were performed by standard techniques, and nonionic contrast was used in all patients.17 All patients were on daily aspirin, and no patients received the antiplatelet agent abciximab. In 33 patients who were receiving intravenous heparin before the procedure, the infusion was interrupted for 30 to 60 minutes before the start of the intervention. The whole-blood ACT was measured with high-range (FTCA 510) tubes and the Hemochron 801 coagulation monitor (International Technidyne) at least twice during the procedure to determine whether additional heparin was necessary. If the ACT was <300 seconds 5 to 10 minutes after the initial bolus of heparin, an additional intravenous bolus of 2000 to 5000 U was given and the ACT was measured again. Additional boluses of heparin were administered until the ACT was >300 seconds. Blood samples were collected through the heparin-bonded catheter in the coronary sinus before the heparin bolus, after arterial sheath insertion and administration of the heparin bolus, and after the intervention.
In the patients without coronary disease undergoing diagnostic angiography, peripheral venous blood samples were obtained, and the heparin-bonded catheter was placed in the coronary sinus as described above. After insertion of the arterial sheath, a single bolus of 1500 to 2000 U heparin IV was administered. Blood samples were collected from the coronary sinus before heparin, 5 minutes after heparin administration, and 5 minutes after angiography.
Blood samples were carefully collected from the heparin-bonded catheter after uninterrupted flow was confirmed. Initially, 3 mL blood was aspirated and discarded; 2 mL blood was then gently collected into heparinized syringes, immediately transferred into sample collection tubes containing 200 μL FPA anticoagulant (Byk-Sangtec), and placed on melting ice. The plasma was separated by centrifugation and then frozen at −70°C until the assays for FPA and F1.2 were performed. The Simmons catheter was flushed with 3 mL heparinized saline (10 U/mL) after each coronary sinus blood sample was obtained.
Cineangiograms from patients undergoing interventions and diagnostic angiograms were analyzed by two of the authors (K.J.W. and D.J.S.), both experienced angiographers, who reached a consensus. All patients without coronary disease had normal coronary angiograms or only minimal arterial plaque. Coronary lesions to be treated with interventional procedures were imaged in orthogonal projections, and the percent diameter stenosis was visually estimated. Lesion morphology was characterized as simple or complex according to the criteria proposed by Ambrose and Israel.19 Intracoronary thrombus was identified as a filling defect surrounded by contrast or the appearance of new thrombus in directional atherectomy samples.
A coronary intervention was considered an angiographic success if the final percent diameter stenosis by visual estimate was <50% and Thrombolysis in Myocardial Infarction Trial (TIMI) grade 3 flow was established at the conclusion of the procedure. Clinical success was defined as angiographic success in the absence of death, nonfatal MI, CABG, or repeat PTCA during the same hospital stay. Procedural angiograms were analyzed for the presence of intraluminal or extraluminal dissection, with or without compromise of distal flow. Threatened abrupt occlusion was defined as a significant coronary dissection accompanied by compromise of the lumen and TIMI grade 2 or 3 flow. Abrupt occlusion was defined as TIMI grade 0 or 1 flow any time during the procedure or during the 48 hours after the procedure. A postprocedure non–Q-wave MI was diagnosed when the creatine kinase MB isoenzyme level was more than three times the upper limit of normal20 ; postprocedure Q-wave MI was identified as elevated myocardial enzymes and the appearance of new Q waves on the ECG >0.04 second in duration.
Assays for FPA and F1.2
FPA was assayed with a radioimmunoassay previously validated in our laboratory that uses a polyclonal antiserum after sample adsorption with bentonite (Byk-Sangtec).13 The lower limit of detection of FPA with this assay is 0.6 nmol/L, and the linear range is 0.6 to 28.0 nmol/L. To assay F1.2, an ELISA was used that is based on a monoclonal antibody specific for a neoepitope expressed on F1.2 that is not present on prothrombin, as previously described.14 21 Reagents were provided by Baxter Diagnostic.
Data are expressed as mean±SEM. Since values for concentrations of FPA and F1.2 were not normally distributed, a log transformation was used before statistical analysis of the data. Within each group of patients, comparisons at different time points were made with a paired t test and ANOVA with repeated measures for multiple comparisons. Comparisons of FPA and F1.2 concentrations with clinical features, angiographic characteristics, and complications of interventions were made with an unpaired t test. Categorical data were analyzed with a χ2 test. All statistical tests were two-tailed. Differences were considered to be significant when P<.05.
Validation of Coronary Sinus Sampling for FPA
In five patients without coronary disease who had adequate peripheral venous access, blood samples to be analyzed for FPA concentrations were obtained before insertion of the femoral venous sheath and coronary sinus catheter. FPA concentrations in the peripheral vein (3.9±0.7 nmol/L) and coronary sinus (3.3±0.8 nmol/L) were not significantly different (P=.24). There was also a good correlation between peripheral and coronary sinus FPA levels (r=.85). In a total of seven patients without coronary disease, concentrations of FPA in coronary sinus blood samples were measured before and after administration of 1500 to 2000 U heparin and after angiography. FPA levels did not change significantly after low-dose heparin and after angiography: they were 3.3±0.7 nmol/L before heparin, 3.1±0.5 nmol/L after heparin, and 2.1±0.3 nmol/L after angiography (P=.10). The 90th percentile of FPA values in coronary sinus blood was 4.9 nmol/L before heparin administration and 3.0 nmol/L after low-dose heparin and angiography.
In 38 patients scheduled for coronary interventions who had adequate peripheral venous access, samples were collected from both a peripheral vein and the coronary sinus before heparin administration. Concentrations of FPA in peripheral venous and coronary sinus blood did not differ (6.9±1.0 versus 7.0±0.9 nmol/L, respectively, P=.86). To determine whether FPA values in blood samples acquired through the heparin-bonded catheter were reproducible, coronary sinus blood samples were obtained 3 minutes apart in 31 patients before heparin administration; the coefficient of variation for the duplicate measurements was .92.
Validation of Coronary Sinus Sampling for F1.2
Validation of F1.2 sampling was performed as described above for FPA determinations. In patients without coronary disease, coronary sinus concentrations of F1.2 before heparin administration were slightly lower than values obtained in peripheral venous samples (0.12±0.02 versus 0.15±0.01 nmol/L, respectively [n=6, P=.04]). Coronary sinus F1.2 concentrations did not change significantly after low-dose heparin and after angiography: they were 0.12±0.02 nmol/L before heparin, 0.14±0.01 nmol/L after heparin, and 0.13±0.01 nmol/L after angiography (P=.16).
In 34 patients undergoing interventional procedures, samples were obtained from a peripheral vein and the coronary sinus before heparin administration; concentrations of F1.2 were not different (0.20±0.02 versus 0.18±0.02 nmol/L, respectively, P=.24). In 16 patients, duplicate coronary sinus samples were obtained 3 minutes apart before administration of heparin; the coefficient of variation for duplicate samples was 0.97.
These data demonstrate that atraumatic femoral venous cannulation does not artifactually elevate FPA or F1.2 concentrations in the coronary sinus compared with the peripheral venous circulation. In addition, concentrations of plasma markers of coagulation obtained from the coronary sinus through heparin-bonded catheters are reproducible.
Patient Characteristics and Results of Coronary Interventions
The clinical and angiographic characteristics of patients enrolled in the study and details of the coronary interventions are listed in Table 1⇓. Thirty-five patients (62%) had unstable angina or recent MI. Thirty-three patients (57%) were treated with intravenous heparin before the procedure. Coronary interventions were angiographically successful in 54 patients (93%). Nineteen patients (33%) had angiographic evidence of minor dissection, with <50% residual stenosis and TIMI grade 3 flow. None of these patients sustained an MI or required CABG; however, 1 patient required a repeat PTCA for recurrent ischemia during the same hospital stay. Seven patients (12%) had a major coronary dissection with threatened or abrupt closure during the procedure; 3 of these required CABG, and 3 other patients developed a non–Q-wave MI. One patient who suffered abrupt closure in the catheterization laboratory developed recurrent coronary occlusion within 48 hours of the initial procedure. This patient underwent successful redilatation and, 4 days later, was sent for elective CABG related to persistent angina and multivessel disease. One patient with an initially successful PTCA developed delayed closure and a non–Q-wave MI 4 days after the procedure; salvage directional atherectomy was successful. No patients died or developed a Q-wave MI. Thus, the initial intervention was clinically successful in 49 patients (85%).
Coronary Sinus Thrombin Activity Before Heparin Administration
In 58 patients undergoing coronary interventions, the mean concentration of FPA in samples obtained from the coronary sinus before the heparin bolus was 7.0±0.9 nmol/L (Fig 1⇓). In 45% of these patients, FPA levels were above the 90th percentile of values obtained before heparin administration in patients without coronary disease (>4.9 nmol/L), despite preprocedural heparin therapy in 57%. Baseline concentrations of FPA in coronary sinus blood were similar in the 33 patients who had received intravenous heparin before the procedure and in the 25 who had not been treated with heparin (6.3±1.2 versus 7.9±1.6 nmol/L, respectively, P=.38).
Plasma concentrations of FPA in coronary sinus blood before the procedure and before administration of the heparin bolus were similar in patients who presented with stable coronary disease (6.3±1.4 nmol/L) and in those with unstable angina or recent MI (7.5±1.3 nmol/L, P=.50). However, this may reflect the fact that preprocedure heparin was given to 67% of patients with unstable angina or recent MI compared with 44% of patients with stable angina. In patients not on heparin before the procedure, there was a trend toward higher coronary sinus FPA concentrations in those with unstable angina or recent MI (10.1±2.4 nmol/L) than in those with stable angina (6.2±2.0 nmol/L), but this difference was not statistically significant (P=.13).
Patients with angiographically complex lesions tended to have higher coronary sinus FPA levels than did patients with simple lesions (8.5±1.8 versus 6.2±1.1 nmol/L, respectively), but this difference was not significant (P=.18). Coronary sinus FPA concentrations were similar before the heparin bolus in patients with and without angiographic evidence of thrombus (6.4±1.3 versus 7.0±1.0 nmol/L, respectively, P=.64).
Suppression of Coronary Sinus Thrombin Activity by Heparin
Concentrations of FPA were measured in blood samples from the coronary sinus of 58 patients before and after the administration of the heparin bolus and after the coronary intervention (Fig 1⇑). FPA concentrations decreased from 7.0±0.9 nmol/L before heparin to 5.2±0.5 nmol/L after heparin and to 2.9±0.2 nmol/L after the procedure (P=.0001). However, despite heparin dosing sufficient to prolong the ACT >300 seconds, after the intervention, FPA concentrations in 26 patients (45%) remained above the 90th percentile of FPA values after angiography in patients without coronary disease (>3.0 nmol/L). The temporary increase in coronary sinus FPA concentrations noted in some patients after heparin administration probably represents a transient procoagulant response to the arterial sheath insertion (Fig 1⇑).16
The relationship between coronary sinus FPA concentrations after the coronary intervention and procedural characteristics is shown in Table 2⇓. FPA levels were not influenced by the type of intervention performed: Values were 2.7±0.3 nmol/L after PTCA (n=21) and 3.1±0.3 nmol/L (n=37) after advanced interventions (P=.51). Concentrations of FPA were similar in patients with successful and unsuccessful procedures, as determined by angiography (2.9±0.2 versus 3.2±0.6 nmol/L, respectively, P=.59) and were not affected by the presence or absence of minor coronary dissections (2.8±0.3 versus 2.7±0.3 nmol/L, respectively, P=.57).
FPA concentrations measured after the procedure were significantly higher in patients with than in those without evidence of intracoronary thrombus (6.2±1.6 versus 2.8±0.2 nmol/L, respectively, P=.01), in patients with clinically unsuccessful procedures than in those with successful clinical outcomes (3.9±0.6 versus 2.8±0.2 nmol/L, respectively, P=.04), and in patients with than those without postprocedural non–Q-wave MI (4.9±1.2 versus 2.8±0.2 nmol/L, respectively, P=.04; Table 2⇑). There was a trend toward higher levels of FPA after the interventional procedure in patients with abrupt coronary occlusion than in those without abrupt closure (4.1±0.8 versus 2.8±0.2 nmol/L, respectively, P=.06; Table 2⇑).
In 78% of the patients with clinically unsuccessful procedures, FPA levels after the intervention were above the 90th percentile of levels measured after angiography in patients without coronary disease (>3.0 nmol/L); this was the case in only 38% of patients without these complications (P=.03). Persistent elevations of coronary sinus FPA concentrations >3.0 nmol/L were observed in all patients with a non–Q-wave MI after interventions and in 41% of those without postprocedural MI (P=.02). FPA concentrations after the intervention were also >3.0 nmol/L in all patients with intracoronary thrombus compared with 42% of those without thrombus (P=.05). These data demonstrate an association between heparin-resistant thrombin activity detected during coronary interventions and acute complications of these procedures, even in the presence of ACT values >300 seconds. In contrast, coronary sinus FPA concentrations before and after the administration of heparin were not predictive of complications (data not shown).
ACT Values and Interventional Complications
After the administration of 9077±292 U heparin, the mean ACT was 394±9 seconds. Only one patient had an ACT <300 seconds during the intervention; this patient had no complications. The correlation between coronary sinus FPA concentrations and ACT values during coronary interventions was poor (r=.08, Fig 2A⇓). There was a weak inverse correlation between coronary sinus FPA levels during interventions and the increment in ACT per 1000 U heparin administered, but this was not significant (r=.15, P=.39, Fig 2B⇓). There was no difference in the ACT values after heparin administration in patients with and without major complications (370±18 versus 397±10 seconds, respectively, P=.30). In addition, no significant differences were observed in procedural ACT values for those with and without abrupt coronary occlusion, intracoronary thrombus, and postprocedural MI (data not shown, P≥.30).
Patients with acute ischemic syndromes were more likely to have been on heparin therapy before the coronary intervention and had higher baseline ACT values than did patients with stable angina (196±7 versus 164±8 seconds, respectively, P=.005). Patients on heparin before the procedure received a smaller heparin bolus (8379±429 U) than those not on heparin (10 000±289 U, P=.005), but the two groups had similar procedural ACT values (388±12 versus 401±13 seconds, respectively, P=.47). After heparin administration, there was no difference between mean ACT values in those with acute coronary syndromes and those with stable angina (392±12 and 396±14 seconds, respectively, P=.81). Thus, although patients with acute ischemic syndromes had smaller increments in ACT after heparin than those with stable angina (180±16 versus 241±25 seconds, respectively, P=.04), this reflects the lower heparin dose given to these patients.
Response of Factor Xa Activity to Heparin
The degree of suppression of factor Xa activity by heparin was characterized by measurement of plasma concentrations of F1.2 in samples from the coronary sinus of 41 patients undergoing interventional procedures. Samples were obtained before and after the heparin bolus and after the procedure. In 37% of patients, coronary sinus blood levels of F1.2 before heparin administration were greater than the 90th percentile of F1.2 values in patients without coronary disease (>0.18 nmol/L). However, concentrations of F1.2 in patients undergoing interventional procedures were within the normal range for the assay (<1.0 nmol/L) and did not change significantly during the procedure: they were 0.18±0.02 nmol/L before heparin, 0.19±0.01 nmol/L after heparin, and 0.19±0.01 nmol/L after the intervention (P=.47).
There was a trend toward higher F1.2 levels in patients with clinically unsuccessful procedures compared with those with successful interventions, but this difference was not significant (0.22±0.02 versus 0.18±0.02 nmol/L, respectively, P=.14; Table 2⇑). There was no difference in coronary sinus F1.2 concentrations after coronary interventions in patients with and without intracoronary thrombus, abrupt closure, and postprocedural MI (P≥.23; Table 2⇑).
The results of this study indicate that the use of high doses of heparin to achieve a whole-blood ACT >300 seconds, as measured by the Hemochron method, attenuates thrombin activity in the coronary circulation in most patients undergoing coronary interventions. However, persistent increases in FPA, a marker of thrombin activity, in samples of coronary sinus blood were documented in many patients despite heparin administration. Heparin-resistant thrombin activity was detected during abrupt coronary occlusion and was associated with intracoronary thrombus, postprocedural MI, and unsuccessful clinical outcome after coronary interventions. Coronary sinus concentrations of F1.2, a marker of factor Xa activity, were low in patients undergoing coronary interventions and were not further suppressed by heparin.
Detection of Procoagulant Activity in Coronary Sinus Blood
In this study, collection of blood samples from the coronary sinus through heparin-bonded catheters was an accurate and reproducible method for characterization of procoagulant activity in the coronary circulation, confirming the original report of Nichols et al.16 These investigators reported that sampling through heparin-bonded catheters did not induce elevations in FPA and markers of platelet secretion. In our study, FPA concentrations were not increased in blood samples obtained from the coronary sinus compared with samples drawn from peripheral veins before femoral venous cannulation. In addition, FPA levels in duplicate samples obtained from the coronary sinus before administration of heparin were highly reproducible. Insertion of the arterial sheath before heparin administration resulted in increased coronary sinus FPA levels in some patients both in our study and in the original report of Nichols et al,16 but this procoagulant stimulus was readily suppressed by heparin.
Inhibition of Procoagulant Activity During Coronary Interventions
In animals, thrombin activity after PTCA has been shown to promote platelet-rich thrombosis. In those studies, heparin, even at very high doses, was ineffective in inhibiting thrombin activity or platelet and fibrin deposition.22 In humans, the extent to which heparin suppresses thrombin activity during PTCA has not been well defined. Heparin is routinely administered as a bolus of at least 10 000 U before coronary interventions, and titrating the dose to maintain the ACT >300 seconds has been recommended, on the basis of the results of observational studies of heparin use during cardiopulmonary bypass, to minimize the risk of thrombotic coronary occlusion.4 7 23
Differences in patient populations and methods of measurement of the ACT have made it difficult to define a suitable threshold for anticoagulation during coronary interventions. Avendano and Ferguson23 reported that ACT values obtained by the Hemochron method were ≈30% higher than those measured with the Hemotec system. Ferguson et al7 also observed that the majority of patients suffering ischemic complications of coronary interventions had ACT values <250 seconds as measured by the Hemotec method. In contrast, Frierson et al24 published data indicating that PTCA may be performed safely in stable patients with Hemotec ACT values <300 seconds.
Results of a recent study by Narins et al2 using the Hemochron method suggested that the incidence of abrupt closure is progressively reduced at ACT values >300 seconds. In this study, no safe threshold for the ACT could be defined. However, it is unlikely that the ACT can be prolonged indefinitely, because excessive anticoagulation is associated with an increase in bleeding complications after PTCA, especially when therapy consists of heparin combined with newer antiplatelet agents.20 25 26 Thus, the ACT neither consistently predicts the degree of anticoagulation required to prevent thrombotic complications during coronary interventions nor directly reflects the extent of suppression of thrombin activity in the coronary circulation.
An alternative approach to the assessment of anticoagulation involves measurement of specific plasma markers of procoagulant activity such as FPA, F1.2, d-dimer, and thrombin–antithrombin III complexes.27 28 29 30 Concern over potential dilution of these markers in peripheral venous blood samples has prompted most investigators to obtain blood samples from the coronary sinus or from the involved coronary artery. Ring et al27 reported that translesional intracoronary concentrations of d-dimer were increased after PTCA in stable patients, suggesting new fibrin formation and degradation. Using a similar sampling technique, Shammas et al29 found no increase in the mean concentration of FPA, F1.2, or platelet β-thromboglobulin after PTCA in patients with stable angina. In contrast, Marmur and coworkers28 noted significantly increased translesional levels of F1.2 after balloon inflation in a subset of patients treated with PTCA for unstable angina. Most patients with increased F1.2 concentrations also had increased levels of FPA.
Sampling of blood from the coronary sinus through heparin-bonded catheters permits characterization of the response to anticoagulation without the need for manipulation of the angioplasty catheter or guidewire, and it obviates potential sampling problems related to artifactual increases in the levels of procoagulant markers.16 Scharf et al30 reported that FPA levels in coronary sinus blood collected through heparin-bonded catheters did not increase after PTCA in a small group of patients with stable angina given 10 000 U heparin before sampling. In contrast to Shammas et al,29 these investigators noted platelet activation during PTCA. Thus, previous studies have reached conflicting conclusions, but they suggest the potential for new thrombin generation, increased thrombin activity, and platelet activation during coronary interventions.
Our observations regarding FPA, a specific biochemical marker of thrombin activity, suggest that in some patients undergoing coronary interventions, procoagulant activity is resistant to high doses of heparin. In the present study, persistent increases in FPA concentrations in the coronary sinus were observed in 45% of patients undergoing interventional procedures. Furthermore, persistent elevation of FPA was associated with intracoronary thrombus, abrupt coronary occlusion, non–Q-wave MI, and clinically unsuccessful interventions. These findings suggest that heparin-resistant thrombin activity may contribute to the ischemic complications observed during coronary interventions despite high doses of heparin.20
The mechanism for heparin-resistant procoagulant activity during coronary interventions is not clear, but in vitro studies suggest that heparin is ineffective in inhibiting thrombus-associated thrombin and factor Xa activity.31 32 Furthermore, complications are more common after interventional procedures in patients with conditions associated with intracoronary thrombosis, such as unstable angina and acute MI.10 11 20 Direct-acting thrombin inhibitors are more effective in inhibiting clot-bound thrombin activity, and initial reports suggest that they may be useful in subsets of high-risk patients.33 34
Our study demonstrates that measurement of concentrations of FPA in the coronary sinus is a promising method for documenting the presence of heparin-resistant thrombin activity in patients treated with PTCA and other interventional modalities. In contrast to the findings of Marmur et al,28 we did not observe an increase in F1.2 concentrations in the coronary sinus after coronary interventions. Possible explanations include a lower sensitivity of F1.2 as a marker when measured in blood sampled from the coronary sinus versus across the lesion and differences in the assays used.35 Our data suggest that concentrations of F1.2 in the coronary sinus during coronary interventions are low and are not suppressed by high doses of heparin.32
It has been suggested that heparin-resistant thrombin activity in patients with acute coronary syndromes may result in a smaller increment in the ACT after fixed doses of heparin.7 36 This hypothesis is supported by the higher incidence of ischemic complications reported in patients with lower ACT values.2 7 However, in our study, as in a previous report by Ferguson et al,7 patients with smaller increases in ACT values received a lower dose of heparin before the procedure. In contrast to FPA measurements, incremental and absolute ACT values failed to correlate with complications of interventions or suppression of thrombin activity in the coronary circulation.
Limitations of the Study
Although the methods used in this study allowed reproducible measurement of specific biochemical markers of procoagulant activity in samples obtained from the coronary sinus, there are limitations to this technique. Nichols et al16 originally observed that insertion of femoral vascular sheaths produced modest increases in peripheral FPA levels. Although obtaining blood samples to be analyzed for FPA through heparin-bonded catheters minimizes artifactual elevation of this marker, it is possible that some of the increases in FPA concentrations in coronary sinus samples may be related to the presence of indwelling vascular sheaths used during coronary interventions, particularly the femoral arterial sheath. However, in patients without coronary disease, FPA concentrations obtained from the coronary sinus after femoral venous cannulation but before heparin administration were not significantly increased compared with baseline peripheral venous levels. In addition, in some patients with coronary artery disease, FPA concentrations in the coronary sinus before heparin administration were higher than peripheral venous levels, suggesting that this technique may be more sensitive to increases in thrombin activity in the coronary circulation.
A further limitation is that the study design did not permit late sampling for procoagulant activity, ie, during the period after heparin was stopped. Recent studies have demonstrated recurrent increases in thrombin and factor Xa activity in peripheral venous blood samples when heparin is withdrawn after PTCA.37 Future investigations should address whether the persistence of increased procoagulant activity in the coronary circulation increases the risk for delayed coronary occlusion, as suggested by an earlier observational study.38
Implications of the Study
Measurement of concentrations of FPA in the coronary sinus by use of heparin-bonded catheters allows accurate and reproducible assessment of procoagulant activity in the coronary circulation. In the future, this technique may permit characterization of the effects of local delivery of anticoagulants, the effectiveness of newer antithrombotic agents, and procoagulant responses after intracoronary stent implantation. While currently used heparin regimens designed to achieve an ACT >300 seconds, as measured by the Hemochron method, suppress thrombin activity in most patients undergoing coronary interventions, there is a subgroup of patients who exhibit heparin-resistant procoagulant activity. Although further studies in larger numbers of patients are required, our results suggest that heparin-resistant thrombin activity is associated with ischemic complications during coronary interventions.
Selected Abbreviations and Acronyms
|ACT||=||activated coagulation time|
|CABG||=||coronary artery bypass graft surgery|
|F1.2||=||prothrombin fragment 1.2|
|PTCA||=||percutaneous transluminal coronary balloon angioplasty|
This study was supported in part by SCOR in Coronary and Vascular Heart Disease (grant HL-17646), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md, and a grant from Mallinckrodt Medical, Inc, St Louis, Mo. The authors gratefully acknowledge Mary Jane Eichenseer for performing all of the assays, Beth Engeszer for editorial review, and Ellen Visse for preparation of the manuscript.
- Received February 13, 1996.
- Revision received May 22, 1996.
- Accepted June 7, 1996.
- Copyright © 1996 by American Heart Association
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