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Stroke. 1995;26:63-69

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*ACETYLSALICYLIC ACID
*COUMARIN
*HEPARIN

(Stroke. 1995;26:63-69.)
© 1995 American Heart Association, Inc.

Articles

Monitoring Combined Antithrombotic Treatments in Patients With Prosthetic Heart Valves Using Transcranial Doppler and Coagulation Markers

Matthias Sturzenegger, MD; Juerg H. Beer, MD Frank Rihs, MD

From the Departments of Neurology (M.S., F.R.) and Internal Medicine, Laboratory for Thrombosis Research (J.H.B.), University of Bern, Inselspital, Bern, Switzerland.

Correspondence to Matthias Sturzenegger, MD, Department of Neurology, University of Bern, Inselspital, CH-3010 Bern, Switzerland.


*    Abstract
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 *Abstract
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 down arrowSubjects and Methods
 down arrowResults
 down arrowDiscussion
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Background and Purpose The combined use of coumarin and low-dose aspirin appears to reduce the risk of systemic embolism at a low risk of bleeding. The remaining incidence of embolism of approximately 2%/y is still high. Methods for real-time detection of embolic events have not been used thus far to monitor the efficacy of therapeutic strategies. They might permit individually tailored, effective treatments.

Methods The frequency of embolic signals in both middle cerebral arteries was monitored using a two-channel 2-MHz transcranial Doppler system. We examined five patients with mechanical prosthetic heart valves suffering from recurrent cerebral ischemic symptoms despite adequate anticoagulant therapy (international normalized ratio, 3.0 to 4.3). Measurements were performed on coumarin alone (four baseline values) and subsequent to the addition of intravenous (500 mg bolus) and oral (100 mg/d for 10 days) aspirin or intravenous (5000 IU bolus) heparin. The prothrombotic markers thrombin–antithrombin III complex, fibrinopeptide A, D-dimer, and platelet ß-thromboglobulin were measured simultaneously.

Results None of the combined drug regimens led to a significant reduction of the emboli count. The values of thrombin–antithrombin III complex, fibrinopeptide A, and D-dimer were already within normal limits with coumarin alone. The ß-thromboglobulin levels, however, were increased, and additional aspirin or heparin did not reduce them. There was no correlation between the emboli count and the prothrombotic markers or between the prothrombotic markers and the different drug regimens.

Conclusions The rate of cerebral emboli measured with transcranial Doppler in the group of high-risk patients studied was not influenced by additional antiplatelet therapy. The emboli are likely to be composed at least in part of platelets, and their generation seems not dependent on thrombin or cyclooxygenase. There is an apparent discrepancy between the unchanged rate of emboli during Doppler monitoring found in this and other studies and the partial efficacy of combined treatment with coumarin and aspirin in clinical long-term studies. This may be explained by differences in the composition or size of the emboli.


Key Words: anticoagulants • antiplatelet agents • heart valve prosthesis • thromboembolism • ultrasonics


*    Introduction
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 *Introduction
down arrowSubjects and Methods
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Thromboembolic events occur despite "adequate" anticoagulation (international normalized ratio [INR], 3 to 4.5) with any type of mechanical prosthetic heart valve (PHV) in any position at a rate of 1%/y to 5%/y.1 2 3 4 The risk is continued and cumulative over the years, involves the cerebral circulation in more than 85% of clinical emboli, and leads to a permanent neurological deficit in 50% and to death in 10%.4 5 Furthermore, it has a considerable socioeconomic impact in view of more than 75 000 implanted PHVs annually throughout the world.6 Whereas the need for lifelong anticoagulant treatment after mechanical valve replacement is generally accepted,7 8 9 uncertainty remains about its optimal dosage and its combination with antiplatelet agents.7 10 11 Adequacy of anticoagulation is crucial, with low INR found in most patients with thromboembolic complications and high INR favoring bleeding, but is difficult to achieve for pharmacokinetic and compliance reasons and also because of technical and methodological problems in the determination of the prothrombin time (PT).7 12 13 In fact, intensive surveillance and counseling at an experienced anticoagulation center appear to result in the lowest rate of embolism (0.6%/patient-year) reported with coumarin alone.11 14 Various combinations of anticoagulants and antiplatelet agents have been studied at different dosages,8 15 16 but the annual incidence of thromboembolic events remains in most studies at an average of 2%/y to 3%/y.

It is obvious that the current antithrombotic treatment must be improved, given that the perfect PHV with respect to thrombogenicity is not available.17 18 19 Previous studies have focused on a long-term analysis of clinical embolic events in large patient groups. However, many individual factors such as type and position of the PHV, concomitant heart disease, and the response to antithrombotic treatment have an important influence on the probability of thromboembolic complications7 13 20 21 and are difficult to evaluate in this setting. Furthermore, the monitoring of the PT values may not provide the information required on adequate suppression of plasmatic coagulation or platelet activation and thus will not properly assess the thromboembolic risk. For all these reasons it would be useful to have an individually tailored treatment for each patient with documented suppression of pathological coagulation and embolization within a short period of therapy. This goal appears achievable with today's sensitive markers of coagulation22 and the recent developments in Doppler techniques. Doppler ultrasound can detect emboli of different composition with high sensitivity because of the differences between their acoustic impedance and the surrounding blood.23 24 25 26 Transcranial Doppler sonography (TCD) enables the detection of emboli in basal intracranial cerebral arteries, eg, during interventions such as carotid endarterectomy25 and open heart surgery27 or spontaneously in carotid disease28 and in patients with PHVs.29

We analyzed the effect of different antithrombotic regimens on the frequency of emboli measured with TCD and on procoagulant markers in five patients with PHVs selected for their high frequency of embolic signals.


*    Subjects and Methods
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 *Subjects and Methods
down arrowResults
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Patients
From 45 patients with PHVs and documented embolic signals during TCD examination in our laboratory, five were selected. Patient histories and neuroradiology and ultrasound findings are outlined in Tables 1Down and 2Down. The five patients had no cerebrovascular events before but suffered from recurrent transient ischemic attacks or stroke after PHV implantation despite adequate anticoagulant therapy. Other sources of emboli were extensively evaluated and could be virtually excluded (Table 2Down). We chose five patients with a high frequency of embolic signals (FES) recorded in their basal intracranial arteries of the anterior and posterior circulation on both sides. This precondition ensures the highest chance to demonstrate an effective therapeutic intervention indicated by a reduced FES for reasons of probability given the limitations of monitoring time.


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  		Table 1. Characteristics of Five Patients With Prosthetic Heart Valves and Recurrent Cerebral Ischemic Symptoms


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  		Table 2. Neuroradiology and Ultrasound Findings

Informed consent was obtained from all patients, and their family physicians were asked for cooperation. The study protocol was approved by the ethical committee of the University of Bern, Switzerland. Patients had discontinued any treatment known to affect coagulation or platelet function except for coumarin therapy (phenprocoumon [Marcoumar], Hoffmann–La Roche) for at least 1 month. Anticoagulant therapy was kept within a stable range (INR, 3 to 4).

Methods
Two baseline examinations of 30 minutes of TCD (see below) and analyses of the procoagulant markers were performed with an interval of 2 to 3 weeks (baseline 1 and baseline 2) while the patients were on coumarin only. After the second baseline examination, 500 mg aspirin (Aspégic, Synthélabo) was injected intravenously, and TCD and laboratory examinations were repeated 30 minutes later (treatment 1). The inhibitory effect of aspirin was documented by the complete suppression of arachidonate-induced platelet aggregation in platelet-rich plasma at concentrations of 0.5 and 1 mmol/L. The patients were then started on aspirin 100 mg/d orally on the following day in combination with coumarin and were reexamined after 12 to 14 days (treatment 2). Oral aspirin therapy was then stopped, and the patients were reexamined after an interval of at least 14 days (baseline 3). After this third baseline examination, 5000 IU of unfractionated heparin (Hoffmann–La Roche) was injected intravenously, and the same examinations were repeated after 10 minutes (treatment 3, consisting of TCD only) and again after 2 hours (treatment 4). Seven to 10 days later, the patients were seen for a fourth baseline examination while they were again on coumarin only. In a pilot trial with two of the patients (patients 4 and 5), we also evaluated the effect of long-term treatment with a low-molecular-weight heparin in combination with coumarin (INR, 3 to 4). For reasons of simplicity (single, daily injection) and safety (low dose), we injected the low-molecular-weight heparin (CY 216, Sanofi, Winthrop, 3075 IU) once daily subcutaneously for 7 days. The patients were reexamined 4 hours after the last dose (treatment 5) because we expected a maximum effect at this interval.

TCD Examination
Studies were performed by means of a two-channel transcranial Doppler system (Multi-Dop X/TCD 7, Firma DWL, Elektronische Systeme GmbH) equipped with a specially developed software for automatic emboli detection (R. Aaslid). Patients were examined under standard conditions: quiet room, supine position, eyes closed, and start of the recording after resting for at least 20 minutes. The heart rate was monitored during each examination. The Doppler frequency spectra of both middle cerebral arteries (MCAs) were recorded simultaneously and continuously during 30 minutes. The ultrasound transducers were fixed over the temporal bone with a special head band after location of the transtemporal "acoustical window," and the sample volume was set at the maximal signal intensity recordable from both MCAs identified according to standard criteria.30 The emitting power and the gain of the channels were set at the lowest intensity required to demonstrate a weak background flow velocity spectrum. This allowed an easy recognition of embolic signals, which appeared as bright spots within the background spectrum (Fig 1Down). The data from the literature24 25 26 and our experience with 45 patients with PHVs who were referred for evaluation of probable cerebral ischemic symptoms and who had frequent embolic signals in their basal intracranial arteries on both sides indicate that this setting is optimal for detection of embolic signals. Emboli were identified by three different methods: (1) visually, on the monitor displaying the fast Fourier transform Doppler color-coded spectra of both MCAs; (2) acoustically, by continuous on-line observation by the examiner using headphones; and (3) computer-assisted, using the system software. Embolic signals were identified by an experienced sonographer (M.S.) according to the following criteria: They were short (<0.1 second), transient, unidirectional, high-amplitude signals, with a narrow spectrum; they occurred at random in the cardiac cycle and changed their frequency/velocity depending on their location in the cardiac cycle and as they passed through the sample volume; and they generated a chirping audio quality, with a harmonic tone24 25 (Fig 1Down). Only signals detected acoustically and visually were taken into consideration. The emboli counts in the left and right MCAs were added to a sum score (FES during 30 minutes) for correlation with drug regimens. The number of embolic signals per time unit is for various reasons the most reliable parameter of the embolic signals recorded by TCD monitoring23 and the only one thus far reported to correlate with neurological deficit.29



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  		Figure 1. Fast Fourier transform spectral display of the left middle cerebral artery (MCA L) Doppler flow signals in a typical patient embolizing from an aortic prosthetic valve. Two examples of an embolic signal are displayed on the velocity spectrum (arrows). They represent the 15th (15 of 29) and 19th (19 of 29) embolic signals of a total of 29 recorded by the automatic detection software during a 30-minute monitoring period. Note the short, transient, high-intensity, unidirectional signals with random occurrence in the cardiac cycle. Abscissa shows 1.1-second time interval; ordinate on left side, velocity in centimeters per second; ordinate on right side, (color-coded) signal intensity scale (decibels). The sample depth is indicated at 56 mm (D=56). =>[ indicates that flow velocities directed toward the Doppler probe are plotted above the zero line.

Laboratory Studies
At each time point of FES analysis (baseline 1 through 4 and treatments 1, 2, 4, and 5, as outlined above), blood was drawn freshly from an antecubital vein by the same physician (J.H.B.), who was specifically trained to ensure an atraumatic vein puncture. An 18-gauge needle under controlled venous stasis of less than 50 mm Hg and the Saarstedt system were used; 9 mL blood was drawn into 1 mL CTAD-PPACK anticoagulant (stock solution containing 25 mL citrate-theophylline-adenosine-dipyridamole [Becton Dickinson] plus 5 mg phenyl-prolyl-arginine-chlormethylketone [CalBiochem], giving a PPACK concentration of 382 nmol/L) for the measurement of fibrinopeptide A (FPA) (radioimmunoassay [RIA] reagents supplied by Imco), thrombin–antithrombin III complex (TAT) (enzyme-linked immunosorbent assay [ELISA]; Enzygnost-TAT, Behring), D-dimer (ELISA, Chromogenix), and ß-thromboglobulin (BTG) (RIA supplied by Amersham). FPA was determined in PPACK-inhibited plasma samples by the RIA as mentioned above by use of polyclonal antibodies. Cross-reacting fibrinogen was eliminated by bentonite adsorption. After this step, the specificity of the FPA RIA reaches 100%. Free antigen was separated from bound antigen by use of a second goat anti-rabbit antibody (Immunobeads, Bio-Rad Laboratories). Next, 4.5 mL blood was drawn into 0.5 mL of 0.106 mol/L trisodium citrate for the assessment of the PT with use of thromboplastin S (Baxter), and 4.5 mL blood was drawn into 5 mg of dry EDTA for leukocyte and platelet count and hemoglobin determination (Coulter Counter S-+, Coulter Electronics). Immediately after the blood was sampled, tubes were put on melting crushed ice for approximately 10 minutes. The tubes were centrifuged at 4°C for 30 minutes at 2000g. Multiple aliquots of plasma were thereafter snap-frozen in liquid nitrogen and stored at -70°C until analysis. Glycocalicin was determined as described.31 . Briefly, 4.5 mL blood was drawn into 0.5 mL EDTA 4 mmol/L containing prostaglandin E1, N-ethylmaleimide, and aprotinin; it was centrifuged sequentially at 2000g, 6000g, and 30 000g for 20 minutes (each step) and analyzed by ELISA. The glycocalicin index is glycocalicin normalized for a platelet count of 250x109/L.

Statistical Analysis
The FES of each patient and of the patients as a group at baseline and after the different drug regimens were compared by means of the Mann-Whitney U test. The FES of each patient before (ie, the baseline value) and after a specific treatment were compared by means of the Wilcoxon signed rank test. The measured coagulation and platelet function parameters of each patient at each examination were compared with the respective emboli frequency by means of simple regression analysis. The individual BTG and INR values were compared for each regimen with the corresponding baseline values by means of the Wilcoxon signed rank test. These values were also compared for the patients as a group by means of the Mann-Whitney U test.


*    Results
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 up arrowSubjects and Methods
 *Results
down arrowDiscussion
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All five patients with recurrent cerebral ischemic symptoms despite anticoagulant treatment (Tables 1Up and 2Up) had a high FES averaging two events in every minute with anticoagulation alone (Table 3Down). No evidence for other sources was found by transesophageal echocardiography and combined extracranial and transcranial Doppler and duplex sonography of the extracranial and basal intracranial cerebral arteries. There were no signs of atherosclerosis. TCD revealed transient and thus most probably embolic stenosis of intracranial arteries in one patient. Embolic signals could be recorded in previous, detailed examinations in all patients in the intracranial branches of both carotid arteries and also the vertebrobasilar system, making a local source in the intracranial and extracranial cerebral arteries impossible (Table 2Up).


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  		Table 3. Doppler Monitoring and Laboratory Findings

Surprisingly, none of the different treatment modalities was able to abolish or even reduce the FES (Table 3Up). No significant difference could be found when the corresponding paired values for baseline and treatments for the individual patients were compared (Wilcoxon signed rank test) or when the baseline values and the values of the different treatments were compared for the whole group (Mann-Whitney U test) (Fig 2Down). Three patients (patients 1, 2, and 5) reported at least one transient ischemic attack during the study. Their occurrence was not related to any specific treatment.




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  		Figure 2. Top, Graph shows frequency of embolic signals (FES; total of both middle cerebral arteries during 30-minute recording) for each of the five patients measured during the different treatment modalities. Baseline (BL) 1-4 indicates coumarin (C) alone; treatment 1, C+aspirin (ASA) 500 mg IV; treatment 2, C+ASA 100 mg orally for 10 days; treatment 3, 10 minutes after heparin 5000 IU IV+C; and treatment 4, 2 hours after heparin 5000 IU IV+C. The figure illustrates the independence of FES of any treatment regimen. Bottom, Graph shows FES of the five patients as a group (mean±SD) during the different treatment regimens. There was no significant difference between the FES values.

Interestingly, we found no evidence of a pathological thrombin or fibrin generation or fibrinolysis in vivo in any of the five patients under oral anticoagulation alone as measured by the TAT, FPA, and D-dimer levels. In sharp contrast, the BTG levels reflecting platelet activation and/or platelet destruction were increased to 2 to 3 times the upper limit; 83% of all BTG determinations were in the pathological range. In concordance with the FES, the different treatments with aspirin or heparin did not reduce the BTG levels, nor did they affect the levels of the prothrombotic markers (TAT, FPA, D-dimer) within the normal range. The level of platelet glycocalicin was nonsignificantly elevated (2.38±0.76 ng/mL [SD]; normal range, 2.04±0.44 ng/mL; P=.052], as was the glycocalicin index (2.26±0.99; normal range, 2.16±0.66), which reflects the platelet turnover in the steady state.31 The platelet counts were all in the normal range. The data collectively suggest platelet activation in vivo and a tendency toward an increased platelet turnover/destruction. A comparison of the FES with the levels of the PTs and the BTG concentrations by means of regression analysis, however, showed no correlation.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
 up arrowResults
 *Discussion
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Thromboembolic complications occur despite modern optimal anticoagulant/antiplatelet treatment5 8 16 and limit the benefits of mechanical PHVs. Mechanisms of thrombus formation and generation of emboli include the following: (1) pathological fibrin and thrombin formation on prosthetic surfaces; (2) platelet adhesion to foreign surfaces32 33 34 and secondary platelet adhesion and activation mediated by adhesion molecules immobilized on the thrombogenic surface; (3) platelet activation by thrombin and perhaps by ADP liberated from damaged red cells or by other platelet agonists including thromboxane34 35 36 ; and (4) platelet activation induced by fluid mechanics such as high shear stress37 38 or cavitation.39 40 41 Our data favor the second and/or the fourth mechanism since we did not find evidence for intravascular thrombin or fibrin formation, nor did aspirin have any influence on the FES. The fourth mechanism, however, appears particularly attractive since all mechanical PHVs create inadequate hemodynamics, causing excessive turbulence and high shear stress.42 43 44 Measured turbulent shear stress magnitudes (800 to 1200 dynes/cm2) may exceed the critical values reported for platelet and red cell lysis,6 34 35 36 43 44 which in turn will enhance platelet activation. Shear stress levels well below the lysis threshold (starting at 60 to 120 dynes/cm2) cause platelet activation and aggregation.34 37 38 Interestingly, a shortened platelet survival time has been demonstrated to correlate with the incidence of thromboembolism in these patients.32 33 In vitro, cavitation at valve closure could be observed with nearly all mechanical PHV types and is dependent on several fluid mechanics.40 41 Therefore, it can be assumed that cavitation, known to cause blood damage,39 also occurs in vivo, which has yet to be demonstrated.

Anticoagulants of the coumarin type help to prevent venous and arterial thrombosis; they are, however, unable to prevent platelet adhesion to prosthetic surfaces32 33 or platelet activation by shear stress or cavitation. This is in accord with our findings of normal levels of plasmatic coagulation markers but of elevated BTG levels. We believe that these levels are real and not an in vitro artifact because FPA levels, which are most sensitive to methodological difficulties, were taken from samples of the same venipuncture and were in the normal range. In addition, 20 normal donors were analyzed for the BTG levels with the same method and were all within the normal range.

The available clinical studies demonstrate an additional protective effect of platelet inhibitors when combined with anticoagulants.5 8 16 In contrast, aspirin did not reduce the FES measured by Doppler monitoring in our study of a selected group of high-risk patients, nor did it prevent platelet activation/destruction (increased BTG levels), indicating that mechanisms independent of cyclooxygenase are involved. Previous studies found no change of FES during various anticoagulant therapies.45 Recent in vitro studies of shear-induced platelet activation suggest that this mechanism is not inhibited by aspirin.37 38 We propose the following two hypotheses to account for the apparent discrepancy between the clinical efficiency on the one hand and the in vitro data, the pathophysiological considerations, and the Doppler results on the other hand. First, Doppler measurements provide no reliable data on the stability, composition, and size of the aggregates. Rapid disaggregation may occur in the presence of aspirin in the cerebral microvasculature, as can be observed in platelet aggregometry with ADP and aspirin. Smaller aggregates may cause less ischemia and fewer clinical symptoms. Such changes may well escape detection by the Doppler method used, which measures FES in the main basal cerebral arteries; this provides information only on the number of emboli shortly after their formation but not on their fate in the cerebral microcirculation. A partial effect of aspirin or an effect at a different dosage therefore does not conflict with our findings in this particular setting. Second, our results do not allow a distinction between platelet emboli and gaseous emboli. Some results from the literature favor a gaseous origin of the signals: (1) Embolic signals in PHV patients showed an overall higher intensity (signal power) than those from patients with carotid stenosis.46 Because of the greater difference in acoustic impedance between blood and air than between blood and solid emboli, the reflected signal from air bubbles has a higher intensity than from particulate emboli of the same size. (2) The discrepancy between the high amount of emboli and rare clinical events also favors a gaseous origin of the signals.45 However, the latter might be subtle and cumulative over a long time, as known from studies of patients undergoing cardiopulmonary bypass that applied neuropsychological test procedures.47 48 (3) The cavitation effect is a physical explanation for the generation of gas bubbles in a closed loop circulatory system with a mechanical PHV.

The problem, however, is not that of air or platelets. The same altered fluid dynamics causing shear stress and platelet activation are also the origin of cavitation. Furthermore, it is well established that air/blood interfaces cause platelet activation49 and endothelial damage,50 which, in turn, will enhance platelet activation. Thus, it is most likely that we record signals from both gaseous and platelet emboli in PHV patients. Even if most embolic signals recorded are clinically asymptomatic, it is reasonable to assume that such events are markers of an embolic source with the potential to also produce larger symptomatic emboli.51 In previous studies the FES was found to be dependent on the valve type, position, and number of replaced valves but not on age, sex, cardiac rhythm, duration of valve insertion, or antithrombotic treatment.45 The findings regarding correlation with neurological events are controversial.29 45 It is evident that a detailed study correlating FES with clinical findings including neuropsychological assessment is needed.

The rationale for evaluating heparin in addition to coumarin in this study was its known inhibition of platelet agglutination due to the binding to von Wille- brand factor (vWF)52 53 in addition to its antithrombin effect. Dramatic inhibition with a single intravenous injection has been observed.52 Since vWF may promote platelet aggregation at high shear rates,54 55 heparin has the potential to attenuate or even block this effect. At the dosages used in this study, however, heparin reduced neither the FES nor the increased BTG values. This finding is supported by limited clinical reports of failure of heparin to prevent thromboembolic complications in PHVs.56

The ultimate therapeutic goal remains the full suppression of emboli formation, which might be approached with new generations of platelet inhibitors that directly block the platelet receptors glycoprotein Ib or IIb/IIIa57 and with a valve design causing lower shear rates and less cavitation.58 Several recent trials have demonstrated that stroke prevention is possible in patients with a variety of potential embolic sources; however, a large number of individuals need to be treated to prevent a single stroke.59 Antithrombotic therapy that is effective for one patient or one type of cardioembolic source may not be effective for another. Emboli monitoring with TCD is a simple, fast, noninvasive, and repeatable procedure. The method may allow the identification of patients who are particularly at risk for thromboembolism and it may permit an individually tailored therapy with immediate control of its effectiveness. In a first step, however, the significance of FES should be determined by correlation with long-term clinical and laboratory data.

We conclude that (1) a high frequency of cerebral emboli can occur in patients with PHVs despite adequate oral anticoagulation; (2) careful anticoagulation alone suppresses pathological thrombin and fibrin formation in vivo but did not appear to suppress increased platelet activation in this selected group of high-risk patients; (3) aspirin did not reduce the FES or the elevated BTG levels in this group, indicating that emboli formation does not depend on cyclooxygenase; (4) heparin had no effect either, emphasizing the already full suppression of thrombin action by oral anticoagulation; it did not appear to inhibit the platelet/vWF interaction at this level in vivo; (5) if the embolic signals should represent in part gaseous microbubbles, this would indirectly document the high shear stress or cavitation causing blood damage and platelet activation; and (6) the data collectively suggest that new antiplatelet agents designed to inhibit platelet glycoprotein Ib/vWF interaction or the amplification response mediated by glycoprotein IIb/IIIa may be effective in these patients.


*    Acknowledgments
 
This study was supported by grant 31-32548.91 from the Swiss National Science Foundation.

Received July 4, 1994; revision received August 19, 1994; accepted September 23, 1994.


*    References
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 up arrowIntroduction
 up arrowSubjects and Methods
 up arrowResults
 up arrowDiscussion
 *References
 

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