(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
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.
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Abstract |
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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
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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.
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Subjects and Methods |
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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 1
and 2. 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 2). 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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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 1). 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 1). 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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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.
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Results |
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All five patients with recurrent cerebral ischemic symptoms despite anticoagulant treatment (Tables 1
and 2) had a high FES
averaging two events in every minute with anticoagulation alone (Table 3). 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 2).
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Surprisingly, none of the different treatment modalities was able to
abolish or even reduce the FES (Table 3). 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 2). 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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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.
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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.
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Acknowledgments |
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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.
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References |
|---|
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
1. Myers ML, Lawrie GM, Crawford ES, Howell JF, Morris GC, Glaeser DH, DeBakey ME. The St. Jude valve prosthesis: analysis of the clinical results in 815 implants and the need for systemic anticoagulation. J Am Coll Cardiol.. 1989;13:57-62. [Abstract]
2. Bloomfield P, Wheatley DJ, Prescott RJ, Miller HC. Twelve-year comparison of a Bjork-Shiley mechanical heart valve with porcine bioprostheses. N Engl J Med.. 1991;324:573-579. [Abstract]
3.
Cerebral Embolism Task Force. Cardiogenic brain embolism: the
second report of the Cerebral Embolism Task Force. Arch
Neurol.. 1989;46:727-743.
4.
Stein B, Fuster V, Halperin JL, Chesebro JH. Antithrombotic
therapy in cardiac disease: an emerging approach based on pathogenesis
and risk. Circulation. 1989;80:1501-1513.
5. Fuster VD, Dyken LM, Vokona PS, Hennekens CH. Aspirin as a therapeutic agent in cardiovascular disease. Circulation. 1993; 87:659-675.
6. Hanle DD, Harrison EC, Yonagathan AP, Allen TD, Corcoran WH. In vitro flow dynamics of four prosthetic aortic valves: a comparative analysis. J Biomech.. 1989;22:597-607. [Medline] [Order article via Infotrieve]
7. Hirsh J, Dalen JE, Deykin D, Poller L. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest. 1992;102(suppl):312S-326S.
8. Altman R, Rouvier J, Gurfinkel E, D'Ortencio O, Manzanel R, de La Fuente L, Favaloro RG. Comparison of two levels of anticoagulant therapy in patients with substitute heart valves. J Thorac Cardiovasc Surg.. 1991;101:427-431. [Abstract]
9. Stein PD, Alpert JS, Copeland J, Dalen J, Goldman S, Turpie AGG. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest.. 1992;102:445S-455S.
10. Saour JN, Sieck JO, Mamo LAR, Gallus AS. Trial of different intensities of anticoagulation in patients with prosthetic heart valves. N Engl J Med.. 1990;322:428-432. [Abstract]
11. Cannegieter SC, Rosendaal FR, Wintzen AR, van der Meer FJM, Briet E. The optimal intensity of oral anticoagulation therapy in patients with prosthetic heart valves. Thromb Haemost.. 1993;69:2363. Abstract.
12.
Cannegieter SC, van der Meer FJM, Briet E, Rosendaal FR.
Warfarin and aspirin after heart-valve replacement. N Engl J
Med.. 1994;330:507-508.
13.
Albers GW. Laboratory monitoring of oral anticoagulant
therapy: are we being misled? Neurology.. 1993;43:468-479.
14. Cortelazzo S, Finazzi G, Viero P, Galli M, Remuzzi A, Parezan L. Thrombotic and haemorrhagic complications in patients with mechanical heart valve prosthesis attending an anticoagulation clinic. Thromb Haemost.. 1993;69:316-320. [Medline] [Order article via Infotrieve]
15. Chesebro JH, Fuster V, Elveback LR, McGoon DC, Pluth JR, Puga FJ, Wallace RB, Danielson GK, Orszulak TA, Piehler JM, Schaff HV. Trial of combined warfarin plus dipyridamole or aspirin therapy in prosthetic heart valve replacement: danger of aspirin compared with dipyridamole. Am J Cardiol.. 1983;51:1537-1541. [Medline] [Order article via Infotrieve]
16.
Turpie AGG, Gent M, Laupacis A, Latour Y, Gunstensen J, Basile
F, Klimek M, Hirsh J. A comparison of aspirin with placebo in patients
treated with warfarin after heart-valve replacement. N Engl J
Med.. 1993;329:524-529.
17. Collins JJ. The evolution of artificial heart valves. N Engl J Med.. 1991;324:624-626. [Medline] [Order article via Infotrieve]
18. Tascon M. Prosthetic heart valves: design considerations. Ann Thorac Surg.. 1989;48:S16-S17.
19. Davila JC. Where is the ideal heart valve substitute? What has frustrated its realization? Ann Thorac Surg.. 1989;48:S20-S23.
20. Hirsh J, Dalen JE, Fuster V, Harker LB, Salzman EW. Aspirin and other platelet active drugs: the relationship between dose, effectiveness, and side effects. Chest. 1992;102(suppl):327S-336S.
21. Hirsh J, Dalen JE, Deykin D, Poller L. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest. 1992;10(suppl):337S-351S.
22. Bauer KA. Laboratory markers of coagulation activation. Arch Pathol Lab Med.. 1993;117:71-77. [Medline] [Order article via Infotrieve]
23. Berger MP, Tegeler CH. Embolus detection using Doppler ultrasonography. In: Babikian VL, Wechsler LR, eds. Transcranial Doppler Ultrasonography. St Louis, Mo: CV Mosby Co–Year Book, Inc; 1993:232-241.
24.
Russel D, Madden KP, Clark WM, Sandset PM, Zivin JA. Detection
of arterial emboli using Doppler ultrasound in rabbits.
Stroke.. 1991;22:253-258.
25.
Spencer MP, Thomas GI, Nicholls SC, Sauvage LR. Detection of
middle cerebral artery emboli during carotid endarterectomy using
transcranial Doppler sonography. Stroke.. 1990;21:415-423.
26.
Markus H. Transcranial Doppler detection of circulating
cerebral emboli: a review. Stroke.. 1993;24:1246-1250.
27. Pugsley W, Klinger L, Paschalis C, Aspex B, Newman S, Harrison M, Treasure T. Microemboli and cerebral impairment during cardiac surgery. Vasc Surg.. 1990;24:34-43.
28.
Siebler M, Sitzer M, Steinmetz H. Detection of intracranial
emboli in patients with symptomatic extracranial carotid artery
disease. Stroke.. 1992;23:1652-1654.
29. Cowburn PJ, Grosset DG, Squire IB, Morris AD, Northridge D, Lees KR, Dargie HJ, Reid JL. Doppler ultrasound detection of cerebral emboli in patients with mechanical heart valves: correlation with neurological deficit. Clin Sci. 1992;82(suppl 26):1P. Abstract.
30. Newell DW, Aaslid R. Transcranial Doppler: clinical and experimental uses. Cerebrovasc Brain Metab Rev.. 1992;4:122-143. [Medline] [Order article via Infotrieve]
31.
Beer JH, Buechi L, Steiner B. Glycocalicin: a new assay: the
normal plasma levels and its potential usefulness in selected diseases.
Blood.. 1994;83:691-702.
32. Harker LA, Slichter SJ. Studies of platelet and fibrinogen kinetics in patients with prosthetic heart valves. N Engl J Med.. 1970;283:1302-1305.
33.
Steele P, Weily H, Davies H, Pappas G, Genton E.
Platelet survival time following aortic valve replacement.
Circulation. 1975;51:358-362.
34.
Sutera SP. Flow-induced trauma to blood cells.
Circ Res.. 1977;41:2-8.
35.
Stein PD, Sabbah HN. Measured turbulence and its effect on
thrombus formation. Circ Res.. 1974;35:608-614.
36. Schoephoerster RT, Chandran KB. Velocity and turbulence measurements past mitral valve prostheses in a model left ventricle. J Biomech.. 1991;24:549-562. [Medline] [Order article via Infotrieve]
37.
Chow TW, Hellums DJ, Moake JL, Kroll MH. Shear stress-induced
von Willebrand factor binding to platelet glycoprotein Ib initiates
calcium influx associated with aggregation. Blood.. 1992;80:113-120.
38.
Moake JL, Turner NA, Stathopoulos NA, Nolasco L, Hellums JD.
Shear-induced platelet aggregation can be mediated by vWF release from
platelets, as well as by exogenous large or unusually large vWF
multimers, requires adenosine diphosphate and is resistant to aspirin.
Blood.. 1988;71:1366-1374.
39. Lamson TC, Rosenberg G, Geselowitz DB, Deutsch S, Stinebring DR, Frangois JA, Tarbell JM. Relative blood damage in the three phases of a prosthetic heart valve flow cycle. ASAIO J.. 1993;39:626-633.
40. Graf T, Fischer H, Reul H, Rau G. Cavitation potential of mechanical heart valve prostheses. Int J Artif Organs.. 1991;14:169-174. [Medline] [Order article via Infotrieve]
41. Graf T, Reul H, Dietz W, Wilmes R, Rau G. Cavitation of mechanical heart valves under physiological conditions. J Heart Valve Dis.. 1992;1:131-141. [Medline] [Order article via Infotrieve]
42. Bokros JC. Carbon in prosthetic heart valves. Ann Thorac Surg.. 1989;48:S49-S50.
43. Einav S, Stolero D, Avidor JM, Elad D, Talbot L. Wall shear stress distribution along the cusp of a tri-leaflet prosthetic valve. J Biomed Eng.. 1990;12:13-18. [Medline] [Order article via Infotrieve]
44. Yonagathan AP, Woo YR, Sung HW, Jones M. Advances in prosthetic heart valves: fluid mechanics of aortic valve design. J Biomater Appl.. 1988;2:579-614.
45. Georgiadis D, Grosset DG, Kelman A, Faichney A, Lees KR. Prevalence and characteristics of intracranial microemboli signals in patients with different types of prosthetic cardiac valves. Stroke.. 1994;25:587-592. [Abstract]
46.
Grosset DG, Georgiadis D, Kelman AW, Lees KR. Quantification
of ultrasound emboli signals in patients with cardiac and carotid
disease. Stroke.. 1993;24:1922-1924.
47. Smith PLC, Treasure T, Newman SP. Cerebral consequences of cardiopulmonary bypass. Lancet.. 1986;1:823-825. [Medline] [Order article via Infotrieve]
48.
Helps SC, Parsons DW, Reilly PL, Gorman DF. The effect of gas
emboli on rabbit cerebral blood flow. Stroke.. 1993;21:94-99.
49. Warren BA, Philp RB, Inwood MJ. The ultrastructural morphology of air embolism: platelet adhesion to the interface and endothelial damage. Br J Exp Pathol.. 1973;54:163-172. [Medline] [Order article via Infotrieve]
50. Haller C, Sercombe R, Verrecchia C, Fritsch H, Seylaz J, Kuschinsky W. Effect of the muscarine agonist carbachol on pial arteries in vivo after endothelial damage by air embolism. J Cereb Blood Flow Metab.. 1987;7:605-611. [Medline] [Order article via Infotrieve]
51. Grosset DG, Georgiadis D, Abdullah I, Bone I, Less KR. Doppler emboli signals vary according to stroke subtypes. Stroke.. 1994;25:382-384. [Abstract]
52. Sobel M, McNeill PM, Carlson PL, Kermode JC, Adelman B, Conroy R, Marques D. Heparin inhibition of von Willebrand factor-dependent platelet function in vitro and in vivo. J Clin Invest.. 1991;87:1787-1793.
53.
Horne MK, Chao ES. Heparin binding to resting and activated
platelets. Blood.. 1989;74:238-243.
54.
Peterson DM, Stathopoulos NA, Giorgio TD, Hellums JD, Moake
JL. Shear-induced platelet aggregation requires von Willebrand factor
and platelet membrane glycoproteins I and IIb-IIIa. Blood.. 1987;69:625-628.
55. Olson JD, Zaleski A, Herrmann D, Flood PA. Adhesion of platelets to purified solid-phase von Willebrand factor: effects of wall shear rate, ADP, thrombin, and ristocetin. J Lab Clin Med.. 1989;14:6-18.
56.
Goldby AJ, Bush EC, DeRook FA, Albers GW. Failure of
high-dose heparin to prevent recurrent cardioembolic strokes in a
pregnant patient with a mechanical heart valve. Neurology.. 1992;42:2204-2206.
57. Coller BS. Antiplatelet agents in the prevention and therapy of thrombosis. Annu Rev Med.. 1992;43:171-180. [Medline] [Order article via Infotrieve]
58. Bluestein D, Menon S, Wu ZJ, Haubold A, Armitage TL, Hwang NH. Closing behaviour of a new bileaflet mechanical heart valve. ASAIO J.. 1993;39:398-402.
59.
Cairns JA. Stroke prevention in atrial fibrillation.
Circulation. 1991;84:933-935.
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