CLINICAL RESEARCH: CONGENITAL HEART DISEASE
Pulmonary thrombosis in adults with Eisenmenger syndrome
Candice K. Silversides, MD*,*,
John T. Granton, MD ,
Eli Konen, MD ,
Michelle A. Hart, BSc*,
Gary D. Webb, MD, FACC* and
Judith Therrien, MD*
* Toronto Congenital Cardiac Centre for Adults, Toronto, Canada
Division of Respirology, University Health Network, University of Toronto, Toronto, Canada
Department of Diagnostic Imaging, University Health Network, University of Toronto, Toronto, Canada
Manuscript received May 5, 2003;
revised manuscript received June 30, 2003,
accepted July 1, 2003.
* Reprint requests and correspondence: Dr. Candice K. Silversides, Beth Israel Deaconess Medical Center, Cardiovascular Division, 330 Brookline Avenue, E/RW-453, Boston, Massachusetts 02215, USA.
csilvers{at}caregroup.harvard.edu
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Abstract
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OBJECTIVES: We sought to determine the prevalence of pulmonary artery thrombosis in patients with Eisenmenger syndrome and to identify individuals at highest risk.
BACKGROUND: Eisenmenger syndrome is associated with pulmonary arterial thrombus formation. Both the prevalence and the determinants of pulmonary arterial thrombosis are unknown.
METHODS: This is a review of patients with Eisenmenger syndrome seen at the Toronto Congenital Cardiac Centre for Adults, Canada. Patients underwent a contrast-enhanced computed tomographic (CT) scan of the thorax.
RESULTS: Forty-nine consecutive patients with Eisenmenger syndrome were seen in our hospital. Fifteen patients did not undergo CT angiograms; therefore, 34 patients (mean age 42 ± 10 years) were included in the study. Responsible shunts included ventricular septal defect (65%), atrial septal defect (15%), patent ductus arteriosus (9%), and other (11%). The prevalence of proximal pulmonary artery thrombus was 21% (7/34) of patients. Evidence of more distal vessel thrombosis was observed in 43% (3/7) of the patients who had visible thrombus in the proximal pulmonary arteries. Patients with thrombus were more likely to be female (86% vs. 37%, p = 0.04) and to have lower oxygen saturations (72% ± 9% vs. 85% ± 6%, p = 0.01). Differences in functional status did not identify patients at highest risk for thrombosis.
CONCLUSIONS: Patients with Eisenmenger syndrome have a substantial risk of pulmonary artery thrombus formation. Women and patients with lower oxygen saturations are at the highest risk of developing thrombosis. In the context of an increased bleeding tendency in these patients, the role of anticoagulation treatment needs to be determined.
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Abbreviations and Acronyms
| | CT | = computed tomography/tomographic | | INR | = international normalized ratio | | NYHA | = New York Heart Association |
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Eisenmenger syndrome, a form of cyanotic congenital heart disease, occurs when original left-to-right shunts increase pulmonary blood flow and pressure. This results in pulmonary vascular disease and right-to-left or bi-directional shunting through the original shunt lesions (1). For patients with Eisenmenger syndrome, conventional medical treatment focuses primarily on avoiding complications. By comparison, patients with primary pulmonary hypertension, where intravascular thrombosis is thought to contribute to progression of the disease, are routinely anticoagulated to improve survival (2,3). The value of anticoagulation in patients with Eisenmenger syndrome has not been established. Indeed, Eisenmenger syndrome has been associated with both bleeding and clotting tendencies (4–9). This paradox makes recommendations regarding anticoagulation in these patients difficult. Although bleeding events are usually mild, more severe events can occur from pulmonary vascular disease with pulmonary hemorrhage or rupture of aneurysmal pulmonary arteries (5–10). Hemostatic mechanisms that contribute to bleeding include thrombocytopenia, abnormal platelet function, clotting factor deficiencies, and depletion of von Willebrand factor (11–15). For these reasons, avoidance of aspirin, heparin, and coumadin in these patients has been advocated by many centers. Paradoxically, these patients are also prone to thrombus such as laminated thrombus in the proximal pulmonary arteries, spontaneous in situ thrombosis, and thrombosis in distal peripheral vessels (4–9). The mechanisms contributing to thrombus formation are poorly understood. Structural changes in the vessels, damage to the endothelium with activation of procoagulants, and impairment in the fibrinolytic system are mechanisms that may contribute to thrombus formation in these individuals (16–20).
Because of the potential for significant adverse effects from pulmonary thromboembolic disease in patients with Eisenmenger syndrome, computed tomographic (CT) angiograms have become a component of routine follow-up at our center. In this study, we sought to determine the prevalence of pulmonary thrombosis and to identify individuals at highest risk for thrombosis.
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Methods
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Study design.
This is a review of patients with Eisenmenger syndrome seen at the Toronto Congenital Cardiac Centre for Adults, Toronto, Canada, from February 2001 to December 2002. All patients with Eisenmenger syndrome seen for routine clinical follow-up or admitted to the Toronto General Hospital during the study period were included. Eisenmenger syndrome was defined as cyanotic heart disease resulting from pulmonary hypertension secondary to reversal or bi-directional shunting across large intracardiac lesions. All patients who had not had a CT angiogram within two years before their clinic visit were scheduled to undergo a contrast-enhanced CT angiogram as part of their clinical assessment. Patients who did not have a CT angiogram were not included in the study. The study was approved by the institutional ethics review board. All patients signed an informed consent form before the CT angiogram.
Baseline data collection.
Patients underwent history, physical exam, complete blood count with iron indices, international normalized ratio (INR) measurement, and a contrast-enhanced CT angiogram. Baseline clinical data were collected at the time of the CT scan. Baseline clinical data included age, gender, underlying cardiac anatomy, history of bleeding tendencies (e.g., gingival bleeding, epistaxis, pulmonary hemorrhage), history of previous thrombotic events (deep vein thrombosis, pulmonary embolus, stroke), family history of thrombotic events, history of pulmonary disease, and the use of anticoagulants or antiplatelet medication. Functional status was graded according to the New York Heart Association (NYHA) functional classification. All patients underwent a standard clinical examination, including oxygen saturation determined by oximetry after at least 5 min of rest. A complete blood count and INR were performed at the time of the clinical visit.
Cardiac imaging.
Transthoracic echocardiograms were performed to verify the underlying anatomical diagnosis, assess the ventricular function, and determine the right ventricular systolic pressures when appropriate. Ventricular function was assessed visually (21). Right ventricular systolic pressures were determined by previously described methods using the peak tricuspid regurgitant velocity (22).
All patients underwent CT angiography of the pulmonary arteries using an air-filtered intravenous (IV) line to protect against paradoxical air bubble emboli. Nonionic iodinated contrast material (Omnipaque 300 [iohexol], Nycomed, New York, New York) was administered into a peripheral vein of the arm, using a power injector at a rate of 5 ml/s and a mean total dose of 90 ml. High-resolution CT scans were performed with a Lightspeed QXi scanner (General Electric Medical Systems, Milwaukee, Wisconsin) using 1.25-mm collimation. The CT images were used to measure the diameter of the main pulmonary artery and to identify thromboses, aneurysms, and mural calcification of the pulmonary arteries. Measurements of the main pulmonary artery were performed in the transverse plane at the level of the pulmonary artery bifurcation. Previously described criteria were used to detect pulmonary thromboembolism (23). Ventilation-perfusion scans were not performed as part of the protocol.
Statistical analysis.
Statistical analysis was performed using the SPSS package (10.1 Chicago, Illinois). Data are presented as a mean ± SD. Comparisons between categorical variables (gender, history of bleeding or thrombosis, functional class, calcification in the pulmonary arteries, and right ventricular dysfunction) in patients with and without pulmonary thrombus were performed using the Fisher exact test. Comparisons between continuous variables (age, body mass index, baseline oxygen saturations, size of main pulmonary arteries, right ventricular systolic pressure, hemoglobin levels, mean corpuscular volume, and platelet count) in patients with and without pulmonary thrombus were performed using the Student t test. The test determined the relationship between gender and baseline oxygen saturations. Statistical significance was set at a p value of <0.05 (two-sided).
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Results
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Forty-nine patients with Eisenmenger syndrome were seen in our hospital during the study period. Fifteen patients did not undergo CT angiography, therefore, 34 patients are included in this study. Baseline characteristics are presented in Table 1 . The mean age of the population was 41 ± 10 years. The majority of patients had ventricular septal defects (65%) as the cause of their Eisenmenger syndrome, followed by atrial septal defects (15%) and patent ductus arteriosus (9%). Four patients had histories of thrombotic events: two patients with pulmonary thrombus and two with cerebrovascular events. Mean baseline oxygen saturations and hemoglobin levels were 82 ± 9% and 188 ± 28 g/l, respectively. The mean INR was 1.4 ± 0.5 IU. Fifteen percent of patients were on anticoagulants at the time of the clinical visit.
Of the 15 patients who did not undergo CT angiograms, 7 had ventricular septal defects, 6 had atrioventricular septal defects, and 2 had atrial septal defects (Table 1). Patients who did not undergo CT angiography were more likely to have atrioventricular septal defects compared to the study group. All patients with atrioventricular septal defects had Down syndrome. Reasons for exclusion included reluctance of patients to undergo additional testing or IV insertion, inability to consent for the CT scan, medical instability, iodine allergy, and renal insufficiency.
Pulmonary artery thrombus.
The prevalence of proximal pulmonary artery thrombus was 21% (7/34) of patients. Anatomical diagnosis of patients with pulmonary thrombus included three ventricular septal defects, one multiple muscular ventricular septal defect, one atrial septal defect, one unrepaired patent ductus arteriosus, and one patient with univentricular anatomy. Of the seven patients with pulmonary thrombus, all had thrombus involving the main pulmonary artery segments. Patients had enlargement of the pulmonary arteries ranging from 37 to 77 mm (Fig. 1). Evidence of more distal vessel thrombosis was observed in 43% (3/7) of the patients who had a visible thrombus in the proximal pulmonary arteries (Fig. 2A and B).
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Figure 1 Axial computed tomography angiography image at the level of the main pulmonary artery bifurcation shows dilation of the main pulmonary arteries and an eccentric 23-mm mural thrombus along the posterior wall of the right pulmonary artery. The thrombus is composed of multiple layers of thrombus with embedded linear calcifications suggesting repeated events during formation. Calcifications are also seen along the anterior free wall of the right pulmonary artery and its main branches (long arrows) and in the left interlobar artery (short arrow). Ao = ascending aorta; MPA = main pulmonary artery.
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Figure 2 (A) Axial computed tomography angiography image at the level of the main pulmonary arteries demonstrates severe dilation, with the main pulmonary artery measuring 71 mm. There is an associated eccentric irregular thrombus in the left main pulmonary artery (short arrows). A tiny focus of calcification is noted in the posterior wall of the right pulmonary artery (long arrow). (B) Axial image at the level of lung bases showing extension of the thrombus into the segmental basal arteries of the left lower lobe (short arrows).
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Clinically, two patients were stable and the thrombus was detected during routine screening at the time of their annual clinical visit. In two other patients, pulmonary thrombus had been previously reported; one patient was on anticoagulants. Both patients had CT scans during the study period, which showed dilated pulmonary arteries and persistent chronic laminated thrombus. Of these two patients, one died suddenly in her sleep during the study period. The other patient, who had been deteriorating clinically, underwent heart-lung transplant and died on the first postoperative day. The remaining three patients presented to our hospital with clinical deterioration (one with seizures and two with functional deterioration) requiring hospital admission.
Prior to the diagnosis of pulmonary thrombus, one patient was on an antiplatelet agent after a cerebral thrombotic event. No patients were on anticoagulants before the diagnosis of pulmonary thrombus. None of the women with documented thrombus were taking oral contraceptive pills or hormone replacement therapy at the time of the clinical visit.
Comparison between patients with and without thrombus.
Difference in baseline characteristics among patients with and without pulmonary thrombus are shown in Table 2 . Compared with patients who did not have evidence of pulmonary thrombus, patients with thrombus were more likely to be female (86% vs. 37%, p = 0.04) and have lower oxygen saturations (72 ± 9% vs. 85 ± 6%, p = 0.01). A statistically significant relationship was observed between gender and oxygen saturations (males 85 ± 6% vs. females 79 ± 10%, p = 0.02). Clinically, we did not observe a difference in baseline NYHA functional status or prevalence of admissions for clinical deterioration between patients with and without pulmonary thrombus. Body mass index was similar in patients with and without pulmonary thrombus. Baseline hemoglobin levels, mean corpuscular volume, and platelet counts were not statistically different in patients with and without thrombus. Although not statistically significant, a history of bleeding (57% vs. 30%, p = 0.21) and thrombotic events (29% vs. 7%, p = 0.18) was more commonly observed in patients with pulmonary thrombus. Anatomical differences in the size of the main pulmonary artery between patients with and without thrombus were not observed (47 ± 15 mm vs. 43 ± 9 mm, p = 0.52); however, patients with pulmonary thrombus were more likely to have calcification in the pulmonary arteries (71% vs. 19%, p = 0.01). Calcifications were typically found embedded in the laminated thrombus. No difference was seen in the right ventricular systolic pressure (113 ± 31 mm Hg vs. 99 ± 32 mm Hg, p = 0.47) or the presence of right ventricular dysfunction (71% vs. 56%, p = 0.63) between the two groups.
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Discussion
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This is the first study to document the prevalence and the determinants of pulmonary thrombus in patients with Eisenmenger syndrome. We have shown a 21% prevalence of pulmonary artery thrombus in this cohort of patients. Forty-three percent of the patients with proximal thrombus also had evidence of more distal vessel thrombosis. The frequent finding of calcification within the laminated thrombus suggests a chronic thrombotic lesion. Thrombus was more likely to develop in women and in patients with lower systemic arterial oxygen saturation.
Mechanisms of pulmonary thrombosis.
Structural and functional changes in the pulmonary artery wall likely contribute to the thrombotic disease that develops in patients with Eisenmenger syndrome. Although the characteristic structural changes of pulmonary hypertension occur in the neomuscularized small arteries, changes also occur in larger vessels. The large arteries may dilate and become aneurysmal (9,10). These changes can contribute to stasis and mural thrombus formation. In addition, injured endothelium, which plays a critical role in the vascular changes occurring during the development of primary pulmonary hypertension, may also contribute to thrombus formation in this group of patients. Endothelium can be damaged by the increased shear stress on the vessel walls, by increased blood viscosity, and by chronic hypoxemia (24). In patients with primary pulmonary hypertension, the damaged endothelium leads to a thrombotic state with decreased fibrinolytic activity and release of procoagulant factors (16–20). Similar mechanisms are likely involved in the thrombus formation in patients with other forms of pulmonary hypertension such as Eisenmenger syndrome. Prognostically, markers of endothelial cell dysfunction have been associated with worse short-term survival in patients with pulmonary hypertension (25). We did not measure markers of endothelial dysfunction in this study. We found that lower oxygen saturations were associated with the presence of pulmonary arterial thrombosis. Poor oxygen saturations likely reflect larger intracardiac right-to-left shunting, lower pulmonary blood flow, more advanced disease, and, in turn, potentially worse endothelial injury.
No studies have examined the predictors of pulmonary thrombus formation in patients with Eisenmenger syndrome. However, in patients with pulmonary embolus, the Prospective Investigation of the Pulmonary Embolism Diagnosis study demonstrated that men were at higher risk of developing pulmonary emboli compared with women (26). By comparison, we found that women with Eisenmenger syndrome were more likely to develop pulmonary thrombosis compared with men. This finding can be at least partially explained by the observation that, in our series, women had lower oxygen saturations when compared with men. Because of the retrospective nature of this study, it is difficult to determine the sequence of events leading to pulmonary thrombosis. The reason why women have lower oxygen saturation and the mechanisms by which these two factors interact require further study.
Other known risk factors for the development of venous thromboembolism include obesity and a history of cigarette smoking. In women, the use of oral contraceptives and hormone replacement therapy confer an additional risk (27–29). In our study none of the women with pulmonary thrombus were on oral contraceptive pills or hormone replacement therapy at the time of the clinical visit, and none of the patients had a history of cigarette smoking. No difference in body mass index was observed between patients with and without pulmonary thrombus.
Finally, we found that pulmonary artery calcification was seen more frequently in patients with pulmonary thrombosis. The calcium, typically embedded in the laminated pulmonary artery thrombus, represents the chronic nature of the thrombus. This feature raises the importance of endothelial damage in the development if in situ thrombosis. Indeed, the source of the thrombosis in these patients was not systematically evaluated. Clearly, the etiology, progression, and ultimately the clinical importance of these pulmonary arterial thromboses needs to be explored.
Clinical implications.
The clinical status of the patients found to have CT evidence of pulmonary thrombus was variable. Although a proportion of the cases of thrombus were found during routine screening, others presented with marked functional deterioration. Because we were unable to clinically identify patients with thrombus, routine screening of patients should be considered.
The presence of more distal thrombosis in several of these patients raises the concern that the pulmonary arterial thrombosis may be contributing to progression of the patients' pulmonary vascular disease through progressive loss of their pulmonary vasculature. The use of anticoagulation in these patients also needs to be revisited. In patients without intracardiac lesions, long-term anticoagulation with coumadin is the treatment of choice for individuals who develop pulmonary thromboembolism (30,31). Furthermore, because of the presence of microvascular thrombosis and the tendency for both endothelial and clotting abnormalities in patients with primary pulmonary arterial hypertension, long-term prophylactic anticoagulation is also recommended and is believed to confer a long-term survival benefit (2,3). However, because of the bleeding risk in patients with Eisenmenger syndrome and the difficulty regulating the INR in cyanotic patients, many consider long-term anticoagulation unsafe. Currently, decisions regarding the use of anticoagulation need to be weighed against the risk of bleeding in any individual patient and the chronic nature of many of the thrombotic lesions. In view of the high prevalence of pulmonary thromboembolic disease and its potential detrimental role to the already abnormal pulmonary vascular bed, a clinical trial to determine the role of anticoagulation in patients with Eisenmenger syndrome would be welcome.
Finally, recent data have demonstrated that bosentan, an endothelin-receptor antagonist, can attenuate the damage caused by overcirculation-induced pulmonary hypertension in animal models (32). Whether an endothelin-receptor antagonist or other vasodilators will prevent damage to the pulmonary endothelium in humans and act as an inhibitor of thrombus formation is unknown.
Study limitations.
In this study we were unable to include all patients presenting to our hospital with Eisenmenger syndrome. However, apart from a higher prevalence of males and a larger proportion of patients with atrioventricular septal defects who refused to enter the study, clinical characteristics were similar to the group of patients who were included. Although low oxygen saturations were associated with pulmonary thrombosis, this association does not imply a cause-and-effect relationship. The mechanism by which thrombus formation develops is unknown. We did not routinely perform tests for coagulopathies other than those described in the Methods section or for other hypercoagulable states. Therefore, we cannot comment on the potential role of coagulopathies as a mechanism of thrombosis formation. Ventilation-perfusion scans were not performed as part of this study; therefore, it is possible that we did not detect more peripheral emboli.
Conclusions.
Patients with Eisenmenger syndrome have a high prevalence of pulmonary arterial thrombotic disease. Women and patients with lower oxygen saturations are at highest risk of developing thrombosis. In the context of an increased bleeding tendency in these patients, the role of anticoagulation treatment in this population needs to be determined.
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Abstract
Methods