Study objectives: The objectives of the study were as follows: (1) to identify differences in endothelial dysfunction and altered hemostasis in patients with chronic thromboembolic pulmonary hypertension (CTEPH) compared with patients with acute pulmonary thromboembolism (APTE) uncomplicated by pulmonary arterial hypertension, by measuring the concentrations of thrombomodulin (TM), a receptor for thrombin and a major anticoagulant proteoglycan on the endothelial membrane, and other plasma factors of coagulation and fibrinolysis; and (2) to examine the effects of thromboendarterectomy on TM levels as a parameter of endothelial cell injury leading to abnormal hemostasis as well as to examine the clinical significance of TM as a marker of endothelial injury.
Design: Prospective comparison of concentrations of TM and other plasma parameters among patients with CTEPH or APTE and control subjects.
Participants: We studied 22 healthy subjects (ie, control subjects), 22 patients who had been clinically stabilized after APTE, and 44 patients with CTEPH. In 21 of the patients with CTEPH, measurements were repeated after they had undergone pulmonary thromboendarterectomy.
Measurements and results: Plasma concentrations of soluble TM in patients with CTEPH were measured and compared with those in patients with APTE. The mean ([+ or -] SD) TM concentration in the CTEPH group (2.5 [+ or -] 0.7 ng/mL) was significantly lower than that in the control group (4.0 [+ or -] 0.6 ng/mL; p < (1.05). In contrast, the mean plasma TM concentration in the APTE group (4.6 [+ or -] 1.9 ng/mL) was similar in that in the control group. After patients underwent pulmonary thromboendarterectomy, the mean TM concentration increased from 2.0 [+ or -] 0.4 to 2.9 [+ or -] 0.7 ng/mL (p < 0.05). In the CTEPH group, the plasma TM concentration was negatively correlated with mean pulmonary arterial pressure and total pulmonary resistance (p < 0.05).
Conclusions: A decreased plasma TM concentration may reflect pulmonary vascular endothelial dysfunction leading to altered anticoagulant and fibrinolytic function in CTEPH, which rarely develops after APTE. Plasma TM measurements may be useful in distinguishing CTEPH with severe pulmonary hypertension from recurrent APTE.
Key words: coagulation; endothelium; pulmonary hypertension; pulmonary thromboembolism; thrombomodulin
Abbreviations: APTE = acute pulmonary thromboembolism; CTEPH = chronic thromboembolic pulmonary hypertension; mPAP = mean pulmonary arterial pressure; PAI = plasminogen activator inhibitor; PPH = primary pulmonary hypertension; PVR = pulmonary vascular resistance; TM = thrombomodulin; tPA = tissue plasminogen activator; TPR = total pulmonary resistance; vWF = von Willebrand factor
Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by chronic and organized thromboembolic obstruction of the main, lobar, and/or segmental pulmonary arteries, and by an increase in pulmonary vascular resistance (PVR), which causes right ventricular failure and death. (1) After acute pulmonary thromboembolism (APTE), most thrombi resolve spontaneously or with thrombolytic therapy with, for example, urokinase or tissue plasminogen activator (tPA). (2) However, in the chronic form of the disease, medical management, including thrombolytic therapy, has been mostly unsuccessful in improving symptoms or in changing the evolution of the disease. (3)
In a small percentage of patients with APTE, the chronicity of the disease is caused by incompletely resolved residual emboli. Furthermore, only 0.01% of patients with chronic pulmonary embolism develop clinically apparent CTEPH. (1) It remains unclear why only a small percentage of patients with pulmonary embolism develop such severe pulmonary hypertension. The pathophysiologic mechanisms causing CTEPH may involve characteristic endothelial dysfunction and coagulation abnormalities that are different from those observed in patients with APTE. However, the different pathophysiologic mechanism of APTE vs CTEPH and the vascular injury leading to CTEPH are difficult to ascertain by the measurement of conventional coagulation and fibrinolytic factors.
Thrombomodulin (TM) is an endothelial cell surface protein that is responsible for binding thrombin, with subsequent activation of protein C, which acts as an anticoagulant. (4) Plasma-soluble TM concentrations are increased in disseminated intravascular coagulation and atheromatous arterial disease. (5,6) A few studies, (7-9) including ours, have shown that plasma TM concentrations in patients with primary pulmonary hypertension (PPH) of secondary pulmonary-arterial hypertension are lower than those in control subjects. These observations suggest that TM may be a useful indicator of endothelial cell injury leading to abnormal hemostasis.
We hypothesized that TM in the blood of patients with CTEPH vs clinically stabilized patients with APTE who do not develop severe pulmonary hypertension may reflect differences in vascular endothelial dysfunction leading to abnormal coagulation and fibrinolytic events. The main purpose of our study was to identify differences in endothelial dysfunction and altered hemostasis in patients with CTEPH, compared with those in patients with APTE, that were uncomplicated by the presence of pulmonary arterial hypertension by measuring TM and other plasma factors of coagulation and fibrinolysis.
Pulmonary thromboendarterectomy in selected patients with CTEPH has been associated with acceptable perioperative mortality and, followed by clinical and hemodynamic benefits, substantially longer survival, higher functional capacity, and higher quality of life for periods ranging between 1 and 16 years, (1,10,11) although patients remain at significant risk of recurrent thromboembolism after undergoing thromboendarterectomy. (12) These data suggest that the beneficial effects of pulmonary thromboendarterectomy are attributable not only to the removal of organized macrothrombi, but also to a continuous improvement in vascular endothelial function, preventing hypercoagulation and microthrombi in the pulmonary circulation. A second objective of this study was to examine the effects of thromboendarterectomy on TM concentrations as a parameter of endothelial cell injury leading to abnormal hemostasis.
MATERIALS AND METHODS
The study population consisted of 22 healthy subjects (ie, control subjects), 22 patients with APTE, and 44 patients with CTEPH. The diagnosis of pulmonary hypertension was defined as a mean pulmonary artery pressure (mPAP) at rest of > 20 mm Hg. The diagnosis of APTE was based on the onset of symptoms within 7 days before presentation of the patient to our institution and on findings of a pulmonary perfusion-scan with [sup.99m]Tc-macroaggregated albumin and a contrast-enhanced CT scan of the chest. (13) Patients with congenital coagulopathies, including deficiency of protein C or protein S, were not included in this study since abnormalities in these proteins may affect the concentrations of activity of TM Blood sampling was performed at least 2 weeks after admission to our hospital and when the patient had been hemodynamically stabilized.
The diagnosis of CTEPH was based on the confirmation of thromboembolism by pulmonary angiography, pulmonary perfusion-scan with [sup.99m]Tc-macroaggregated albumin, and contrast-enhanced CT scan of the chest in patients with a history consistent with chronic pulmonary thromboembolism who had remained clinically stable for > 6 months. (1,3,10,14) Anticoagulant therapy with warfarin was prescribed to all patients with diagnoses of APTE and CTEPH. Heparin, platelet inhibitors, or thrombolytic agents were not administered during the study period.
Twenty-two subjects without apparent cardiopulmonary disease, or disorders, which may have interfered with measurements of TM, (4-9) served as control subjects. The baseline characteristics of the three study groups, including pulmonary hemodynamic measurement, findings of lower extremity deep venons thrombosis on venous ultrasonography, and the number of patients with positive titers for antiphospholipid antibodies are shown in Table 1. The prevalence of antiphospholipid antibody was similar to that reported by others. (15) The purpose of the study was explained to all study participants, and they granted informed consent.
Right heart catherization was performed in both groups of patients. mPAP, pulmonary capillary wedge pressure, and systemic arterial pressure were measured at end-expiration. Cardiac output was determined by the Fick method. Total pulmonary resistance (TPR) was calculated by dividing mPAP by cardiac output and was expressed in Wood units. PVR was calculated as PVR = (mPAP-pulmonary capillary, wedge pressure)/cardiac output (in Wood units). The hemodynamic studies were performed within 1 week before of after baseline blood sampling occurred. In 21 patients with CTEPH who underwent pulmonary thromboendarterectomy, these hemodynamic measurements were repeated within 2 months after the operation. The background therapy of all patients remained unchanged during the study period.
Assay of Plasma Parameters
Venous blood samples were collected and underwent anticoagulation in plastic tubes containing trisodium citrate at a concentration of 0.01 mol/L. Plasma samples were separated by centrifugation at 3,500 revolutions per minute for 10 min at 4[degrees]C and were stored at -80[degrees]C until the assay was performed. Plasma TM concentration was determined by a one step sandwich enzyme immunoassay for soluble TM, using two monoclonal antibodies for human TM. (5) The percentage of the coefficient of variation standards was examined at seven different soluble human TM concentrations (ie, from 1 to 64 [micro]g per 1 [micro]g standard solution). Coefficient of variation values obtained from eight repeat analyses of the same samples were 2.8 to 6.6%. (5) Other hemostatic factors, including antithombin III, thrombin-antithrombin III complex, fibrinogen degradation products, tPA, plasminogen activator inhibitor (PAI)-1, plasminogen, [[alpha].sub.2]-plasmin inhibitor, and von Willebrand factor (vWF), were measured by standard clinical laboratory methods at our institution. The plasma-soluble form of P selectin was measured as previously described, using a sandwich enzyme-linked immunosorbent assay technique, with two distinct murine monoclonal antibodies against P selectin (PL7 6 and WGA-1) [GMP-140-EIA Kit; Takara Biomedicals; Shiga, Japan]. (16) All assays for these plasma factors were performed by standard methods with an established normal range based on the mean [+ or -] 2 SDs of at least 30 healthy individuals.
In 9 men and 12 women between the ages of 21 and 64 years (mean [+ or -] SD] age, 48 [+ or -] 15 years) in the CTEPH group who underwent pulmonary thromboendarterectomy, plasma concentrations of TM were measured at baseline and 2 months after the operation. Other measurements of plasma markers, including tPA, PAI-1, vWF, and soluble P selectin also were repeated during this period. All patients were treated with warfarin at the time of blood sampling, before and after undergoing thromboendarterectomy. The operation described by Jamieson et al (10) was performed via midline sternotomy, and under cardiopulmonary bypass and deep hypothermia with intermittent circulatory arrest. Incisions were made in both pulmonary arteries into the lower lobe branches, and pulmonary thromboendarterectomy was performed bilaterally with the removal of the organized thrombus and endarterectomy in all involved vessels. All patients were discharged from the surgical ICUs within 14 days after the operation.
To compare the effects of thromboendarterectomy on TM concentrations with the effects of warfarin treatment, of as a function of time, plasma TM concentrations in 22 patients in the APTE group and in 21 patients in the CTEPH group who did not undergo surgical treatment were measured 3 months after the baseline measurements. During this 3-month follow-up period, drug therapy was continued, including warfarin, and the patients remained clinically stable.
The data ore presented as the mean + SD. The significance of differences among the three groups was tested by one-way analysis of variance with multiple comparisons. Differences were considered significant at p < 0.05 using the Scheffe test. Differences in mPAP, TPR, and PVR between the APTE and CTEPH groups were examined by the Mann-Whitney nonparametric test. The correlations between plasma TM concentrations and pulmonary hemodynamic variables, mPAP, TPR, and PVR were examined by simple regression test. In patients who were treated by pulmonary thromboendarterectomy, the significance of changes from baseline in plasma measurements and hemodynamic variables was assessed by the Student paired t test.
The baseline characteristics of the three study groups are shown in Table 1. There was no significant difference in mean age, sex distribution, and prevalence of lower extremity deep venous thrombosis between patients with APTE and patients with CTEPH. In contrast, mPAP, TPR, and PVR were consistent with considerably more severe pulmonary hypertension in the CTEPH group than in the APTE group (p < 0.05).
TM and Other Plasma Measurements
The mean ([+ or -] SD) plasma concentrations of TM in the control group, APTE group, and CTEPH group are shown in Figure 1. The mean plasma concentration of TM in the CTEPH group (2.5 + 0.7 ng/mL) was significantly lower than that in the control group (4.0 [+ or -] 0.6 ng/mL) and the APTE group (4.6 [+ or -] 1.3 ng/mL; p < 0.01). With respect to other hemostatic factors, the mean plasma concentrations of thrombin-antithrombin bin-antithrombin III complex, fibrinogen degradation products, tPA, PAI-1, vWF antigen, and P selectin were significantly higher in both the CTEPH and APTE groups than in the control group, and the ratio of ristocetin cofactor to vWF antigen in both patient groups was lower than that in the control group. There was no significant difference in any of the measurements between the APTE and the CTEPH groups (Table 2).
[FIGURE 1 OMITTED]
mPAP (r = 0.403: p < 0.05) and TPR (r = 0.340; p < 0.05) were negatively correlated with plasma TM concentration in the CTEPII group, but PVR was not significantly correlated (r= 0.310; p = 0.07). There was no correlation between mPAP, TPR, or PVR and TM concentration in the APTE group, and other plasma measurements were not correlated with any pulmonary hemodynamic parameters in either patient group.
Effects of Thromboendarterectomy on Plasma TM
After thromboendarterectomy, pulmonary hemodynamic parameters, including mPAP (before thromboendarterectomy, 49 [+ or -] 9 mm Hg; after thromboendarterectomy, 18 [+ or -] 5 mm Hg), TPR (before thromboendarterectomy, 17-+ 5 Wood units; after thromboendarterectomy, 5 [+ or -] 2 Wood units), and PVR (before thromboendarterectomy, 14 [+ or -] 5 Wood units; after thromboendarterectomy, 3 [+ or -] 2 Wood units), were consistently improved (p < 0.001 [paired t test]). The mean plasma TM concentration increased from 2.1 [+ or -] 0.4 ng/mL at baseline to 3.0 [+ or -] 0.6 ng/mL 2 months after the operation (p < 0.01, paired t test). TM concentrations increased in all patients (Fig 2), and a significant improvement, which was defined as an increase of > 20%, was observed in 15 of the 21 patients (71%). In contrast, the patients with APTE and the patients with CTEPH who did not undergo pulmonary thromboendarterectomy had no significant changes in TM concentrations between baseline and 3 mouths after surgery (Table 3). Other plasma marker levels, including tPA, PAI-1, vWF, and soluble P selectin, did not change significant from before the operation to after the operation, although they tended to decrease during the follow-up period (Table 4).
[FIGURE 2 OMITTED]
We have established that the plasma concentration of TM is consistently lower in patients with CTEPH than in control subjects and in patients with APTE. These abnormal values of TM, along with the pulmonary hemodynamic measurements, returned toward normal after pulmonary thromboendarterectomy.
Few studies have examined the differences in endothelial dysfunction leading to pulmonary hypertension between patients with APTE and CTEPH by measuring conventional coagulation and fibrinolytic parameters. The prevalence of hereditary thrombotic risk is not increased in CTEPH patients, (17) although, in one study, (15) phospholipid-dependent antibodies were positive in [less than or equal to] 20% of patients. In vitro studies have revealed no difference in the expression of tPA and PAI-1 by pulmonary endothelial cells between CTEPH patients and control subjects. (18) However, few studies have explained acquired abnormalities in coagulation or fibrinolytic factors in clinical situations, especially comparing CTEPH with the chronic phase of APTE.
TM concentration, but no other hemostatic factors that were measured in this study, detected differences between patients with APTE and patients with CTEPH. This observation suggests that the same mechanisms related to platelet activation, thrombus formation, or abnormal thrombolysis playa role in the development of both APTE and CTEPH. Furthermore, the levels of markers of endothelial function, tPA, PAI-1, vWF antigen, and soluble P selectin were significantly increased in both the APTE and the CTEPH groups. This may indicate equivalent degrees of endothelial injury in both groups and does not support the hypothesis of greater pulmonary vascular dysfunction in CTEPH patients than in APTE patients. Indeed, similar increases in tPA, PAI-1, vWF-antigen, and P selectin have been reported in studies of PPH. (9,18-20) However, the clinical manifestations of CTEPH are distinctly different from those of APTE. We hypothesized that these differences in plasma TM concentrations, and not in the other hemostatic factors, may explain the differences between CTEPH and the stable phase of APTE, which does not evolve toward pulmonary hypertension.
Plasma TM concentration appears to be initially increased with acute vascular injury, perhaps through cleavage flora the cell surface, and then decreased with the subsequent down-regulation of production as the process becomes chronic. (21,22) This loss of TM activity could result in a failure to inactivate locally generated thrombin and a decrease in protein C activation at the site of vessel injury, resulting in local thrombosis. (23) We further hypothesize that the decreased plasma TM concentrations documented in our study may reflect a decreased expression of TM on the pulmonary vascular endothelium, which can lead to a loss of thrombolytic activity in the vascular wall and can cause CTEPH. Therefore, compared to APTE, patients with CTEPH may have a unique pathologic characteristic, that is, a lower expression of TM on the pulmonary vascular endothelium, which was apparent as decreased plasma TM concentrations. It also may he hypothesized that a decreased expression of TM is the mechanism behind the development of pulmonary hypertension in the minority of patients with APTE who ultimately develop CTEPH.
Plasma TM concentration was negatively correlated with mPAP and TPB in patients with CTEPH, but not in those with APTE or in control subjects. Besides the above-mentioned mechanism related to the loss of TM, vascular wall injury due to shear stress from increased pulmonary arterial pressures also may influence the expression of TM on endothelial cells. (23) However, this correlation observed in the CTEPH group should be interpreted cautiously since it was weak, suggesting that the development of pulmonary hypertension was due mainly to other unidentified factors. Furthermore, the correlation is probably not CTEPH-specific since we have observed a similar correlation in PPH. (9) The decreased TM concentrations and increased concentrations of other plasma markers of thrombosis and endothelial injury in CTEPH patients are concordant with the results of studies of pulmonary arterial hypertension, including PPH. Therefore, our results may be explained by the mechanisms mentioned earlier, including ongoing endothelial dysfunction, altered hemostasis, and shear stress to the vascular wall as well as PPH. (9,23,24)
TM concentrations increased after patients underwent pulmonary thromboendarterectomy. This study did not address the mechanism of this postoperative increase in plasma TM concentrations. Thromboendarterectomy as well as the regression of pulmonary hypertension probably played an important role in this decrease in TM concentrations, since it was not observed in patients with APTE of in patients with CTEPH who did not undergo pulmonary thromboendarterectomy. A hypothetical mechanism is the recovery of anticoagulant activity by endothelial cells from neointimal proliferation after the operation. A decrease in shear stress to the pulmonary vascular wall by lower pulmonary pressures is an alternate putative mechanism, since it may lead to an increase in TM expression on the intact or regenerated pulmonary endothelium. Finally, an improvement in systemic circulation by a higher cardiac output also may contribute to changes in TM.
We do not have a conclusive explanation for the increase in TM while other factors remained unchanged following thromboendarterectomy. In vitro studies (25) have shown that hypoxia decreases the expression of TM on the membrane of vascular endothelial cells, and that this down-regulated expression of TM was restored by cyclic adenosine monophosphate. Therefore, the hypoxia present in CTEPH patients, and its marked relief after undergoing thromboendareterctomy, may explain the decreased TM concentration preoperatively as well as its increase after the operation, a change not observed with other markers.
Our study needs to be interpreted in the light of a few limitations. First, abnormal concentrations of TM in venous blood may reflect vascular injury and microthrombosis in the lungs as well as in the systemic circulation. However, no patient in this study experienced other disorders known to influence the concentration of TM. The effect of anticoagulation with warfarin on TM or other plasma factors is another consideration. However, plasma TM concentrations in the CTEPH group were statistically different from those in the APTE group, while anticoagulant therapy with warfarin was prescribed in both patient groups, and its effectiveness, measured as prothrombin time, was the same in both groups. Furthermore, in a previous study, we observed no significant difference between patients treated with warfarin vs those not treated with warfarin, whether they had severe pulmonary arterial hypertension or normal PVR. (9) Second, concentrations of protein C in plasma could not be precisely measured since warfarin was prescribed in both the APTE group and the CTEPH group. Since TM acts via activated protein C, the finding of decreased concentrations of activated protein C might have supported our hypothesis. Third, we did not follow patients past 3 months after thromboendarterectomy. Therefore, the long-term effects of this treatment on pulmonary hemodynamics, TM concentration, or other variables remain to be studied. (11,12)
In conclusion, we have documented decreased plasma concentrations of soluble TM in patients with CTEPH, compared with healthy subjects and with patients with APTE. The abnormally low concentrations of TM increased after pulmonary thromboendarterectomy. These observations suggest that decreased concentrations of TM associated with CTEPH reflect a suppression of antithrombotic activity due to endothelial injury, which may contribute further to the pathogenesis of CTEPH.
ACKNOWLEDGMENT: The authors thank Makoto Handa, MD, at Keio University for his helpful advice, and Katsushi Mori, Koji Yoneda, and Masahiro Fujino for their excellent technical assistance in the assays of TM and P selectin.
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* From the Division of Cardiology and Pulmonary Circulation, Department of Medicine, National Cardiovascular Center, Osaka, Japan.
This work was supported by the Ministry of Health, Labour, and Welfare of Japan (grant No. 9809) and by a grant from the Japan Heart Foundation Research.
Manuscript received June 24, 2002: revision accepted May 2, 2003.
Correspondence to: Fumio Sakamaki, MD, Department of Medicine, Tachikawa Hospital, National Public Service Personnel Mutual Aid Associations. 4-2-22 Nishikicho Tachikawa, Tokyo 190-8531, Japan; e-mail: email@example.com
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