Association of Plasma Fibrinogen and Plasminogen With Prognosis of Inoperable Chronic Thromboembolic Pulmonary Hypertension

Abstract

Background: It is unclear whether abnormalities of coagulation or fibrinolysis are associated with disease progression of chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to investigate the association of these factors with the severity and prognosis of CTEPH.

Methods and Results: Between 1986 and 2011, plasma fibrinogen and plasminogen were measured in 89 of 106 consecutive patients with inoperable CTEPH (17 men; mean age, 55.9±14.1 years old; mean pulmonary arterial pressure, 44.0±12.4 mmHg) and the association of level with severity and prognosis were also examined. Seventeen patients had high fibrinogen and low plasminogen (medians, ≥291 mg/dl and <101%, respectively). These patients had significantly lower cardiac index (2.26±0.68 vs. 2.70±0.57 L·min^–1 ·m^–2, P=0.007), higher pulmonary vascular resistance (PVR; 13.29±7.54 vs. 9.15±4.14 Wood units, P=0.003), and poor survival (5-year survival, 35.3% vs. 88.0%, P<0.001) compared to the other 72 patients. Additional analysis showed significantly poor survival in these patients compared with the other patients who did not have modern therapy. On multivariate analysis plasma fibrinogen, plasminogen and PVR were independent predictors of survival in medically treated patients.

Conclusions: High plasma fibrinogen and low plasminogen are associated with poor survival in CTEPH patients without modern therapy. (Circ J 2014; 78: 1754–1761)

Thrombotic obstruction of the pulmonary arteries and progressive pulmonary hypertension are the main features of chronic thromboembolic pulmonary hypertension (CTEPH). Abnormalities in the coagulation and fibrinolysis systems, including elevated tissue type plasminogen activator (t-PA), type 1 plasminogen activator inhibitor (PAI-1), and clotting factor VIII, as well as decreased concentration of thrombomodulin (TM) have been previously reported in patients with CTEPH.^1–4 It has been unclear, however, whether the severity or prognosis of CTEPH is related to abnormalities in the coagulation and fibrinolysis systems.

Increased coagulation and decreased fibrinolysis have been postulated to contribute to the progression of CTEPH. Hypercoagulability due to high fibrinogen or decreased fibrinolysis due to low plasminogen may exaggerate organization of thrombi. We thus sought to determine if plasma fibrinogen or plasminogen are associated with disease progression in patients with inoperable CTEPH. The aim of this study was to investigate the influence of plasma fibrinogen and plasminogen on disease severity and prognosis in patients with CTEPH.

Methods

Subjects

Between 1986 and 2011, 217 patients were diagnosed with CTEPH at Chiba University Hospital. CTEPH was defined as mean pulmonary arterial pressure (mPAP) ≥25 mmHg with a normal wedge pressure in patients with dyspnea on exertion for >6 months. An additional requirement was segmental or larger defects on lung perfusion scans in patients with normal ventilation scans. Helical computed tomography (CT) angiography was done to confirm the diagnosis and to exclude large vessel arteritis and tumors. Chronic thromboembolic findings were confirmed on pulmonary angiography. The selection criteria for pulmonary endarterectomy (PEA) were slightly modified from those defined by Moser et al.⁵ The present criteria were: (1) mean mPAP >30 mmHg, resulting in a calculated pulmonary vascular resistance (PVR) >300 dyne·s·cm^–5 (3.75 Wood units [WU]), even after oral anticoagulant therapy for >6 months; (2) World Health Organization (WHO) functional class ≥2; (3) thrombi accessible to current surgical techniques (ie, presence at main, lobar or segmental arteries); and (4) absence of severe associated disease.⁵ One hundred and eleven patients who fulfilled these criteria and consented to surgical therapy underwent PEA. The remaining 106 patients were considered to have inoperable CTEPH. Patients in whom plasma fibrinogen and plasminogen could not be measured were excluded from the study.

Eighty-nine patients out of the 106 with consecutive inoperable CTEPH met the inclusion criteria. All patients received warfarin and 83 patients received ambulatory oxygen therapy. Patients with CTEPH progression were treated with beraprost sodium (n=41), epoprostenol sodium (n=2), sildenafil (n=29), bosentan (n=17), tadalafil (n=2) or other oral drugs undergoing clinical trials (n=2).

This study was approved by the ethics committee of Chiba University and written informed consent was obtained from each patient before catheterization.

Data Acquisition

Venous blood samples were collected during right heart catheterization prior to diagnosis. Samples were collected in plastic tubes containing trisodium citrate at a concentration of 3.13%, and plasma was obtained by centrifugation at 1,880 g for 10 min at 25°C. Fibrinogen was measured on light scattering photometry. Plasminogen was measured using a synthesized substrate assay. d-Dimer was measured on immune nephelometry.

Patients were divided into 2 groups each, based on median fibrinogen (291 mg/dl) and plasminogen (101%). Patients were further subcategorized based on both fibrinogen and plasminogen (high fibrinogen and low plasminogen, group A; all others, group B).

Experienced physicians performed right heart catheterization with a Swan-Ganz catheter. Pressure measurements included mPAP and pulmonary capillary wedge pressure (PCWP). Cardiac output (CO) and cardiac index were estimated using the thermodilution method. PVR was calculated as PVR = (mPAP–PCWP) / CO. Following catheterization, pulmonary angiography using Berman catheters was done to determine operability. Central disease score (Bergin) was calculated using pulmonary angiogram and contrast conventional CT before the year 1998, and with contrast helical CT thereafter.⁶

Modern pulmonary arterial hypertension (PAH) therapy was defined as treatment with epoprostenol sodium, sildenafil, bosentan, tadalafil or other oral drugs undergoing clinical trials. Beraprost sodium was excluded from this definition. Coagulopathy was defined as positive anti-phospholipid antibody (APA), deficiencies in protein C/S and anti-thrombin III, and thrombocytosis.

Survival Analysis

In December 2011, follow-up data were obtained from all 89 patients by either direct contact or with their primary physicians. Sixty-four patients survived to follow-up and 25 patients did not. Survival time was calculated from the date of diagnosis on right heart catheterization. One patient had undergone balloon pulmonary angioplasty during the follow-up period and was thus treated as a censored case.

Clinical characteristics, pulmonary hemodynamics and survival were compared between 2 groups each based on median fibrinogen (291 mg/dl) and plasminogen (101%), and between groups A and B. Prognostic factors were determined on univariate and multivariate analyses of age, sex, and clinical parameters such as pulmonary hemodynamics, modern PAH therapy, fibrinogen and plasminogen levels, group A (vs. B), and d-dimer.

Statistical Analysis

Categorical data and continuous variables were analyzed with the chi-squared test and Student’s t-test. The Kaplan-Meier method was used to estimate survival. Differences in survival were then compared with the log-rank test. Univariate and multivariate Cox proportional hazard analyses were used to determine independent prognostic factors. P<0.05 was considered significant. Statistical analysis was performed using JMP version 9.0 (SAS Institute).

Results

Patient Characteristics

Baseline characteristics of all 89 medically treated patients are listed in Table 1. The mean age at diagnosis was 55.9±14.1 years. Of the 89 patients, 17 were male and 72 were female. Most patients were classified as WHO class ≥III. Baseline mPAP, cardiac index and PVR were 44.0±12.4 mmHg, 2.62±0.61 L·min^–1 ·m^–2 and 9.94±5.18 WU, respectively. The majority of patients were found to have relatively peripheral disease with central disease scores of 0 or 1. Mean plasma fibrinogen level at diagnosis was 296.4±63.1 mg/dl, and the median was 291 mg/dl. The mean plasma plasminogen level was 99.2±14.6%, and the median was 101%. The proportion of patients with d-dimer ≥1.0 μg/ml was 18.1%. Baseline characteristics of all 217 patients including operative and medically treated patients are also given for reference.

Table 1. Baseline Patient Characteristics

	Medically treated patients	All patients	Normal range
n	89	217
Age (years)	55.9±14.1	54.8±12.8
Sex (M/F)	17/72	66/151
Modern PAH therapy	44.9	28.1
Coagulopathy	32.6	32.7
APA positive	28.1	26.7
WHO class
I	3	3
II	27	55
III	54	143
IV	5	16
Central disease score
0	46	65
1	28	66
2	12	56
3	3	24
4	0	6
Plasma fibrinogen (mg/dl)	296.4±63.1 (291)	301.3±71.2 (290.5)	130–316
Plasma plasminogen (%)	99.2±14.6 (101)	98.5±15.4 (100)	80–120
d-Dimer ≥1 μg/ml	18.1	31.9
mPAP (mmHg)	44.0±12.4	44.8±11.4
Cardiac index (L·min–1·m–2)	2.62±0.61	2.60±0.63
PVR (WU)	9.94±5.18	10.11±4.69

Data given as n, %, or mean±SD (median). APA, anti-phospholipid antibody; mPAP, mean pulmonary artery pressure; PAH, pulmonary arterial hypertension; PVR, pulmonary vascular resistance; WHO, World Health Organization.

Comparison of Baseline Characteristics Subcategorized by Fibrinogen Value, Plasminogen Value, and Group A and B

There was no significant difference in baseline clinical characteristics based on median fibrinogen (291 mg/dl; Table 2). There was no significant difference in baseline clinical characteristics based on median plasminogen (101%) except for significantly younger patients in the low plasminogen group (Table 3).

Table 2. Comparison of Patient Characteristics According to Plasma Fibrinogen Value

	Plasma fibrinogen		P-value
	≥291 mg/dl	<291 mg/dl
n	45	44
Age (years)	57.4±13.4	54.3±14.8	NS
Sex (M/F)	10/35	7/37	NS
Duration of symptoms (months)	28.7±23.0	29.7±31.6	NS
Modern PAH therapy	40.0	50.0	NS
Coagulopathy	31.1	34.1	NS
APA positive	26.7	29.6	NS
d-Dimer ≥1 μg/ml	21.4	14.6	NS
mPAP (mmHg)	44.2±12.4	43.7±12.6	NS
Cardiac index (L·min–1·m–2)	2.57±0.66	2.67±0.56	NS
PVR (WU)	10.72±6.02	9.15±4.06	NS

Data given as n, %, or mean±SD. Abbreviations as in Table 1.

Table 3. Comparison of Patient Characteristics According to Plasma Plasminogen Value

	Plasma plasminogen		P-value
	≥101%	<101%
n	46	43
Age (years)	58.8±11.5	52.7±16.0	0.041
Sex (M/F)	8/38	9/34	NS
Duration of symptoms (months)	25.6±22.3	33.0±31.9	NS
Modern PAH therapy	43.5	46.5	NS
Coagulopathy	28.3	37.2	NS
APA positive	23.9	32.6	NS
d-Dimer ≥1 μg/ml	18.6	17.5	NS
mPAP (mmHg)	41.8±11.3	46.3±13	NS
Cardiac index (L·min–1·m–2)	2.74±0.55	2.49±0.7	NS
PVR (WU)	9.03±4.35	10.92±5.84	NS

Data given as n, %, or mean±SD. Abbreviations as in Table 1.

Seventeen patients were classified into group A (high fibrinogen and low plasminogen), and all other patients were classified into group B. Group A had significantly lower cardiac index and higher PVR than patients in group B, and included more patients who were not treated with modern PAH therapy (Table 4).

Table 4. Comparison of Patient Characteristics Categorized by Fibrinogen and Plasminogen Value

	Group A High fibrinogen (≥291 mg/dl) and low plasminogen (<101%)	Group B All other patients	P-value
n	17	72
Age (years)	54.9±15.5	56.1±13.8	NS
Sex (M/F)	5/12	12/60	NS
Duration of symptoms (months)	30.6±22.6	28.8±28.6	NS
Modern PAH therapy	23.5	50.0	0.048
Coagulopathy	41.2	30.6	NS
APA positive	35.3	26.4	NS
d-Dimer ≥1 μg/ml	33.3	14.7	NS
mPAP (mmHg)	48.0±14.9	43.0±11.7	NS
Cardiac index (L·min–1·m–2)	2.26±0.68	2.70±0.57	0.007
PVR (WU)	13.29±7.54	9.15±4.14	0.003

Data given as n, %, or mean±SD. Abbreviations as in Table 1.

Survival Analysis

The 5-year survival rate from the date of diagnosis in all patients was 77.3%. For the 25 patients who died, the cause of death was right ventricular failure or sudden death (n=24) and multiple myeloma (n=1). The patients with higher fibrinogen had significantly poorer survival than the patients with fibrinogen <291 mg/dl (5-year survival, 66.6% vs. 88.6%; log-rank test, P=0.031; Figure 1). The patients with lower plasminogen tended to have decreased survival compared to those with higher plasminogen (5-year survival, 71.8% vs. 82.3%, P=0.098; Figure 2). Group A had a significantly lower survival than group B (5-year survival, 35.3% vs. 88.0%; log-rank test, P<0.001; Figure 3).

Figure 1.

Kaplan-Meier survival estimates of patients with medically treated chronic thromboembolic pulmonary hypertension. Patients were classified according to median fibrinogen level (red, fibrinogen ≥ 291 mg/dl; blue, fibrinogen <291 mg/dl). Patients with high fibrinogen had significantly decreased survival relative to patients with lower fibrinogen (5-year survival, 66.6% vs. 88.6%, P=0.031 log-rank test).

Figure 2.

Kaplan-Meier survival estimates of patients with medically treated chronic thromboembolic pulmonary hypertension. Patients were classified according to median plasminogen level (red, plasminogen <101%; blue, plasminogen ≥ 101%). There was no significant difference between patients with lower and higher plasminogen levels (5-year survival, 71.8% vs. 82.3%, P=0.098 log-rank test). Patients with lower plasminogen, however, tended to have decreased survival compared to those with higher plasminogen.

Figure 3.

Kaplan-Meier survival estimates of patients with medically treated chronic thromboembolic pulmonary hypertension. Patients were classified based on the median plasma fibrinogen and plasminogen levels. Group A (red), 17 patients with high fibrinogen and low plasminogen; group B (blue), all other patients. Patients in group A had significantly decreased survival compared to patients in group B (5-year survival, 35.3% vs. 88.0%, P<0.001 log-rank test).

Prognostic Factors

On univariate analysis treatment with modern PAH therapy, high mPAP, low cardiac index, high PVR, high plasma fibrinogen, low plasma plasminogen, and group A (vs. B) were associated with poor prognosis (Table 5).

Table 5. Prognostic Factors in Medically Treated CTEPH

Parameter	Univariate HR (95% CI)	P-value	Multivariate HR 1 (95% CI)	P-value	Multivariate HR 2 (95% CI)	P-value
Age per unit increase	1.003 (0.974–1.036)	NS
Sex (M vs. F)	0.961 (0.319–2.380)	NS
Modern PAH therapy	0.381 (0.126–0.945)	0.037	0.303 (0.099–0.772)	0.011	0.406 (0.130–1.055)	NS
mPAP per unit increase	1.038 (1.007–1.070)	0.017
Cardiac index per unit increase	0.344 (0.145–0.740)	0.005
PVR per unit increase	1.174 (1.095–1.257)	<0.001	1.167 (1.095–1.244)	<0.001	1.140 (1.069–1.215)	<0.001
d-Dimer ≥1 μg/ml	1.574 (0.609–3.638)	NS
Plasma fibrinogen per unit increase	1.007 (1.001–1.013)	0.031	1.007 (1.001–1.014)	0.030
Plasma plasminogen per unit increase	0.964 (0.934–0.995)	0.024	0.957 (0.923–0.990)	0.011
Group A (vs. B)	5.500 (2.454–12.218)	<0.001			3.456 (1.368–8.414)	0.01

PVR was chosen to represent hemodynamics in multivariate analysis. CI, confidence interval; CTEPH, chronic thromboembolic pulmonary hypertension; HR, hazard ratio. Other abbreviations as in Table 1.

PVR is a well-known prognostic factor for CTEPH and correlates with mPAP and cardiac index.^7,8 We thus used PVR to represent pulmonary hemodynamics in multivariate analysis.

Multivariate analysis was performed twice to account for the fact that group A vs. B was based on plasma fibrinogen and on plasminogen. Multivariate hazard ratio (HR) 1 excluded group A (vs. B). In contrast, multivariate HR 2 excluded plasma fibrinogen and plasminogen. On analysis of HR 1, plasma fibrinogen, plasma plasminogen, PVR, and treatment with modern PAH therapy were significant independent predictors of survival (Table 5). On analysis of HR 2, groups A and B and PVR were significant independent predictors of survival, but treatment with modern PAH therapy was not.

Discussion

We found that high fibrinogen and low plasminogen at the time of diagnosis were independent negative predictive factors of survival in patients with medically treated CTEPH. To our knowledge, this is the first study to show that these common laboratory markers are indicators of poor prognosis in medically treated CTEPH patients. Although most of the present patients had plasma fibrinogen and plasminogen within the normal range, patients with high plasma fibrinogen and low plasminogen had significantly decreased 5-year survival rates. The plasminogen level in the present study was similar to that reported by Sakamaki et al,³ but, even in patients in whom fibrinogen or plasminogen are within the normal range, differences in levels may have a profound effect on prognosis.

Several issues must be considered when interpreting these results. It remains uncertain as to why patients with acute pulmonary embolism develop CTEPH and why the disease progresses in medically treated patients who are anticoagulated with warfarin. It is therefore important to determine prognostic factors that might be managed in these patients. Several prognostic factors have been determined in medically treated CTEPH patients, including decreased cardiac index, increased PAP, elevated right atrial pressure, increased PVR, decreased exercise tolerance, associated medical conditions (ventriculo-arterial shunt, infected pacemaker, splenectomy, etc), the coexistence of chronic obstructive pulmonary disease, and the absence of modern PAH therapy.^7–10

It has been reported that fibrinogen level correlates with vascular events in patients with stroke and coronary and peripheral vascular disease.^11,12 An association between fibrinogen and CTEPH prognosis, however, has not been established. Recently, it was reported that inflammatory markers including fibrinogen and C-reactive protein (CRP) are associated with an increased risk of recurrent vascular events and vascular death after stroke.^13–15 In the present study, mean CRP was within normal limits (0.27±0.37 mg/dl, median 0.1 mg/dl) and it was not a significant prognostic factor (data not shown). The possibility, however, that an inflammatory state indicated by markers such as elevated fibrinogen levels affected poor prognosis in patients with CTEPH cannot be excluded.

Fibrinogen is a soluble plasma glycoprotein that is converted by thrombin into fibrin. Coagulation is promoted by this conversion.¹⁶ Therefore, altered plasma fibrinogen level is one indicator of coagulopathy. Plasminogen is an inactive form of plasmin. Plasmin has been shown to resolve fibrin blood clots. Hence, altered plasminogen level indicates aberrant fibrinolysis.¹⁷ Increased coagulation and decreased fibrinolysis may contribute to the progression of CTEPH. In the present study, no significant inverse correlation was observed between plasma fibrinogen and plasminogen (r=0.16, P=0.13; data not shown). Additionally, there was no significant inverse correlation between these levels in group A (r=–0.01, P=0.98; data not shown). There was a weak correlation between plasma fibrinogen and plasminogen in group B (r=0.362, P=0.002; data not shown), but no inverse correlations were observed in either group A or B. On multivariate analysis, high fibrinogen and low plasminogen, in addition to high PVR, were found to be independent predictors of poor outcome in patients with medically treated CTEPH.

Olman et al found elevated plasma t-PA and PAI-1 antigen in patients with CTEPH.¹ Sakamaki et al observed decreased concentration of TM in these patients, as well as increased thrombin-antithrombin complex (TAT), fibrinogen degradation products, t-PA, PAI-1, von Willebrand factor, and soluble P selectin.³ Elevated factor VIII has also been observed in CTEPH patients.^2,4 Hypercoagulability, shown as high fibrinogen, and decreased fibrinolysis, shown as low plasminogen, may exaggerate organization of thrombi.

In the present study, patients were classified into group A or B, but patients could be further subdivided into 4 categories using median fibrinogen and plasminogen as cut-offs (subgroup 1, lower fibrinogen and higher plasminogen; subgroup 2, lower fibrinogen and lower plasminogen; subgroup 3, higher fibrinogen and higher plasminogen; subgroup 4, higher fibrinogen and lower plasminogen [=group A]). Age, sex, modern PAH therapy, coagulopathy, APA-positive status, d-dimer, mPAP, cardiac index and PVR were compared in these 4 subgroups on chi-squared test or 1-way ANOVA followed by the Tukey-Kramer method. As a result, there was no significant difference in baseline clinical characteristics, except for significantly higher PVR in subgroup 4 (group A) compared with subgroup 1 or 3 (subgroup 1, PVR 8.83±4.49 WU; subgroup 2, 9.37±3.82 WU; subgroup 3, 9.16±4.33 WU; subgroup 4, 13.29±7.54 WU, 1-way ANOVA, P=0.028; Tukey-Kramer test: subgroup 1 vs. 4, P=0.047; subgroup 3 vs. 4, P=0.042; data not shown). There was a tendency for PVR to be the lowest in subgroup 1, intermediate in subgroups 2 and 3, and the highest in subgroup 4. Furthermore, on survival analysis, subgroup 4 had significantly decreased survival compared to the other subgroups (5-year survival: subgroup 1, 74.5%; subgroup 2, 100%; subgroup 3, 86.7%; subgroup 4, 35.3%; Figure S1).

Patients who had high fibrinogen (≥291 mg/dl, median) and low plasminogen (<101%, median) were less likely to be treated with modern PAH therapy (Group A; Table 4). Therefore, additional survival analysis was performed only in patients without modern PAH therapy, considering the effect of uneven distribution of use of modern PAH therapy (n=49). This analysis produced a similar result: that group A had a significantly lower survival than group B (5-year survival, 30.8% vs. 79.2%, log-rank test P<0.001; Figure S2B). It was difficult to compare survival rates only in patients under modern PAH therapy because of their low mortality (only 5 of 40 patients died; Figure S2A). The survival of group B, however, was better than that of group A even in patients with modern PAH therapy (5-year survival, 100% vs. 66.7%, log-rank test, P=0.198). Nishimura et al, at the present institution, recently reported that the use of modern PAH therapy was a significant predictor of increased survival.⁸ In the present study, on univariate analysis, modern PAH therapy was predictive of increased survival. Similarly, multivariate analysis indicated that plasma fibrinogen, plasma plasminogen, PVR and modern PAH therapy were all significant, independent prognostic factors for survival (Table 5). In the second analysis, however, groups A and B and PVR were significant independent prognostic factors for survival, but modern PAH therapy did not reach significance (Table 5). This suggests that classification into group A was a strong negative prognostic factor for survival. However, the use of modern PAH therapy could be important for survival. There were some differences in patient selection between the present study and the Nishimura et al study of the same cohort.⁸ First, in the present study only patients with data for plasma fibrinogen and plasminogen were selected. Second, the Nishimura et al study excluded patients with low PVR (<3.75 WU).⁸ Thus, in the present study, we performed additional multivariate analysis of modern PAH therapy, PVR, and group A and B only in patients with high PVR (>3.75 WU, n=84). As a result, PVR and group A and B maintained significance (HR, 1.135; 95% CI: 1.064–1.210, P<0.001; HR, 3.290; 95% CI: 1.312–7.991, P=0.012; respectively), and modern PAH therapy was also almost significant (HR, 0.385; 95% CI: 0.123–1.006, P=0.051), similar to the Nishimura et al study (data not shown).

We analyzed fibrinogen and plasminogen only in medically treated patients. Group A had significantly lower cardiac index and higher PVR than group B, even when all patients (as well as surgical cases) were included (cardiac index, 2.22±0.62 vs. 2.65±0.60 L·min^–1 ·m^–2, P<0.001; PVR, 12.91±6.34 vs. 9.87±4.12 WU, P=0.001), although there was no significant difference in operative mortality between groups A and B (6.7% vs. 13.9%, P=0.44; data not shown). Thus, group A may be associated with severe hemodynamics in CTEPH.

The present study had several limitations. First, it was a retrospective study. It remains unclear if increased plasma fibrinogen and decreased plasminogen are a cause or a result of CTEPH. Second, most of the present patients received anticoagulant therapy (on anticoagulant therapy, n=82; without anticoagulant therapy, n=1; unclear, n=6) and some received PAH therapy (beraprost sodium, n=21; bosentan, n=3; nothing, n=67) at the time that plasminogen and fibrinogen were measured. It is possible that these medications alter fibrinogen and plasminogen levels. For anticoagulant therapy, the proportion of patients within the therapeutic window for anticoagulant therapy (activated partial thromboplastin time ≥40 s, prothrombin time [PT]–international normalized ratio ≥1.5, or PT ≥18 s) was 75.3% at the time of blood sampling, but there was no significant difference in plasma fibrinogen and plasminogen levels between those patients within the therapeutic window or not (fibrinogen, 294.9±67.0 vs. 301.0±50.7 mg/dl; plasminogen, 99.0±15.5 vs. 100.1±11.7%; data not shown). Regarding PAH therapy, 22 patients out of 89 received PAH pretreatment, including bosentan or beraprost sodium, at the time of blood sampling. There were no significant differences, however, in plasma fibrinogen and plasminogen levels between patients with and without pretreatment (fibrinogen, 296.0±80.3 vs. 296.5±57.1 mg/dl; plasminogen, 98.4±17.1 vs. 99.5±13.8%; data not shown). Third, the levels of fibrinogen and plasminogen may vary during the course of treatment or in the natural course of CTEPH. Thus, the levels may depend on the time at which they are measured, but no significant correlation was observed between the duration of symptoms before diagnosis and plasma fibrinogen and plasminogen levels (duration of symptoms and fibrinogen, r=0.01, P=0.92; duration of symptoms and plasminogen, r=–0.10, P=0.37; data not shown). There were also no significant differences in the duration of symptoms based on median fibrinogen and plasminogen or between group A and B (Tables 2 – 4). Additionally, follow-up data on plasma fibrinogen and plasminogen levels were obtained in 44 of 89 patients in 4.4±4.0 years. There was no significant difference in plasma fibrinogen level between the time of diagnosis and follow-up (283.4±50.2 vs. 285.5±65.1 mg/dl, paired t-test not significant). Plasma plasminogen level at diagnosis was significantly higher than that at follow-up (98.7±13.7% vs. 92.7±17.4%, paired t-test P=0.027). There were no clear reports to show a time-dependent change in plasminogen level. Kostka et al showed that plasma plasminogen decreased with advancing age in an elderly population aged 65–79 years old.¹⁸ It is possible that we observed only the age-dependent natural course of plasma plasminogen level, but it was difficult to interpret this decrease because follow-up samples were not obtained at a predetermined time. Follow-up blood samples were more likely to be obtained either at hospitalization for medical treatment for exacerbation of CTEPH or right heart failure, or for assessing the therapeutic effects. Furthermore, we had few chances to obtain follow-up data for the patients with extremely poor prognosis. In order to clarify the relationship between CTEPH and the coagulation and fibrinolysis systems, accumulation of further evidence is needed.

Conclusions

High plasma fibrinogen and low plasminogen are associated with poor survival in inoperable CTEPH without modern PAH therapy. Long-term study is needed to investigate survival in a larger group of CTEPH patients with modern PAH therapy.

Acknowledgments

This study was supported in part by a grant to the Respiratory Failure Research Group from the Ministry of Health, Labor and Welfare of Japan (K.T.), and a research grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan (25461148) (N.T.).

Supplementary Files

Supplementary File 1

Figure S1. Kaplan-Meier survival estimates of patients with medically treated chronic thromboembolic pulmonary hypertension.

Figure S2. Kaplan-Meier survival estimates of patients with medically treated chronic thromboembolic pulmonary hypertension (A) with or (B) without modern pulmonary arterial hypertension (PAH) therapy.

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-13-1535

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