Chest
Volume 110, Issue 3, September 1996, Pages 710-717
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clinical investigations
Coagulation and Fibrinolytic Profiles in Patients With Severe Pulmonary Hypertension

https://doi.org/10.1378/chest.110.3.710Get rights and content

Study objectives

Although in situ thrombosis is a prominent finding in lung vessels from patients with primary and secondary pulmonary hypertension, to our knowledge, plasma coagulation factors that might contribute to a hypercoagulable state have not been fully investigated. We hypothesized that the local coagulation environment in the lung vasculature is important to progression if not initiation of pulmonary hypertension.

Design

Quasi−experimental cross−sectional design with concurrent controls.

Setting

Referral clinics and inpatient services of a University Hospital and a Veterans Administration Medical Center.

Participants

To investigate the role of plasma coagulation factors in severe pulmonary hypertension, we sampled plasma from patients with primary pulmonary hypertension, patients with pulmonary hypertension secondary to a discernible etiology, and normal adult control subjects.

Results

We detected abnormalities of the thrombomodulin/protein C anticoagulant system, evidenced by a decrease in soluble thrombomodulin, in patients with primary pulmonary hypertension. In the patients with primary pulmonary hypertension, we found impaired fibrinolytic activity, with a rise in the fibrinolytic inhibitor plasminogen activator 1 and elevated euglobulin lysis time. Lower fibrinolytic activity correlated with high mean pulmonary artery pressure. In contrast, in patients with secondary pulmonary hypertension, von Willebrand factor antigen and fibrinogen levels were increased, and fibrinolytic activity decreased.

Conclusions

Different patterns of coagulation and fibrinolytic abnormalities are apparent in plasma from patients with primary and secondary pulmonary hypertension. Although we are unable to address causality with this study, we speculate that abnormalities of these coagulation mechanisms may initiate or play a role in perpetuation of pulmonary hypertension.

Section snippets

Population

We enrolled patients from University of Colorado Health Sciences Center, Denver Veterans Administration Medical Center, and normal control subjects. Patients with PPH were evaluated in the Pulmonary Hypertension Center at the University of Colorado Health Sciences Center. All potential PPH patients underwent right heart catheterization prior to enrollment and were carefully classified as having PPH after exclusion of other causes by history, radiography, ventilation perfusion scanning,

Results

Demographic characteristics of the patients are displayed in Table 1. The age of the subjects with pulmonary hypertension from secondary causes was significantly greater than for PPH patients or control subjects (p>0.01). There were no significant differences in smoking status or gender of subjects by χ2 analysis (Table 1).

Diseases associated with SPH included COPD (five patients), obstructive sleep apnea (four patients), obesity/hypoventilation (five patients), restrictive lung disease (two

Patient Hemodynamics

Thirteen of the 25 SPH and 12 of 12 PPH patients had complete hemodynamic data during right heart catheterization. There were clear differences in pulmonary vascular hemodynamics and respiratory parameters between the patients with PPH and SPH. Mean pulmonary artery pressure and pulmonary vascular resistance were significantly higher in the PPH group (Table 2). Systolic, but not mean, aortic pressures were higher in the SPH group. Spirometry values were lower for the group of patients with SPH.

Protein C/TM System

Plasma TM was significantly decreased in patients with PPH (p>0.02) compared to both control subjects and patients with SPH (Fig 2, Table 3). There was no difference in APC activity among groups, and there was no correlation between soluble TM and APC activity (Spearman rank coefficient p=0.12). Protein C and protein S levels were not lower than control in the PPH and SPH groups. The presence of APC resistance was similar among groups, with one third of subjects in each group, including control

Fibrinolytic Activity

ELT for patients with both PPH and SPH was significantly prolonged compared to that for control subjects (Fig 3). PAI−1 levels were significantly higher in PPH compared to SPH patients and control subjects (Fig 4). tPA levels were not different among groups, although there was a trend to elevation in the SPH group (Table 3; p=0.09). There were no differences in α2−antiplasmin or plasminogen among groups.

There was a linear correlation between loss of fibrinolytic activity and increased pulmonary

vWF Antigen and Activity

There were increased vWF antigen levels in the group with SPH compared to control subjects (Table 3, p>0.01). Ristocetin activity showed a trend to increase in the SPH group (Table 3, p=0.054). There was a disparity between vWF antigen levels and ristocetin activity for SPH patients with pulmonary hypertension, with significantly higher antigen vs activity levels (paired t test, p>0.05) for the SPH patients (190±19% vs 142±14%) but not control subjects (104±16% vs 105±10%) or the PPH group

Coagulation Activation Markers and Activation Inhibitors

There were no differences in F1.2 and TAT levels between groups (Table 3). Antithrombin III and tissue factor pathway inhibitor levels showed no differences among groups (Table 3). Tests of activation of coagulation (TAT, F1.2) failed to correlate with mean pulmonary artery pressure.

In 22 patients, clinical laboratory assays of bilirubin, serum glutamic oxaloacetic transaminase (SGOT), and uric acid were available for analysis. By linear regression analysis, vWF and tPA levels correlated with

Discussion

In situ thrombosis is a prominent finding in lung vessels from patients with PPH and SPH. Precise mechanisms of this finding are not defined, but likely include an altered procoagulant/fibrinolytic balance in the pulmonary circulation, with resultant thrombus formation. In this study, we investigated several aspects of coagulation in the plasma of three groups of subjects, patients with PPH and SPH, and normal control subjects: the protein C natural anticoagulant system, fibrinolytic activity,

Acknowledgments

The authors wish to acknowledge Kristinne Wynne for her help with patient recruitment and to Norbert F. Voelkel, MD, for his support.

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    This project was supported in part by a grant from the Department of Veterans Affairs (MERIT Review Grant to Dr. Marlar) and in part by the Pulmonary Hypertension Center at the University of Colorado Health Sciences Center.

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