Primary pulmonary hypertension

Background: D-dimer, a degradation product of fibrin, has been increasingly used as a marker or prognostic factor in various thrombotic diseases.

Objective: To assess the significance of a d-dimer test in patients with primary pulmonary hypertension (PPH).

Patients and methods: Fourteen patients with PPH (12 women and 2 men) aged 25 to 68 years (mean [+ or -] SD age, 50 [+ or -] 14 years) entered the study. Plasma d-dimer was determined by Miniquant assay (Biopool International; Venture, CA) 3 [+ or -] 5 months after the disease onset, and patients were followed up for 1 year. We compared the d-dimer levels to the demographic, clinical, and hemodynamic data of the patients.

Results: D-dimer levels were positively correlated with New York Heart Association classification (r = 0.59, p = 0.01) and pulmonary artery pressure (r = 0.43, p = 0.03) and were negatively correlated with oxygen saturation (r = -0.45, p = 0.03) and 6-min walk distance (r = - .49, p = 0.04). One-year survival was also negatively correlated with d-dimer (point-biserial r = -0.71, p = 0.004), with a higher d-dimer value associated with poorer survival. No significant correlations were found between d-dimer values and sex, age, diffusing capacity of the lung for carbon monoxide, or cardiac index.

Conclusion: D-dimer levels may have a role in the evaluation of patients with PPH. This simple, noninvasive test may be helpful for identifying patients who are at a higher risk for severe disease. (CHEST 2002; 122:1674-1678)

Key words: cardiac index; d-dimer; 6-min walk test; New York Heart Association; primary pulmonary hypertension; pulmonary artery pressure

Abbreviations: CI = cardiac index; DLCO = diffusing capacity of the lung for carbon monoxide; NYHA = New York Heart Association; PAP = pulmonary artery pressure; PPH = primary pulmonary hypertension; SAT = oxygen saturation at rest

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Primary pulmonary hypertension (PPH) is a rare condition characterized by sustained elevations of pulmonary arterial pressure (PAP) without a demonstrable cause. The disorder causes significant morbidity and mortality, with a mean survival time of 2.8 years after diagnosis for patients who do not undergo heart-lung transplantation. (1-5) Although the pathogenesis of the increased vascular resistance in PPH remains unknown, vasoconstriction, vascular wall remodeling, and thrombosis in situ are all considered possible etiologies. (2,6-8)

In situ thrombosis is a prominent finding in lung vessels from patients with PPH. (8-13) It may result from injury to the endothelium, abnormal fibrinolysis, enhanced procoagulant activity, and platelet abnormalities. (5,14-16) Welsh et al (8) found coagulation activity that correlated with high mean PAP. A similar tendency has also been observed by Eisenberg et al. (7) The latter also found increased levels of fibrinopeptide A, a marker of thrombin action on fibrinogen in patients with PPH. All these finding suggest that there is a persistent activity of thrombin in patients with PPH.

D-dimer assay, a specific marker for cross-linked fibrin, is often used as a marker for disseminated intravascular coagulation. (17-20) In patients without evidence of coagulopathy, the d-dimer may represent mierovascular thrombosis. (19,20) Therefore, we hypothesized that the d-dimer level might be associated with the seventy of PPH. We measured d-dimer levels in 14 patients with PPH and compared these values to their demographic, clinical, and hemodynamic data.

MATERIALS AND METHODS

Population

The study group consisted of 14 patients with PPH evaluated at the Rabin Medical Center, Beilinson Campus, between June 2000 and October 2001. All patients met the National Institutes of Health registry guidelines for the diagnosis of PPH. None had a history of pulmonary thromboembolism or deep vein thrombosis, and all had a ventilation-perfusion lung scan finding negative or low probability for pulmonary thromboembolism. All patients treated with anticoagulation at doses adjusted to achieve an international normalized ratio of approximately 1.5 to 2.5. No changes in warfarin doses were made during the 14 days prior to commencement of the study. All patients were treated also with prostacyclin. Seven patients were treated with IV continuous epoprostenol (prostacyclin), two patients received intermittent prostaglandin [E.sub.2] (Iloprost: Schering; Berlin, Germany) 5 days per month, and five patients received continuous subcutaneous UT-15 (United Therapeutics; Research Triangle Park, NC), a prostacyclin analog. The d-dimer blood test was performed 3 [+ or -] 5 months after disease onset. Patients who underwent recent surgery and patients with acute infection 1 month prior to the study period were excluded. After initial laboratory determinations, the patients were followed up for 1 year. Study protocols were approved by the institutional human subjects review board.

Sample Collection and Analysis

After obtaining informed consent, 4 mL of blood were collected in 3.2% buffered sodium citrate and centrifuged at 3,000 revolutions per minute for 15 min within 4 h after collection. Platelet-poor plasma was divided and then frozen at -70[degrees]C for analysis. Prior to analysis, all samples were thawed and re-centrifuged. Plasma fibrin d-dimer was assayed as recommended by the kit manufacturer using the commercial kits and assay (Miniquant d-dimer; Biopool International; Venture, CA). Each specimen batch was assayed together with controls purchased from the manufacturer.

Data Collection

Data were obtained from all subjects regarding demographic, clinical, pulmonary, and hemodynamic variables, including age, sex, functional capacity according to the New York Heart Association (NYHA) classification, 6-min walk test, diffusing capacity of the lung for carbon monoxide (DLCO), PAP, cardiac index (CI), oxygen saturation at rest (SAT), and survival during the follow-up period. All the hemodynamic variables and pulmonary function tests were collected at the time of obtaining the d-dimer tests.

Statistical Analysis

Associations between dependent and independent variables were computed using the Kendall [tau]-b correlation coefficient. The Kendall [tau]-b, which measures the association between rank orders of variables, is not limited by the constraints of normality required for the Pearson correlation coefficient, and thus may lie used for nonparametric quantitative and ordered category data. It is the preferred correlation coefficient for small data sets with tied ranks, and may provide a better estimate of correlation in the population than other coefficients. A point-biserial correlation coefficient was computed for the dichotomous variable survival. Analyses were performed using SPSS for Windows (Release 10.0.5; SPSS; Chicago, IL). All reported p values are two-tailed, and values < 0.05 were considered statistically significant.

RESULTS

Fourteen patients with PPH entered the study. Table 1 shows the demographic, clinical, pulmonary, and hemodynamic characteristics of the patients. Twelve patients were young women. Nine patients had NYHA class III or IV symptoms. Four patients had low SAT ([less than or equal to] 90%). DLCO was decreased in 10 patients, with a mean of 57 [+ or -] 17%. Mean 6-min walk score was 373 [+ or -] 102 m (range, 219 to 572 m), while three patients with advanced disease could not perform the test. Mean PAP value was 71.4 [+ or -] 27.2 mm Hg. Mean CI was 1.98 [+ or -] 0.83 L/min/[m.sup.2]. During 1 year of follow-up, three patients died (21.4%). Mean d-dimer level was 1,620 [+ or -] 2,120 [micro]g/L (range, 20 to 6,200 [micro]g/L).

Correlation of d-dimer Levels With Study Variables

Correlation coefficients for the study variables are presented in Table 2 and Figure 1. NYHA classification (r = 0.59, p = 0.01) and PAP (r = 0.43, p = 0.03) were found to be positively correlated with d-dimer values, indicating that higher d-dimer values were associated with higher values for these variables (Fig 1). SAT (r = -0.45, p = 0.03) and 6-rain walk distance (r = -0.49, p = 0.04) were found to be negatively correlated with d-dimer values, indicating that higher d-dimer, values were associated with lower values for these variables (Fig 1). One-year survival was also negatively correlated with d-dimer (point-biserial r = -0.71, p = 0.004), with a higher d-dimer value associated with poorer survival. No significant correlations were found between d-dimer values and sex, age, DLCO, or CI levels.

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DISCUSSION

This study demonstrates that high d-dimer levels are associated with the status of disease severity in patients with PPH, as measured by NYHA classification, SAT, PAP, and survival. Prognosis in PPH is determined by several factors; the severity of right ventricular dysfunction is among the most important. Indeed, hemodynamic parameters such as CI, right atrial pressure, and PAP, which are closely related to right ventricular performance, have been used as indicators of prognosis in PPH. (21,22) Miyamoto et al (23) found that the 6-min walk test has a strong, independent association with mortality in PPH by multivariate analysis; no significant correlation was found, however, between the 6-min walk test and the PAP.

Laboratory Markers and Disease Severity

Several studies also showed correlation between laboratory markers and the severity of PPH. Lopes and Maeda (24) found correlation between plasma von Willebrand factor antigen, a marker of endothelial cell dysfunction and survival in PPH. Nagaya et al (25) found correlation between serum uric acid, the final product of purine degradation, and the severity and mortality rate of PPH. Nagaya et al (26) also found that the plasma brain natriuretic peptide level increases in proportion to the degree of dysfunction in PPH. Treatment with prostacyclin led to a significant decrease of plasma brain natriuretic peptide during follow-up. Another study found that urinary cyclic guanosine monophosphate, which is commonly raised in patients with congestive heart failure, correlates closely with hemodynamic parameters and disease severity in patients with PPH. (27)

Clinical outcome data suggest that thrombosis is important in the pathophysiologic state of PPH. Anticoagulant therapy is thought to benefit patients with PPH based on both a retrospective study of 120 patients, in which those receiving anticoagulant therapy with warfarin lived longer (28) and the PPH registry in which those who received warfarin, in addition to a calcium channel blocker, had improved survival. (29) More directly, pathologic examination supports a role for thrombosis in PPH. In PPH, autopsy studies show that one third to one half of cases classified as primary plexogenic arteriopathy show features of in situ thrombosis. (30)

D-dimer is a marker that effectively determines the presence of stabilized fibrin and thus the presence of microvascular thrombosis. Recently, we found significantly high d-dimer levels in patients with PPH, compared with matched healthy control subjects. (31) In this study, we have demonstrated that d-dimer is also associated with the severity of disease and serves as a prognostic marker.

It will be interesting also to see whether d-dimer decreases following treatment. These data may help in the future to follow up patient responses to therapies involving the coagulation system.

Our results should, however, be interpreted with caution, in view of the small number of patients in the study. We believe that a larger study would have shown an association of d-dimer with additional study variables such as CI.

This study supports the possibility that in situ thrombosis is a predominant etiology of PPH. Moreover, our findings suggest that d-dimer test may also have a role in the evaluation of patients with PPH. We believe that this simple, noninvasive test may be helpful in identifying patients who are at a higher risk for poor prognosis, although these results should be confirmed in larger study population.

* From the Pulmonary Institute (Drs. Shitrit, Bendayan, Fink, and Kramer), Rabin Medical Center, Petach-Tiqwa, Israel; and Internal Medicine (Drs. Huerta and Bar-Gil-Shitrit) and Department of Clinical Laboratories (Dr. Rudensky), Shaare-Zedek Medical Center, Jerusalem, Israel.

REFERENCES

(1) D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension: results from a national prospective registry. Ann Intern Med 1991; 115:34:3-349

(2) Farber HW, Loscalzo J. Prothrombotic mechanisms in primary pulmonary hypertension. J Lab Clin Med 1999; 134: 561-566

(3) Hassell KL. Altered hemostasis in pulmonary hypertension. Blood Coagul Fibrinolysis 1998; 9:107-117

(4) Chaouate A, Weitzenblum E, Higenbottam T. The role of thrombosis in severe pulmonary hypertension. Eur Respir j 1996; 9:356-363

(5) Glies F. Endothelial dysfunction providing the basis for the treatment of pulmonary hypertension. Chest 1998; 114:72S-79S

(6) Rich S. Clinical insights into the pathogenesis of primary pulmonary hypertension. Chest 1998; 114:237S-241S

(7) Eisenberg PR, Lurcore C, Kaufman L, et al. Fibrinopeptide A levels indicative of pulmonary vascular thrombosis in patients with primary pulmonary hypertension. Circulation 1990; 82:841-847

(8) Welsh CH, Hassell KL, Badesch DB, et al. Coagulation and fibrinolytic profiles in patients with severe pulmonary hypertension. Chest 1996; 110:710-717

(9) Rubin L. Primary pulmonary hypertension. Chest 1993; 104:236-250

(10) Fuster V, Steele PM, Edwards WD, et al. Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation 1984; 70:580-587

(11) Levy PS, Kaufmann E, Rich S. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992; 327:76-81

(12) Rubin LJ. Primary pulmonary hypertension: N Engl J Med 1997; 336:111-117

(13) Quinn DA, Fogel RB, Smith CD, et al. D-dimer in the diagnosis of pulmonary embolism. Am J Respir Crit Care Med 1999; 159:1445-1449

(14) Wagenvoort CA, Mulder GH. Thrombotic lesions in primary plexogenic arteriopathy. Chest 1993; 103:844-849

(15) Voelkel NF, Tuder RM, Weir EK. Pathophysiology of primary pulmonary hypertension: from physiology to molecular mechanisms. In: Rubin LJ, Rich S, eds. Primary pulmonary hypertension. New York, NY: Marcel Dekker, 1997; 83-133

(16) Inglesby TV, Singer Jw, Gordon DS. Abnormal fibrinolysis in familial pulmonary hypertension. Am J Med 1973; 55:5-14

(17) Carey MJ, Rodgers GM. Disseminated intravascular coagulation: clinical and laboratory aspects. Am J Hematol 1998; 59:65-73

(18) Francis CW, Marder VJ, Barlow GH. Plasmin degradation of crosslinked fibrin. J Clin Invest 1980; 33:1033-1043

(19) Rowbothanl BJ, Marder VJ, Barlow GH. Measurment of crosslinked fibrin in diagnosis of venous thrombosis. Thromb Haemost 1987; 57:59-61

(20) Bonnanleaux H, de Moerloose P, Perrier A, et al. Plasma measurement of D-dimer as diagnosis aid in suspected venous thromboembolism: overview. Thromb Haemost 1994; 71:1-6

(21) Rich S, Levy PS. Characteristics of surviving and nonsurviving patients with primary pulmonary hypertension. Am J Med 1984; 76:573-578

(22) McGoon MD. Prognosis and natural history. In: Rubin LJ, Rich S, eds. Primary pulmonary hypertension. New York, NY: Marcel Dekker, 1997; 305-317

(23) Miyamoto S, Nagaya N, Satoh T, et al. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension: comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Meal 2000; 161:487-492

(24) Lopes AAB, Maeda NY. Circulating yon Willebrand factor antigen as a predictor of short-term prognosis in pulmonary hypertension. Chest 1998:114:1276-1282

(25) Nagaya N, Uematsu M, Satoh T, et al. Serum uric acid correlate with the severity and the mortality of primary pulmonary hypertension. Am J Respir Crit Care Med 1999; 160:487-492

(26) Nagaya N, Nishikimi T, Uematsu M, et al. Plasma brain natriuremic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation 2000; 102:865-870

(27) Bogdan M, Humbert M, Francoual J, et al. Urinary cGMP concentrations in severe primary pulmonary hypertension. Thorax 1998; 53:1059-1062

(28) Fuster V, Steele PM, Edwards WD, et al. Primary pulmonary hypertension: natural history and importance of thrombosis. Circulation 1984; 70:580-587

(29) Rich S, Kaufmann E, Levy PS. The effect of the high doses of calcium channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992; 327:76-81

(30) Wagenvoort CA, Wagenvoot N. Primary pulmonary hypertension: a pathologic study of the lung vessels in 156 clinically diagnosed cases. Circulation 1970; 42:1163-1184

(31) Shitrit D, Bendayan D, Rudensky B, et al. Elevation of ELISA D-dimer levels in patients with primary pulmonary hypertension. Respiration 2002; 69:327-329

Manuscript received January 15, 2002; revision accepted May 24, 2002.

Correspondence to: Mordechai R. Kramer, MD, FCCP, Pulmonary Institute, Rabin Medical Center, Beilinson Campus, Petach Tiqwa 49100, Israel; e-mail: pulm@netvision.net.il

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