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Continuous Infusion of Prostacyclin Normalizes Plasma Markers of Endothelial Cell Injury and Platelet Aggregation in Primary Pulmonary Hypertension

Originally published 1997;96:2782–2784


    Background Primary pulmonary hypertension (PPH) is characterized by vascular injury of pulmonary arterioles, in which endothelial dysfunction may play a major role. Although continuous infusion of prostacyclin (prostaglandin I2, a potent vasodilator released by vascular endothelial cells) improves the clinical status and survival in PPH, its mechanism or mechanisms of action remain unclear.

    Methods and Results We measured endothelium-derived clotting factors and assayed platelet aggregation in 64 patients (26 adults and 38 children) with PPH before long-term PGI2 therapy. Repeat studies were performed in 42 patients (18 adults, 24 children) after one year of PGI2 therapy. At baseline, 87% of adults and 79% of children had abnormal platelet aggregation. In addition, factor VIII, von Willebrand (vW) antigen, and ristocetin cofactor levels were abnormally high in 92%, 72%, and 52%, respectively, of the adults versus 29%, 16%, and 16%, respectively, of the children (P<.005 adults versus children). With long-term PGI2, platelet aggregation normalized in 83% of the adults and 80% of the children who had platelet aggregation abnormalities at baseline (P<.01). Factor VIII, vW antigen, and ristocetin cofactor also decreased with long-term PGI2 in both groups (P<.02). The ratio of ristocetin cofactor to vW antigen, which may reflect biological activity of vW factor, increased with long-term PGI2 in adults from an abnormally low level (0.6±0.2) to normal level (1.1±0.4), and in children the ratio increased from 0.8±0.3 to 1.3±0.4 (normal, 0.8 to 1.4).

    Conclusions Alterations in the coagulation system may contribute to the pathogenesis of PPH; the normalization of these endothelial markers concomitant with improvement in hemodynamic parameters with long-term PGI2 suggests that long-term PGI2 remodels the pulmonary vascular bed with subsequent decreases in endothelial cell injury and hypercoagulability.

    PPH is characterized by progressive elevation of pulmonary artery pressure and vascular resistance that leads to right ventricular failure and death.1 Histopathological studies demonstrate a marked heterogeneity of pulmonary vascular lesions, with coexistence of thrombotic and plexiform lesions.2 Although the cause or causes remain unknown, endothelial dysfunction and abnormalities in platelet/endothelial cell interactions have been implicated in its pathogenesis and pathophysiology.1 The reduced excretion in patients with PPH of a stable metabolite of PGI2, a potent vasodilator released by vascular endothelial cells, suggests that dysfunctional endothelial responses occur in PPH.3 Continuous infusion of PGI2 has resulted in clinical and hemodynamic improvement as well as increased survival.4 In addition, significant hemodynamic improvements have been demonstrated in patients in whom no significant changes occurred with acute PGI2 administration.5 These data suggest that the beneficial effects of PGI2 may be due to effects other than as a vasodilator (ie, remodeling of the pulmonary vascular bed and subsequent attenuation of hypercoagulation). The objectives of this study were to determine abnormalities in the endothelium-derived clotting factors (factor VIII and vW factor) and platelet aggregation in patients with PPH as well as to evaluate the effects of continuous infusion of PGI2 on these parameters. We looked at both children and adults because histopathological and acute vasodilator studies suggest that children have a more reactive pulmonary vascular bed and possibly less endothelial dysfunction.6,7


    After giving informed consent, 64 patients with PPH were evaluated; the study group consisted of 26 adults (37±12 years old; PAPm, 62±15 mm Hg; CI, 2.7±1.6 L · min−1 · M · 2) and 38 children (9±4 years; mean pulmonary artery pressure, 75±24 mm Hg; cardiac index, 3.7±1.9 L · min−1 · m−2). The diagnosis of PPH was made in all patients on the basis of the criteria of the National Institutes of Health Registry on Primary Pulmonary Hypertension.8 At baseline, before the start of long-term PGI2 therapy, all patients underwent right-heart cardiac catheterization, and levels of factor VIII, vW antigen, and vW ristocetin cofactor were measured. The ratio of ristocetin cofactor to vW antigen was also calculated to reflect the biological activity of vW factor. Platelet aggregation was evaluated with collagen, ADP, epinephrine, and ristocetin. Aggregation was considered abnormal if the response to one or more of the aggregating agents was abnormal. After 1 year of PGI2 therapy, right-heart cardiac catheterization and coagulation assays were repeated in 42 patients (18 adults and 24 children). Results are reported as mean±SD for continuous variables and as prevalence for categorical variables. The significance of changes from baseline for continuous variables was assessed by paired t test. Changes in categorical variables were tested using McNamar’s tests. The relationship between clotting factors and hemodynamic variables was tested using Pearson’s correlation when the variables were continuous and Spearman’s correlation when any of the variables were categorical. Because of the large number of associations examined, a value of P=.01 was used for significance.


    The baseline abnormalities in coagulation factors and platelet aggregation are shown in Table 1. Factor VIII and vW antigen levels were abnormally high (>150% for factor VIII and >130% for vW antigen) in 92% (24 of 26) and 72% (18 of 25), respectively, of adult patients versus 29% (11 of 38) and 16% (6 of 38), respectively, of the children (P<.001 for adults versus children). Ristocetin cofactor values, which are used to measure vW antigen function, were abnormally high (>120%) in 52% (13 of 25) of adults versus 16% (6 of 37) of the children (P<.005 for adults versus children). The ratio of ristocetin cofactor to vW antigen was below the normal range in 84% of adults versus 54% of children (P<.05 for adults versus children). A low ratio suggests defective circulating vW molecules. Liver-derived clotting factors did not show any significant abnormalities. Platelet aggregation studies demonstrated significant abnormalities in both adults (87%) and children (79%): the platelet response to the agonists ex vivo was depressed.

    After 1 year of intravenous PGI2 therapy, factor VIII, vW antigen, and ristocetin cofactor decreased in both the adults and children (Table 2). In addition, the ratio of ristocetin cofactor to vW antigen increased in adults from an abnormally low level to normal, and in the children the ratio increased as well, although the ratio was only at the lower limits of normal before the start of long-term PGI2 therapy. Abnormalities in platelet aggregation normalized in 83% of the adults and 80% of the children with long-term PGI2. Despite concomitant improvement in hemodynamic parameters and endothelial function markers in all patients with long-term PGI2 (Table 2), the only significant correlations were the improvement in platelet aggregation and decrease in pulmonary artery pressure (P<.005) and the improvement in the ratio of ristocetin cofactor to vW antigen and decrease in pulmonary artery pressure (P<.01).


    Although the role of endothelial dysfunction in PPH remains unclear, improvement in endothelial cell function appears to parallel the clinical improvement observed in patients receiving a continuous infusion of PGI2. The observed difference in adults versus children may reflect a greater degree of endothelial damage in adults, which is consistent with previous studies suggesting greater medical hypertrophy and pulmonary vasoreactivity concomitant with less intimal damage in children versus adults.6,7 In our study, despite high levels of circulating vW antigen, baseline ristocetin cofactor levels were elevated but not to the extent of the other two clotting factors (factor VIII and vW factor). In addition, they fell largely within normal range in both the adults and children. Decreased function of vW factor may be the clinical manifestation of altered multimeric composition described previously.9-11 Calculation of the ratio of ristocetin cofactor to vW antigen quantifies this observation of decreased function. Although differences in levels of factor VIII, vW antigen, and ristocetin cofactor between adults and children before PGI2 therapy were significant, platelet aggregation abnormalities were detected in a very high percentage in both groups. This suggests that the etiology of the platelet aggregation abnormalities may be independent of the clotting factor alterations. The observation that the platelet response to the agonists ex vivo was depressed is consistent with platelet activation in vivo.12,13 Furthermore, in vivo platelet activation may contribute to the increased thromboxane metabolites reported in patients with PPH.3 With long-term PGI2, factor VIII, vW antigen, and ristocetin cofactor levels decreased and/or normalized in most patients. In addition, the ratio of ristocetin cofactor to vW antigen normalized in 82% of patients. Repeat platelet aggregation studies with long-term PGI2 normalized in >80% of patients in whom platelet aggregation studies were abnormal at baseline. This normalization of platelet activation ex vivo suggests an improvement in in vivo platelet function concomitant with the improvement in vascular injury.

    Our data are consistent with two previous studies suggesting that long-term PGI2 therapy in PPH results in remodeling of the pulmonary vascular bed.14,15 These data support the hypothesis that endothelial cell injury and dysfunction initiate and/or exacerbate the pulmonary vascular disease in PPH. Furthermore, these alterations in the coagulation system make contribute to the pathogenesis of PPH by promoting a prothrombotic state, and the normalization of these endothelial cell markers with long-term PGI2 suggests that long-term PGI2 allows remodeling of the pulmonary vascular bed with subsequent decrease in endothelial cell injury and hypercoagulability. We speculate that this biological normalization is induced by the effects of PGI2 on vascular growth, remodeling, hypercoagulation, and platelet function, in addition to its vasodilator actions. Further studies are needed to disclose the involvement and significance of these biological derangements in the pathogenesis and pathophysiology of PPH. Recognition of the impact of endothelial dysfunction should lead to therapeutic interventions that are capable of improving endothelial function and ultimately benefiting patients with PPH.

    Selected Abbreviations and Acronyms

    PGI2=prostacyclin (prostaglandin I2)
    PPH=primary pulmonary hypertension
    vW=von Willebrand

    Presented at the American College of Cardiology 46th Annual Scientific Session, 19 March 1997, Anaheim, Calif.

    Table 1. Baseline Clotting Factors, Platelet Aggregation Studies, and Hemodynamic Parameters

    All Patients (n=64)Adults (n=26)Children (n=38)
    Endothelial function markers
    Factor VIII, %156±74201±68125±62
    vW antigen, %143±97213±10696±52
    vW ristocetin cofactor, %85±31103±2373±30
    Ratio, (ristocetin cofactor:vW antigen)0.7±0.30.6±0.20.8±0.3
    Platelet aggregation abnormalities, % patients1828779
    Hemodynamic parameters
    PAPm, mm Hg70±2162±1575±24
    RAPm, mm Hg8 ±712±85±4
    CI, L · min−1 · m23.2±1.82.7±1.63.7±1.9
    PVRI, U · m226±1427±1424±14
    MV sat, %60±1254±1264±10

    PAPm indicates mean pulmonary artery pressure; RAPm, mean right atrial pressure; CI, cardiac index; PVRI, pulmonary vascular resistance index; and MV sat, mixed venous oxygen saturation.

    1Sample size for platelet aggregation studies: adults, n=23; children, n=26.

    Values are mean±SD.

    Table 2. Effects of Long-term Prostacyclin Administration on Clotting Factors, Platelet Aggregation Studies, and Hemodynamic Parameters

    All Patients (n=42)Adults (n=18)Children (n=24)
    Endothelial function markers
    Factor VIII, %1169±8196±53226±364134 ±364138±7275±32
    vW antigen, %2136±8956 ±50184±12884±7798±4342±21
    wV ristocetin cofactor, %384±2558±3497±2169±3677 ±2652±31
    Ratio (ristocetin cofactor:vW antigen)20.8 ±0.31.2±0.40.6±0.21.1±0.50.9±0.31.3±0.4
    Hemodynamic parameters
    PAPm, mm Hg273±2355±2067±1655±1578±2655 ±21
    RAPm, mm Hg7±67±511±78±55 ±36±4
    CI, L · min−1 · m233.3±1.84.9±2.62.8±1.74.4 ±2.23.6±1.85.3±2.8
    PVRI, U · m2227±1512±828±1413±926 ±1612±7
    MV sat, %360±1068±757 ±1164±762±871±6

    Abbreviations as in Table 1; follow-up after 1 year on long-term PGI2.

    1P<.0005 vs baseline,

    2P<.005 vs baseline, and

    3P<.02 vs baseline (for each group at follow-up vs baseline).

    This study was supported in part by grant RR-00645 from the National Institutes of Health, National Center for Research Resources. The authors thank Robert R. Sciacca, EngScD, for statistical analyses.


    Correspondence to Dr Robyn J. Barst, Columbia University College of Physicians & Surgeons, 3959 Broadway, BHN 2-262, New York, NY 10032.


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