Coagulation and fibrinolytic parameters in patients with pulmonary hypertension

Altman, Raúl; Scazziota, Alejandra; Rouvier, Jorge; Gurfinkei, Enrique; Favaloro, Roberto; Perrone, Sergio V.; Fareed, Jawed

doi:10.1002/clc.4960190706

Cited by 47 publications

(33 citation statements)

References 23 publications

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“…Increased antigenic concentration has been reported (8), while baseline activity of PAI-1 has been shown to be normal in these patients (7,8). In spite of previous observation of hypoxia-induced transcription of the PAI-1 gene in vascular endothelial cells (28), we failed to demonstrate any significant differences in baseline PAI-1 between the study groups and controls.…”

Section: Discussioncontrasting

confidence: 73%

“…Although previous studies have demonstrated abnormal endothelial function and altered coagulation and fibrinolysis in patients with pulmonary hypertension (6)(7)(8)(9)(10)(11)(12)(13)(14)(15), there are few reports focusing on endothelial dysfunction and intravascular coagulation in the particular setting of the Eisenmenger syndrome. Decreased plasma thrombomodulin has been observed in these patients, suggestive of decreased availability of this anticoagulant proteoglycan on the surface of endothelial cells (5,16).…”

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confidence: 99%

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Long-term Behavior of Endothelial and Coagulation Markers in Eisenmenger Syndrome

Caramurú

Lopes

Maeda

et al. 2006

Clin Appl Thromb Hemost

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The long-term behavior of endothelial markers was studied in patients with Eisenmenger syndrome who were subjected to conventional therapy (no vasodilators) and observed for 18 months. Biochemical markers were analyzed comparatively in patients with class II or III symptoms (group 1, n=10) and patients with class IV symptoms (group 2, n=7). Plasma von Willebrand factor antigen (vWF: Ag), thrombomodulin, tissue-type plasminogen activator (t-PA) and its inhibitor (PAI-1), and D-dimer were determined by immunoenzymatic assay at baseline, and at 6, 12, and 18 months. At baseline, the main clinical difference between groups was a decreased peripheral oxygen saturation in group 2 versus group 1 (77±5% and 86±4%, respectively, p=0.001). Basal vWF: Ag and t-PA were increased and thrombomodulin was decreased in both groups in comparison with controls (p<0.0001), while D-dimer was increased in group 2 only (p=0.0003). In response to treatment, there was a decrease in vWF: Ag in both groups (19% and 23%, respectively in groups 1 and 2, at 18 months vs. baseline, p<0.0001) and t-PA in group 1 (38% vs. baseline, p=0.0485). Plasma vWF: Ag tended to be higher in group 2 in comparison with group 1 during the whole follow-up. Levels of PAI-1 greater than 38.4 ng/mL (upper 90% limit for normals) and D-dimer greater than 500 ng/mL were detected in individual patients (both groups) during the follow-up period. Thrombomodulin remained decreased in both groups. Thus, severity of symptoms in the Eisenmenger syndrome appears to correlate with low oxygen saturation and higher vWF: Ag levels. Improvement of endothelial dysfunction may occur in response to treatment, although increased risk for thrombosis persists, in view of residual abnormalities.

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Section: Discussioncontrasting

confidence: 73%

mentioning

confidence: 99%

Long-term Behavior of Endothelial and Coagulation Markers in Eisenmenger Syndrome

Caramurú

Lopes

Maeda

et al. 2006

Clin Appl Thromb Hemost

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“…In humans, increased pulmonary expression of TF, an increase in TF-bearing microparticles, and a decrease in circulating forms of TFPI have been noted (26,27). TF is also expressed in pulmonary plexiform-like lesions in humans and in a rat model of severe pulmonary hypertension (28,29).…”

mentioning

confidence: 99%

Tissue Factor Pathway Inhibitor Overexpression Inhibits Hypoxia-Induced Pulmonary Hypertension

White

Witt

Pan

et al. 2010

Am J Respir Cell Mol Biol

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Pulmonary hypertension (PH) is a commonly recognized complication of chronic respiratory disease. Enhanced vasoconstriction, pulmonary vascular remodeling, and in situ thrombosis contribute to the increased pulmonary vascular resistance observed in PH associated with hypoxic lung disease. The tissue factor pathway regulates fibrin deposition in response to acute and chronic vascular injury. We hypothesized that inhibition of the tissue factor pathway would result in attenuation of pathophysiologic parameters typically associated with hypoxia-induced PH. We tested this hypothesis using a chronic hypoxia-induced murine model of PH using mice that overexpress tissue factor pathway inhibitor (TFPI) via the smooth muscle-specific promoter SM22 (TFPI SM22 ). TFPI SM22 mice have increased pulmonary TFPI expression compared with wild-type (WT) mice. In WT mice, exposure to chronic hypoxia (28 d at 10% O 2 ) resulted in increased systolic right ventricular and mean pulmonary arterial pressures, changes that were significantly reduced in TFPI SM22 mice. Chronic hypoxia also resulted in significant pulmonary vascular muscularization in WT mice, which was significantly reduced in TFPI SM22 mice. Given the pleiotropic effects of TFPI, autocrine and paracrine mechanisms for these hemodynamic effects were considered. TFPI SM22 mice had less pulmonary fibrin deposition than WT mice at 3 days after exposure to hypoxia, which is consistent with the antithrombotic effects of TFPI. Additionally, TFPI SM22 mice had a significant reduction in the number of proliferating (proliferating cell nuclear antigen positive) pulmonary vascular smooth muscle cells compared with WT mice, which is consistent with in vitro findings. These findings demonstrate that overexpression of TFPI results in improved hemodynamic performance and reduced pulmonary vascular remodeling in a murine model of hypoxia-induced PH. This improvement is in part due to the autocrine and paracrine effects of TFPI overexpression.

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“…These mechanisms are mediated by 1 or more molecular and cellular processes, including the following: reduced prostacyclin availability caused by diminished endothelial cell prostacyclin synthase activity 25 ; elevated endothelin levels resulting from enhanced production and reduced pulmonary clearance [26][27][28] ; decreased nitric oxide synthase expression 29,30 ; elevated plasma levels and low platelet 5-hydoxytryptamine levels 31 ; down-regulation of voltage-gated potassium (eg, Kv1.5) channels of pulmonary vascular smooth muscle cells 32,33 ; activity of autoantibodies and proinflammatory cytokines 34,35 ; and prothrombotic states arising from endothelial, coagulation, and fibrinolytic cascade and platelet dysfunction. [36][37][38][39] These abnormalities give rise to a predisposition to vasoconstriction over vasodilation of the pulmonary vascu-FIGURE 1. The 3 mechanistic pathways known to be disturbed in patients with pulmonary arterial hypertension (PAH).…”

Section: Molecular and Cellular Mechanismsmentioning

confidence: 99%

Pulmonary Hypertension: Diagnosis and Management

McGoon

Kane

2009

Mayo Clinic Proceedings

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Pulmonary arterial hypertension is a progressive, symptomatic, and ultimately fatal disorder for which substantial advances in treatment have been made during the past decade. Effective management requires timely recognition and accurate diagnosis of the disorder and appropriate selection among therapeutic alternatives. Despite progress in treatment, obstacles remain that impede the achievement of optimal outcomes. The current article provides an overview of the pathobiologic mechanisms of pulmonary arterial hypertension, including genetic substrates and molecular and cellular mechanisms, and describes the clinical manifestations and classification of pulmonary arterial hypertension. The article also reviews established approaches to evaluation and treatment, with emphasis on the appropriate application of calcium channel blockers, prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase 5 inhibitors. In addition, the authors discuss unresolved issues that may complicate patient management, such as the clinical importance of mild or exercise-related pulmonary arterial hypertension, and they identify avenues by which treatment may advance in the future through the use of combination treatment, outcomes assessment, and exploration of alternative pharmacologic strategies. Mayo Clin Proc. 2009;84(2):191-2075-HTT = 5-hydroxytryptamine transporter; BMPR2 = bone morphogenetic protein receptor, type II; FDA = Food and Drug Administration; IPAH = idiopathic pulmonary arterial hypertension; mPAP = mean pulmonary arterial pressure; PAH = pulmonary arterial hypertension; PASP = pulmonary arterial systolic pressure; PCWP = pulmonary capillary wedge pressure; PDE5 = phosphodiesterase 5; PH = pulmonary hypertension; TGF-β β β β β = transforming growth factor β β β β β; WHO = World Health Organization T he diagnosis, management, and pathobiologic mechanisms of pulmonary arterial hypertension (PAH) have been of intense interest during the past decade, in large part because of the development of effective treatments that have enhanced the outcome for patients. In the absence of effective treatments, patients with PAH had a median life expectancy of only 2.8 years. Current approaches to the evaluation and management of PAH and to the understanding of the underlying pathophysiologic mechanisms of this condition have been well outlined in recent reviews.

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Coagulation and fibrinolytic parameters in patients with pulmonary hypertension

Cited by 47 publications

References 23 publications

Long-term Behavior of Endothelial and Coagulation Markers in Eisenmenger Syndrome

Long-term Behavior of Endothelial and Coagulation Markers in Eisenmenger Syndrome

Tissue Factor Pathway Inhibitor Overexpression Inhibits Hypoxia-Induced Pulmonary Hypertension

Pulmonary Hypertension: Diagnosis and Management

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