scholarly journals Coagulation Profiles of Pulmonary Arterial Hypertension Patients, Assessed by Non-Conventional Hemostatic Tests and Markers of Platelet Activation and Endothelial Dysfunction

Diagnostics ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 758
Author(s):  
Eleni Vrigkou ◽  
Argyrios E. Tsantes ◽  
Petros Kopterides ◽  
Stylianos E. Orfanos ◽  
Apostolos Armaganidis ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Endothelial Dysfunction ◽  
Arterial Hypertension ◽  
Platelet Activation ◽  
Light Transmission ◽  
Thromboxane A2 ◽  
Coagulation Cascade ◽  
Laboratory Findings ◽  
Hemostatic Tests ◽  
Pulmonary Arterial

Many pathophysiologic processes of pulmonary arterial hypertension (PAH), namely, excess vasoconstriction, vascular remodeling and in situ thrombosis, involve the coagulation cascade, and more specifically, platelets. The aim of this study was to globally assess coagulation processes in PAH, by using non-conventional hemostatic tests, along with markers of platelet activation and endothelial dysfunction. We studied 44 new PAH patients (22 with idiopathic PAH and 22 with connective tissue disease) and 25 healthy controls. The following tests were performed: platelet function analyzer-100 (PFA-100), light transmission aggregometry (LTA), rotational thromboelastometry (ROTEM), endogenous thrombin potential (ETP), serotonin, thromboxane A2 and p-selectin plasma levels, and von Willebrand antigen (VWF:Ag) and activity (VWF:Ac). Our results showed that PAH patients had diminished platelet aggregation, presence of disaggregation, defective initiation of the clotting process and clot propagation, and diminished thrombin formation capacity. Serotonin, thromboxane A2 and p-selectin levels were increased, and VWF:Ag and VWF:Ac decreased in the same population. The results of this study suggest that the platelets of PAH patients are activated and present functional abnormalities. The procoagulant activity, in general, appears to be impaired probably due to a sustained and prolonged activation of the procoagulant processes. Larger observational studies are warranted to confirm these laboratory findings.

Platelet activation markers in children with congenital heart disease associated with pulmonary arterial hypertension

2018 ◽  
Vol 13 (4) ◽  
pp. 506-511 ◽  
Author(s):  
Timur Mese ◽  
Baris Guven ◽  
Murat Muhtar Yilmazer ◽  
Cem Karadeniz ◽  
Rahmi Ozdemir ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Platelet Activation ◽  
Congenital Heart ◽  
Activation Markers ◽  
Pulmonary Arterial

Acute pulmonary arterial hypertension modeling in swine using a stable thromboxane A2 analogue (U46619): dose adjustment and assessment of hemodynamic reactions

2020 ◽  
Vol 170 (12) ◽  
pp. 709-714
Author(s):  
N. S. Goncharova ◽  
◽  
E. M. Andreeva ◽  
A. D. Vakhrushev ◽  
H. I. Condori Leandro ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Dose Adjustment ◽  
Thromboxane A2 ◽  
Pulmonary Arterial ◽  
Thromboxane A2 Analogue

scholarly journals Aberrant Chloride Intracellular Channel 4 Expression Contributes to Endothelial Dysfunction in Pulmonary Arterial Hypertension

Circulation ◽  
2014 ◽  
Vol 129 (17) ◽  
pp. 1770-1780 ◽  
Author(s):  
Beata Wojciak-Stothard ◽  
Vahitha B. Abdul-Salam ◽  
Ka Hou Lao ◽  
Hilda Tsang ◽  
David C. Irwin ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Endothelial Dysfunction ◽  
Arterial Hypertension ◽  
Pulmonary Arterial ◽  
Intracellular Channel

Peripheral Arterial Stiffness and Endothelial Dysfunction in Idiopathic and Scleroderma Associated Pulmonary Arterial Hypertension

2009 ◽  
Vol 36 (5) ◽  
pp. 970-975 ◽  
Author(s):  
NIR PELED ◽  
DAVID SHITRIT ◽  
BENJAMIN D. FOX ◽  
DEKEL SHLOMI ◽  
ANAT AMITAL ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Endothelial Dysfunction ◽  
Arterial Stiffness ◽  
Endothelial Function ◽  
Arterial Hypertension ◽  
Systolic Pressure ◽  
Vascular Involvement ◽  
Pulmonary Pressure ◽  
Pulmonary Arterial ◽  
Peripheral Arterial

Objective.Pulmonary endothelial dysfunction and increased reflection of pulmonary pressure waves have been reported in pulmonary arterial hypertension (PAH). However, the systemic vascular involvement is not fully understood. Our study focused on the systemic arterial stiffness and endothelial involvement in idiopathic and scleroderma associated PAH.Methods.Peripheral arterial stiffness and endothelial function were evaluated in 38 patients with idiopathic (n = 28) and scleroderma associated (n = 10) PAH, and 21 control subjects (13 healthy; 8 with scleroderma and normal pulmonary pressure). All participants underwent clinical and cardiopulmonary evaluation. Arterial stiffness was measured through the fingertip tonometry derived augmentation index (AI), which is the boost increase in the late systolic pressure wave after the initial systolic shoulder. Endothelial function was measured by forearm blood flow dilatation response to brachial artery occlusion by a noninvasive plethysmograph (EndoPAT 2000), which is associated with nitric oxide-dependent vasodilatation and yields a peripheral arterial tone (PAT) ratio.Results.Mean systolic pulmonary pressure was 70.5 ± 21.6 mm Hg (idiopathic-PAH) and 69.3 ± 20 mm Hg (scleroderma-PAH). AI was higher in scleroderma patients (10.5% ± 19.6% in healthy controls, 9.0% ± 21.5% in idiopathic-PAH, 20.1% ± 19.1% in scleroderma-PAH, and 24.4% ± 18.9% in scleroderma-controls; nonsignificant). PAT ratio was significantly lower (p < 0.05) than control values in idiopathic-PAH and scleroderma-PAH (PAT ratio: control 2.20 ± 0.25; idiopathic 1.84 ± 0.51; scleroderma 1.66 ± 0.66). AI was not correlated to endothelial dysfunction. There were no differences between the 2 PAH patient groups in age, body mass index, New York Heart Association classification, or 6-min walk test.Conclusion.Our study shows a trend towards increased arterial stiffness in scleroderma (nonsignificant), and also peripheral endothelial dysfunction in idiopathic-PAH and in scleroderma-PAH. These findings suggest involvement of different vessels in scleroderma-PAH compared to idiopathic-PAH.

scholarly journals Peripheral endothelial dysfunction in patients with pulmonary arterial hypertension

2008 ◽  
Vol 102 (12) ◽  
pp. 1791-1796 ◽  
Author(s):  
Nir Peled ◽  
Daniele Bendayan ◽  
David Shitrit ◽  
Ben Fox ◽  
Liora Yehoshua ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Endothelial Dysfunction ◽  
Arterial Hypertension ◽  
Pulmonary Arterial

scholarly journals The FGL2 prothrombinase contributes to the pathological process of experimental pulmonary hypertension

2019 ◽  
Vol 127 (6) ◽  
pp. 1677-1687
Author(s):  
Cheng Fan ◽  
Jue Wang ◽  
Chaoqin Mao ◽  
Wenzhu Li ◽  
Kun Liu ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arterial Hypertension ◽  
Endothelial Dysfunction ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Thrombus Formation ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Potential Therapeutic Target ◽  
Pulmonary Arterial

In situ thrombus formation is one of the major pathological features of pulmonary hypertension (PH). The mechanism of in situ thrombosis has not been clearly identified. Fibrinogen-like protein 2 (FGL2) prothrombinase is an immune coagulant that can cleave prothrombin to thrombin, which then converts fibrinogen into fibrin. This mechanism triggers in situ thrombus formation directly, bypassing both the intrinsic and extrinsic coagulation pathways. FGL2 prothrombinase is mainly expressed in endothelial cells and mediates multiple pathological processes. This implies that it may also play a role in PH. In this study, we examined the expression of FGL2 in idiopathic pulmonary arterial hypertension (IPAH) patients, and in monocrotaline-induced rat and hypoxia-induced mouse PH models. Fgl2−/− mice were used to evaluate the development of PH and explore associated pathological changes. These included in situ thrombosis, vascular remodeling, and endothelial apoptosis. Following these analyses, we examined possible signaling pathways downstream of FGL2 in PH. We show FGL2 is upregulated in pulmonary vascular endothelium in human IPAH and in two animal PH models. Genetic knockout of Fgl2 limited the development of PH, indicated by decreased in situ thrombus formation, less vascular remodeling, and reduced endothelial dysfunction. In addition, loss of FGL2 downregulated PAR1 (proteinase-activated receptor 1) expression and decreased the overactivation and consumption of platelets in hypoxia-induced PH. These results indicate FGL2 participate in the development of PH and loss of FGL2 could attenuate PH by reducing in situ thrombosis and suppressing PAR1 signaling. Thus we provide evidence that suggests FGL2 prothrombinase presents a potential therapeutic target for clinical treatment of PH. NEW & NOTEWORTHY This is the first study to demonstrate that fibrinogen-like protein 2 (FGL2) participates in the pathological progression of pulmonary hypertension (PH) in human idiopathic pulmonary arterial hypertension, a monocrotaline rat PH model, and a hypoxia mouse PH model. Genetic knockout of Fgl2 significantly limited the development of PH indicated by reduced in situ thrombosis, vascular remodeling, and endothelial dysfunction, and suppressed PAR1 (proteinase-activated receptor 1) signaling and overactivation of platelets on PH. These results suggest FGL2 presents a potential therapeutic target for clinical treatment of PH.

Platelets from Patients with Sickle Cell Disease and Pulmonary Arterial Hypertension Are Hypersensitive to Agonist-Induced Activation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1239-1239
Author(s):  
Jose D. Villagra ◽  
James T. Nichols ◽  
Mark T. Gladwin ◽  
Gregory J. Kato
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Arterial Hypertension ◽  
Sickle Cell Disease ◽  
Arterial Hypertension ◽  
Platelet Activation ◽  
Whole Blood ◽  
Cell Disease ◽  
Intravascular Hemolysis ◽  
Free Hemoglobin ◽  
Pulmonary Arterial

Abstract Pulmonary arterial hypertension (PAH) in sickle cell disease (SCD) is associated with chronic hemolysis and nitric oxide (NO) consumption and characterized by abnormal vascular tone, vascular proliferation and thrombosis. In previous studies, we demonstrated that increased platelet activation is linked to the severity of PAH in SCD. In addition, we reported that patients with SCD and secondary PAH have decreased platelet activation when given sildenafil, a finding that highlights the role of nitric oxide inhibition by hemolysis in this pathological mechanism. Since the vascular homeostasis is altered by the release of hemoglobin in plasma, we hypothesized that platelets of patients with PAH may show an enhanced degree of reactivity to platelet agonists released during hemolysis. Whole-blood samples were used to determine the in vivo baseline and stimulated platelet activation from SCD patients with PAH, without PAH during steady state (not in pain crisis) and healthy controls. PAH was defined by a tricuspid regurgitant jet velocity ≥ 2.5 m/sec by Doppler echocardiography. Upon withdrawal, citrated venous whole blood was mixed gently with either phosphate-buffered saline (PBS) or escalating doses (1 – 10 μM final concentration) of adenosine diphosphate (ADP), a platelet agonist present in red blood cells. Platelet activation was measured by the flow cytometry detection of activated fibrinogen receptors (activated GPIIb/IIIa) and surface expression of P-selectin. Patients with SCD and PAH reached high degrees of activation with significantly lower concentrations of ADP (EC50 0.88 μM, 95% confidence interval 0.64 to 1.23, n=5) compared to controls (1.3 μM, 1.00 to 1.64, p &lt; 0.01, n=8), and particularly to patients without PAH (1.7μM, 1.31 to 2.27, n=5)(Figure below, left panel). Similar results were observed in parallel experiments with thrombin-receptor activating peptide, another strong platelet agonist. In separate experiments on platelets from healthy subjects, the addition of cell-free plasma hemoglobin induced platelet activation in dose-dependent fashion (p&lt;0.05), supporting intravascular hemolysis as a mechanism of platelet activation in SCD (Figure below, right panel). Furthermore, cell-free hemoglobin blocked the ex vivo platelet inhibitory effects of an exogenous NO donor, MAHMANONOate (p&lt;0.05), consistent with NO scavenging by cell-free hemoglobin. These findings suggest that platelets from patients with SCD and PAH are unusually sensitive to activation. Our data also suggests that most of the variability in platelet hyperreactivity observed by other groups in SCD is primarily associated with PAH. Our data support a role for intravascular hemolysis and NO scavenging by cell-free hemoglobin in platelet hyperreactivity. Additional research is needed to define this mechanistic pathway in more detail. Figure Figure

scholarly journals Endothelial dysfunction in pulmonary arterial hypertension: an evolving landscape (2017 Grover Conference Series)

2017 ◽  
Vol 8 (1) ◽  
pp. 204589321775291 ◽  
Author(s):  
Benoît Ranchoux ◽  
Lloyd D. Harvey ◽  
Ramon J. Ayon ◽  
Aleksandra Babicheva ◽  
Sebastien Bonnet ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Endothelial Dysfunction ◽  
Arterial Hypertension ◽  
Molecular Mechanisms ◽  
Right Heart Failure ◽  
Vascular Pathology ◽  
Mesenchymal Transition ◽  
Conference Series ◽  
Major Player ◽  
Pulmonary Arterial

Endothelial dysfunction is a major player in the development and progression of vascular pathology in pulmonary arterial hypertension (PAH), a disease associated with small vessel loss and obstructive vasculopathy that leads to increased pulmonary vascular resistance, subsequent right heart failure, and premature death. Over the past ten years, there has been tremendous progress in our understanding of pulmonary endothelial biology as it pertains to the genetic and molecular mechanisms that orchestrate the endothelial response to direct or indirect injury, and how their dysregulation can contribute to the pathogenesis of PAH. As one of the major topics included in the 2017 Grover Conference Series, discussion centered on recent developments in four areas of pulmonary endothelial biology: (1) angiogenesis; (2) endothelial-mesenchymal transition (EndMT); (3) epigenetics; and (4) biology of voltage-gated ion channels. The present review will summarize the content of these discussions and provide a perspective on the most promising aspects of endothelial dysfunction that may be amenable for therapeutic development.

Pulmonary arterial hypertension in systemic sclerosis: Diagnosis and treatment according to the European Society of Cardiology and European Respiratory Society 2015 guidelines

2018 ◽  
Vol 4 (1) ◽  
pp. 35-42 ◽  
Author(s):  
Nicola Giordano ◽  
Claudio Corallo ◽  
Chiara Chirico ◽  
Angelica Brazzi ◽  
Adriana Marinetti ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Systemic Sclerosis ◽  
Pulmonary Arterial Hypertension ◽  
Endothelial Dysfunction ◽  
Arterial Hypertension ◽  
Correct Diagnosis ◽  
European Respiratory Society ◽  
Long Term Outcome ◽  
Screening Programs ◽  
Pulmonary Arterial

Scleroderma (systemic sclerosis) is an autoimmune connective tissue disease which presents endothelial dysfunction and fibroblast dysregulation, resulting in vascular and fibrotic disorders. Pulmonary hypertension is frequent in patients with systemic sclerosis: the natural evolution of the disease can induce the development of different forms of pulmonary hypertension, representing one of the main causes of death. Among the different forms of pulmonary hypertension in systemic sclerosis, pulmonary arterial hypertension is the most frequent one (rate of occurrence is estimated between 7% and 12%). This pulmonary vascular complication should be treated with a combination of drugs that is able to counteract endothelial dysfunction, antagonizing the endothelin-1 system and replacing prostaglandin I2 and nitric oxide activity. A correct diagnosis is mandatory, because it is possible only for pulmonary arterial hypertension to use specific drugs that are able to control the symptomatic condition and the evolution of the disease. According to the most recent guidelines, for the patients with systemic sclerosis, also without pulmonary hypertension symptoms, echocardiography screening for the detection of pulmonary hypertension is recommended. Pulmonary arterial hypertension screening programs in systemic sclerosis patients is able to identify milder forms of the disease, allowing earlier management and better long-term outcome.

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