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Endocardial Endothelial Dysfunction Progressively Disrupts Initially Anti then Pro-Thrombotic Pathways in Heart Failure Mice.

Schoner A, Tyrrell C, Wu M, Gelow JM, Hayes AA, Lindner JR, Thornburg KL, Hasan W - PLoS ONE (2015)

Bottom Line: An experimental model of endocardial thrombosis has not been developed and endocardial endothelial dysfunction in heart failure (HF) is understudied.Endocardial thrombi incidence was confirmed with immunohistochemistry and histology.Attenuation of the anti-coagulant APC pathway promotes endocardial thrombosis in early and acute decompensated phases of HF.

View Article: PubMed Central - PubMed

Affiliation: Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, United States of America.

ABSTRACT

Objective: An experimental model of endocardial thrombosis has not been developed and endocardial endothelial dysfunction in heart failure (HF) is understudied. We sought to determine whether disruption of the endothelial anti-coagulant activated protein C (APC) pathway in CREBA133 HF mice promotes endocardial thrombosis in the acute decompensated phase of the disease, and whether alterations in von Willebrand factor (vWF) secretion from HF endocardium reduces thrombus formation as HF stabilizes.

Approach and results: Echocardiography was used to follow HF development and to detect endocardial thrombi in CREBA133 mice. Endocardial thrombi incidence was confirmed with immunohistochemistry and histology. In early and acute decompensated phases of HF, CREBA133 mice had the highest incidence of endocardial thrombi and these mice also had a shorter tail-bleeding index consistent with a pro-thrombotic milieu. Both APC generation, and expression of receptors that promote APC function (thrombomodulin, endothelial protein C receptor, protein S), were suppressed in the endocardium of acute decompensated HF mice. However, in stable compensated HF mice, an attenuation occurred for vWF protein content and secretion from endocardial endothelial cells, vWF-dependent platelet agglutination (by ristocetin), and thrombin generation on the endocardial surface.

Conclusions: CREBA133 mice develop HF and endocardial endothelial dysfunction. Attenuation of the anti-coagulant APC pathway promotes endocardial thrombosis in early and acute decompensated phases of HF. However, in stable compensated HF mice, disruptions in endothelial vWF expression and extrusion may actually reduce the incidence of endocardial thrombosis.

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Related in: MedlinePlus

Tail clot assay (A) and platelet aggregometry (B-D) in wildtype, all HF (HF), early HF, acute HF, and chronic HF mice.The bleeding index, reflecting time to clot and total blood loss, is decreased in early and acute HF mice compared to wildtype and chronic HF mice (A; p<0.005). Platelet aggregation with ADP is similar across all groups (B). In contrast, platelet agglutination with ristocetin is attenuated overall in HF mice (p<0.05; representative trace in C, data in D), particularly in acute HF mice.
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pone.0142940.g005: Tail clot assay (A) and platelet aggregometry (B-D) in wildtype, all HF (HF), early HF, acute HF, and chronic HF mice.The bleeding index, reflecting time to clot and total blood loss, is decreased in early and acute HF mice compared to wildtype and chronic HF mice (A; p<0.005). Platelet aggregation with ADP is similar across all groups (B). In contrast, platelet agglutination with ristocetin is attenuated overall in HF mice (p<0.05; representative trace in C, data in D), particularly in acute HF mice.

Mentions: The bleeding index, reflecting time to clot and total blood loss, showed a significant decrease in clotting time in early and acute HF mice (77%) compared to wildtype mice (Fig 5A), consistent with a pro-thrombotic phenotype in these mice. Platelet aggregation with adenosine-5'-diphosphate (ADP) was similar between all groups of mice (Fig 5B). However, vWF-dependent platelet agglutination with ristocetin (Fig 5C and 5D) was lower in both acute (70%) and chronic (49%) HF mice.


Endocardial Endothelial Dysfunction Progressively Disrupts Initially Anti then Pro-Thrombotic Pathways in Heart Failure Mice.

Schoner A, Tyrrell C, Wu M, Gelow JM, Hayes AA, Lindner JR, Thornburg KL, Hasan W - PLoS ONE (2015)

Tail clot assay (A) and platelet aggregometry (B-D) in wildtype, all HF (HF), early HF, acute HF, and chronic HF mice.The bleeding index, reflecting time to clot and total blood loss, is decreased in early and acute HF mice compared to wildtype and chronic HF mice (A; p<0.005). Platelet aggregation with ADP is similar across all groups (B). In contrast, platelet agglutination with ristocetin is attenuated overall in HF mice (p<0.05; representative trace in C, data in D), particularly in acute HF mice.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4643996&req=5

pone.0142940.g005: Tail clot assay (A) and platelet aggregometry (B-D) in wildtype, all HF (HF), early HF, acute HF, and chronic HF mice.The bleeding index, reflecting time to clot and total blood loss, is decreased in early and acute HF mice compared to wildtype and chronic HF mice (A; p<0.005). Platelet aggregation with ADP is similar across all groups (B). In contrast, platelet agglutination with ristocetin is attenuated overall in HF mice (p<0.05; representative trace in C, data in D), particularly in acute HF mice.
Mentions: The bleeding index, reflecting time to clot and total blood loss, showed a significant decrease in clotting time in early and acute HF mice (77%) compared to wildtype mice (Fig 5A), consistent with a pro-thrombotic phenotype in these mice. Platelet aggregation with adenosine-5'-diphosphate (ADP) was similar between all groups of mice (Fig 5B). However, vWF-dependent platelet agglutination with ristocetin (Fig 5C and 5D) was lower in both acute (70%) and chronic (49%) HF mice.

Bottom Line: An experimental model of endocardial thrombosis has not been developed and endocardial endothelial dysfunction in heart failure (HF) is understudied.Endocardial thrombi incidence was confirmed with immunohistochemistry and histology.Attenuation of the anti-coagulant APC pathway promotes endocardial thrombosis in early and acute decompensated phases of HF.

View Article: PubMed Central - PubMed

Affiliation: Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, United States of America.

ABSTRACT

Objective: An experimental model of endocardial thrombosis has not been developed and endocardial endothelial dysfunction in heart failure (HF) is understudied. We sought to determine whether disruption of the endothelial anti-coagulant activated protein C (APC) pathway in CREBA133 HF mice promotes endocardial thrombosis in the acute decompensated phase of the disease, and whether alterations in von Willebrand factor (vWF) secretion from HF endocardium reduces thrombus formation as HF stabilizes.

Approach and results: Echocardiography was used to follow HF development and to detect endocardial thrombi in CREBA133 mice. Endocardial thrombi incidence was confirmed with immunohistochemistry and histology. In early and acute decompensated phases of HF, CREBA133 mice had the highest incidence of endocardial thrombi and these mice also had a shorter tail-bleeding index consistent with a pro-thrombotic milieu. Both APC generation, and expression of receptors that promote APC function (thrombomodulin, endothelial protein C receptor, protein S), were suppressed in the endocardium of acute decompensated HF mice. However, in stable compensated HF mice, an attenuation occurred for vWF protein content and secretion from endocardial endothelial cells, vWF-dependent platelet agglutination (by ristocetin), and thrombin generation on the endocardial surface.

Conclusions: CREBA133 mice develop HF and endocardial endothelial dysfunction. Attenuation of the anti-coagulant APC pathway promotes endocardial thrombosis in early and acute decompensated phases of HF. However, in stable compensated HF mice, disruptions in endothelial vWF expression and extrusion may actually reduce the incidence of endocardial thrombosis.

Show MeSH
Related in: MedlinePlus