Interruption of vascular thrombus formation and vascular lesion formation by dietary n-3 fatty acids in fish oil in nonhuman primates.

Harker, Laurence A.; Kelly, Andrew B.; Hanson, Stephen R.; Krupski, William C.; Bass, Arie; Østerud, Bjarne; Ga, FitzGerald; Goodnight, Scott H.; Connor, William E.

doi:10.1161/01.cir.87.3.1017

Cited by 97 publications

(35 citation statements)

References 77 publications

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“…Omega-3 fatty acids are thought to increase bleeding time and suppress thrombosis through COX-1-dependent generation of bioactive lipids that have platelet inhibitory actions (Fig. 5D) (36,37). Our data indicate that DHA-containing PE is less able to support thrombin generation, indicating a unique mechanism for the anti-coagulant actions of this lipid, unrelated to eicosanoid generation.…”

Section: -4 and Si Results)mentioning

confidence: 79%

Characterization of platelet aminophospholipid externalization reveals fatty acids as molecular determinants that regulate coagulation

Clark

Thomas

Hammond

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Aminophospholipid (APL) trafficking across the plasma membrane is a key event in cell activation, apoptosis, and aging and is required for clearance of dying cells and coagulation. Currently the phospholipid molecular species externalized are unknown. Using a lipidomic method, we show that thrombin, collagen, or ionophoreactivated human platelets externalize two phosphatidylserines (PSs) and five phosphatidylethanolamines (PEs). Four percent of the total cellular PE/PS pool (∼300 ng/2 × 10 8 cells, thrombin), is externalized via calcium mobilization and protease-activated receptors-1 and -4, and 48% is contained in microparticles. Apoptosis and energy depletion (aging) externalized the same APLs in a calciumdependent manner, and all stimuli externalized oxidized phospholipids, termed hydroxyeicosatetraenoic acid-PEs. Transmembrane protein-16F (TMEM-16F), the protein mutated in Scott syndrome, was required for PE/PS externalization during thrombin activation and energy depletion, but not apoptosis. Platelet-specific APLs optimally supported tissue factor-dependent coagulation in human plasma, vs. APL with longer or shorter fatty acyl chains. This finding demonstrates fatty acids as molecular determinants of APL that regulate hemostasis. Thus, the molecular species of externalized APL during platelet activation, apoptosis, and energy depletion were characterized, and their ability to support coagulation revealed. The findings have therapeutic implications for bleeding disorders and transfusion therapy. The assay could be applied to other cell events characterized by APL externalization, including cell division and vesiculation.

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Section: -4 and Si Results)mentioning

confidence: 79%

Characterization of platelet aminophospholipid externalization reveals fatty acids as molecular determinants that regulate coagulation

Clark

Thomas

Hammond

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…In patients receiving EPA, adhesion of platelets to the vessel wall was reported to be markedly reduced. 24 In addition, it has been reported that EPA can inhibit thrombosis, 25 augment endothelial cell-dependent vasodilatation through nitric oxide and PG, 26 increase nitric oxide production by endothelial cells, 27 and increase the production and release of endothelium-derived relaxing factor that has a local antiplatelet effect in the vascular wall. 28 Because of these properties, EPA may have prevented vascular endothelial dysfunction after BMT, thus significantly decreasing the levels of indicators of such dysfunctions like thrombomodulin and PAI-1 in the EPA group.…”

Section: Discussionmentioning

confidence: 99%

Oral eicosapentaenoic acid for complications of bone marrow transplantation

Takatsuka

Takemoto

Iwata

et al. 2001

Bone Marrow Transplant

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Summary:The 'systemic inflammatory response syndrome' (SIRS) may represent the underlying cause of complications after bone marrow transplantation (BMT). This study was conducted to determine whether blocking the etiologic factors of SIRS could improve the complications of BMT. Sixteen consecutive patients with unrelated donors were allocated alternately to two groups. Seven patients received 1.8 g/day of eicosapentaenoic acid (EPA) orally from 3 weeks before to about 180 days after transplantation, while nine patients did not. These two groups were compared with respect to complications, survival, and various cytokines and factors causing vascular endothelial damage. All seven patients receiving EPA survived and only two had grade III graft-versus-host disease (GVHD). Among the nine patients not receiving EPA, three had grade III or IV GVHD. In addition, thrombotic microangiopathy developed in four patients and cytomegalovirus disease occurred in four. Five patients died in this group. The levels of leukotriene B 4 , thromboxane A 2 , and prostaglandin I 2 were significantly lower in patients receiving EPA than in those not receiving it (all P Ͻ 0.01). Cytokines such as tumor necrosis factor-␣, interferon-␥, and interleukin-10 were also significantly decreased by EPA (P Ͻ 0.05), as were factors causing vascular endothelial damage such as thrombomodulin and plasminogen activator inhibitor-1 (P Ͻ 0.05). The survival rate was significantly higher in the group given EPA (P Ͻ 0.01). EPA significantly reduced the complications of BMT, indicating that these complications may be manifestations of the systemic inflammatory response syndrome. Bone Marrow Transplantation (2001) 28, 769-774.

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“…23 Recently it has been demonstrated that dietary administration of fish oil to nonhuman primates impairs TF expression by endotoxin-stimulated mononuclear cells. 24 In this study we demonstrate that supplementa-tion with n-3 fatty acids enriched in eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids to healthy volunteers and to hypertriglyceridemic patients reduces TF activity generation in adherent monocytes in the unstimulated condition as well as after stimulation with endotoxin.…”

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confidence: 86%

n-3 fatty acid ethyl ester administration to healthy subjects and to hypertriglyceridemic patients reduces tissue factor activity in adherent monocytes.

Tremoli

Eligini

Colli

et al. 1994

Arterioscler Thromb

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n-3 Fatty acids are known to influence several functions of monocytes, including adhesion, cytokine synthesis, and superoxide generation. Monocytes express tissue factor, a membrane-bound grycoprotein, that acts as a catalyst in the coagulation cascade. In this study we evaluated the effects of administration of n-3 fatty acid ethyl esters to healthy volunteers and to hypertriglyceridemic patients on tissue factor activity (TF activity) in adherent monocytes. n-3 Fatty acids containing 75% eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (ratio of EPA to DHA, 1.34) were administered (3 g/d) to normal volunteers for 18 weeks. In addition, the effects of this treatment were evaluated in 30 hypertriglyceridemic patients for 24 weeks by using a doubleblind, placebo-controlled study. TF activity in adherent monocytes was evaluated with a one-stage clotting assay. Plasma and monocyte fatty acid compositions were determined by gasliquid chromatography. In healthy volunteers, n-3 fatty acids significantly reduced TF activity in adherent monocytes either E pidemiological and interventional studies suggest that consumption of fish or fish oil containing elevated levels of n-3 poh/unsaturated fatty acids confers protection against ischemic heart disease.

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Interruption of vascular thrombus formation and vascular lesion formation by dietary n-3 fatty acids in fish oil in nonhuman primates.

Cited by 97 publications

References 77 publications

Characterization of platelet aminophospholipid externalization reveals fatty acids as molecular determinants that regulate coagulation

Characterization of platelet aminophospholipid externalization reveals fatty acids as molecular determinants that regulate coagulation

Oral eicosapentaenoic acid for complications of bone marrow transplantation

n-3 fatty acid ethyl ester administration to healthy subjects and to hypertriglyceridemic patients reduces tissue factor activity in adherent monocytes.

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