Abstract:• Untargeted and targeted metabolomics showed association of low plasma acylcarnitines levels with venous thrombosis risk.• Long-chain acylcarnitines are anticoagulants that inhibit factor Xa by binding to factor Xa outside the g-carboxy glutamic acid domain.In many patients with deep vein thrombosis and pulmonary embolism (venous thromboembolism, VTE), biomarkers or genetic risk factors have not been identified. To discover novel plasma metabolites associated with VTE risk, we employed liquid chromatography-m… Show more
“…A variety of minor abundance soluble plasma lipids manifest either procoagulant or anticoagulant properties by affecting thrombin generation (Figure 2A). Biochemical studies of plasma lipids and thrombin generation show that functionally important lipid binding sites are located on factor Xa outside its N-terminal Gla-domain 32,33 (Factor 2B) which historically has been to only region on factor Xa widely accepted to bind lipids. Thus, the canonical paradigm for clot- Table S2) might act to regulate inflammatory events such as cell proliferation at the same time they act to alter thrombin generation.…”
Section: Discussionmentioning
confidence: 99%
“…Studies that challenged the widely accepted, simple paradigm for PL‐Gla‐domain lipid effects on prothrombinase structure and activity involved synthetic, soluble dicaproyl‐PS that was reported to promote prothrombinase activity by binding to factor Xa outside the Gla‐domain (Figure B) . Similarly, recent publications both extend and challenge the simple classical paradigm for PL‐Gla‐domain‐factor Xa interactions because it was shown that several plasma lipids carried by lipoproteins or proteins such as albumin and/or lipid binding proteins (e.g, sphingosine, sphinganine, acyl‐carnitines [ACs], and lyso‐sulfatide [LSF]), so called “soluble” lipids, bind factor Xa and alter its procoagulant activity (Figure B), supporting and extending the challenge of the classical, simple paradigm for lipid‐clotting factor interactions. In summary, innovative findings show that certain, minor abundance plasma lipids can bind directly to factor Xa outside the Gla domain and modulate thrombin generation by the prothrombinase complex (Figure B), leading to an expanded framework for the paradigm for lipid‐clotting factor interactions …”
Section: Thrombosis Blood Coagulation and Thrombin Generationmentioning
confidence: 99%
“…In summary, innovative findings show that certain, minor abundance plasma lipids can bind directly to factor Xa outside the Gla domain and modulate thrombin generation by the prothrombinase complex ( Figure 2B), leading to an expanded framework for the paradigm for lipid-clotting factor interactions. 32,33 F I G U R E 1 Blood coagulation and protein C pathways. Thrombin is the major product of the blood coagulation pathways involving sequential enzymatic activations of serine protease zymogens enhanced by nonenzymatic cofactors, factors Va and VIIIa.…”
Section: Imbalances Of Thrombin Generation Caused By Imbalances In Plmentioning
confidence: 99%
“…When the association of VTE with GlcCer and PE levels was studied, VTE was associated with plasma GlcCer deficiency but not with any changes in PE plasma levels. 40 Sphingosine 0-70 nmol/L 2.5 [31] Lysosulfatide~5 μmol/L 4 [32] Long-chain acylcarnitine 1-2 μmol/L 5-10 [33] PEA, SEA, AEA 1-6 nmol/L 0.0002 [59] The Table summarizes phosphatidylserine. 56 Their plasma levels can reach 1.5, 35, 1.5, and 1.6 μmol/L in acute coronary syndrome patients.…”
Section: Clinical Associationmentioning
confidence: 99%
“…Total long-chain ACs (acyl chains >10 carbons) circulate in plasma, with reported concentrations ranging between 1 and 4 μmol/L, 33,[80][81][82] and their levels can reach to 10-30 μmol/L under certain metabolic conditions. [83][84][85][86] Long-chain ACs are lipid metabolites with a hydrophobic side chain and a free amine like sphingosine (Figure 4), but they belong to the long-chain AC family which plays an important role in energy metabolism through mitochondrial β-oxidation of fatty acids.…”
Summary
Different minor abundance plasma lipids significantly influence thrombin generation in vitro and significant differences in such lipids are linked to risk for venous thrombosis. Some plasma sphingolipids including glucosylceramide, lyso-sulfatide and sphingosine have anticoagulant properties whereas, conversely, some plasma phospholipid derivatives, including certain lyso-phospholipids and ethanolamides, have procoagulant properties. Plasma metabolite profiling of venous thrombosis patients showed association of venous thrombosis with decreased plasma long-chain acylcarntines, leading to discovery of their anticoagulant activity as inhibitors of factor Xa. Inhibition of factor Xa by acylcarnitines does not require the protein’s Gla-domain, emphasizing an expanded framework for the paradigm for lipid-clotting factor interactions. Overall, whether by genetics or environment, alterations in the dynamics of lipid metabolism linked to an altered lipidome may contribute to regulation of blood coagulation because imbalances between physiologic procoagulant and anticoagulant lipids may contribute to excessive thrombin generation that augments risk for thrombosis.
“…A variety of minor abundance soluble plasma lipids manifest either procoagulant or anticoagulant properties by affecting thrombin generation (Figure 2A). Biochemical studies of plasma lipids and thrombin generation show that functionally important lipid binding sites are located on factor Xa outside its N-terminal Gla-domain 32,33 (Factor 2B) which historically has been to only region on factor Xa widely accepted to bind lipids. Thus, the canonical paradigm for clot- Table S2) might act to regulate inflammatory events such as cell proliferation at the same time they act to alter thrombin generation.…”
Section: Discussionmentioning
confidence: 99%
“…Studies that challenged the widely accepted, simple paradigm for PL‐Gla‐domain lipid effects on prothrombinase structure and activity involved synthetic, soluble dicaproyl‐PS that was reported to promote prothrombinase activity by binding to factor Xa outside the Gla‐domain (Figure B) . Similarly, recent publications both extend and challenge the simple classical paradigm for PL‐Gla‐domain‐factor Xa interactions because it was shown that several plasma lipids carried by lipoproteins or proteins such as albumin and/or lipid binding proteins (e.g, sphingosine, sphinganine, acyl‐carnitines [ACs], and lyso‐sulfatide [LSF]), so called “soluble” lipids, bind factor Xa and alter its procoagulant activity (Figure B), supporting and extending the challenge of the classical, simple paradigm for lipid‐clotting factor interactions. In summary, innovative findings show that certain, minor abundance plasma lipids can bind directly to factor Xa outside the Gla domain and modulate thrombin generation by the prothrombinase complex (Figure B), leading to an expanded framework for the paradigm for lipid‐clotting factor interactions …”
Section: Thrombosis Blood Coagulation and Thrombin Generationmentioning
confidence: 99%
“…In summary, innovative findings show that certain, minor abundance plasma lipids can bind directly to factor Xa outside the Gla domain and modulate thrombin generation by the prothrombinase complex ( Figure 2B), leading to an expanded framework for the paradigm for lipid-clotting factor interactions. 32,33 F I G U R E 1 Blood coagulation and protein C pathways. Thrombin is the major product of the blood coagulation pathways involving sequential enzymatic activations of serine protease zymogens enhanced by nonenzymatic cofactors, factors Va and VIIIa.…”
Section: Imbalances Of Thrombin Generation Caused By Imbalances In Plmentioning
confidence: 99%
“…When the association of VTE with GlcCer and PE levels was studied, VTE was associated with plasma GlcCer deficiency but not with any changes in PE plasma levels. 40 Sphingosine 0-70 nmol/L 2.5 [31] Lysosulfatide~5 μmol/L 4 [32] Long-chain acylcarnitine 1-2 μmol/L 5-10 [33] PEA, SEA, AEA 1-6 nmol/L 0.0002 [59] The Table summarizes phosphatidylserine. 56 Their plasma levels can reach 1.5, 35, 1.5, and 1.6 μmol/L in acute coronary syndrome patients.…”
Section: Clinical Associationmentioning
confidence: 99%
“…Total long-chain ACs (acyl chains >10 carbons) circulate in plasma, with reported concentrations ranging between 1 and 4 μmol/L, 33,[80][81][82] and their levels can reach to 10-30 μmol/L under certain metabolic conditions. [83][84][85][86] Long-chain ACs are lipid metabolites with a hydrophobic side chain and a free amine like sphingosine (Figure 4), but they belong to the long-chain AC family which plays an important role in energy metabolism through mitochondrial β-oxidation of fatty acids.…”
Summary
Different minor abundance plasma lipids significantly influence thrombin generation in vitro and significant differences in such lipids are linked to risk for venous thrombosis. Some plasma sphingolipids including glucosylceramide, lyso-sulfatide and sphingosine have anticoagulant properties whereas, conversely, some plasma phospholipid derivatives, including certain lyso-phospholipids and ethanolamides, have procoagulant properties. Plasma metabolite profiling of venous thrombosis patients showed association of venous thrombosis with decreased plasma long-chain acylcarntines, leading to discovery of their anticoagulant activity as inhibitors of factor Xa. Inhibition of factor Xa by acylcarnitines does not require the protein’s Gla-domain, emphasizing an expanded framework for the paradigm for lipid-clotting factor interactions. Overall, whether by genetics or environment, alterations in the dynamics of lipid metabolism linked to an altered lipidome may contribute to regulation of blood coagulation because imbalances between physiologic procoagulant and anticoagulant lipids may contribute to excessive thrombin generation that augments risk for thrombosis.
This study analyzed a lipidomic profile of platelets from blood stasis rats by liquid chromatography‐tandem mass spectrometry. The blood stasis rat was established by low‐dose continuous subcutaneous injection of adrenaline, and the evaluation indexes included hemorheology and platelet aggregation. Principal component analysis and partial least‐squares discriminant analysis were used to analyze platelet lipidomics, and p‐value < 0.05, fold change > 1.5, and variable importance plot > 2 were used to screen potential biomarkers. Then, the biomarkers were optimized by the receiver operating characteristic curve. Compared with the normal rat, the blood stasis model group's whole blood viscosity and platelet aggregation rate were also significantly increased at different shear rates (p < 0.05). Twenty‐four potential lipid biomarkers showed significant changes in platelets between the two groups. Among them, six long‐chain acylcarnitine components and three sphingosine components showed a consistent downward trend, suggesting that these two kinds of components may play an essential role in the process of platelet aggregation. Liquid chromatography‐tandem mass spectrometry‐based lipidomics studies provide much information to understand the pathology of platelets in blood stasis.
Venous thromboembolism (VTE) is a major cause of morbidity and mortality. The impact of the Surgeon General's Call to Action in 2008 has been lower than expected given the public health impact of this disease. This scientific statement highlights future research priorities in VTE, developed by experts and a crowdsourcing survey across 16 scientific organizations. At the fundamental research level (T0), researchers need to identify pathobiologic causative mechanisms for the 50% of patients with unprovoked VTE and better understand mechanisms that differentiate hemostasis from thrombosis. At the human level (T1), new methods for diagnosing, treating, and preventing VTE will allow tailoring of diagnostic and therapeutic approaches to individuals. At the patient level (T2), research efforts are required to understand how foundational evidence impacts care of patients (eg, biomarkers). New treatments, such as catheter-based therapies, require further testing to identify which patients are most likely to experience benefit. At the practice level (T3), translating evidence into practice remains challenging. Areas of overuse and underuse will require evidence-based tools to improve care delivery. At the community and population level (T4), public awareness campaigns need thorough impact assessment. Large population-based cohort studies can elucidate the biologic and environmental underpinings of VTE and its complications. To achieve these goals, funding agencies and training
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