Minor Plasma Lipids Modulate Clotting Factor Activities and May Affect Thrombosis Risk

Abstract

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.

Keywords: Venous Thromboembolism; blood coagulation; lipids; phospholipids; sphingolipids; thrombin.

Figure 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.14, 15 Thrombin is generated by the “prothrombinase” complex which is formed by binding of factor Xa to factor Va on a phospholipid (PL) surface in the presence of Ca²⁺ ions. Small amount of thrombin can be generated by tissue factor with activation of factors VII and X via the extrinsic pathway or following activation of factors XI, VIII, IX, and X via the intrinsic pathway. Once generated, thrombin activates platelets and factor V, factor VIII, and factor XI, thereby stimulating multiple steps in the intrinsic pathway and amplifying thrombin generation. For negative feedback downregulation of thrombin generation, thrombin generates the potent anticoagulant, activated protein C (APC), when it is bound to thrombomodulin (TM) and protein C (PC) is bound to the endothelial protein C receptor (EPCR)16

Figure 2

Plasma lipids can exert procoagulant or anticoagulant activity. (A) Thrombin generation balance. Anticoagulant and procoagulant physiologic plasma lipids of minor abundance can alter the balance for thrombin generation and altered levels of some of these lipids are found in VTE patients. (B) Lipid modulators of factor Xa. The physiologic plasma sphingolipids, long chain acylcarnitines and lyso‐sulfatide, are anticoagulant and bind to factor Xa whereas the synthetic lipid, dicaproyl‐PS (C6PS), is prothrombotic. In a potential paradigm shift for how lipids regulate factor Xa activity, the factor Xa region that binds anticoagulant long chain acylcarnitines and LSF is not the Gla domain. In contrast, sphingosine inhibition of factor Xa requires its Gla‐domain. Color highlighting indicates whether a particular lipid inhibits thrombin generation (blue) or enhances thrombin generation (pink). PEA, palmitoyl‐ethanolamide; SEA, stearoyl‐ethanolamide; and AEA, arachidonoyl‐ethanolamide

Figure 3

Lipid metabolic regulation on coagulation system. The dynamic metabolic balances among various sphingolipid and phospholipid metabolites may be shifted by a variety of factors and influences, and such changes in the relative concentrations of sphingolipids or phospholipids might regulate inflammatory events such as cell proliferation and also might down‐regulate blood coagulation and thrombin generation. A variety of enzymes that regulate sphingolipid metabolism are capable of shifting the balance between sphingosine and ceramide, sphingosine and sphingosine‐1‐phosphate, GlcCer and ceramide, etc.37, 38 Similarly, a variety of enzymes that regulate PL metabolism are capable of shifting the balance between PLs, LPLs, and ethanolamides.53, 54, 60, 61 More detailed information including related metabolic enzymes is presented in Figure S1 and Table S2. *Indicates the effect is on the contact phase; **Indicates the effect is on vWF release. Color highlighting indicates whether a particular lipid inhibits thrombin generation (blue) or enhances thrombin generation (red) or has no effect (green). Square boxes with colored background indicates lipids whose effects on coagulation are discussed in this review. Sph, sphingosine; GlcCer, glucosylceramide; LacCer, lactosylceramide (CD17), GalCer, galactosylceramide; SF, sulfatide; LSF, lyso‐sulfatide; SM, sphingomyelin; LSM, lyso‐sphingomyelin; Cer, ceramide; sph, sphingosine; sphA, sphinganine; S1P, sphingosine‐1‐phosphate; 16:0 AC, 16:0 acylcarnitine (palmitoylcarnitine); PC, phosphatidylcholine; PG, phosphatidylglycerol; PA, phosphatidic acid; PS, phosphatidylserine; PE, phosphatidylethanolamine; LPC, lyso‐phosphatidylcholine; LPG, lyso‐phosphatidylglycerol; LPA, lyso‐phosphatidic acid; LPS, lyso‐phosphatidylserine; LPE, lyso‐phosphatidylethanolamine; oxPC, oxidized phosphatidylcholine; PEA, palmitoyl‐ethanolamide; SEA, stearoyl ethanolamide; AEA, arachidonoyl ethanolamide

Figure 4

Structures of some plasma minor abundance lipids. Color highlighting indicates whether a particular lipid can contribute to inhibition of thrombin generation (blue) or to enhancement of thrombin generation (red). Sph, sphingosine; GlcCer, glucosylceramide; SF, sulfatide; LSF, lyso‐sulfatide; AC, acylcarnitine; and PEA, palmitoyl‐ethanolamide