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Arterial thrombosis—insidious, unpredictable and deadly
The formation of blood clots—thrombosis—at sites of atherosclerotic plaque rupture is a major clinical problem despite ongoing improvements in antithrombotic therapy. Progress in identifying the pathogenic mechanisms regulating arterial thrombosis has led to the development of newer therapeutics, and there is general anticipation that these treatments will have greater efficacy and improved safety. However, major advances in this field require the identification of specific risk factors for arterial thrombosis in affected individuals and a rethink of the 'one size fits all' approach to antithrombotic therapy.
Adhesion and activation mechanisms supporting the hemostatic and prothrombotic function of platelets.
Major ligands and receptors mediating platelet adhesion and activation at sites of vascular injury.
Platelets are captured in the injured vessel wall from flowing blood through the specific interaction of the platelet GPIb-V-IX complex with collagen-bound vWF exposed on the subendothelium (top).
This ligand-receptor interaction has a rapid on-off rate that supports platelet translocation at the vessel wall.
Stable platelet adhesion occurs through the binding of platelet GPVI to fibrillar collagen as well as the ligation of multiple β1 integrins, including the collagen α2β1 interaction and fibronectin engagement of α5β1.
Once firmly adhered, platelets undergo a series of biochemical changes that induce integrin αIIbβ3 activation, leading to the high affinity interaction with adhesion proteins including vWF, fibrinogen and fibronectin.
These adhesive interactions are indispensable in the ability of platelets to form stable aggregates with other activated platelets and promote thrombus growth.
Activated platelets release or locally generate soluble agonists, including ADP, TXA2 and thrombin, that can induce autocrine or paracrine platelet activation (bottom).
Each agonist activates specific G protein–coupled receptors on the platelet surface, including ADP-P2Y1 or ADP-P2Y12, TXA2-TP and thrombin–human PAR1 or PAR4, stimulating intracellular signaling events that induce cytosolic calcium mobilization.
This second messenger has a key role in promoting integrin αIIbβ3 activation, TXA2 generation, granule secretion and in the procoagulant function of platelets.
Differential composition and localization of arterial thrombi relative to hemostatic plugs.
(a) Occlusive arterial thrombi at sites of atherosclerosis plaque rupture. Angioscopy studies of the coronary arteries of people with an acute myocardial infarction have shown the presence of a white thrombus (platelet-rich mural thrombus) developing at the site of atherosclerotic plaque rupture.
A 'red thrombus', composed of red blood cells and fibrin, preferentially forms in the low flow recirculation zones on the downstream margin of the developing thrombus.
The distinct spatial localization of platelets and fibrin is directly caused by local blood flow alterations at the site of vascular injury.
(b) A primary hemostatic plug forms rapidly at the site of vascular injury, extending into the extravascular space created by the wound.
Notably, there is minimal extension of the clot into the lumen of the healthy artery.
In contrast, a platelet-rich thrombus builds up on the surface of a disrupted atherosclerotic plaque,
beginning in the intima and propagating into the intraluminal space,
where it can induce major hemodynamic changes at the site of injury.
The antiadhesive phenotype of endothelial cells is maintained through four intrinsic pathways: ecto-ADPase, prostaglandin I2 (PGI2), nitric oxide (NO) and the thrombomodulin (TM)-activated protein C (APC) pathways.
In a hyperlipidemic milieu, the endothelium becomes inflamed and activated as a result of modified lipoprotein particles (cholesterol) and reactive oxygen species (ROS) accumulating in the intima.
This leads to the expression of adhesive ligands (including vWF and P-selectin (P-Sel)) on the endothelium that support platelet tethering and rolling.
Subsequent stable platelet adhesion occurs through the binding of αIIbβ3-fibrinogen complexes with endothelial αvβ3 or intercellular adhesion molecule-1 (ICAM-1).
Adherent platelets secrete numerous bioactive substances that alter the chemotactic and adhesive properties of the endothelium.
Platelet-derived IL-1β induces endothelial secretion of IL-6 and IL-8 as well as surface expression of ICAM-1, αvβ3 and monocyte chemotactic protein-1 (MCP-1).
Platelet CD40 ligand (CD40L) binds CD40 on endothelial cells, resulting in upregulation of adhesive molecules (ICAM-1, vascular cell adhesion molecule-1 (VCAM-1), E-selectin and P-selectin), cytokine and tissue factor release and reduction in NO synthesis.
In addition, platelet-leukocyte cross-talk promotes atherogenesis by recruiting leukocytes to endothelial-bound platelets through a multistep coordinated process.
Initial tethering of leukocytes is mediated by the interaction of P-selectin expressed on the platelet surface with its cognate receptor leukocyte P-selectin glycoprotein ligand-1 (PSGL-1).
Ligation of PSGL-1 promotes activation of leukocyte β2 integrins (Macrophage adhesion molecule-1 (Mac-1) and LFA-1), necessary for stable leukocyte adhesion.
Bioactive mediators derived from α-granules of activated platelets, including platelet factor 4 (PF4), synergizes with RANTES (regulated upon activation, normal T-cell expressed and secreted) to enhance leukocyte adhesion and monocyte differentiation.
Upregulation of COX-2 in monocytes via pathways involving IL-1β and P-selectin results in increased production of proinflammatory mediators including platelet-activating factor (PAF) and leukotrienes via transcellular eicosanoid metabolism.
Arterial thrombosis and the rapid progression of atherosclerotic lesions.
Leukocyte-platelet and leukocyte-endothelial interactions are crucial for initiating and propagating the development of atherosclerotic lesions.
During stable progressive disease, the slow progressive recruitment of proatherogenic leukocytes and foam cells to sites of atherosclerosis and the development of a collagen-rich fibrous cap help stabilize the plaque.
In contrast, during unstable rapid progression, there is development of a necrotic lipid core, inflammatory infiltrates and a thinning of the fibrous cap, which are all characteristic features of an unstable atherosclerotic plaque.
Erosion or disruption of the fibrous cap exposes thrombogenic matrix proteins that promote platelet accumulation and local fibrin generation.
Re-endothelialization of the lesion and incorporation of the organizing thrombus into the plaque leads to the progression of the atherosclerotic lesion.
With repeated cycles of plaque injury and thrombus formation, progressive stenosis of the vessel lumen occurs,
leading to marked reduction in blood flow and transient tissue ischemia (unstable angina) or total thrombotic occlusion of the artery and tissue infarction (acute myocardial infarction (AMI)).
Platelet procoagulant activity necessary for α-thrombin generation, fibrin formation and thrombus stability.
Thrombin generation and fibrin accumulation occur at spatially discrete sites during thrombus formation (top).
Fibrin generation at the site of vascular injury has a crucial role in anchoring the thrombus to the vessel and depends on tissue factor (TF) expression on the surface of smooth muscle cells and fibroblasts.
Endothelial- and monocyte-derived tissue factor may also contribute to this process.
Fibrin generation throughout the body of the thrombus, and in fibrin tails that form on the downstream margin of the thrombus, is thought to be primarily dependent on the procoagulant function of platelets.
Tissue factor–bearing microparticles and leukocytes incorporated into the body of the thrombus may also enhance local thrombin generation.
The regulation of platelet-derived procoagulant activity involves different factors and pathways (bottom).
Platelets support the initiation of the contact phase of blood coagulation, particularly the activation of FXII, by releasing inorganic polyphosphates (Poly P) from the dense granules of activated platelets, which results in the production of thrombin and, ultimately, fibrin.
The platelet provides a suitable surface for the assembly of coagulation protein complexes by expressing phosphatidylserine (PS).
The exteriorization of phosphatidylserine is mediated by the calcium-dependent regulation of a phospholipid scramblase called TMEM16F.
Platelet procoagulant function is tightly linked to the induction of platelet cell death pathways, including apoptotic and necrotic cell death.
Both pathways perturb mitochondrial function through distinct mechanisms that ultimately lead to marked alterations in the platelet ultrastructure and surface membranes, leading to phosphatidylserine exposure.
PC, phosphatidylcholine; Xa, coagulation factor Xa; Va, coagulation factor Va; Bak, Bcl-2 homologous antagonist/killer; Bax, Bcl-2-associated X protein.
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