Page 2388 - Hematology_ Basic Principles and Practice ( PDFDrive )

2130 Part XII Hemostasis and Thrombosis

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were seen in platelets from mouse models of hyperlipidemia, such as (see Fig. 144.8) in the form of TF-expressing MPs. MPs are vesicular
the apoE-null strain, which was fed a high-fat diet. Of note, the time fragments that bud off from cells during either activation or apoptosis.
to form occlusive thrombi after arterial injury in vivo was accelerated They are 200–1000 nm in size and possess different antigenic proper-
in hyperlipidemic mice compared with controls. In that context, ties depending on the cell from which they are derived. MPs can be
much attention has been paid to identifying and characterizing recep- generated from platelets, monocytes, erythrocytes, leukocytes, or
tors on the platelet surface that recognize specific classes of lipids and endothelial cells during vascular injury and have been shown to
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lipoproteins. The receptors fall into two main groups: pattern rec- become incorporated into developing thrombi in vivo. MPs, mostly
ognition innate immune receptors, including CD36, SRA, TLR4, of platelet origin, can be detected in the circulation of normal human
and LDL receptor–like protein (LRP)-8 (also known as apoER2), and subjects, but markedly increased numbers of circulating MPs have
G-protein–coupled receptors, including receptors for lysophospha- been reported in patients with a variety of inflammatory and pro-
tidic acid (LPA), platelet-activating factor, and thromboxane. thrombotic disorders including ACS.
CD36 (also known as platelet glycoprotein IV or IIIb) is of particu- MPs contribute to thrombus formation through several mecha-
lar interest because of its known function on macrophages as a nisms. A general feature of MP generation is loss of membrane
high-affinity signaling receptor for oxLDL, and because oxLDL and asymmetry so that anionic phospholipids normally oriented in the
oxidized phospholipids are readily detectable in circulating plasma of inner membrane leaflet become exposed on the outer leaflet. Surface-
experimental animals and patients with atherosclerosis and hyperlip- exposed phosphatidylserine (PS) is a site for catalytic assembly of
idemia. Indeed, recent studies showed that oxLDL bound to CD36 the prothrombinase complex and thrombin generation. Furthermore,
on the surface of platelets in a specific, concentration-, and time- PS on the surface of MP also has the capacity to bind to platelet
dependent manner. At high concentrations, such as might occur CD36 and enhance platelet reactivity via the same mechanism
during acute plaque rupture, oxLDL activates platelets, and at lower as oxLDL.
concentrations, such as those observed in the circulation of individu- It is important to note that MPs derived from some cells (e.g.,
als with atherosclerosis, oxLDL augmented platelet-aggregation monocytes, macrophages, smooth muscle cells, and tumor cells) are
responses to low doses of “classic” platelet agonists, such as ADP and a source of circulating TF. A mechanistic link between atherogenesis
collagen. More recently platelet CD36 was shown to bind MP and and thrombosis may be oxLDL, which in vitro can induce TF-positive
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advanced glycated proteins, suggesting that circulating endogenous MP generation from blood-derived monocytes. Of interest, a recent
“danger signals” generated by oxidant stress, hyperglycemia, and large clinical trial (JUPITER) testing the efficacy of statins in subjects
inflammation could induce a prothrombotic state through this with normal LDL, but elevated levels of hsCRP, showed that rates of
pathway. 27 venous thrombosis, as well as coronary events, were significantly
Platelets also express SRB1, a CD36 family protein that functions decreased. In animal models, statins decrease circulating levels of
in the liver as a cholesterol acceptor for HDL. The function of SRB1 oxLDL and also decrease circulating MP levels and levels of other
on platelets is not well understood, but at least one study showed that prothrombotic and proinflammatory biomarkers, even in the absence
oxHDL, but not native HDL, inhibited platelet reactivity to multiple of lowering cholesterol, suggesting that oxLDL-mediated prothrom-
agonists, including ADP, collagen, and thrombin via binding to botic activities may be important targets for thromboprevention in
SRB1. HDL is at least as susceptible to oxidation in vitro and in vivo patients with atherosclerosis. These studies also support those showing
as LDL, and it is possible that the balance between oxLDL and that statins may have antiinflammatory and antithrombotic activities
oxHDL and the relative expression levels of CD36, SRB1, and other independent of lipid lowering. Because HMGCoA reductase is also
receptors may determine platelet reactivity in patients with hyperlip- the limiting step in biosynthesis of isoprenoids, it has been postulated
idemia and oxidant stress. that statins may dampen signaling pathways mediated by small-
Atherosclerotic plaque and so-called “minimally” oxLDL contain molecular-weight G proteins (e.g., Ras) in which membrane targeting
LPA, a family of biologically active lipids generated by the action of by protein isoprenylation is required (see Fig. 144.2).
phospholipases on LDL and cell membrane lipids. Platelets express In mice, the contact activating system and intrinsic coagulation
at least three different G-protein–coupled LPA receptors but the in cascade have been shown to participate in arterial thrombosis after
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vivo relevance of this system has not been demonstrated. Ex vivo injury and to have proatherogenic properties. Targeting these
studies, however, demonstrated that minimally oxLDL at high con- systems is attractive in that patients with known deficiencies in factor
centrations could induce platelet shape change and sensitize platelets XII or contact system proteins have no obvious phenotype and do
to aggregate in response to other agonists. Epidemiologic studies have not have a bleeding diathesis, thus presumably an antithrombotic
also associated levels of soluble phospholipase A2 with cardiovascular effect could be achieved without altering normal hemostasis.
risk. In addition to participating in LPA biosynthesis, this family of
enzymes generates free fatty acids from phospholipids that serve as
substrates for cyclooxygenase and lipoxygenases, producing both CROSS-TALK BETWEEN COAGULATION AND
pro- and antiatherogenic eicosanoids. INFLAMMATION SYSTEMS IMPACT ATHEROGENESIS
LRP-8 (particularly a splice variant known as apoER2) binds lipi-
dated apoE3 (e.g., chylomicrons and remnant particles), resulting in As noted previously, atherosclerosis can be thought of as a chronic,
enhanced nitric oxide production and inhibition of platelet activation low-grade inflammatory disease of the artery wall. Clinical studies
by ADP and other agonists. On the other hand, LRP-8 has also been based on biomarkers, such as hsCRP, MPO, and IL-6, also suggest
shown to bind apoB-containing lipoproteins, leading to enhanced that advanced atherosclerosis is associated with a systemic state of
thromboxane generation and sensitization of platelets to other ago- chronic inflammation and that the degree of inflammation reflects
nists. Consistent with this, in mice genetic deletion of LRP-8 has an the level of risk for major complications, possibly because the more
antithrombotic effect in models of arterial injury. inflamed the plaque, the more vulnerable the lesion. It is also now
In addition to platelet hyperreactivity, it is also quite likely that clear that mediators of inflammation, such as IL-1, LPA, oxLDL, and
systemic activation of the coagulation cascade contributes to the circulating MPs may interact with platelets and the coagulation
prothrombotic state associated with advanced atherosclerosis. This is cascade to promote a hypercoagulable, prothrombotic state. Further-
consistent with studies showing that atherosclerosis is associated with more, mediators of coagulation, such as thrombin, TF–factor VIIa
increased risk for venous thromboembolic disorders, as well as arterial complexes, and factor Xa, may contribute to the proinflammatory
thrombosis. Elevated levels of circulating D-dimer and thrombin– state by interacting with protease-activated receptors on endothelial
antithrombin complexes have been reported in patients with ACS, cells and leukocytes. Activated platelets can contribute to inflamma-
and D-dimer levels tend to track with hsCRP. Large-scale population tion by facilitating monocyte adhesion to endothelium and by
studies have identified elevated fibrinogen and factor VIII levels as secreting small molecules (ATP, pyrophosphates, and serotonin),
risk factors for atherosclerosis. Recent studies suggest that a key cytokines, and growth factors that have proinflammatory activity.
initiator of thrombin generation in these settings is circulating TF Thus bidirectional cross-talk between the inflammation and