Page 2083 - Hematology_ Basic Principles and Practice ( PDFDrive )

1852 Part XII Hemostasis and Thrombosis

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vasodilation. ATP/ADP can stimulate purinoreceptors on endothelial to contribute to coagulation. Although most microparticles prob-
cells, resulting in synthesis and release of PGI 2 and NO. 219 ably are derived from platelets and monocytes, endothelial-derived
Endothelial cells use three main pathways to inhibit thrombin microparticles may be an important source of circulating TF under
generation and limit coagulation 213,215,220,221 : conditions of drastic activation. 229,230

1. Antithrombin system: Heparan sulfate proteoglycans are secreted
onto the luminal surface of endothelial cells and into the suben- Control of Vascular Tone
dothelium. Heparan sulfates are capable of binding and activating
antithrombin III, thereby accelerating inactivation of several Control of vascular tone is orchestrated primarily by a balance
procoagulant serine proteases, including thrombin, factor Xa, and between endothelium-derived vasodilators (NO, PGI 2, and
factor IXa. endothelium-derived hyperpolarizing factor [EDHF]) and vasocon-
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2. Protein C : Thrombomodulin on the surface of endothelial cells strictors (endothelin-1 [ET-1], thromboxane (TXA 2) and superoxide).
binds thrombin. This coupling inhibits the coagulant properties In addition to inhibiting platelet aggregation, NO and PGI 2 act as
of thrombin and increases its affinity for protein C, which it vasodilators. 231,232 NO is produced by conversion of L-arginine to
cleaves and activates. Activation of protein C by the thrombin– L-citrulline by NO synthase (NOS). Three forms of NOS exist: a
thrombomodulin complex is augmented by its binding to the constitutive NOS in neuronal tissue; an inducible enzyme found in
endothelial cell protein C receptor. Protein S, which is thought to macrophages and other cells that plays a role in NO-induced cyto-
be synthesized primarily by the endothelial cell, acts as a cofactor toxicity; and a constitutively active endothelial form, NOSIII
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for protein C but itself also has anticoagulant properties. Indepen- (eNOS). The inducible form of NOS also is present in endothelial
dent of the presence of activated protein C, free protein S is able cells and may be responsible for the uncontrolled vasodilation seen
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to inhibit the prothrombinase and intrinsic tenase complexes and in septic shock. Injection into the forearm of L-arginine analogues
interact directly with factors Va and VIIIa. that inhibit NOS causes substantial vasoconstriction. Conversely,
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3. Tissue factor pathway inhibitor (TFPI) : TFPI is a Kunitz-type eNOS-deficient mice are hypertensive, suggesting that NO release is
serine protease inhibitor that modulates TF-initiated coagulation. crucial for maintaining basal vasodilation. 231,232 The major physiologic
TFPI binds to and directly inhibits the TF–factor VIIa–factor Xa stimulus for continuous production of NO in vivo is shear stress. The
complex. It is mainly produced by and bound to endothelial cells, action of NO on platelets (antiaggregatory), endothelial cells, and
likely to surface glycosaminoglycans. There is also a plasma pool smooth muscle cells (relaxation) is caused by activation of guanylyl
bound to low-density lipoprotein. cyclase and formation of cyclic guanosine 3′,5′-cyclic monophos-
phate. Whereas NO is quite unstable, the formation of S-nitrosothiols
If coagulation occurs despite the many anticoagulant mechanisms, in the presence of oxygen and thiols provides a stable reservoir of
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endothelial cells also provide proteins to promote fibrinolysis. NO. Hemoglobin is an avid scavenger of NO, which may account
Endothelium is a major source of t-PA. 224,225 Approximately 40% of for the vasoconstriction observed with administration of cell-free,
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t-PA is bound to its inhibitor, PAI-1, which is also secreted by hemoglobin-based RBC substitute. Physiologically, however,
endothelial cells. Stresses such as exercise, acidosis, hypoxia, shear S-nitrosohemoglobin acts as a regulator of blood flow. Deoxygenation
forces, increased venous pressure, and thrombin cause release of is accompanied by an allosteric change in S-nitrosohemoglobin that
t-PA, 224,225 and presumably activate plasminogen. Receptors for releases the NO group, relaxing blood vessels to bring blood flow in
plasminogen and t-PA are present on the endothelial cell surface, line with local oxygen requirements. 236
allowing for effective localized production of fibrinolytic activity. Prostacyclin (PGI 2 ), on the other hand, does not appear to have
Although intact endothelium is necessary to maintain blood in a as global a role in vasodilation as does NO. PGI 2 is synthesized
fluid state and inhibit coagulation under normal conditions, injured mainly by endothelial cells and acts locally at sites of injury. It may
endothelium can rapidly downregulate its anticoagulant functions counterbalance the vasoconstriction induced by the platelet-produced
and become procoagulant even without overt vascular damage as arachidonic acid metabolite thromboxane A 2 (TXA 2 ). Most PGI 2 is
occurs with trauma or surgery. Further tissue injury or vascular released luminally, where it has an antiplatelet effect. Whereas PGI 2
pathology also leads to exposure of the underlying matrix, which is transduces a cellular signal by increasing the levels of cyclic AMP
procoagulant by virtue of its binding to and activation of platelets. (cAMP), TXA 2 signals via the phosphoinositol pathway and lowering
Endothelial cells that have been induced to undergo apoptosis in vitro of cAMP levels. Synthesis of prostaglandins is catalyzed by the action
become procoagulant. Apoptotic endothelial cells expose phosphati- of cyclooxygenases (COX-1 and COX-2) on arachidonic acid. Aspirin
dylserine on their surface and downregulate their anticoagulant inhibits COX irreversibly in both platelets and endothelial cells.
properties. Apoptotic endothelial cells and vascular smooth muscle However, the clinical effect is seen primarily in platelets for two
cells also increase thrombin formation in recalcified citrated plasma, reasons. 232,233 One reason is that platelets, being nonnucleated, cannot
and apoptotic endothelial cells show increased adhesion to unacti- synthesize new COX, but endothelial cells can. Therefore TXA 2
vated platelets. 180,181,226 Thrombosis resulting from procoagulant synthesis recovers only when new platelets enter the circulation, but
changes induced by endothelial apoptosis could contribute to the COX production by endothelial cells restores PGI 2 levels within a
pathogenesis of diverse diseases. 227 few hours. The second reason is that platelets encounter orally
Even without endothelial death, perturbation of the vascular administered aspirin before it is deacetylated by the liver and diluted
lining by inflammatory mediators could tip the balance such that the by the venous circulation. The important balance in the activity of
endothelium converts from a nonthrombogenic to a procoagulant PGI 2 and TXA 2 to homeostasis in the healthy vessel becomes evident
surface because of downregulation of anticoagulant properties as well when using selective COX-2 inhibitors to reduce inflammation,
as induction of procoagulant properties. For example, the setting of which decreases the production of PGI 2 without affecting the produc-
acute inflammation is associated with increased release of vWF, tion of TXA 2 resulting in vasoconstriction and platelet aggregation
platelet-activating factor, and fibronectin, all of which may potentiate unopposed by PGI 2 , and increased risk for cardiac events.
thrombus formation. Tumor necrosis factor (TNF), IL-1, and lipo- Early experimental evidence suggested that endothelial cells
polysaccharide can increase the expression of PAI-1 in endothelial release other relaxing factors (i.e., EDHF), which act by increasing
cells with downregulation or no change in t-PA levels, thereby impair- the membrane potential of smooth muscle cells. Hyperpolarization
ing fibrinolysis. TNF, IL-1, and lipopolysaccharide also have been of isolated coronary arteries occurs in the presence of an arginine
shown to downregulate thrombomodulin as well as to induce expres- analogue, a NOS inhibitor, and indomethacin, a COX inhibitor,
sion of TF on cultured endothelial cells. However, whether endothelial suggesting that EDHF, NO, and prostanoids contribute differen-
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cells express TF on their luminal surfaces in vivo is controversial. tially to relaxation in human coronary arteries. The nature of
More recently, circulating microparticles generated by leukocytes and EDHF is unclear, but it encompasses different biologic mechanisms.
vascular cells have been shown to be a source of blood-borne TF and These mechanisms involve an increase in intracellular calcium