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1832 Part XII Hemostasis and Thrombosis

Antiplatelet Anticoagulant Profibrinolytic
Heparan
NO CD39 Prostacyclin sulfate TM EPCR TFPI t-PA u-PA

Endothelium

Fig. 122.1 THE ANTITHROMBOTIC FUNCTIONS OF THE ENDOTHELIUM. The healthy endo-
thelium has (a) antiplatelet activity because of synthesis and release of prostacyclin and nitric oxide (NO) and
expression of CD39, a membrane-associated ectoADPase; (b) anticoagulant activity because of heparan sulfate
proteoglycan-mediated activation of antithrombin and expression of thrombomodulin (TM) and endothelial
protein C receptor (EPCR), which are involved in protein C activation, and surface-bound tissue factor
pathway inhibitor (TFPI); and (c) profibrinolytic activity because of release of tissue and urokinase-type
plasminogen activator (t-PA and u-PA, respectively).

diphosphate (ADP), which is a platelet agonist, CD39 attenuates Vascular Tone and Permeability
platelet activation.
In addition to synthesizing potent vasodilators, such as prostacyclin
and nitric oxide, endothelial cells also produce a group of counter-
Anticoagulant Activity regulatory peptides known as endothelins that induce vasoconstric-
tion. Endothelial cell permeability is influenced by the connections
Intact endothelial cells play an essential part in the regulation of that join endothelial cells to their neighbors. Macromolecules traverse
thrombin generation through a variety of mechanisms. Endothelial the endothelium via patent intercellular junctions, by endocytosis, or
cells produce heparan sulfate proteoglycans, which bind circulating through transendothelial pores. Vasodilatation, severe thrombocyto-
antithrombin and accelerate the rate at which it inhibits thrombin penia, and high doses of heparin can increase endothelial permeability,
and other coagulation enzymes. Tissue factor pathway inhibi- which may contribute to bleeding. Activated protein C may also
tor (TFPI), a naturally occurring inhibitor of coagulation, binds contribute to the barrier function of the endothelium.
5
heparan sulfate on the endothelial cell surface. Administration
of heparin or low-molecular-weight heparin (LMWH) displaces
glycosaminoglycan-bound TFPI from the vascular endothelium, and Platelets
released TFPI may contribute to the antithrombotic activity of these
drugs. Platelets are anucleate cellular particles released into the circulation
Endothelial cells regulate thrombin generation by expressing after programmed fragmentation of bone marrow megakaryocytes
thrombomodulin and endothelial cell protein C receptor (EPCR) on (see Chapter 124). Because they are anucleate, platelets have limited
their surfaces. Thrombomodulin binds thrombin and alters this capacity to synthesize proteins. Consequently, platelet protein
enzyme’s substrate specificity such that it no longer acts as a proco- composition is determined by the parent cell as well as by those
agulant but becomes a potent activator of protein C (see Chapter factors endocytosed from the circulation. Thrombopoietin, a glyco-
127). Activated protein C serves as an anticoagulant by degrading protein synthesized in the liver and kidneys, regulates megakaryo-
and inactivating activated factor V and factor VIII (factor Va and cytic proliferation and maturation as well as platelet production.
VIIIa, respectively), key cofactors involved in thrombin generation. Once they enter the circulation, platelets have a life span of 7 to
Protein S acts as a cofactor in this reaction, and EPCR enhances this 10 days.
pathway by binding protein C and presenting it to the thrombin– Damage to the intimal lining of the vessel exposes the underlying
thrombomodulin complex for activation. In addition to its role as an subendothelial matrix. Platelets home to sites of vascular disruption
anticoagulant, activated protein C also regulates inflammation and and adhere to the exposed matrix proteins (see Chapter 125). Adher-
preserves the barrier function of the endothelium. 6 ent platelets undergo activation and not only release substances that
recruit additional platelets to the site of injury, but also promote
thrombin generation and subsequent fibrin formation (Fig. 122.2).
Fibrinolytic Activity A potent platelet agonist, thrombin amplifies platelet recruitment and
activation. Activated platelets then aggregate to form a plug that seals
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The vascular endothelium promotes fibrinolysis by synthesizing and the leak in the vasculature. An understanding of the steps in these
releasing tissue-type and urokinase-type plasminogen activator (t-PA highly integrated processes helps pinpoint the sites of action of
and u-PA, respectively), which initiate fibrinolysis by converting antiplatelet drugs and rationalizes the utility of anticoagulants for the
plasminogen to plasmin (see Chapter 126). Endothelial cells in most treatment of arterial thrombosis and venous thrombosis.
vascular beds synthesize t-PA constitutively and release it in response
to stimuli such as thrombin or bradykinin. In contrast, perturbed
endothelial cells produce u-PA in the settings of inflammation and Adhesion
wound repair.
Endothelial cells also produce type 1 plasminogen activator Platelets adhere to exposed von Willebrand factor (vWF) and colla-
inhibitor (PAI-1), the major regulator of both t-PA and u-PA. There- gen, originating from endothelial cells and the subendothelium,
fore net fibrinolytic activity depends on the dynamic balance between respectively. The platelet monolayer promotes thrombin generation
the release of plasminogen activators and PAI-1. Fibrinolysis localizes and subsequent fibrin formation. These events depend on constitu-
to the endothelial cell surface because these cells express annexin II, tively expressed receptors on the platelet surface, α 2β 1 and glycopro-
a coreceptor for plasminogen and t-PA that promotes their interac- tein (GP) VI , which bind collagen, and GPIbα and GPIIb/IIIa
tion. Therefore healthy vessels actively resist thrombosis and help (α IIb β 3), which bind vWF. The platelet surface is crowded with recep-
maintain platelets in a quiescent state. tors, but those involved in adhesion are the most abundant: every