Page 250 - Small Animal Internal Medicine, 6th Edition

222 PART I Cardiovascular System Disorders

(outside the blood, TF-dependent) and intrinsic (within the There are multiple physiologic mechanisms that limit the
blood, contact-dependent), considered to be two alternative extent of thrombus formation in addition to the fibrinolytic
VetBooks.ir pathways for eventual activation of factor Xa (FXa). FXa system. As previously discussed, inherent properties of
healthy vascular endothelium effectively localize coagulation
activation then initiates the final “common pathway”: activa-
tion of prothrombin to thrombin, followed by cleavage of
produced by the liver, is responsible for most of the antico-
fibrinogen to fibrin. Although the cascade model historically only to sites of injury. Antithrombin (AT), a small protein
explained many aspects of coagulation in vitro, more recent agulant effect of plasma. Along with its co-factor heparan
models have been proposed that highlight the role of cell sulfate, AT binds to and inactivates many coagulation pro-
membranes in the process of hemostasis in vivo. teins, including thrombin; FIXa, FXa, FXIa, and FXIIa; and
The currently advocated cell-based model of hemostasis is kallikrein. Protein C (and its co-factor Protein S) are vitamin
divided into three sequential but overlapping phases: initia- K–dependent glycoproteins that inactivate FVa and FVIIIa.
tion, amplification, and propagation. During initiation, vas- Proteins C and S are stimulated by thrombin (via formation
cular injury exposes subendothelial cells expressing TF, of the thrombin-thrombomodulin complex), thus acting as
which binds to factor VIIa (FVIIa) in circulating blood. The a negative feedback loop during the coagulation process.
complex of TF-FVIIa activates FXa to produce small amounts Endothelial-derived TFPI also limits hemostasis by inhibit-
of thrombin (FIIa), which attracts and activates nearby plate- ing FVIIa and TF. Malfunction of one or more of these
lets. In the amplification phase, platelet activation by throm- control systems promotes thrombosis.
bin results in platelet shape change, platelet degranulation,
and expression of platelet surface receptors. Platelet granules Pathophysiology
release substances that attract and activate other platelets TE disease is more likely when changes in normal hemo-
(including thromboxane A 2 , serotonin, adenosine diphos- static processes create conditions that favor clot formation
phate [ADP], calcium, and fibrinogen). Different types of or impair fibrinolysis. Three general situations (so-called
platelet receptors bind to subendothelial von Willebrand “Virchow’s triad”) promote pathologic thrombosis: abnor-
factor (glycoprotein [GP] I b -IX) or to other platelets via mal endothelial structure or function, slowed or static blood
fibrinogen (GPα IIb β 3 , formerly known as GPII b -III a ). This flow, and a hypercoagulable state (from either increased pro-
recruitment and aggregation creates a “plug” of fibrinogen- coagulant substances or decreased anticoagulant or fibrino-
linked platelets. The platelet plug helps limit blood loss lytic substances). A number of common diseases produce
through small vessels; more importantly, however, the acti- such conditions (Box 12.1).
vated platelet membranes (with exposed PTS) create a sub- Diseases that induce severe or widespread endothelial
strate for the propagation phase of hemostasis. In the injury promote thrombosis via loss of the antiplatelet, anti-
propagation phase, activated coagulation factors react on the coagulant, and fibrinolytic functions of normal endothelium.
activated platelet surface in a series of steps to generate more Injured endothelium also releases TF and antifibrinolytic
activated FXa, which along with its co-factor FVa cleaves factors. Subendothelial tissue, exposed because of endothe-
prothrombin into thrombin (FIIa). Formation of large lial cell damage, promotes thrombosis by acting as a sub-
amounts of thrombin is the “final step” in the cell-based strate for clot formation and stimulating platelet adherence
model of coagulation. Thrombin converts fibrinogen into and aggregation. Systemic release of inflammatory cytokines
fibrin monomers, which polymerize to soluble fibrin, which (e.g., tumor necrosis factor [TNF], various interleukins,
is then cross-linked by the action of thrombin-activated platelet activating factor, nitric oxide) can cause widespread
FXIII (or fibrin-stabilizing factor). This insoluble fibrin sta- endothelial injury, induce TF expression, and inhibit antico-
bilizes the clot. agulant mechanisms. This occurs in patients with sepsis and
After a thrombus forms, several mechanisms limit its likely other systemic inflammatory conditions as well. Neo-
extent and promote its breakdown. Thrombolysis requires plastic invasion, vascular disruption resulting from other
plasmin. Its inactive precursor, plasminogen, is converted to disease, and postischemic injury also induce endothelial
plasmin by tissue plasminogen activator (t-PA) when fibrin damage. Microparticles, small membrane-bound vesicles
is present. During activation of the coagulation cascade, derived from platelets or other cell types in certain disease
endothelial cells simultaneously release t-PA. Several other states, can provide a procoagulant phospholipid membrane
substances also can act as plasminogen activators. Plasmin surface for pathologic thrombosis. Mechanical trauma to the
degrades fibrinogen and soluble (noncross-linked) fibrin to vascular endothelium (as with catheterization) can also pre-
yield fibrinogen/fibrin degradation products (FDPs). Plasmin cipitate TE disease, especially when other predisposing con-
also cleaves cross-linked fibrin in stabilized clots into large ditions exist. Pulmonary artery endothelial injury resulting
fragments (x-oligomers) that are further broken down into from heartworm disease (HWD) is well known (see Chapter
D-dimers and other fragments. D-dimers are produced only 10). The inflammatory reaction to dead or dying worms and
with active coagulation and subsequent fibrinolysis. There worm fragments exacerbates the endothelial damage and
also are negative feedback constraints on fibrinolysis (e.g., prothrombotic conditions.
plasminogen activator inhibitors [PAI], α 2 -antiplasmin, Stagnant blood flow promotes thrombosis by impeding
thrombin-activated fibrinolytic factor). Defective fibrinolysis the dilution and clearance of coagulation factors, as well as
is thought to play a role in pathologic thrombosis. increasing time for blood components to contact vessel