Page 249 - Small Animal Internal Medicine, 6th Edition

CHAPTER 12
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Thromboembolic Disease

GENERAL CONSIDERATIONS more reactive phospholipids, phosphatidylserine (PTS) and
phosphatidylethanolamine (PEA), are localized to the inner
Thromboembolic (TE) disease involves either a locally membrane. This asymmetry in the lipid bilayer is maintained
formed (in situ) aggregation of platelets and other blood by active transport of phospholipids by the ATP-dependent
elements (thrombus), or a thrombus or other aggregate that enzymes flippase and floppase. After cell injury, the enzyme
breaks away from its origination site (embolus) and is carried scramblase shuffles phospholipids between the inner and
downstream by blood flow. Both thrombi and emboli can outer membranes, resulting in PTS and PEA expression on
partially or completely obstruct blood flow, either in a vessel the outer membrane. Membranes with exposed PTS provide
or in the heart. TE disease can occur whenever normal a substrate that supports and catalyzes coagulation reactions,
hemostatic mechanisms are disturbed. Most clinically recog- whereas such reactions occur very slowly on membranes
nized TE events involve the distal aorta, pulmonary arteries, lacking PTS. Finally, healthy endothelium actively produces
heart, or cranial vena cava. (For additional information on substances that inhibit both platelet adhesion and coagu-
the pathogenesis of thromboembolism, see Chapter 87.) lation. Antiplatelet substances produced by vascular endo-
The clinical sequelae of TE disease depend mainly on the thelium include nitric oxide, prostacyclin, and adenosine
size and location of the thrombus/thrombi. These factors diphosphatase (ADPase). Anticoagulant substances syn-
determine how much functional compromise occurs and in thesized by intact endothelium include thrombomodulin,
which organs and tissues. Acute, profound clinical signs of protein S, heparin sulfated proteoglycans (HSPGs), and
pain and organ dysfunction result from some thromboem- tissue factor pathway inhibitor (TFPI).
boli. Others cause subclinical tissue damage and varying Damaged endothelial cells promote thrombus formation.
degrees of pathology. TE disease is sometimes suspected Although this reduces blood loss in the event of vascular
antemortem; in other cases, it is discovered at necropsy (or damage, in other settings TE disease results. Endothelial
not at all). damage contributes to thrombus formation in several ways.
First, injured endothelial cells release endothelin, which pro-
NORMAL HEMOSTATIC MECHANISMS motes vasoconstriction and slows local blood flow, allowing
There is normally interplay among the different factors that more time for blood components to interact with the vessel
promote coagulation, inhibit coagulation, and promote fibri- wall. Second, as previously discussed, presence of PTS on the
nolysis. A proper balance of these factors maintains blood outer lipid membrane of damaged cells dramatically increases
fluidity and minimizes loss when vessels are damaged. Plate- speed of coagulation reactions. Perhaps most importantly,
lets, the vascular endothelium, coagulation proteins, and the damaged endothelium exposes cells expressing tissue factor
fibrinolytic system are all involved in normal hemostasis. (TF or thromboplastin), which is the key step to initiate
Injury to the vascular endothelium quickly induces several thrombus formation.
reactions that cause vasoconstriction, hemostatic plug for- Traditional models of hemostasis involve a temporal and
mation, and attempts at vascular repair to prevent blood loss. functional division of thrombus formation into primary
Intact endothelium exerts anticoagulant properties via hemostasis (formation of the primary platelet plug), second-
several mechanisms. First, the endothelium represents a ary hemostasis (coagulation proteins creating cross-linked
physical barrier that is negatively charged, discouraging and fibrin), and fibrinolysis (thrombus breakdown). Secondary
repelling platelet adhesion. Second, the arrangement of phos- hemostasis has been further modeled as a “cascade” of coag-
pholipids in healthy cell membranes inhibits coagulation. ulation proteins involving sequential cleavage of proen-
In normal endothelial cells and platelets, the outer mem- zymes, each step activating the next coagulation factor in the
brane of the lipid bilayer contains neutral phospholipids; the series. This cascade was historically divided into extrinsic

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