Chapter 4: Thrombosis

Question 1

Are endothelial cells thrombotic or anti-thrombotic?

Answer 1

Anti-thrombotic

Question 2

The anti-thrombotic properties of endothelium can be divided into different categories. Which? (3 answers)

Answer 2

Platelet inhibitory effects, anticoagulant effects and fibrinolytic effects

Question 3

Describe the platelet inhibitory effects

Answer 3

An obvious effect of intact endothelium is to serve as a barrier that shields platelets from subendothelial vWF and collagen. However, normal endothelium also releases a number of factors that inhibit platelet activation and aggregation. Among the most important are prostacyclin (PGI2), nitric oxide (NO), and adenosine diphosphatase; the latter degrades ADP, already discussed as a potent activator of platelet aggregation. Finally, endothelial cells bind and alter the activity of thrombin, which is one of the most potent activators of platelets.

Question 4

Describe the anti-coagulant effects

Answer 4

Normal endothelium shields coag- ulation factors from tissue factor in vessel walls and expresses multiple factors that actively oppose coag- ulation, most notably thrombomodulin, endothelial protein C receptor, heparin-like molecules, and tissue factor pathway inhibitor. Thrombomodulin and endothe- lial protein C receptor bind thrombin and protein C, respectively, in a complex on the endothelial cell surface. When bound in this complex, thrombin loses its ability to activate coagulation factors and platelets, and instead cleaves and activates protein C, a vitamin K–dependent protease that requires a cofactor, protein S. Activated protein C/protein S complex is a potent inhibitor of coagulation factors Va and VIIIa. Heparin-like molecules on the surface of endothelium bind and activate anti- thrombin III, which then inhibits thrombin and factors IXa, Xa, XIa, and XIIa. The clinical utility of heparin and related drugs is based on their ability to stimulate anti- thrombin III activity. Tissue factor pathway inhibitor (TFPI), like protein C, requires protein S as a cofactor and, as the name implies, binds and inhibits tissue factor/factor VIIa complexes.

Question 5

Describe the fibrinolytic effects

Answer 5

Normal endothelial cells synthesize t-PA, as a key component of the fibrinolytic pathway.

Question 6

The primary abnormalities that lead to intravascular thrombosis is the Virchow triad. What are the abnomalities of the Virchow triad?

Answer 6

(1) endothelial injury, (2) stasis or turbulent blood flow, and (3) hypercoagulability of the blood

Question 7

severe endothelial injury may trigger thrombosis by exposing VWF and tissue factor. However, inflammation and other noxious stimuli also promote thrombosis by shifting the pattern of gene expression in endothelium to one that is “prothrombotic.” How is this change also called?

Answer 7

Endothelial activation or dysfunction

Question 8

What are different exposures that cause endothelial activation (for illustration)

Answer 8

physical injury, infectious agents, abnormal blood flow, inflammatory mediators, metabolic abnormalities, such as hypercholesterolemia or homocystinemia, and toxins absorbed from cigarette smoke

Question 9

What are the two major thrombotic alterations?

Answer 9

• Procoagulant changes
• anti-fibrinolytic effects

(more are explained in Ch10-11)

Question 10

What are procoagulant changes?

Answer 10

Active endothelial cells downregulate thrombomodulin. This causes thrombin to stay active and augment inflammation via PARs expressed on platelets an inflammatory cells. Inflamed ndothelial cells also downregulate expression of other anti-coagulants (such as protein C).

Question 11

What are anti-fibrinolytic effects?

Answer 11

Activated endothelial cells secrete Plasminogen activator inhibitors (PAI), which limit fibrinolysis and downregulate the expression of t-PA, alterations that also favor the development of thrombi.

Question 12

What is the name for chaotic blood flow

Answer 12

Turbulence

Question 13

What is turbulence?

Answer 13

Turbulence is the chaotic flow of blood. It causes endothelial injury/dysfunction and forms countercurrents and local pockets of stasis. Therefore contributes to arterial and cardiac thrombosis.

Question 14

True/false: stasis plays a major factor in the development of venous thrombi

Answer 14

True

Question 15

Fill in: under normal conditions, platelets (and other blood cells) are found mainly on the edge / in the center of the vessel lumen

Answer 15

in the center, white blood cells more to the edges of the vessel lumen!

Question 16

What are the deleterious effects of stasis and turbulence?

Answer 16

• Both promote endothelial cell activation and enhanced procoagulant activity, in part through flow-induced changes in endothelial gene expression.
  • Stasis allows platelets and leukocytes to come into contact with the endothelium when the flow is sluggish.
  • Stasis also slows the washout of activated clotting factors and impedes the inflow of clotting factor inhibitors.

Question 17

Fill in: Abnormal aortic and arterial dilations called aneurysms create local turbulence/stasis and consequently are fertile sites for thrombosis

Answer 17

stasis

Question 18

Mitral valve stenosis results in…

Answer 18

left atrial dilation

Question 19

In conjunction with atrial fibrillation, a dilated atrium also produces …. and is a prime location for the development of thrombi

Answer 19

stasis

Question 20

Fill in: Hyperviscosity syndromes increases/decreases resistance to flow and cause small vessel stasis

Answer 20

increases

Question 21

The deformed red cells in sickle cell anemia cause vascular occlusions, and the resultant … also predisposes to thrombosis.

Answer 21

stasis

Question 22

What is hypercoagulability?

Answer 22

Hypercoagulability refers to an abnormally high ten- dency of the blood to clot, and is typically caused by alterations in coagulation factors

Question 23

The alterations of coagulation pathways that predispose affected persons to thrombosis can be divided into two disorders. Which two?

Answer 23

Primary (genetic) and secondary (acquired) disorders

Question 24

Approximately 2-15% of whites carry a special mutation. What is it?

Answer 24

Factor V/Leiden mutation. The mutation alters an amino acid residue in factor V and renders it resistant to proteolysis by protein C. Thus, an important anti-thrombotic counterregulatory mechanism is lost.

Question 25

What are (besides factor V/Leiden) common genetic mutations? (not v important i think)

Answer 25

• A single-nucleotide substitution (G to A) in the 3′-untranslated region of the prothrombin gene is a fairly common allele (found in 1%–2% of the general population). This variant results in increased prothrom- bin transcription and is associated with a nearly three- fold increased risk for venous thromboses.
• Elevated levels of homocysteine contribute to arterial and venous thrombosis, as well as to the development of atherosclerosis (Chapter 10). The prothrombotic effects of homocysteine may be due to thioester linkages formed between homocysteine metabolites and a variety of proteins, including fibrinogen. Marked elevations of homocysteine may be caused by an inherited deficiency of cystathione β-synthetase.
• Less common primary hypercoagulable states include inherited deficiencies of anti-coagulants such as anti- thrombin III, protein C, or protein S; affected patients typically present with venous thrombosis and recurrent thromboembolism in adolescence or in early adult life.

Question 26

Two particularly important clinical problems of the thrombophilic states deserve special mention. What are these?

Answer 26

Heparin-induced thrombocytopenia (HIT) syndrome and Anti-phospholipid antibody syndrome.

Question 27

What is the HIT syndrome?

Answer 27

This syndrome occurs in up to 5% of patients treated with unfractionated heparin (for therapeutic anti-coagulation). It is marked by the development of autoantibodies that bind complexes of heparin and platelet membrane protein (platelet factor-4)

Question 28

What is anti-phospholipid antibody syndrome?

Answer 28

This syndrome (previously called the lupus anti-coagulant syndrome) has protean clinical manifestations, including recurrent thromboses, repeated miscarriages, cardiac valve vegetations, and thrombocytopenia. Depending on the vascular bed involved, the clinical presentations can include pulmonary embolism (following lower extremity venous thrombosis), pulmonary hypertension (from recurrent subclinical pulmonary emboli), stroke, bowel infarction, or renovascular hypertension

Question 29

Thrombi can develop anywhere in the cardiovascular system. But what are the most common sites?

Answer 29

Arterial or cardiac thrombi typically arise at sites of endothelial injury or turbulence; venous thrombi characteristically occur at sites of stasis.

Question 30

Thrombi are focally attached to the underlying vascular surface and tend to propagate toward the heart. Explain what happens to arterial and venous thrombi.

Answer 30

Arterial thrombi grow in a retrograde direction from the point of attachment, whereas venous thrombi extend in the direction of blood flow

Question 31

Which is NOT better attached, the retrograde or the propagating portion of the thrombus? And

Answer 31

the propagating portion, and is therefore prone to fragmentation and migration through the blood as an embolus

Question 32

Thrombi can have grossly (and microscopically) apparent laminations. What are these laminations called? And what are they?

Answer 32

Lines of Zahn (these represent pale platelet and fibrin layers alternating with darker red cell-rich layers)

Question 33

True/false: Lines of Zahn are only found in thrombi that form in flowing blood

Answer 33

True

Question 34

How are thrombi occuring in heart chambers or in the aortic lumen called?

Answer 34

Mural thrombi

Question 35

What promotes mural thrombi and aortic thrombosis?

Answer 35

Abnormal myocardial con- traction (arrhythmias, dilated cardiomyopathy, or myocardial infarction) or endomyocardial injury (myocarditis, catheter trauma) promote cardiac mural thrombi (Fig. 4.13A), whereas ulcerated atherosclerotic plaques and aneurysmal dilation promote aortic thrombosis (Fig. 4.13B).

Question 36

True/false: arterial thrombi are occlusive

Answer 36

yes, frequently

Question 37

True/false: venous thrombi (phlebothrombosis) are occlusive

Answer 37

yes, almost always

Question 38

Are venous thrombi more often found in the lower/upper extremities?

Answer 38

lower (90%)

Question 39

How can a postmortem clots and venous thrombi be distinguished?

Answer 39

At autopsy, postmortem clots can sometimes be mistaken for venous thrombi. However, the former are gelatinous and because of red cell settling they have a dark red dependent portion and a yellow “chicken fat” upper portion; they also are usually not attached to the underlying vessel wall. By contrast, red thrombi typically are firm, focally attached to vessel walls, and they contain gray strands of deposited fibrin.

Question 40

How are thrombi on heart valves called?

Answer 40

Vegetations

Question 41

Bacterial or fungal bloodborne infections can cause valve damage, leading to the developement of large thrombotic masses. How are these masses called?

Answer 41

Infective endocarditis

Question 42

If a patient survives an initial thrombotic event, during the ensuing days to weeks the thrombus evolves through some combination of four processes. What are these four?

Answer 42

• Propagation
• Embolization
• Dissolution
• Organization and recanalization

Question 43

What happens in propagation (a process of thrombus)?

Answer 43

he thrombus enlarges through the accretion of additional platelets and fibrin, increasing the
odds of vascular occlusion or embolization.

Question 44

What happens in embolization (a process of thrombus)?

Answer 44

Part or all of the thrombus is dislodged

and transported elsewhere in the vasculature.

Question 45

What happens in dissolution (a process of thrombus)?

Answer 45

If a thrombus is newly formed, activation of fibrinolytic factors may lead to its rapid shrinkage and complete dissolution. With older thrombi, extensive fibrin polymerization renders the thrombus substantially more resistant to plasmin-induced proteolysis, and lysis is ineffectual. This acquisition of resistance to lysis has clinical significance, as therapeutic administration of fibrinolytic agents (e.g., t-PA in the setting of acute coronary thrombosis) generally is not effective unless administered within a few hours of thrombus formation.

Question 46

What happens in organization and recanalization (a process of thrombus)?

Answer 46

Older thrombi become organized by the ingrowth of endothelial cells, smooth muscle cells, and fibroblasts (Fig. 4.14). In time, capillary channels are formed that—to a limited extent—create conduits along the length of the thrombus, thereby reestablishing the continuity of the original lumen

Question 47

What are the clinical features of thrombi? (just read it 1-2x, just for illustration)

Answer 47

Thrombi are significant because they cause obstruction of arteries and veins and may give rise to emboli. The effect that is of the greatest clinical importance depends on the site of thrombosis. Thus, although venous thrombi can cause congestion and edema in vascular beds distal to an obstruction, they are most worrisome because of their potential to embolize to the lungs and cause death. Conversely, whereas arterial thrombi can embolize and cause tissue infarction, their tendency to obstruct vessels (e.g., in coronary and cerebral vessels) is considerably more important.

Question 48

The balance between the anticoagulant and procoagulant
activities of endothelium often determines whether clot formation, propagation, or dissolution occurs. The endothelium has platelet inhibitory effects, how can endothelium inhibit platelet activation and aggregation?

Answer 48

The endothelium serves as a barrier between platelets and vWF and collagen (so that it cannot bind/react). Endothelium also releases factors that inhibit platelet activation and aggregation (PGI2, NO, adenosine diphosphatase).

Question 49

The balance between the anticoagulant and procoagulant
activities of endothelium often determines whether clot formation, propagation, or dissolution occurs. What are the anticoagulant effects of endothelium?

Answer 49

The endothelium serves as a barrier between coagulation factors and tissue factors. It also expresses several factors that inhibit coagulation (thrombomodulin, endothelial protein C receptor). Besides this, heparin-like molecules on endothelium also expresses anti-thrombin III.

Question 50

What is the function of thrombomodulin and endothelial protein C receptor in inhibiting coagulation?

Answer 50

These proteins bind thrombin and protein C in a complex on the endothelial cell surface. Thrombin then loses its ability to activate coagulation factors and platelets.

Question 51

What happens when endothelial protein C binds with thrombin?

Answer 51

It activates protein C, that forms a complex with protein S. This compelx inhibits coagulation factors.