Chapter 4: Thrombosis Flashcards
Are endothelial cells thrombotic or anti-thrombotic?
Anti-thrombotic
The anti-thrombotic properties of endothelium can be divided into different categories. Which? (3 answers)
Platelet inhibitory effects, anticoagulant effects and fibrinolytic effects
Describe the platelet inhibitory effects
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.
Describe the anti-coagulant effects
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.
Describe the fibrinolytic effects
Normal endothelial cells synthesize t-PA, as a key component of the fibrinolytic pathway.
The primary abnormalities that lead to intravascular thrombosis is the Virchow triad. What are the abnomalities of the Virchow triad?
(1) endothelial injury, (2) stasis or turbulent blood flow, and (3) hypercoagulability of the blood
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?
Endothelial activation or dysfunction
What are different exposures that cause endothelial activation (for illustration)
physical injury, infectious agents, abnormal blood flow, inflammatory mediators, metabolic abnormalities, such as hypercholesterolemia or homocystinemia, and toxins absorbed from cigarette smoke
What are the two major thrombotic alterations?
- Procoagulant changes
- anti-fibrinolytic effects
(more are explained in Ch10-11)
What are procoagulant changes?
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).
What are anti-fibrinolytic effects?
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.
What is the name for chaotic blood flow
Turbulence
What is turbulence?
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.
True/false: stasis plays a major factor in the development of venous thrombi
True
Fill in: under normal conditions, platelets (and other blood cells) are found mainly on the edge / in the center of the vessel lumen
in the center, white blood cells more to the edges of the vessel lumen!
What are the deleterious effects of stasis and turbulence?
- 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.
Fill in: Abnormal aortic and arterial dilations called aneurysms create local turbulence/stasis and consequently are fertile sites for thrombosis
stasis
Mitral valve stenosis results in…
left atrial dilation
In conjunction with atrial fibrillation, a dilated atrium also produces …. and is a prime location for the development of thrombi
stasis
Fill in: Hyperviscosity syndromes increases/decreases resistance to flow and cause small vessel stasis
increases
The deformed red cells in sickle cell anemia cause vascular occlusions, and the resultant … also predisposes to thrombosis.
stasis
What is hypercoagulability?
Hypercoagulability refers to an abnormally high ten- dency of the blood to clot, and is typically caused by alterations in coagulation factors
The alterations of coagulation pathways that predispose affected persons to thrombosis can be divided into two disorders. Which two?
Primary (genetic) and secondary (acquired) disorders
Approximately 2-15% of whites carry a special mutation. What is it?
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.
What are (besides factor V/Leiden) common genetic mutations? (not v important i think)
- 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.
Two particularly important clinical problems of the thrombophilic states deserve special mention. What are these?
Heparin-induced thrombocytopenia (HIT) syndrome and Anti-phospholipid antibody syndrome.
What is the HIT syndrome?
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)
What is anti-phospholipid antibody syndrome?
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
Thrombi can develop anywhere in the cardiovascular system. But what are the most common sites?
Arterial or cardiac thrombi typically arise at sites of endothelial injury or turbulence; venous thrombi characteristically occur at sites of stasis.
Thrombi are focally attached to the underlying vascular surface and tend to propagate toward the heart. Explain what happens to arterial and venous thrombi.
Arterial thrombi grow in a retrograde direction from the point of attachment, whereas venous thrombi extend in the direction of blood flow
Which is NOT better attached, the retrograde or the propagating portion of the thrombus? And
the propagating portion, and is therefore prone to fragmentation and migration through the blood as an embolus
Thrombi can have grossly (and microscopically) apparent laminations. What are these laminations called? And what are they?
Lines of Zahn (these represent pale platelet and fibrin layers alternating with darker red cell-rich layers)
True/false: Lines of Zahn are only found in thrombi that form in flowing blood
True
How are thrombi occuring in heart chambers or in the aortic lumen called?
Mural thrombi
What promotes mural thrombi and aortic thrombosis?
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).
True/false: arterial thrombi are occlusive
yes, frequently
True/false: venous thrombi (phlebothrombosis) are occlusive
yes, almost always
Are venous thrombi more often found in the lower/upper extremities?
lower (90%)
How can a postmortem clots and venous thrombi be distinguished?
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.
How are thrombi on heart valves called?
Vegetations
Bacterial or fungal bloodborne infections can cause valve damage, leading to the developement of large thrombotic masses. How are these masses called?
Infective endocarditis
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?
- Propagation
- Embolization
- Dissolution
- Organization and recanalization
What happens in propagation (a process of thrombus)?
he thrombus enlarges through the accretion of additional platelets and fibrin, increasing the
odds of vascular occlusion or embolization.
What happens in embolization (a process of thrombus)?
Part or all of the thrombus is dislodged
and transported elsewhere in the vasculature.
What happens in dissolution (a process of thrombus)?
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.
What happens in organization and recanalization (a process of thrombus)?
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
What are the clinical features of thrombi? (just read it 1-2x, just for illustration)
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.
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?
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).
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?
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.
What is the function of thrombomodulin and endothelial protein C receptor in inhibiting coagulation?
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.
What happens when endothelial protein C binds with thrombin?
It activates protein C, that forms a complex with protein S. This compelx inhibits coagulation factors.
