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HMS Pathology > Endothelium Homeostasis and Thrombosis > Flashcards

Endothelium Homeostasis and Thrombosis Flashcards

1
Q

Homeostatic arrest of hemorrhage

A

The spontaneous arrest of hemorrhage by a physiologic process based on the reactions of the blood and vascular tissue to injury. An adaptive response which (ideally) stops bleeding from a site of vascular injury, without permanently interrupting blood flow to tissues

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2
Q

Formation of the homeostatic clott plug involves coordination of. . .

A
  1. The blood vessel wall
  2. Platelets
  3. Plasma clotting factors
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3
Q

Layers of the endothelium

A
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4
Q

The principal product of arachidonic acid metabolism in endothelium is ___.

A

The principal product of arachidonic acid metabolism in endothelium is PGI2, aka prostacyclin.

It is a potent inhibitor of platelet aggregation and its production is unique to the endothelium.

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5
Q

Mechanisms by which the endothelium prevents clotts from disrupting bloodflow

A
  1. The endothelial cell surface has associated with it highly sulfated glycosaminoglycans which resemble the anticoagulant heparin
  2. PGI2 / prostacyclin production
  3. ADP (which serves as a platelet aggregating agent) and other seroactive amines are taken up and degraded by the endothelium
  4. Endothelium can release tissue plasminogen activator (tPA), which ultimately acts to dissolve blood clots
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6
Q

Acutely following vascular injury, the endothelium. . .

A

Downregulates its anti-clotting mechanisms and up-regulates tissue factor, a glycoprotein which activates the plasma clotting system. All of this is done locally, usually only the endothelial cells that are actually damaged change their expression.

Subsequent regeneration of the endothelial lining plays an important role in restoring normal vessel patency and thromboresistance.

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7
Q

The immediate response to endothelial injury

A

vasoconstriction

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8
Q

Subendothelial connective tissues (amorphous basement membrane, microfibrils, collagens) are . . .

A

thrombogenic

They are recognized by thrombocytes and immediately induce clott. This is important as they are only exposed when there is an endothelial injury.

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9
Q

What happens when platelets see a sub-endothelial connective tissue layer?

A

They 1) adhere to the tissue,

2) change their shape (become spherical with many sticky pseudopods),
3) express integrins to establish a firm connection and flatten out as a result,
4) Degranulate, releasing ADP and thromboxane A2,
5) Via these factors, recruit other thrombocytes to fill the clott

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10
Q

Platelet release reaction

A

The degranulation event triggered by thrombocyte-connective tissue binding.

It results in rapid secretion of packets of potent mediators precisely at the site of vessel injury; and results in amplification of the number of activated platelets involved in this (autocatalytic) response

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11
Q

The activated platelet can be thought of as a ____

A

The activated platelet can be thought of as a miniature secretory organ

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12
Q

Activated platelet cross-section

A
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13
Q

Two prominent types of membrane-bound storage granules found in platelets

A
  1. Alpha granules: contain fibrinogen, fibronectin, von Willebrand Factor, thrombospondin, and an antiheparin (platelet factor 4 or PF4), which are involved in hemostasis, as well as lysosomal enzymes and other mediators that augment the inflammatory response. Alpha granules also contain a PDGF to stimulate smooth myocyte and fibroblast proliferaiton.
  2. Dense bodies: concentrate serotonin from plasma, and also are rich in ADP and calcium. Serotonin release may also contribute to localized vasoconstriction in small vessels.
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14
Q

Role of ADP in platelet aggregation

A

ADP is a potent mediator of platelet release and aggregation; its release from adherent platelets serves to recruit other platelets in the vicinity of a hemostatic response.

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15
Q

Primary vs secondary hemostasis

A

Primary: Triggered by low amounts of ADP, reversible platelet clott

Secondary: Triggered by high amounts of ADP and concurrent thrombin generation, resulting in a fibrous coating of the clott, irreversible

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16
Q

Eicosanoids in clotting

A
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17
Q

thromboxane A2

A

very potent platelet aggregator and smooth muscle contractor

very short-lived

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18
Q

prostacyclin

A

potent inhibitor of platelet activation and a smooth muscle relaxer

very short lived

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19
Q

PGE2 , PGF2a, PGD2

A

may inhibit aggregation and release, or influence vascular tone and permeability

much more stable than prostacyclin or thromboxane A2

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20
Q

Exogenous mediators that promote aggregation (like thrombin). . .

A

bind to receptors on the platelet membrane and inhibit adenylate cyclase

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21
Q

Increases in intracellular calcium within platelets

A

trigger platelet activation (contraction, aggregation, release). Under physiologic circumstances, cAMP may play a role in regulating intracellular calcium concentration

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22
Q

cAMP and platelet aggregation

A

Decreased levels of cAMP are associated with increased aggregation, and increased cAMP levels with decreased aggregation.

Inverse relationship

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23
Q

Role of Fibrinogen in clotting

A

The aggregation reaction primarily results from the coordinated binding of plasma fibrinogen (a dimeric, high molecular weight glycoprotein) by integrins on the surface of adjacent activated platelets.

Fibrinogen (in the presence of ionized calcium) thus forms a “molecular bridge”, supporting platelet aggregation.

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24
Q

The coagulation cascade is only activated in. . .

A

secondary hemostasis

Where the insult is too large for primary hemostasis to cover it without depositing more fibrin.

25
Q

Producing a clot in a vessel larger than a capillary

A

by necessity requires secondary hemostasis via clotting cascade activation.

26
Q

The central event of the coagulation cascade is. . .

A

. . .conversion of the inactive zymogen (pro-enzyme) prothrombin into its active proteolytic form, thrombin, which converts fibrinogen (insoluble) to fibrin (soluble).

Fibrin monomers then polymerize into an insoluble, fibrous meshwork.

27
Q

Rough clotting cascade outline

A
28
Q

Common clotting cascade pathway

A
29
Q

Synthesis of coagulation factors

A

The liver is the site of synthesis of most coagulation factors, and synthesis of four of them (prothrombin and factors VII, IX, and X) requires vitamin K as a cofactor

30
Q

factor XII

A

First step in intrinsic pathway. Activated by contact with a “foreign” surface (subendothelial collagen in vivo or the glass wall of the test tube in vitro).

In addition to XIIa (active form) activating the clotting cascade, it also initiates the kinin cascade that will ultimately result in generation of bradykinin. It can also activate plasmin to activate the fibrinolytic system.

31
Q

thromboplastin

A

Another name for tissue factor. Initiates the extrinsic pathway.

32
Q

Both the intrinsic and extrinsic clotting pathways converge on generation of the ____.

A

Both the intrinsic and extrinsic clotting pathways converge on generation of the tenase complex.

capable of conversion of factor X (inactive) to Xa (active)

33
Q

In addition to activated coagulation factors, the tenase complex requires the presence of. . .

A

. . . membrane phospholipids and calcium (Ca++) ions, both of which are provided by platelets

34
Q

Xa

A

Once activated, factor Xa forms a complex with factor Va that, in the presence of membrane phospholipids and Ca++ (again), catalyzes conversion of prothrombin to thrombin. This is known as the prothrombinase complex.

35
Q

There is enough thrombin potentially available in a standard blood sample to clot. . .

A

There is enough thrombin potentially available in a standard blood sample to clot the entire circulating blood volume in a person.

36
Q

Control mechanisms of thrombosis

A
  • Removal/neutralization of activated clotting factors (Blood flow tends to dilute the local concentration of activated factors, slowed flow facilitates their accumulation)
  • Activation of coagulation inhibitors (A novel surface membrane protein of endothelium, thrombomodulin, activates Protein C in the plasma to generate anticoagulative/fibrolytic activity, also activating plasmin. In the presence of heparin on the vascular endothelium, plasma antithrombin III neutralize thrombin, Xa, and other clotting factors)
  • Stimulation of prostacyclin production in the endothelium (which inhibits platelet aggregatio)
37
Q

Fibrinolytic system

A
38
Q

plasminogen is cleaved by. . .

A

. . . tissue plasminogen activators or XIIa

39
Q

α2-antiplasmin

A

endogenous plasmin inhibitor that circulates in the blood to ensure that plasmin activity is kept local and does not dissemiante in the bloodstream.

40
Q

Aspirin in coagulation

A

inhibits platelet activation by preventing generation of thromboxane A2

Anticoagulant

41
Q

Purified heparin in coagulation

A

widely used clinically to treat or prevent intravascular coagulation

42
Q

Warfarin in coagulation

A

Aka Coumadin

blocks synthesis of vitamin K-dependent clotting factors (thrombin and factors VII, IX and X).

43
Q

Recombinant tPA (tissue plasminogen activator)

A

used therapeutically as a “clot-busting” agent to treat thrombosis

44
Q
A

Artery clogged by thrombus

45
Q

thrombus

A

A thrombus is a pathologic clot that forms within an intact vessel, resulting in occlusion of the vessel and ischemia (and possibly infarction) of the tissue supplied by the blocked vessel. It can be thought of as a misplaced homeostatic plug.

46
Q

lines of Zahn

A

Alternating celldense and cell-poor layers within a thrombus. Indicate that the clot formed under conditions of flowing blood

47
Q

Virchow’s triad

A
48
Q

Common sources of hypercoagulability

A
  • Interited mutations (factor V Leiden)
  • Smoking
  • Pregnancy
  • Cancer
49
Q

Patterns of abnormal bloodflow which may lead to thrombosis

A
  • Stasis
  • Turbulent flow (Narrowing, valves, etc)
50
Q

Clots are most commonly found at ____.

A

Clots are most commonly found at vascular branch points, since this is where flow transitions from laminar to turbulent

51
Q

embolus

A

When any substance dislodges and travels through the bloodstream, causing pathology at the site where it lands.

An embolus resultant from clotting is a thromboembolus

52
Q

mural thrombi

A

Form at sites of local stasis on the wall of the heart and may cause cardiac pathology. May also dislodge and result in embolism in the arterial system.

53
Q

Disseminated intravascular coagulation

A
54
Q

Almost ironically, much of the lethality of disseminated intravascular coagulation is from ____.

A

Almost ironically, much of the lethality of disseminated intravascular coagulation is from bleeding complications / hemorrhages, as a result of clotting factor consumption.

55
Q

The possible fates of a thrombus

A
  • Lysis by plasmin
  • Propagation / expansion
  • Embolization
  • Organization (chronic inflammation takes over, fibrosis)
56
Q

Evolution of a thrombus

A
57
Q

Why is aspirin so effective in preventing clotting?

A

Because of the interplay between prostacyclin and thromboxane, and because platelets don’t have nuclei!

Endothelial cells can always make more PGI2 synthase, but platelets are stuck with the Tx synthase that they have. Since aspirin is an irreversible inhibitor, that means that you will need to make new platelets (~7-8 days) to have thromboxane generation again.

58
Q

After organization, clotts. . .

A

. . . look more uniform and more like connective tissue, with new vasculature.

HMS Pathology (7 decks)

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