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Coagulation > Fibrinolytic System Physiology > Flashcards

Fibrinolytic System Physiology Flashcards

1
Q

What are the key ways fibrin is broken down in the body ?

A
  • fibrin is a temporary substance
  • macrophages and fibroblasts can break it down with fibrinolytic system
    • primarilty removed by leukocytes and fibroblasts
  • Fibrinolyitic system - series of proteins that ultimately produce enzyme Plasmin
    • Plasmin cleaves fibrin into soluble fragments
  • Fibrinolytic system has two components
    • Intravascular
      • regulates formation and removal fibrin at sites of vascular injury
    • Extravascular
      • key to tissue remodeling and cell migration
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2
Q

How is intravascular fibrinolysis initiated ?

A
  • initiated by Tissue plasminogen activator (tPA) which is released by the endothelial cells
    • ​tPA cleaves plasminogen into active plasmin
  • formation of a large thrombus indicates that fibrinolytic regulation has been overcome either because of excessive clotting or decreased fibrinolytic activity
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3
Q

What is D-dimer composed of ?

A
  • consists of Factor XIIIa cross-linked ends of two fibrin molecules

The concentration of D-dimer in the blood is an indication of the amount of cross-linked fibrin in the vascular system.

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4
Q

What molecule increases the speed of tPA conversion of

plasminogen to plasmin ?

A
  • tPA has a one chain and a two chain form
    • in the absence of fibrin, the conversion of plasminogen to plasmin is quite slow
    • with fibrin present, conversion 1000x faster
  • Urokinase plasminogen activator
    • similar rate of conversion as tPA
  • IMP: there is essentially no circulating active plasmin in normal blood (inhibited by alpha-2 plasmin), so most tPA and uPA circulate in the single chain form.
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5
Q

What forms does Plasminogen Activator Inhibitory 1 (PAI-1)

inhibit for tPA and uPA ?

A
  • one chain and two chain tPA can be inactivated
  • only the two chain uPA is inactivated

Note: UPA is the primary extravascular plasminogen activator secreted by several different tissue types.

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6
Q

How have the facets of the contact system been

implicated in the activation of fibrinolysis ?

A
  • Kallikrein activation causes scuPA activation
  • Bradykinin causes release of tPA from endothelial cells
  • Factor XIIa helps with activation of plasminogen
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7
Q

What is the role of plasminogen in fibrinolysis ?

A
  • binds to fibrin
  • activated form degrades fibrin
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8
Q

What is the role of tPA in fibrinolysis ?

A
  • binds to fibrin
  • converts plasminogen to plasmin
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9
Q

What is the role of urokinase plasminogen activator ?

A
  • intravascular and extravascular localization
  • activated form converts plasminogen to plasmin
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10
Q

What is the role of Factor XII (Hageman Factor) ?

A
  • activated form promotes conversion of plasminogen to plasmin
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11
Q

What is the role of HMW Kininogen in fibrinolysis ?

A
  • activated form stimulates tPA release from endothelial cells.
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12
Q

What is the role of prekallikrein (Fletcher factor) in fibrinolysis ?

A
  • activated form promotes activation of uPA
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13
Q

What are the key fibrinolytic inhibitors and what

is their role ?

A
  • alpha2-antiplasmin: binds plasmin
  • plasminogen activator inhibitor-I (PAI-1): binds tissue plasminogen activator and urokinase plasminogen activator
  • thrombin-activatable fibrinolysis inhibitor (TAFI): activated form removes lysine binding sites for plasminogen/plasmin from fibrin
    IMP: TAFI protects the Fibrin clot against lysis and stabilizes it.
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14
Q

What tissues release plasminogen activator inhibitor-1 (PAI-1) ?

A
  • liver, adipose tissue, megakaryocytes
  • possibly vascular endothelium

Note: platelets contain substantial amounts of PAI-1

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15
Q

What are the clinical findings of a deficiency of PAI-1 ?

A
  • there is moderate bleeding
  • caused by uncontrolled plasminogen activation
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16
Q

What other proteins can plasmin degrade ?

A
  • Fibrin
  • Factors V and VIII
  • platelet glycoprotein

Note: primary inhibitor of plasmin is alpha2-antiplasmin (fastest one)

  • alpha2 antiplasmin is cross-linked to fibrin by factor XIIIa
17
Q

The liver produces what fibrinolytic

pathway molecules?

A
  • fibrinogen
  • plasminogen
  • antiplasmin
18
Q

When can you see high levels of PAI-2

in the peripheral blood?

A
  • usually not measureable in normal plasma but it is secreted by the placenta and reaches high levels in plasma during pregnancy.
  • role in regulating fibrinolysis is unclear
19
Q

What molecule has been found to inhibit

fibrinolysis more than PAI-1 ?

A
  • alpha-2 antiplasmin plays a more important role in inhibiting fibrinolysis
  • Complete homozygous deficiency of alpha-2 antiplasmin
    • moderate to severe bleeding syndrome
    • causes uncontrolled fibrinolysis
20
Q

What is TAFI and it’s role in fibrinolysis regulation ?

A
  • protein secreted by the liver and produced by megakaryocytes
  • platelest have a small amount in alpha granules, most just circulates in the blood
  • protein is a carboxypeptidase
    • removes newly exposed lysine molecules on fibrin
    • loss of lysine slows plasminogen activation, lysis of fibrin
      • makes plasmin more susceptible to alpha-antiplasmin
      • overall stabilizes fibrin clot
  • circulates in an inactive form
    • converted by proteolytic cleavage by thrombin-thrombomodulin complex and lesser extent by plasmin
21
Q

What three process affect the plasma levels of fibrinolytic factors ?

A
  • release of fibrinolytic proteins into plasma
  • inhibition of active proteins
  • clearance of proteins from the plasma
22
Q

How can tPA be increased in the plasma ?

A
  • generally tPA is released at a constant rate
  • it can be increased in two ways
    • endothelial cells have a storage pool of tPA which can be released in seconds when stimulated by:
      • vasoactive substances such as epinephrine, bradykinin or vasopressin
    • increased in association with acute phase inflammatory response
      • process requires new protein production so takes a little bit of time
23
Q

What is the pattern of release of PAI-1 ?

A
  • highly variable in humans
  • follows a circadian variation
    • peak activity in the morning
    • nadir in the afternoon and evening

IMP: PAI-1 is also an acute phase reactant similar to tPA, although it increases by significantly more

24
Q

How are tPA and PAI-1 cleared from the body ?

A
  • both active tPA and PAI-1 complex are cleared from the blood by the liver
    • clearance is dependent on liver blood flow, so it is slowed by cirrhosis
    • also SUPER delayed at the end of liver transplant before the new liver is connected, essentially no clearance until that happens
  • TPA clearance is rapid
    • 2-4 minutes
  • tPA-PAI-1 clearance
    • 4-6 minutes
25
Q
A

Coagulation (17 decks)

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