Fibrinolytic System Physiology Flashcards
What are the key ways fibrin is broken down in the body ?
- 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
- Intravascular
How is intravascular fibrinolysis initiated ?
- 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
What is D-dimer composed of ?
- 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.
What molecule increases the speed of tPA conversion of
plasminogen to plasmin ?
- 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.
What forms does Plasminogen Activator Inhibitory 1 (PAI-1)
inhibit for tPA and uPA ?
- 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.
How have the facets of the contact system been
implicated in the activation of fibrinolysis ?
- Kallikrein activation causes scuPA activation
- Bradykinin causes release of tPA from endothelial cells
- Factor XIIa helps with activation of plasminogen
What is the role of plasminogen in fibrinolysis ?
- binds to fibrin
- activated form degrades fibrin
What is the role of tPA in fibrinolysis ?
- binds to fibrin
- converts plasminogen to plasmin
What is the role of urokinase plasminogen activator ?
- intravascular and extravascular localization
- activated form converts plasminogen to plasmin
What is the role of Factor XII (Hageman Factor) ?
- activated form promotes conversion of plasminogen to plasmin
What is the role of HMW Kininogen in fibrinolysis ?
- activated form stimulates tPA release from endothelial cells.
What is the role of prekallikrein (Fletcher factor) in fibrinolysis ?
- activated form promotes activation of uPA
What are the key fibrinolytic inhibitors and what
is their role ?
- 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.
What tissues release plasminogen activator inhibitor-1 (PAI-1) ?
- liver, adipose tissue, megakaryocytes
- possibly vascular endothelium
Note: platelets contain substantial amounts of PAI-1
What are the clinical findings of a deficiency of PAI-1 ?
- there is moderate bleeding
- caused by uncontrolled plasminogen activation
What other proteins can plasmin degrade ?
- 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
The liver produces what fibrinolytic
pathway molecules?
- fibrinogen
- plasminogen
- antiplasmin
When can you see high levels of PAI-2
in the peripheral blood?
- 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
What molecule has been found to inhibit
fibrinolysis more than PAI-1 ?
- 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
What is TAFI and it’s role in fibrinolysis regulation ?
- 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
What three process affect the plasma levels of fibrinolytic factors ?
- release of fibrinolytic proteins into plasma
- inhibition of active proteins
- clearance of proteins from the plasma
How can tPA be increased in the plasma ?
- 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
- endothelial cells have a storage pool of tPA which can be released in seconds when stimulated by:
What is the pattern of release of PAI-1 ?
- 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
How are tPA and PAI-1 cleared from the body ?
- 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
