Fibrinolysis Flashcards
Fibrinolysis definition
Removing unwanted fibrin deposits
Fibrin is cleaved enzymatically to soluble fragments
RES system removes fragments
Re-establisheds blood flow previously occluded by thrombus
fibrinogen
soluble
coagulation cascade
fibrin
insoluble
fibrinolysis
FDPs
soluble
plasmin
Acts on fibrin to produce lysis of clot.
Generated from plasminogen
Plasmin is activated by
Tissue plasminogen activator (tPA) - other possibilities: XIIa, Kallikrein and HMWK
inhibitors of plasmin function to keep fibrinolysis in check
a2 antiplasmin
a2 macroglubolin
many more
tPA is produced by
vascular endothelial cells
tPA selectively binds and…
activates fibrin bound plasminogen
- does not activate circulating plasminogen
idea therapeutic fibrinolytic agent
Plasmin action:
destroys fibrinogen and fibrin non-selectively
Plasmin produces
FDPs - fibrin(ogen) degradation products
increases vascular perm.
interfere with thrombin induced fibrin formation
produces D dimer - degradation product from fibrin polymer
Plasmin destroys these factors
V
VIII
IX
XI
plasmin indirectly enhances
conversion of XII –> XIIa
Plasmin enhances conversion of PK to
Kallikrein
Plasmin cleaves
C3 into fragments (complement system)
Plasmin is an _ able to break down _ and _
endopeptidase
fibrinogen
fibrin
fibrinogen is in the bridges,
connecting platelets and fibrin is in the polymer form creating the fibrin clot
Plasmin action on fibrinogen
splitting off pieces of a, b, y polypeptides. These pieces are not present in the fibrin polymer
What is left: X monomer
X monomer
2 D parts, and 1 central E part
(still thrombin clottable)
From this point, fibrin and fibrinogen degradation is similar
Continued fibrinogen and fibrin (plasmin acting)
Plasmin then cleaves off one D fragment
This leaves a D fragment and a Y monomer.
Y consists of 1D part and 1 E part
- NOT thrombin clottable
Last,
Plasmin cleaves Y monomer which leaves the product: D fragment, E fragment, D fragment
Plasmin acting on fibrin and fibrinogen product
D fragment, E fragment, D fragment
Early FDP
X monomer vs Y monomer
X: D-E-D
Y: E-D or D-E
Late FDP
D fragment (2 separate)
E fragment
Fibrin polymers are connected by
the outside D parts
When plasmin cleaves the E part
This leaves 2 D parts connected together (polymer)
D Dimer (End product)
lab test - D dimer
Quantitative test
D dimer is product of a dissolved clot. - evidence there was a fibrin polymer
elevated D dimer test seen in
thrombotic conditions
DIC
Deep vein Thrombosis
Pulmonary Embolism
Kinin System
Important in inflammation, vascular permeability and chemotaxis
Activated kinin system
Coagulation (Factor XII)
Fibrinolytic (plasmin) system
Kinin system enhances
Coagulation system
Fibrinolytic system
kinin end product
Bradykinin
Bradykinin functions
increase vascular permeability
contracts smooth muscle
dilates small blood vessels
induces inflammation and pain
Stimulates release of
prostaglandins from tissues
Coagulation inhibitory systems
Serine protease inhibitory System
Tissue factor pathway inhibitor
Antithrombin
Plasmin, kvllikrein and serine protease enzymes continue to
circulate after they are needed
Coag factors are eliminated by
Liver hepatocytes
Mononuclear Phagocytic system
Serine protease inhibitors in plasma - serine protease inhibitors bind and inactive them.
Serine protease inhibitor
Protein C
Protein C consists of
Thrombin (enzyme)
Thrombomodulin ( cofactor)
Protein S (cofactor)
Protein C end product
cleaves Va and VIIIa
TPFI
associated with a lipoprotein that inhibits plasma coagulation
TPFI binds the
activated form of factor IXa or Xa
Complex of TPFI-Xa or TPFI-IXa binds
cofactor VIIa on membrane and further restricts activation of the common pathway
Heparin cofactor I
AT (antithrombin)
AT funciton
inactivator of thrombin and Xa (common pathway)
> 90% of antithrombin activity is derived from AT
Action is increased by heparin
Lab test - Anti-Factor Xa Assay
inhibition of Xa will occur in proportion to amount of heparin present.
Any uninhibited activated Xa will cleave a substrate, producing a color change. Chromogenic assay.
Degree of color is inversely proportional to heparin in sample
Lupus anticoagulant - falsely though inhibitor
Antibodies against phospholipid - binding proteins.
First discovered in SLE patients
Lupus anticoagulant in vivo
agonist, leading to increased thrombosis and non-needing clotting
Lupus anticoagulant in vitro
inhibitor leading to delay in clotting assays including PT and APTT
APTT/PT are useful in
identifying factor deficiencies and coag inhibitors
