Transcript Fibrinolysis

MLAB 1227- Coagulation
Keri Brophy-Martinez
Fibrinolytic System
Fibrinolysis

Process of
removing fibrin
from the
vasculature

Key Players
◦ Plasminogen (PLG)
◦ Plasminogen activators (PA)
◦ Active enzyme plasmin
(PLN)
◦ Fibrin
◦ Fibrin/Fibrinogen
degradation products
◦ Plasminogen activator
inhibitor
Fibrinolytic System
Sensitive to imbalances
 Restricts fibrin formation to area of injury
 Initiated when coagulation cascade begins
 Dissolves clot by digestion of fibrin

Overview
Under the influence of thrombin.
 Fibrinogen cleaved into fibrin monomers
 Fibrin monomers are cleaved into fibrin
degradation products or fibrin split
products

Process summary

Once clotting begins, the fibrinolytic
system comes to life
1. Plasminogen (PLG) binds to fibrin in the developing
thrombus
2. Tissue-type PLG activator (tPA) also binds to fibrin,
increasing its enzymatic activity to convert
plasminogen to plasmin (PLN)
3. Complex formation of tPA, PLG and fibrin results in
the break-down of fibrin
4. PLN then further digest fibrin to soluble
degradation products making fibrin fragments
Plasminogen
◦ Produced in the liver
◦ Found in normal plasma
◦ Following injury, binds to fibrin during clot
formation along with plasminogen activators
Activators of Fibrinolysis

Contact Phase/Intrinsic
◦ Occurs by interactions of the contact factors (XIIa, HMWK, and PK)
following intrinsic pathway activation(collagen exposure)

Physiologic
 Activators released from tissues extrinsic to the blood
 tPA: tissue- type PLG activator
 Found in endothelial cells of small vessels
 uPA: urokinase-type PLG activator
 Made in renal tubular epithelium and vascular epithelium
 Found in urine and plasma
◦
Exogenous activation
 Via medications given to lyse pathogenic clots (i.e. pulmonary emboli)
 Example includes Streptokinase
Activators
Plasmin

Proteolytic enzyme
 Dissolves fibrin/fibrinogen clots into protein
fragments that are cleared from plasma by the
liver
 Provides a positive feedback loop for forming
more plasminogen



Highly regulated
Temporarily active
Local
Fibrinogen and Fibrin

Fibrin degradation products are the protein fragments of fibrin or
fibrinogen.
◦ The protein fragments are designated X,Y, D, and E
◦ Fragments are strong inhibitors of further coagulation by
 interfering with the action of thrombin
 interfering with platelet aggregation
 In the lab, referred to as FDPs or FSPs
 Fibrin degradation products are cleared by the liver

Fibrinogen and fibrin yield essentially the same fragments; however
degradation of cross-linked fibrin is slower and leads to fragments
that contain D-dimer.
Plasmin Degradation of Fibrinogen
Fibrinogen
D
E
D
plasmin
D
E
Fragment X: small
D
peptides from carboxyl
end of α chain removed
plasmin
D
E
D
Fragment Y +
Fragment D
plasmin
D
E
Fragment D +
Fragment E
Plasminogen
Intrinsic/contact activation
Physiologic activation
Exogenous activation
Plasmin
Fibrin clot
Fibrin
Degradation
Products
X,Y,D=D,E
Fibrinogen
Fibrinogen
Degradation
Products
X,Y,D,E,D
Inhibitors of Fibrinolysis
Used to regulate and limit plasmin
activity and fibrinolysis
 Also referred to as an antiplasmin
 How?

◦ Target plasminogen activation step
◦ Target plasmin
Inhibitors of Fibrinolysis
Inhibitors
Inhibitors
Specific Inhibitors

Plasminogen Activator Inhibitor (PAI)
◦ PAI-1: most significant
◦ Inhibits tPA and uPA
◦ Acute phase reactant protein

Thrombin Activatable Fibrinolysis
Inhibitor (TAFI)
◦ Eliminates fibrin binding sites for plasminogen
Specific Inhibitors

alpha-2-antiplasmin
◦ Rapid inhibitor of plasmin
◦ Functions to “catch” leaked plasmin in the
circulation, thus limiting activity to fibrin clot
◦ Produced in liver and α granules in
platelets

alpha-2-macroglobulin
◦ Slower inhibitor of plasmin
References

McKenzie, Shirlyn B., and J. Lynne.
Williams. "Chapter 30." Clinical
Laboratory Hematology. Boston:
Pearson, 2010. Print.