MLAB 1227- Coagulation Keri Brophy-Martinez

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MLAB 1227- CoagulationKeri Brophy-Martinez

• Fibrinolytic System

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Fibrinolysis

• Process of removing fibrin from the vasculature

• Key Players
• Plasminogen
• Plasminogen activators (PA)
• Active enzyme plasmin (PLN)
• Fibrin
• Fibrin/Fibrinogen degradation products
• Inhibitors of plasminogen activators and PLN

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Fibrinolytic System

• Sensitive to imbalances
• Restricts fibrin formation to area of injury
• Initiated when coagulation cascade begins
• Dissolves clot by digestion of fibrin

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Overview

• Under the influence of thrombin.
• Fibrinogen cleaved into fibrin monomers
• Fibrin monomers are cleaved into fibrin
  degradation products or fibrin split products

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Process summary

• Once clotting begins, the fibrinolytic system
  comes to life
• Plasminogen (PLG) binds to fibrin in the
  developing thrombus
• Tissue-type PLG activator (tPA) also binds to
  fibrin, increasing its enzymatic activity to
  convert plasminogen to plasmin (PLN)
• Complex formation of tPA, PLG and fibrin results
  in the break-down of fibrin
• PLN then further digest fibrin to soluble
  degradation products making fibrin fragments

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Plasminogen

• Produced in the liver
• Found in normal plasma
• Following injury, binds to fibrin during clot
  formation along with plasminogen activators

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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

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Activators
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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

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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.

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Plasmin Degradation of Fibrinogen

E
Fibrinogen
D
D
plasmin
E
D
D
Fragment X small peptides from carboxyl end of a
chain removed
plasmin
E
Fragment Y Fragment D
D
D
plasmin
E
D
Fragment D Fragment E
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• Plasminogen
• Intrinsic/contact activation
  Physiologic activation
• 
  Exogenous activation
• Plasmin
• Fibrin clot Fibrinogen
• Fibrin
• Degradation Fibrinogen
• Products Degradation
• Products
• X,Y,DD,E X,Y,D,E,D

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Inhibitors of Fibrinolysis

• Used to regulate and limit plasmin activity and
  fibrinolysis
• Also referred to as an antiplasmin
• How?
• Target PLG activation step
• Target plasmin

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Inhibitors of Fibrinolysis
Inhibitors
Inhibitors
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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

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Specific Inhibitors

• alpha-2-antiplasmin
• Rapid inhibitor of plasmin
• Functions to catch leaked PLN in the
  circulation, thus limiting activity to fibrin
  clot
• Produced in liver and a granules in platelets
• alpha-2-macroglobulin
• Slower inhibitor of plasmin

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References

• McKenzie, Shirlyn B., and J. Lynne. Williams.
  "Chapter 30." Clinical Laboratory Hematology.
  Boston Pearson, 2010. Print.