FIBRINOLYSIS

• Plasminogen Activators

  Facilitate the plasminogen activation (plasminogen becoming plasmin)
• Fibrinolysis


  Physiological process that removes insoluble fibrin deposits by enzymatic digestion of the stabilized fibrin polymers
• Bacterial Products


  Enzymes that can help lyse the clot by converting plasminogen to plasmin (Staphylokinase and Streptokinase)
• Components of Fibrinolysis

  • Plasminogen: inactive protein synthesized by the liver
  • Plasmin: activated form of plasminogen
  • Plasminogen Activators: t-PA, urokinase-PA, contact phase activators, bacterial products
  • Fibrinogen and Fibrin
  • Inhibitors: TAFI, PAI-1, a2-antiplasmin
• TAFI, PAI-1, a2-antiplasmin are inhibitors of fibrinolysis
• Urokinase-PA


  Activator derived from the genitourinary tract
• Plasmin cannot separate the D-Dimer. D-Dimer can be binded on X or Y, then the plasmin will separate all of them (X, Y, D-Dimer)
• 1. Dimer

  Positive on fibrinolysis. If present, fibrinolysis is classified as primary or secondary depending on the presence or absence of a clot
• If D-Dimer is present, fibrinolysis is classified as primary
• Plasmin


  Responsible for forming degradation or fibrin split products consisting of intermediate fragments X and Y, and fragments D and E
• Fibrinolysis


  • Refers to the processes involved in removing a clot
  • Hemostasis refers to the process of maintaining blood in its liquid state, achieved through a check and balance mechanism
  • After injury or bleeding stops, clots should be destroyed and removed
  • In the absence of an injury, regulatory proteins or inhibitors should be present to prevent the formation of a clot
• Tissue Plasminogen Activator (t-PA)

  Most potent and number one activator released by the endothelial cells. It is only released if there is an injury
• Fibrin


  The active form of fibrinogen. Fibrin has different peptides (monomers). Factor XIIIa stabilizes the link between those monomers
• Plasmin will destroy both fibrin and fibrinogen surrounding the injury site to stop the further production of clot
• If D-Dimer is absent, fibrinolysis is classified as secondary
• Contact Phase Activators

  Clotting factors that can activate plasminogen to become plasmin. Factors XIIa, XIa, and K can convert plasminogen to plasmin
• Primary fibrinolysis means there is lysis because there is a clot. Secondary fibrinolysis is the continuous lysis even if there is no clot
• Plasmin cleaving fibrinogen


  Fragment X (D, E, D) is formed (still capable of forming a clot)
• Inhibitors of fibrinolysis


  • TAFI
  • PAI-1
  • a2-antiplasmin
• If there is fibrin

  Plasminogen has a very high affinity on the clot
• PLASMIN


  • Destroys other clotting factors
  • Can destroy Factors V, VIII, IX, XI
  • Complement activation by cleaving a portion of C3
  • Activates kinin system inducing inflammation
• α2 – macroglobulin


  Used when α2-antiplasmin is saturated
• Plasmin further lyses Fragment Y

  Forming D, E fragments (dead end), total separation
• Anti-thrombin III


  Special regulatory protein used to stop fibrinolysis
• Plasminogen activator inhibitor-1 (PAI-1)


  Inhibits the conversion of plasminogen to plasmin
• Fibrinolysis


  Continuous lysis even if there is no clot
• Convert plasminogen to plasmin to lyse clot


  1. Plasminogen is converted to plasmin to circulate in plasma

  2. Cannot remove a lot, lysis dot and fibrinogen having a lot of plasmin can cause bleeding

  3. Activate plasminogen (PLASMIN) from kidney cells, contact group factors (t-xu.xi.HMWK.PK)
• 1. PA converts plasminogen to plasmin


  The destruction of clots starts
• Fragment X further lysed by plasmin

  Fragment Y (D, E) but still capable of forming a clot
• Thrombin-activatable fibrinolysis inhibitor (TAFI)


  Prevents binding of plasminogen to clot
• α2 – antiplasmin

  Stops/inhibits plasmin
• Removal of fragments

  With the help of WBCs through phagocytosis
• α1 – antirypsin


  Used when α2-macroglobulin is saturated
• Fragment D-dimers can still form a clot
• Plasma base clotting involves in most coagulation tests
• References: 'Prof. Antonio C. Pascua Jr., RMT, MSMT. HEMA312 Lecture. Our Lady of Fatima University, Valenzuela City; Rodak’s Hematology: Clinical Principles and Applications, 6th Edition; Clinical Hematology: Theory and Procedures, 5th Edition, Turgeon, M.L.; Steininger, Cheryl et al. Clinical Hematology: Principles, Procedures and Correlations'
• Thrombin-activatable fibrinolysis inhibitor (TAFI) prevents the binding of plasminogen to clot
• Irreversible plasmin inhibitor (Irypsin) is used when a2-macroglobulin is saturated
• 1. Dimers are used to check for excessive fibrinolysis
• Anti-thrombin III is a special regulatory protein used to stop fibrinolysis by stopping thrombin, which in turn stops the release of t-PA out of the endothelial cell