Anticoagulation / fibrinolytic pathway

Topic Completed: 1 June 2012

Minor changes: 24 February 2021

Copyright: 2002-2021,, Inc.

PubMed Search: Antithrombin [title] coagulation

Jeremy C. Parsons, M.D.
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Cite this page: Parsons JC. Anticoagulation / fibrinolytic pathway. website. Accessed October 25th, 2021.
Fibrinolysis pathway
  • Process of degrading the fibrin clot when it is no longer needed
  • Also prevents extension of clot beyond site of injury

tPA and uPA
  • Fibrinolysis initiated by tPA (tissue plasminogen activator) or uPA (urokinase-like plasminogen activator), which convert plasminogen to plasmin in the presence of fibrin by cleaving the Arg561-Val562 peptide bond
  • Plasmin degrades the fibrin clot and intact fibrinogen to soluble fibrin / fibrinogen degradation products (FDP)
  • Plasmin also inactivates factors Va and VIIIa (as do Protein C and Protein S)
  • tPA is produced by endothelial cells; its activation of plasminogen is major mechanism for lysis of fibrin clots
  • Recombinant tPA is used to treat myocardial infarction, stroke and some cases of acute thrombosis
  • uPA is found in urine and plasma
    • Keeps renal tracts free of blood clots
    • Also is important for other cell surfaces and initiating nonfibrinolytic activities of plasmin
  • Excessive fibrinolysis is prevented by plasmin inhibitor (antiplasmin, formerly called alpha2-antiplasmin) and plasminogen activator inhibitor 1 (PAI-1, inhibits tPA and uPA)

  • PAI-1 is synthesized by hepatocytes and endothelial cells, is present in platelets and plasma
    • Can bind to fibrin and inhibit plasminogen activators tPA and uPA
  • PAI-1 is an acute phase reactant protein, and may increase 30 - 50 fold over baseline, possibly immediately inactivating systemically administered tPA

Deficiency conditions
  • Homozygous deficiency of plasminogen is associated with ligneous conjunctivitis (rare form of chronic pseudomembranous conjunctivitis), and replacement therapy with plasminogen is therapeutic
  • Neither heterozygous plasminogen deficiency (0.5 to 2.0% of patients with thrombosis) nor tPA deficiency are associated with increased risk of thrombosis
  • References: Arch Pathol Lab Med 2002;126:1376, Clin Lab Med 2009;29:159
Proteins C and S
  • Pathway is a physiologic anticoagulant system to limit blood clot formation (i.e. fibrinogen to fibrin conversion) to site of vessel injury
  • Major anticoagulant systems are protein C and protein S, antithrombin and tissue factor pathway inhibitor (TFPI, see extrinsic pathway)
  • Protein C and S: Vitamin K dependent anticoagulant proteins produced mainly in liver ("C" because was third peak to elute from a diethylaminoethyl affinity column and "S" because it was discovered in Seattle, WA)
  • Activation:
    • Endothelial cell protein C receptor binds thrombin-thrombomodulin complex, which activates protein C, which binds to free protein S on endothelial or platelet phospholipids surfaces
    • This protein C / protein S complex degrades factors Va and VIIIa, which reduces fibrin formation
    • Activated protein C also indirectly promotes fibrinolysis
    • 60 - 70% of protein S is bound to and inactivated by C4b binding protein, an acute phase reactant
  • Clinical note:
    • Since C4b increases during pregnancy, the protein S level will routinely fall below the normal non-pregnant range
    • Protein C has the shortest half life of the vitamin K dependent proteins
      • When placed on warfarin the patient loses the anticoagulant properties of protein C much more quickly than the pro-coagulation effects of factor VII, II, IX and X
      • This leads to warfarin necrosis which can be prevented by bridging with heparin
  • References: Arch Pathol Lab Med 2002;126:1337, Goodnight: Disorders of Hemostasis & Thrombosis, 2nd Edition, 2000
  • Intrinsic membrane glycoprotein on luminal surface of endothelial cells that binds thrombin and facilitates the activation of protein C
  • C/T dimorphism at nucleotide 1418 is associated with premature myocardial infarction, but no definite association with venous thromboembolism
  • See also discussion in Stains chapter
  • References: BMC Neurol 2004;4:21
Diagrams / tables

Images hosted on other servers:

Natural anticoagulants

Thrombomodulin function

Thrombomodulin protein

Counterbalance of clotting pathway

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