Midterm #3: Coagulation Cascade Flashcards Preview

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Flashcards in Midterm #3: Coagulation Cascade Deck (39):

Purpose of Clotting Cascade


  • Plasma proteins that rapidly form a clot at damage site to minimize blood loss (hemorrage) and to maintain homeostasis 



  • refers to the maintenance of the fluid state of the blood
  • Requires a delicate balance between procoagulation (clot formation), anticoagulation, and fibrinlysis (clot dissolution)
  • Dozens of plasma proteins are involved, as well as tissue protiens, blood platelets and surfaces of endotheilial cells that line vessels
  • Defects in these can lead to pathological bleeding or thrombosis (clotting)


The 5 phases of Coagulation: Overview

  1. ​Vasocontriction
  2. Formation of hemostatic plug
  3. Formation of a blood clot
  4. Control of coagulation
  5. Fibrinolysis



  • Damage to vessel walls leads to smooth muscle spasm that results in narrowing of blood vessel diameter
  • Limits blood flow to the damaged area and to allow localization of platelets and clotting factors
  • Can last up to 30 min
  • Vessel damage exposes collagen to the blood which is an important trigger for subsequent phases of coagulation


Formation of a Hemostatic Plug  

  • platelets bind to the site of damage (adhesion)
  • release signaling factors (activation)
  • and stick together to form a scaffold for clotting (aggregation)


Formation of a Blood Clot 

  • cross-linked fibrin reinforces the platelet plug to form a clot via a cascade of enzymatic reactions  


Control of Coagulation 

  • negative feedback signaling ensures that clot formation does not continue unchecked. 



  • the clot is removed after the underlying problem (injury, infection, etc.) is dealt with. 



  • circulating, anuclear cells that are fragments of megakaryocytes, which are produced in the bone marrow
  • contain mitochondria and glycogen granules 
  • No DNA or protein synthetic capability 
  • contain ADP, serotonin (5-HT), and platelet factors (PFs) that play important roles in vasoconstriction, the formation of a platelet plug, and clotting.  



  • damage to endothelial cells exposes collagen to which platelets bind, and releases the von Willebrand factor (vWF) which enhances collagen:platelet binding. 



  • binding stimulates the platelets to release ADP, serotonin (5-HT), thromboxane A2 (TxA2) and “platelet factors”. These compounds mediate further vasoconstriction and the transition to a “sticky” platelet. 



  • Sticky platelets form form a hemostatic plug that serves as a scaffold for the subsequent clotting cascade. 


prostacyclin (PGI2)  

  • produced by undamaged endothelial cells. 
  • causes vasodilation and inhibits platelet aggregation. 


Phase 2 Diagram

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The Anti-Platelet Activity of Aspirin


  • covalently inactivates cyclooxygenase in both platelets and endothelial cells. 
  • Shuts down thromboxane synthesis and inhibits platelet aggregation 
  • Inhibition of endothelial COX shuts down prostacyclin synthesis, which has the opposite effect. 
  • At lower asprin concentration, platelet COX inactivated and cannot be regenerated
    • Endothelial can synthesize more enzyme

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Name This Structure

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  • Clopidogrel 
  • Anti-platelet drug
  • Inhibits a platelet ADP receptor and thereby inhibits aggregation 


Phase 3: Formation of a Blood Clot

  • Cascade (amplified series of signals) results in proteolysis of fibrinogen (soluble plasma protein) to fibrin monomer
  • Fibrin monomers polymerize to form a mesh network, the fibrin clot that traps blood cells and helps plug the leaking vessel 
  • Strengthened by cross-links between Lys and Arg residues catalyzed by a transglutaminase enzyme

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Getting to Know the Clotting Factors 

  • Most numbered I to XIII and are synthesized as inactive zymogens (proenzymes
  • Each factor must be activated often involving proteolysis
  • Vitamin K Dependent Factors:
    • IX, VII, X, and II (prothrombin)
    • Require Ca++ for activity
  • Thrombin Sensitive Factors
    • V, VIII, XIII, and I (fibrinogen)
  • Named clotting factors:
    • Fibrinogen (I) and fibrin (Ia)
    • Prothrombin (II) and thrombin (IIa)
    • Tissue Factor (III)
    • Transglutaminase (XIIIa)
    • Prothrombinase (complex of Xa and Va)
    • Tenase (VIIa or a complex of VIIIa and IXa; activate X and operate in extrinsic and intrinsic pathways respectively)


Overview of the Clotting Cascade: Intrinsic and Extrinsic Pathways

  • Intrinsic Pathway: triggered by exposed collagen and von Willebrand factor
  • Extrinsic Pathway: triggered by tissue factor released by damaged epithelial cells 


Overview of Clotting Cascade: Diagram

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The Extrinsic Clotting Pathway 

  • a.k.a. the Tissue Factor Pathway 
  • Damaged blood vessels release Tissue Factor (factor III) 
  • TF binds to the Factor VII and activates it 
    • limits coagulation to injury site
  • VIIa is a Ca2+-dependent protease that converts X to Xa (tenase activity) 
  • Factor Xa is a Ca2+-dependent protease that, with factor Va, cleaves prothrombin (factor II) to thrombin (factor IIa) 
  • Va also binds to activated platelets 
    • localizes clotting
  • Thrombin is a Ca -dependent protease that 
 cleaves fibrinogen (I) to fibrin (Ia) 
  • Fibrin polymerized to form a soft fibrin clot
  • Thrombin also activates Factor XIII, which is a transglutaminase that cross-links fibrin polymers to form a mesh network: the hard fibrin clot

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The Intrinsic Clotting Pathway  

  • a.k.a. the Contact Clotting Pathway
  • Damaged blood vessels expose collagen 
  • Factor XII binds to the site of the injury (aided by the other contact activation factors: prekallikrein and high-molecular-weight kininogen [HK]) and autoactivates to XIIa 
    • vWF promotes this process
  • Factor XIIa proteolytically activates XI to XIa 
    • XIa activates factor IX which, together with factor VIIIa, activates factor X to Xa (tenase activity). 
  • Remainder of pathway leading to fibrin activation is the same as the extrinsic pathway

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The Central Role of Thrombin 

  • Thrombin proteolytically activates V, VIII and XIII
    • promotes coagulation via feedback activation
  • Thrombin also activates platelets by proteolysis of the thrombin receptor in the platelet cell membrane 
  • Cascade is amplifying because each protease is a catalyst for the activation of another catalyst
    • Very small amount of Factor VIIa can generate larger amount of Factor Xa, which can then generate an even larger amount of thrombin 
  • Tissue factor pathway more important in vivo and generates a "thrombin burst" required for efficient & timely clotting 

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Phase 4: Control of Coagulation and Clot Retraction 

  • Initation of coagulation cascade activates am=nti-coagulation proteins (feedback inhibition)
  • Tissue Factor Pathway Inhibitor (TFPI): is a plasma protein that inhibits thrombin and Xa. The Xa:TFPI complex further inhibits VIIa
  • Anti-Thrombin (AT) inactivates thrombin and Xa. AT inhibition is strongly stimulated by heparan sulfate a glycoaminoglycan composed of repeats of sulfated disaccharides
  • Protein C and Protein S: Protein C is activated by a complex of thrombin and thrombomodulin (found on the surface of endothelial cells) and then binds to Protein S. The complex inhibits Va and VIIIa
  • activated platelets in the clot physically contract, shrinking the fibrin network and making the clot denser and mechanically stronger

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Phase 5: Fibrinolysis

  • After clot formation, underlying problem can be repaired
  • Blood clot must be removed to restore normal blood flow
    • Funx of fibrinolytic pathway
  • Thrombin:thrombomodulin complex induces the release of tissue plasminogen activator (tPA) which activates plasminogen to plasmin
  • Plasmin is a protease that degrades fibrin to soluble degradation products
  • Urokinase (produced in the kidneys) and streptokinase (produced by bacteria) can also activate plasmin 
  • Fibrinolysis can be inhibited in 2 ways:
    • direct inhibition of plasmin by alpha2-antiplasmin
    • inhibition of plasminogen activation by plasminogen activator inhibitor (PAI)

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  • hereditary disease that impair coagulation process
  • vonWillebrand diesase: deficiency of vWF
  • hemophilia A: Factor VIII deficiency
  • hemophilia B: Factor IX deficiency 
  • Can get recombinant factors VIII, and IX


Hypercoagulability disorders (a.k.a. congenital thrombophilias) 

  • defects in anticoagulation 
  • such as Factor V Leiden thrombophilia  
  • mutation in factor V that prevents inactivation by PC:PS complex



  • Accumulation of cholesterol rich plaques in vessels
  • Can become calcified
  • Can narrow vessel 
  • Block occur when clot forms from when plaques rupture of when inflammation causes tissue factor exposure


myocardial infarction, stroke, pulmonary embolism

  • A clot in coronary artery: myocardial infarction
  • A clot in cerebral artery: stroke
  • Deep vein thrombosis during periods of stasis or immobilization. Can dislodge and travel to the lung and cause pulmonary embolism 



  • glycosaminoglycan similar to heparan sulfate, but is more highly sulfated and is produced solely by basophils and mast cells
  • promotes inhibition of thrombin (IIa) and Xa by anti-thrombin 
  • Must be given via injection, can have significant side effects like thrombocytopenia and needs closely monitored therapy
  • Unfractionated heparin (12-15 kDa)
  • Low Molecular Weight heparins (<8 kDa): more predictable activity, shorter half-life, and lower incidiences of side effects


Name this structure

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  • pentasaccharide that binds to anti-thrombin and inhibits Factor Xa, but not thrombin
  • Used to treat DVTs and pulmonary embolism 


Recombinant tPA, streptokinase, urokinase

  • may be used as thrombolytics
  • disrupt blood clots in the first few hours following a stroke or MI


Name this structure

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gamma-glutamyl carboxylase

  • Factors II (thrombin), VII, IX, and X contain multiple glutamate residues that must be postranslationaly modified to gamma-carboxyglutamate residue via gamma-glutamyl carboxylases
  • These dicarboxylate side chains tightly bind Ca enabling tight binding to phospholipids at the platelet surface and anchoring these proteins to the damaged site 
  • Vitamin K is essential co-factor for gamma-glutamyl carboxylase



  • inhibits vitamin K epoxide reducatse (VKOR)
  • Vary widely depending on the genotype of CYP2C9
  • Patients with cerebral infarct, DVT or PE are started on heparin then transitioned to warfarin 
  • Direct thrombin inhibitors might be used in place of heparin or warfarin in certain clnical situations

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Name this structure

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Vitamin K


Name this structure

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