Regulation Mechanics Flashcards
Pray to the Hemostatic Deities for Mercy
List of Procoagulants
- Coag Factors
- Collagen/Vasculature
- Platelets
- vWF
List of Anticoagulants
- Protein Z & ZPI
- TFPI
- Antithrombin
- Heparin Cofactor II
- Protein C & Protein S
List of Profibrinolytics
- Plasminogen → Plasmin
- Kallikrein & XIIa
- Urokinase
- Protein C & Protein S
List of Antifibrinolytics
- Antithrombin
- α2-antiplasmin
- α2-macroglobulin
- TAFI
- PAI 1 (most common) & 2 (lesser)
- Factor XIa
Anticoagulant Function
Warfarin
Not Naturally in Body
Inhibits the Vit K dependent Magic Four (II, VII, IX, X)
Keeps Vitamin K in storage form and unable to be properly utilized
Also technically inhibits anticoagulants that are Vit K dependent
Anticoagulant Function
Protein Z
- Vitamin K dependent
- Produced in Liver
- Cofactor to ZPI
- Major role is degrading Xa
- Slow acting on it’s own
- Requires Ca2+ and Phospholipids
Non-proteolytic & no activation site, unlike Vit K dependent factors
Anticoagulant Function
Protein Z-Related Protease Inhibitor (ZPI)
- Vitamin K dependent
- Produced in Liver
- Cofactor to Protein Z
- Accelerated 1000x by Protein Z
- Major role of degrading Factor Xa
- Minor role of degrading Factor XIa (does not require Protein Z for this aspect)
Anticoagulant Function
Tissue Factor Pathway Inhibitor (TFPI)
- Low Concentration Inhibitor of Extrinsic Pathway
- Secreted into plasma by Endothelial Cells
- Inhibits TF3/VIIa complex (Extrinsic Tenase Complex)
Anticoagulant Function
Antithrombin (AT)
- Produced in Liver
- Forms irreversible complex w/ Factors IIa, IXa, Xa, XIa, XIIa, and plasmin; leading to slow neutralization
Anticoagulant Function
Antithrombin Interaction with Heparin
- Heparin causes conformational change in AT that increases inhibitory effect
- Heparin is not consumed in this process, can dissociate and serve as cofactor for additional AT molecules
Anticoagulant Function
Heparin Therapy Effects on AT Levels
- Often results in decreased levels of circulating AT
- Enhanced AT can lead has a negative feedback loop with itself
- Can predispose a patient to thrombosis if not weaned off Heparin properly while oral anticoagulants are being introduced
Anticoagulant Function
Heparin Cofactor II (HC-II)
- Produced by Liver
- Specificity solely to Thrombin (IIa) neutralization
- Accelerated activity in presence of Heparin (but less than boosted AT)
- Also present in platelets and may play a role in platelet surface thrombin regulation
Think HC-II in relation to IIa neutralization
Anticoagulant Function
Protein C
- Vitamin K dependent
- Produced in the Liver
- Activation via Thrombin-Thrombolmodulin complex
- Inactivates Va and VIIIa
- Liberates tPA from Endothelial Cells
- Protein S is cofactor
Anticoagulant Function
Protein S
- Vitamin K dependent
- Produced in Liver
- Non-proteolytic
- 60% bound to C4b
- 40% free - this is the active anticoag molecule
- Serves as Cofactor for Protein C
Anticoagulant Function
Inhibited by Activated Protein C
Factors Va & VIIIa
Profibrinolytic Function
Plasmin
- Lyses Fibrinogen (1° Fibrinolysis) & Fibrin (2° Fibrinolysis) - Major Function
- Inactivates Va & VIIIa
- Degrades XIIa into inactive fragments
Profibrinolytic Function
Activated Protein C
Liberates Tissue Plasminogen Activator (tPA) from Endothelial Cells
Profibrinolytic Function
Plasminogen Activators
Endogenous
- Urokinase
- Kallikrein & XIIa
- Activated Protein C → Liberated tPA
Some evidence that XIa plays a minor role
Profibrinolytic Function
Plasminogen Activators
Exogenous
- tPA
- Streptokinase
- Urokinase
Antifibrinolytic Function
Antithrombin
Plasmin bound in irreversible complex that forms along with IIa, IXa, Xa, XIa, XIIa
Antifibrinolytic Function
α2-Antiplasmin
- Produced in Liver
- Binds & Inactivates free circulating plasmin
- Rapid inhibitor
- Prevents lysis of of fibrinogen
- Prevents degradation of Factors V & VIII
Not very effective at inactivating plasmin already bound to fibrin
Antifibrinolytic Function
α2-Macroglobulin
- Serves as plasmin inhibitor ONLY when α2-Antiplasmin binding sites are saturated
- Slower inhibitor than α2-Antiplasmin
- Same functions as α2-Antiplasmin
Antifibrinolytic Function
Plasminogen Activator Inhibitors (PAI-1 & PAI-2)
- Most important inhibitor to the plasminogen activator system is PAI-1
- Released from injured endothelial cells and activated platelets
- Functions to neutralize tPA (and urokinase)
Antifibrinolytic Function
Thrombin Activatable Fibrinolytic Inhibitor (TAFI)
- Activated by Thrombin-Thrombomodulin complex
- Functions to alter the fibrin clot to make it less recognizable by plasmin, therefore inhibiting fibrinolysis
- Enhanced by Factor XIa
Antifibrinolytic Function
Factor XIa
Enhances TAFI production
Deficit leads to unmodified clots and increased fibrinolysis & bleeding
Results of Deficiencies
Anticoagulants
Thrombosis
Results of Deficiencies
Profibrinolytics
Thrombosis
Results of Deficiencies
Antifibrinolytics
Bleeding Issues
Results of Deficiencies
Procoagulants (Non-Exceptions)
Bleeding Issues
Results of Deficiencies
Procoagulants (XIIa)
Thrombosis
Results of Deficiencies
Procoagulants (PK)
Thrombosis
Results of Deficiencies
Procoagulants (HWMK)
Thrombosis
Results of Deficiencies
Procoagulants (Factor I/Ia Dysfunction)
Unable to be recognized by Plasmin → Can’t be broken down → Thrombosis
