Topic 1 Flashcards
Homeostasis
Normal blood circulation is maintained by a system of checks and balances
- preservation of blood fluidity
- ability to seal off any site of bleeding
Anticoagulant factors are released by
Endothelial cells
(prostacyclin, vascular plasminogen activator)
-These tend to be released from the lining of the vascular garden hose
Procoagulant factors include
platelets and plasma proteins – inactive state (zymogen)
-These tend to be released when the lining of that vascular garden hose gets disrupted
Three Phase Model includes
Initiation
Amplification
Propagation
Phase I: Initiation- In vivo
The activity of the FVIIa/TF (Tissue Factor) complex is THE most significant event to initiate coagulation
Phase I: Initiation-
Activation of FVII
Vascular damage exposes TF (a membrane-bound protein) to plasma. TF is both a receptor and cofactor for FVII. When the zymogen FVII binds TF it converts to FVIIa and forms the FVIIa/TF complex.
Phase I: Initiation-
After the FVIIa/TF complex activates the FIX and FX zymogens…. then…
FXa formed on the TF-bearing cell interacts with cofactor Va to form a prothrombinase complex and generates a very small amount of “priming” thrombin on the surface of TF-bearing cells. FXa remains on the cell surface
Phase I: Initiation-
When does FIXa not interact further with the TF-bearing cell and is no longer involved in Phase I: Initiation
After the priming thrombin is formed.
However, if tissue injury occurrs and activates near by platelets, FIXa will diffuse to those platelets, bind to their surface, and (in conjunction with cofactor VIIIa) activate zymogen FX to FXa
Phase I: Initiation-
TF-bearing cells appear to bind to
FVIIa and low levels of FIXa and FXa even in the absence of injury but are separated from the Phase II: Amplification components by the normally intact blood vessel wall.
Whats the signal for Phase II: Amplification
The thrombin generated on the TF-bearing cell serves as the “signal” for Phase II: Amplification to begin
Phase II: Amplification-
When sufficient thrombin (FIIa) is generated on or adjacent to TF-bearing cells…then…
platelets are activated
NOTE: At this point there is not nearly a sufficient amount of thrombin to cause formation of a clot
Phase II: Amplification-
The small amount of TF-bearing cell-generated thrombin activates…
Activates platelets
Activates FVa from FV
Activates FVIIIa and dissociates it from vWF
Activates XIa from XI
Phase III: Propagation-
First step is…
The production of vast amounts of thrombin on the surface of activated platelets
Phase III: Propagation-
When vascular injury occurs, platelets leave the blood vessel…then…
bind to collagen/vWF/blood vessel wall receptors and are activated by a combination of those factors and the “priming” dose of thrombin
-This adherence of platelets to the damaged tissue is the first step in the formation of the platelet “plug” necessary for primary hemostasis
Phase III: Propagation-
The newly-activated platelets bind to…
FVa and FVIIIa
FIXa is freshly-liberated by the FVIIa/TF complex
Phase III: Propagation-
Freshly-generated XIa binds to…
the freshly-activated platelet (effectively bypassing the need for FXIIa). Membrane-bound FXIa keeps on activating FIX to FIXa
Phase III: Propagation-
FVIIIa and co-factor FIXa form
platelet tenase complex (PTC)
Phase III: Propagation-
The PTC activates even more…
FX to FXa.
Phase III: Propagation-
FXa combines with FVa to form
Prothrombinase complex
Phase III: Propagation-
The XaVa “Prothrombinase” complex causes…
the EXPLOSIVE burst of thrombin that helps produce a stable fibrin clot
Arterial circulation requires
rapid response system to seal off any bleeding sites.
-platelets take leading role followed by fibrin formation
Venous circulation has a
slower response.
-rate of thrombin generation takes leading role
Arterial circulation uses what to prevent coronary thrombosis
antiplatelet agents
Venous circulation uses what to prevent deep venous thrombosis
antithrombin agents
What Happens When An Arterial Blood Vessel Is Damaged? (7)
- Vascular constriction
- Platelet adhesion
- Platelet activation- formation of the platelet plug
- Activation of cell-based coagulation cascade- formation of fibrin clot
- Clot retraction
- Activation of fibrinolytic cascade
- Vessel repair / regeneration
Vascular Constriction is seen when
blood vessel itself is injured
-persistent constriction of the smooth muscles
Vascular Constriction is most prominent following
severe crushing type injuries
Describe the smooth muscle layers typically found in blood vessels
- Tunica Intima -contains the endothelium
- Tunica Media- circularly arranged smooth muscle cells and sheets of elastin. Maintains blood pressure and continuous blood circulation
- Tunica Externa- loosely woven collagen fibers
protect and reinforce the vessel, and anchor it to surrounding structures
Main Platelet Adhesion - PROBLEM
Shear stress along vessel wall
Shear stress inversely related to
flow velocity
Shear stress values at vessel wall for large arteries
500/sec
Shear stress values at vessel wall for arterioles
5,000/sec
Shear stress opposes any tendency of flowing blood to clot because it
- limits time available for procoagulant reactions to occur
2. displaces cells or proteins not tightly bound to the vessel wall
Platelets are able to adhere to cell walls despite shear stress because
platelets are pushed to vessel perimeter by larger erythrocytes & leukocytes (coaxial migration)
Platelet Adhesion-
Adhesion must occur very
rapidly – i.e. instantaneously
Platelet Adhesion-
“Capture” depends on several binding sites:
- subendothelial molecules of vWf and collagen
- platelet surface receptor: Glycoprotein Ib (GPIb)
Platelet Adhesion-
vWf is held in place by binding to
subendothelial collagen
Platelet Adhesion-
GPIb binds easily with
vWf, but it is a low-affinity interaction
- - Slows, but does not stop the platelet – tumbles slowly over endothelium
Platelet Adhesion-
Interaction between platelet GPIb and the vWf molecule causes
transmembrane signaling
Platelet Adhesion-
Transmembrane signaling coupled with high shear stress results in
activation of the platelet
After platelet activation, the platelet loses
normal discoid shape
Platelet activation-
Platelet receptor GPIIb/IIIa undergoes
conformational change
Platelet activation-
GPIIb/IIIa now able to bind to another binding site on…
vWf
- high-affinity bond that secures activated platelet to subendothelium
- (GPIIb/IIIa site of action of newer antiplatelet agents)
Platelet activation-
Subendothelial collagen binds with…
- platelet receptor GPIa/IIa-at medium shear stress strong enough to bind platelet to subendothelium
- platelet receptor GPIV which causes activation of the platelet
Platelet Activation - Goals (5)
- Recruitment of additional platelets
- Vasoconstriction of smaller arteries
- Local release of ligands needed for stable platelet-platelet matrix
- Localization and acceleration of platelet-associated fibrin formation
- Protection of clot from fibrinolysis
Activated platelets release
platelet agonists
3 platelet agonists
Thromboxane A2 (TXA2) Serotonin Adenosine diphosphate (ADP)
Thromboxane A2 (TXA2)
platelet agonist and vasoconstrictor
- formed in cytosol following cyclooxygenase cleavage of arachidonic acid
- cyclooxygenase activity irreversibly inhibited by aspirin= no TXA2 formation
Serotonin
released from platelet granules - platelet agonist and vasoconstrictor
Adenosine diphosphate (ADP)
released from platelet granules - platelet agonist no known vasoactive role
Formation of Platelet Plug-
Surface receptor GPIIb/IIIa undergoes
calcium dependent conformational change
-able to bind with fibrinogen or vWf
Formation of Platelet Plug-
Fibrinogen and vWf stored in…
alpha-granules within platelet – released following activation
Formation of Platelet Plug-
Fibrinogen and vWf bonds form between
platelets binding them together in a tight matrix
Formation of Platelet Plug-
More than ______ GPIIb/IIIa receptors present on platelet surface
50,000
– additional receptor molecules available within cytoplasm
Clotting Factor I
Fibrinogen
Clotting Factor II
Prothrombin
Clotting Factor III
Tissue thromboplastin
Clotting Factor IV
Calcium
Clotting Factor V
Proaccelerin
Labile factor
Clotting Factor VII
Proconvertin
Stable factor
Clotting Factor VIII
Antihemophilic factor A
Clotting Factor IX
Plasma thromboplastin component
Antihemophilic factor B
Christmas factor
Clotting Factor X
Stuart factor
Stuart-Prower
Clotting Factor XI
Plasma thromboplastin antecedent
Antihemophilic factor C
Clotting Factor XII
Hageman factor
Antihemophilic factor D
Clotting Factor XIII
Fibrin stabilizing factor
Laki-Lorand factor
Additional Clotting Factors (9)
- Prekallikrein
- High-molecular-weight kininogen
- Antithrombin; Antithrombin III
- Lipoprotein-associated coagulation inhibitor (extrinsic pathway inhibitor)
- Antiplasmin
- Plasminogen activator inhibitor
- alpha2-Macroglobulin
- Protein C
- Protein S
Phase IV: Termination-
4 autologous anticoagulants help control the spread of coagulation activation
- Tissue Factor Pathway Inhibitor (TFPI)
- Protein C (PC)
- Protein S (PS)
- Antithrombin III (AT or AT-III)
Phase IV: Termination-
TFPI forms a quarternary complex called the
TF/FVIIa/FXa/TFPI which inactivates various factors and limits coagulation
Phase IV: Termination-
Proteins C and S inactivate
FVa and FVIIIa cofactors
Phase IV: Termination-
PC is a
vitamin K-dependent plasma glycoprotein which helps break down FVa and FVIIIa
Phase IV: Termination-
PC is activated by
thrombin (negative feedback loop?) and its activity is increased by PS (which is also vitamin K-dependent)
Phase IV: Termination-
AT inhibits thrombin and the
“Serine Proteases”-such as FIXa, FXa, FXIa, and FXIIa
Fibrinolysis-
What signals the Fibrinolytic phase of coagulation
The production of plasmin
Fibrinolysis-
Plasmin is produced from the zymogen plasminogen by the action of
urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA)
Fibrinolysis-
uPA & tPA are regulated by
Plasminogen Activator Inhibitors 1 & 2 (PAI-1 & PAI-2)
Fibrinolysis-
tPA is released by
endothelial cells and activated by thrombin (negative feedback loop) and venous occlusion
Fibrinolysis-
tPA and plasminogen bind to the
growing fibrin polymer as fibrinogen (FI) is converted into fibrin (Fia)
Fibrinolysis-
plasminogen is activated to
plasmin which cleaves fibrin strands
Fibrinolysis-
Cleaved fibrin produces
Fibrin Degradation Products (FDPs or Fibrin Split Products)
Fibrinolysis-
FDPs are measured to help determine the
amount of fibrinolysis occurring
Endogenous Anticoagulants
Prevent clotting – keep blood liquid
Require intact endothelial cell barrier
endothelial cells negative charge repels
platelets
endothelial release of _______ – inhibit platelet adhesion and aggregation
nitric oxide (endothelium-derived relaxant factor) & prostacyclin (PGI2)
endothelial release of ______ – inactivates platelet released ADP limiting ability to recruit other platelets
ADPase
Effect of Bypass/Surgery on Coagulation:
Activates what pathways
intrinsic and extrinsic coagulation pathways
- large negatively charged surface activates intrinsic pathway (which also activates fibrinolysis which activates complement)
- coronary suction introduces tissue factor from damaged cells which activates the extrinsic pathway
Effect of Bypass/Surgery on Coagulation:
Activates what cells
neutrophils and monocytes
-activation of complement cascade results in leukocyte activation
Effect of Bypass/Surgery on Coagulation:
Surgery will expose the
Subendothelium
-stimulates coagulation
Effect of Bypass/Surgery on Coagulation:
Platelet activation
contact with foreign surface of the circuit
activation of intrinsic and extrinsic pathways
Effect of Bypass/Surgery on Coagulation:
_______ cell activation
Vascular endothelial