coagulation review Flashcards
circulatory homeostasis is maintained
preservation of blood fluidity and ability to seal off bleeding
anticoagulant factors are released by
endothelial cells (prostacylcin ,vascular plasminogen activator) tend to be released from lining
procoagulant factors
platelets, plasma proteins-inactive state (zymogen) tend to be released when lining is disrupted
most significant event in vivo to initiate coag.
Factor VIIa/TF is the most significant event to initiate coagulation
phase1 :initiation activation of factor VII
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 (we don’t know exactly why) and forms the FVIIa/TF complex
PHASE 1 INITIATION : The FVIIa/TF complex activates
the FIX and FX zymogens (what are those again?)
FXa formed on the TF-bearing cell interacts with cofactor Va to form a prothrombinase complex and (very importantly) generates a very small amount of “priming” thrombin on the surface of TF-bearing cells.
FXa remains on the cell surface
PHASE 1 INITIATION: FATE OF IXa
The FIXa does not interact further with the TF-bearing cell and is no longer involved in Phase I: Initiation
However, if tissue injury has occurred and activated platelets are in the neighborhood, FIXa will diffuse to those platelets, bind to their surface, and (in conjunction with cofactor VIIIa) activate zymogen FX to FXa
phase 1 initiation: Tissue factor in the absence of injury
TF-bearing cells appear to bind 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.
signal for phase 2 amplification
The thrombin generated on the TF- bearing cell serves as the “signal” for Phase II: Amplification to begin
Phase II: Amplification:platelet activation
When sufficient thrombin (FIIa) is generated on or adjacent to TF-bearing cells, platelets are activated
NOTE: At this point there is not nearly a sufficient amount of thrombin to cause formation of a clot (that is, effectively convert fibrinogen to fibrin)
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 von Willebrand Factor (vWF)
Activates XIa from XI
first step in phase 3 propagation
The production of vast amounts of thrombin on the surface of activated platelets
phase 3 propagation: when vascular injury occurs platelets
eave the blood vessel, bind to collagen/vWF/blood vessel wall receptors and other extravascular “stuff”, 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 3 propagation The newly-activated platelets bind
FVa and FVIIIa and the FIXa freshly-liberated by the FVIIa/TF complex
Freshly-generated XIa binds to the freshly-activated platelet (effectively bypassing the need for FXIIa)
Membrane-bound FXIa keeps on activating FIX to FIXa
FVIIIa and co-factor FIXa form what is called the “platelet tenase complex (PTC)”
phase 3 propagation The PTC activates even more
FX to FXa
FXa combines with FVa to form the creatively- monikered “Prothrombinase” complex
phase 3:The XaVa “Prothrombinase” complex causes
EXPLOSIVE burst of thrombin that helps produce a stable fibrin clot
Interestingly (well, maybe not to you) it has been discovered that most of the thrombin produced is generated after the initial fibrin clot is formed and that the thrombin produced does other stuff to help the clot such as:
Continues to activate FXIII and other factors (there are LOTS!)
Helps to keep constructing the platelet/thrombin clot
Arterial circulation
requires rapid response system to seal off any
bleeding sites
platelets take leading role followed by fibrin formation (antiplatelet agents used to prevent coronary thrombosis)
Venous circulation
slower response acceptable
rate of thrombin generation takes leading role (antithrombin agents used to prevent deep venous thrombosis)
What Happens When An Arterial Blood Vessel Is Damaged?
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
Slide 30
Vascular Constriction
Vascular Constriction
Seen when blood vessel itself is injured
persistent constriction of the smooth muscles
Most prominent following severe crushing type injuries
platelet adhesion problem:
Shear stress along vessel wall
Shear stress inversely related to flow velocity
Values at vessel wall: 500/sec larger arteries; 5,000/sec arterioles
Opposes any tendency of flowing blood to clot limits time available for procoagulant reactions to
occur
displaces cells or proteins not tightly bound to the vessel wall
coaxial migration
platelets pushed to vessel perimeter by larger erythrocytes & leukocytes
apture” depends on several binding sites such as
von Willebrand’s factor (vWf) and collagen
platelet surface receptor called Glycoprotein Ib (GPIb)
vWf held in place by binding to
subendothelial collagen
GPIb binds easily with vWf, but it is a low-affinity interaction so it
slows, but does not stop the platelet – tumbles slowly over endothelium
Interaction between platelet GPIb and the vWf molecule causes
transmembrane signaling
Transmembrane signaling coupled with high shear stress results in
activation of platelet
platelet activation
Platelet loses normal discoid shape Platelet receptor GPIIb/IIIa undergoes conformational
change
GPIIb/IIIa now able to bind to another binding site on vWf (GPIIb/IIIa site of action of newer antiplatelet agents)
high-affinity bond that secures activated platelet to subendothelium
Subendothelial collagen binds with platelet receptor GPIa/IIa
at medium shear stress strong enough to bind platelet to subendothelium
Subendothelial collagen also binds with platelet receptor GPIV which causes activation of the platelet
Platelet Activation - Goals
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
thromboxane
A2 (TXA2) important 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 Fibrinogen and vWf stored in alpha-granules
within platelet – released following activation
Fibrinogen and vWf bonds form between platelets binding them together in a tight matrix
More than 50,000 GPIIb/IIIa receptors present on platelet surface – additional receptor molecules available within cytoplasm
clotting factors
I: Fibrinogen X: Stuart factor; Stuart-
II: Prothrombin
III: Tissue thromboplastin
IV: Calcium
V: Proaccelerin; Labile factor
VII: Proconvertin; Stable factor
VIII: Antihemophilic factor A
IX: Plasma thromboplastin component; Antihemophilic factor B; Christmas factor
Prower
XI: Plasma thromboplastin antecedent; Antihemophilic factor C
XII: Hageman factor; Antihemophilic factor D
XIII: Fibrin stabilizing factor; Laki-Lorand factor
There is no factor VI
Additional Clotting Factors
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 Four 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)
TFPI forms a quarternary complex called
TF/FVIIa/FXa/TFPI which inactivates various factors and limits coagulation
Proteins C and S inactivate
FVa and FVIIIa cofactors
PC
s a vitamin K-dependent plasma glycoprotein which helps break down FVa and FVIIIa
-PC is activated by thrombin (negative feedback loop?) and its activity is increased by PS (which is also vitamin K- dependent)
AT
inhibits thrombin and the “Serine Proteases” (that might be important later on) such as FIXa, FXa, FXIa, and FXIIa.
Fibrinolysis
The production of plasmin signals the Fibrinolytic phase of coagulation
Plasmin is produced from
he zymogen plasminogen by the action of urokinase- type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA)
uPA & tPA are regulated by
Plasminogen Activator Inhibitors 1 & 2 (PAI-1 & PAI-2)
tPA is released by
endothelial cells and activated by thrombin (there’s another negative feedback loop) and venous occlusion
tPA and plasminogen bind to
the growing fibrin polymer as fibrinogen (FI) is converted into fibrin (Fia)
plasminogen is activated to plasmin which
cleaves fibrin strands
fibrinolysis
Cleaved fibrin produces Fibrin Degradation Products (FDPs or Fibrin Split Products)
FDPs are measured to help determine the amount of fibrinolysis occurring (when might that be important?)
What effect does coagulation have on cardiac surgery and cardiopulmonary bypass?
Bleeding
bad outcome; increased cost; increased exposure to blood products; increased chance of infection
Circuit integrity
large foreign surface stimulates coagulation cascade; concerned with coagulation monitoring / treatment of circuit surface / protocols
Inflammation coagulation cascade will stimulate inflammation activities
Disease state of patient what patient conditions will affect coagulation status? diabetes; liver disease; obesity, sepsis
Effect of Bypass/Surgery on Coagulation
Activates 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 Activates neutrophils and monocytes
activation of complement cascade results in leukocyte activation
Surgery will expose the Subendothelium stimulates coagulation
Platelet activation contact with foreign surface of the circuit activation of intrinsic and extrinsic pathways
Vascular endothelial cell activation not sure how, but it happens
