Intrinsic and Extrinsic Coagulation Pathways (choudhury) Flashcards
hemostasis
regulated process that maintains blood in a fluid state
thrombosis
pathological counterpart of hemostasis, results in clot within vessels
5 major events in physiological clotting
1) Initial vascular injury
2) Primary hemostasis
3) Secondary hemostasis
4) Antithrombosis
5) Fibrinolysis
What properties do endothelial cells exhibit normally
Antiplatelet
Anticoagulant
fibrinolytic
Antiplatelet properties of endothelial cells
NO
PGI2
Adenosine Diphosphatase
make sure platelets don’t stick
Anticoagulant properties of endothelial cells
Heparin Sulfate
Thrombomodulin
Protein S
TFPI
Fibrinolytic properties of endothelial cells
t-PA
this is a protease secreted by endothelium that cleaves plasminogen to form plasmin
plasmin then cleaves fibrin into FDP, essentially degrading thrombi
Hemostasis and thrombosis involves
Endothelium (vascular wall)
Platelets
Coagulation cascade
Fibrinolysis
NO
vasodilator antiplatelet aggregator (platelets don't stick to endothelial membrane)
Layers of normal endothelium
Innermost Endothelial cells ECM Smooth muscle layer outer connective tissue layer outermost
PGI2
Prostacyclin
anti platelet component of endothelial cells
vasodilator in lungs/blood vessels
ADP phosphatase
degrades ADP and inhibit platelet adhesion and aggregation
Heparin Sulphate (HS)
Anticoagulant of endothelial cells
HS hooks onto antithrombin III (AT III) and activated AT III
AT III inactivates Thrombin, Factor 10, Factor 9a
Thrombomodulin (TM)
Anticoagulant property
binds to thrombin and converts it form procoagulant into anticoagulant via thrombin’s ability to activate protein C
Protein C activated inhibits factors 5 and 8
What does Protein C require
Cofactor protein S
Protein S
Cofactor for Protein C
necessary for anticoagluant effects of protein C
TFPI
Tissue factor pathway inhibitor
anticoagulant property of endothelial
directly inhibits factor 7 and 10
when is a platelet plug formed
primary homeostasis
this is a temporary patch formed at endothelial injury site
what occurs during homeostasis
the initial platelet plug is enlarged and stabilized by adding a structural matrix of fibrin (coagulation) to form a coagulum or “clot”
Antithrombosis
Once a stable and effective clot forms then additional clot formation has to cease
Fibrinolysis
last major step in hemostasis to remove clot and restore normal blood flow through the vessel
phospholipid platform
Formed during secondary hemostasis
activated platelets undergo conformation change exposing a phospholipid-rich portion of the platelet surface cell membrane
this platform dramatically accelerates fibrin production by bringing in close proximity the enzymatic rxns of the intrinsic/common pathways
Thrombosis
results from impairment in ability to limit/terminate clot propagation
Initial vascular injury (what happens)
Transient vasconstriction and vasospasm
ECM is exposed
vWF produced by endothelial cells, acts as vital link “glue” for platelet adherence and activation
fibrinogen (factor 1)
plasma protein produced by the liver
“bridges” between platelets
allows for platelet aggregation
converted to fibrin by thrombin
calcium
without calcium would not be able to form any coagulation
what synthesizes vWF factor
endothelial cells
Endothelin
vasoconstrictor released by injured endothelium
Platelet process in primary homeostasis
Leads to formation of initial platelet hemostatic plug
1) Platelet adhesion
2) Shape change
3) Granule Release
4) Recruitment
5) Aggregation (plug)
How does the body keep the platelet plug in the specific site of injury
uninjured endothelium surrounding the injury site continues to release NO and Prostacyclin which inhibit platelet aggregation
what synthesizes vWF factor
endothelial cells
Thrombin (factor 2)
Most important coagulation factor
Converts fibrinogen (soluble) into fibrin (insoluble gel)
also activates fibrin-stabilizing factor (factor XIII) which in the presence of Ca2+ stabilizes fibrin polymer through covalent bonding of fibrin monomers
Fibrin (factor 1a)
Insoluble form, hold platelets together
“cement”
forms meshlike network at the site of vascular damage
How do platelets bind to vWF
via glycoprotein Ib (GpIb) receptors
TXA2
released by platelets
vasoconstrictor and platelet aggregator
Delta Granules release….
SAC
Serotonin- vasoconstrictor
ADP-platelet activator and aggregator
Calcium- activate coagulation factors
Alpha granules release….
CF- coagulating factors
Fibrinogen
PDGF- more platelets come/recruited
Initial vascular injury (what happens)
Transient vasconstriction and vasospasm
ECM is exposed
vWF produced by endothelial cells, acts as vital link “glue” for platelet adherence and activation
Secondary hemostasis
Clot propagation and stabilization by coagulation (fibrin production)
Tissue factor released by platelets activates coagulation cascade
This results in fibrin formation “cementing” that is put on top of primary plug
Forms the secondary hemostatic plug (5-10 min)
Also forms Phospholipid platform
Fibrin
Insoluble form, hold platelets together
“cement”
phospholipid platform
Formed during secondary hemostasis
activated platelets undergo conformation change exposing a phospholipid-rich portion of the platelet surface cell membrane
this platform dramatically accelerates fibrin production by bringing in close proximity the enzymatic rxns of the intrinsic/common pathways
fibrinogen
“bridges” between platelets
allows for platelet aggregation
made into fibrin by coagulation cascade
Antithrombosis
Limitation and cessation of clot production
Coagulation cascade
Part of secondary hemostasis
amplifying series of enzymatic conversions
each step proteolytically cleaves and inactive prenzyme into activated enzyme–> leading to thrombin formation
process where soluble fibrinogen is converted to fibrin (insoluble)
Thrombin
Most important coagulation factor
Converts fibrinogen (soluble) into fibrin (insoluble gel)
XIIIa (8)
Stabilizes and cross-links fibrin fibrin polymers
Intrinsic and extrinsic pathways converge on the activation of ….
factor X (10)
calcium
without calcium would not be able to form any coagulation
what does tissue factor activate
factor 7
what does factor seven activate
factor 9 as well as factor 10
Christmas factor
Factor 9
in the intrinsic pathway
activated by factor 11 in the presence of Ca2+
Anti-hemophlic factor
Factor 8 (intrinsic)
activated by Christmas factor (9)
activates stuart factor (10)
Extrinsic pathway
Tissue factor–> factor 7—> factor 10
Stuart factor
Factor 10 (intrinsic) activated by antihemophilic factor- 8
Hageman factor
Factor 12 (intrinsic)
activated by exposed collagen
activates Factor 11
Factor 11
intrinsic
activates Christmas factor (9)
Accelerin (Factor V)
with factor X and the presence of calcium this helps form prothrombin
Prothrombinase
converts Prothrombin to thrombin
Thrombin in hemostasis
makes fibrin by cleaving fibrinogen
activates XIII with Ca2+
induces platelet aggregation and TxA2 production and activates EC’s to express adhesion molecules, t-PA, NO, PGI2 and PDGF
activates leukocytes
VERY IMPORTANT
Plasminogen
Circulating non-enzymatic protein converted by t-PA into plasmin
Plasmin
Responsible for the enzymatic degradation of fibrin
t-PA
this is a protease secreted by endothelium that cleaves plasminogen to form plasmin
it’s activity is increased 500-fold by fibrin
u-PA
secreted by kidneys
circulates in plasma and converts plasminogen into plasmin
thrombus
produced if a clot size becomes progressively larger than needed
can cause:
vascular obstruction (altered blood flow)
framgentation and movement in direction of flow (embolism)
Thrombosis
results from impairment in ability to limit/terminate clot propagation
what activates the intrinsic pathway
when hageman factor (XII) is activated by contact with exposed collagen at a damaged vessel surface or by contact with a foreign surface
brings about clotting within damaged vessels and clotting of blood samples in test tubes
how is the extrinsic pathway activated
initiated when factor X is activated by tissue factor released from damaged tissue
the extrinsic pathway causes clotting of blood that escapes from blood vessels into the surrounding tissue
