Hemostasis and Coagulation: Intrinsic and Extrinsic 8/23 Flashcards
Hemostasis vs. Thrombosis
- Hemostasis = regulated process that maintains blood in a fluid state in normal vessels
- Thrombosis= pathological counterpart of hemostasis, that results in blood clot (thrombus) formation within vessel
- normal hemostasis is maintained by:
1. endothelium: endothelial cells exhibit antiplatelet properties, anticoagulant properties, and fibrinolytic properties.
Normal Hemostasic Events to an injury
- Vasoconstriction: After a vascular injury local neurohumoral factors induce a transient vasoconstriction
- Primary Hemostasis: Platelets bind via glycoprotein Ib (GpIb) receptors, to von Willebrand factor (vWF) on exposed ECM and are activated, undergoing a shape change and granule release. Releaseed adenosine diphosphate (ADP) and thromboxane A2 (TxA2) induce additional platelet aggregation through platelet GpIIb-IIIa receptor binding to fibrinogen. this forms the **primary hemostatic plug. **
- Secondary Hemostasis: Local activation of the coagulation cascaderesults in fibrin polymerization, “cementing” the platelets into a definitive secondary hemostatic plug.
- Thrombus and anti-thrombus events: counter-regulatory mechanisms, mediated by tissue plasminogen activator (t-PA, a fibrinolytic product) and thrombomodulin, confine the hemostatic process to injury site
- Fibrinolysis: clot dissolution; re-establsh vascular integrity
Antiplatelet Effects of the Endothelium: PGI2, NO, ADPase,
- nonactivated platelets do not adhere b/c:
1. prostacyclin (PGI2) and nitric oxide (NO) are produced by endothelial cells to impede platelet adhesion. They bind to activated plaetlets and inactiave the receptors on platelets. They are also potent in vasodilation and inhibition of platelet aggregation.
2. Adenosine diphosphatase (degrades ADP)
Anticoagulant effects of endothelial membrane: heparin-like molecules, anti-thrombin III, thrombomodulin, proteinC, TFPI
- heparin-like molecules: act indirectly as cofactors that greatly enhance the inactibation of thrombin by antithrombin III.
- Thrombomodulin: binds to thrombin and converts it from a procoagulant into an anticoagulant via activation of protein C- which inhibits clotting by inactivating factors Va and VIIIa (Protein S is required in this)
- Tissue factor pathway inhibitor (TFPI): is a cell surface protein that directly inhibits tissue factor VIIa and activates factor Xa.
Fibrinolytic effects of endothelial cells
Endothelial cells synthesize tissue0type plasminogen activator (t-PA), which is a protease that cleaves plasminogen to form plasmin.
- plasmin then cleaves fibrin –> degrade thrombin
What is the first thing that happens when Endothelium is damaged to initiate the Thrombotic events?
- Causes transient vasoconstriction exposes the extracellular matrix:
1. Endothelin: injured endothelium produce vasoconstrictors which acts on smooth muscle and cause constriction
2. damaged smooth muscle goes myogenic constriction
3. damaged nerve ending-releases neurogenic reflex vasoconstrictors by local hormones
Primary hemostasis
- ECM is exposed, which in turn exposes von Willebrand Factor (vWF) located on the basolaterla surface of the endothelial cells.
- _vWF binds GpIb recepto_r on platelet –> this results in intial aggregation–> and activation of platelet
- Aggregation is accomplished by fibrinogen bridging GpIIb-IIIa receptors on different platelets.
- activated platelet undergoes a shape change and releases thromboxane A2, delta (dense) granule and alpha granules
Alpha Granule
-a granules contains lots of factors:
CF: coagulating factors
Fibrinogen: aggregates platelets by bridging GPIIb-IIIa receptors
PDGF: platelet derived growth factor
Delta Granule
d granules contains SAC:
S: serotonin-vasoconstrictor
A: ADP-platelet activator and aggregator
C: calcium: activate coagulation factors
Secondary Hemostasis
Extrinsic Pathway: Tissue factor is released by injured endoethelial cells which activated the “extrinsic Pathway” through binding with factor VII–> Factor VIIa
Intrinsic Pathway: directed internallly. Ca2+ initiates the clot (normally neutralized by citrate): leads into pathway by VIIIa
Both Pathways require Ca2+ to initiate the cascade:
- Convert X–>Xa
- Xa activates Prothrombin –> Thrombin (this is catalyzed by thrombin, phospho surface and Ca2+)
- Thrombin converts fiibrinogen –> fibrin
Nitric Oxide
- Released by endothelial cell –> results in vasodilation and impedes platelet adhesion by inactivating platelet receptors
- this is important in the antiplatelet effects of endothelial cells
Prostacyclin
PGI2: is produced by endothelial cells.
Impedes platelet adhesion by inactivating platelet receptors.
Necessary for antiplatelet effects
PGI2 and TXa2 are balanced to effectively modulate platelt and vasular wall function
Adenosine diphosphatase
- released by delta granule
- a potent activator of platelet aggregation that results in further ADP release and amplifies the aggregation process
Thromboxane A2
TXA2= vasoconstrictor and platlet aggregator released by platelet upon platelet activation
Phospholipid Platform
- Necessary for secondary hemostasis
- activated platetls undergo a confomational change, exposing a phospholipid rich portion of the platelet surface cell membrane called “phospholipid platform”
- this accelerates fibrin production by bringing in close proximity the sequential enzymatic reaction of the intrinsic and common pathways
- from VIIIa –> X (mediated by Ca2+)
- and Xa for Prothrombin–>thrombin
Fibrin
Prothrombin is converted to Thrombin through teh coagulation cascade.
Thrombin then goes to convert fibrinogen to fibrin.
Fibrin is necessary for cementing the platelets into place, and forming the secondary hemostatic plug. It encases platelets and other circulating cells and covalently cross-links through stabilization via factor 13a
Fibrinogen
- Molecule that connects platelets through binding of GpIIb-IIIa receptors on platelet cells.
- Filapodia connect activated platlets together through incorporating circulating fibrinogen as interlinking molecules.
- also important as it is converted to fibrin in the secondary hemostatic plug through the action of thrombin
Thrombin
- Thrombin binds to a protease-activated receptor (PAR) on the platelet membrane and in concert with ADP and TxA2 causes further platelet aggregation
- this is followed by platlet contraction
- Thrombin also converts fibrinogen to fibrin which cements the platelets into place
- Thrombin also is important in propogating the cascade by feeding back positively into 11–>11a, 7–>7a and 5–>5a
- Thrombin also drives thrombus-associated inflammation by directly stimulating neutrophila dn monocyte adhesion by generating chemotactic fibrin split products during fibrinogen cleavage.
Prothrombin
Factor II, important in common pathway to convert fibrinogen to fibrin in conjunction with Ca2+
Prothrombin is converted to thrombin via prothrombinase
Extrinsic Coagulation Pathway
Tissue injury results in release of tissue factor (thromboplastin)
- Thromboplastin (Factor III) combines with Ca2+ and factor 7 to make factor 7a
- 7a links into the common pathway
Intrinsic Coagulation Pathway
- Normally is inhibited by citrate binding Ca2+ in the blood - but granule delta secretes large amounts of Ca2+
- exposed collage activates Hageman factor (12) which starts the cascade
- Platelets –> Factor 12 –>Factor 11 –> factor 9 (christmas factor) –> Factor 8 (anti-hemophilic factor)
- conversion of factor 9 to 8 requires Ca2+ and PF3
- 11 and 8 are further enhanced by thrombin
Coagulation cascade - common pathway
- enzyme (activated coagulation factor), substrate (proenzyme form of coagulation factor), cofactor (reaction accelerator)
- Ca2+ (Ca2+ is normally prevented by presence of Ca2+ chelators)
- intrinsic and extrinsic converge on the activation of factor X. Factor X in the presence of ca2+ forms complexes with accelerin (factor V) to form prothrombin activator (factor II)
- Factor II is converted to factor IIa and in conjuction with Ca2+ converts fibrinogen to fibrin
Aspirin
Permanently blocks platelet TxA2 synthesis, and thus is used to treat people with coronary thrombosis.
Aspirin also inhibits PGI2 production, however endothelial cells can overcome the blockade.
Thromboplastin
“Tissue Factor” - released by endothelial cells in injury. It catalyzes the extrinsic pathway by combining with 7 to make Tissue factor 7a.
Hagemann Factor
Factor Xii (12) activates the intrinsic pathway through conversion to Xiia
Christmas Factor
Factor IX
important in intrinsic pathway, for coversion to VIII
Anti-hemophilic factor
factor VIII (entrance point into common cascade from intrinsic pathway)
Fibrin Stabilizing Factor
Factor XIII - in the presence of CA2+ stabilizes the fibrin polymer through covalent bonding of fibrin monomers
Fibrinolysis
- Plasminogen: circulating non-enzymatic protein converted by tissue plasminogen activator (tPA) to Plasmin
- Plasmin degrades fibrin
- activation of a coagulation cascade sets into motion the fibrionolytic cascade that moderates the size of the ultimate clot
t-PA and u-PA
Convert Plasminogen –> Plasmin
t-PA= Tissue plasminogen activator (secreted by endothelium)
u-PA= urokinase-plasminogen activator (secreted by kidney)
clot, thrombus, thrombosis
Thrombus: when a clot becomes larger than necessary, which can result in vascular obstruction (altered blood flow) or fragmentation and movement in direction of flow (embolism)
Thrombosis = physiological process that leads to formation of thrombus
Thrombosis is the result of failure of a physiological mechanism of antithrombosis, and/or inability to terminate clot propagation.
