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10/9/2016 1
DefinitionDefinition
�Normal hemostasis
Tightly regulated processes
Maintain blood in a fluid state in normal vessels
�Thrombosis
Pathologic counterpart Pathologic counterpart
Thrombus within intact vessels
Three components:
1.
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EndotheliumEndotheliumKey players in the regulation of homeostasis
Have Anti- and prothrombotic activities ;
Thrombus formation
Propagation, or
Dissolution occursDissolution occurs
exhibit
Antithrombotic activity:
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Mediated by;
Physical Barrier
Prostacyclin (PGI2)
AntiAntithrombotic thrombotic activityactivity
Prostacyclin (PGI2)
Nitric oxide (NO)
ADPase
�inhibits platelet aggregation
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These effects are mediated by:
Endothelial membrane-associated
They are cofactors
Enhance plasma protein antithrombin III activityEnhance plasma protein antithrombin III activity
modulates the activity of Thrombin
Cell surface protein
Directly inhibits tissue factor,VIIa & Xa
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3. Fibrinolytic properties3. Fibrinolytic properties
Endothelial cells synthesize:
Tissue-type plasminogen activator (t-PA)
A protease that cleaves plasminogen to form
plasmin
PlasminPlasmin, in turn, cleaves fibrin to degrade PlasminPlasmin, in turn, cleaves fibrin to degrade
thrombi
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Exposure & contact of platelets to ECM
Adhesion mediated by vWF
Endothelial release of tissue factor
Catalytic function factors IXa and Xa
� Plasminogen activator inhibitors (PAIs)
� Limit fibrinolysis & favor thrombosis
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In summaryIn summary
� Intact, nonactivated endothelial cells Antithrombotic
� Endothelial injury or activation Prothrombotic
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Platelets Platelets
Disc-shaped
AnucleateAnucleate cell fragments
2-3 ꭒm in diameter
8-10 days of half-life
Originate from MEGAkaryocytesMEGAkaryocytesOriginate from MEGAkaryocytesMEGAkaryocytes
Play a critical role in normal hemostasishemostasis
vascular defects
Provide a surface for activated coagulation factors
Contain 2 types of cytoplasmic granules
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� P-selectin
� Fibrinogen
� Fibronectin,
� Factors V and VIII
� Platelet factor 4
� PDGF
� ADP
� ATP
� Calcium
� Histamine
� Serotonin
� Epinephrine
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� PDGF
� TGF-β
� Epinephrine
Normal HemostasisNormal Hemostasis• general sequence of events in hemostasis
1.Transient arteriolar vasoconstriction
Mediated by:
Reflex Neurogenic mechanisms
Myogenic reflex contraction, andMyogenic reflex contraction, and
Endothelin
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2. Primary hemostasis
Endothelial injury exposes HTSECM,
Patelet adherence and activation
Dramatic shape changeDramatic shape change
Release of secretory granules
Recruit additional platelets (aggregation) to form a
hemostatic plug
Platelet adhesionPlatelet adhesion
Via interactions with vWF
Other components of the ECM (e.g., fibronectin)
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Degranulation
Importance
� Ca+2Ca+2Ca+2Ca+2 is required in the coagulation cascade
� ADPADPADPADP is a potent platelet aggregator
� Platelet activation negatively charged � Platelet activation negatively charged
phospholipids on their surfaces
�Bind calcium and serve as critical nucleation
sites
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Follows adhesion and granule release
• ADP
• Noncleaved fibrinogen
• TxA2 amplifies platelet aggregation primary primary hemostatic plughemostatic plug
Aggregation is reversible Aggregation is reversible
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3. Secondary Hemostasis(factor III or thromboplastin)(factor III or thromboplastin)
Membrane-bound procoagulant glycoprotein synthesized by endothelial cells
Exposed at the site of injury
With factor VII , in vivo initiator of the coagulation With factor VII , in vivo initiator of the coagulation cascade
Thrombin generation
Cleavage of fibrinogen into insoluble fibrin
Creation a fibrin meshwork
Further platelet recruitment and activation
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Coagulation Cascade Coagulation Cascade
The 3rd arm of the hemostatic process
Amplifying series of enzymatic conversions
Each step proteolytically cleaves an inactive
proenzyme
ThrombinThrombin formation is the targetThrombinThrombin formation is the target
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� Each reaction in the pathway results from
interaction of
•• EnzymeEnzyme Activated coagulation factor
•• SubstrateSubstrate proenzyme coagulation factor
•••• CofactorCofactor Reaction accelerator
� Assembled on a phospholipid surface and
� Held together by calcium ions
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