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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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