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HRM Week 2 - Introduction 2020 - Handouts
HRM Week 2 - Introduction 2020 - Handouts
Hemostasis
Learning Outcomes
Hemostasis
• The process of blood clotting and then the subsequent dissolution of the clot, following repair of the injured
tissue
Hemostasis
• Normal - physiological process
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Haemostatic Response
• Primary Phase (Primary Hemostasis) – Blood vessel and platelets
Blood Coagulation
Hemostasis Vasoconstriction.
Smooth muscle contracts to constrict vessel
lumen
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Vasoconstriction
• Vessel spasm is initiated by endothelial
injury
• Only for small blood vessel
• Caused by local and humoral mechanisms
• Reflex contraction of smooth muscle of small
blood vessels
• Neural reflexes and thromboxane A2 (TXA2),
and serotonin contribute to vasoconstriction
• The most powerful vasoconstrictor
endothelin is released from endothelial cells
Platelets
Platelet Factors:
• From two specific types of granules (α- and δ-granules)
• - granules -Fibrinogen, von Willebrand factor (vWF), fibronectin, factors V
and VIII, PDGF
• δ-granules (dense granules) - ADP and ATP, ionized calcium, histamine,
serotonin, and epinephrine
• Other platelet factors - Glycoproteins, phospholipids, Actin, Myosin,
Thrombasthenin, Thromboxane A2
Platelet production is controlled by
thrombopoietin (TP)
Causes proliferation and maturation of
Platelet Properties: megakaryocytes
TP from - liver, kidney, smooth muscle,
▪ Adhesion – due to thromboxane A2, ADP, & von Willebrand factor and bone marrow
▪ Aggregation – activated platelets become sticky due to ADP and
thromboxane A2
Functions of Platelets
▪ Agglutination – clumping of platelets to form platelet plug
• Hemostasis –Vasoconstriction and Platelet
Plug
• Blood Coagulation – Phospholipids
• For Clot Retraction – Contractile Proteins
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Lumen of
blood vessel Release of platelet factors
Prevents
platelet Factors attract more platelets.
Intact endothelium adhesion
releases prostacyclin
and nitric oxide (NO).
Platelets aggregate into
platelet plug.
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Platelet Aggregation
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Platelet Aggregation
Platelets Endothelium
Thromboxane A 2 Prostacyclin (PGI2)
cAMP cAMP
cytosolic Ca 2+ cytosolic Ca 2+
++
AGGREGATION
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Aggregation
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Blood Clotting
• Two pathways - Extrinsic and Intrinsic
• Initiated by two distinct mechanisms
• Converge on a Common Pathway
• Intrinsic pathway - activated when blood comes into contact with a negatively
charged surface
• The chain reaction occurs mainly at the membrane of activated platelets
• Extrinsic pathway - activated when blood comes in contact with material from
damaged cell membranes
• The reactions occur mainly at a tissue factor that is membrane bound
• Clot formation in response to tissue injury is the result of the extrinsic pathway
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Regulatory Proteins
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Clotting Factors
Vit K Dependent
Contact Factors Fibrinogen Group
Factors
All consumed
Do not need Ca 2+ Need Ca2+ for
during
activation
coagulation
Not consumed in
Increases in
coagulation
pregnancy
[Except II]
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Intrinsic Pathway
• A cascade of protease reactions initiated by factors that are all present within blood
• Activated when plasma comes in contact with constituents of sub endothelial
tissues
• This results in the exposure of;
- Collagen and Damaged platelets (release of phospholipids)
• The initial triggering event - the activation of FXII
• Factor XI, Pre Kallikrein and HMWK are also involved (XI, XII, HMWK, PK – contact
group)
• Autoactivation of FXII and PK occurs - whenever blood contacts an artificial surface
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Intrinsic Pathway
• Factor XIIa (together with HMWK) proteolytically
cleaves factor XI to factor XIa
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Intrinsic Pathway
• “Waterfall” sequence/Enzyme
cascade
• Thrombin activation leading to fibrin
clot
• Thrombin-induced ‘amplification’
and ‘propagation’
• Contact factors -
prekallikrein,HMWK, XII,XI
• Serine proteases (Factor IX and X)
and co-factors (Factor VIII, Factor V)
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Extrinsic Pathway
• Begins with activation of tissue factor
• Tissue factor (tissue thromboplastin, or factor III) – Integral membrane protein expressed in the non-vascular
cells
• Tissue factor is a receptor for factor VII
• When an injury to the endothelium allows factor VII to come into contact with tissue factor - the tissue factor
activates factor VII to VIIa
• Tissue factor, factor VIIa, and Ca2+ form a trimolecular complex, which proteolytically cleaves the factor X to
Xa
• Exposed TF forms a complex with activated factor VII, which activates factors IX and X
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Extrinsic Pathway
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Thrombin
• Thrombin has widespread effects on multiple areas of coagulation
• Thrombin can catalyze the formation of new thrombin from prothrombin and can also catalyze the formation
of the cofactors Va and VIIIa
• Procoagulant -
• Also cleaves vWF off of FVIII to release FVIII and then activates FVIII to FVIIIa
• Anticoagulant -
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• Inflammation can trigger peripheral blood monocytes and The in vivo pathway begins with tissue factor–factor
endothelial cells to express tissue factor, increasing the risk VIIa complex activating factor X and also factor IX.
of coagulation Factor XI is activated by thrombin
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THROMBIN
Endothelium Receptor
THROMBOMODULIN
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Anti-thrombin Mechanism
• Antithrombin III – in plasma and endothelium
• Inactivates thrombin
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PLASMINOGEN PLASMIN
+ +
FIBRINOGEN FIBRIN
DEGREDATION PRODUCTS
FIBRIN DEGRADATION PRODUCTS
• The process begins with the conversion of plasminogen to plasmin
• Plasminogen - mainly made by the liver
• t-PA, from endothelial cells
• u-PA, is present in plasma
• Plasmin is a serine protease - breaks down fibrin and fibrinogen
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Anticoagulant Therapy
• Heparin
• Heparin is naturally formed and released in small amounts by mast cells in connective tissue surrounding
capillaries
• Inhibition of blood clotting – rapid action
• Binds to antithrombin III, causing a conformational change that increases the ability of AT III to inactivate
thrombin, factor Xa, and other clotting factors
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• Antiplatelet therapy
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