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HEMOSTASIS
Department of Surgery
FEU-NRMF MEDICAL CENTER
HEMOSTASIS
balance of the physiological processesprevent excessive bleeding after vessel injurymaintain a viable circulation by keeping the
blood in an uncoagulated state“Self-sealing” system to prevent
excessive bleeding and potentially life threatening states
Four components
Vessel function constriction of injured vessels
Platelet function formation of platelet plugs
Coagulation formation of fibrin plugs
Fibrinolysis dissolution of blood clots
Normal Hemostasis
ExcessiveBleeding
ExcessiveClotting
VesselInjury
Means stopping of blood – prevents blood loss Imbalance in one direction may lead to excessive bleeding, imbalance in
the other may lead to thrombus formation
Overview of blood coagulation
PRIMARY HEMOSTASIS
SECONDARY HEMOSTASIS
Primary HemostasisFormation of platelet plug
Secondary HemostasisFormation of blood clot
Hemostasis
response is dependent on overlapping and interdependent responses
Vascular Endothelium
Blood vessel wall integrity is essential for prevention of blood loss – provides potent anticoagulation surface.
Vascular Endothelium
ECs form monolayer resting on continuous basement membrane; constitutes first barrier of defense from hemostasis and thrombosis
EC Products Secreted into the Subendothelium
EC surface products secreted into the blood stream
LUMEN
ECs provides numerous proteins to subendothelium essential for cell–to-cell interactions and formation of diffusion barrier to prevent blood loss.
Vascular Endothelium
EC Products Secreted into the Subendothelium
● basement membrane ● elastin ● fibronectin● collagen III and IV ● lamilin ● mucopolysaccharides● microfibrils ● vibronectin ● vWf
● protease inhibitors
These proteins essential for cell–to-cell interactions and formation of diffusion barrier to prevent blood loss into extravascular spaces.
Vascular Endothelium
ECs also secrete numerous substances into the vascular lumen to prevent clotting (e.g. heparin)
which promote fluidity of the blood
EC surface products secreted into the blood stream
● PGI2 ●glycosaminoglycans ● tissue factor● EDRF ● ATIII/heparin sulfate ● vWf● t-PA ● protein kinase/thrombomodulin ● Factor V● urokinase ● plasminogen activators ● inhibitors (PAI-1, PAI-2● nitric oxide ATIII)
● IL1, TNFα ● endothelin-1 ● PAF
Anticoagulants Procoagulants
These substances promote fluidity of the blood.
Vascular Endothelium
Normal endothelium acts as a potent anti-coagulation surface, upon stimulation or injury, endothelium transforms into a potent pro-coagulation surface as subendothelial collagen is exposed
Primary Hemostasis
Primary Hemostasis
response to vascular injury that produces a platelet plug at the site of damage
immediately limit bleeding through the formation of a loose platelet plug
Platelets
Minute round or oval discs (1-4 mm diameter).
Do not have a nucleus and can not divide.Formed from megakaryocytes in bone
morrowNormally 150-450,000 per ml of blood
Platelets
Adhering to the endothelial wall at the site of injury
Releasing potent anticoagulant compounds
Aggregating to form a plug Providing a phospholipid surface for
activated coagulation enzyme complexes
Platelets
Have many functional characteristics of whole cells Contains contractile proteins (actin, myosin and
thrombosthenin) Residuals of ER and Golgi apparatus Mitochondria and enzymes to form ATP and ADP Can synthesis prostaglandins (thromboxane A2) Forms fibrin stabilizing factor Forms growth factors
Platelets Cell membrane contains glycoproteins that reduces
adherence to normal endothelium yet promotes adherence to injured areas of vessel wall,
especially injured ECs and collagen of subendothelium. Membrane also contains phospholipids that play
activating role at multiple points in the clotting process. Platelets have a half life of 8-12 days Eliminated from the circulation mainly by tissue
macrophages, especially in spleen.
Platelets
Endothelial cell injury exposes subendothelial collagen which causes change in platelet shape and adherence.
vWf- bridges platelet membrane glycoprotein to the exposed collagen at site of injury.
Vascular Injury
INJURED
Vasoconstriction
an immediate reflex
Initial response to injurydiminishing blood
lossLocal constriction
of smooth muscle
Vasoconstriction
Transient, typically lasts minutes (severed limbs)
Result of release of local humoral actors, neural reflexes (caused by pain), local myogenic spasm
Small blood vessels, release of vasoconstrictor thromboxane A2 from platelets is primarily responsible
Platelet adhesion
Exposed collagen from the damaged site will promote the platelets to adhereundergo degranulation and release
cytoplasmic granules Occurs within 15 secs after injury
Platelet adhesion
Injury to intima
Subendothelial collagen
(Glycoprotein receptor Ib)
Platelet adhesionvWF
Von Willebrand factor (vWF)
Multimeric plasma glycoprotein required for normal hemostatic platelet plug formation
Forms a bridge between platelet glycoprotein IB and exposed collagen in the subendothelium
It is the “glue” that binds platelets to collagen.
vWF is also responsible for the binding and transport of factor VIII (antihemophilic factor), a procoagulant protein in plasma.
Platelet adhesion
cytoplasmic granules serotoninADP and Thromboxane A2
Platelet adhesion
serotonin, a vasoconstrictor ADP attracts more platelets to the area thromboxane A2 promotes platelet
aggregation, degranulation, and vasoconstriction
EM of normal and activated platelets
Normal Aggregated Platelets
ADP and thromboxane A2 promote more platelet adhesion therefore more ADP and thromboxane“Second wave”
Platelet plug
The positive feedback promotes the formation of a platelet plug
Primary platelet plug is only good for stopping bleeding in the first minute- it can not sustain
hemostasis. Heparin does NOT interfere with this reaction
Arachidonic acid pathway
ASPIRIN and other NSAID
Primary hemostasis
Defects : associated with mucocutaneous bleeding, characterized by epistaxis, ecchymosis, genitourinary bleeding, or gingival bleeding “first wave” of aggregation“second wave” ( granule release )
Secondary Hemostasis
Secondary Hemostasis
Cascade of enzymatic reactions that ultimately results in the conversion of fibrinogen to fibrin monomers
cross-linked into insoluble strands that serve to stabilize the loose platelet clot formed in primary hemostasis
Secondary Hemostasis
triggered by the release of tissue factor from epithelial cellsPlatelets, vascular wall and multiple
circulating or membrane-bound coagulation factors
Formation of Prothrombin Activator
Prothrombin activator formed in two ways:Extrinsic pathway Intrinsic pathway
In both pathways, inactive forms of blood clotting factors are converted to active forms.
Designated by Roman numerals, small “a” for active
The common pathway
p ro th ro m bin * th ro m bin
fib rino ge n
F ib rin m on om er
F ib rin po ly m erC L O T
* X a
X III X IIIa
Va V
C o m m o np a thwa y
Ca++
Note that both the Extrinsic and Intrinsic Pathways converge on Factor X
Prothrombin Activator Complex (rate limiting step)
Vessel Injury
Characteristics of clotting reactions in the cascade
A proteolytic enzyme generates the next enzyme in the cascade by cleavage of a proenzyme
The reactions occur on a phospolipid surface ( platelet membrane )
Each reaction requires a helper protien to bring the enzyme and substrate together
Clotting Factors in the BloodFactor Common Name Pathway Function
I Fibrinogen Common Fibrin clotII 1Prothrombin* Common Generates fibrinIII Tissue factor (Thromboplastin) Extrinsic Receptor for VIIaIV Calcium All Co-factorV Proaccelerin Common Receptor for XaVII 1Proconvertin* Extrinsic Activates IX and XVIII Antihemophilic factor Intrinsic Receptor for IXaIX 1Christmas factor* Intrinsic Activates XX 1Stuart factor* Common Activates prothrombin and VIIXI Plasma thrombin antecedent* Intrinsic Activates IXXII Hageman factor* Intrinsic Activates XIXIII Transglutamidase Common Cross-links fibrin
Von Willebrand factor Platelets Platelet activation and bindingPrekallikrein* Intrinsic Activates XIIKininogen Intrinsic Receptor for kallikrein and XII
Extrinsic PathwayProcess begins with trauma to vascular
wallinitiated by tissue factor release by damaged
tissue initiated by contact with Factor VII and
platelets with collagen in vessel wallClotting begins within seconds
Extrinsic Pathway Release of Tissue Factor (thromboplastin).
Functions as a proteolytic enzyme complex Activation of Factor X.
Tissue Factor further complexes with Factor VII which in the presence of Ca++ activates Factor X to Xa.
Formation of Prothrombin Activator Xa combines with phospholipids and Factor V to form
prothrombin activator complex In the presence of Ca++, this splits prothrombin into
thrombin in the Common Pathway
Extrinsic Pathway
Release of Tissue Factor (thromboplastin).Functions as a proteolytic enzyme complex
Extrinsic Pathway
Activation of Factor X. Tissue Factor further complexes with Factor
VII which in the presence of Ca++ activates Factor X to Xa.
Extrinsic Pathway
Formation of Prothrombin ActivatorXa combines with phospholipids and Factor V
to form prothrombin activator complex
Extrinsic and common pathways
pro th rom bin * th rom b in
fib rinogen
F ibrin m onom er
F ib rin po lym erC L O T
*X a
X
X III X IIIa
*V IIa
T F
In ju redC ells
V II
Va V
unk .
Extrinsicp a thwa y
C o m m o np a thwa y
= C a lcium & P L com plex
* = ac tive serine p ro tease Tissue Factor
Tissue Trauma
Intrinsic Pathway
Initiated by trauma to blood or exposure of blood to vascular wall collagen
Takes 1-6 minutes to cause clotting All components are “intrinsic to the circulating
plasma” and NO surface is required to initiate clotting
Intrinsic Pathway
Causes activation of Factor XII (to XIIa) and release of platelet phospholipids
Activation of Factor XI by Factor XII. This reaction also requires High Molecular Weight (HMW) kininogen and is accelerated by prekallikrein.
pro th rom bin * th rom b in
fib rinog en
F ibrin m onom er
F ib rin po lym erC L O T
*X a
X
X III X IIIa
*IX a
IX
*X Ia
X I
*X IIa
X IIW O U N D surface
*ka llik rein
k in inog en (H M W K )
prekallik re in
Va
V IIIa V III
V
Intrinsic p a thwa y
C o m m o np a thwa y
= C a lcium & P L com plex
* = ac tive serine p ro tease
Intrinsic and common pathways
Prothrombin Activator
Factor X activation
Extrinsic XaseTF- VIIa
Intrinsic XaseVIIIa-XIa
50x more effective at catalyzing factor X activation
Functions of thrombin
Conversion of fibrinogen to fibrin Activation of factors V, VIII, XI and XIII
Prothrombin unstable plasma protein that splits in half to
form thrombin. Made by liver and requires vitamin K
Common Pathway
In the presence of Ca++, this splits prothrombin into thrombin in the Common Pathway
Prothrombin Activator Complex
Thrombin Activation
co llagen
WO UNDv W F
endo th eliu m
p la te le tPL surfa c e
C a
C a
Va
Xa
C ircu la tio n
N H2C O O H
G la G la
P ro -T h ro m b in
SS
p ro teo ly tic cu t
N H2C O O H
G la G la
T h ro m b inP ro -
SS
Phospholipid surface
Common Pathway
Fibrinogen large plasma protein formed in liver Acted on by thrombin (removes 4 peptides) to form fibrin which
polymerizes into fibrin fibers
Common Pathway
Fibrin-stabilizing factor from platelets trapped in clot is activated which causes formation of covalent bonds between fibrin monomer molecules
BLOOD CLOT
INTRINSIC PATHWAY (12-11-9-8-10)
XII (Hageman Factor)
XIIa
XI XIa + Ca ++
IXa + VIII + Ca++ + phospholipid, F3,Plt
Xa
Prothrombin (Factor II)
Thrombin
Fibrinogen Fibrin ClotXIII a
EXTRINSIC PATHWAY
Tissue thromboplastin + VII + Ca++
V
All coagulation factors synthesized in the liver except for thromboplastin, Ca++
Factors 2,7,9,10 – vitamin K dependent
The coagulation system
Regulated system In addition to Clot formation :
Balanced the propagation of clotFeedback inhibition of cascadeMechanism of fibrinolysis
Feedback inhibition of cascade
Tissue factor pathway inhibitor (TFPI )Antithrombin IIIProtien C system
Tissue factor pathway inhibitor (TFPI )
pro th rom bin * th rom b in
fib rinogen
F ibrin m onom er
F ib rin po lym erC L O T
*X a
X
X III X IIIa
*V IIa
T F
In ju redC ells
V II
Va V
unk .
Extrinsicp a thwa y
C o m m o np a thwa y
= C a lcium & P L com plex
* = ac tive serine p ro tease Tissue Factor