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8/12/2019 Blood Lecture 4
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Adelina Vlad
MD PhD, Lecturer
Hemostasis and Fibrinolysis
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Hemostasis Hemostasis, from the Greek hemos (blood) and stasis
(standing), is the arrest of bleeding from an injured blood vessel
Involves well regulated interactions between components of the
vessel wall, blood platelets and plasma proteins
Subendothelial matrixWBC
Platelets
Hemostatic plug
Fibrin
Endothelial cell
RBC
WBC
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Why Should We Study Hemostasis? Hemorrhage, intravascular thrombosis and embolism are clinical
manifestation of many diseases
Hemorrhage
occurs when disease or trauma damages large arteries andveins and normal hemostasis is overwhelmed
less frequently, is caused by an inherited oracquired
disorder of the hemostatic machinery itself
Thrombosis and embolism can be caused by unregulated activation of the hemostatic
system
may reduce blood flow to critical organs such as brain or the
heart
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Why Should We Study Hemostasis?
Accurate diagnosis and treatment of patients with either bleeding
or thrombosis require knowledge of the physiology andpathophysiology of hemostasis
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Hemostasis Initiated when trauma, surgery or disease disrupts the vascular
endothelium, exposing blood to the subendothelial connective
tissue
Achieved by:
1) Vasonstriction
2) Formation of a platelet plug
3) Formation of a blood clot as
a result of blood coagulation
4) Growth of fibrous tissue into the blood clot
Primary
hemostas is
Secondary
hemostas is
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Fluido-Coagulant Equilibrium A balance normally exists between the factors that stimulate clot
formation and forces acting to delay this process
The mechanisms that prevent hemostasis from running out of
control involve anticoagulants and fibrinolytic factors
(fibrinolysis = breakdown of stable fibrin present inside a clot)
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Primary Hemostasis
Vascular Factors
Platelet Plug Formation
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Primary Hemostasis
Is the first physiological response to vascular injury
Occurs within seconds of injury
Important in capillaries, small arterioles, venules
Triggers secondary hemostasis (coagulation proteins)
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Primary Hemostasis Vascular factors reduce blood loss from trauma through:
Local vasocon str ic t ion; results from:
1) local myogenic spasm - initiated by direct damage to the
vascular wall2) local autacoid factors t h romboxane A2 (TXA2) and
serotoninreleased by activated platelets; endothel in-1
(ET-1) produced by the endothelium in response to
thrombin
3) nervous reflexes - initiated by pain nerve impulses
Comp ression of in jured vessels by extravasation of blood
into surrounding tissues
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Primary Hemostasis Platelet plug formation involves:
1) Platelet adhesion via stimulators such as thrombin
2) Platelet activation
3) Platelet aggregation
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The Platelets
Resting
plateletsActivated
platelet
Blood smear with red
blood cells and platelets
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Genesis
Time interval from differentiation of the stem cell to theproduction of platelets (thrombocytopoiesis) ~ 10 days
Controlled by growth inducers and differentiations inducers:
thrombopoietin, IL-6, IL-3, vitamin B12, GM-CSF
Mpl-L / TPO (megapoietin, a glycosylated hormone) is thehomeostatic regulator of platelet production; acts onmegakaryocyto-poiesis and thrombocytopoiesis
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Features Disc-shaped nucleus-free fragments, 2-3 m diameter
150,000 450,000 platelets/ L in normal blood
Lifespan of about 10 days; eliminated from the circulation mainly
by the tissue macrophage system, more than 50% in the spleen
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Platelet Membrane
Phospholipids - activate multiple stages in the blood-clotting
process
Platelet receptors = glycoproteins in the platelet membrane
involved in adhesion, activation and aggregation processes
Provides procoagulant surface on which coagulation
proteins can interact
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Platelet Cytoplasm
Platelet cytoplasm has: Residual Golgi & ER that form a circumferential skeleton of
microtubules
synthesize enzymes, PG,TXA2
store large quantities of calcium ions
Mitochondria and enzyme systems that form ATP and ADP
Lysosomes containing heparin-cleaving enzyme
Fibrin-stabilizing factor (F XIII)
Actin, myosin, thrombosthenin - can cause the platelets to
contract and release the granules content Open membrane canalicular system
facilitates the exocytose of platelet granules
provides a large reactive surface for coagulation proteins
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Granules:
Electron-dense granules contain calcium ion s, ADP,
serotonin
-Granules store several proteins, such as:
platelet factor 4 (PF4) - a heparin antagonist,
von Willebrand factor (vWf),
PDGF platelet derived growth factor, causes vascular
endothelial cells, vascular smooth muscle cells, and
fibroblasts to multiply, helping repair damaged vascular
walls
two clotting factors f ibr inogenand c lot t ing factor V
Glycogen for anaerobic glycolysis
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Cross-section of an activated platelet
Cross-section of a resting platelet
Open
canalicular
system
Granules
Microtubules
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Platelet Plug Formation
Adhesion
Activation
Aggregation
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Platelet Adhesion Is the binding of platelets to themselves or to other components Occurs in response to vessel injury that expose platelet
receptors to ligands present in the subendothelial matrix
Platelet receptors involved in adhesion:
Glycoprotein Ib/Ia (GP Ib/Ia)
Lingand: von Willebrand factoro a glycoprotein present in plasma
o produced in endothelial cells and megacariocytes
o vWf forms a link between platelets and collagen fibers;stabilizes the interaction with collagen
Glycoprotein Ia/IIa (GP Ia/IIa) Ligand: collagen
Glycoprotein Ic/IIa (GP Ic/IIa)
Ligand: fibronectin, laminin
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Platelet Adhesion
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Why?
Due to:
prostacyclin and nitric
oxide released by
endothelial cells that
maintain circulating
platelets in an inactive
state
CD39 present on the
surface of endothelial
cells, an enzyme that
converts to inactive AMP
any small amounts of
ADP that might activate
platelets
Normally platelets do not adhere
to themselves, to other blood cells,or to endothelial membranes
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Platelet Activation Triggered by platelet activating agents (vWf, collagen,
thrombin, epinephrine) that bind to surface receptors
signaling events: changes in the level of cyclic nucleotides,
the influx of calcium, hydrolisis of membrane PL,
phosphorylation of critical proteins
Signaling leads to:
Cytoskeletal and morphological changes formation of
finger-like filopodia
Granule release
Lysosomes heparin-cleaving enzyme
Dense granules ADP, serotonin, calcium ions
-Granules growth factors, hemostatic factors (vWf,
fibrinogen, Factor V)
Synthesis and release of TXA2 from arachidonic acid by
using cyclooxigenase (COX)
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Resting and activated platelet
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Platelet Aggregation Signaling molecules released by activated platelets activate
additional platelets:
ADP, binds to P2Y12 receptors on platelets
Serotonin and TXA2
vWf released by activated platelets, binds to Gp Ib/Ia
activating them and forming molecular bridges betweenplatelets
Recruitment of platelets that promotes platelet aggregation
Platelet activation
conformational change in Gp IIb/IIIa,another platelet receptor, endowing it with the capacity to bind
fibrinogen fibrinogen bridges between platelets
platelet plug formation
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Adhesion
GpIIb/IIIa
Activation Pathways
GpIIb/IIIaGpIIb/IIIa Aggregation
ADP
Adrenaline Platelet
Exposed Collagen
Endothelium
vWF
COLLAGEN
GpIIb/IIIaGpIIb/IIIa AggregationGpIIb/IIIaGpIIb/IIIa Aggregation
AdhesionAdhesion
ADP
Adrenaline
THROMBIN
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Aggregation
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Platelet Plug Formation- Summary -
At sites of vascular injury,endothelial cells are damaged or
removed exposes collagen
fibrils, to which platelets adhere
with help from von Willebrand
factor, a blood proteinsynthesized by endothelial cells
Once activated in this way,
platelets secrete ADP and
thromboxane A2.
These molecules bind to receptorson circulating platelets they
become activated and recruite
into the growing platelet plug.
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Tests for Primary Hemostasis Bleeding time: skin incision time to stop bleeding; global
screen of platelet role in hemostasis
Platelet count; Mean Platelet Volume (MPV) indicates theuniformity of size of a platelet population
vWf assays: vWf Ag, vWf:RCof - measure the amount and
function of vWf; assesses function of VWF ligand in itsinteraction with platelet Gp Ib/Ia receptor
Platelet aggregometry: in vitro full platelet aggregation inresponse to various stimulation - ADP, epinephrine, collagen,thrombin, ristocetin; predominantly assesses function of plateletglycoprotein IIb/IIIa receptor
Membrane glycoproteins: Gp Ib/Ia, Gp IIb/IIIa measured usingmonoclonal antibodies and flow cytometry
Platelet granule content: electron microscopy
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Antiplatelet Drugs Acetylsalicylic acid (aspirin)
Target: COX-1 and -2, irreversibly inactivated by acetylation
Effect: prevents TXA2 synthesis impairment of platelet secretionand aggregation
Thienopyridines (ticlopidine, clopidogrel)
Target: platelet ADP receptors (P2Y12), selectively and irreversiblyinhibited
Effect: prevents ADP-induced platelet activation and aggregation
Gp IIb/IIIa antagonists (abciximab, eptifibatide, tirofibam)
Target: Gp IIb/IIIa receptors
Effect: prevents platelet aggregation
Antiplatelet therapy reduces overall mortality from vasculardisease by 15% and nonfatal vascular events by 30%
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theroscleroticlaque
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Secondary Hemostasis
Blood Clot Formation
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Secondary Hemostasis Blood clot a semisolid mass made of platelets and a fibrin
network that entraps erythrocytes, leukocytes and serum
Thrombus an intravascular blood clot; can be red, when fibrin
predominates (thrombus of the venous circulation) or white,
when a higher proportion of platelets is present (thrombus of
arterial circulation)
Primary and secondary hemostasis are related events:
activated platelets release some clotting factors
several clotting factors (thrombin, fibrinogen) play a role in
platelet-plug formation
they may occur in parallel or in the absence of the other
Secondary hemostasis is also called blood coagulation
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Red blood cellsentrapped in the fibrin
network
Platelets, red blood cells andfibrin
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Secondary Hemostasis Mechanism:
Coagulation proteins work in concert to generate prothrombin
activator orprothrombinase (step 1)
Prothrombinase acts on prothrombin, a plasma protein, to
form thrombin (step 2)
Thrombin converts fibrinogen to fibrin (step 3);
fibrin consolidates the platelet plug made in primaryhemostasis such that a fibrin clot (secondary hemostatic
plug) is formed
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Classic Model Two distinct events can induce blood clotting:
The contact of blood with the vascular endothelial collagen or
with the surface of an activated platelet triggers the intrinsic
pathway or con tact phase of coagulat ion; the trigger is
inside the vascular system
The interaction of blood with material from damaged cell
membranes (tissue factor) activates the extrinsic pathway or
t issue factor d ependent pathway; the trigger is outside the
vascular system
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Classic Model In response to the triggering event, an inactive plasma
proenzyme is converted to a reactive enzyme that, in turn,
converts another proenzyme to its active form
= the waterfall or cascadeconcept
! The cascades do not occur in the fluid phase of the blood, but
at the membrane of activated platelets (intrinsic pathway)
or
at a tissue factor that is membrane bound (extrinsic pathway)
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Waterfall Scheme of Coagulation
Extrinsic
Pathway
IntrinsicPathway
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NAME ALETERNATE NAME PROPERTIES
Factor I Fibrinogen
Factor Ia FibrinFactor II Prothrombin Synthesis in liverrequires
Vitamin K
Factor IIa Thrombin
Factor III (cofactor) Tissue factor
Tissue thromboplastin
An integral membrane
glycoprotein
Receptor for Factor VIIaFactor IV Ca2+
Factor V Labile factor
Proaccelerin
Accelerator globulin
Synthesized by liverand stored in
platelets
Factor Va (cofactor) Heterodimer held together by a
single Ca2+ ionHighly homologous to Factor VIIIa
Factor VII Stable factor
Serum prothrombin
conversion accelerator
(SPCA)
Proconvertin
Synthesis in liver requires
Vitamin K
PROCOAGULANT FACTORS
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Intrinsic Pathway Three plasma proteins form a complex on vascular endothelial
collagen or on the surface of activated platelets: Hageman factor
(XII), HMWK and prekallikrein (PK)
HMWK is a product of platelets that may help anchoring XII to
trigger surfaces; after binding to HMWK, XII slowly activates to
XIIa XIIa with HMWK as an anchor activates XI to XIa and converts
PK to kallilkrein
Kallikrein accelerates the conversion of XII to XIIa = positive
feedback
! Patients with deficit of XII, HMWK or PK have apparently normal
hemostasis an alternative mechanism for activation of XI may
exist
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Contact Activation
Trigger SurfaceXII
FXIIa
Thrombin Generation
XIa
XII
FXIIa
FXI
HK
PK
HK
FXIIa
Kallikrein
XII
Kallikrein
FXIIa
PK
HK
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Intrinsic Pathway
XIa bound on HMWK activates IX to IXa
IXa, together with Xaand th rombin(downstream activated
factors from the cascade = positive feedback), activate VIII to
VIIIa, a cofactor in the next reaction
IXa, VIIIa, calcium ions (provided on the spot by activated
platelets), and phospholipids form a complex called tenase
Tenase convert X to Xa
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Extrinsic Pathway
The extrinsic pathway is a cascade of protease reaction initiatedby factors that are outside the vascular system
Tissue factor, TF (tissue thromboplastin or factor III) is
a membrane protein expressed by nonvascular cells
a receptor for factor VIIa
TF-Bearing Cell
TF VIIa
Xa
XCa++
After a vessel injury, VII
comes in contact with TF that
activates it to VIIa
TF + VIIa + calcium ions =
= a complex analogous to
tenase that cleaves X to Xa
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Common Pathway
Xa produced by either intrinsic or extrinsic pathway is the firstprotease of the common pathway
Thrombin activates V (provided by activated platelets) to
cofactor Va (positive feedback)
Xa + Va + calcium ions + phospholipids = prothrombinase
Prothrombinase form thrombin by cleaving prothrombin
Thrombin
Main effect: catalyse the proteolysis of soluble plasma
fibrinogen to form soluble fibrin monomers that polymerize insoluble fibrin polymers gel that traps blood cells
Activates factor XIII, released by activated platelets, to XIIIa
covalent crosslinking of the fibrin polymers mesh called
stable fibrin
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Intrinsic pathway Extrinsic pathway
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Thrombin - other effects
Positive feedback at upstream levels of the cascade
Can cathalyze the formation of new thrombin from
prothrombine
Activates VIII and V, accelerate the actions of Factors
IX, X, XI, XII
Blood clot continues to grow until bleeding is stopped
Paracrine actions linked to hemostasis
Stimulates endothelial cells to produce NO, PGI2, ADP,vWf, tissue plasmin activator
Activates platelets, a process that may lead to more
thrombin formation (positive feedback)
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Thrombin positive feedback at upstream levels of the cascade
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Actual Concept: Coagulation as a
Connected Diagram Intrinsic and extrinsic pathways seem to be connected during
in vivo hemostasis
Clinical evidence suggest that initiation of physiologic
coagulation depends largely on the extrinsic pathway:
factors IX and X can be activated by the TF - VIIa - calcium
ions complex
TF can be exposed inside the vessels by peripheral blood
cells, particularly leukocytes, and activated endothelial
cells; both of them do not express normally TF activity on their
surface
TF-VIIa is inhibited by TFPI (tissue factor pathway inhibitor)
susta ined activation of X by IXa and VIIIa on the intrinsic
pathway becomes critical for normal hemostasis; XI is activated
to XIa mainly by the positive feedback effect of thrombin
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Initiation Phase
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Amplification Phase
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Propagation Phase
C l i P h
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Contact Tissue Factor + VII
XIIIa
XIII
Thrombin
Fibrin(strong)
Fibrinogen Fibrin(weak)
IX
XI
XIa
IXa
XaVa
XIIa
Prothrombin
TF-VIIa
(Prothrombinase)
PL
PL
(Tenase)
VIIIa
PL
X
Intrinsic Pathway
HKa
Extrinsic Pathway
Common Pathway
TF Pathway
Coagulation Pathways
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TF-VIIa
TFPI
TFPI
Questions left unanswered by
the classic view of hemostasis:
Why factor XII deficiency does notcause bleeding?
Why do deficiencies in factors VIII
or IX (hemophilia) produce dramatic
bleeding even though the extrinsic
pathway stays intact?
Answers:
Initial activation of IX by TF-VIIa
complex compensates for
deficiencies in XII
TF-VIIa is inhibited by TFPI (tissue
factor pathway inhibitor)sustained activation of X by IXa and
VIIIa becomes critical for normal
hemostasis
coagulation as a connected
diagram
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Secondary Hemostasis
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Clot Retraction
The fibrin fibers adhere to damaged surfaces of blood vessels the blood clot becomes adherent to any vascular opening
After a clot is formed, it begins to contract:
activation of platelet thrombosthenin, actin, and myosin
molecules cause strong contraction of the platelet spiculesattached to the fibrin
the fluid expressed is called serum because fibrinogen and
most of the other clotting factors have been removed
as the clot retracts, it becomes more tight and stable;
furthermore, the edges of the broken blood vessel are pulledtogether
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Coagulation: A Balancing Act
The cardiovascular system maintains a precarious balancebetween two pathological states: inadequate clotting that would
lead to blood loss, and overactive clotting that would cause
thrombosis and cessation of blood flow
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Only small amounts of each coagulation factor is activated theclot does not propagate beyond the site of injury
Blood fluidity is maintained by
The flow of blood
The adsorption of coagulation factors to surfaces and their
trapping in the emerging clot
Paracrine factors
Anticoagulant factors
How is Clotting Limited?
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Produced by endothelial cells
Prostacyclin (PGI2)
Inhibits platelet activation
Promotes vasodilation and thus blood flow
Nitric oxide
Following thrombine stimulation
Inhibits platelet adhesion and aggregation via cGMP
Paracrine Factors
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Anticoagulant Factors
Tissue factor pathway inhibitor (TFPI) Plasma protein that binds to TF-VIIa complex and blocks the
protease activity of VIIa
Linked to the endothelial cell membrane where it maintains an
antithrombotic surface
Antithrombin III (AT III)
Binds to and inhibits Xa and thrombin
Its activity is much increased by heparan sulfate (present on most
cells surface) and heparin (released by mast cells and basophils)
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Thrombomodulin
Produced by endothelial cells, present at their surface
Binds thrombin, removing it from the circulation
Binds protein C
Protein C
Binds to the thrombomodulin-thrombin complex gets activated by
thrombin protein Ca, a protease (! Ca means protein C activated,
not calcium)
Protein Ca + protein S (cofactor) inactivates Va and VIIIa
Protein S
Cofactor for protein C
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NAME ALTERNATE NAMES PROPERTIES
TFPI Tissue factor pathway
inhibitor
Protease inhibitor produced by
endothelial cells
Linked to the cell membrane
Antithrombin III AT III A plasma protein
Inhibits Factor Xa and thrombin, and
probably also Factors XIIa, XIa, and
IXa
Heparan and heparin enhance theinhibitory action
Thrombomodulin (cofactor) Glycosaminoglycan on surface of
endothelial cell
Binds thrombin and promotes
activation of protein C
Protein C Anticoagulant protein C
Autoprothrombin IIA
A plasma protein
Synthesis in liver requires Vitamin KProtein S (cofactor) A plasma protein
Synthesis in liver requires Vitamin K
Cofactor for protein C
ANTICOAGULANT FACTORS
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Routine Coagulation Assays
Prothrombin Time (PT) Activated Partial Thromboplastin Time (APTT)
Quantitative Fibrinogen (FIB)
Thrombin Time (TT)
Assays for specific coagulation factors
Factors assessed by a PT-based test system: FVII, FV, FX,
and FII
Factors assessed by an APTT-based test system: FXII, FXI,
FIX, and FVIII
Tests for fibrinogen
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International Normalized Ratio,
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Anticoagulant Drugs
Used to prevent and treat thrombosis in medical and surgicalpatients
Heparin (unfractioned heparin UFH, low-molecular-weight
heparin LMWH, heparinoids):
AT III binds to heparin binding and inactivation of Xa andthrombin; heparin is destroyed in the blood by an enzyme
known as heparinase (1.5 4 hours)
Direct thrombin inhibitors (DTI): hirudin, lepirudin, argatroban,
bivalirudin, xilemagatran
Coumarin derivatives: bishydroxycoumarin (dicumarol),
warfarin (coumadin)
Inhibit vitamin K synthesis of hypofunctional prothrombin,
factor VII, IX, X, protein C and protein S
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Hemostasis: A Delicate Balance
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Time Frame for Hemostasis
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Fibrinolysis
Fibrinolysis is the breakdown of stable fibrin; starts immediatelyafter the formation of the definitive hemostatic plug
Begins with the conversion of plasminogen (plasma protein) to
plasmin, catalysed by tissue-type plasminogen activator (t-
PA) or urokinse-type plasminogen activator (u-PA)
t-PA:
serine protease produced by endothelial cells
fibrin accelerates the conversion of plasminogen to plasmin
u-PA or urokinase
serine protease present in plasma
the proteolysis occurs when u-PA attaches to urokinase
plasminogen activator receptor (u-PAR) on the cell surface
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Fibrinolysis
Plasminogen
Plasmin
Fibrin, fibrinogen
Activation
Extrinsic: t-PA, urokinase
Intrinsic: factor XIIa, HMWK, kallikrein
Exogenous: streptokinase
Fibrin(ogen)degradation products
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Fibrinolysis Regulators
Catecholamines and bradykinin increase t-PA levels Serine protease inhibitors (serpins):
Plasminogen activator inhibitor-1 (PAI-1) inhibits t-PA
Plasminogen activator inhibitor-2 (PAI-2) inhibits u-PA
2-Antiplasmin (
2-AP), inactivates plasmin when is not bound
to fibrin the presence of a clot (fibrin) promotes thebreakdown of the clot (fibrinolysis)
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FIBRINOLYTIC FACTORSNAME ALTERNATE NAMES PROPERTIES
Tissue-type plasminogen
activator
t-PA A serine protease that catalyzes hydrolysis of
plasminogen at the junction between the N-
terminal heavy chain and C-terminal light chain
N terminus contains two loop structures called
kringles
Urokinase-type
plasminogen activator
u-PA A serine protease
Urokinase-type
plasminogen activatorreceptor
u-PAR Binds to and required for the activity of u-PA
Plasminogen Single-chain plasma glycoprotein with large N-
terminal and small C-terminal domain.
N terminus contains five kringles
Plasmin Fibrinolysin A serine protease
Plasminogen activator
inhibitor-1
PAI-1 A serpin (serine protease inhibitor)
In plasma and platelets
Forms 1:1 complex with t-PA in blood
Plasminogen activator
inhibitor-2
PAI-2 A serpin (serine protease inhibitor)
Detected only in pregnancy
2-Antiplasmin
2-AP A serpin (serine protease inhibitor)
Forms 1:1 complex with plasmin in blood
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Fibrinolysis Cascade
The injured tissues and vascular endothelium release slowlyt-PA and u-PA that enter the fibrin clot and convert
plasminogen into plasmin
Plasmin proteolitically cleaves stable fibrin to fibrin
degradation products, cleared by the macrophages
Plasmin digests some other protein coagulants such asfibrinogen, Factor V, Factor VIII, prothrombin, and Factor XII
(sometimes even causing hypocoagulability of the blood)
Plasmin can degrade fibrinogen, but the reaction remains
localized because
t-PA and u-PA activate plasminogen more effectively when it is
adsorbed to fibrin clots
any free plasmin is complexed with 2-AP
endothelial cells release PAI-1 that blocks t-PA
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Breakdown of Fibrin(ogen)
Following fibrin(ogen)cleavage D, E
fragments are liberated
Plasmin acting on
stable fibrin (covalently
cross-linked fibrinpolymers) releases D-
dimers plasma D-
dimer assay = test of
fibrin degradation
Fibrin(ogen) degradation products have anticoagulant andantiplatelet actions, enhancing the net antithrombotic effect of
fibrinolysis
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Tests for Fibrinolysis
Plasminogen activity assay Euglobulin lysis time; diluted whole blood clot lysis
Plasma fibrinogen
Fibrin split products assay
Plasma D-Dimer assay
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Fibrinolytic Agents
Most currently available thrombolytic agents are plasminogenactivators (PA)
Convert patient plasminogen to plasmin which acts on fibrin
within a thrombus
Additionally can breakdown fibrinogen (fibrinogenolysis)
Therapeutic doses of PA overwhelm PAI-1 and 2-antiplasmin
Beneficial effect is reduction of thrombus size (thrombolysis)
Negative effect is that hemostatic plugs are also lysed
Most commonly used agents are: Streptokinase (SK), Alteplase(tPA), Reteplase (r-PA), and Tenecteplase (TNK-tPA)
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Fibrinolytic Agents
Streptokinase, obtained from cultures of beta-hemolyticstreptococci; complexed with plasminogen can convert other
plasminogen molecules to plasmin; it is not fibrin selective
(produces lysis of fibrinogen and fibrin)
u-PA, native, obtained from human fetal kidney cell cultures;
recombinant; it is not fibrin selective rt-PA, recombinant t-PA, with some fibrinogen selectivity
t-PA variants: recombinant PA (reteplase, r-PA), TNK-rt-PA, with
increased resistance to PAI-1 and a better fibrin selectivity
Newer non-t-PA fibrinolytics: more potent and fibrin-selective
PAs, or direct fibrinolytic (not PA) agents (alfimiprase)
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Thrombosis: Balance is Disrupted
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Summary
Primary hemostasis, a platelet-dependent process, forms plateletplugs when a vessel is injured
Secondary hemostasis, a coagulation factor-dependent process,
begins with Tissue Factor exposure
Small amounts of thrombin are generated via FXa formation
by the TF:FVIIa complex (Extrinsic Pathway) Sustained thrombin generation depends on FXa formation via
FIXa and FVIIIa-mediated complexes on an activated platelet
surface
Amount of stable fibrin generated dictates bleeding or
thrombotic risk