disorders
Questions?
Why dont we normally form blood clots in
normal and uninjured blood vessel?
How and why do we form clots when our
small vessels are injured?
Normal hemostasis
Four phases .
1. Vascular phase
2. Platelet phase
3. Coagulation phase
4. Fibrinolytic phase
Vascular phase
Platelet phase
Coagulation phase
Fibrinolytic phase
Vascular phase
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Platelet phase
Adhesion: GpIb receptors on the platelets
adhere to exposed vWF in damaged endothelial
cells.
Release reaction: release of ADP causes platelet
aggregation.
Synthesis and release of TXA2: vessels constrict
, reducing blood flow; this action further
enhances platelet aggregation
Temporary platelet plug stops bleeding:
aggregated platelets with fibrinogen attached to
their GpIIb-IIIa receptors form a plug.
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Coagulation phase:
Thrombin produced by activation of
coagulation cascade converts fibrinogen
into insoluble fibrin to form a stable
plug.
Fibrinolytic phase:
Plasmin breaks insoluble fibrin to reestablish the blood flow
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Vascular
phase
Platelet phase
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Coagulation phase
Fibrinolytic phase
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Platelets
Structure:
Alpha granules contain:
vWF, fibrinogen
Platelet factor 4 (PF4)
heparin neutralizing factor
Dense bodies or delta granules contain
ADP: an aggregating agent,
Calcium (Ca2+) : a binding agent for vitamin K
dependent factors
Contractile elements:
Thrombosthenin
Helps in clot retraction.
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Coagulation factors
Total of 12 factors
Named according to order of discovery
No factor VI
The factors are proenzymes that must be
converted to active form.
An activated coagulation factor has enzymatic
activity (e.g. activated factor XII XIIa).
Some conversions occur on phospholipid surface
Some conversions require calcium.
Source: synthesized in liver ( severe liver disease
bleeding tendency).
Some factors require vitamin K dependent
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carboxylation to function.
COAGULATION FACTORS
FACTOR
NAME
Fibrinogen
II
Prothrombin
III
IV
V*
No factor VI
VII
VIII
Antihemophilic factor
IX
X
Stuart factor
XI
XII
Hageman factor
XIII
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Coagulation cascade
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XII
Intrinsic system
Collagen
HMWK
Extrinsic system
Tissue
thromboplastin
XIIa
VII
XI
VIIa
XIa
IX
IXa
VIII+IXa+PF3+Ca2+
Xa
X
V+Xa+PF3+Ca2+
Thrombin
Prothrombin
Fibrin monomer
Fibrinogen
Fibrin
monomer aggregate
Soluble fibrin
XIII
XIIIa
Thrombin
Cross linked
insoluble fibrin
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Coagulation cascade
Extrinsic pathway: factor VII
Begins with activation of factor VII
Tissue thromboplastin released from injured
tissue activates factor VII resulting in
formation of factor VIIa
VII
Tissue thromboplastin
VIIa
Coagulation cascade
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Intrinsic pathway
XIa activates factor IX to form IXa
IXa complexes with factor VIII, Ca++ and
PF3 to form a four component complex
(factor IXa, factor VIII, PF3, Ca2+).
In the final common pathway, this complex
activates factor X.
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Functions of Thrombin:
Acts on fibrinogen to produce soluble
fibrin monomers.
Activates fibrin stabilizing factor XIII
Activated fibrin stabilizing factor
XIIIa converts soluble fibrin monomers
to insoluble fibrin
by enhancing cross linking between
proteins to strengthen the fibrin
clot.
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Pharmacologic anticoagulants
Heparin:
Increases Antithrombin III activity.
Warfarin ( coumadin)
Inhibits vitamin K dependent
carboxylation of factors II,VII,IX and
X
Present in rat poison
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Fibrinolytic system
Breaks down the stable clot in order to restore
blood flow.
Activated by:
tPA : activates plasminogen to form the
enzyme plasmin
Functions of plasmin:
Cleaves insoluble fibrin monomers and
fibrinogen into fibrin degradation products
(FDPs).
Fragments of cross linked insoluble fibrin
monomers are called D-dimers.
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Platelet tests:
1. Platelet count
2. Bleeding time
3. Test for vWF: Ristocetin cofactor assay
Coagulation system tests:
1. Prothrombin time (PT)
2. Activated partial thromboplastin time (aPTT)
3. Thromboplastin time (TT)
4. Mixing studies
5. 5 molar urea clot solubility test
Fibrinolytic system tests:
1. FDP assay
2. D dimer assay
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Platelet tests
Platelet count:
most cost effective test
Normal count is 150,000 to 400,000
cells/uL.
A normal count does not guarantee normal
platelet function.
Bleeding time:
Evaluates platelet function upto the formation
of temporary platelet plug.
Normal range: 2-7 min
Abnormal if defect in platelet
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Number or Function
Nature of defect
Aspirin or NSAIDs
Bernard-Soulier
syndrome
Glanzmanns disease
Renal failure
Thrombocytopenia
Von Willebrands
disease
Scurvy
( TxA2)
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Prothrombin time
Evaluates the extrinsic & common pathway down
to the formation of a clot.
Tests factors: VII,X,V,II,I.
A deficiency of one or more of the above
factors prolongs the PT.
Normal range: 11 to 15 sec.
International normalized ratio (INR):
Standardizes the reporting of PT results in
patients taking warfarin.
Results are the same regardless of the
reagents used to perform the test.
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Prothrombin time
Uses of PT:
Follow patients who are taking warfarin
for anticoagulation.
PT elevated
Evaluating the severity of liver disease.
Elevated PT indicates severe liver
dysfunction
Confirming factor VII deficiency
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