Hemostasis/T
Normal HemostaAssessment of C
Thrombosis I
asis/Thrombosis; Clotting System
HEMOSTASIS &
• Platelets• Coagulation Cascade• Coagulation Cascade• Regulation of Coagula
& THROMBOSIS
tion
CIRCULATO• Low volume high pres• Low volume, high pres• Efficient for nutrient d
P l k 2º• Prone to leakage 2º todamageS ll l l l• Small volume loss lnutrient deliveryMi i l t ti• Minimal extravasation
irreparable damage
ORY SYSTEMssure systemssure systemelivery to tissues
d h li l fo endothelial surface
l d ilarge decrease in
i iti lin critical arease/death of organism
HEMOSPrimary vs. Secon
• Primary Hemostasis• Primary Hemostasis– Platelet Plug Formation– Dependent on normal platelp p– Initial Manifestation of Clot F
• Secondary Hemostasis– Activation of Clotting Cascad
Fibrin• Tertiary Hemostasis• Tertiary Hemostasis
– Dissolution of Fibrin Clot– Dependent on Plasminogen
STASISndary vs. Tertiary
et number & functionFormation
de Deposition & Stabilization of
Activation
HEMOSTATICHEMOSTATICSuspi
S t bl di• Spontaneous bleeding• Prolonged or excessive
procedures or trauma• Simultaneous bleedingg
C DISORDERSC DISORDERSicions
e bleeding after
g from multiple sitesg p
HEMOSTATI
B l e e d in gP r o b l e m
P la t eD i s o r
P e te c h ia e +
B le e d in gS i t e s
M u c oM e m b
T im e o fo n s e t o fb l d i
I m m e d
b le e d in g
E c c h y m o s e s +y/ H e m a t o m a s
IC DEFECTS
e l e tr d e r
C o a g u l a t i o nA b n o r m a l i t y
-
o u sr a n e
D e e p T is s u e
d ia t e D e la y e d
+
HEMOSTATIC AHEMOSTATIC A"Screening Te
• Dental Extractions• Prior Surgery/Biopsy• Prior Surgery/Biopsy• Easy bruising• Heavy menses• Deliveries• Blood transfusion
ABNORMALITIESABNORMALITIESests" (History)
PLATE• Anucleate cellular fragmentg
organelles• Synthesis controlled by IL-6
thrombopoietin• Circulate as inactive, non-b• On stimulation, undergo ma• Develop receptors for clottip p• Develop ability to bind to ea
ELETSts; multiple granules, multiple ; p g , p
6, IL-3, IL-11, &
inding concave discsajor shape changeng factorsgach other & subendothelium
PLATELET APLATELET A
RestingPlatelets
ACTIVATIONACTIVATION
vWF
PlateletPlateletAdhesion
Initial Thromb
IIaTR
bin Formation
X XaII IIa
VIIa-TF
X Xa
PLATELET APLATELET A
PlateletA ti tiActivation
ACTIVATIONACTIVATION
X XaII IIa
VIIa-TF
X Xa
Platelet
TxASSerFibThr
Release
A2, ADP, irotonin,
rinogen, rombospondin
X XII IIa
VIIa-TF
X Xa
TF
PLATELET PLUGPLATELET PLUGG FORMATIONG FORMATION
COAGULATIOCOAGULATIOGeneral
• Zymogens converted t• Zymogens converted tproteolysis
• Complex formation req• Complex formation reqphospholipid surface,
• Thrombin converts fib• Thrombin converts fibmonomer
• Fibrin monomer crossl• Fibrin monomer crossl• Forms "glue" for plate
ON CASCADEON CASCADEFeatures
to enzymes by limitedto enzymes by limited
quiring calciumquiring calcium,cofactorsrinogen to fibrinrinogen to fibrin
linked to fibrinlinked to fibrinlet plug
COAGULATIOON CASCADE
THRO• Serine protease• Serine protease• Cleaves fibrinogen to f
A i V V VIII• Activates V to Va, VIII• Activates platelets-clea• Activates XIII to XIIIa• In presence of thrombp
Protein C to APC
OMBIN
fibrinI VIIII to VIIIaaves thrombin receptor
bomodulin activates
COAGULATIOON CASCADE
Platelet
TxASSerFibThr
IX
Release
A2, ADP, irotonin,
rinogen, rombospondin
VIII VIIIa
X XII IIaX IXaV Va
VIIa-TF
X XaVIIa-TF TF
Tenase/Prothrombina
VIIIa/IXa
X XaII IIa
VIIIa RVIIIa/IXa
Va/XaVa R
ase complex assembly
FIBRIN FOA
B
T
F XIIIa
ORMATIONA
B
VITAMIN K DEPEND• Post translational modific• Post-translational modific• Factors II, VII, IX, X; pro• Converts 1st 7-12 glutam• Converts 1st 7-12 glutamγ-carboxyglutamic acid
• Confers calcium binding agproteins
• Without vitamin K, secretγ-carboxyglutamic acid co(inactive in coagulation)
DENT CARBOXYLASEcationcationoteins C & Smic acids tomic acids to
and lipid binding on these p g
te des-ontaining proteins
γ -CARBOXYG
COO-
CH2O CO
CH2
O2,CO
CHNH3+
Vit KCarboxyla
COO-Carboxyla
Glu
GLUTAMIC ACID
COO-COO-
CHO
CH2
O2
CHNH3+
aseCOO-ase
γ-carboxy Glu
PLATELET FUNC
• Bleeding Time• Bleeding Time• Platelet Count• Platelet Aggregation S
CTION STUDIES
Studies
BLEEDING TIME vs
300350400
x 10
00)
150200250
t cou
nt (x
050
100
Plat
elet
3.5 4 4.5 5 5.5
. PLATELET COUNT
7 9 12 15 25 30
Minutes
COAGULATIOON CASCADE
Clotting• Recalcification times• Recalcification times• Blood collected in sodi
calcium chelatorcalcium chelator• Amount designed to d
concentration to < 1 mconcentration to < 1 m• At that level, blood wo
RBC’ & l t l t t• RBC’s & platelets centplasma (unclotted liqu
g Tests
ium citrate, a weak
drop calcium mMmMon’t clot spontaneouslyif d ff l irifuged off, leaving
uid portion of blood)
Prothrom
Mi t f• Mixture of: – 50% patient’s platelet – 25% Mixture of Tissue
species2 % C l i hl id– 25% Calcium chloride concentration to c. 3-5Ti t l t f ti– Time to clot formation
mbin Time
poor plasmaFactor & phospholipid
( b i fi l l i(to bring final calcium 5 mM)
dmeasured
COAGULATIO
ProthrombinTime (PT)
Middle Components
V VT
Middle Components
Common Pathway
ON CASCADE
FVII
EXTRINSIC PATHWAY
TF FVIIFVIIa
Ca+2
VIIa/TFVIIa/TFFX
Va/Xa/PLVa/Xa/PLVa
Ca+2FXFXa Ca+2
Va/Xa/PLVa/Xa/PL
FG
Ca+2PTT
F
aPTT (activated partia
50% ti t’ l t l t• 50% patient’s platelet• 25% mixture of phosp
agent (Celite, Kaolin)• 25% Calcium Chloride
concentration to 3-5 m• Time to clot formationTime to clot formation
l thromboplastin time)
l-poor plasmapholipid & surface active
e to bring calcium gmMn measuredn measured
COAGULATIO
FXIIFXIIa Surface Active
Components
INTRINSIC PATHWAY
HMWKFXIFXIa
FIX
Components
VIIIa/IXVIIIa/IX
Ca+2FIXFIXa Ca+2
VIII VIIIaT
F
V VaT
FMiddle Components
V Va
Common Pathway
ON CASCADE
aPTT
Xa/PLXa/PL
FX
Va/Xa/PLVa/Xa/PL
Ca+2FXFXa Ca+2
Va/Xa/PLVa/Xa/PL
FG
Ca+2PTT
FGF
COAGULATIOContact
P k llik iPrekallikrein
F XI
ON CASCADEct Phase
Kallikrein
I HMWK
Kallikrein
F XIIa
HMWK
F XI
F XIa
COAGULATIOIntermedi
VIIa/TF/PF IX
XIa
I
F IX
F IXa
Ca+2 Ca+2
VIII VIIIa +T
F
ON CASCADEiate Phase
F VII/TFCa+2
F VIIa/TF
PL
IXa/VIIIa/PL Tenase Complex
Ca+2
XF Xa
COAGULATIOCommonCommon
IXa/VIIIa/PL VF X
F XaV Va +Ca+2
Prothrombinase Complex
ON CASCADEn Path an Pathway
VIIa/TF/PLF X
2
Xa/Va/PLCa+2
PTT
Ca+2
TFibrinogen
Fibrin monomer
CLOTTINGCLOTTINGSpecific facto
• Deficiency states of every• 50% of any clotting facto
and/or aPTTand/or aPTT• Mix 1/2 patient plasma w
plasma; then perform PTplasma; then perform PT • Factor deficient plasma w
prolonged clotting time; a• If more than one clotting
inhibitor to clotting protei
G ASSAYSG ASSAYSors/Inhibitors
y clotting protein describedor will yield normal PT
with 1/2 factor deficient and/or aPTTand/or aPTT
with missing factor will all others WNLassay prolonged, implies
in
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