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