Coagulation and Hemostasis Joy Loy, M.D. MetroHealth Medical Center December 2006.

Coagulation Coagulation and and

HemostasisHemostasis

Joy Loy, M.D.Joy Loy, M.D.MetroHealth Medical CenterMetroHealth Medical Center

December 2006December 2006

• Hemostatic processHemostatic process

• Coagulation cascadeCoagulation cascade

• FibrinolysisFibrinolysis

• Laboratory studiesLaboratory studies

• MedicationsMedications

• Coagulation disordersCoagulation disorders

HemostasisHemostasis PurposePurpose

Ensure that coagulation mechanisms Ensure that coagulation mechanisms

areare

activated when there is injuryactivated when there is injury

not unnecessarily activatednot unnecessarily activated

Restore tissue blood flow after repair of Restore tissue blood flow after repair of

injury (fibrinolysis) injury (fibrinolysis)

Hemostatic ProcessHemostatic Process

3 main steps3 main steps

Primary hemostasis: local vasoconstriction Primary hemostasis: local vasoconstriction

& platelet plug formation& platelet plug formation

Coagulation cascadeCoagulation cascade

FibrinolysisFibrinolysis

Hemostatic ProcessHemostatic ProcessPlatelet Plug FormationPlatelet Plug Formation

• • vascular injuryvascular injury

• • release and binding of vWF to exposed release and binding of vWF to exposed

blood vessel collagenblood vessel collagen

• • glycoprotein IB on platelet surface glycoprotein IB on platelet surface

membrane binds to vWFmembrane binds to vWF

• • TxATxA2 2 →→ vasoconstriction & platelet vasoconstriction & platelet

adhesionadhesion

• • platelet factor 3 (PF3) phospholipid layer platelet factor 3 (PF3) phospholipid layer

(procoagulant)(procoagulant)

Platelet Activation & AggregationPlatelet Activation & Aggregation

exposed endothelial surfaceexposed endothelial surface

platelets exposed to collagenplatelets exposed to collagen

““activated”activated”

release contents of cytoplasmic granulesrelease contents of cytoplasmic granules

adenosine diphosphate (ADP)adenosine diphosphate (ADP) thromboxane thromboxane

(Tx A(Tx A22))

accelerates platelet accelerates platelet vasoconstriction vasoconstriction aggregation/activationaggregation/activation ↑ ↑ ADP release from ADP release from plateletsplatelets

Hemostatic ProcessHemostatic ProcessCoagulation CascadeCoagulation Cascade

to stabilize and reinforce the weak to stabilize and reinforce the weak

platelet plugplatelet plug

fibrinogen fibrinogen → → fibrinfibrin

3 main steps:3 main steps:

1.1. formation of prothrombin activatorformation of prothrombin activator

2.2. conversion of prothrombin into thrombinconversion of prothrombin into thrombin

3.3. conversion of fibrinogen to fibrinconversion of fibrinogen to fibrin

Coagulation CascadeCoagulation Cascade

TF =tissue factorPK = prekallikreinHK=high molecular kininogena = activated

Roberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

Coagulation MechanismCoagulation Mechanism

activation of clotting factorsactivation of clotting factors

requires a phospholipid surfacerequires a phospholipid surface tissue factor (TF) extrinsic to the bloodtissue factor (TF) extrinsic to the blood

activated platelet (platelet factor 3 activated platelet (platelet factor 3

phospholipid) intrinsic to blood phospholipid) intrinsic to blood

vitamin-K dependent factors (II, VII, IX, X)vitamin-K dependent factors (II, VII, IX, X)

formation of reaction complexformation of reaction complex labile factors : factors V and VIIIlabile factors : factors V and VIII

Factor VIIIFactor VIII

extrahepatic originextrahepatic origin

2 components (separate genetic control)2 components (separate genetic control)

1.1. VIII R : Ag VIII antigen + vWFVIII R : Ag VIII antigen + vWF

2.2. VIII : C coagulant activity VIII : C coagulant activity

*absence *absence →→ hemophilia Ahemophilia A

von Willebrand factor (vWF)von Willebrand factor (vWF)

•• mediates adhesion of platelets to surface collagenmediates adhesion of platelets to surface collagen

• • carrier of VIII:Ccarrier of VIII:C

• • vWD: vWD: appears to have defect in primary appears to have defect in primary

hemostasis & hemophilia Ahemostasis & hemophilia A

Factor VIIIFactor VIII

F VIII:CF VIII:C F VIII:vwFF VIII:vwF

hemophilia Ahemophilia A decreasedecrease ----------------

vWD type 1vWD type 1 decreasedecrease decreasedecrease

vWD type 2vWD type 2 normalnormal decreasedecrease

Coagulation CascadeCoagulation Cascade

TF =tissue factorPK = prekallikreinHK=high molecular kininogena = activated


Newer Concepts of Coagulation ReactionsNewer Concepts of Coagulation Reactions

2 main functions of tissue factor (TF) 1) to activate factor X to Xa 2) to activate factor IX to IXa

Control MechanismsControl Mechanisms

1) TF pathway inhibitor

2) Protein C system

3) Antithrombin (e.g. AT III)

4) Glycoaminoglycans

APC: activated protein CAT : antithrombinGAG: glycoaminoglycansT : thrombinPC : protein CS : protein STF : tissue factorTM : thrombomodulin

Antithrombin III (AT III)Antithrombin III (AT III)

naturally-occuring anticoagulantnaturally-occuring anticoagulant

binds to factors IXa, Xa, XIa, XIIa (slow)binds to factors IXa, Xa, XIa, XIIa (slow)

accelerated by accelerated by heparinheparin manyfold manyfold

Implication:Implication:

Heparin has almost Heparin has almost NONO anticoagulant anticoagulant

action action without without AT III AT III

Coagulation FactorsCoagulation Factors

FACTORSFACTORS PLASMA t ½PLASMA t ½

(hrs)(hrs)

Fibrinogen (I)Fibrinogen (I) 72-12072-120

Prothrombin Prothrombin (II)(II)

60-7060-70

VV 12-1612-16

VIIVII 3-63-6

VIIIVIII 8-128-12

IXIX 18-2418-24

XX 30-4030-40

FACTORSFACTORS PLASMA t ½ PLASMA t ½

(hrs)(hrs)

XIXI 5252

XIIXII 6060

Protein CProtein C 66

Protein S Protein S (total)(total)

4242

Tissue factorTissue factor ----

ThrombomodulThrombomodulinin

----

antithrombinantithrombin 7272


FibrinolysisFibrinolysis

Plasminogen Plasminogen →→ plasmin plasmin

Release of tPA by the Release of tPA by the

endotheliumendothelium

Lysis of clotLysis of clot→ → FDPs or FSPsFDPs or FSPs

Reopening of blood vesselReopening of blood vessel

Laboratory MonitoringLaboratory MonitoringProthrombin Time (PT)Prothrombin Time (PT)

test of test of extrinsicextrinsic pathway activity pathway activity

measures vitamin K - dependent factors measures vitamin K - dependent factors

activity (factors II, VII, IX, X)activity (factors II, VII, IX, X)

thromboplastin + Cathromboplastin + Ca+2+2 to plasma = clotting to plasma = clotting

timetime

normal values: 12-14 secondsnormal values: 12-14 seconds

International Normalized Ratio (INR)International Normalized Ratio (INR)

▪ ▪ standardizes PT reportingstandardizes PT reporting normal values: 0.8 -1.2 secondsnormal values: 0.8 -1.2 seconds

Laboratory MonitoringLaboratory Monitoring Prothrombin Time (PT)Prothrombin Time (PT)

monitors coumadin therapymonitors coumadin therapy

most sensitive to alteration in F VII levelsmost sensitive to alteration in F VII levels

prolonged: 55 % prolonged: 55 % ↓ ↓ of normal F VII activityof normal F VII activity

antithrombotic activity: reduction of factor antithrombotic activity: reduction of factor

II and factor X activity (after several days)II and factor X activity (after several days)

Laboratory MonitoringLaboratory Monitoring Activated Partial Prothrombin Time (aPTT)Activated Partial Prothrombin Time (aPTT)

test for test for intrinsicintrinsic and and commoncommon pathways pathways

dependent on activity of all coagulation dependent on activity of all coagulation

factors, except VII and XIIIfactors, except VII and XIII

normal values: 25 -35 secondsnormal values: 25 -35 seconds

monitors heparin tx & screen for hemophiliamonitors heparin tx & screen for hemophilia

Laboratory MonitoringLaboratory Monitoring Activated Prothrombin Time (aPTT)Activated Prothrombin Time (aPTT)

prolonged: heparin, thrombin inhibitors, prolonged: heparin, thrombin inhibitors,

fibrin degradation products (FDP)fibrin degradation products (FDP)

citrated plasma + surface activators + citrated plasma + surface activators +

phospholipid phospholipid

prolonged only if coagulation factors prolonged only if coagulation factors

reduced to < 30 % of normalreduced to < 30 % of normal

Laboratory MonitoringLaboratory Monitoring Activated Clotting Time (ACT)Activated Clotting Time (ACT)

monitors heparin anticoagulation in the monitors heparin anticoagulation in the

OR (cardiac and vascular surgeries)OR (cardiac and vascular surgeries)

normal values: 90 - 120 seconds normal values: 90 - 120 seconds

Laboratory MonitoringLaboratory MonitoringThrombin Clotting Time (TCT)Thrombin Clotting Time (TCT)

reflects abnormalities in fibrinogen reflects abnormalities in fibrinogen → → fibrinfibrin

plasma + excessive amount of thrombinplasma + excessive amount of thrombin

prolonged: heparin, thrombin inhibitors, prolonged: heparin, thrombin inhibitors,

low fibrinogen, dysfibrinogenemialow fibrinogen, dysfibrinogenemia

monitors hirudin, bivalirudin, LMWH txmonitors hirudin, bivalirudin, LMWH tx

INR & PT may be normal or INR & PT may be normal or ↑ ↑

TTCT prolonged with adequate therapeutic CT prolonged with adequate therapeutic

levelslevels

Laboratory MonitoringLaboratory Monitoring

Thromboelastography (TEG)Thromboelastography (TEG) continuous profiles during all phases of continuous profiles during all phases of

clot formationclot formation

provides more accurate picture of in vivo provides more accurate picture of in vivo

coagulation processcoagulation process to evaluate:to evaluate:

• • hypo / hypercoagulable state hypo / hypercoagulable state

• • hemophiliahemophilia

• • dilutional coagulopathydilutional coagulopathy

• • rare coagulation disorders anticoagulation txrare coagulation disorders anticoagulation tx

• • coagulation problems with liver coagulation problems with liver transplantationtransplantation

Thromboelastogram

(TEG)

Bleeding timeBleeding time

monitors platelet functionmonitors platelet function

not specific indicator of platelet not specific indicator of platelet

functionfunction

not very reliablenot very reliable

very operator - dependentvery operator - dependent

variable from each institutionvariable from each institution

Bleeding timeBleeding time

other factors: degree of venostasis, depth other factors: degree of venostasis, depth

and direction of incisionand direction of incision

no evidence as no evidence as

• • a predictor of risk of hemorrhagea predictor of risk of hemorrhage

• • useful indicator of efficacy of antiplatelet useful indicator of efficacy of antiplatelet

therapytherapy

insensitive to mild platelet defects insensitive to mild platelet defects

Laboratory MonitoringLaboratory Monitoring Platelet Function Analyzer (PFA) - 100Platelet Function Analyzer (PFA) - 100

relatively new global test of platelet relatively new global test of platelet

adhesion and aggregationadhesion and aggregation

advantagesadvantages noninvasive, simple, easy to performnoninvasive, simple, easy to perform

very sensitive in detecting platelet defectsvery sensitive in detecting platelet defects

associated with vWDassociated with vWD

sensitive to dx of acquired platelet defects sensitive to dx of acquired platelet defects

(ASA, NSAID, dietary factors: excessive (ASA, NSAID, dietary factors: excessive

cocoa intake)cocoa intake)

monitors pro-hemostatic treatmentmonitors pro-hemostatic treatment

DDAVP & platelet transfusionsDDAVP & platelet transfusions

Laboratory MonitoringLaboratory Monitoring

PFA-100PFA-100

LimitationsLimitations

■ ■ inflexibilityinflexibility

■ ■ results should be interpreted in the results should be interpreted in the

context of either a simultaneously or context of either a simultaneously or

recently drawn full blood countrecently drawn full blood count

■ ■ platelet count < 80,000 or Hct < 30% platelet count < 80,000 or Hct < 30%

will prolonged CT even if no platelet will prolonged CT even if no platelet

abnormalabnormal

LABORATORY LABORATORY

TESTTESTCOMPONENTS COMPONENTS

MEASUREDMEASURED

NORMAL NORMAL VALUESVALUES

Bleeding timeBleeding time platelet functionplatelet function

vascular integrityvascular integrity

3 - 10 3 - 10 minsmins

PTPTI, II, V, VII, IX, XI, II, V, VII, IX, X

12 - 14 12 - 14 secssecs

PTTPTTI, II, V, VIII, IX, X, XI, XIII, II, V, VIII, IX, X, XI, XII

24 - 35 24 - 35 secssecs

Thrombin timeThrombin time I, III, II 12 - 20 12 - 20 secssecs

Implications for TherapyImplications for Therapy

Congenital & acquired factor Congenital & acquired factor

deficienciesdeficiencies historyhistory

medicationsmedications

congenital factors: vWD, hemophilia, platelet disorderscongenital factors: vWD, hemophilia, platelet disorders

acquired disorders: multifactor-renal, hepatic, DICacquired disorders: multifactor-renal, hepatic, DIC

Antiplatelet medicationsAntiplatelet medications

AnticoagulantsAnticoagulants

Drugs affecting CoagulationDrugs affecting Coagulation

HEMOSTATICHEMOSTATIC

PROCESSPROCESS

AFFECTEDAFFECTED

CLASS OF CLASS OF

DRUGSDRUGS SPECIFICSPECIFIC

DRUGSDRUGS

1º platelet plug 1º platelet plug formation inhibitionformation inhibition

antiplatelet drugsantiplatelet drugs reversible: NSAIDreversible: NSAID

irreversible: ASAirreversible: ASA

coagulation coagulation cascadecascade

IV anticoagulantsIV anticoagulants

oral anticoagulantsoral anticoagulants

standard and LMW standard and LMW heparinsheparins

warfarinwarfarin

fibrinolysisfibrinolysis fibrinolytic agentsfibrinolytic agents StreptokinaseStreptokinase

UrokinaseUrokinase

t-PAt-PA

Prostaglandin SynthesisProstaglandin Synthesis

arachidonic acidarachidonic acid cyclooxygenasecyclooxygenase

prostaglandin Gprostaglandin G22

peroxidaseperoxidase

prostaglandin Hprostaglandin H22

prostacyclinprostacyclin thromboxanethromboxane

synthetasesynthetase synthetase synthetase

prostacyclinprostacyclin thromboxane Athromboxane A22

PG FPG F1a1a thromboxane Bthromboxane B22

Mechanism of ActionMechanism of ActionASPIRINASPIRIN

arachidonic acidarachidonic acid ASPIRINASPIRIN

cyclooxygenasecyclooxygenase

prostaglandin Gprostaglandin G22





prostacyclinprostacyclin thromboxane A2thromboxane A2

PG FPG F1a1a thromboxane B2thromboxane B2

Mechanism of ActionMechanism of Action

ASPIRIN and NSAIDSASPIRIN and NSAIDS

arachidonic acidarachidonic acid ASPIRINASPIRIN

cyclooxygenasecyclooxygenase

prostaglandin Gprostaglandin G22 NSAIDSNSAIDS





prostacyclinprostacyclin thromboxane A2thromboxane A2

PG FPG F1a1a thromboxane B2thromboxane B2

Antiplatelet MedicationsAntiplatelet Medications

DRUGDRUG

SITE OFSITE OF

ACTIONACTION ROUTROUTEE

PLASMPLASMAA

t 1/2t 1/2

META-META-

BOLISBOLISMM

Ø PRIORØ PRIOR

PROCEDURPROCEDUREE

↑ ↑ PT / PT /

PTTPTT

ANTI – ANTI –

DOTEDOTE

AspirinAspirin COX 1COX 1

and 2 and 2 oraloral 20 min20 min hepatihepati

cc 7 days7 days No/NoNo/No nonenone

Dipyrida-Dipyrida-molemole

adenosinadenosinee

oraloral 40 min40 min hepatihepaticc

24 hrs24 hrs No/NoNo/No nonenone

ClopidogrClopidogrelel (Plavix)(Plavix)

ADPADP oraloral 7 hrs7 hrs hepatihepaticc

5 days5 days No/NoNo/No nonenone

TiclodipinTiclodipinee (Ticlid)(Ticlid)

ADPADP oraloral 4 days4 days hepatihepaticc

10 days10 days No/NoNo/No nonenone

AbciximaAbciximabb (ReoPro)(ReoPro)

GPIIb-IIIaGPIIb-IIIa IVIV 30 min30 min renalrenal 72 hrs72 hrs No/NoNo/No nonenone

EptifibatidEptifibatidee

GPIIb-IIIaGPIIb-IIIa IVIV 2.5 2.5 hrshrs

renalrenal 24 hrs24 hrs No/NoNo/No nonenone

TirobanTiroban GPIIb-IIIaGPIIb-IIIa IVIV 2 hrs2 hrs renalrenal 24 hrs24 hrs No/NoNo/No hemo-hemo-dialysisdialysis


Non-steroidal Anti-inflammatory MedicationsNon-steroidal Anti-inflammatory Medications

DRUGDRUG

SITE OFSITE OF

ACTIONACTION ROUTROUTEE

PLASMPLASMAA

t 1/2t 1/2

META-META-

BOLISBOLISMM

Ø PRIORØ PRIOR

PROCEDURPROCEDUREE

↑ ↑ PT / PT /

PTTPTT

ANTI – ANTI –

DOTEDOTE

PiroxicamPiroxicam COX 1 & COX 1 & 22

oraloral 50 hrs50 hrs hepatichepatic 10 days10 days No/NoNo/No nonenone

Indome –Indome –

thacinthacinCOX 1 & COX 1 & 22

oral/oral/

suppsupp 5 hrs5 hrs hepatichepatic 48 hrs48 hrs No/NoNo/No nonenone

KetorolacKetorolac COX 1 & COX 1 & 22

oral / oral /

IVIV 5-7 5-7 hrshrs

hepatichepatic 48 hrs48 hrs No/NoNo/No nonenone

IbuprofenIbuprofen COX 1 & COX 1 & 22

oraloral 2 hrs2 hrs hepatichepatic 24 hrs24 hrs No/NoNo/No nonenone

naproxennaproxen COX 1 & COX 1 & 22


DiclofenaDiclofenacc

COX 1 & COX 1 & 22


CelecoxibCelecoxib COX 2COX 2 oraloral 10-1710-17

hrshrshepatichepatic nonenone No/NoNo/No nonenone


Anticoagulants & ThrombolyticsAnticoagulants & Thrombolytics

DRUGDRUG SITE OF SITE OF ACTIONACTION

ROUTROUTEE

PLASMPLASMAA

t 1/2t 1/2

EXCRE-EXCRE-

TIONTIONØ PRIORØ PRIOR

PROCEDURPROCEDUREE

↑ ↑ PT / PT /

PTTPTT

ANTI – ANTI –

DOTEDOTE

UnfractionUnfraction-ated -ated heparinheparin

IIa/XaIIa/Xa IV/SCIV/SC 1.5 hrs1.5 hrs hepatichepatic

6 hrs6 hrs No/No/

YesYesprotaminprotaminee

LMWHsLMWHs XaXa

IIIaIIIa SCSC 4.5 hrs4.5 hrs renalrenal 12-24 hrs12-24 hrs No/NoNo/No protaminprotamin

ee

(partial)(partial)

Strepto - Strepto - kinasekinase

plasmi –plasmi –

nogennogen IVIV 23 23

minsmins hepatichepatic

3 hrs3 hrs Yes/Yes/

YesYesantifibri-antifibri-

nolyticsnolytics

t-PAt-PA plasmi –plasmi –

nogennogen IVIV <5 min<5 min

hepatichepatic 1 hr1 hr Yes/Yes/

YesYesantifibri-antifibri-nolyticsnolytics

OralOral

AnticoaguAnticoagu--

lantslants

vit-K vit-K dep.dep.

factorsfactors

OralOral 2-2-4days4days

hepatichepatic

2-4 days2-4 days Yes/Yes/NoNo

Vit. K, Vit. K, rFVIIarFVIIa

Plasma, Plasma, ProthromProthrom. . complex complex conc.conc.


Other AnticoagulantsOther Anticoagulants

DRUGDRUG

SITE SITE OFOF

ACTIOACTIONN

ROUTROUTEE

PLASMPLASMAA

t 1/2t 1/2

META-META-

BOLISMBOLISMØ PRIORØ PRIOR

PROCEDURPROCEDUREE

↑ ↑ PT/ PT/ PTT PTT

ANTI – ANTI –

DOTEDOTE

Pentasac- Pentasac-

charidecharide XaXa IVIV 14-17 14-17

hrshrs renalrenal 4 days4 days No/NoNo/No rFVIIa?rFVIIa?

BivalirudinBivalirudin IIaIIa IVIV 25 min25 min hepatichepatic 2-3 hrs2-3 hrs Yes/Yes/

YesYesNoneNone

ArgatrobanArgatroban IIaIIa IVIV 45 min45 min hepatichepatic 4-6hrs*4-6hrs* Yes/Yes/

YesYesNoneNone

HirudinHirudin IIaIIa IVIV 1.5 hr1.5 hr renalrenal 8 hrs*8 hrs* Yes/Yes/

YesYesPMMA PMMA dialysidialysiss

Activated Activated Protein CProtein C

(APC)(APC)

Va/Va/

VIIIaVIIIa IVIV 2 hrs2 hrs hepatichepatic 12 hrs12 hrs No/No/

YesYesnonenone

XimelagatrXimelagatranan

IIaIIa IVIV 3 hrs3 hrs renalrenal 24 hrs24 hrs Yes/Yes/

YesYesnonenone

PMMA= polymethyl-methyl acrylatePMMA= polymethyl-methyl acrylate

*Argatroban &lepirudin may *Argatroban &lepirudin may ↑↑ the normal PT 4-5 secs the normal PT 4-5 secsRoberts HR, et al. Current Concepts for Hemostasis. Anesthesiology 2004;100:3. 722-30.

Oral AnticoagulantsOral AnticoagulantsWarfarinWarfarin

inhibits synthesis of vitamin - k inhibits synthesis of vitamin - k

dependent factors II, VII, IX, X and dependent factors II, VII, IX, X and

protein C & Sprotein C & S

reversal:reversal: stopping medication and waiting for ~4 stopping medication and waiting for ~4

days for PT normalizationdays for PT normalization

vitamin K PO or IV (1-2mg)vitamin K PO or IV (1-2mg)

immediate: rFVIIa, FFP (1-2 units),immediate: rFVIIa, FFP (1-2 units),

prothrombin complex concentrateprothrombin complex concentrate

check PT prior to surgerycheck PT prior to surgery

Oral AnticoagulantsOral AnticoagulantsWarfarinWarfarin

biphasic effect on PT and INRbiphasic effect on PT and INR initial initial ↑↑: : ↓↓ F VII (shortest t ½) to 55 % F VII (shortest t ½) to 55 %

of normalof normal

subsequent subsequent ↑↑: ↓ : ↓ F II and X – therapeutic F II and X – therapeutic

anticoagulantanticoagulant

discontinuationdiscontinuation return to normal: F VII followed by F II & Xreturn to normal: F VII followed by F II & X

caution: INR =/< 1.4 no assurance of caution: INR =/< 1.4 no assurance of

normal coagulationnormal coagulation

Unfractionated HeparinUnfractionated Heparin

negatively charged, water - soluble negatively charged, water - soluble

glycosaminoglycanglycosaminoglycan

extracted from porcine gut or bovine lungextracted from porcine gut or bovine lung

binds and binds and ↑↑ anti - thrombin III (AT III) activity anti - thrombin III (AT III) activity

to 1,000 fold to 1,000 fold →→binds & inactivates factors IIabinds & inactivates factors IIa

and factor Xaand factor Xa

degree of inhibition: F Xa = IIa degree of inhibition: F Xa = IIa

* * LMWH inhibition of Xa > IIaLMWH inhibition of Xa > IIa

lesser inhibition on F XIa, XIa and F XIIalesser inhibition on F XIa, XIa and F XIIa

Unfractionated HeparinUnfractionated Heparin

Low-dose or “minidose”Low-dose or “minidose”

5,000 U SC q 12 hrs for 5,000 U SC q 12 hrs for

thromboprophylaxisthromboprophylaxis

peak action: 40 - 50 minutespeak action: 40 - 50 minutes

duration 4 - 6 hrsduration 4 - 6 hrs

low risk for hemorrhage during anesthesia low risk for hemorrhage during anesthesia

or surgeryor surgery

4 reported cases of SEH with CNB4 reported cases of SEH with CNB

Unfractionated HeparinUnfractionated HeparinStandard DoseStandard Dose

regular doses for therapeutic anticoagulationregular doses for therapeutic anticoagulation

high risk of bleeding during & after surgeryhigh risk of bleeding during & after surgery

stop at least 6 hrs before surgerystop at least 6 hrs before surgery

restarted ~ 12 hrs postop if needed with close restarted ~ 12 hrs postop if needed with close

monitoringmonitoring

immediate reversal: protamineimmediate reversal: protamine

Low Molecular Weight Heparin (LMWH)Low Molecular Weight Heparin (LMWH)

4,000-6,500 daltons (vs. standard heparin 4,000-6,500 daltons (vs. standard heparin

3,000 -30,000 daltons3,000 -30,000 daltons

retains anti-Xa activityretains anti-Xa activity

less anti -IIa than standard heparinless anti -IIa than standard heparin

enhances AT-III interaction with F IIa & F Xaenhances AT-III interaction with F IIa & F Xa

degree of inhibition: F Xa > IIa degree of inhibition: F Xa > IIa

LMWH in the U.S.LMWH in the U.S.

LMWHLMWH TRADETRADE

NAMENAME

MOLECULAMOLECULARR

WEIGHTWEIGHT

(daltons)(daltons)

HALF - LIFEHALF - LIFE

(minutes)(minutes)Anti Xa: Anti Xa: Anti IIaAnti IIa

DaltepariDalteparinn

FragminFragmin 5,0005,000 120120 2:12:1

EnoxapariEnoxaparinn

LovenoxLovenox

4,5004,500 150150 2.7:12.7:1

DanaparoDanaparoidid

OrgaranOrgaran 6,5006,500 1,1001,100 20:120:1

ArdeparinArdeparin NormifloNormiflo

6,0006,000 200200 2:12:1

Standard Standard HeparinHeparin

14,00014,000 60-9060-90 1:11:1

Standard Heparin vs. LMWHStandard Heparin vs. LMWH

PARAMETERSPARAMETERS STANDARD HEPARINSTANDARD HEPARIN LMWHLMWH

MOLECULAR MOLECULAR WEIGHTWEIGHT

3, 000 - 30,000 daltons3, 000 - 30,000 daltons 4,000-6,500 daltons4,000-6,500 daltons

BIOAVAILABILITYBIOAVAILABILITYvariable due to binding to variable due to binding to

plasma protein & plasma protein &

macrophagesmacrophages

predictablepredictable

MONITORINGMONITORING PTTPTT

dose adjusted based on dose adjusted based on

PTTPTT

no need for no need for

monitoring monitoring

no dose adjustmentsno dose adjustments

HALF – LIFEHALF – LIFEvariable; dose-dependent variable; dose-dependent

(30 min for 25 u/kg, 150 (30 min for 25 u/kg, 150

mins with 400 u/kg)mins with 400 u/kg)

4-6 hrs4-6 hrs

CLEARANCECLEARANCE hepatichepatic renalrenal

Standard Heparin vs. LMWHStandard Heparin vs. LMWH PARAMETERSPARAMETERS STANDARD HEPARINSTANDARD HEPARIN LMWHLMWH

EFFECT ON EFFECT ON PLATELETSPLATELETS

Higher incidence of HITHigher incidence of HIT

Inhibition of platelet Inhibition of platelet

functionfunction

Inhibits platelet-Inhibits platelet-

endotheliumendothelium

interactioninteraction

Lower incidence of Lower incidence of

HITHIT

Less inhibitionLess inhibition

No interactionNo interaction

RISK OF RISK OF BLEEDINGBLEEDING

higherhigher LowerLower

ANTI Xa: IIa ANTI Xa: IIa ACTIVITYACTIVITY

1:11:1 2:12:1

REVERSALREVERSAL protamineprotamine Only anti-IIa (90%) but Only anti-IIa (90%) but

not anti-Xa (60%) not anti-Xa (60%)

activity reversed by activity reversed by

protamine (1 mg/100 protamine (1 mg/100

anti-Xa units LMWHanti-Xa units LMWH

COSTCOST inexpensiveinexpensive expensiveexpensive

Recombinant Factor VIIaRecombinant Factor VIIa(NovoSeven)(NovoSeven)

FDA approved for use in hemophilia & patients FDA approved for use in hemophilia & patients

with inhibitorswith inhibitors

enhances the TF pathwayenhances the TF pathway

binds loosely to platelets and directly activates binds loosely to platelets and directly activates

F X F X →→ ↑↑ thrombin generation with F Va present thrombin generation with F Va present

never completelynever completely normalizes thrombin normalizes thrombin

generation but enhances hemostasisgeneration but enhances hemostasis

dose: 90-120 mcg/kg q 2 hrs x 1dose: 90-120 mcg/kg q 2 hrs x 1stst 24 hrs 24 hrs

Recombinant Factor VIIaRecombinant Factor VIIa

variable individual thrombin- variable individual thrombin-

generating capacitygenerating capacity megadoses: 150-300 mcg/kgmegadoses: 150-300 mcg/kg

““off label” use (non - FDA approved)off label” use (non - FDA approved) liver diseaseliver disease

liver transplantliver transplant

traumatrauma

ICHICH

platelet disordersplatelet disorders

Recombinant Factor VIIaRecombinant Factor VIIa

common denominator: defective thrombin common denominator: defective thrombin

generationgeneration

thrombocytopenia ▪ thrombocytopenia ▪ hypothermiahypothermia

↓↓ plasma coagulation proteins plasma coagulation proteins ▪ ▪ hyperfibrinolysishyperfibrinolysis

dilutional coagulopathydilutional coagulopathy

prophylactic use reported for retropubic prophylactic use reported for retropubic

prostatectomy, hepatectomyprostatectomy, hepatectomy

potential use: Jehovah’s witnesspotential use: Jehovah’s witness

Coagulation DisordersCoagulation Disorders

Disorders of Hemostatic MechanismDisorders of Hemostatic Mechanism

Classification: depends on involvement ofClassification: depends on involvement of

platelets and/or clotting factorsplatelets and/or clotting factors

and/or presence of inhibitors (such as FDP)and/or presence of inhibitors (such as FDP)

TreatmentTreatment

• • transfusion of platelets and/or clotting factorstransfusion of platelets and/or clotting factors

• • pharmacologic agents affectingpharmacologic agents affecting

Platelets fx (DDAVP, antiplatelet drugs)Platelets fx (DDAVP, antiplatelet drugs)

Clotting factors (vit. K, coumadin, heparin)Clotting factors (vit. K, coumadin, heparin)

Inhibitors (antifibrinolytics, protamine, fibrinolytics)Inhibitors (antifibrinolytics, protamine, fibrinolytics)

Hereditary Platelet DisorderHereditary Platelet Disordervon Willebrand Disease (vWD)von Willebrand Disease (vWD)

most common congenital bleeding most common congenital bleeding

disorderdisorder

quantitative or qualitative abn. of vWFquantitative or qualitative abn. of vWF

Type 1: most common formType 1: most common form

partial partial quantitativequantitative deficiency of vWF deficiency of vWF

autosomal dominantautosomal dominant

mucocutaneous bleedingmucocutaneous bleeding

hematology consult prior to surgeryhematology consult prior to surgery

prolonged bleeding time, normal plateletprolonged bleeding time, normal platelet

Hereditary Platelet DisordersHereditary Platelet Disordersvon Willebrand Disease (vWD)von Willebrand Disease (vWD)

Type 2: Type 2: qualitativequalitative alterations in the vWF structure alterations in the vWF structure

& function& function

Type 3: least common and most severeType 3: least common and most severe

Complete Complete absenceabsence of vWF in plasma or storage of vWF in plasma or storage

organelleorganelle

Autosomal recessiveAutosomal recessive

acquired vWDacquired vWD

Lymphoproliferative disease ▪ cardiac/valvular diseaseLymphoproliferative disease ▪ cardiac/valvular disease

Tumors ▪ medications (valproic acid)Tumors ▪ medications (valproic acid)

Autoimmune diseaseAutoimmune disease ▪ hypothyroidism ▪ hypothyroidism

Hereditary Platelet DisordersHereditary Platelet Disordersvon Willebrand Diseasevon Willebrand Disease

Treatment:Treatment: Desmopressin (DDAVP) Desmopressin (DDAVP)

synthetic analog of vasopressinsynthetic analog of vasopressin

↑↑ both F VIII and vWF 3 - 5x in 30 minsboth F VIII and vWF 3 - 5x in 30 mins

preop prophylactic dose: 0.3 mcg/kg IV in preop prophylactic dose: 0.3 mcg/kg IV in

50 -100 ml NS infused 30-60 mins q 12-24 50 -100 ml NS infused 30-60 mins q 12-24

hrs PRNhrs PRN

duration 8-10 hrsduration 8-10 hrs

intranasal dose: 300 mcg – for home intranasal dose: 300 mcg – for home

treatment, not for preop prophylaxistreatment, not for preop prophylaxis

Hereditary Bleeding DisordersHereditary Bleeding Disordersvon Willebrand Diseasevon Willebrand Disease

DDAVPDDAVP

vasomotor effect: flushing, vasomotor effect: flushing, ↑↑HRHR, , headacheheadache

SE: hyponatremia, seizuresSE: hyponatremia, seizures

not for children < 3 yrs oldnot for children < 3 yrs old

unresponsive to DDAVP (15%)unresponsive to DDAVP (15%)

cryoprecipitatecryoprecipitate

FFPFFP

factor VIII / vWF concentratefactor VIII / vWF concentrate

Acquired Platelet DisordersAcquired Platelet Disorders

Thrombocytopenia : platelets <150,000/mmThrombocytopenia : platelets <150,000/mm33

inadequate production by bone marrowinadequate production by bone marrow

splenic sequestrationsplenic sequestration

consumption coagulopathyconsumption coagulopathy

dilutional thrombocytopeniadilutional thrombocytopenia

immunogenic destructionimmunogenic destruction

Platelet dysfunctionPlatelet dysfunction myeloproliferative and myelodysplastic myeloproliferative and myelodysplastic

syndromessyndromes

renal failure, liver disease, DIC, CPBrenal failure, liver disease, DIC, CPB

drugs: NSAIDS, ASAdrugs: NSAIDS, ASA

* * DDAVP: tx platelet dysfunction due to uremia, liver DDAVP: tx platelet dysfunction due to uremia, liver

disease, and patients on ASA for CABGdisease, and patients on ASA for CABG

Hereditary Factor DeficienciesHereditary Factor DeficienciesHemophiliaHemophilia

x-linked recessive conditions (males only)x-linked recessive conditions (males only)

type A : F VIII:C deficiency (Classical type A : F VIII:C deficiency (Classical

Hemophilia)Hemophilia)

B : F IX deficiency (Christmas disease)B : F IX deficiency (Christmas disease)

C : F XI deficiency C : F XI deficiency

unexplained bruising or bleeding in young unexplained bruising or bleeding in young

males, usually ~ 1 yr of agemales, usually ~ 1 yr of age

joint & muscle bleeding joint & muscle bleeding → → arthropathyarthropathy

Hereditary Factor DeficienciesHereditary Factor DeficienciesHemophiliaHemophilia

■ ■ screening: prolonged PTTscreening: prolonged PTT

■ ■ hemophilia Ahemophilia A

mildmild

moderatemoderate

severe : life-threatening (CNS severe : life-threatening (CNS

bleed)bleed)

treatmenttreatment

factor replacementfactor replacement

rFVIIarFVIIa

Factor VIII Concentrate Necessary for Factor VIII Concentrate Necessary for HemostasisHemostasis

Factor VIII Factor VIII ConcentrateConcentrate

(% of normal)(% of normal)

Spontaneous hemorrhageSpontaneous hemorrhage 1-3 %1-3 %

Moderate traumaModerate trauma 4-8 %4-8 %

Hemarthrosis/deep skeletal Hemarthrosis/deep skeletal

muscle hemorrhagemuscle hemorrhage

10-15 %10-15 %

Major surgeryMajor surgery > 30%> 30%

Acquired Factor DeficienciesAcquired Factor Deficiencies

Vitamin - K deficiencyVitamin - K deficiency

malabsorption syndromesmalabsorption syndromes

pancreatic insufficiencypancreatic insufficiency

biliary obstructionbiliary obstruction

GI obstructionGI obstruction

treatment: vitamin Ktreatment: vitamin K

Platelet Dysfunction, Factor Deficiencies & Platelet Dysfunction, Factor Deficiencies & Presence of InhibitorsPresence of Inhibitors

Liver diseaseLiver disease

• • synthesis of coagulation factors (except VIII),synthesis of coagulation factors (except VIII),

anticoagulants, ATIII, protein C & S, plasminogenanticoagulants, ATIII, protein C & S, plasminogen

• • clearance of activated clotting factors, tPA, FDPsclearance of activated clotting factors, tPA, FDPs

DICDIC

Hypercoagulable StatesHypercoagulable StatesFactor V Leiden MutationFactor V Leiden Mutation

glutamine is substituted for arginine at glutamine is substituted for arginine at

position 506position 506→ → resistant to inactivation by resistant to inactivation by

protein Cprotein C

dx: genetic screening dx: genetic screening

↑↑ risk for DVT in lower extremities & brainrisk for DVT in lower extremities & brain

homozygous (20x) >heterozygous (7x)homozygous (20x) >heterozygous (7x)

if asymptomatic: no anticoagulationif asymptomatic: no anticoagulation

Hypercoagulable StatesHypercoagulable States

Factor V Leiden MutationFactor V Leiden Mutation

TreatmentTreatment

▪ ▪ warfarin x 6 mos or until warfarin x 6 mos or until

thrombosis free for 2 mosthrombosis free for 2 mos

▪ ▪ LMWH x 2 wks after warfarin LMWH x 2 wks after warfarin

then retestedthen retested

▪ ▪ long term anticoagulation if long term anticoagulation if

persist persist

or recurrent thrombotic eventor recurrent thrombotic event

Idiopathic Thrombocytopenic PurpuraIdiopathic Thrombocytopenic Purpura(ITP)(ITP)

more commonly found in childrenmore commonly found in children

diagnosis of exclusiondiagnosis of exclusion

petechia <20,000x 10petechia <20,000x 1099/l platelets/l platelets

bleeding <10,000x 10bleeding <10,000x 1099/l/l

medical managementmedical management

Blood Component TherapyBlood Component TherapyPlatelet TransfusionPlatelet Transfusion

1 unit 1 unit ↑ ↑ platelets count 10,000 mmplatelets count 10,000 mm33

adult dose: 1 unit/10 kg BW within 24 hrsadult dose: 1 unit/10 kg BW within 24 hrs indications (NIH)indications (NIH)

▪ ▪ thrombocytopenia with clinical coagulopathythrombocytopenia with clinical coagulopathy

10, 000 in ITP10, 000 in ITP

20, 000 in bone marrow suppression20, 000 in bone marrow suppression

40,000 during massive transfusion40,000 during massive transfusion

▪ ▪ pplatelet dysfunction even with latelet dysfunction even with platelets>100,000platelets>100,000

CPBCPB drugs (ASA, etc)drugs (ASA, etc)

uremiauremia thrombastheniathrombasthenia

Blood Component TherapyBlood Component TherapyTransfusion of FFPTransfusion of FFP

1) replacement of isolated factor deficiency1) replacement of isolated factor deficiency

2) reversal of coumadin2) reversal of coumadin

3) antitrombin III deficiency3) antitrombin III deficiency

4) treatment of immunodeficiencies4) treatment of immunodeficiencies

5) treatment of TTP5) treatment of TTP

6) massive blood transfusion6) massive blood transfusion

Blood Component TherapyBlood Component TherapyCryoprecipitateCryoprecipitate

contains significant levels of factor contains significant levels of factor

VIIIC, factor VIII: vwF, XIII, fibrinogenVIIIC, factor VIII: vwF, XIII, fibrinogen

indications:indications:

1) hemophilia1) hemophilia

2) von Willebrand disease2) von Willebrand disease

3) fibrinogen deficiencies3) fibrinogen deficiencies

4) uremic platelet dysfunction4) uremic platelet dysfunction

ReferencesReferences

Roberts HR, Monroe DM, Escobar MA. Current Concepts of Roberts HR, Monroe DM, Escobar MA. Current Concepts of Hemostasis. Anesthesiology 2004; 100:722-30.Hemostasis. Anesthesiology 2004; 100:722-30.

De Souza GJ. Anticoagulation and Central Neuraxial Anesthesia. De Souza GJ. Anticoagulation and Central Neuraxial Anesthesia. Progress in Anesthesiology. 2000;vol XIV, Chap 9: 132-148.Progress in Anesthesiology. 2000;vol XIV, Chap 9: 132-148.

Petrovich, CT. An approach to the patient who may have a Petrovich, CT. An approach to the patient who may have a bleeding disorder. 2005 ASA nnual Meeting Refresher Course bleeding disorder. 2005 ASA nnual Meeting Refresher Course Lectures. Atlanta, GA. 2006;241:1-6.Lectures. Atlanta, GA. 2006;241:1-6.

Kelly RE, Yao FF. Hemophilia and Coagulation Disorders. Yao & Kelly RE, Yao FF. Hemophilia and Coagulation Disorders. Yao & Artusio’s Problem Oriented Anesthesiology 4Artusio’s Problem Oriented Anesthesiology 4thth Ed. Lippincott Ed. Lippincott Williams & Wilkins. 1998. Chapter 40, pp 763-774.Williams & Wilkins. 1998. Chapter 40, pp 763-774.

Fleisher LA. Evidence-based Practice of Anesthesiology. Saunders. Fleisher LA. Evidence-based Practice of Anesthesiology. Saunders. 2004.2004.

Stoelting RK,Dierdorf, SF. Coagulation Disorders. Anesthesia and Stoelting RK,Dierdorf, SF. Coagulation Disorders. Anesthesia and Co-existing diseases 3Co-existing diseases 3rdrd Ed. Churchill Livingston. 1993. Chapter 25, Ed. Churchill Livingston. 1993. Chapter 25, p 407-426.p 407-426.

Coagulation and Hemostasis Joy Loy, M.D. MetroHealth Medical Center December 2006.

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