2-3 OTTOBRE 2009 IL LABORATORIO NELLE URGENZE …Manu.pdf · Activated clotting time = 30 % ... (heparin-resistance; ... only on the time of onset of clot formation

2-3 OTTOBRE 2009

IL LABORATORIO NELLE URGENZE ED

EMERGENZE

Gestione POCT: punto di vista clinico.

Università degli Studi

di Roma

TOR VERGATA

Dott.ssa Manuela Moresco

Anestesia e Rianimazione

Modern concept of coagulation

The Cell-based Model of Coagulation

VIIIaIXa

Hoffman M & Munroe DM. A cell-based model of hemostasis.Thromb Haemost 2001; 85: 958-965

+ activates various factors

Initiation

Amplification

Propagation

Haemoscope Thrombelastograph® Haemostasis

Analyser (TEG®)

Historical notes

• Developed by Hartet in Heidelgerg, Germany 1948

• Clinical practice by Kang in the setting of liver

transplantation at Pittsburg, USA 1985

Relationship between conventional

tests and post-operative bleeding

Predictive values for post operative

bleeding & re-operative rates

Activated clotting time = 30 %

Coagulation profile = 50 %

Thrombelastograph® = 87 %

Spiess et al. J.Clin Monitor 1987; 3

TEG® Applications

– Liver transplants

– ICU

– Cardiac Surgery

– Vascular Surgery

– Cath lab

– Trauma

– Orthopedics

– Obstetrics

– Gyneacology

– Burn wound unit

– Etc...

Detection of

– Heparin Effect

(Hepcon HMS-plus or Hemocron-response)

– LMWH Effect

– Warfarin Effect

– rFVIIa Effect

– ATIII Deficiency

(heparin-resistance; Hepcon HMS-plus or Hemocron-response)

– Functional Fibrinogen & Platelet Contribution

– Fibrinolysis (primary and secondary)

TEG® Technology

TEG is a global assessment of hemostatic

function

Parameters of TEG analysis

• r = coagulation activation

• k = dynamics of clot formation

• angle = kinetics of fibrin cross-linking

• MA = strenght of a clot

• Ly 30,60 = stability of the clot

R R é il tempo di latenza dal momento di inserimento del campione di sangue

nel TEG® fino alla formazione iniziale di fibrina.

L’angolo misura la rapidità (cinetica) di formazione di fibrina e del cross-

linking, cioé della velocità con cui si rinforza il coagulo.

K K é il tempo necessario a raggiungere un certo livello di forza del coagulo

MA MA, o Massima Ampiezza, é funzione diretta delle massime proprietà

dinamiche dell’aggregazione fibrine-piastrine via GPIIb/IIIa e rappresenta la forza

finale del coagulo.

LY30 LY30 misura la percentuale di riduzione dell’ampiezza 30 minuti dopo

l’MA. Questa misura indica la stabilità del coagulo.

PARAMETRI DEL TEG

r


R (or R-Time) = Reaction time

• time from start of measurement until the beginning of

clot formation

• explores the enzimatic part of coagulation

• prolonged by anticoagulants and factor

deficiencies

• shortened by hypercoagulable conditions

r k

20mm


K (or K-time) = Clot growth kinetics

• time from the beginning of clot formation until a fixed

level of clot firmness (amplitude of 20 mm) is reached

• explores the kinetics of clot formation

• is related to platelet function and plasma components

• prolonged by anticoagulants that affect fibrinogen

and

platelet function

• shortened by increased levels of fibrinogen and

platelet function

r k


(or angle)

• explores the rate of clot growth

• function of rate of polymerization

• expression of fibrinogen level

• prolonged by anticoagulants that affect fibrinogen and

platelet function

• shortened by increased levels of fibrinogen and

platelet function

r

MA

k


MA = Maximum Amplitude

• maximum strenght of the developed clot

• ability of the clot to form hemostasis

• depends

- on adequate fibrin formation and polymerization

in a 3D network and

- on its interaction with platelet via the Gp IIb/IIIa

receptor


MA = Maximum Amplitude

• conventional coagulation tests (PT, aPTT) are based

only on the time of onset of clot formation

• blood clot firmness is an important parameter

for in-vivo haemostasis because the clot must

stand the shear stress at the site of vascular injury


G

• 5000 A / (100 - A) dyn/cm2

• elastic shear modulus

• measures the resistance of clot to deformation


CI = Coagulation Index

• derived from r, k, MA and

• describes global balance of coagulation

• CI > + 3 = hypercoagulation

• CI < - 3 = hypocoagulation

r

MA

k

30 min

LY30


LY30, LY60 = Clot stability

• measures the percentage change in clot strenght at 30

or 60 min after MA

• refers to the potential of the clot to redissolve as a

result of circulating fibrinolytic activators which activate

the plasminogen incorporated in the clot

• LY30 > 7,5% hyperfibrinolysis

MA

LY 30

R time (reaction time)– Time taken to first fibrin strand formation

Reaction time

R

K & Angle

K & – Reflect the kinetics of the interaction of fibrin/fibrinogen with platelets

K=Time to reach amplitude of 20mm

MA

MA, maximum clot strength

MA- Maximum Amplitude – Reflects the ultimate strength of the clot due to fibrin/fibrinogen interaction with the GPIIb/IIIa receptor on

functioning platelets

Normal Tracing

Elongated R

Elongated R

• Intrinsic contact pathway inibition (aprotinin)

• Tissue factor inibition

• Warfarin therapy

• FXa inibition (LMWH)

• Low prothrombin level

• Thrombin inibition (HMWH; r-irudin; etc.)

• Low fibrinogen level

• Hypothermia

Heparinase cup Plain cup

Heparin effect

Low platelet function

Fibrinolysis

Secondary Fibrinolysis

Hypercoagulability

Timing for the use of heparinase and

TEG in cardiac surgery

• Pre-CPB

• Shortly before the termination of CPB (with heparinase)

• 10 minutes and 60 minutes after protamine administration (with and without heparinase)

In case of elongated R-time TEG with heparinase or HMS-plus for detection of HMWH!

Ho AM et al. 2003 Jun;17(3):413-14

TEG Pattern Recognition

TEG trace in cardiac surgey

Pre-CPB

During CPB (test without heparinase)

During CPB (test with heparinase)

Colella D, MD

LMWH and TEG

12 h after LMWH withdrawal

Colella D, MD

Coumadin

Coumadin BaseCoumadin Base

Coumadin 24 ore

Coumadin 36 ore

Summary

CVVHDF HMWH

Elongated R (test with heparinase: neg)

Hepcon HMS-plus: no residual HMWH

PT= 60% (15’’) INR= 1,45

APTT= 32,5’’ RATIO= 0,9

Fibrinogen= 254 mg/dl

PLT= 294000/mmc

ACT= 145’’

Postoperative bleeding

Post infusion of 5 units of platelets

Still bleeding!

4 units of FFP

Post infusion of 1000 IU prothrombin complex concentrate

(VII, IX, X)

Stop bleeding!

Ticlopidine and TEG

Colella D, MD

Aspirin

Colella D, MD

TEG selective analysis of effects of

platelet inhibiting drugs on ADP, AA and

IIb/IIIa receptors

New Developement: Platelet Mapping™

Materials and methods

• Clear “cup and pin” and/or blue

(heparinase) “cup and pin”

• Kaolin

• Novel activator (P1)

• ADP (P2)

• Arachidonic acid AA (P3)

Colella D, MD

Channel 1

•Whole blood

•Kaolin

Channel 2

•Whole blood

• Heparin

•Novel activator

Channel 3

•Whole blood

•Heparin

•Novel activator

•ADP

Channel 4

•Whole blood

•Heparin

•Novel activator

•AA

Max MA using

commonly protocol

with Kaoline

Unique

contribution of

fibrin to MA

Contribution to MA

of fibrin and

uninhibited platelets

by ADP or IIbIIIa

inhibitors

Contribution to

MA of fibrin and

uninhibited

platelets by NSAID

Clopidogrel 75 mg die from 3 months

Case report 1

• 54 years, male, 65 kg, 168 cm

Diagnosis:

• AMI with previous PCI

• CAD: LM with unstable angina

• Type II diabete mellitus

• Dyslipidemia ??

Preoperative therapy

• -blockers

• Ace-inhibitors

• Aspirin 100 mg

• Atorvastin 20 mg

• Clopidogrel 75 mg (for 3 months)

• HMWH 1000 IU/h

Standard coagulation tests

PLT count: 150k

pT: 14,3 s

INR: 1,3

aPTT: 80 s

ACT: 190 s

Fibr: 350 mg/dL

ATIII: 84%

Is clopidogrel really working?

Which kind of tests can we perform?

What intraoperative interventions

could we perform to optimize the

patient’s coagulation status?

Pharmacologic agents CPB technologies

Heparin effect

R=15,6

TEG trace with heparin

TEG trace with heparinase

Clopidogrel effect (ADP)

Novel activator (no thrombin platelet activity; fibrin contribution only)

ADP (decreased activity 27,1 %)

Thrombin (max platelet activity)

Aspirin effect (AA)


AA P3 (decreased activity 95,8 %)


Comments

• Heparin efficacy (prolonged R time; 15.6 min)

• Strong (95.8%) aspirin contribution to % MA

reduction

• Very low efficacy (27.1%) of clopidogrel to % MA

reduction

(statins therapy or genetic resistance)

Clopidogrel resistance is associated with increased risk of recurrent

atherothrombotic events in patients with acute myocardial infarction.

Matetzky S et al. Circulation 2004,109

Contribution of hepatic P450 3A4 metabolic activity to the phenomen

of clopidogrel resistance. Lau WC et al. Circulation 2004,109

Case report 2

• 67 years, male, 70 Kg, 173 cm

• PCI procedure for STEMI

(intra-stent restenosis)

Preoperative therapy

• -blockers

• Ace-inhibitors

• Aspirin 100 mg

• Atorvastin 20 mg

Standard coagulation tests

PLT count: 220k

pT: 12,8 s

INR: 1,1

aPTT: 31 s

ACT: 145 s

Fibr: 380 mg/dL

ATIII: 110%

• Abciximab (Reopro) 18 mg bolus iv

• Abciximab (Reopro) 10 mcg/Kg/hr

Periprocedure therapy

Failed PTA

Need for CABG on CPB(Normothermic CPB, Coated circuits, Heparin dose-

response test, Tranexamic acid 15mg/kg)

Platelet mapping on TEG



ADP/Reopro (decreased activity 81%)

• Strong contibution of abciximab to % MA

reduction (81%)

Comments

Suggested treatment (cardiac surgery)

anticoagulant of choiceProthrombotic stateLY30 < 7.5%, C.I. > 3.0

anticoagulant of choiceSecondary fibrinolysisLY30 at 7.5% or greater, C.I. > 3.0

antifibrinolytic of choicePrimary fibrinolysisLY30 at 7.5% or greater, C.I. < 3.0

.06 u/kg cryo fibrinogen levelless than 45

x10 platelet units platelet functionMA at 40 mm or less

x5 platelet units platelet functionMA between 41 -48 mm

0.3mcg/kg DDAVP platelet functionMA between 49 -54 mm

x 4 FFP or 16 ml/kg clotting factorsR greater than 14 min

x 2 FFP or 8 ml/kg clotting factorsR between 11-14 min

x 1 FFP or 4 ml/kg clotting factorsR between 7 - 10 min

Suggested TreatmentClinical causeTEG® value

Treatment protocol

Shore-Lesserson L et al. Anest Analg 1999

• TEG is very sensible to the presence of HMWH

• TEG is a very sensible test but does not identify

any specific alteration of clotting factors

• TEG parameter MA is both a sensible and

specific test for platelet dysfunction

• TEG is both a sensible and specific test for

fibrinolysis

Conclusions II

• Modified TEG

- native whole-blood

- celite

- kaoline

- heparinase

- ADP, AA and novel activator (Platelet Mapping)

- tissue factor (Hemoliance)

- abciximab

- ATIII (heparin resistance detection)

- urokinase

- heparinase/abciximab

- heparinase/fresh frozen plasma

- in vitro effect of colloids, cristalloids, plasma, amniotic fluid etc

LAVORIAMO INSIEME !!!!!!!!!!!!!!!!!!!!!

GRAZIE !!!!!!!

2-3 OTTOBRE 2009 IL LABORATORIO NELLE URGENZE …Manu.pdf · Activated clotting time = 30 % ... (heparin-resistance; ... only on the time of onset of clot formation

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