Monitoring Coagulation

in

Intensive Care Unit

Consultant, Critical Care Medicine

Axon Criticare

Hyderabad

Palepu Gopal MD,FRCA

Coagulation Monitoring

Bleeding Clotting

Why Monitor Coagulation in ICU

Routine ?Coagulopathy Sepsis

DIC & ThrombocytopaeniaLiver DiseaseTrauma

Post-Surgical CABGOn Pro-coagulants Correct Coagulopathy On Anticoagulants and/or Antiplatelets

DVT ProphylaxisAnti-thrombotic treatmentCAD Thrombolysis

Coronary stentsArrhythmias

CVAExtracorporeal devices

IABP,RRT, MARS, ECMOOn Anti-fibrinolytics

Laboratory Based Coagulation TestsNon-Viscoelastic Tests

Issues:

1. Sampling to Results Delay

2. Plasma Values rather than whole blood

3. No information on Platelet function

4. Performed at standard room temperature

Techniques & Advantages • Full blood count and Coagulation screen (TT, APTT, PT, and

fibrinogen)– Quick, easy, reproducible, understandable

• Whole Blood tests No sample preparation – Microaggregation, Thrombelastography, & WB analysers – Easy

• Purified Platelet tests– Microaggregation Easy– Macroaggregation Precise defect– Platelet function analysers Precise defect

• Skin bleeding time– Whole body answer

Limitations of Techniques• Full blood count

– Number not function

• Coagulation screen (TT, APTT, PT, and fibrinogen)– 20 to 30 minutes, no fibrinolytic assessment

• Whole Blood tests– Microaggregation No commercial kit

• Purified Platelet tests

• Have to prepare the sample– Microaggregation No commercial kit– Macroaggregation Experienced

technician– Platelet function analysers ?

• Skin bleeding time– Invasive, not specific

Tests of Coagulation - PlateletsQuantitative Measure Automated cell counters or Mannual

Laser technology or Automated flow cytologyPlatelet Function TestsStatic Tests β –hromboglobulin, ADP release, No of surface receptorsDynamic Tests Bleeding Time

VEPOC Tests ( TEG / ROTEM / Sonoclot )Platelet Response to Stimuli

Ultegra PLT response to Thrombin Receptor agonist Peptide( TRAP)useful in GPIIb / III a inhibitors

Clot Signature analyzer CPB related PLT functionPlatelet function Analyzer PFA 100Platelet Works Coulter counter with antagonistPlatelet aggregometry Photo-optical instrument

Fibrinogen Concentration Clottable Protein method (Clauss method)End-point detection technique

Haemochron POC TechniqueImmunochemical testsNormal 180 -220 mg / dL

Time taken for conversion of Fibrinogen to FibrinTechnidyne POC testNormal Whole Blood 39 - 53 secs

Citrated Blood 43 -63 secsSpecifically measures activity of Thrombin

Sensitive to HeparinExcludes Intrinsic & Extrinsic pathwayElevated In Heparin Presence

HypofibrinogenamiaDysfibrinogenaemiaAmyloidosisThrombin Antibodies

Appropriate test for Thrombolytics

Prolongation by 1.5 – 5 times Effective Therapy

Prolongation by > 7 times Risk of bleeding

Absence of Prolongation Failed Fibrinolysis

Thrombin Time

Activated Partial Thromboplastin Time

Tests Intrinsic and Final Coagulation pathway

Thromboplastin is Tissue factor + Phospholipids

Activated with kaolin (celite-diamataceous-earth)

Prolonged with even low dose heparin

Prolonged aPTT in

Deficiencies of Factors XII,XI,IX,VIII

HMW Kininogen

Kallikrein

Normal Value 28 -32 secs

Prothrombin Time

Tests Extrinsic and common Coagulation pathway

PT elevated in Deficiency of Factor VII

Deficiency of Vit K

Warfarin therapy

Monitor heparin / Warfarin crossover

Normal PT values 12 – 14 secs

International Normalized Ratio (INR) = (PT patient / PT mean normal) ISI

ISI = international Sensitivity Index

INR target ranges are specified by patient populations

DVT, AF INR= 2.0 - 3.0

Mitral mechanical heart valve INR= 2.5 – 3.5

Hypercoagulable disorders INR= 1.5 – 2.5

Non-Viscoelastic POC Monitors

Coagucheck

PT & aPTT Coagucheck ( Roche)

Hemochron (ITC)

Ciba Corning Biotrack 512

Good correlation with Lab values

Reiner JS:CCD 1994: 32(1)

Been used in Transfusion algorithms

Hemochron

Fibrinolysis

Primary & Secondary fibrinolysis

Direct Measurement Clot Lysis Time

End Product Measurement FDP

d - dimers

Unfractionated Heparin (UFH)

• Exerts its anticoagulant effect via antithrombin

• Heparin binds to and produces a conformational change in antithrombin.

• Anticoagulant effect reversed with protamine.

UFH - Monitoring

• Heparin Concentration – Not standardized

• Hepcon POC for WB Heparin concentration

• Activated clotting time (ACT)

• ACT POC test used for high doses heparin therapy

• Lab aPTT stronger correlation to Heparin

con. than POC aPTT and ACT

Ann Pharmacother 2002;36:7-11

High dose Thrombin Time (HiTT)Hemochron

LMWH

• Binds to antithrombin and inactivates thrombin to a lesser extent than UFH because the smaller molecule fragments cannot bind thrombin and antithrombin simultaneously.

LMWH – Monitoring

Anti-Xa assay is generally used

Limitations

Not been demonstrated to be good predictor of

- Bleeding Risk

- Antithrombotic efficacy

Relative anti-Xa and anti-IIa activities vary between preparations

Antithrombin activity more important in Kinetic studies

Comparability of anti-Xa chromogenic assays is poor

Assays should be LMWH, method and equipment specific.

Thromb Haemost 2002;87:163-164

Point of Care Coagulation Monitoring (POC)

Viscoelastic Point of Care Tests

Advantages:

1. Bedside – faster turnaround time

2. Coagulation status of whole blood

3. Clot development in real time

4. Performed at patient’s temperature

5. Therauptic agents added

However:

In vitro vs in vivo differences

Lack of standardization

Coagulation under static cuvette conditions (no flow)

Non-laboratory personnel

Viscoelastic POC Devises (VEPOCD)

Thromboelastography Rotation TEROTEM

Sonoclot

1.Rotating Cup with Blood2.Activator/ Inhibitor3.Pin & Torsion wire4.Electromech transducer5.Data Processor

1.Cuvette with Blood2.Pipette with activator/ Inhibitor3.Pin & Rotating Axis4.EM & Light source, Mirror5.Data Processor

1.Cuvette with Blood2.Activator/ Inhibitor3.Disp plastic probe4.EM Transducer5.Data Processor

Sonoclot Tests : Reference Values

Sonoclot Assay SonACT kACT gbACT aiACT

Activated Clotting Time 85 -1 45 s 94 -178 s 119-195 s 62 -93 s(ACT)

Clot Rate (CR) 15 – 45 15 -33 7 -23 22 – 41 U / min U / min U / min U / minLow dose Heparin Overall coag

& PLT function

PF 0 - 5

Qualitative GraphQualitative Graph

Entire Haemostasis

ACT CR PF

TEG & ROTEM Display

TEG

ROTEM

Assay Activator/ Inhibitor Indication & AssessmentTEGNative None Custom Haemostsis testKaolin Kaolin Overall coagulation & PLT FunctionHeparinase Kaolin+Heparinase Specific detection of HeparinPlatelet Mapping ADP Arachidonic acid PLT Function, Monitoring anti-PLT therapyROTEMNa-TEM None Custom Haemostsis testex-TEM Tissue Factor Extrinsic PW, Clot Formation & Fibrinolysisin-TEM Contact activator Intrinsic PW, Clot formation &Fibrin Polymerizfib-TEM TF+ PLT Antagonist Qualitative assessment of Fibrinogen levelap-TEM TF+Aprotinin Fibrinolytic PW + FibrinolysisHep –TEM CA+ Heparinase Detection of Heparineca-TEM Ecarin Management of Direct Thrombin Inhibitorstif-TEM 1:1000 TF Ex PW:monitoring rF VIIa SonoclotNative None Custom Haemostsis testgbACT Glass Beads Overall coagulation & PLT functionH-gbACT Glass beads + Heparinase + Presence of HeparinmicroPT 1:1000 TF Ex PW:monitoring rF VIIa SonACT Celite Large dose Heparin without AprotininkACT Kaolin Large dose Heparin +/- AprotininaiACT Celite+Clay Large dose Heparin with Aprotinin

Tests of Viscoelastic POC Devices

Nomenclature & Reference Values of TEG & ROTEM

TEG ROTEM

Clotting Time R(reaction Time) CT(clotting Time)Period to 2 mm amplitude N(WB) 4 – 8 mins N(Cit,in-TEM) 137-246 secs

N(Cit,Kaolin) 3- 8 mins N (Cit, ex-TEM) 42 – 74 secs

Clot kinetics K (kinetics) CFT (Clot formation time) Period from 2 to 20 mm N (WB) 1- 4 mins N (Cit,in-TEM) 40 -100 secs

N(Cit,Kaolin) 1-3 mins N (Cit, ex-TEM46 -148 secs

Clot strengthening α (slope between r & k) α (slope of tangent at 2mm ampli)(Alpha angle) N(WB) 470 to 740 N (Cit,in-TEM) 710 -820 N(Cit,kaolin) 550 780 N (Cit, ex-TEM) 630 -810

Amplitude A A(at set time) MA(maximum amplitude) MCF (maximum clot firmness)

N (WB) 55 -73 MM N (Cit,in-TEM) 52 – 72 mm N(Cit,kaolin) 51 -69 mm N (Cit, ex-TEM) 9 -25 mm

Lysis (at fixed time) CL30, CL 60 LY30,LY60

Post Cardiac Surgery Reduce Transfusion requirement in adults & children

Spalding GJ : Cardiothoracic Surg:2007 :31-1052

Heparinase TEG based algorithm – ↓Transfusion

Royston D:BJA 2001: 86-575

Novel TEG based ACT Chavez JJ Anesth Analg 2004:99:1290

Hepatology CLD & ALF - Defective synthesis & Hyperfibrinolysis

Post OLT – Haemorrhagic, Hypercoagulable & Thrombotic

Coakley M,J CT Vasc Anaesth2006:20:548

Hypercoagulability Short R/CT time & Increased MA/MCF

Mc Crath DJ: Anaesth Analg 2005;100:1576

Trauma Trauma related coagulopathy

Obstetrics PET + HEELP

TEG / ROTEM POC Coagulation Monitoring in ICU

TEG & ROTEM DisplayStandard TEG Images

Monitoring Anticoagulant Therapy

Heparin Therapy VEPOCD ACT

VEPOCD with Heparinase

LMWH & Heparinoids Danaparoid

Corpel JA Haemophelia 2005

Direct Thrombin Inhibitors Hirudin, Bivaluridin, Argobatron, Ximelagatran

For ACS, VTE & HITS

VEPOCD with Ecarin Clotting Time

Caroll RC Anaesth Analg: 2006: 102: 1316

Monitoring Procoagulant Therapy

Specific component Therapy

Fibrinogen levels MCF / MA of VEPOCD

Antifibrinolytic drugs Aprotinin, Tranexaemic acid & EACA

ap-TEM

Pre rVIIa adminstration

Post rVIIa adminstration

Shortened CT Increased α angleIncreased MCF

Cyclooxygenase 1/ Thromboxane A2 Inhibitors

Asprin

ADP Receptor inhibitor - Clopidogrel

GP II b / III a Inhibitor – Abiciximab & Tirofiban

Traditional Turbidimetric Platelet Aggrgometry

Labour Intensive, Expensive, Time consuming

Expertise to perform and interpret

VEPOCD MA / MCF reflects PF & Fibrinogen levels

Platelet Mapping With TEG – Arachidonic acid or ADP added

PF in presence of antiplatelet therapy

Antiplatelet Therapy

Where do we Stand?

Time honoured lab tests are still routine

High precision, specialists research units are shifting to POCDs

VEPOCD have made their entry and are here to stay

They give opportunity virtual invivo monitoring of

Coagulopathy &

Intervention

Standardization, education and training are needed

Good scope for further research

Intensivists need patient oriented problem solving workshops

Thank you