Bench to Bedside

1. Monitoring Coagulation
in
Intensive Care Unit
Palepu Gopal MD,FRCA
Consultant, Critical Care Medicine
Axon Criticare
Hyderabad

2. Coagulation Monitoring
Bleeding Clotting

3. Why Monitor Coagulation in ICU
Routine ?
Coagulopathy Sepsis
DIC & Thrombocytopaenia
Liver Disease
Trauma
Post-Surgical CABG
On Pro-coagulants Correct Coagulopathy
On Anticoagulants and/or Antiplatelets
DVT Prophylaxis
Anti-thrombotic treatment
CAD Thrombolysis
Coronary stents
Arrhythmias
CVA
Extracorporeal devices
IABP,RRT, MARS, ECMO
On Anti-fibrinolytics

4. Laboratory Based Coagulation Tests
Non-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

5. 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

6. 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

7. Tests of Coagulation - Platelets
Quantitative Measure Automated cell counters or Mannual
Laser technology or Automated flow cytology
Platelet Function Tests
Static Tests β –hromboglobulin, ADP release, No of surface receptors
Dynamic 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 function
Platelet function Analyzer PFA 100
Platelet Works Coulter counter with antagonist
Platelet aggregometry Photo-optical instrument
Fibrinogen Concentration Clottable Protein method (Clauss method)
End-point detection technique
Haemochron POC Technique
Immunochemical tests
Normal 180 -220 mg / dL

8. Thrombin Time
Time taken for conversion of Fibrinogen to Fibrin
Technidyne POC test
Normal Whole Blood 39 - 53 secs
Citrated Blood 43 -63 secs
Specifically measures activity of Thrombin
Sensitive to Heparin
Excludes Intrinsic & Extrinsic pathway
Elevated In Heparin Presence
Hypofibrinogenamia
Dysfibrinogenaemia
Amyloidosis
Thrombin 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

9. 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

10. 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

11. Non-Viscoelastic POC Monitors
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
Coagucheck
Hemochron

12. Fibrinolysis
Primary & Secondary fibrinolysis
Direct Measurement Clot Lysis Time
End Product Measurement FDP
d - dimers

13. Unfractionated Heparin (UFH)
• Exerts its anticoagulant
effect via antithrombin
• Heparin binds to and
produces a
conformational change
in antithrombin.
• Anticoagulant effect
reversed with
protamine.

14. 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

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

16. 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

17. 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

18. Viscoelastic POC Devises (VEPOCD)
Thromboelastography Rotation TE
ROTEM
Sonoclot
1.Rotating Cup with Blood
2.Activator/ Inhibitor
3.Pin & Torsion wire
4.Electromech transducer
5.Data Processor
1.Cuvette with Blood
2.Pipette with activator/ Inhibitor
3.Pin & Rotating Axis
4.EM & Light source, Mirror
5.Data Processor
1.Cuvette with Blood
2.Activator/ Inhibitor
3.Disp plastic probe
4.EM Transducer
5.Data Processor

19. Sonoclot Tests : Reference Values
Entire Haemostasis
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 / min
Low dose Heparin Overall coag
& PLT function
PF 0 - 5
Qualitative Graph Qualitative Graph
ACT CR PF

20. TEG & ROTEM Display
TEG
ROTEM

21. Tests of Viscoelastic POC Devices
Assay Activator/ Inhibitor Indication & Assessment
TEG
Native None Custom Haemostsis test
Kaolin Kaolin Overall coagulation & PLT Function
Heparinase Kaolin+Heparinase Specific detection of Heparin
Platelet Mapping ADP Arachidonic acid PLT Function, Monitoring anti-PLT therapy
ROTEM
Na-TEM None Custom Haemostsis test
ex-TEM Tissue Factor Extrinsic PW, Clot Formation & Fibrinolysis
in-TEM Contact activator Intrinsic PW, Clot formation &Fibrin Polymeriz
fib-TEM TF+ PLT Antagonist Qualitative assessment of Fibrinogen level
ap-TEM TF+Aprotinin Fibrinolytic PW + Fibrinolysis
Hep –TEM CA+ Heparinase Detection of Heparin
eca-TEM Ecarin Management of Direct Thrombin Inhibitors
tif-TEM 1:1000 TF Ex PW:monitoring rF VIIa
Sonoclot
Native None Custom Haemostsis test
gbACT Glass Beads Overall coagulation & PLT function
H-gbACT Glass beads + Heparinase + Presence of Heparin
microPT 1:1000 TF Ex PW:monitoring rF VIIa
SonACT Celite Large dose Heparin without Aprotinin
kACT Kaolin Large dose Heparin +/- Aprotinin
aiACT Celite+Clay Large dose Heparin with Aprotinin

22. 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

23. TEG / ROTEM POC Coagulation Monitoring in ICU
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

24. TESGt &an RdOaTrEdM T DEiGsp Ilmayages

25. 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

26. 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 angle
Increased MCF

27. Antiplatelet Therapy
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

28. 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