This document summarizes key points about coagulation in patients with cirrhosis. Some of the main points covered include: - Cirrhosis represents a state of delicately balanced hemostasis rather than an auto-anticoagulated state as previously thought. - Conventional coagulation tests like PT/INR do not accurately predict bleeding risk in cirrhosis as they do not account for the complex balance between pro- and anti-coagulant factors. - Viscoelastic tests (VETs) like thromboelastography (TEG) and thromboelastometry (ROTEM) provide more useful information about hemostasis in cirrhosis compared to conventional tests

1. COAGULATION IN CIRRHOSIS
Presenter-Dr. Shiv Ratan Pathak.
Moderator – Dr. Sandip Pal.

2. INTRODUCTION
• Cirrhosis –
• Not” auto-anticoagulated state” as previously thought
• A state of delicately rebalanced hemostasis
• Increased risk of bleeding –variceal, non variceal GI bleed, procedure
related
• Increased risk of thrombosis-PVT,DVT and VTE

3. CIRRHOSIS-BALANCE OF PRO AND
ANTI COAGULANT STATE
Tripodi et al, N Engl J Med 2011

4. A DELICATE BALANCE
• This delicate but precarious balance may be tipped by:
• Uremia-GSA> NO induced
• Infection-HLE
Norris et al, Blood 1990 Montalto et al, JOH 2002

5. CASCADE MODEL OF HEMOSTASIS
Ist initiating Event
• Classical teaching - Y shaped pathway- a
cascade or waterfall model.
• Intrinsic pathway – has everything
needed for pathway in plasma
• Extrinsic factor- Needs tissue factor
• Unanswered questions-Hemophilia A
and B, Factor XII deficiency
Prothrombinase
complex
Davie et al,Science 1964.
Macfarlane et al, Nature 1964.

6. CELL BASED MODEL OF
HEMOSTASIS
• Initiation
• Amplification
• Propagation
Hoffman et al, Thromb Haemost 2001
Monroe et al, Clin Liver Dis 2009
( Starts with break in vessel wall- contact
Of plasma with TF)
(Role of thrombin in Procoagulant
complex assembly)
f.VIIIa/Ixa(Tenase complex) and
f.Xa/Va complexes

7. COAGULATION TESTING
• Conventional coagulation tests
• Viscoelastic testing
• Thrombin generation assays

8. PT-INR
• Two fold use conventionally-
• Synthetic function-prognosis(MELD,CTP)-fairly justified
• Bleeding risk assessment-wrong
• Measures time till clot formation after addition of CaCl2 and
thromboplastin(tissue factor)
• Utilises coagulation via extrinsic pathway (VII, X, V, II and I)

9. WHATS WRONG WITH PT AND INR
• PT detects procoagulant deficiency, not the counter balance by
anticoagulant deficiency
• Inter lab variabilty-thromboplastin use-extract /recombinant
• INR standardized for patients on VKA and not for liver ds.
• Does not correlate with in vivo environment as it does not count the
effect of thrombomodulin and protein C.
• Detects clot formation at 5% thrombin generation
• Multiple studies showing lack of correlation with bleeding risk.
Mann KG, Chest 2003

10. Thrombin generation is normal in cirrhotics
despite increase in PT
Tripodi A et al, Hepatology 2005

11. INR
1. The INR scale is most accurate in the range 1.5–4.5.
This
is because only patients on VKA within the above
limits of
anticoagulation are included in the calibration model
(see
Fig. 1).
2. The ISI and the conversion of PT results into the INR
scale are valid only for patients on VKA. This is
because PTs from patients on VKA are inserted in the
calibration plot
Tripodi A et al, APT, 2007

12. • N=200
• Measured liver bleeding time in patients
undergoing liver biopsy.
• No correlation in indices of coagulation and
bleeding

13. SEVERITY OF UGI BLEED IS NOT PREDICTED BY
PT
Schemer et al ,WJG 2006

14. Derranged PT does not predict complications
after invasive procedures
Segal et al, Transfusion, 2005

15. OTHER EXPRESSIONS OF PT
Robert A ,Hepatology 1996

16. OTHER EXPRESSIONS OF PT
Robert A, Hepatology, 1996

17. INR Liver vs INR VKA N=57(A=20,B=19,C=18)
CV=8% CV=1%
Tripodi et al, Hepaology 2007

18. INR LD
Bellest L et al, Hepatology 2007

19. Do these modifications resolve
the issue of predicting
bleed/thrombosis in cirrhosis?
A BIG NO

20. Does PT/INR guided FFP transfusion help
decrease bleeding risk?
NO
Stanworth HJ et al, BJH 2004

21. VISCOELASTIC TESTS OF COAGULATION(VET)
• Developed in 1948- in vogue for Trauma and cardiac sx
• Consider cell based model of hemostasis
• Gives info on-
• Dynamics of clot formation
• Clot strength
• Clot stability
• 2 commercially available platforms:
• TEG(USA)
• ROTEM(Germany)

22. PRINCIPLE OF VISCOELASTIC TESTS
• Movements of blood filled cuvette are transmitted via a pin to obtain
a trace
• A Cup holds 0.36 ml of blood and oscillates through an angle of 4° 45’
with each rotation cycle lasting 10 sec.
• Formation of fibrin‐platelet bonds between the wall of the cup and
the pin ->increased movement of the pin ->displayed as graphical
output over time .
Davis et al, Ann of Hepat 2018

23. Ganter et al, Anesthesia & Analgesia, 2008
Whiting et al,American Journal of Hematology, 2014

24. VISCOELASTIC TESTS OF COAGULATION
Montalto et al, JOH 2002

25. AIIMS TEG normative data
Arul selvi S, Saxena R et al, ISRN hematology 2014
N=200
n=150

26. Davis et al, Ann of Hepat 2018

27. VET in Liver diseases-Transplant setting
Correlation with Conventional Coagulation Tests
&Transfusion Guidance
• RCT-TEG guided vs SOC
Wang SC et al, Transplant pro 2010

28. VET in liver disease-Non transplant setting
Correlation with CCT
ROTEM
• MCF and CFT correlate with
platelet and FBG
• FIBTEM MCF correlates with FBG
level
TEG
• MA correlates with Plt
• But PT doesn't correlate with K
time/R time
Tripodi A et al, Thromb res 2009
Vucelli D et al, Thromb res 2015
Shin KH et al, Ann Lab Med 2017

29. Pietri et al, Hepatology 2016
• 60 patients randomized
to SOC and TEG group
• Included patients had
platelets < 50,000 and
INR>1.8
• Mean MELD =20 and
60% were child C
• Only 1 bleeding in SOC
TEG guided transfusion decreases undue transfusions with
no increase in bleeding risk

30. AIIMS Data-RCT-TEG guided tx in Invasive high risk
procedures
Shalimar et al, 2019 (unpublished data)

31. AIIMS Data- RCT-TEG guided tx in AVB
Rout G et al,JCG 2019
10.0%
36.0%

32. AIIMS data-TEG in ACLF
Goyal S, Annals of hepat 2019

33. ILBS DATA-TEG guided Tx in Non variceal bleed in
cirrhotics
Manoj K et al, Hepatology 2019
TEG (n=49) SOC(n=47)
FFP (per/pt) * 440mL 880 mL
Plt(pools)* 26 71
Cryo* 78 814
TRALI * 6 23
TACO 5 10
Failure to control bleed = =
rebleed = =
Mortality = =

34. TEG in Infection induced coagulopathy in cirrhotics
Montalto et al,JOH 2002

35. Thrombin Generation Assay
• Ist tried in 1950
• Principle- citrated test platelet rich plasma is tested by adding TF,PL,
CaCl2, thrombin fluorogenic substrate-> thrombin generation is
followed by activity of fluorogenic substrate and a curve is drawn
depecting the thrombin concentration over time(as balanced by
pocoagulant and decay factors)
• Correlates closely with in vivo conditions
• No yet widely available

36. Thrombin Generation Assays
• Lag time - equivalent of the clot- ting time
• Time to Peak - the velocity of thrombin
generation
• Peak Height - Highest thrombin
concentration that can be generated
ETP - Total thrombin that a plasma sample
can generate under the action of the 2
opposing (pro- and anticoagulant) drivers
Tripodi et al,Clinical Chemistry 2016

37. TGA interpretation

38. Thrombin Generation Assay- Role of Thrombomodulin
Thrombin generation is same in cirrhotics and control
Tripodi et al, Hepatology 2005

39. CLINICAL ISSUES WITH
COAGULATION IN CIRRHOSIS

40. PVT
• Epidemiology:
• 1% in compensated cirrhosis
• 8-25% in decompensated cirrhosis
• 40% in HCC
• Not just prothrombotic state but other factors responsible-Virchows
triad:
• Venous stasis
• Vessel wall damage
• Viscosity
Okuda K et al,Gastroenterology 1985 Francoz C et al,Gut 2005

41. PVT
• Clinical significance:
• Increased decompensation and mortality
• Poorer outcomes of variceal bleed
• Poorer outcomes in LT
• Poor outcome in HCC
• Pretreatment assessment:
• UGIE screen for high risk vx and endoscopic or pharmacologic prophylaxis
warranted
Stine JG, et al World J Hepatol 2015 D’Amico G et al Hepatology 2003 Francoz C et alJ Hepatol 2012

42. Effects of Anticoagulants in Patients With
Cirrhosis and Portal Vein Thrombosis: A
Systematic Review and Meta-analysis
• 8 studies involving 353 patients
• Complete Recanalization in
Anticoag vs control i.e. 53 % vs 33%,
OR=3.4
• PVT progression in anticoag vs
control i.e. 9% vs 33%, OR=0.14
• Rate of variceal bleeding lower in
anticoag vis a vis control i.e. 2% vs
12 %, OR=0.23
Loffredo et al, Gastroenterology 2017

43. • LMWH not warfarin is significantly associated with complete PVT
resolution
• Both LMWH and warfarin associated with prevention of PVT progression
• No increased risk with anticoagulation and bleeding
• Most of the warfarin studies were retrospective
Anticoagulation in PVT – Meta-analysis

44. NOAC in PVT
• No prospective data
• Clinical trials have traditionally excluded pts with cirrhosis
• Caution warranted in Child B/C
• Similar risk of bleeding as traditional AC
Intagliata et al, DDS 2015

45. Patients with liver disease are not protected
from VTE events
Cases=99,444 and controls 4,96,872
Sogaard et al, AJG 2009

46. Venous Thromboembolism(VTE) risk and
prophylaxis
• Epidemiology:
Ambrosino P et al. Thromb Haemost 2017

47. VTE risk in acutely ill cirrhosis
• Hospitalised acutely ill patients-4-15% risk
• In cirrhotics- 11%
• PPS>4 correlates with risk in cirrhotics(OR 12.7)
Bogari H et al,Thromb Res 2014

48. VTE prophylaxis in cirrhosis
Yerke J et al, WJH 2019

49. VTE treatment
• Majority of data extrapolated from use of AC in PVT
• In peripheral VTE alone sparse data

50. Microthrombi
• Parenchymal extinction hypothesis
Parenchymal extinction hypothesis
Wanless et al,Hepatology 1995

51. Enoxaparin prevents PVT and decompensation in
cirrhosis
• Nonblinded, RCT,, 70 patients with cirrhosis (CTP 7–10), Mean MELD
– (12-13) with demonstrated patent portal veins
• Cases – Enoxaparin 4000 IU/day X 48 weeks, controls – No Rx
• Primary end point – Prevention of PVT at 2 years
Secondary end point – Prevention of liver decompensation and
overall survival and transplant free survival
Villa E et al, Gastroenterology 2012

52. Anticoag vs control
0%(0/34) vs 27.6%(10/36
11%(4/34) vs 59.4%(21/36)

53. • Enoxaparin treated patients had improvement in Serum Bilirubin,
Albumin and INR at 48 weeks.
• Probability of worsening CTP scope was statistically significant in
control group vs enoxaparin group .
• More patients in control group have SBP/bacteremia vs Enoxaparin
group i.e. 33.3(12/36) vs 8%(3/34)
• Occurrence of bleeding episodes did not differ in two groups

54. TAKE HOME POINTS
• Cirrhosis patients are not auto-anticoagulated
• Cirrhosis is a state of rebalanced hemostasis
• Cirrhosis patients are at risk of thrombosis
• PT/INR not a useful marker of bleeding risk in cirrhosis
• VET perform better than CCT in cirrhosis
• VET guided Tx strategies are better
• AC is safe and effective in cirrhosis

55. THANK YOU

56. BRAKES IN THE COAGULATION CASCADE

57. FIBRINOLYTIC SYSTEM

58. Coagulation in cirrhosis
Correction Of Abnormal Coagulation In Chronic Liver Disease By Combined
Use Of Fresh-frozen Plasma And Prothrombin Complex Concentrates.
30 patients randomized to FFP, PCC and both.
Improvement in INR and aPTT
Suggested role of transfusions before invasive procedure.
Mannucci, Lancet 1976

60. • Clotting time (CT) for ROTEM and reaction rate (R) for TEG - defined
as the time taken by clot to reach an amplitude of 2 mm.
• Clot formation time (CFT) and kinetics time (K) are defined as the
time necessary for clot amplitude to increase from 2 to 20 mm.
• Angle (a) is determined by creating a tangent line from the point of
clot initiation (CT or R) to the slope of the developing curve.
• Maximum clot firmness (MCF) for ROTEM and maximum amplitude
(MA) for TEG are the peak amplitudes (strength) of the clot.
Whiting et al,American Journal of Hematology, 2014

61. Modifications of TEG
Davis et al, Annals of Hepat, 2018

62. Modifications of ROTEM
Davis et al, Annals of Hepat, 2018

63. AIIMS data-TEG in ACLF
Goyal S et al, Annals pf hepat 2009

64. Safety and Efficacy of Anticoagulation Therapy With Low Molecular Weight
Heparin for Portal Vein Thrombosis in Patients With Liver Cirrhosis
• Study population – 39 Non
neoplastic cirrhotics
• 28 received enoxaparin X 6 months
• Doppler USG Done at 6 months
interval
• No adverse events requiring
interruption of therapy
Amritano, J Clin Gastroenterol 2010
Anticoag + (n=28)
Complete Recanalization 9(33%)
No response 5(16.7%)
Partial recanalization 14(50%)
In partially recanalized patients, Anticoagulation continued
and 12 recanalized in median 11 months

65. Clinical and Molecular Hepatology 2014;
• Retrospective analysis of cirrhotics with PVT diagnosed via MDCT
• Anticoagulation with warfarin and effect of anticoagulation assessed via repeat
MDCT after 3 months
• N=14, warfarin; N=14, No anticoagulation
Response Warf+ (n=14) No Warf(n=14) P value
Thrombus
Resolution
11(6+5) 5(3+2) 0.022
Non Resolution 3 9
More patients in Warfarin group had resolution of thrombus.
Factors associated with non resolution – PVT detection to anticoagulation duration>6
months(66% vs 0%; P value = 0.03)

66. • ROTEM
• EXTEM MCF 40mm and FIBTEM
MCF 8 mm correlate with low
platelets and low FBG
respectively
• ROTEM vs SOC
• NS trend towards less tx in ROTEM
group(10 vs 13)
Blassi A et al, Transfusion 2012
Trzebicki et al, Ann Transplant 2010