1. Coagulopathy in acute and chronic liver diseases - Transfusion choices based on Coagulation screen for procedures
Ashish Goel
Department of Hepatology
Christian Medical College, Vellore
11/22/18
TRANSMEDCON-2018, Kochi

2. Overview Precarious balance
Hypercoagulability – Consequences and management
Hypocoagulability - Management
11/22/18
TRANSMEDCON-2018, Kochi

3. Is Cirrhosis an acquired bleeding disorder ?
Decrease in clotting factors – Raised PT & aPTT
Reduction in number and function of platelets
Infection and endogenous heparinoids
Hyperfibrinolysis
Lisman T. Blood 2010
11/22/18
TRANSMEDCON-2018, Kochi

4. Are the patients with cirrhosis really AUTO-ANTICOAGULATED
Factors favouring bleed
Decreased Clotting factors
Decreased Platelets
Heparinoids
Hyperfibrinolysis
11/22/18
TRANSMEDCON-2018, Kochi

5. Are the patients with cirrhosis really AUTO-ANTICOAGULATED --- NO
Factors favouring clotting
Factors favouring bleed
Decreased Protein C/ antithrombin III
ADAMTS13-vWF imbalance
Increased Factor VIII
Decreased Clotting factors
Decreased Platelets
Heparinoids
Hyperfibrinolysis
Rebalanced Hemostasis
11/22/18
TRANSMEDCON-2018, Kochi

6. The traditional tests overestimate the bleeding risk
Rebalanced Hemostasis – But Precarious
Infection
Active GI bleed
HCC
Renal failure
Hemodynamic instability
Stravitz RT. Hepatol Int 2018
11/22/18
TRANSMEDCON-2018, Kochi

7. Evidence for rebalanced hemostasis
No spontaneous bleeds (except PHTN related)
Liver bleeding time (observed per-op) was not related to parameters1
Decreasing transfusion during OLTx may partly be due to avoiding pre-op correction of ‘coagulopathy’1
Increasing transfusion free liver transplants2
Transfusion requirement during OLTx not related to MELD or PT3
Transfusion free transplants are not feasible for true coagulopathies like hemophilia
Ewe K. Dig Dis Sci. 1981
de Boer MT et al. Dig Surg. 2005
Massicotte L et al. Transplantation. 2009
11/22/18
TRANSMEDCON-2018, Kochi

8. 'Coagulation failure’ is defining feature of ACLF
ROTEM (more hypocoagulable) – Does not predict bleed
Exaggerated abnormalities – Still rebalanced ?
SIRS
Activated platelets
↑ Factor VIII ↑
microparticles
↑ vWF
Infection
Renal failure
Hemodynamic instability
Stravitz RT. Hepatol Int 2018
11/22/18
TRANSMEDCON-2018, Kochi

9. Standard available tests for coagulation often give incomplete picture
Prothrombin time
APTT
Platelet count and function
Clotting time
Fibrinogen
Fibrin degradation products/ D-dimer
Individual factor levels – e.g. Factor VIII in DIC
11/22/18
TRANSMEDCON-2018, Kochi

10. There are at present no validated tests looking at the global coagulation balance
Visco-elastic testing devices – TEG/ ROTEM
Thrombin generation tests
11/22/18
TRANSMEDCON-2018, Kochi

11. Thromboelastometry (ROTEM)
11/22/18
TRANSMEDCON-2018, Kochi

12. Thromboelastometry (ROTEM)
20 mm CT
CFT
MCF ML
AMPLITUDE (MM)
TIME IN MINUTES
11/22/18
TRANSMEDCON-2018, Kochi

13. Thromboelastometry (ROTEM)
20 mm CT
CFT
MCF ML
AMPLITUDE (MM)
Time (minutes)
CT : Clotting factors + ---
CFT : Clotting factors
α – Angle : Clotting factors + --
MCF : Platelets +Fibrinogen
ML : Maximal Lysis (Fibrinolysis)
11/22/18
TRANSMEDCON-2018, Kochi

14. Representative tracings
11/22/18
TRANSMEDCON-2018, Kochi

15. Hyper-coagulability – Potential consequences
Macro-thrombotic complications – Portal vein thrombosis, Deep vein thrombosis etc.
Micro-thrombotic complications – Parenchymal extinction, porto-pulmonary hypertension
11/22/18
TRANSMEDCON-2018, Kochi

16. Relative Risk – Danish registry (N~106 cases)
Cirrhotics may be more prone to thrombosis
Relative Risk – Danish registry (N~106 cases)
Sogaard KK et al. Am J Gastroenterol 2009; 104:96 – 101
11/22/18
TRANSMEDCON-2018, Kochi

17. Portal Vein Thrombosis ↑with severity & is due to local/ systemic factors
Compensated 1%
Decompensated
8-25%
5-10% develop PVT each year in advanced cirrhotics
Tripodi A et al. NEJM 2011
Fontana et al. Gastroenterol 2012
11/22/18
TRANSMEDCON-2018, Kochi

18. Portal Vein thrombosis can :
Worsen liver failure/ Portal hypertension
Complicate potential liver transplant
Affect survival post transplant
11/22/18
TRANSMEDCON-2018, Kochi

19. Endothelial dysfunction in cirrhotics
ADAMTS13 = vWF cleaving protease.
Imbalance in ADAMTS13 : vWF levels ↓
platelet thrombi in microcirculation.
Goel et al. JCEH 2014
11/22/18
TRANSMEDCON-2018, Kochi

20. Progression of liver disease
vWF
Progression of liver disease
Ferlitsch et al. Hepatology 2012
11/22/18
TRANSMEDCON-2018, Kochi

21. Progression of liver disease
ADAMTS13
Progression of liver disease
Uemera et al. Thromb Hemost 2008
11/22/18
TRANSMEDCON-2018, Kochi

22. Progression of liver disease Increase in coagulability
vWF
ADAMTS13
11/22/18
TRANSMEDCON-2018, Kochi

23. Endothelial dysfunction may play a key role in continued worsening in ACLF
Prasanna et al. IJG 2016
11/22/18
TRANSMEDCON-2018, Kochi

24. Endothelial dysfunction may play a key role in continued worsening
Secondary Thrombotic micro-angiopathy
Brain
Liver
Lung
Kidney
11/22/18
TRANSMEDCON-2018, Kochi

25. Parenchymal extinction
Progression of liver fibrosis may be related to progressive occlusion of portal hepatic vessels
Parenchymal extinction
Wanless IR et al. Hepatology 1995
11/22/18
TRANSMEDCON-2018, Kochi

26. Parenchymal extinction
Progression of liver fibrosis may be related to progressive occlusion of hepatic vessels
Parenchymal extinction
Progression of cirrhosis
Wanless IR et al. Hepatology 1995
11/22/18
TRANSMEDCON-2018, Kochi

27. Role of prophylactic anticoagulation in cirrhotics
RCT with CTP –B/C patients; N=70
Duration of LMWH : 1 year; Follow up : > 2 years
LMWH group
Control group
PVT 9%
28%
Decompensation
33%
83%
Death
24%
36%
Villa E et al. Gastroenterology 2012
11/22/18
TRANSMEDCON-2018, Kochi

28. Thrombotic mileu may be present BUT
Bleeding is rare
Thrombotic mileu may be present
BUT
Anticoagulation practically difficult
In PVT
Clot extending to superior mesentric vein
Presence of known pro-coagulant factor e.g. JAK-2 mutation
??? On waiting list of liver transplant ???
Chronicity of thrombus
Occlusive v/s non-occlusive
Presence of HCC
Reliability of follow up
Availability of monitoring
11/22/18
TRANSMEDCON-2018, Kochi

29. Perception of bleeding risk
Featre
Cirrhosis
ALF
ACLF
PHTN
+++ -
Raised INR +
Low platelets ++
Systemic inflammation
Stravitz RT. Hepatol Int 2018
11/22/18
TRANSMEDCON-2018, Kochi

30. Higher ICU risk of bleed in ACLF
211 patients admitted to ICU
35 patients had major bleeding
Independent predictor of bleed
Fibrinogen < 60 mg/dl
Platelets <30000/cmm
aPTT>100s
INR was not predictive
Drolz A et al. HEPATOLOGY 2016
11/22/18
TRANSMEDCON-2018, Kochi

31. Management of bleeding complications
Guiding principles :
Variceal bleed is dependent on portal pressures and not coagulopathy
INR does not correlate with bleeding risks
Use of blood products to be restricted
11/22/18
TRANSMEDCON-2018, Kochi

32. Prevention of bleeding in cirrhosis
N=60 with ‘‘significant coagulopathy’’ - INR > 1.8 and/or platelet count<50,000
RCT : Standard of care v/s TEG directed Tx for pre-procedure prophylaxis
No difference in procedure related bleeding
De PL et al. HEPATOLOGY. 2016
11/22/18
TRANSMEDCON-2018, Kochi

33. Transfusions in case of cirrhotic bleed
Avoid over transfusion (target Hb ~ 7g/dl)
No recommended threshold for INR correction
Platelets of >60000 adequate for thrombin generation (in-vitro and clinical studies)1
Low fibrinogen (<100 mg/dl) can increase the chance of bleed
1. Tripodi A et al HEPATOLOGY. 2006
11/22/18
TRANSMEDCON-2018, Kochi

34. Tx algorithm in cirrhotics
For prophylaxis
Active bleeding
Platelet Tx
correct to >/=60,000/cmm
Cryo-precipitate
Correct to >/=100mg/dl
RBC Tx
Correct to Hb >/=7
Plasma Tx
No threshold recommendation
Platelet Tx
>/=60,000/cmm
Cryo-precipitate
>/=100mg/dl
RBC Tx
Hb >/=7
Stravitz RT. Hepatol Int 2018
11/22/18
TRANSMEDCON-2018, Kochi

35. Consider replacing ADAMTS13 (FFP) prior to platelet transfusions
Secondary Thrombotic micro-angiopathy
Eapen CE. Curr. Sci. 2016
Brain
Liver
Lung
Kidney
11/22/18
TRANSMEDCON-2018, Kochi

36. Bleeding in ACLF No data Can use similar guidelines as in cirrhosis ?
Can consider plasma infusion prior to procedure
Anticoagulants in ACLF ????
11/22/18
TRANSMEDCON-2018, Kochi

37. Management of bleeding complications
Vitamin K (1-25 mg)
Fresh Frozen plasma (10-15 ml/kg)
Platelet (1 unit ~5000/cmm)
Cryoprecipitate (1 bag/10 kg)
Recombinant activated factor VIIA (40 µgm/kg)
Tranexamic acid
Renal support therapy
Desmopressin
11/22/18
TRANSMEDCON-2018, Kochi

38. Preliminary experience with recombinant activated factor VII in control of bleed in Acute fatty liver of pregnancy (AFLP)
Indian J Gastroenterol 2013
11/22/18
TRANSMEDCON-2018, Kochi

39. Management of bleeding complications
Active bleeding
TEG (esp. fibrinolysis)
Routine assays (PT, Platelets, Fibrinogen etc)
Hematocrit,
SEPSIS
Renal dysfunction
Platelets (60,000)
Fibrinogen (100mg/dl)
? Antifibrinolytics
11/22/18
TRANSMEDCON-2018, Kochi

40. Take home message
Cirrhotics are not auto-anticoagulated and may carry an excess risk of thrombotic complications
If needed, carefully monitored anticoagulation may be tried in a highly selected subgroup of cirrhotics
ADAMTS13-vWF imbalance worsens with progression of liver damage and may contribute to parenchymal extinction
Blood product use to be rationalized in bleeding complications
11/22/18
TRANSMEDCON-2018, Kochi

41. Thank YOU
11/22/18
TRANSMEDCON-2018, Kochi