Presentation on Anticoagulation in patients with liver cirrhosis including normal physiology of hemostasis, the role of the liver in hemostasis, effect of liver cirrhosis in hemostatic system and indication and use of anticoagulant in portal vein thrombosis & DVT

2. Anticoagulant in Liver Cirrhosis
By
Mohamed Abdel Ghani Soliman
Demonstrator of Tropical Medicine
Assiut University

3. The liver
&
haemostasis
Coagulation
factors
Anticoagulant
proteins
Fibrinolytic
system
Clearing
coagulation
factors
Introduction

4. Ascites
Spontaneous
bacterial
peritonitis
Variceal
bleeding
Hepatic
encephalopathy
Hepatorenal
syndrome
Hematologic
abnormalities.
Hematologic
abnormalities.

5. The aetiology of impaired
haemostasis in liver disease is
multifactorial and may include:
– Impaired coagulation factor synthesis.
– Synthesis of dysfunctional coagulation
factors.
– Increased consumption of coagulation
factors.
– Altered clearance of activated
coagulation factors.
– Quantitative and qualitative platelet
disorders.

6. • Impaired prothrombin time in
cirrhotic patients has led to a
theory of "autoanticoagulation"

7. Should we give thromboprophylaxis
to patients with liver cirrhosis and
coagulopathy?

8. Our Topics:
• Physiology of haemostasis.
• The liver & the haemostatic system.
• Cirrhosis & haematological changes
– Bleeding VS Thrombosis.
• Anticoagulant in liver disease.

9. Physiology of haemostasis

10. Hemostasis is a cellular process with
the activated platelet as the primary
effector and enabler of coagulation.
The structure of a clot is a platelet
plug restrained by a fibrin mesh
formed by the conversion of
fibrinogen to fibrin by the enzyme
thrombin.
Tripodi, et al. Abnormalities of hemostasis and bleeding in chronic liver disease. Intern Emerg Med 2010.

11. The process involves 3 phases:
Primary
hemostasis
by activated platelets.
Seconary
hemostasis
Coagulation, fibrin mesh construction,
and clot fortification by the plasma
procoagulant proteins.
Fibrinolysis by plasma anticoagulant proteins.

12. Virchow’s Triad

13. Platelet Activation and Factors for Clot
Formation
https://www.youtube.com/watch?v=R8J
MfbYW2p4
Coagulation Cascade Animation
https://www.youtube.com/watch?v=cy3
a__OOa2M

14. Intrinsic
pathway
Externsic
pathway
X Xa
Fibrinogen Fibrin
Prothrombin Thrombin
Antithrombin
III
Degradation
Plasmin
Plasminogen
tPA

15. Primary Hemostasis Coagulation:
Extrinsic and
Intrinsic Pathway
Fibrinolysis
Component
Activated platelets
and Thrombin burst
Builds the fibrin
mesh
Controls the
propagation of the fibrin
mesh and dissolves clot
when hemostasis is
achieved
Measured by
• Platelet count
• vWF
• Platelet function
analysis
• Bleeding time
• PT/INR
• aPTT
• Specific factors
levels
• Fibrinogen level
• Protein C and S levels
• Antithrombin III level
• Euglobulin lysis time
• Anticoagulants levels
(PAI-1, TAFI)
SUMMARY FOR THE STEPS & HOW TO EVALUATE EACH STEP

16. HEMOSTASIS IN
CHRONIC LIVER DISEASE

17. Haemostatic abnormality Mechanism
Quantitative and qualitative
platelet defects:
Thrombocytopenia
Thrombocytopathies
 Decreased bone marrow production
(due to decreased thrombopoietin)
 Splenic sequestration
 Immune-mediated platelet
destruction
 Folate and vitamin B12 deficiencies
 Direct effect of ethanol
 Non-specific platelet aggregation
Abnormalities

18. Haemostatic abnormality Mechanism
Hypocoagulability  Decreased synthesis of coagulation
factors (except VIII and VWF)
 Hypofibrinogenaemia
 Vitamin K deficiency (II, VII, IX, X)
 Decreased clearance of degraded
coagulation factors
Hypercoagulability  Decreased synthesis of natural
anticoagulant proteins
antithrombin (AT), proteins C, S and Z
 Decreased clearance of activated
coagulation factors

19. Haemostatic abnormality Mechanism
Dysfibrinogenaemia
Hyperfibrinolysis
 Synthesis of abnormal fibrinogen
 Increased levels of circulating tPA
activity due to impaired hepatic
clearance
 Decreased synthesis of fibrinolytic
inhibitors (PAI-1 and a2-antiplasmin)
 Decreased thrombin-activatable
fibrinolytic inhibitor (TAFI)

21. Portal Vein Thrombosis
Prevalence of portal vein thrombosis:
• Lower than 1% in compensated cirrhosis.
• (10%–25%) of candidate for liver transplant.

22. Local Risk Factors for Portal Vein Thrombosis

23. Risk factors for the development of PVT:
 Decreased portal flow velocity.
 Genetic prothrombotic factors
(i.e. MTHFR677-TT polymorphism)
leading to ↑ thrombin generation.
 High FVIII combined with low
Protein C .

24. Deep Venous Thrombosis

25. Deep Venous Thrombosis
 The incidence of DVT/PE ranges from 0.5% to 1.9%,
similar to patients without comorbidities.
 Risk factors:
serum albumin level was independently
associated with the occurrence of thrombosis.
Gulley, et al. Deep vein thrombosis and pulmonary embolism in cirrhosis patients (2008).

26. Deep Venous Thrombosis
Gulley, et al. Deep vein thrombosis and pulmonary embolism in cirrhosis patients (2008).
Risk factors:
liver resection can unbalance the haemostatic equilibrium.
share the same risk factors as general population
such as venous stasis, infection, congestive heart failure,
acute respiratory disease, surgery (orthopaedic) and
immobilization.

27. Arterial Thrombosis
 Hepatic artery thrombosis following liver
transplantation which worsen the prognosis.
 It seems to be related to a hypercoagulable
state in the postoperative period.

28. Arterial Thrombosis
Patients with chronic liver disease could
develop atherothrombosis.
It is not clear if there is an increased risk of
coronary heart disease or stroke in these cases.

30. Bleeding Thrombosis
Decrease level of
ADAMTS 13
Elevated level of
vWF
Platelet function
defect
Thrombocytopenia

31. Bleeding Thrombosis
Decrease level of a2
macroglobulin &
heparin cofactor II
Decrease level of
Protein C, S & AT III
Elevated levels of F
VIII
Vitamin K deficiency
Low levels of factors
II, V, VII, IX, X & XI
Dysfibrinogenemia

33. Should we give thromboprophylaxis
to patients with liver cirrhosis and
coagulopathy?

35. Intrinsic
pathway
Externsic
pathway
X Xa
Fibrinogen Fibrin
Prothrombin Thrombin
Antithrombin
III
Degradation
Plasmin
Plasminogen
tPA
Antithrombin
III
Xa
Thrombin

36. HEPARINS

38. Unfractionated heparin
 Inhibits thrombin by accelerating the
activity of antithrombin.
 Dose of heparin
Treatment: 80 units/kg IV bolus (if desired)
then 18 units/kg/hr IV infusion. Check aPTT
6 hours after bolus and adjust infusion to
maintain aPTT within the therapeutic range
established by the local laboratory.
It is recommended to use an algorithm-based
dosing protocol
Prophylaxis: 5000 units sc q12hr (or q8hr if
obese i.e. weight >120 kg).

39. Low Molecular Weight Heparin
Enoxaparin (Lovenox®)
Dalteparin (Fragmin®)
Tinzaparin (Innohep®)
Directly inhibits factor Xa activity
Dose of enoxaparin
Treatment: 1.5 mg/kg sc qday
or 1 mg/kg sc BID.
Prophylaxis: 40 mg sc qday

40. Low Molecular Weight Heparin
 Dose of dalteparin
 Treatment: 200 units/kg sc qday
 Prophylaxis: 5000 units sc qday
 Dose of tinzaparin
 Treatment: 175 units/kg sc qday
 Prophylaxis: 3500 units/kg sc qday
 Monitoring
 Routine monitoring is not required for LMWHs
 Anti Xa levels in the following situations
Renal failure
Extreme weights
Pregnancy
Recurrent thromboses on therapeutic doses

41. Warfarin (Coumadin®)

42. Warfarin (Coumadin®)
 Inhibits the proper synthesis of the vitamin K-
dependent clotting factors.
 Initiate warfarin at 5-10 mg po qday.
Consider lower doses in the elderly, patients
with impaired nutrition, liver failure,
congestive heart failure, or with a high risk of
bleeding.
 An initial INR should be done on Day 3.
 In the absence of any bleeding, the warfarin
dose should be adjusted based on the table
below.
 An INR should then be done every 3-4 days,
until the INR is therapeutic and stable.

43. Warfarin (Coumadin®)

52. Management of Some Common
Clinical Issues Related to
Coagulation in Liver Disease

53. Xingshun, et al. Management of portal vein thrombosis in liver cirrhosis. NATURE REVIEWS
GASTROENTEROLOGY & HEPATOLOGY ( 2014)

54. PVT
Acute or subacute PVT can be
treated with therapeutic
anticoagulation (LMWH) and may
prolong survival in these patients.
Esophageal varices should be
treated aggressively endoscopically
before anticoagulation.
PATRICK , et al. Coagulation in Liver Disease: A Guide for the Clinician.
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY (2013).

55. Currently available VKAs have a very
narrow therapeutic window in
cirrhosis patients and are problematic
in patients with baseline elevated INR.
Patients with chronic PVT and
cavernous transformation are less likely
to benefit from anticoagulation.
Premature discontinuation of
anticoagulation (before transplant) is
likely to result in thrombus recurrence.
PATRICK , et al. Coagulation in Liver Disease: A Guide for the Clinician.
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY (2013).

56. Deep vein thrombosis or
pulmonary embolus
Consider medical prophylaxis in all
hospitalized cirrhosis patients as
with any medical inpatient.
Medical therapy for acute VTE
should be with LMWH in therapeutic
doses similar to PVT treatment
unless contraindicated.
PATRICK , et al. Coagulation in Liver Disease: A Guide for the Clinician.
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY (2013).

57. Do not assume the hospitalized
cirrhosis patient is “auto-
anticoagulated” because the INR is
elevated.
Presence of nonbleeding esophageal
varices should not preclude VTE
prophylaxis.
PATRICK , et al. Coagulation in Liver Disease: A Guide for the Clinician.
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY (2013).

58. Performance of invasive
procedures
If high-risk procedure, transfuse
prophylactic platelets to a target of
at least 50–60 X 109/L or closer to
100 X 109/L for very high risk.
If postprocedural bleeding occurs
in mucosal sites or from puncture
wounds, consider hyperfibrinolysis.
PATRICK , et al. Coagulation in Liver Disease: A Guide for the Clinician.
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY (2013).

59. Treat underlying disorders
aggressively before elective
procedures (infection, renal failure,
etc).
Intranasal Desmopressin Acetate
(DDAVP®) may be an effective and
economical alternative prophylactic
measure in procedures such as dental
extractions.
PATRICK , et al. Coagulation in Liver Disease: A Guide for the Clinician.
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY (2013).

60. Do not use a moderately elevated
INR (3) as a measure of procedural
bleeding risk.
Avoid using FFP for prophylaxis, but
if used, consider adequate dosing to
replace factors is 20–40 mL/kg .
PATRICK , et al. Coagulation in Liver Disease: A Guide for the Clinician.
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY (2013).

61. • Do not use prophylactic transfusion
of FFP or platelets in ALF without
clinically evident bleeding.

62. CONCLUSION
• The liver plays major role in
hemostasis.
• Liver disease affect all phases of
haemostasis.
• Auto-anticoagulated.
• Rebalancing
• INR as single test doesn’t
determine the true state of
coagulation

63. CONCLUSION
• Consider the use of
thromboprophylaxis in cirrhotic
patients if there is a risk for
thrombosis.
• There is a need to revise the
guidelines regarding anticoagulation
in this special population.

64. CONCLUSION
We suffers from a lack of accurate,
reliable, and clinically available
testing methods to properly assess
the true state of hemostasis.
Because some patients with chronic
liver disease are predisposed for
bleeding, some for hypercoagulation,
and some in a stable balance.