Coagulation

1. Coagulation In Cirrhosis
Dr. Khushboo Priya
DM Resident
Department Of Gastroenterology
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2. Learning Objectives
• To understand how alterations in hemostasis in liver disease
result in a rebalance between procoagulant, anticoagulant, and
fibrinolytic systems
• To understand the limitations of currently available laboratory
tests for evaluating the coagulopathy of liver disease
• To identify triggers of acute bleeding in liver disease
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3. • Patients with cirrhosis have profoundly altered hemodynamics and
hemostatic pathways with procoagulant and anticoagulant mechanisms,
resulting in a tenuous “rebalanced” state in the setting of portal
hypertension.
• This balance could be tipped toward either a procoagulant or
anticoagulant phenotype by superimposed conditions.
• Specific coagulation factor (F) V (FV), FVII, FIX, FX, FXI, prothrombin,
protein C, and protein S are reduced with concomitant increased FVIII
and von Willebrand factor (vWF) activity in cirrhosis.
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4. • Thrombocytopenia, increased nitric oxide, and prostacyclin inhibit
platelet function (PF), and higher vWF and FVIII activity support
platelet aggregation.
• Thrombocytopenia is the result of splenic sequestration in portal
hypertension, decreased hepatic thrombopoietin synthesis, and
immune-mediated platelet destruction due to glycoprotein IIb/IIIa
platelet surface antigen-antibody interaction triggered by
inflammation or sepsis.
4

5. • Patients with acute liver failure (ALF) have a markedly prolonged international
normalized ratio (INR) but preserved thrombin generation potential, and they
tend not to bleed.
• In cirrhosis, INR increases modestly with synthetic dysfunction and reflects
short-term patient mortality, but not bleeding risk, during invasive procedures
because of adequate thrombin generation potential.
• In ACLF, coagulation switches from a procoagulant to an anticoagulant
phenotype with the onset of systemic inflammation and endothelial
activation, which is compounded by sepsis
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6. • Patients with compensated liver cirrhosis have a rebalanced
coagulation profile.
• An elevated INR is not a predictor of bleeding, nor is a therapeutic
correction target in a bleeding patient.
• Progression of chronic liver failure is associated with derangement of
coagulative balance, and the balance shifts from a procoagulant to
anticoagulant phenotype.
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7. 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.
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9. The process involves 3 phases:
Primary
hemostasis by activated platelets.
Seconary
hemostasis
z
Coagulation, fibrin mesh construction, and clot
fortification by the plasma procoagulant proteins.
Fibrinolysis by plasma anticoagulant proteins.
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10. Primary
Hemostasis
Coagulation:
Extrinsic and
Intrinsic Pathway
Fibrinolysis
SUMMARY FOR THE STEPS & HOW TO EVALUATEEACH STEP
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)
10

11. Quantitative and
qualitative platelet
defects:
Thrombocytopenia
Thrombocytopathies
Haemostatic abnormality
 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
Mechanism
11

12. Haemostatic abnormality Mechanism
Hypocoagulability
Hypercoagulability
 Decreased synthesis of
coagulation factors (except
VIII and VWF)
 Hypofibrinogenaemia
 Vitamin K deficiency (II, VII, IX,
X)
 Decreased clearance of
degraded coagulation
factors
 Decreased synthesis of natural
anticoagulant proteins
antithrombin (AT), proteins C, S and Z
 Decreased clearance of activated
coagulation factors
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13. Haemostatic abnormality
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)
Mechanism
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15. BLEEDING
THROMBOSIS
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20.  Major mechanisms of bleeding in cirrhosis include portal
hypertension related bleeding (primarily pressure driven) and
mucosal/wound bleeding (primarily driven by disordered
procoagulant pathways).
 A conventional measure, like the INR (international normalized
ratio), which measures only procoagulant factors, does not
provide an estimate of either bleeding or clotting risk in these
patients, as both pro and anticoagulant factors are affected by
liver dysfunction.
 The paradox of two enhanced, but opposing phenomena –
bleeding and clotting – highlights the challenge that clinicians
face when caring for these patients.
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21. Clinical laboratory tests of the coagulation system in cirrhosis
Conventional testing:
 Conventional tests include the prothrombin time (PT), the PT related INR,
and the activated partial thromboplastin time (aPTT), which measure the
classical extrinsic and intrinsic coagulation cascades.
 The PT INR and aPTT are sensitive to factor deficiencies (measuring only
procoagulant factors) and are also used clinically to guide warfarin and
heparin dosing.
 In cirrhosis, inter laboratory variation in the INR is well known and can be
ameliorated by measuring the thromboplastin against a panel of cirrhotic
controls. Despite this limitation, the INR remains a part of the ‘Model for
End Stage Liver Disease’ (MELD) scoring system, which is a reliable means
of gauging liver disease severity. Thus, use of PT and INR to predict
bleeding risk in cirrhosis is not recommended
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22. The American Association for the Study of Liver
Disease (ASSLD) Practice Guidelines for liver biopsy
acknowledge that there is no specific PT/INR cutoff
at or above which bleeding complications can be
reliably predicted. There is evidence that the
platelet count is a better predictor of bleeding than
the INR. In several studies, a platelet count 56 000
was associated with a significantly increased rate of
post-procedure bleeding.
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23. Single factor measures:
• Measurements of isolated factor levels and other constituents of the
coagulation system, such as platelets, are routinely performed in
clinical practice
• In vitro analysis with the thrombin generation assay showed that a
platelet level of 56 000/uL is sufficient to generate thrombin at a level
similar to healthy controls
• All coagulation factors are reduced in cirrhosis, except for endothelial
derived factor VIII and wVF, which are elevated.
• Measurement of factor VIII can help distinguish AICF from DIC and
with protein C can provide an indirect measure of haemostatic balance
• Fibrinogen measurement and replacement if needed appear to be
especially important in cirrhosis with bleeding or with prophylaxis
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24. Global measures:
• Whole blood ‘global’ measures of coagulation include the
thrombin generation assay (TGA) and viscoelastic tests (TEG,
ROTEM, and emerging sonorheometry).
• TGA has been studied extensively in patients with cirrhosis and
has valuable characteristics offering a more accurate portrayal
of the entire coagulation system.
• These tests are currently used to guide therapy in liver
transplant surgery and application outside of surgery is
increasing in cirrhosis patients
• Limitations include a lack of validation and standardization in
the cirrhosis population, insensitivity to certain
coagulopathies, and requirement of centre expertise for
operation and interpretation. 24

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26. Prophylaxis and therapy for bleeding in cirrhosis
Bleeding complications in chronic liver disease are infrequently
related to abnormal hemostasis. The majority of clinically signifi-
cant bleeding episodes are due to increased portal pressure rather
than deranged hemostasis.
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27. Prevention of bleeding
Vitamin K
 Patients with cirrhosis and abnormal coagulation screening tests often
receive vitamin K despite a lack of evidence supporting benefit.
Supplemental vitamin K may correct abnormal coagulation tests in patients
at high risk for deficiency due to biliary disease or gut sterilization from
broad-spectrum antibiotics. However, in cirrhotic patients with reduced
synthetic function, the benefit of vitamin K is uncertain.
 A single 10 mg dose of vitamin K resulted in minimal improvement in PT
and PTT in patients with cirrhosis with no effect on the levels of several
vitamin K dependent proteins. Cirrhotic patients had normal PIVKA (Protein
Induced in Vitamin K Absence) levels suggesting vitamin K deficiency does
not play a major role in the coagulopathy of liver disease.
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28. Fresh frozen plasma
 The routine use of FFP for primary prophylaxis prior to invasive
procedures is not recommended.
 Prevention of bleeding should not be aimed at correcting abnormal
routine coagulation tests (INR,PTT).
 The large volumes of FFP required to significantly increase clotting factor
levels may result in volume overload and exacerbation of portal
hypertension paradoxically increasing the risk of bleeding.
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29. Platelets
 There are no prospective studies demonstrating that
prophylactic platelet transfusions reduce the risk of bleeding
associated with liver biopsy or other invasive procedures.
Thrombopoietin receptor agonists
 The demonstration of reduced TPO production and activity in
chronic liver disease provides a rationale for use of
thrombopoietinreceptor (TPO R) agonists to increase platelet
production.
 In a recent phase II study, patients with chronic hepatitis C,
cirrhosis,and thrombocytopenia (50 0000) received romiplostim
for up to 4 weeks prior to elective surgery.
 A fixed 2 mcg weekly dose increased the platelet count above
the target threshold value of 70 000 required for surgery in 94%
of patients and there were no bleeding or thrombotic
complications. 29

30. A randomized trial in patients with chronic liver disease and
thrombocytopenia (50 000) demonstrated that administration of the
oral TPO R agonist, eltrombopag for 14 days prior to elective invasive
procedures reduced the need for platelet transfusion (28% patients)
compared with placebo (81% patients). The study was terminated
early because of an increased incidence of portal vein thrombosis in
patients receiving eltrombopag (4%) versus placebo (1%).
Additional trials are necessary before TPO R agonists can be routinely
recommended for patients with liver disease undergoing elective
invasive procedures or surgery.
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31. Recombinant factor VIIa:
 Several randomized studies found the use of rFVIIa in addition to
standard pharmacologic and endoscopic therapy no beneficial effect
on clinically relevant outcomes in patients with cirrhosis and active
variceal bleeding.
 Recombinant FVIIa is not approved for use in liver disease and off-
label use is associated with an increased risk of arterial
thromboembolism.
Prothrombin complex concentrates (PCCs):
PCCs are plasma-derived products that contain vitamin K-dependent
coagulation factors (FII, FVII, FIX, FX) and anticoagulant proteins
(protein C and protein S).
A multicenter randomized trial is currently investigating the efficacy of
preoperaive administration of PCC in patients undergoing liver
transplantation. In the absence of evidence confirming benefit, the
routine use of PCC for bleeding complications of chronic liver disease is
not recommended. 31

32. • Optimization of underlying risk factors such as renal function
and infection, avoidance of volume expansion, and transfusion
of platelets to greater than 50 000/uL (if low), and use of
cryoprecipitate to increase fibrinogen levels above 120 mg/dL
for high risk procedures is our recommended approach
although prospective controlled trials are lacking
32

33. Villa E, Camma C, Marietta M et al. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients
with advanced cirrhosis. Gastroenterology 2012; 143(5): 1253–1260.e1– 4.
Thrombosis
• Protein C, a potent anticoagulant, is reduced in cirrhosis and may explain
thrombotic tendencies. The extent of vWF elevation and the ratio of
elevated FVIII to diminished protein C ratio predicted PVT and poorer
outcomes.
• Furthermore, beyond clinical events like VTE or PVT, activation of the
clotting cascade at the sinusoidal level may contribute to development
of fibrosis, increase in portal pressure, and hepatic decompensation
• In support of this, a recent study demonstrated that prophylactic low
molecular weight heparin (LMWH) prevents development of PVT and
reduces likelihood of hepatic decompensation .
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34. Medical prophylaxis and therapy for thrombosis in cirrhosis
• The risk of VTE in cirrhosis is related to changes in the haemostatic
balance noted earlier and to factors similar to other hospitalized
medical patients, including immobility and acute infection. If no
contraindication exists, use of LMWH or unfractionated heparin (UFH)
is safe and generally recommended in this population
• Currently, no clear evidence-based recommendations can be made
with respect to VTE prophylaxis and therapy in patients with end-stage
liver disease.
• Clinical practice must be individualized in this complex patient
population.
• VTE treatment should be used in patients with minimal varices, no
evidence of clinical bleeding and with an appropriate clinical
indication.
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Practicing Guidelines :-
 PRACTICE ADVICE 1: Global tests of clot formation, such as rotational thromboelastometry,
thromboelastography, sonorheometry, and thrombin generation, may eventually have a role in
the evaluation of clotting in patients with cirrhosis, but currently lack validated target levels.
 BEST PRACTICE ADVICE 2: In general, clinicians should not routinely correct thrombocytopenia
and coagulopathy before low-risk therapeutic paracentesis, thoracentesis, and routine upper
endoscopy for variceal ligation in patients with hepatic synthetic dysfunction-induced
coagulation abnormalities.
 BEST PRACTICE ADVICE 3: Blood products should be used sparingly because they increase
portal pressure and carry a risk of transfusion-associated circulatory overload, transfusion-
related acute lung injury, infection transmission, alloimmunization, and/or transfusion
reactions.
 BEST PRACTICE ADVICE 4: The following transfusion thresholds for management of active
bleeding or high-risk procedures may optimize clot formation in advanced liver disease:
hematocrit ≥25%, platelet count >50,000, and fibrinogen >120 mg/dL. Commonly utilized
thresholds for international normalized ratio correction are not supported by evidence.

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 BEST PRACTICE ADVICE 5: Thrombopoietin agonists are a good alternative to platelet
transfusion, but require time (about 10 days) to elevate platelet levels.
 BEST PRACTICE ADVICE 6: The large volume of fresh frozen plasma required to reach an
arbitrary international normalized ratio target, limitations of the usual target, minimal
effect on thrombin generation, and adverse effects on portal pressure limit the utility of this
agent significantly.
 BEST PRACTICE ADVICE 7: The 4-factor prothrombin complex concentrate contains both
pro- and anticoagulant factors that offer an attractive low-volume therapeutic to rebalance
a disturbed hemostatic system. However, dosage is, in part, based on international
normalized ratio, which is problematic in cirrhosis, and published experience in liver disease
is limited.
 BEST PRACTICE ADVICE 8: Anti-fibrinolytic therapy may be considered in patients with
persistent bleeding from mucosal oozing or puncture wound bleeding consistent with
impaired clot integrity. Both ε-aminocaproic acid and tranexamic acid inhibit clot
dissolution. Neither is believed to generate a hypercoagulable state, although both may
exacerbate pre-existing thrombi.

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 BEST PRACTICE ADVICE 9: Desmopressin releases von Willebrand factor as its
primary hemostatic mechanism. As this factor is usually elevated in cirrhosis, the
agent lacks a sound evidence-based foundation, but may be useful in patients with
concomitant renal failure.
 BEST PRACTICE ADVICE 10: Systemic heparin infusion is recommended for
symptomatic deep vein thrombosis and portal and mesenteric vein thrombosis, but
there are unresolved issues regarding monitoring with both the anti-Xa assay and
the partial thromboplastin time due to cirrhosis-related antithrombin deficiency
(heparin cofactor).
 BEST PRACTICE ADVICE 11: Treatment of incidental portal and mesenteric vein
thrombosis depends on estimated impact on transplantation surgical complexity vs
risks of bleeding and falls. Therapy with low-molecular-weight heparin, vitamin K
antagonists, and direct-acting anticoagulants improve portal vein repermeation vs
observation alone.
 BEST PRACTICE ADVICE 12: Direct-acting anticoagulants, such as the factor Xa and
thrombin inhibitors, are relatively safe and effective in stable cirrhotic patients, but
are in need of further study in patients with more advanced liver disease.

44. CONCLUSION
• Cirrhosis represents a unique and complex acquired
coagulopathy that possesses both hypercoagulable
tendency and bleeding risk and exposes the limitations
of currently available laboratory measures in
coagulation.
• Unfortunately a complete global measure of coagulation
does not currently exist.
• The INR is inextricably linked to chronic liver disease by
virtue of its use in the MELD scoring system, yet is a poor
measure of coagulation.
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45. • Global assays, like TGA and viscoelastic testing, hold
promise, but need further validation and testing in
patients with cirrhosis before clinical use becomes
reality.
• As our understanding of the coagulation system in
cirrhosis continues to evolve, studies to understand the
effects of therapy and prophylaxis are needed.
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46. References
• AASLD Guidelines 2019
• Sleisenger and fordtran's gastrointestinal and liver
disease 11th edition
• Sherlock's Disease of The Liver and Billiary System,
13th Edition.
• AGA Clinical Practice Update: Coagulation in
Cirrhosis 2019
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