Effect of chronic liver diseases on coagulation, rebalanced haemostasis and transfusion management

2. DIPLOMA IN TRANSFUSION MEDICINE
EXAMINATION 2018
8. A 48 year old male, known alcoholic is awaiting surgery for obstructed
inguinal hernia
• FBC
• Hb – 9.8g/dL
• Platelets – 80x106/L
• WBC – 7x109/L
• Coagulation screen
• PT – 22s
• INR – 2.2
• aPTT – 43s
• USS abdomen – mildly enlarged liver and spleen
• All the other investigations are normal. He has no history of any other
medical or surgical problems

3. DIPLOMA IN TRANSFUSION MEDICINE
EXAMINATION 2018
8.1 – Comment with reasons on the following transfusions for
this patient
8.1.1 Red cell concentrates 25 marks
8.1.2 Platelet concentrates 25 marks
8.1.3 Plasma components 25 marks
8.2 – What measures would you take to minimize the
transfusion need for this patient 25 marks

4. LIVER DISEASE,
COAGULOPATHIES AND
TRANSFUSION THERAPY
DR. G.D.A. SAMARANAYAKA
REGISTRAR IN TRANSFUSION MEDICINE
NATIONAL BLOOD TRANSFUSION SERVICE

5. INTRODUCTION
• Chronic liver disease and acute liver failure - changes of
the hemostatic profile
• Historically, these changes were interpreted as
predisposing for a bleeding tendency
• Prophylactic transfusions prior to invasive procedures
with the aim of reducing the bleeding risk
• With novel insights - prophylactic use of blood products
may paradoxically contribute to bleeding rather than
prevent it

6. COAGULATION AND ANTICOAGULATION

8. EFFECTS OF LIVER DISEASE ON
COAGULATION
• Primary haemostasis
• Secondary haemostasis
• Anticoagulants
• Fibrinolysis

9. PRIMARY HEMOSTASIS
• Platelet number and function - adversely
affected
• Mild to moderate thrombocytopenia - in
76% of patients with cirrhotic liver
disease
• Platelet sequestration due to congestive
splenomegaly - portal hypertension
• Platelet counts correlate inversely with
spleen size in some but not all studies
• Impaired platelet production - bone
marrow suppression
• Antiviral therapy
• Alcohol
• Folate deficiency

10. PRIMARY HEMOSTASIS
• Impaired hepatic synthesis of thrombopoietin
• primary physiologic regulator of platelet production – thrombocytopenia
• Platelet consumption increases
• Hypersplenism” reflects an exaggeration of the normal function of splenic
macrophages to remove senescent cells
• Immune-mediated platelet destruction - hepatitis C and primary biliary cirrhosis
• Cirrhosis related hypercoagulability resulting in platelet activation - possibly
triggered by oxidative stress
• Decline in ADAMTS13 – less cleavage of HMW vWF multimers
• vWF levels are markedly elevated
• Reduced clearance from liver
• counteract - thrombocytopenia and platelet dysfunction.
• high VWF levels - restore platelet adhesion to the subendothelium

11. SECONDARY HAEMOSTASIS
• Liver parenchymal cells - all of the coagulation factors except for
FVIII
• FVIII - synthesized by the hepatic endothelium and extrahepatic
endothelial cells
• Chronic liver disease - reduced synthesis of procoagulant proteins
(FII, FV, FVII, FIX, FX, and FXI)
• Factor levels usually fall in parallel with the progression of liver
disease
• loss of function of the failing liver
• ongoing low-grade intravascular or intrahepatic activation of
coagulation

12. SECONDARY HAEMOSTASIS
• Fibrinogen levels are normal or
increased in most patients with
stable cirrhosis
• An acquired dysfibrinogenemia -
50%- 78% of patients with chronic
liver disease
• Regenerating hepatocytes
synthesize an abnormal fibrinogen -
impair polymerization of fibrin
monomers.
• FVIII levels are often increased
• increased synthesis – by cytokine
release from necrotic tissue
• reduced clearance due to impaired
hepatic function

13. ANTICOAGULATION
• Natural anticoagulant protein levels
fall progressively with increasing
severity of liver disease
• Antithrombin, protein C and protein
S - 10% to 65% of normal
• Tissue factor pathway inhibitor
(TFPI) - synthesized by endothelial
cells.
• TFPI - normal or elevated in patients
with chronic liver disease.
• However, TPFI anticoagulant
pathway is functionally impaired by
low levels of protein S

14. FIBRINOLYSIS
• All of the profibrinolytic and antifibrinolytic proteins are synthesized by
the liver except tissue plasminogen activator (tPA) and PAI-1
• PAI-1 is produced by a variety of sources including adipose tissue –
normal or increased
• Levels of plasminogen, 2antiplasmin, thrombin-activatable fibrinolysis
inhibitor (TAFI), and FXIII levels are often reduced
• In contrast, plasma levels of tPA are usually elevated due to release by
activated endothelial cells and reduced hepatic clearance
• Parallel changes in profibrinolytic and antifibrinolytic proteins –
rebalanced fibrinolysis
• Hyperfibrinolysis
• shift the balance between profibrinolytic and antifibrinolytic factors.
• triggered by additional insults - surgery or sepsis

15. REBALANCED HEMOSTASIS
• Hemostatic alterations that occur result in
a new balance within and between
procoagulant, anticoagulant and
fibrinolytic systems
• Relative deficiency of procoagulant and
anticoagulant factors
• hemostatic balance is more precarious
• may tip toward bleeding or thrombosis
depending on provoking circumstantial risk
factors.

18. LABORATORY TESTS

19. PREDICTION OF BLEEDING –
CONVENTIONAL TESTS
• PT/INR and aPTT do not reliably predict the risk of bleeding
• They do not fully reflect the derangement in hemostasis
• Do not reflect the reduction in anticoagulant factors
• Do not reflect complex interactions between cells and coagulation factors in
whole blood.
• Do not measure clot strength and stability - endpoint of these tests is the
initiation of fibrin polymerization, which occurs at very low levels of thrombin
generation.
• There is no evidence that a prolonged PT/INR predicts bleeding at the
time of invasive diagnostic procedures.
• Association for the Study of Liver Disease (ASSLD) Practice Guidelines
for liver biopsy - there is no specific PT/INR cutoff at or above which
bleeding complications can be reliably predicted

20. PREDICTION OF BLEEDING
• Platelet count is a better predictor of bleeding than the INR.
• In several studies, a platelet count 60 000-75 000 was
associated with a significantly increased rate of post-
procedure bleeding
• However, a threshold platelet count below which the
bleeding risk clearly increases has not been defined.

21. GLOBAL COAGULATION ASSAYS
• Global coagulation assays reflect the interaction between
procoagulants, natural anticoagulants, platelets, and the
fibrinolytic system.
• Thrombin generation assays
• Viscoelastic tests

22. THROMBIN GENERATION TESTS
• Thrombin generation tests (TGT) dynamically measure the total amount of
thrombin generated during in vitro coagulation.
• Vs PT and aPTT - measure the time it takes to form a plasma clot.
• In the presence of thrombomodulin, the primary physiologic activator of protein
C, the TGT measures the balance between procoagulant and anticoagulant
factors in liver disease.
• TGT is still primarily a research tool and not validated for predicting bleeding risk
• It has been shows despite a prolonged PT and APTT in LD pts - generate
thrombin at a normal to increased rate

23. VISCOELASTIC TESTS
• Thromboelastography (TEG, Hemonetics Corporation, Braintree, MA)
• Thrombelastometry (ROTEM, TEM International GmbH, Munich, Germany)
• ReoRox (Medirox)
• Analyze all components of hemostasis
• the dynamics of clot formation (balance of procoagulant and anticoagulant factors)
• clot strength (platelets and fibrinogen)
• clot stability (fibrinolysis and FXIII).
• Widely used during liver transplantation to guide transfusion, coagulation factor
replacement, and antifibrinolytic therapy.

25. MANAGEMENT AND
PREVENTION OF
BLEEDING

26. PATHOPHYSIOLOGY
• Bleeding complications in chronic liver disease are infrequently related
to abnormal hemostasis.
• Esophageal varices - 25% to 35% of patients with cirrhosis
• Accounts for 80% to 90% of bleeding
• Most of clinically significant bleeding episodes -> rupture of varices
• Portal hypertension
• Local vascular abnormalities
• Rebalanced hemostasis in patients with liver disease is potentially
unstable
• Tipped toward hemorrhage by
• progression of portal hypertension
• renal failure
• infection

28. MANAGEMENT BASICS

29. MANAGEMENT BASICS
• Watchful waiting is superior to preventive correction of
laboratory tests.
• Treat bleeding (using blood components/drugs) due to
problems in haemostasis (vs surgical bleeding)
• multiple simultaneous bleeding sites
• persistent oozing from a nonidentifiable source
• delayed bleeding after adequate hemostasis

30. MANAGEMENT BASICS
• In portal hypertension
• pooling of blood on the venous side of the circulation
• arterial hypotension.
• Additional fluid -> venous overload
• Therefore maintain a low splanchnic and portal pressure and a low total
circulating volume
• Use CVP as a guide. Maintain low CVP but with sufficient tissue perfusion.
• Adequate surveillance for and treatment of infections before invasive
procedures is recommended.
• Anesthetists should maintain
• Normothermia
• free ionized calcium - regularly and corrected to at least 1 mmol/L
• acid-base balance - acidosis impairs clot formation and reduces clot strength

31. PREVENTION OF
BLEEDING

32. VITAMIN K
• Patients with cirrhosis and abnormal coagulation screening
tests - often receive vitamin K despite a lack of evidence
supporting benefit.
• Correct abnormal coagulation tests in patients at high risk
for deficiency due to biliary disease or gut sterilization from
broad-spectrum antibiotics.
• In cirrhotic patients with reduced synthetic function, the
benefit of vitamin K is uncertain.

33. FFP
• Often used for prophylaxis prior to invasive procedures in patients with cirrhosis
despite the absence of clinical trials demonstrating benefit.
• Minimal effect on a mildly prolonged INR.
• In cirrhosis - despite prolonged routine coagulation tests – normal thrombin
generation – prophylactic FFP infusion has no clinical benefit
• 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).
• large volumes of FFP required to significantly increase clotting factor levels
• volume overload and exacerbation of portal hypertension - increasing the risk of bleeding.
• Prophylactic infusion of FFP may also delay procedures and expose patients to
unnecessary risks.

34. PLATELETS
• No consensus on the threshold platelet count for prophylactic
transfusion
• In vitro studies - severe thrombocytopenia may limit thrombin
generation
• AASLD guidelines for liver biopsy – platelet count <50 000-60 000 -
consider platelet transfusion prophylactically
• However – no studies demonstrating that prophylactic platelet
transfusions reduce the risk of bleeding associated with invasive
procedures.
• Prophylactic platelet transfusions do not ensure adequate hemostasis.

35. THROMBOPOIETIN RECEPTOR AGONISTS
• Romiplostim, eltrombopag, avatrombopag
• Rationale
• Chronic liver disease - reduced TPO
production and activity
• TPO R - increase platelet production.
• Termination of trials with eltrombopag –
due to increased portal vein thrombosis
• Additional trials are necessary before TPO-
R agonists can be routinely recommended

36. MANAGEMENT OF
BLEEDING

37. ACTIVE BLEEDING MANAGEMENT
• For acute variceal bleeding
• Vasoconstrictors
• vasopressin or its analog
terlipressin
• somatostatin
• Endoscopic therapy
• Ligation (EVL)
• endoscopic injection
sclerotherapy (EIS)

38. TRANSFUSION
• Restrictive transfusion policy – improve control of variceal bleeding
• Over transfusion (RCC, FFP) – increased intravascular – increased portal pressure
• RCC transfusion – Target HB 7-8g/dL
• Platelet transfusion – for thrombocytopenia with active bleeding – maintained
>50 000 during acute bleeding
• Poor platelet increment
• hypersplenism
• active bleeding
• coexistent infection
• Cryoprecipitate - fibrinogen level >100 is usually recommended although a
threshold hemostatic fibrinogen level is also not well defined.
• No evidence that prophylactic plasma or platelet transfusions reduce the risk of
re-bleeding in patients with varices.

39. RECOMBINANT FACTOR VIIA
• rFVIIa normalizes a prolonged PT/INR - but no evidence it reduces
bleeding.
• A Cochrane systematic analysis also found that rFVIIa did not reduce
mortality in patients with liver disease and upper GI bleeding
• rFVIIa is not approved for use in liver disease and off-label use is
associated with an increased risk of arterial thromboembolism.
• Could be used in uncontrolled bleeding requiring urgent control – risk vs
benefit

40. PROTHROMBIN COMPLEX
CONCENTRATES
• Three factor PCC
• very low concentration of FVII
• Little or no protein C and S
• Four factor PCC – II, VII, IX, X and Protein C and S
• Advantages over FFP
• smaller volume with a 25-fold higher concentration of coagulation factors
• rapid correction of hemostatic parameters.
• However there is no evidence that administration of PCC as adjunctive
or rescue therapy in cirrhotic patients with active bleeding improves
outcome.
• PCC may increase thrombotic risk in patients with liver disease.
• Not recommended to use routinely for bleeding

41. DESMOPRESSIN
• stimulates the release of von Willebrand factor (vWF) from the Weibel–
Palade bodies of endothelial cells
• No evidence that desmopressin improves control of bleeding or clinical
outcome in patients with variceal bleeding.
• DDAVP may have minimal hemostatic benefit in cirrhotic patients with
elevated baseline VWF and FVIII levels

42. ANTIFIBRINOLYTIC AGENTS
• Antifibrinolytic agents (ex:-tranexamic acid) - reduce blood loss during
liver transplantation
• Currently insufficient evidence to support the routine use of tranexamic
acid in the setting of acute variceal hemorrhage or other bleeding.
• HALT-IT (hemorrhagic alleviation with tranexamic acid-intestinal system)
trial is investigating the effectiveness and safety of tranexamic acid in
patients with GI bleeding

43. MANAGEMENT OF
THROMBOSIS

44. THROMBOSIS
• Incorrectly assumed that patients with liver disease are auto-
anticoagulated and therefore protected against thrombotic
complications
• Portal vein thrombosis – 8-26%
• Some studies - risk of venous thrombosis is significantly higher in
patients with liver disease as compared with individuals without liver
disease
• Incidence of thrombosis in liver disease may be underreported
• symptoms of DVT/pulmonary embolism are nonspecific
• clinicians may be less attentive to the possibility of thrombosis in this group of
(critically ill) patients.
• Thrombosis prevention schemes related to immobilization or invasive
procedures should not be withheld from the patients with cirrhosis and
abnormal coagulation test results

45. MANAGEMENT
• Using anticoagulant drugs - complicated
• Anticoagulant potency of LMWH appears to be increased in patients
with liver disease
• anti-Xa assay underestimates the true LMWH mass in patients
• Already increased INR – unclear optimal target
• Currently no evidence-based guidelines or target ranges for the various
anticoagulant drugs
• Patients who are operated on under low CVP, physiological blood
pressure must be restored postop
• low flow of blood - risk factor for thrombosis (Virchow triad)

46. CONCLUSION
• Rebalanced haemostasis in chronic liver diseases.
• Fragile
• may be perturbed by various causes – renal failure, infections
• Platelet count, PT, and APTT are poor predictors of bleeding risk
• prophylactic correction of these parameters does not reduce bleeding.
• Blood products - severe adverse effects may cause bleeding by
increasing volume load.
• Global assays of hemostasis better for assessing bleeding risk and
guiding therapy
• but high quality data validating their use is still lacking.

47. REFERENCES

48. THANK YOU