Anticoagulation in patients with liver cirrhosis copy

Anticoagulant in Liver Cirrhosis

By

Mohamed Abdel Ghani SolimanDemonstrator of Tropical Medicine

Assiut University

The liver

& haemostasis

Coagulation factors

Anticoagulant proteins

Fibrinolyticsystem

Clearing coagulation

factors

Introduction

Ascites

Spontaneous bacterial

peritonitis

Variceal bleeding

Hepatic encephalopathy

Hepatorenalsyndrome

Hematologic abnormalities. Hematologic

abnormalities.

The aetiology of impairedhaemostasis in liver disease ismultifactorial and may include:

– Impaired coagulation factor synthesis.

– Synthesis of dysfunctional coagulationfactors.

– Increased consumption of coagulationfactors.

– Altered clearance of activatedcoagulation factors.

– Quantitative and qualitative plateletdisorders.

• Impaired prothrombin time in

cirrhotic patients has led to a

theory of "autoanticoagulation"

Should we give thromboprophylaxisto patients with liver cirrhosis and coagulopathy?

Our Topics:

• Physiology of haemostasis.

• The liver & the haemostatic system.

• Cirrhosis & haematological changes

– Bleeding VS Thrombosis.

• Anticoagulant in liver disease.

Physiology of haemostasis

Hemostasis is a cellular process withthe activated platelet as the primaryeffector and enabler of coagulation.

The structure of a clot is a plateletplug restrained by a fibrin meshformed by the conversion offibrinogen to fibrin by the enzymethrombin.

Tripodi, et al. Abnormalities of hemostasis and bleeding in chronic liver disease. Intern Emerg Med 2010.

The process involves 3 phases:

Primary hemostasis

by activated platelets.

Seconaryhemostasis

Coagulation, fibrin mesh construction, and clot fortification by the plasma

procoagulant proteins.

Fibrinolysis by plasma anticoagulant proteins.

Virchow’s Triad

Platelet Activation and Factors for Clot Formationhttps://www.youtube.com/watch?v=R8JMfbYW2p4

Coagulation Cascade Animationhttps://www.youtube.com/watch?v=cy3a__OOa2M

https://www.youtube.com/watch?v=R8JMfbYW2p4

https://www.youtube.com/watch?v=cy3a__OOa2M

Intrinsic pathway

Externsicpathway

X Xa

Fibrinogen Fibrin

Prothrombin Thrombin

AntithrombinIII

Degradation

Plasmin

Plasminogen

tPA

Primary Hemostasis Coagulation: Extrinsic and

Intrinsic Pathway

Fibrinolysis

ComponentActivated 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

HEMOSTASIS IN

CHRONIC LIVER DISEASE

Haemostatic abnormality Mechanism

Quantitative and qualitative platelet defects:

ThrombocytopeniaThrombocytopathies

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


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 naturalanticoagulant proteinsantithrombin (AT), proteins C, S and Z

Decreased clearance of activatedcoagulation factors


Dysfibrinogenaemia

Hyperfibrinolysis

Synthesis of abnormal fibrinogen

Increased levels of circulating tPAactivity due to impaired hepatic clearance

Decreased synthesis of fibrinolyticinhibitors (PAI-1 and a2-antiplasmin)

Decreased thrombin-activatablefibrinolytic inhibitor (TAFI)

Portal Vein Thrombosis

Prevalence of portal vein thrombosis:

• Lower than 1% in compensated cirrhosis.

• (10%–25%) of candidate for liver transplant.

Local Risk Factors for Portal Vein Thrombosis

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 .

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).


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.

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.

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.

Bleeding Thrombosis

Decrease level of ADAMTS 13

Elevated level of vWF

Platelet function defect

Thrombocytopenia

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

Should we give thromboprophylaxisto patients with liver cirrhosis and coagulopathy?

Intrinsic pathway

Externsicpathway

X Xa

Fibrinogen Fibrin

Prothrombin Thrombin

AntithrombinIII

Degradation

Plasmin

Plasminogen

tPA

AntithrombinIII

Xa

Thrombin

HEPARINS

Unfractionated heparin

Inhibits thrombin by accelerating the activity of antithrombin.

Dose of heparinTreatment: 80 units/kg IV bolus (if desired)

then 18 units/kg/hr IV infusion. Check aPTT6 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).

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

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 failureExtreme weightsPregnancyRecurrent thromboses on therapeutic doses

Warfarin (Coumadin®)

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.

Warfarin (Coumadin®)

Management of Some Common Clinical Issues Related to

Coagulation in Liver Disease

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

PVT

Acute or subacute PVT can betreated with therapeuticanticoagulation (LMWH) and mayprolong survival in these patients.

Esophageal varices should betreated aggressively endoscopicallybefore anticoagulation.

PATRICK , et al. Coagulation in Liver Disease: A Guide for the Clinician. CLINICAL GASTROENTEROLOGY AND HEPATOLOGY (2013).

Currently available VKAs have a verynarrow therapeutic window incirrhosis patients and are problematicin patients with baseline elevated INR.

Patients with chronic PVT andcavernous transformation are less likelyto benefit from anticoagulation.

Premature discontinuation ofanticoagulation (before transplant) islikely to result in thrombus recurrence.


Deep vein thrombosis orpulmonary embolus

Consider medical prophylaxis in allhospitalized cirrhosis patients aswith any medical inpatient.

Medical therapy for acute VTEshould be with LMWH in therapeuticdoses similar to PVT treatmentunless contraindicated.


Do not assume the hospitalizedcirrhosis patient is “auto-anticoagulated” because the INR iselevated.

Presence of nonbleeding esophagealvarices should not preclude VTEprophylaxis.


Performance of invasiveprocedures

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.


Treat underlying disordersaggressively before electiveprocedures (infection, renal failure,etc).

Intranasal Desmopressin Acetate(DDAVP®) may be an effective andeconomical alternative prophylacticmeasure in procedures such as dentalextractions.


Do not use a moderately elevatedINR (3) as a measure of proceduralbleeding risk.

Avoid using FFP for prophylaxis, butif used, consider adequate dosing toreplace factors is 20–40 mL/kg .


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

CONCLUSION

• The liver plays major role inhemostasis.

• Liver disease affect all phases ofhaemostasis.

• Auto-anticoagulated.

• Rebalancing

• INR as single test doesn’tdetermine the true state ofcoagulation

CONCLUSION

• Consider the use ofthromboprophylaxis in cirrhoticpatients if there is a risk forthrombosis.

• There is a need to revise theguidelines regarding anticoagulationin this special population.

CONCLUSION

We suffers from a lack of accurate,reliable, and clinically availabletesting methods to properly assessthe true state of hemostasis.

Because some patients with chronicliver disease are predisposed forbleeding, some for hypercoagulation,and some in a stable balance.

Health & Medicine

Anticoagulation in patients with liver cirrhosis copy