Coagulation & Liver : Effect of Liver Dysfunction

Hemostasis

• Set of well-regulated processes that accomplish 2 important functions :

1. maintain blood in fluid clot free state in normal vessels 2. induce a rapid & localized haemostatic plug at a site of

vascular injury• Thrombosis : pathologic opposite • Haemostatic system : delicate balance between pro- and

antihaemostatic processes. • Alterations : a bleeding diathesis or thrombotic disorder.

• 3 general components :

1. Vascular wall 2. Platelets 3. Coagulation cascade

NORMAL COAGULATION

There are 3 stages in normal coagulation

• Primary hemostasis is provided by platelets

• Secondary hemostasis is provided by the plasma protein clotting factors, ie, fibrin clot formation

• Tertiary hemostasis is the formation of fibrin polymers and their subsequent resolution through fibrinolysis.

Normal Hemostasis – current insights

Primary haemostasis

• Platelets : crucial role• Produced from megakaryocytes in the bone marrow• Thrombopoietin: - a hormone synthesized by the liver - regulates platelet production

SECONDARY HEMOSTASIS

• loose aggregation of platelets in the temporary plug converted into the definitive clot by FIBRIN

• Fundamental reaction : soluble fibrinogen to insoluble fibrin

• Coagulation cascade :

• Process requires plasma proteins, phospholipids and calcium

System for naming blood-clotting factors

• I Fibrinogen• II Prothrombin• III Thromboplastin• IV Calcium• V labile factor, Proaccelerin• VII Stable factor , Proconvertin• VIII Antihemophilic factor (AHF),

System for naming blood-clotting factors

• IX Christmas factor ,(PTC)• X Stuart-Prower factor• XI Plasma thromboplastin antecedent (PTA)• XII Hageman factor, glass factor• XIII Fibrin-stabilizing factor, Laki-Lorand factor• HMW-K Fitzgerald factor• Pre-Ka Prekallikrein, Fletcher factor• Ka Kallikrein• PL Platelet phospholipid

Secondary hemostasis

Fibrin

Coagulation Pathway

Extrinsic pathway (Tissue factor)

Prothrombin

Thrombin

Fibrinogen

Intrinsic pathway (Contact)

X XaXaXaXa

ThrombinThrombin

Extrinsic pathway

Coagulation cascade

XII

XI

IX

XVIII

Prothrombin (II)

thrombin

fibrinogen fibrin

STABILISED FIBRIN

V, Ca, P/L

VII

Intrinsic pathway

Extrinsic pathway

XIII

APTT

PT

Inhibitors Of Coagulation

1. TFPI2. Antithrombin : - serine protease inhibitor - inactivates thrombin & F IXa, Xa & X1a - Inhibitory action potentiated by heparin / GAG

present on vessel wall3. Heparin cofactor 11(HC11) & Alpha 2

Macroglobulin

Extrinsic pathway

Protein C & S

• Produced by liver• Vitamin K dependent• Inactivates factors V and VIII• Protein C is activated by thrombomodulin-

bound Thrombin (IIa)• Enhancement of Protein C anticoagulant

functions is achieved by Protein S.• Patients with Protein C and/or Protein S

deficiencies have a thrombotic tendency. • Patients also may acquire deficiencies of

Protein C and Protein S with liver disease and disseminated intravascular coagulation (DIC).

Fibrinolysis

• The last stage of coagulation is fibrinolysis , which is the dissolution and localization of a fibrin clot.

• Prevents excessive fibrin deposition

Components: fibrinolysis

• Plasminogen -> plasmin

• Plasminogen activators

• Inactivators of plasminogen

• Inhibitors of plasmin

Fibrinolysis

• Plasminogen is activated and converts to plasmin by factor XII, HMWK,and PK

• Plasmin = enzyme which dissolves fibrin clots into protein fragments that are cleared from plasma by the liver

• Fibrin degradation products are breakdown fragments of fibrin or fibrinogen.

1. The protein fragments are designated X, Y, D, and E

2. Fragments are strong inhibitors of further coagulation by

a. interfering with the action of thrombinb. interfering with platelet aggregation

Fibrinolysis

• Role of thrombin: Inhibits fibrinolysis• 2 mechanisms : 1. Activates FX111- :stabilizes fibrin clot by cross linking : also cross links alpha2 antiplasmin

to the fibrin clot 2. Activate TAFI (Thrombin activatable fibrinolysis

inhibitor) : prevents t PA & plasminogen binding to fibrin

Liver dysfunction & coagulation

Factors contributing to abnormalities of coagulation

• Bleeding Risk : 1. Dec. production of non-endothelial cell- derived coag factors 2. Thrombocytopenia & thrombesthenia 3. Abn. Of fibrinogen 4. Dec. TAFI

Liver dysfunction & coagulation

• Increased Thrombotic risk :

1. Dec. synthesis of Protein C & S2. Dec. Antithrombin levels3. Dec. Plasminogen4. Elevated levels of endothelial cell-derived

Factor VIII & vWF

• Delicate balance between pro & antithrombotic factors reset to a lower level

• Patients not really anticoagulated in stable condition & bleeding may be caused only when additional factors like infection supervene.

• Bleeding Risk :

1. Dec. production of non-endothelial cell- derived coag factors 2. Thrombocytopenia & thrombesthenia 3. Abn. Of fibrinogen 4. Dec. TAFI

HYPOCOAGULABILITY

• Dec. coagulation factors :

1. Vit K dependent facors(II,VII,IX,X): - absolute/ relative

2. dec. fibrinogen, factors V,XI,XII,PK,kininogen

Elevated PT/INR & aPTT

• Bleeding Risk :

1. Dec. production of non-endothelial cell- derived coag factors 2. Thrombocytopenia & thrombesthenia 3. Abn. Of fibrinogen 4. Dec. TAFI

HYPOCOAGULABILITY

• Abnormalities of Platelets

• Causes for thrombocytopenia :1. dec. thrombopoeitin levels(TPO)2. splenic sequestration3. auto-antibody destruction4. bone marrow supression

HYPOCOAGULABILITY

• Platelet Dysfunction

- Platelet –endothelial adhesion dysfunction sub-optimal clot formation

- Corrected by addition of recombinant factor VIIa (in vitro model)

- In Hepatorenal syndrome : platelet dysfunction due to Uremia & changes in vessel wall endothelial fuction

HYPOCOAGULABILITY

• Platelet count & thrombin generation

- Platelets important in potentiating clotting cascade

- Pl. count 50,000-60,000 : adequate thrombin production

- Pl. count > 1,00,000 : optimal thrombin production

• Bleeding Risk :

1. Dec. production of non-endothelial cell- derived coag factors 2. Thrombocytopenia & thrombesthenia 3. Infection 4. Abn. Of fibrinogen 5. Dec. TAFI

• Bleeding Risk :

1. Dec. production of non-endothelial cell- derived coag factors 2. Thrombocytopenia & thrombesthenia 3. Infection 4. Abn. Of fibrinogen 5. Dec. TAFI

• Bleeding Risk :

1. Dec. production of non-endothelial cell- derived coag factors 2. Thrombocytopenia & thrombesthenia 3. Infection 4. Abn. Of fibrinogen 5. Dec. TAFI

• Bleeding Risk :

1. Dec. production of non-endothelial cell- derived coag factors 2. Thrombocytopenia & thrombesthenia 3. Infection 4. Abn. Of fibrinogen 5. Dec. TAFI

HYPOCOAGULABILITY

• Infection & Endogenous heparinoids

- Incidence of infection 30%

- affects platelet function, production & adhesion

- Increase in endogenous Heparinoids: Heparan & Dermatan sulphate

( endothlial dysfn mediated by infection related changes in nitric oxide metabolism)

HYPOCOAGULABILITY

• HYPERFIBRINOLYSIS

- Evidence of systemic fibrinolysis 30-40% CLD pts

- Parallels degree of liver dysfunction

- Clinically evident hyperfibrinolysis less common

HYPERFIBRINOLYSIS

• Mechanism : dysregulation of a complex set of interactiong factors including :

1. t PA2. PAI-1- Neither synthesized in liver- Both have altered clearance in cirrhotics

3. TAFI –Liver synthesized

HYPERFIBRINOLYSIS

• Role in discrete clinical situations:

1. Exacerbating factor in variceal rupture2. Potentiates bleeding following dental

extractions, biliary tree & urinary bladder3. Systemic hyperfibrinolysis : attributed ascitic

fluid fibrinolytic activity4. Liver tx : high levels of t PA in the recipient

may result in hyperfibrinolysis

HYPERCOAGULABILITY

• Increasingly recognized aspect of CLD• Underestimated problem : lack of

measurement tools / reliance on c/l end points(DVT/PVT)

• “Auto-anticoagulation” : unfounded , old dogma

HYPERCOAGULABILITY

• Reduction in procoagulant factors, (reflected in a prolonged PT & INR), offset by decreased levels of anticoagulant factors( Protein C&S, Antithrombin) of potentially equal or greater magnitude

• Increased endothelium-derived procoagulant factors : F VIII & vWF( due to c/c inflammatory state)

Liver dysfunction & coagulation

• Increased Thrombotic risk

1. Dec. synthesis of Protein C & S2. Dec. Antithrombin levels3. Dec. Plasminogen4. Elevated levels of endothelial cell-derived

Factor VIII & vWF

Hypercoagulability & Complications.

• Macro-thrombotic complications : include portal vein thrombosis, deep vein thrombosis, and pulmonary embolism

• Micro-thrombotic complications :- subtle and typically run a chronic course- Parenchymal extinction : Liver atrophy, severe decompensated

cirrhosis- Platelet aggregation and activation in these microscopic lesions

may also contribute to fibrosis and possibly to thrombocytopenia.- lung microvasculature :portopulmonary hypertension.; important

ramifications in transplant eligibility, outcomes and survival

Fibrinogen

• acute-phase reactant: remains normal or increased in patients with liver disease

• Low concentrations due to decreased synthesis( yet above 100mg/dL) are only seen with very severe liver disease

• high fibrinogen concentrations: chronic hepatitis, cholestatic jaundice and hepatocellular carcinoma

- does not result in increased clot formation - most is a non-functional fibrinogen

COAGULOPATHY IN ACUTE LIVER FAILURE

• Diagnostic criteria of acute liver failure (ALF)

1. clinically evident hepatic encephalopathy

2. laboratory evidence of coagulopathy (usually prolongation of the PT and/or INR)

- within 24 weeks of the new onset of acute liver disease with no history of prior liver abnormalities.

COAGULOPATHY IN ACUTE LIVER FAILURE

• Prolongation of the PT and INR : due to impaired synthesis of coagulation factors especially factors VII and V.

• Half-life of factor V -36 hours ,factor VII -4 to 6 hours. • Relatively rapid depletion of these factors and prolongation of the

PT and the INR. • ? Increased bleeding• When present, bleeding is usually limited to capillary and mucosal

bleeding • Although this may be relatively minor, the need for multiple

invasive procedures increases the concern regarding iatrogenic bleeding.

• Because of prolongation of the PT and INR, patients with ALF may be treated with fresh frozen plasma (FFP), especially prior to invasive procedures

• high INR values may require a significant volume of FFP• large volumes of plasma may worsen body edema and

intracranial hypertension • recombinant activated factor VII (rFVIIa) has become a

conventional means of correcting the INR

TESTS OF COAGULATION IN LIVER DISEASE

• Prothrombin time (PT) - assess the extrinsic pathway of clotting: tissue

factor and factor VII- common pathway (prothrombin (factor II),

factors V and X, and fibrinogen)- vitamin K-dependent factors

TESTS OF COAGULATION IN LIVER DISEASE

• Platelet level and function- quantitative measurement of circulating

platelets- platelet function : - Clot Signature Analyzer, the Thrombotic Status Analyzer, and the Platelet Function Analyzer - measure platelet plug formation within capillary tubes- ? relevance to bleeding in patients with

cirrhosis

TESTS OF COAGULATION IN LIVER DISEASE

• Bleeding time in cirrhosis- indirect measure of platelet function- variably reported as being prolonged in

cirrhosis- Test results and the range of normal values

are very user dependent

• Fibrinogen and individual factor levels

• Factor VIII levels : - distinguish superimposed DIC from liver failure. - DIC : severely decreased factor VIII levels - liver failure : significantly increased levels.

• Factor V and VII levels ; - used prognostically in acute liver failure - distinguish vitamin K deficiency from liver failure - liver failure : Proportional reduction in both factors - vitamin K deficiency: greater reduction in factor VII than in factor

V

• Fibrinogen levels : - guides use of fibrinogen-rich cryoprecipitate, as - levels below 120 mg/dL : diminished clot formation and resistance to procoagulants such as recombinant factor VIIa

• Dysfibrinogenemia : - fibrin clot formation, thrombin time, reptilase time, and fibrinogen clotting activity-antigen ratio - not widely available - significance of dysfibrinogenemia in liver disease has not been fully established

• Thromboelastography and thromboelastometry  - functional measures of clot formation and stability in whole blood samples• Thromboelastography (TEG) : measurement of torque on a pin

as a cup containing whole blood is rotated at a constant rate. As clot formation begins, the torque increases, and then with clot breakdown from fibrinolysis, the torque decreases

• Thromboelastometry (ROTEM) : similar to the TEG but involves a stationary cup and rotating pin.

- Both assays detect dynamic aspects of clot formation and lysis

Liver dysfunction & coagulation

• Liver derangement is accompanied by multiple changes in the haemostatic system:

1. Reduced plasma levels of proteins involved in haemostasis : majority synthesized by the liver

2. Reduced clearance : activated haemostatic proteins or protein-inhibitor complexes from the circulation.

3. Platelets: number and function can be affected 4. decreased levels of anticoagulant factors

The global effect of liver disease with regard to hemostasis is complex, so that patients with advanced liver disease can experience severe bleeding or thrombotic complications