la coagulazione nel cirrotico: mito o realtà? - gastrolearning®

A.TRIPODI

La Coagulazione nel Cirrotico: Mito e Realtà

Prof. Armando TripodiAngelo Bianchi Bonomi

Hemophilia and Thrombosis CenterDept. of Clinical Sciences and Community Health

University of Milano

La coagulazione nel cirrotico: mito o realtà?

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Alteration of Hemostasis in CirrhosisPotential Implicated Mechanisms

•Primary Hemostasis

• Fibrinolysis

• Coagulation

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Dual Role of Platelets in Hemostasis

•Primary hemostasis Adhesion to the subendothelium

Aggregation one another

•Coagulation Support thrombin generation

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vWF

High levels of VWF in cirrhosis

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Alteration of Hemostasis in CirrhosisPotential Implicated Mechanisms

• Primary Hemostasis

•Fibrinolysis • Coagulation

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Fibrinolysis in CirrhosisBackground

• Cirrhosis is characterized by hyperfibrinolysis (?)

• This complex defect can be documented in plasma through global fibrinolytic tests or through the measurement of individual components

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Cirrhosis and Fibrinolysis

• Decreased levels

Plasminogen

- Anti-plasmin

- FXIII

- TAFI

• Increased levels

- tPA

- PAI-1

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Hyperfibrinolysis and Cirrhosis

• Deficiency of TAFI in cirrhotics is not associated with increased plasma fibrinolysis

Lisman T et al. Gastroenterology 2001; 121: 131

• Deficiency of TAFI in cirrhotics is associated with increased plasma fibrinolysis

Colucci M, et al, Hepatology 2003; 38: 230

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Alteration of Hemostasis in CirrhosisPotential Implicated Mechanisms

• Primary Hemostasis

• Fibrinolysis

•Coagulation

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Coagulation in Chronic Liver DiseaseThe Facts….

• Cirrhosis is characterized by an impaired synthesis of all clotting factors (except FVIII and VWF)

• This complex defect has historically been documented through the prolongation of PT & APTT

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Coagulation in Chronic Liver DiseaseThe Dogma…

• The concept of a causal relationship between abnormal coagulation and bleeding is widely accepted

• Common practice of screening patients with hemostasis tests

• Treating patients with abnormal values in order to correct the identified abnormalities prior to liver biopsy

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Te Challenge of the Dogma (1)

• Liver transplantation was initially associated with dramatic transfusion requirements

but…

• The need of transfusion declined dramatically in the last 20 years, despite no major change in medication

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Transplantation 2008; 85: 956

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Te Challenge of the Dogma (2)

Conventional hemostasis tests do correlate poorly with gastrointestinal bleeding or after

biopsy

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Poor Correlation between Global Conventional Hemostasis Tests and Bleeding

Review of the Literature

• Ewe K. Dig Dis Sci 1981; 26; 388• Segal JB & Dzik WH. Transfusion 2005; 45:1413• Boks AL, et al. Hepatology 1986; 6: 79• Diaz LK &Teruya J. New Engl J Med 2001;344:2030• Grabau CM et al. Hepatology 2004;40:484• Terjung B et al. Digestion 2003; 67: 138• Mc Gill DB et al. Gastroenterology 1990; 99: 1396 • Vieira da Rocha E et al.Clin Gastroenterology and

Hepatol 2009; 7: 988    

A.TRIPODI Ewe, 1981

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Why Conventional Coagulation Tests do not Correlate with Bleeding in

Cirrhosis ?

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Coagulation in Liver DiseaseConsiderations on the value of PT &

APTT• PT & APTT might be inadequate to reflect the

coagulation balance as it occurs in vivo especially in cirrhosis

- Protein C and antithrombin are reduced in cirrhosis

- Protein C in vitro is activated to a limited extent in the absence of thrombomodulin

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PROTEIN C is activated by THROMBIN

VaVIIIa

ViVIIIi

PSAPC

membraneTM

T PC

PC

T

EPCR

APC

EPCR

PS

It should be noted that plasma and reagents needed to perform PT & APTT do not contain TM

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PT & APTT are responsive only toprocoagulant factors

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…and much less to the anticoagulantfactors

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PT & APTT as Tools to Investigate the Balance of Coagulation

• PT & APTT can tell us whether a patient is deficient in one (or more) pro-coagulants

• ….but not whether this deficiency is counterbalanced by a concomitant deficiency of the anti-coagulants

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0

100

200

300

400

500

600

700T

hro

mb

in G

ener

atio

n E

TP

(F

UX

min

)

withoutthrombomodulin

Controls Cirrhotics

withthrombomodulin

Controls Cirrhotics

Platelet-free PlasmaTripodi et al, Hepatology 2005; 41: 553

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Thrombin Generation in Platelet-free Plasmas

Summary of findings • Plasma coagulation is not abnormal in cirrhosis when

assessed with global tests reflecting the function of both pro- and anti-coagulants

• The findings question

- The usefulness of traditional coagulation tests in assessing hemorrhagic risk in cirrhosis

- And the use of procoagulant agents to correct the coagulopathy

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Poor Efficacy of Activated FVII to Stop Bleeding in Cirrhosis

• Bosch J et al, 2004

• Lodge JP et al, 2005

• Planinsic RM et al, 2005

• Bosch J et al, 2008

Platelets & Thrombin Generation

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0

500

1,000

1,500

2,000

2,500

3,000

3,500

ET

P (

Th

rom

bin

) n

M X

min

Controls Cirrhotics

Without Thrombomodulin

P<0.001

1,965

1,365

Controls Cirrhotics

With Thrombomodulin

N.S.

1,140 1,117

Platelet-Rich Plasma (Plt.s count adjusted to 100,000/L)

Tripodi et al, Hepatology 2006

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0

500

1,000

1,500

2,000

2,500

3,000

3,500

ET

P (

Th

rom

bin

) n

M X

min

Without Thrombomodulin

Controls Cirrhotics

P<0.001

1,919

1,280

Controls Cirrhotics

With Thrombomodulin

P<0.001

1,221

929

Platelet-Rich Plasma(Plt.s adjusted to the original patient’s count)

Tripodi et al, Hepatology 2006

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0

500

1000

1500

2000

2500

0 100 200 300

Platelet numbers (X 109/L)

ET

P (

thro

mb

in)

nM

Rho=0.50, p<.001

60

Thrombin Generation and Platelet Numbers

Tripodi et alHepatology, 2006

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Thrombin Generation in Platelet-Rich Plasma

Summary of Findings

• Platelets from cirrhotics are qualitatively suitable to support thrombin generation

• The numbers of platelets in cirrhosis might be the limiting factor for thrombin generation

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Why do Patients with Cirrhosis Occasionally Bleed?

• The “restored” hemostatic balance in cirrhosis may not be as stable as in healthy individuals and, therefore, slight alterations may lead to hemorrhage or thrombosis

• Conditions underlying bleeding

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Conditions Underlying Bleeding in Cirrhosis

• Portal Hypertension

• Endothelial dysfunction

• Bacterial infections

• Renal failure

Therapeutic interventions correcting these abnormalities might be more effective

than correcting coagulopathy

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The Balance of Hemostasis

Healthy subjectExcess pro- &anti-coagulants

CirrhosisRelative deficit pro-

& anti-coagulants

Hemorrhage Thrombosis

A.TRIPODI Am J Gastroenterol 2006;101:1524

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Am J Gastroenterol 2009; 104: 96

These observations suggest a procoagulant imbalance

in plasma from patients with cirrhosis

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Is there any biomarker to identify the procoagulant imbalance in cirrhosis?

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0

100

200

300

400

500

600

700

ET

P (

FU

Xm

in)

58% Difference

32% Difference

A.Tripodi et al, Hepatology 2005

Controls

No TM

450

TM

200

Cirrhotics

No TM

300

TM

210

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0

100

200

300

400

500

600

700

ET

P (

FU

Xm

in)

200/450 = 0.44 210/300 = 0.70

A.Tripodi et al, Hepatology 2005

Controls

No TM

450

TM

200

Cirrhotics

No TM

300

TM

210

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Study on the Procoagulant Imbalance in Cirrhosis

•Aim of the Study- To detect biochemical signs of

procoagulant imbalance

•Laboratory tools- Measurement of pro- and anti-coagulants

- Measurement of thrombin generation assessed as ratio of values with/without thrombomodulin

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Case Material

•Patients- 134 patients with cirrhosis with graded

severity according to the Child-Pugh score

•Controls - 131 healthy subjects matched for age

and gender to the patients

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Results

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Pro-coagulants Anti-coagulants

Pro-coagulant Drivers in Cirrhosis

A.TRIPODI et al, Gastroenterology 2009

Healthysubjects

CHILDA

CHILDB

CHILDC

0

100

150

Fac

tor

II (

%)

50

p < 0.001

p < 0.001

Factor II

A.TRIPODI et al, Gastroenterology 2009

p < 0.001

Healthysubjects

CHILDA

CHILDB

CHILDC

0

300

Fac

tor

VII

I (%

)

200

100

p = 0.02

Factor VIII

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Pro-coagulantsAnti-

coagula

nts

Anti-coagulant Drivers in Cirrhosis

A.TRIPODI et al, Gastroenterology 2009

Healthysubjects

CHILDA

CHILDB

CHILDC

Protein Cdeficiency

0

50

150

Pro

tein

C (

%)

100

p < 0.001

p < 0.001

p = 0.03

Protein C

A.TRIPODI et al, Gastroenterology 2009

Healthysubjects

CHILDA

CHILDB

CHILDC

0

40

100

120

An

tith

rom

bin

(%

)

60

80

20

p < 0.001

p < 0.001

Antithrombin

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Pro-coagulants Anti-co

agulants

Balance of Pro- vs Anti-coagulant Drivers in Cirrhosis

Assessed as ratio of thrombin generation

with/without thrombomodulin

A.TRIPODI et al, Gastroenterology 2009

0.0

0.4

1.0

1.2

Rat

io E

TP

(w

ith/w

ithou

t th

rom

bom

odul

in)

0.6

0.8

0.2

Healthysubjects

CHILDA

CHILDB

CHILDC

Protein Cdeficiency

p < 0.001

p = 0.03

Ratio of thrombin generation (with/without TM)

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Summary of Findings

• Cirrhotics present with significantly higher ratios of thrombin generation with/without thrombomodulin than controls

• These ratios increase progressively from Child A to Child C

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….how can this procoagulant imbalance be explained?

A.TRIPODI et al, Gastroenterology 2009

Healthysubjects

CHILDA

CHILDB

CHILDC

0

5

15

10R

atio

(F

acto

r V

III/

Pro

tein

C)

p < 0.001

p < 0.001Ratio FVIII/protein C

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Summary of findings

• Cirrhotics present with

- High factor VIII (pro-coagulant driver)- Low protein C (anti-coagulant driver)• The ratio of pro- vs anti-coagulant drivers is much

higher than the unity and increases progressively from Child A to C

The increased ratios are consistent with the procoagulant imbalance detected

by thrombin generation

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Procoagulant Imbalance in Patients with Chronic Liver Disease

• Tripodi et al, Hepatology 2010

• Lisman et al, J Hepatol 2010

• Gatt et al, J Thromb Haemost 2010

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Overall Conclusions

• The re-assessment of hemostasis in cirrhosis questions consolidated therapeutic strategies

• “Correcting” abnormal traditional hemostasis tests prior to invasive procedure should be reconsidered

• While platelet transfusion may be useful, plasma, anti-fibrinolytics, or pro-coagulants should be used on individual basis

• Patients with cirrhosis are not auto-anticoagulated• Hyper- rather than hypo-coagulability might be the

distinctive feature of cirrhosis

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Practical Implications of the Procoagulant Imbalance in Chronic Liver Disease

• Secondary prevention of VTE (VKA or LMWH) should be more extensively used in cirrhosis

• Primary PVT prevention should be considered in patients awaiting liver transplantation

- Villa E. et al, Gastroenterology 2012

• Other (non coagulation) thrombin effect should be considered in patients with cirrhosis

- Tripodi et al, J Thromb Haemost 2010

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Acknowledgements

• M. Primignani• A. Dell’Era• V. Chantarangkul• M. Clerici• P.M. Mannucci• F. Salerno• M. Colombo• R. de Franchis

• Patients Care

• Data management

• Testing• Advice