La Coagulazione nel Cirrotico: Mito e Realtà               La coagulazione nel              cirrotico: mito o realtà?     ...
Alteration of Hemostasis in Cirrhosis     Potential Implicated Mechanisms• Primary Hemostasis• Fibrinolysis• CoagulationA....
Dual Role of Platelets in Hemostasis• Primary hemostasis­ Adhesion to the subendothelium­ Aggregation one another• Coagula...
vWF            High levels of VWF in cirrhosisA.TRIPODI
Alteration of Hemostasis in Cirrhosis     Potential Implicated Mechanisms• Primary Hemostasis• Fibrinolysis• CoagulationA....
Fibrinolysis in Cirrhosis                   Background• Cirrhosis is characterized by  hyperfibrinolysis (?)• This complex...
Cirrhosis and Fibrinolysis• Decreased levels       • Increased levels­ Plasminogen            ­ tPA­ Anti­plasmin         ...
Hyperfibrinolysis and Cirrhosis• Deficiency of TAFI in cirrhotics is not  associated with increased plasma  fibrinolysis  ...
Alteration of Hemostasis in Cirrhosis     Potential Implicated Mechanisms• Primary Hemostasis• Fibrinolysis• CoagulationA....
Coagulation in Chronic Liver Disease              The Facts….• Cirrhosis is characterized by an  impaired synthesis of all...
Coagulation in Chronic Liver Disease               The Dogma…• The concept of a causal relationship between  abnormal coag...
Te Challenge of the Dogma (1)• Liver transplantation was initially associated  with dramatic transfusion requirements     ...
Transplantation 2008; 85: 956A.TRIPODI
Te Challenge of the Dogma (2) Conventional hemostasis tests do correlate poorly with gastrointestinal bleeding or after   ...
Poor Correlation between Global Conventional      Hemostasis Tests and Bleeding                Review of the Literature • ...
A.TRIPODI   Ewe, 1981
Why Conventional Coagulation Tests    do not Correlate with Bleeding in               Cirrhosis ?A.TRIPODI
Coagulation in Liver DiseaseConsiderations on the value of PT & APTT• PT & APTT might be inadequate to  reflect the coagul...
PROTEIN C is activated by THROMBIN                 T                                  PS                                  ...
PT & APTT are responsive only to            procoagulant factorsA.TRIPODI
…and much less to the anticoagulant        factorsA.TRIPODI
PT & APTT as Tools to Investigate the        Balance of Coagulation• PT & APTT can tell us whether a patient is  deficient...
Thrombin Generation ETP (FUXmin)                                   700              Platelet-free Plasma                  ...
Thrombin Generation in Platelet-free                Plasmas            Summary of findings• Plasma coagulation is not abno...
Poor Efficacy of Activated FVII to       Stop Bleeding in Cirrhosis•   Bosch J et al, 2004•   Lodge JP et al, 2005•   Plan...
Platelets & Thrombin GenerationA.TRIPODI
Platelet-Rich Plasma                                              (Plt.s count adjusted to 100,000/µL)                    ...
Platelet-Rich Plasma                                       (Plt.s adjusted to the original patient’s count)               ...
Thrombin Generation and Platelet Numbers                                 2500             ETP (thrombin) nM               ...
Thrombin Generation in Platelet-Rich               Plasma            Summary of Findings• Platelets from cirrhotics are qu...
Why do Patients with Cirrhosis           Occasionally Bleed?• The “restored” hemostatic balance in  cirrhosis may not be a...
Conditions Underlying Bleeding in Cirrhosis • Portal Hypertension • Endothelial dysfunction • Bacterial infections • Renal...
The Balance of Hemostasis                           Hemorrhage                  Thrombosis         Healthy subject        ...
A.TRIPODI   Am J Gastroenterol 2006;101:1524
Am J Gastroenterol 2009; 104: 96           These observations suggest a              procoagulant imbalance       in plasm...
Is there any biomarker to identify the    procoagulant imbalance in cirrhosis?A.TRIPODI
58%                             32% Difference                 700                               Difference               ...
200/450 = 0.44                 210/300 = 0.70                 700                 600                 500  ETP (FUXmin)   ...
Study on the Procoagulant              Imbalance in Cirrhosis• Aim of the Study- To detect biochemical signs of  procoagul...
A.TRIPODI
Case Material• Patients- 134 patients with cirrhosis with graded  severity according to the Child-Pugh  score• Controls- 1...
ResultsA.TRIPODI
Pro-coagulant Drivers in Cirrhosis                                                       ts   Pr                          ...
Factor II                                         150                 p < 0.001                                         10...
Factor VIII                                                p < 0.001                                                      ...
Anti-coagulant Drivers in Cirrhosis    Pr                                            ts       o-         co               ...
Protein C                               150                                                            p < 0.001          ...
Antithrombin                                                    p < 0.001                                            120  ...
Balance of Pro- vs Anti-coagulant                  Drivers in Cirrhosis                                                   ...
Ratio of thrombin generation (with/without TM)                                                                            ...
Summary of Findings• Cirrhotics present with significantly  higher ratios of thrombin generation  with/without thrombomodu...
….how can this procoagulant         imbalance be explained?A.TRIPODI
Ratio FVIII/protein C                                                        p < 0.001                                    ...
Summary of findings• Cirrhotics present with- High factor VIII (pro-coagulant driver)- Low protein C (anti-coagulant drive...
Procoagulant Imbalance in Patients with        Chronic Liver Disease• Tripodi et al, Hepatology 2010• Lisman et al, J Hepa...
Overall Conclusions• The re-assessment of hemostasis in cirrhosis  questions consolidated therapeutic strategies• “Correct...
Practical Implications of the Procoagulant      Imbalance in Chronic Liver Disease• Secondary prevention of VTE (VKA or LM...
A.TRIPODI
Acknowledgements•   M. Primignani      • Patients Care•   A. Dell’Era•   V. Chantarangkul   • Data management•   M. Cleric...
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La coagulazione nel cirrotico: mito o realtà? - Gastrolearning®

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La coagulazione nel cirrotico: mito o realtà? - Prof. A. Tripodi (Università di Milano)

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La coagulazione nel cirrotico: mito o realtà? - Gastrolearning®

  1. 1. La Coagulazione nel Cirrotico: Mito e Realtà La coagulazione nel cirrotico: mito o realtà? Prof. Armando Tripodi Angelo Bianchi Bonomi Hemophilia and Thrombosis Center Dept. of Clinical Sciences and Community Health A.TRIPODI University of Milano
  2. 2. Alteration of Hemostasis in Cirrhosis Potential Implicated Mechanisms• Primary Hemostasis• Fibrinolysis• CoagulationA.TRIPODI
  3. 3. Dual Role of Platelets in Hemostasis• Primary hemostasis­ Adhesion to the subendothelium­ Aggregation one another• Coagulation­ Support thrombin generationA.TRIPODI
  4. 4. vWF High levels of VWF in cirrhosisA.TRIPODI
  5. 5. Alteration of Hemostasis in Cirrhosis Potential Implicated Mechanisms• Primary Hemostasis• Fibrinolysis• CoagulationA.TRIPODI
  6. 6. Fibrinolysis in Cirrhosis Background• Cirrhosis is characterized by hyperfibrinolysis (?)• This complex defect can be documented in plasma through global fibrinolytic tests or through the measurement of individual components A.TRIPODI
  7. 7. Cirrhosis and Fibrinolysis• Decreased levels • Increased levels­ Plasminogen ­ tPA­ Anti­plasmin ­ PAI­1­ FXIII- TAFIA.TRIPODI
  8. 8. 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: 230A.TRIPODI
  9. 9. Alteration of Hemostasis in Cirrhosis Potential Implicated Mechanisms• Primary Hemostasis• Fibrinolysis• CoagulationA.TRIPODI
  10. 10. Coagulation in Chronic Liver Disease The 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 & APTTA.TRIPODI
  11. 11. Coagulation in Chronic Liver Disease The 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 A.TRIPODI
  12. 12. 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 A.TRIPODI
  13. 13. Transplantation 2008; 85: 956A.TRIPODI
  14. 14. Te Challenge of the Dogma (2) Conventional hemostasis tests do correlate poorly with gastrointestinal bleeding or after biopsyA.TRIPODI
  15. 15. 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: 988A. TRIPODI
  16. 16. A.TRIPODI Ewe, 1981
  17. 17. Why Conventional Coagulation Tests do not Correlate with Bleeding in Cirrhosis ?A.TRIPODI
  18. 18. 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 A.TRIPODI
  19. 19. PROTEIN C is activated by THROMBIN T PS Va Vi PC VIIIa VIIIi T E PS E PC APC APC P P TM C C membrane R R It should be noted that plasma and reagents needed to perform PT & APTT do not contain TMA.TRIPODI
  20. 20. PT & APTT are responsive only to procoagulant factorsA.TRIPODI
  21. 21. …and much less to the anticoagulant factorsA.TRIPODI
  22. 22. 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-coagulantsA.TRIPODI
  23. 23. Thrombin Generation ETP (FUXmin) 700 Platelet-free Plasma Tripodi et al, Hepatology 2005; 41: 553 600 500 400 300 200 100 0 Controls Cirrhotics Controls Cirrhotics without with A.TRIPODI thrombomodulin thrombomodulin
  24. 24. 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 coagulopathyA.TRIPODI
  25. 25. 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, 2008A.TRIPODI
  26. 26. Platelets & Thrombin GenerationA.TRIPODI
  27. 27. Platelet-Rich Plasma (Plt.s count adjusted to 100,000/µL) P<0.001 N.S. 3,500ETP (Thrombin) nM X min 3,000 2,500 2,000 1,965 1,500 1,365 1,140 1,117 1,000 500 0 Controls Cirrhotics Controls Cirrhotics Without Thrombomodulin With Thrombomodulin Tripodi et al, A. TRIPODI Hepatology 2006
  28. 28. Platelet-Rich Plasma (Plt.s adjusted to the original patient’s count) P<0.001 P<0.001 3,500ETP (Thrombin) nM X min 3,000 2,500 2,000 1,919 1,500 1,280 1,221 1,000 929 500 0 Controls Cirrhotics Controls Cirrhotics Without Thrombomodulin With Thrombomodulin Tripodi et al, A. TRIPODI Hepatology 2006
  29. 29. Thrombin Generation and Platelet Numbers 2500 ETP (thrombin) nM 2000 1500 1000 500 Rho=0.50, p<.001 0 0 60 100 200 300 Platelet numbers (X 109/L) Tripodi et al A.TRIPODI Hepatology, 2006
  30. 30. 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 generationA.TRIPODI
  31. 31. 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 bleedingA.TRIPODI
  32. 32. Conditions Underlying Bleeding in Cirrhosis • Portal Hypertension • Endothelial dysfunction • Bacterial infections • Renal failureTherapeutic interventions correcting these abnormalities might be more effective than correcting coagulopathy A.TRIPODI
  33. 33. The Balance of Hemostasis Hemorrhage Thrombosis Healthy subject Excess pro- & Cirrhosis anti-coagulants Relative deficit pro- A.TRIPODI & anti-coagulants
  34. 34. A.TRIPODI Am J Gastroenterol 2006;101:1524
  35. 35. Am J Gastroenterol 2009; 104: 96 These observations suggest a procoagulant imbalance in plasma from patients with cirrhosis A.TRIPODI
  36. 36. Is there any biomarker to identify the procoagulant imbalance in cirrhosis?A.TRIPODI
  37. 37. 58% 32% Difference 700 Difference 600 500 ETP (FUXmin) 450 400 300 300 200 210 200 100 0 No TM TM No TM TM Controls CirrhoticsA.TRIPODI A.Tripodi et al, Hepatology 2005
  38. 38. 200/450 = 0.44 210/300 = 0.70 700 600 500 ETP (FUXmin) 450 400 300 300 200 210 200 100 0 No TM TM No TM TM Controls CirrhoticsA.TRIPODI A.Tripodi et al, Hepatology 2005
  39. 39. 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 thrombomodulinA.TRIPODI
  40. 40. A.TRIPODI
  41. 41. 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 patientsA.TRIPODI
  42. 42. ResultsA.TRIPODI
  43. 43. Pro-coagulant Drivers in Cirrhosis ts Pr la n o- u ag co co ag nt i- ul an A tsA.TRIPODI
  44. 44. Factor II 150 p < 0.001 100 Factor II (%) p < 0.001 50 0 A.TRIPODI et al, Healthy CHILD CHILD CHILD Gastroenterology 2009 subjects A B C
  45. 45. Factor VIII p < 0.001 p = 0.02 300 Factor VIII (%) 200 100 0 Healthy CHILD CHILD CHILD subjects A B C A.TRIPODI et al, Gastroenterology 2009
  46. 46. Anti-coagulant Drivers in Cirrhosis Pr ts o- co ul an ag o ag ul c an i- ts AntA.TRIPODI
  47. 47. Protein C 150 p < 0.001 100 p < 0.001 Protein C (%) p = 0.03 50 0 Healthy CHILD CHILD CHILD Protein C subjects A B C deficiencyA.TRIPODI et al,Gastroenterology 2009
  48. 48. Antithrombin p < 0.001 120 p < 0.001 100 Antithrombin (%) 80 60 40 20 0 Healthy CHILD CHILD CHILD A.TRIPODI et al, subjects A B C Gastroenterology 2009
  49. 49. Balance of Pro- vs Anti-coagulant Drivers in Cirrhosis ts an Pr ul o- o ag co c i- ag nt u A la nt s Assessed as ratio of thrombin generationA.TRIPODI with/without thrombomodulin
  50. 50. Ratio of thrombin generation (with/without TM) p < 0.001 1.2 p = 0.03 Ratio ETP (with/without thrombomodulin) 1.0 0.8 0.6 0.4 0.2 0.0A.TRIPODI et al, Healthy CHILD CHILD CHILD Protein CGastroenterology 2009 subjects A B C deficiency
  51. 51. 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 CA.TRIPODI
  52. 52. ….how can this procoagulant imbalance be explained?A.TRIPODI
  53. 53. Ratio FVIII/protein C p < 0.001 p < 0.001 15 Ratio (Factor VIII/Protein C) 10 5 0 A.TRIPODI et al, Healthy CHILD CHILD CHILD Gastroenterology 2009 subjects A B C
  54. 54. 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 A.TRIPODI
  55. 55. 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 2010A.TRIPODI
  56. 56. 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 A.TRIPODI
  57. 57. 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 2010A.TRIPODI
  58. 58. A.TRIPODI
  59. 59. Acknowledgements• M. Primignani • Patients Care• A. Dell’Era• V. Chantarangkul • Data management• M. Clerici • Testing• P.M. Mannucci • Advice• F. Salerno• M. Colombo• R. de FranchisA.TRIPODI

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