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Clotting made easy

Clotting made easy. H.C.Hemker S.Béguin R.Wagenvoord R.AlDieri P.W.Hemker and others. The contribution of thrombin generation to the understanding and diagnosis of thrombotic and haemorrhagic disease. Ca rdiovascular R esearch I nstitute M aastricht The Netherlands.

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Clotting made easy

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  1. Clotting made easy H.C.Hemker S.Béguin R.Wagenvoord R.AlDieri P.W.Hemker and others The contribution of thrombin generation to the understanding and diagnosis of thrombotic and haemorrhagic disease Cardiovascular Research Institute Maastricht The Netherlands

  2. You are an MD so you will encounter a bleeding or a thrombosis problem at least once a week (unless you are a psychiatrist) And if you are a geriatrist, surgeon, orthopedist, internist etc. you will encounter bleeding or thrombosis problems every day.

  3. Clinical importance of haemostasis and thrombosis Venous thrombosis causes over 500 000 deaths in Europe every year, that is more than due to breast cancer, AIDS, and traffic accidents combined Thrombosis / Haemostasis is a pathogenetic mechanism that is as important as e.g. the Immune System or the Regulation of Cell Division Coronary artery disease is the single most common cause of death in Europe, accounting for nearly 2.000.000 deaths per year. Stroke 1 million people / year in Europe Brainin e.a. Eur J Neurol 2000 7 5-10 Atrial fibrillation: 4.5 million people in the European Union, major risk of stroke Severe traumatic injury, hemorrhage: > 40% of deaths; Of which ~75% with coagulopathy: > 4-fold higher mortality,

  4. You are an MD so you learned that the clotting system is tested by measuring clotting times You also learned that the prothrombin time indicates oral anticoagulation and liver function and the aPTT heparin treatment and hemophilia. And you know that there is a lot more to be said which is known by haematologists and which is as complicated as brain anatomy and such hyperspecialistic knowledge.

  5. But you in this audience are haematologist so they ask you: Why APTT for heparin and PT for OAC? Why does a normal APTT not exclude perioperative bleeding risk? My patient with cirrhosis has a long PT but does not bleed Why is the APTT normal in my patient with thrombosis ? Why is the “pill” a risk for thrombosis without influence on clotting times ? Etc…….etc…….etc…….......

  6. As a haematologist you will have to admit that clotting times: • Need different types for different purposes • Do not detect a thrombotic tendency • Do not detect mild bleeding tendency • Are not proportional to clinical risks • Do not detect platelet problems (And that a bleeding time is hardly useful Its coefficient of variation being 35%)

  7. And as soon as we start explaining: Fibrinogen, Prothrombin, factor V, factorX, factorIX, factorVII, Contact activation, Phospholipids, Platelets, AntithrombinIII, ProteinS, Protein C, Hageman factor, FactorXI, Extrinsic System, Intrinsic System, FactorVII,TissueFactor, TM, TFPI

  8. Most colleagues back out

  9. What we should like to have in thrombotic and bleeding disease: (Something like blood-glucose in diabetesor clearance in kidney disease) • A defined normal range • Thrombosis risk when too big • Bleeding risk when too small • Danger proportional to value found • Showing effect of antithrombotic therapy • Showing effect of substitution therapy • Easy and precise

  10. Clot forms Clotting Time Blood clots because THROMBIN generates But look how it develops when blood clots: 200 Thrombin (nM) Ca++inPlasma 100 Time (min) 0 5 10 15 Plasma clots when < 2% of all thrombin is formed > 98 % of all thrombin forms explosively in the clot

  11. Todays central and most important issue: The force of the explosion is more important than the moment at which it exactly occurs.

  12. What appeared: The Power of Thrombin, is the important thing Not the Time that it takes before it starts being formed NOT the clotting time

  13. The power of thrombin = The “man hours” of thrombin activity = The area Under the TG-curve = Endogenous Thrombin Potential (ETP)

  14. The Endogenous Thrombin Potential (ETP) Holds more important information than the clotting time Why this is deserves a separate lecture 0 Clotting time

  15. thrombin substrate Prothrombin (Plasma) Thrombin fluorescent product Inactive Thrombin (Serum) If thrombin action is so important, then let us measure thrombin action by adding a fluorogenic thrombin substrate

  16. fluorescence Thrombin concentration Fluorescence Thrombin 0 5 10 15 Time (min) Thrombin concentration can be calculated from the fluorescence measured in a 96-well fluorometer.

  17. Very Low Tissue Factor No Heparin Low Tissue Factor No Heparin Low Tissue Factor Heparin Very Low Tissue Factor Heparin 12 experiments can be measured simultaneously (4 x 3)

  18. Calibrated Automated Thrombinography CAT

  19. Calibrated Automated Thrombinography CAT

  20. Calibrated Automated Thrombinography CAT

  21. Calibrated Automated Thrombinography CAT

  22. Calibrated Automated Thrombinography CAT

  23. Calibrated Automated Thrombinography CAT

  24. Calibrated Automated Thrombinography CAT

  25. Calibrated Automated Thrombinography CAT

  26. After the run an analysis program calculates mean curves and parameters

  27. Notably the Endogenous Thrombin Potential (ETP) The method is operative in ~ 400 labs over the world

  28. 350 300 250 200 150 100 50 0 1980 1985 1990 1995 2000 2005 2010 Year Thrombin generation is becoming a ‘hot’ subject. More and more publications appear each year. What has been found ?

  29. The more Thrombin, the less Bleeding but the more Thrombosis, The less Thrombin, the more Bleeding but the less Thrombosis C.H. The results can be summarised in one simple phrase: The first law of haemostasis and thrombosis:

  30. A: All congenital and acquired thrombotic tendencies: B: All congenital or acquired bleeding tendencies C: If : Thrombotic tendency D: If : Bleeding tendency TG TG TG TG Examples :

  31. TG All congenital and acquired thrombotic tendencies: No Addition +TM 500 500 500 + APC No Addition No Addition +TM thrombin (nM) thrombin (nM) thrombin (nM) +TM + APC + APC 0 0 0 0 5 10 15 20 0 5 10 15 20 0 5 10 15 20 time (min) time (min) time (min) Factor V Leiden + Hyperprothrombinaemia Factor V Leiden Normal Control Effect is additive !

  32. TG If : More venous Trombosis Retrospective: Dargaud 2006 Brandts 2007 Van Hylckama 2007 Tripodi 2007 Ten Cate-Hoek 2008 Wichers 2009 Prospective Hron 2006 Eichinger 2008 Besser 2008 Tripodi 2008 Lutsey 2009

  33. TG If : Trombotic Tendency Recurrence in persons with TG above normal mean Recurrence in persons with TG below normal mean Recurrence of idiopathic venous thrombosis, No Therapy From « Identification of Patients at low risk of recurrent venous embolism by measuring thrombin generation » Hron, Kollars, Binder, Eichinger, Kyrle. JAMA July 2006 vol 296 p. 397-402

  34. Coronary Artery Disease TG Arterial Trombosis : Acute myocardial infarction (N=60) Stable CAD (N=35) Controls (N=15) * * p<0.05) compared to stable CAD Courtesy of Mojca StegnarUniversity Medical Centre Ljubljana, Slovenia Orbe J, et al. Thromb Haemost 2008;99:382

  35. Congenital or acquired bleeding tendencies TG All congenital deficiencies causing ETP < 20% have a bleeding tendency (Factors II,V,VII,VIII,IX,X,XII) Al Dieri R, Peyvandi F, Santagostino E, Giansily M, Mannucci PM, Schved JF, Béguin S, Hemker HC. The thrombogram in rare inherited coagulation disorders: its relation to clinical bleeding. Thromb Haemost 2002;88:576-82. Dargaud Y, Béguin S, Lienhart A, Al Dieri R, Trzeciak C, Bordet JC, Hemker HC, Negrier C. Evaluation of thrombin generating capacity in plasma from patients with haemophilia A and B. Thromb Haemost 2005;93:475-80

  36. TG All congenital or acquired bleeding tendencies: 200 control 2% 150 1% 0.5% Thrombin (nM) 100 0% 50 0 0 5 10 15 20 Time (min) Example: Factor V deficiencies Also for II, VII, X and XI: AlDieri Thr&Haem. 88: 576 (2002)

  37. 400 Therapy for Bleeding: TG 1 hr 300 24 hrs 200 Thrombin (nM) 60 hrs 100 Baseline 0 30 20 10 Time (min) Thrombin generation after factor VIII infusion in a haemophiliac

  38. Illustration of the first law: Four Antithrombotics – Four Modes of Action Oral Anticoagulants diminish Prothrombin Four Modes of Action, One Effect: Less Thrombin Aspirin inhibits platelets required for Prothrombinase Thrombin Antithrombin DTI and hirudin act directly Inactive Thrombin Heparinenhances

  39. NP NP INR 2 INR 3 INR 4 INR 5 INR 6 Effect of Oral Anticoagulation 300 200 Thrombin (nM) 100 0 0 5 10 15 20 Time (min)

  40. 120 Control 90 0.1 µg/ml 0.2 µg/ml Thrombin (nM) 0.3 µg/ml 60 0.4 µg/ml 30 0 0 10 20 clot Time (min) Thrombin generation: effect of heparin

  41. Also the modern anticoagulants Uninhibited PLasma Dermatan sulfate Heparin Fondoparinox Melagatran Otamixaban Otamixaban,,Melagatran,,Heparin,,Dermatan sulfate,,Fondoparinox

  42. Summary:Why Thrombin Generation ? 1: Predicts thrombosis risk2: Monitors ALL antithrombotic treatment 3: Reflects bleeding risk in haemophilia4: Predicts blood loss in surgery (not shown) 5: Indicates H&T side effects of drugs (pill and others) 6: Facilitates search for new antithrombotics 7: Epidemiology / Public Health In short: Works where clotting times fail

  43. PT, APTT, WBCT, TEG If only you forget about clotting times Haemostasis &Thrombosis is easy to understand

  44. Thrombosis Normal thrombin Bleeding time Clotting made easy : The more thrombin the less bleeding but the more thrombosis The less thrombin the more bleeding but the less thrombosis Thrombosis Risk > 110 % Normal Range 84 - 116 % Thrombosis Prevention 25 - 60 % Bleeding Risk < 20 %

  45. Calibrated Automated Thrombin Generation TheCAT Summary:How Thrombin Generation ?

  46. Questions? HC.Hemker@Thrombin.Com

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