1. Haemostasis

2. Indications for hemostasis test – Identify patients presenting with bleeding that have a correctable bleeding tendency – Identify patients presenting with acute clots that have a correctable clotting tendency – Monitor response to anticoagulant medications – Prognosis for patients with liver failure (MELD score, discriminant function) – Screen for DIC in patients with severe sepsis – Screen for occult bleeding disorders prior to surgery

3. Hemostasis tests Common platelets PT/INR (a)PTT Fibrinogen D-dimer Specific Mixing! TT Activated whole blood clotting time (ACT) Anti-Xa activity Ecarin clotting time (ECT) Antiphospholipid antibodies Platelet function Heparin induced thrombocytopenia test

4. Platelet count thrombocytopenia  destruction Medications, alcohol Autoimmune disease (ITP) DIC  production BM disease Factor deficiency Sequestration (spleen)

5. Platelet count thrombocytosis Primary MPD Secondary (reactive) Infection Post-surgery Post-splenectomy Malignancy Acute blood loss

6. Pseudothrombocytopenia Common! Incomplete mixing of blood sample which causes clots to form EDTA-dependent Peripheral blood smear!

7. PT

10. Extrinsic and common pathways

11. PT Normal range for PT is 11-14 s. High variation – Manufacturers’ thromboplastins – Incubation time – Storage condition – Detection system INR (International Normalised Ratio)

12. PT 0.8-1.2

13. High INR Anticoagulants Vitamin K antagonists (warfarin, coumadin)  Synthesis of clotting factors Chronic liver disease Vitamin K deficieny (malabsorption, malnutrition, antibiotics)  Consumption of clotting factors sepsis DIC

14. APTT

17. Intrinsic (contact) and common pathways

18. APTT Normal range for PT is 25-40 s. No standardization of the APTT

19. High APTT Anticoagulants heparin  Synthesis of clotting factors vWD Hemophilia  Consumption of clotting factors sepsis DIC Antiphospholipid antobodies Antiphospholipid syndrome

20. Fibrinogen Glycoprotein important for the formation of the platelet plug and the precursor of fibrin

21. Fibrinogen Produced in the liver Normal range 200-400 mg/dl Thrombophilic and hemorrhagic versions of congenital dysfibrinogenemia are known

22. Quantitative disorders High fibrinogen APP Pregnancy (normal) Low fibrinogen Liver failure DIC

23. D-dimer Most clinically relevant of the various FDP Made up of two D domains of adjacent fibrin monomers Presence of D-dimers indicates recent intravascular coagulation! <0.5 mg/dl (500 ucg/dl)

24. Elevated D-dimer Venous thromboembolism (PE) Arterial clot DIC Sepsis Malignancy Recent surgery or trauma Liver disease Pregnancy (normal)

26. Coagulation profiles ConditionPLTINRAPTTFibrinogenD-dimer Advanced liver disease  Normal or   vWD Normal or  Normal or  Normal DIC  Normal or  Normal or  Normal or   HemohpiliaNormal  Antiphospholipid syndrome (APS) Normal  Pregnancy Normal or  Normal  DIC – MAHA!

27. Antiphospholipid syndrome (APS) associated with persistently elevated anticardiolipin antibodies and/or lupus inhibitor (lupus anticoagulant). A woman presenting with multiple spontaneous abortions should also be suspect for the antiphospholipid syndrome. Lupus anticoagulant (LA) syndrome! – patients with APS may not necessarily have systemic lupus erythematosus (SLE)systemic lupus erythematosus – LA is associated with thrombotic rather than hemorrhagic complications

28. Antiphospholipid antibody

29. Von Willebrand disease (vWD)

30. vWD the most common hereditary coagulation abnormality! vWD Hereditary vWD type 1 (heterozygous) vWD type 2 (qualitative) vWD type 3 (homozygous) Aquired Abs Pseudo vWD (platelet type)

31. Mixing test Clotting tests abnormal Clotting factor deficiency Inhibitor of factor activity Abs

32. Mixing test

33. Algorithm for investigation of abnormal coagulation tests

34. Antocoagulation and thrombolytics Warfarin (coumadin)HeparinFactor Xa inhibitorsDirect thrombin inhibitorsThrombolytics (t-PA)

35. Indications Prevention of stroke (AF, prosthetic heart valves, LV thrombus) Prevention and treatment of DVT and PE Treatment of acute coronary syndrome Treatment of genetic and aquired thrombolitic disorder (Factor V Leiden, antiphospholipid antibody syndrome)

36. Anticoagulation system - overview Leiden mutation (APCR)

37. Warfarin Developed as a rat poison Inhibits vitamin K enzyme (epoxide reductase), which recycles Vit. K after it has been used in post-translational modifications of several factors (II, VI, IX, X, C, S) PIVKA – protein induced by vitamin K absence Narrow therapeutic window!

38. Warfarin Anticoagulation effect is not predictable from dosage! INR must be used to remain within the terapeutic window Target INR is 2.0-3.0

39. Heparin (UFH) Variable dose-effect relationship Must be monitored using APTT Every batch of thromboplastin is different, differing dosing algorithms should be determined by each individual hospital High intensity (PE) and low intensity (ACS) protocols