1. 1 Bleeding disorders K. Bernášková

2. 2 The Hemostatic System

3. 3 Hemostasis (clot formation) Primary hemostasis = function of blood vessels and platelets: Vasoconstriction Platelet plug formation Secondary hemostasis = function of coagulation factors Definitive (insoluble) plug formation

4. 4 Primary hemostasis (a) Platelet adhesion (b) P. aggregation (c) P. activation 1. Vasoconstriction 2. Primary clot formation sympaticus serotonin TXA 2 axo-axonal reflex

5. 5 Secondary hemostasis Coagulation factors NoClotting factor Liver Vit K. I.Fibrinogen II.Prothrombin III.Tissue factor (thromboplastin) IV.Calcium V.Proaccelerin VII.Proconvertin VIII.AHF A, vW IX.Christmas factor (AHF B) X.Stuart – Prower factor XI.Plasma thromboplastin antecedent (AHF C) XII.Hageman factor XIII.Fibrin stabilizing factor

6. 6 Secondary hemostasis Coagulation factors NoClotting factor Liver Vit K. I.Fibrinogen + II.Prothrombin + + III.Tissue factor (thromboplastin) - IV.Calcium - V.Proaccelerin + VII.Proconvertin + + VIII.AHF A, vW+(-) IX.Christmas factor (AHF B) + + X.Stuart – Prower factor + + XI.Plasma thromboplastin antecedent (AHF C) + XII.Hageman factor + XIII.Fibrin stabilizing factor (+)

7. 7 Secondary hemostasis

8. 8

9. 9 Laboratory Diagnosis of Bleeding and Coagulation Disorders Patient ID Date Special Studies PT Cont. INR APTT BT Plat. TT Fibr. FDP D-Dimer HEMOSTASIS Prothrombin time (Quick) N = 16 s International normalized ratio N = 1 ± 0,2 Activated ProThrombine Time N = 35 s Bleeding Time N = 1-6 min Platelet count N = 150 -300 000/  l Thrombine time N < 22s Fibrinogen N = 1.5-2.77 g/l Fibrin Degradation Products D-dimers < 0,25 mg/L

10. 10 Laboratory Diagnosis of Bleeding and Coagulation Disorders 1. Tests of Primary Hemostasis –Bleeding Time –Platelet Count –(Capillary fragility test) http://www.nlm.nih.gov/medlineplus/bleedingdisorders.html

11. 11 Signs of primary hemostasis failure Petechiae Ecchymoses

12. 12 Signs of primary hemostasis failure Purpura Epistaxis Haevy menstrual bleeding Easy bruising Superficial bleeding into the skin and mucous membranes

13. 13 Laboratory Diagnosis of Bleeding and Coagulation Disorders 2. Tests of Secondary Hemostasis Partial Thromboplastin Time (PTT), activated partial thromboplastin time (aPTT). (INR) –Normal range = 25-35 seconds –The PTT is commonly used to monitor heparin therapy. Prothrombin Time (PT) –Normal range = 11-13 seconds (INR = 1 ± 0,2) –The PT is commonly used to monitor coumarin therapy. Thrombin Time (TT) –Normal range = < 22 seconds

14. 14 Signs and symptoms of secondary hemostasis failure Suffusions Bleeding into deep tissues (muscles, joints)

15. 15 Signs and symptoms of secondary hemostasis failure Epistaxis Haevy menstrual bleeding Easy bruising (deep tissues) Bleeding into the deep tissues, muscles, joints Delayed bleeding, healing disorders

16. Laboratory Diagnosis of Bleeding and Coagulation Disorders 3. Tests of fibrin degradation FDP (fibrin degradation products) D-dimers Plazmin Fibrinogen, Fibrin monomer Fibrin polymer FDP D-dimers

17. Coagulation disorders - Bleeding 17 Stay calm, there is no danger, we have stopped bleeding

18. 18 Case 1 What phase of hemostasis is affected? What test(s) is (are) most likely to be performed next? 3

19. 19 Case 1 The patient is thrombocytopenic indicating a defect of primary hemostasis. The most likely test to follow: bone marrow examination 32 x10 9 /l 3

20. 20 Primary hemostasis defect Thrombocytopenia Decreased production  Myelophthisic process  Ineffective thrombopoiesis  Bone marrow suppression  Dilutional loss  Non-immune destruction  Immune destruction  Hypersplenism  Hepatosplenomegally Sequestration Increased destruction or loss

21. 21 Case 2 Patient ID Date Special Studies PT Cont. INR APTT BT Plat. TT Fibr. FDP D-Dimer HEMOSTASIS 12.1 Sec. 12.4 Sec. 1.1 30.0 Sec. >15 Min. 302 x10 9 /L What conclusion can be drawn from this data? What disorders can lead to these findings?

22. 22 Case 2 Patient ID Date Special Studies PT Cont. INR APTT BT Plat. TT Fibr. FDP D-Dimer HEMOSTASIS 12.1 Sec. 12.4 Sec. 1.1 30.0 Sec. >15 Min. 302 x10 9 /L The increased bleeding time and normal platelet count  primary hemostasis function problem.  platelet function or vascular disorders

23. 23 Primary hemostasis defects Thrombocytopathias (failure in the adherence, aggregation or secretion of thrombocytes) ➢ Inherited (v Wilebrand disease, Glanzmann thrombasthenia, Heřmanský – Pudlák sy, Chediak-Higashi sy) ➢ Acquired (drugs (aspirin), uremia)

24. 24 Primary hemostasis defects Vascular Defects (structurally weak vessels or vessels damaged by inflammation) ➢ Inherited vessel wall defects (M. Rendu Osler), (Connective tissue defects: Marfan‘s syndrome, M. Ehlers – Danloss) ➢ Acquired vessel wall defects (Vitamin C deficiency) ➢ Vessel wall inflammation (Immunocomplex vasculitis)

25. 25 Morbus Rendu Osler

26. 26 Marfan‘s syndrome

27. 27 Morbus Ehlers - Danloss

28. 28 Scorbut

29. 29 Case 3 Patient ID Date Special Studies PT Cont. INR APTT BT Plat. TT Fibr. FDP D-Dimer HEMOSTASIS 12.1 Sec. 12.4 Sec. 1.1 60.5 Sec. 6.0 Min. 332 x10 9 /L What conclusions can be drawn from this data? What tests are likely to be ordered next?

30. 30 Case 3 Patient ID Date Special Studies PT Cont. INR APTT IBT Plat. TT Fibr. FDP D-Dimer HEMOSTASIS 12.1 Sec. 12.4 Sec. 1.1 60.5 Sec. 7.0 Min. 332 x10 9 /L The abnormal APTT  defect of the secondary hemostasis, the intrinsic pathway TT Factor concentrations

31. 31 Secondary hemostasis defects Inherited coagulation defects Hemophilia A,B,C Parahemophilias Hypofibrinogenemia Acquired diseases Avitaminosis K Liver diseases Drugs (antibiotics, coumarine derivatives)

32. 32 Secondary hemostasis diseases NoClotting factor Liver Vit K. Diseases I.Fibrinogen + Afibrinogenaemia II.Prothrombin + + III.Tissue factor (thromboplastin) IV.Calcium V.Proaccelerin +Parahemophilia VII.Proconvertin + + VIII.AHF A, vW +Hemophilia A IX.Christmas factor (AHF B) + +Hemophilia B X.Stuart – Prower factor + + XI.Plasma thromboplastin antecedent (AHF C) +Hemophilia C XII.Hageman factor + XIII.Fibrin stabilizing factor (+)

33. 33 Primary hemostasis defects - survey Positive tests Signs Vascular disorders Vessel wall failure Morbus Rendu – Osler Morbus Ehlers – Danloss Vitamin C deficiency Vessel wall inflammation Immunocomplex vasculitis Rumpel–Leede Duke (Platelet count) Petechias Purpura Easy bruising Haevy menstrual bleeding Epistaxis Platelet defects ( number, adherence or aggregation failure) Thrombocytopenias Decreased plt. production Decreased plt. survival Increased pooling of plt. Thrombocytopathias Inherited (v Wilebrand‘s disease, Glanzmann‘s thrombasthenia) Acquired (drugs, uremia)

34. 34 Secondary hemostasis defects - survey Coagulopaties Positive tests Signs Coagulation defects (Deficiencies of one or more clotting factors) Inherited Haemophilias (A,B,C) Parahaemophilias Acquired Vitamin K disorders Liver diseases Abnormal consumption (DIC) APTT Quick FDP  Concentration of Factors Bleeding into deep tissues Larger ecchymoses Suffusions

35. 35 Clinical evaluation of bleeding DisordersPrimary hemostasisSecondary hemostasis Sex distributionfemales > malesfemales < males Family history of bleeding rarely positive (except vWD) usually positive Trauma relationshipimmediatedelayed (often 2 – 3 days) Prolonged after cutyes (30 min)no Direct pressure controls bleeding effectivenot effective Petechiaevery commonnot common Ecchymosessmall, multiplenone – or large and solitary Hemarthrosis/ deep hematomas noyes Screening testprolonged bleeding time prolonged PT or PTT

36. 36 Patterns of haemostatic tests Platelet count (Plat.) Bleeding time (BT) aPTTPT ITP (Idiopathic thrombocytopenic purpura)   N N Haemophilia A Haemophilia B N N  N von Willebrand disease N  N (or slightly  ) N DIC    

37. Hypercoagulability states 37

38. 38

39. 39 Endothelial injury Alteration of blood flow Increased coagulability

40. Virchows trias 1. 40 Endothelial injury Trauma or surgery Venipuncture Heart valve disease or replacement Atherosklerosis Acute myocardial infarction Indwelling catheters

41. Virchows trias 2. Alteration of blood flow Atrial fibrillation, left heart failure Immobility Long flights Venous insuficiency or varicous veins Venous obstruction (pelvic tumours) 41

42. Virchows trias 3. Increased coagulability Increased viskozity (malignancy, pregnancy) Protein C + S deficiency Nephrotic sy Hyperfibrinogenemia (metabolic sy) 42

43. 43

44. 44 A 25 year old female medical student is found to be anemic by her gynecologist. Her Hgb is 7.0 g/dl, Hct is 21%, and her MCV is 60. She reports heavy menstrual bleeding throughout her life. She also complains of epistaxis and a "funny rash" on her lower extremities whenever she takes aspirin. Her mother needed several transfusions with delivery of each of her children. 1.Does this patient have any type of anaemia? Which? 2.What might be the cause of this state? 3.Which type of coagulation abnormality are you suspicious for? 4.Which other signs and symptoms could she have? 5.How would you treat this patient?

45. 45 A 3 year old boy presents with a painful left elbow after mild trauma. Evaluation reveals a hemarthrosis. The child is adopted so no family history is available. The patients mother reports no other problems with the child. A PT is normal, an aPTT is prolonged. 1.Is there primary or secondary hemostasis failure? Why? 2.What does mean, that PT is normal and aPTT is prolonged? 3.Which mechanism might cause the prothrombine time to be longer? 4.Discuss the genetics of the disease. 5.Discuss therapy of this disorder.

46. Thank you for your attention 46