1. Hemophilia Coagulopathie Prof. Dr. Gyula Domján

2. disorders of primery hemostasys Vascular disorders, thrombocytes(platelet quantity,platelet quality disorders of secondary hemostasys Coagulations factors, controlling systems Disorders of fibrinolysis

3. Congenital disorders absence of coagulation factors vWf absence Acquired disorders appropriation (DIC) disorder of synthesis Liver diseases Iatrogeny: overdose of coagulation inhibitors anti factor antibodies dysproteinaemies toxic effects

4. Von Willebrand disease The vWf giant glycoprotein Role: FVIII stabilisation Thrombocyta adhesion In the absence of it: Both primary and secondary hemostasys will be disordered

5. Von Willebrand disease frequency, distribution Disease needing a treatment:1/10.000 Majority of bearers are symptompless Type 1 (70%): quantitative decrease Type 2: function disturbance, heterogenic group Type 3: vWf absence, serious hemophilia

6. Von Willebrand disease Clinicum Bleeding occurring at operations and traumas Significant bleeding from surficial skin injuries menorrhagia

7. Von Willebrand disease Diagnosis Bleeding time  FVIII activity  Ristocetin-induced thrombocyta aggregation  vWf ag  (not in Type 2) Special examinations ”high shear test”

8. Von Willebrand disease Treatment DDAVP mobilising own vWf from EC in Type 3: vWf concentrate (Wilfactin) Thrombocyta concentrate Applying antifibrinolytics In case of alloantibody formation: high dose vWf concentrate, applying FVIII, FVII

9. HEMOPHILIAS  Hemofilia A FVIII absence  Hemofilia B FIX absence, disfunction  FVIII and F IX genes on the X chromosome  Female bearers (heterozygotes)  Males getting diseased (homozygotes)  Rarely females can get diseased too (gene inactivation, mosaicism, child of bearer mother and diseased father)  cannot be separated clinically

10. Role of VIII f: activating FX In its absence: thrombin is not produced

11. SERIOUSNESS OF DISEASE Depends on the factor level Serious: < 1% Medium:1-5 % Mild:> 5 %

12. HEMOPHILIA A The most frequent inherited disorder of coagulation No hemophilia in the family in 30 %: new mutation Genetic background: Heterogenic diversions: point mutation, inversion, deletion

13. HEMOPHILIA A Clinicum seriousness depends on the factor level In a new-born baby profuse bleeding after circumcision Tooth extraction Hematuria Joint bruising – deformities Spontaneous intracerebral bleeding ”rebleeding”

14. Arthropathy

15. HEMOPHILIA A Laboratorial diversions aPTI prolonged corrigible with normal plasma FVIII level decreased normal vWf antigen level bleeding time, normal PI

16. HEMOPHILIA A Recognition of bearers Detecting mutant allele through DNA examination antenatal diagnosis chorion biopsia performed at the 8th-10th week of pregnancy – DNA examination VIIIf level examination of foetalis blood

17. HEMOPHILIA A Treatment Caring: in special hemophilia centre Treatment of bleeding episode: FVIII concentrate Desmopressin (DDAVP) (synthetic vasopressin derivative, increasing vWf level) Spontaneous bleeding avoidable if VIII f level > 20% To be increased to 100 % before operation Possibility of home care Dental check-up

18. HEMOPHILIA A Complications Infections transmitted by blood products (1980s) Hepatitis C, B, HIV serious H most frequent deaths: AIDS Prevention: Donor screening! Vaccination! Recombinant factor products

19. HEMOPHILIA A Complications 5-10 % anti VIIIf antibodies exhibited VIII factor becomes ineffective Great dose is needed Immune suppression Recombinant VII factor

20. HEMOPHILIA B FIX absence, Christmas-disease Difference: only in specific coagulation factor examinations Coding gene on the X chromosome, close to the FVIII gene, much smaller gene Treatment: IXf concentrate To be added more rarely (longer IXf T 1/2 )

21. Differential diagnosis „A”: vWD FXI absence Acquired hemophilia with inhibitor-bodies „B” K vitamin absence Coumarin treatment Liver disease APS Antibody against FIX

22. Other, inherited absence of coagulational factor All factors can be missing, it’s rare, however fVII absence PI prolonged, aPTI normal fXI absence Mild clinical picture Significant labour diversions fXIII absence Serious hemophilia, miscarriage, disorder of wound healing Normal coagulation examinations Examination of stability of coagulation (urea-lyophilism) fXII absence Thromboembolisms! Treatment FFP, prothrombin-complex concentrate, Novoseven (VIIf), DDAVP, fibrinolysis inhibitors

23. ACQUIRED COAGULOPATHIES

24. More frequent Absence condition influencing more factors Absence of vitamin K dependent factors Disseminated intravascular coagulation Other: dysproteinaemies heparin, thrombolysis, antifibrinolyticum massive transfusional syndrome

25. Absence of vitamin K dependent factors Hemorrhagic disease at newborns Biliary occlusion Malabsorption Vitamin K antagonist treatment Liver diseases

26. LIVER DISEASES Synthesis of vitamin K dependent coagulational factors AT III , vWf  Decreased spontaneous PI, TI, aPTI (INR-based judgement of liver’s synthetic activity) Liver biopsy danger! Splenomegalia- hypersplenia- thrombocytopenia

27. MALABSORPTIONS vitamin K: lipid soluble K vitamin absorption decreases Coagulation factor synthesis in liver  Malabsorption Crohn disease, coeliacia impairment of intestinal flora after enduring application of antibiotics

28. Coumarin treatment Decreases vitamin K synthesis Coagulation factors synthesis in liver decreases Syncumar, Marfarin Effect realises slowly (3-7 days) Role of diet (vitamin K input) green leaves, spinach, cabbage, liver Role of medicines Importance of regular control!

29. Role of vitamin K Posttranslational modification gamma-carboxylation of N-terminal glutamate group Ca is bound by gamma- carboxylated glutamate, this is how protein can be bonded to fosfolipid

30. Nephrosis syndrome Urination of proteins But: AT III level decreases more, clinically thrombotic disposition  liver diseases

31. DIC: Disseminated intravascular coagulopathy

32. DIC: The intravascular activation of coagulation Utilisation of coagulation factors Increasing fibrinolysis Always secondary Acute, chronic

33. DIC Pathogenesis extended vein injury, thrombocyta activation, aggregation boosted by procoagulant materials getting into the circulation system Formation of intravascular thrombin Fibrin deposition Fibrin polymerisation is inhibited by fibrin degradation products

34. DIC Consequence: Utilisation of coagulation factor Fibrinolysis disorder Thrombocyta utilisation Intravascular thrombosis Utilisation-induced bleeding

35. DIC Root cause: Obstetrical, gynaecological event: amniotic fluid embolism early placental abruption eclampsia Infection, sepsis Gram neg., meningococcus viral infection septic abortus Malignant diseases: AML/PML mucin-producing adenocarcinoma (stomach) Extended tissue damage Trauma operation Incompatible blood transfusion Other serpent poison burning

36. DIC Different laboratory parameters: Acute: no coagulation Thrombocyta number  Fibrinogene  Thrombin time  FDP  Prothrombin time, aPTI  (acute) FV, FVIII, ATIII  Peripheral smear: microangiopathic hemolytic anemy: fragmentocytes

37. DIC AML/PML

38. DIC Thrombocytopenia, fragmentocytes (Wright dyeing X1000)

39. Gangraena meningococcus in sepsis

40. DIC Massive transfusional syndrom Because of previous blood loss Coagulation factors, thrombocyta  Dilution Microaggregates, cell fragments

41. DIC Scoring System ++++NA- Fibrin split products NA <100>100 Fibrinogen level, mg/dL NA63-60-3 PT prolongation, NA<50 X 10 9 /L <100 X 10 9 /L >100 X 10 9 /L Platelet count 3210 Score Measure NA = not applicable.

42. DIC caused by serpent poison

43. DIC Treatment treatment of primary disease Heparin at the beginning of procedure: avoiding thrombosis In case of bleeding: vvt, FFP, fibrinogene, thrombocyta concentrate

44. Screening examinations of coagulopathies Hemophilia A, B, WB Fibrinogene, absence or inhibition of II, V, VIII, IX, X, XII, vWf Partial thromboplastin time (aPTI) DIC, heparin, liver disease, coumarin Fibrinogene, absence or inhibition of II, V, VII factors Prothrombin time (PI) DIC heparin treatment Fibrinogene absence heparin, FDP Thrombin time (TI) CausePathologic parameter Laboratorical test

45. Primary hyperfibrinolysis Prostata tumor, operation Extracorporeal circulation Pulmonary resection Iatrogeny Separation from DIC Thrmobocyta number, FV, FVIII normal/mild  Short euglobulin lysis time treatment: fibrinolysis inhibitors