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H emophilia C oagulopathie

Prof. Dr. Gyula Domján. H emophilia C oagulopathie. disorders of primery hemostasy s V ascular disorders , thrombocytes (platelet quantity,platelet quality disorders of secondary hemostasy s Coagulations factors, controlling systems Disorders of fibrinolysis. Congenital disorders

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H emophilia C oagulopathie

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  1. Prof. Dr. GyulaDomján Hemophilia Coagulopathie

  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 • DDAVPmobilising 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 AFVIII 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 T1/2)

  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. ACQUIREDCOAGULOPATHIES

  24. ACQUIRED COAGULOPATHIES • More frequent • Absence condition influencing more factors • Absence of vitamin K dependent factors • Disseminated intravascular coagulation • Other:dysproteinaemiesheparin, thrombolysis, antifibrinolyticummassive 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  • MalabsorptionCrohn 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 embolismearly placental abruptioneclampsia • Infection, sepsisGram neg., meningococcusviral infectionseptic abortus • Malignant diseases:AML/PMLmucin-producing adenocarcinoma (stomach) • Extended tissue damageTraumaoperation • Incompatible blood transfusion • Otherserpent poisonburning

  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. Measure Score 0 1 2 3 Platelet count >100 X 109/L <100 X 109/L <50 X 109/L NA PT prolongation, 0-3 3-6 6 NA Fibrinogen level, mg/dL >100 <100 NA NA Fibrin split products - NA + +++ DIC Scoring System NA = not applicable.

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

  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

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