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Hemophilia Coagulopathie
Prof. Dr. Gyula Domján
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disorders of primery hemostasys
• Vascular disorders, thrombocytes(platelet quantity,platelet quality
• disorders of secondary hemostasys
• Coagulations factors,
• controlling systems
• Disorders of fibrinolysis
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• 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
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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
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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
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Von Willebrand disease
• Clinicum
• Bleeding occurring at operations and traumas
• Significant bleeding from surficial skin injuries
• menorrhagia
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Von Willebrand disease
• Diagnosis
• Bleeding time • FVIII activity • Ristocetin-induced thrombocyta
aggregation • vWf ag (not in Type 2)
• Special examinations
• ”high shear test”
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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
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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
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• Role of VIII f:• activating FX
• In its absence:• thrombin is not
produced
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SERIOUSNESS OF DISEASE
• Depends on the factor level
• Serious: < 1%
• Medium: 1-5 %
• Mild: > 5 %
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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
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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”
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• Arthropathy
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HEMOPHILIA A• Laboratorial diversions• aPTI prolonged• corrigible with normal plasma• FVIII level decreased• normal vWf antigen level• bleeding time, normal PI
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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
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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
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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
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HEMOPHILIA A
• Complications
• 5-10 % anti VIIIf antibodies
• exhibited VIII factor becomes ineffective
• Great dose is needed
• Immune suppression
• Recombinant VII factor
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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)
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Differential diagnosis
• „A”:• vWD• FXI absence• Acquired hemophilia with inhibitor-bodies
• „B”• K vitamin absence• Coumarin treatment• Liver disease• APS• Antibody against FIX
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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
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ACQUIRED COAGULOPATHIES
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ACQUIRED COAGULOPATHIES
• More frequent
• Absence condition influencing more factors
• Absence of vitamin K dependent factors
• Disseminated intravascular coagulation
• Other:dysproteinaemiesheparin, thrombolysis, antifibrinolyticummassive transfusional syndrome
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Absence of vitamin K dependent factors
• Hemorrhagic disease at newborns
• Biliary occlusion
• Malabsorption
• Vitamin K antagonist treatment
• Liver diseases
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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
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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
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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!
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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
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Nephrosis syndrome
• Urination of proteins
• But: AT III level decreases more,
• clinically thrombotic disposition
liver diseases
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DIC: Disseminated intravascular coagulopathy
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DIC:
The intravascular activation of coagulation
Utilisation of coagulation factors
Increasing fibrinolysis
Always secondary
Acute, chronic
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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
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DIC
• Consequence:
• Utilisation of coagulation factor
• Fibrinolysis disorder
• Thrombocyta utilisation• Intravascular thrombosis
• Utilisation-induced bleeding
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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• Other
serpent poisonburning
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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
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DIC
• AML/PML
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DIC
• Thrombocytopenia, fragmentocytes (Wright dyeing X1000)
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Gangraena meningococcus in sepsis
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DIC
• Massive transfusional syndrom
• Because of previous blood loss
• Coagulation factors, thrombocyta • Dilution
• Microaggregates, cell fragments
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DIC Scoring System
++++NA-Fibrin split products
NANA<100>100Fibrinogen level, mg/dL
NA63-60-3PT prolongation,
NA<50 X 109/L <100 X 109/L >100 X 109/L
Platelet count
3210
ScoreMeasure
NA = not applicable.
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DIC caused by serpent poison
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DIC
• Treatment
• treatment of primary disease
• Heparin at the beginning of procedure: avoiding thrombosis
• In case of bleeding: vvt, FFP, fibrinogene, thrombocyta concentrate
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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)
DICheparin
treatment
Fibrinogene absence
heparin, FDP
Thrombin time (TI)
CausePathologic parameter
Laboratorical test
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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