Hemophilia Coagulopathie

Prof. Dr. Gyula Domján

disorders of primery hemostasys

• Vascular disorders, thrombocytes(platelet quantity,platelet quality

• disorders of secondary hemostasys

• Coagulations factors,

• controlling systems

• Disorders of fibrinolysis

• 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

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

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

Von Willebrand disease

• Clinicum

• Bleeding occurring at operations and traumas

• Significant bleeding from surficial skin injuries

• menorrhagia

Von Willebrand disease

• Diagnosis

• Bleeding time • FVIII activity • Ristocetin-induced thrombocyta

aggregation • vWf ag (not in Type 2)

• Special examinations

• ”high shear test”

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

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

• Role of VIII f:• activating FX

• In its absence:• thrombin is not

produced

SERIOUSNESS OF DISEASE

• Depends on the factor level

• Serious: < 1%

• Medium: 1-5 %

• Mild: > 5 %

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

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”

• Arthropathy

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

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

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

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

HEMOPHILIA A

• Complications

• 5-10 % anti VIIIf antibodies

• exhibited VIII factor becomes ineffective

• Great dose is needed

• Immune suppression

• Recombinant VII factor

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)

Differential diagnosis

• „A”:• vWD• FXI absence• Acquired hemophilia with inhibitor-bodies

• „B”• K vitamin absence• Coumarin treatment• Liver disease• APS• Antibody against FIX

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

ACQUIRED COAGULOPATHIES

ACQUIRED COAGULOPATHIES

• More frequent

• Absence condition influencing more factors

• Absence of vitamin K dependent factors

• Disseminated intravascular coagulation

• Other:dysproteinaemiesheparin, thrombolysis, antifibrinolyticummassive transfusional syndrome

Absence of vitamin K dependent factors

• Hemorrhagic disease at newborns

• Biliary occlusion

• Malabsorption

• Vitamin K antagonist treatment

• Liver diseases

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

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

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!

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

Nephrosis syndrome

• Urination of proteins

• But: AT III level decreases more,

• clinically thrombotic disposition

liver diseases

DIC: Disseminated intravascular coagulopathy

DIC:

The intravascular activation of coagulation

Utilisation of coagulation factors

Increasing fibrinolysis

Always secondary

Acute, chronic

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

DIC

• Consequence:

• Utilisation of coagulation factor

• Fibrinolysis disorder

• Thrombocyta utilisation• Intravascular thrombosis

• Utilisation-induced bleeding

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

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

DIC

• AML/PML

DIC

• Thrombocytopenia, fragmentocytes (Wright dyeing X1000)

Gangraena meningococcus in sepsis

DIC

• Massive transfusional syndrom

• Because of previous blood loss

• Coagulation factors, thrombocyta • Dilution

• Microaggregates, cell fragments

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.

DIC caused by serpent poison

DIC

• Treatment

• treatment of primary disease

• Heparin at the beginning of procedure: avoiding thrombosis

• In case of bleeding: vvt, FFP, fibrinogene, thrombocyta concentrate

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

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