Hemophilia A, BVon Willebrand

disease

Theo Audi Yanto

Hemophilia AHemophilia B

•Hemophilia- “love of bleeding”

•2 types: A and B

•Hemophilia A:

•X linked recessive hereditary disorder that is due to defective or deficient factor VIII

Definition

Incidence

•It is the second most common inherited clotting factor abnormality (after von Willebrand disease)

•1 in 5000-10000 live male births

•No difference between racial groups

Genetics

•Transmitted by females, suffered by males

•The female carrier transmits the disorder to half their sons and the carrier state to half her dtrs

•The affected male does not transmit the disease to his sons (Y is nl) but all his dtrs are all carriers (transmission of defected X)

Spanish House

Russian House

British House

Hemophilia A

Factor VIII deficiency1 in 5000-10000 males

60% with severe disease

Actvitiy < 1%

Hemophilia B

Factor IX deficiency1 in 25000-35000 males30% spontaneous mutation50% with mild to moderate diseaseActivity > 1%

Christmas disease (1952)

•Deficiency of factor VIII or IX affects the propagation phase of coagulation•Most likely to cause bleeding in situations where tissue factor exposure is relatively low

BleedsBleeds in in HemophiliaHemophilia

• Minor BleedsMinor Bleeds

– Oral mucosaOral mucosa

– Intra-articularIntra-articular

– GI/GUGI/GU

– IntramuscularIntramuscular

• Major BleedsMajor Bleeds

– RetroperitonealRetroperitoneal

– RetropharyngealRetropharyngeal

– IntracranialIntracranial

ACUTE COMPLICATIONS OF HEMOPHILIAACUTE COMPLICATIONS OF HEMOPHILIA

Muscle hematoma (pseudotumor)Hemarthrosis

(joint bleeding)

16

Clinical Manifestations:Hemarthrosis• The most common, painful and most

physically, economically and psychologically debilitating manifestation.

• Clinically:

Aura: tingling warm sensation

Excruciating pain

Generally affects one joint at the time

Most commonly: knee; but there are others as elbows, wrists and ankles.

Edema, erythema, warmth and LOM

If treated early it can subside in 6 to 8 hs and disappear in 12 to 24 hs.

Ddx: DJD

Complications: Chronic involvement with joint deformity complicated by muscle atrophy and soft tissue contractures

LONG-TERM COMPLICATIONS LONG-TERM COMPLICATIONS OF HEMOPHILIAOF HEMOPHILIA

Joint destruction Nerve damage

Clinical ManifestationsHemarthrosis-

Images

• Stage III- early subchondral cyst

Stage IV- narrowing of intraarticular space

Clinical ManifestationsHematomas• Subcutaneous and muscular hematomas

spread within fascial spaces, dissecting deeper structures

• Subcutaneous bleeding spreads in characteristic manner- in the site of origin the tissue is indurated purplish black and when it extends the origin starts to fade

• May compress vital structures: such as the airway if it is bleeding into the tongue throat or neck; it can compromise arteries causing gangrene and ischemic contractures are common sequelae, especially of calves and forearms

• Muscle hematomas: 1)calf,2)thigh,3)buttocks,4)forearms

• Psoas hematoma- if right sided may mimic acute appendicitis

• Retroperitoneal hematoma: can dissect through the diaphragm into the chest compromising the airway. It can also compromise the renal function if it compresses the ureter

Clinical manifestationsPseudotumors• Dangerous and rare

complication

• Blood filled cysts that are gradually expanding

• Occur in soft tissues or bones.

• Most commonly in the thigh

• As they increase in size they erode contiguous structures.

• May require radical surgeries or amputation, and surgery is often complicated with infection

A pseudotumor is deforming the cortex of the femur (arrow).

Other ossified masses in the soft tissues (arrowheads) are probably soft-tissue pseudotumors.

Clinical manifestations

Intracranial hemorrhage

• Leading cause of death of hemophiliacs

• Spontaneous or following trauma

• May be subdural, epidural or intracerebral

• Suspect always in hemophilic patient that presents with unusual headache

• If suspected- FIRST TREAT, then pursue diagnostic workup

• LP only when fVIII has been replaced to more than 50%

Clinical manifestations

• Frequency and severity of bleeding are related to F VIII levels

Severity F VIII activity Clinical manifestations

Severe <1%Spontaneous hemorrhage from early

infancyFreq sp hemarthrosis

Moderate 2-5%Hemorrhage sec to trauma or surgery

Occ sp hemarthrosis

Mild >5%Hemorrhage sec to trauma or surgery

Rare sp bleeding

Coinheritance of prothrombotic mutations (i.e. Factor V Leiden) can decrease the risk of bleeding

History taking

•sign of Hemorrhage

•Family history

•infection related transfusion:

•HIV, hepatitis realated symptom

Physical examination

•Sign of bleeding

•Vital sign: tachycardia, tachypnea, hypotension, orthostasis

•Organ system-specific sign of hemorrhage:

•MSK, CNS, GI, GUT

Hemophilia: Work-up

Hgb/Hct nml/lowPT nmlaPTT high/nmlPlatelets nmlFactor levels (50-150%)

Mild > 5%Moderate 1-5%Severe < 1%

Inhibitor levelsLow titer 0-10 Bethesda UHigh titer > 10 Bethesda U

2828

Normal PTAbnormal PTT

Test for factor deficiency: Isolated deficiency in intrinsic pathway

(factors VIII, IX, XI) Multiple factor deficiencies (rare)

Repeatwith

50:50mix

50:50 mix is normal

50:50 mix is abnormal

Test for inhibitor activity: Specific factors: VIII,IX, XI

Non-specific (anti-phospholipid Ab)

3030

•Give factor q 12 hours for 2-3 days after major surgery, continue with daily infusions for 7-10 days•Trough factor levels with q 12 h dosing after major surgery should be at least 50-75%

•Most joint and muscle bleeds can be treated with “minor” (50%) doses for 1-3 days without monitoring

Treatment: The Old Days

Factor replacement Units = (wt[kg]) x (50mL plasma/kg) x (1 U factor/mL plasma) x

(desired factor level – native factor level)

FFP: 10-20 mL/kg BB will increase factor level 20-30%

Number of unit : desire dose (mL)/200 mL/unit

Plasma concentratesThousands of donors

Hepatitis B, CHIV (60-70%)

3333

Cryoprecipitate AHF (Antihemophilic Factor)

Berisi Faktor VIIIFaktor XIIIVon Willebrand Factor dan

fibrinogen (suhu simpan ≤30°C)Kandungan: 70 IU/unit F VIII dan >

140mg/unit fibrinogen

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Replacement Therapy

Plasma-derivedHeatingSolvent-

detergent mixture

Hep AParvovirus B19CJD

Recombinent1990sCost 2-3 x

Persistent inhibitors 10-15%

3535

Factor VIII containing products

Factor VIII, human plasma derived :Monarc M, Monoclonat, hemofil M, Koate-DVI, recombinate, kogenate, helixate, advate, xyntha

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Factor VIII concentrates differ in purity and Factor VIII concentrates differ in purity and manufacturing processesmanufacturing processes

PlasmaPlasma-derived-derived RecombinantRecombinant

IntermediateIntermediate HighHigh UltrapureUltrapure StandardStandard Human Human albumin-freealbumin-free

Humate-PHumate-P Koate-HPKoate-HP Hemofil-MHemofil-M RecombinatRecombinatee

AdvateAdvate

AlphanateAlphanate MonoclateMonoclate KogenateKogenate ReFacto-AFReFacto-AF

Monarc-MMonarc-M HelixateHelixate

ReFactoReFacto

A little about A little about costcostProductProduct Cost/doseCost/dose

Recombinant FVIIIRecombinant FVIII $4400$4400

Monoclonal FVIIIMonoclonal FVIII $3300$3300

BeneFIXBeneFIX $8800$8800

MononineMononine $8300$8300

FEIBAFEIBA $5000$5000

NovoSevenNovoSeven $6500 x 2$6500 x 2

Other meds

•Amicar (epsilon aminocaproic acid) (antifibrinolytic)

•DDAVP (antihemophilic)

Von Willebrand Disease

•Inherited

•Deficiency or dysfunction of vWF

•vWF, a large, multimeric glycoprotein

•mediate adhesion of platelet

•bind and stabilized procoagulant FVIII

vWF

•125/1.000.000

•severe disease only 0.5-5/million

•Male and female equaly

•mild and manageable bleeding

vWD

•1) partial quantitative deficiency (type I)

•(2) qualitative deficiency (type II)

•(3) total deficiency (type III)

Work Up

•Bleeding time

•PT and aPTT

•vWD Factor Antigen

•Ristocetin activity

•vWD multimeric Panel

•Genetic Testing

Presentation

•Easily bruising

•prolonged bleeding

•severe hemorrhage after surgery

•menorrhagia

•Physical finding: usually normal, only sign of bleeding or bruises

Treament

•Desmopressin DDAVP

•150 mcg intra nasal 2 h prior to procedure

•Transfusion: Cryoprecipitate

•Plasma derived: Humate-P (intermediate)

Disorder BT Plt PT aPTT TT Fib

Vasculopathies, connective tissue diseases, or collagen disorders affecting skin

Long Normal Normal Normal NormalNormal or increased*

Thrombocytopenia

Long Low Normal Normal Normal Normal

Qualitative platelet abnormalities

LongNormal or low• Normal Normal Normal Normal

Hemophilia A (factor VIII deficiency)

Normal Normal Normal Long Normal Normal

von Willebrand disease

Long Normal** Normal LongΔ Normal Normal

Disseminated intravascular coagulation

Long Low Long Long Long Low