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Hemophilia B

Bijan Keikhaei, Ahvaz Jundishapur

University of Medical Sciences

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Hemophilia BHemophilia B, or Christmas disease, is an inherited, X-linked, recessive disorder that results in deficiency of functional plasma coagulation factor IX.

As many as 1/3 of all cases are the result of spontaneous mutation.

Hemophilia B occurs in about one in 25,000 male births andaffects about 3,300 people in the United States.

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Severity of Hemophilia BThe normal range of FVIII and FIX is between 50% and 150%. Hemophilia severity is classified as follows:

Hemophilia B constitutes about 20% of hemophilia cases, about 50% of cases→ factor IX <l%= Severe

30% of cases→ factor IX <l-5%= Moderate20% of cases→ factor IX >6-40%= Mild

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Hemophilia B-Inheritance

Hemophilia B-Inheritance

Hemophilia B-Inheritance

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Women with Hemophilia B

There are circumstances, however, when females can experience bleeding symptoms.

Symptomatic carriers

Daughters of a father with hemophilia and a carrier mother

Turner’s syndrome

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Hemophilia B-Signs & Symptoms

Neonates: Prolonged bleeding and/or severe hematoma following procedures such as circumcision, phlebotomy, and/or immunizations; intracranial hemorrhage.

Toddler: Trauma-related soft-tissue hemorrhage; oral bleeding during teething

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Hemophilia B-Signs & Symptoms

Children and Adults: Hemarthrosis and hematomas with increasing physical activity; chronic arthropathy (late complication); traumatic intracranial hemorrhage (life threatening)

Diagnosis

1-Personal history of bleeding.2-Family history of bleeding and its inheritance pattern.

3-Laboratory testing.Usually, the activated partial thromboplastin time (aPTT) is prolonged; however, a normal aPTT does not exclude mild or even moderate hemophilia because of the relative insensitivity of the test. The aPTT

is significantly prolonged in severe hemophilia .

FVIII deficiency or hemophilia A can be diagnosed at birth because newborns should have normal levels of FVIII. In contrast, FIX levels are low during the newborn period and may take 6 months to reach

normal levels .The diagnosis of mild FIX deficient hemophilia, therefore, may be more difficult in the newborn period.

Sites of bleeding in hemophilia

Life-threateningIntracranialNeck/throatGastrointestinal

SeriousJoints (Hemarthrosis)

Muscles, especially deep compartments (iliopsoas,calf, and forearm)Mucous membranes in the mouth, gums, nose, andgenitourinary tract

Joint hemorrhage (Hemarthrosis)

A joint bleed is defined as an episode characterized by rapid loss of range of motion as compared with baseline that is associatedwith any combination of the following: pain or an unusual sensation in the joint, palpable swelling and warmth of the skin over the joint.

The onset of bleeding in joints is frequentlydescribed by patients as a tingling sensation andtightness within the joint. This “aura” precedesthe appearance of clinical signs.

Joint hemorrhage (Hemarthrosis)

A target joint is a joint in which 3 or more spontaneous bleeds have occurred within a consecutive 6-month period.

ArthrocentesisArthrocentesis (removal of blood from a joint)may be considered in the following situations:

a bleeding, tense, and painful joint, which shows no improvement 24 hr after conservative Treatment.

evidence of neurovascular compromise of the limb

unusual increase in local or systemic temperature and other evidence of infection (septic arthritis).

When necessary, arthrocentesis should be performed under factor levels of at least 30– 50 IU Dl for 48–72 hr .

Bleeds requiring admission

Suspected intracranial haemorrhage.Bleeding into neck/throat.

Forearm/calf bleed with suspicion or evidence of compartment syndrome.

Bleeding into hip or inguinal area, suspected iliopsoas haemorrhage.Undiagnosed abdominal pain.Persistent hematuria.Bleeds causing severe pain.

General Measures - Joint and Muscle Bleeds

R = Rest (in position of comfort)I = Ice (Cold pack to reduce bleeding and pain)C = gentle compression bandageE = ElevationS = splint

Treatment

Mild hemorrhages (ie, early Hemarthrosis, epistaxis, gingival bleeding): Maintain a FIX level of 30%

Major hemorrhages (ie, Hemarthrosis or muscle bleeds with pain and swelling, prophylaxis after head trauma with negative findings on examination): Maintain a FIX level of 50%

Life-threatening bleeding episodes (ie, major trauma or surgery, advanced or recurrent Hemarthrosis): Maintain a FIX level of 80-90%. Plasma levels are

maintained above 40-50% for a minimum of 7-10 days.

Type of bleed Haemophilia A  Haemophilia B  Comment

  Recombinant FVIII Recombinant FIX  Joint 40 units/kg Day 1

20 units/kg or usual homeprophylaxis dose Day 2 & 4

50 units/kg Day 1

25 units/kg or usual home prophylaxis dose Day 2 & 5

Factor replacement may be modified when intravenous access is difficult, particularly in toddlers. E.g. 40 units/kg Day 1 & Day 2. Intravenous cannula may be left insitu with patient returning for Day 2 dose. (As an outpatient, intravenous cannula should not be left insitu for > 24 hours.) 

Muscle (minor) 30 units/kg 50 units/kg  Muscle (major) 50 units/kg 75 units/kg Calf and forearm bleeds may lead to compartment

syndrome and be limb threatening. Arrange haematology and surgical reviewInvolvement of ileopsoas muscle may be associated with significant blood loss and mandates haematology

review .

Oral Mucosa & Dental 30 units/kg 50 units/kg Antifibrinolytic therapy is critical.Epistaxis (active) 30 units/kg 50 units/kg Apply local measures (pressure). Antifibrinolytic

therapy effective in preventing recurrence.

Gastrointestinal 50 units/kg 75 units/kg Haematology and gastroenterology review required. Lesion is usually found. Antifibrinolytic therapy may be helpful.

Genitourinary 50 units/kg 75 units/kg Evaluate for all causes however lesion not usually found. Antifibrinolytic therapy contraindicated in haematuria.

CNS/head 75 units/kg 125 units/kg Always treat with factor replacement prior to CNS imaging. Haematology & Neurosurgical review.

Trauma or surgery 50 - 75 units/kg 75 - 125 units/kg Consultation with haematologist essential.

Recommended clotting factor dosage

Analgesia

Paracetamol/codeine is sufficient in most cases, however morphine, tramadol can be used for

severe pain. Splinting/immobilisation is an effective adjunct for

reducing pain. Do not use products containing aspirin or NSAIDS (eg. ibuprofen, diclofenac).

Antifibrinolytic Therapy (tranexamic acid), Adjunctive management

Reduces breakdown of blood clots and is effective for treating and preventing recurrence of mouth bleeds and epistaxis.Contraindicated for treatment of haematuria .

Dose of tranexamic acid 25mg/kg/dose (max:1.5g/dose) tds orally for 5-7 days.

Tranexamic acid should not be given to patientswith FIX deficiency receiving prothrombin complexconcentrates, as this will exacerbate the riskof thromboembolism.

Antifibrinolytic Therapy (tranexamic acid)

Weight (kg) Tranexamic acid <20 Kg 250 mg tds

20 – 30 Kg 500 mg tds30 – 40 Kg 750 mg tds

>40 Kg 1 g tds

Definitions of factor replacement therapy protocols

Protocol Definition

Episodic Treatment given at the time of clinically evident bleeding

Continuous prophylaxis :primary,Secondary,Tertiary,Intermittant

Surgery and invasive procedures

Preoperative assessment should include inhibitor screening and inhibitor assay, particularly if the recovery of the replaced factor is significantly less than expected.

Surgery should be scheduled early in the week and early in the day .Adequate quantities of clotting factor concentrates.

Infusion of factor concentrates/hemostatic agentsis necessary before invasive diagnostic proceduressuch as lumbar puncture, arterial blood gas determination,or any endoscopy with biopsy.

Recombinant FIX

Benefix 250 ,500 ,1000 ,2000

Plasma derived FIX

Monofix 500 ,1000

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Hemophilia –B Factor IX

In absence of an inhibitor, each unit of FIX per kilogram of body weight infused intravenously will raise the plasma FIX level approximately 1 IU Dl.

The half-life is approximately. 18–24 hr.

Recombinant FIX (rFIX) :each unit of FIX per kg body weight infused will raise the FIX activity by approximately 0.8 IU dL in adults and 0.7 IU dL1 in children under15 years of age.

Prophylaxis-long acting

The long-acting recombinant Fc fusion factor IX (rFIXFc), Alprolix, was approved by the FDA in March 2014 for patients with hemophilia B .

Improvement of health and quality of life of people with hemophilia

Joint and muscle damage and other sequelaeof bleeding.

Inhibitor development.

Viral infection(s) transmitted through bloodProducts.

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obligate carrier of hemophilia B

The biological daughter of a man who has hemophilia.

The biological mother of more than one son with hemophilia.

The biological mother of at least one son with hemophilia and has at least one other blood relative with the disorder.

Definition of response to treatment of acute Hemarthrosis

Excellent :Complete pain relief within 8 hours and/or complete resolution of signs of bleeding after the initial injection and not requiring any further replacement therapy within 72 hours.

Good :Significant pain relief and/or improvement in signs of bleeding within approximately 8 hours after a single injection, but requiring more than one dose of replacement therapy within 72 hours for complete resolution

Moderate :Modest pain relief and/or improvement in signs of bleeding within approximately 8 hours after the initial injection and requiring more than one injection within 72 hours but without complete resolution

None :None or minimal improvement, or condition worsens, within approximately 8 h after the initial injection.

Muscle hemorrhage

Sites of muscle bleeding that are associated withneurovascular compromise, such as the deep flexor muscle groups of the limbs, require immediate management to prevent permanent damage and loss of function. These groups include:

the iliopsoas muscle (risk of femorocutaneous,crural, and femoral nerve palsy)

the superior-posterior and deep posterior compartmentsof the lower leg (risk of posterior tibial and deep peroneal nerve injury).

the flexor group of forearm muscles (risk of Volkmann’s ischemic contracture).

Principles of care

The primary aim of care is to prevent and treatbleeding with the deficient clotting factor.

2 .Whenever possible, specific factor deficiencyshould be treated with specific factor concentrate.

3 .People with hemophilia are best managed in acomprehensive care setting.

4 .Acute bleeds should be treated as quickly as possible,preferably within 2 h. If in doubt, treat

Definitions of factor replacement therapy protocols

Secondary prophylaxis Regular continuous treatment started after2 or more bleeds into large joints and before the onset of joint disease documented by physical examination and imaging studies.

Tertiary prophylaxis Regular continuous treatment started after the onset of joint disease documented by physical examination and plain radiographs of the affected joints.

Intermittent (periodic) prophylaxis: Treatment given to prevent bleeding for periods not exceeding 45 weeks in a year.

Vein Access

They are the lifelines for a person with hemophilia.23 -or 25-gauge butterfly needles are

recommended. Never cut down into a vein, except in an

emergency.Apply pressure for 3–5 min after venipuncture.

Venous access devices should be avoidedwhenever possible, but may be required insome children.

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Severity of Hemophilia B Mild hemophilia : bleeding typically occurs only after injury,

trauma, or surgery. About 25% of the hemophilia population has mild deficiency.

Moderate hemophilia :bleeding tends to occur after minor injuries, though spontaneous bleeding episodes may occur. About 15% of the hemophilia population has moderate deficiency.

Severe hemophilia :may experience not only bleeding after injury, trauma, or surgery, but also spontaneous bleeding into joints and muscles. About 60% of the hemophilia population has severe factor deficiency.

Joint hemorrhage (Hemarthrosis)

The goal of treatment of acute Hemarthrosis isto stop the bleeding as soon as possible. This should ideally occur as soon as the patient recognizes the “aura”, rather than after the onset of overt swelling and pain.

Further evaluation is necessary if the patient’ssymptoms continue longer than 3 days. The presence of inhibitors, septic arthritis, or fractureshould be considered if symptoms and findingspersist.

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Hemophilia B-Signs & Symptoms

The hallmark of hemophilia is hemorrhage into the joints(typically the ankles in children, and the ankles, knees, and elbows in adolescents and adults).

This bleeding is painful.

Management

Most bleeds will require factor replacement except for bruises and minor soft tissue injuries that do not

impact on function and mobility .

Invasive procedures such as arterial puncture, lumbar puncture must only be performed after clotting factor replacement.

Do not give IM injections.

Physical activity

Non-contact sports such as swimming ,

walking,golf,

badminton ,archery ,cycling ,rowing ,

sailing, table tennis