Hemophilia B is a disorder resulting in deficiency of functional plasma coagulation factor IX.
It could be inherited as X-linked, recessive condition or occur following spontaneous mutation. Acquired immunologic processes can also result in this disorder.
The incidence of hemophilia B is estimated to be approximately 1 case per 25,000-30,000 male births.
Hemophilia B is much less common than hemophilia A. Of all hemophilia cases, 80-85% are hemophilia A, 14% are hemophilia B.
Being X-linked recessive condition, hemophilia predominantly occurs in males. Females usually are asymptomatic carriers [Carriers may have mild hemophilia though]
Females may have clinical bleeding due to hemophilia if one of the following conditions is present:
- Inactivation [extreme lyonization] of the normal factor IX allele in one of the X chromosomes
- Homozygosity for the hemophilia gene
- Turner syndrome (XO) associated with the hemophilia gene.
Significant deficiency in factor IX may become evident in the neonatal period and continue through the life. But absence of bleeding does not exclude hemophilia.
Pathophysiology of Hemophilia B
Factor IX is present in plasma in a concentration of 4-5 µg/mL. It has a half-life of approximately 18-24 hours. Factor IX distributes in both the extravascular and intravascular compartments.
Like factor VIII, factor IX circulate in an inactive form. When activated, these 2 factors act to cleave and activate factor X which controls the conversion of fibrinogen to fibrin in coagulation cascade.
Therefore, factor IX deficiency, dysfunction or inhibitors lead to disruption of the normal intrinsic coagulation cascade, resulting in spontaneous hemorrhage and/or excessive hemorrhage in response to trauma.
Common sites of hemorrhage are
- Central nervous system
- Gastrointestinal system
- Genitourinary system
- Pulmonary system
- Cardiovascular system.
The gene for factor IX [like the gene for factor VIII] is located on the long arm of chromosome X, within the Xq27 region.
Approximately 3-5% of patients with severe hemophilia B develop alloantibody inhibitors to factor IX.
Both genetic and environmental factors determine the frequency of inhibitor development.
Classification of Severity
The classification of the severity of hemophilia has been on plasma procoagulant levels
- < 1% normal factor (<0.01 IU/mL) – Severe hemophilia
- 1-5% normal factor (0.01-0.05 IU/mL) – moderately severe hemophilia.
- >5% but < 40% normal factor (>0.05 to <0.40 IU/mL) -mild hemophilia.
But the severity of deficiency may not exactly correlate with levels of factors.
The Leyden phenotype of hemophilia B manifests as severe childhood disease, which subsequently improves at the onset of puberty, possibly due to androgen effect.
Clinical Presentation of Hemophilia B
A history of bleeding disproportionate to trauma or of spontaneous hemorrhage suggest hemophilia.
There could be a family history of bleeding problems.
Approximately 30-50% of patients with severe hemophilia present with manifestations of neonatal bleeding (eg, after circumcision). About 1-2% of neonates have intracranial hemorrhage. Other n may present with severe hematoma and prolonged bleeding from the cord or umbilical area.
After neonatal period, bleeding is uncommon in infants until they become toddlers. In toddlers, trauma-related soft-tissue hemorrhage occurs.
Oral bleeding at tooth eruption may be seen.
With physical activity in children, hemarthrosis and hematomas occur. Chronic arthropathy may result in a joint that is repeatedly affected.
Mild hemophilia would bleed only with trauma or surgery and may go unsuspected.
Joint and muscle hemorrhage are the most common manifestations of moderate and severe hemophilia. Weight-bearing joints, flexor groups of the arms and gastrocnemius of the legs may occur. Iliopsoas bleeding can result in the large volumes of blood loss and compression of the femoral nerve.
Bleeding may occur in genitourinary tract [presents as hematuria], GI tract and central nervous system..
There would be signs of blood loss in acute cases. These are
Organ system–specific signs of hemorrhage should be looked for. For example tenderness in joints or confusio
Patients should be thoroughly examined for bone and joint examination, jaundice, deformties. Also known cases of hemophilia should be looked for signs of liver failure and signs of opportunistic infections in patients who are HIV seroconverted.
- Dermatofibrosis Lenticularis (Buschke-Ollendorf Syndrome)
- Ehlers-Danlos Syndrome
- Factor V Deficiency
- Factor VII Deficiency
- Factor XI Deficiency
- Glanzmann Thrombasthenia
- Hemophilia C
- Hemophilia A
- Physical Child Abuse
- Platelet Disorders
- von Willebrand Disease
Diagnostic Work Up
Laboratory studies for suspected hemophilia B include
- Complete blood cell count – usually normal
- Coagulation studies
- Normal bleeding time and prothrombin time
- Prolonged activated partial thromboplastin time (aPTT)
- a normal aPTT does not exclude mild or even moderate hemophilia.
- Factor IX assay
- > 5% – mild
- 1-5% – moderate
- <1% – severe
- von Willebrand factor
- Low FVIII and low vWF indicate vWF deficiency as the primary diagnosis.
For neonatoal diagnosis cord blood assays can be done. But physiologic reduction of vitamin K–dependent factors may complicate the values.
In patients with an established diagnosis of hemophilia B, periodic screening for the presence of factor IX inhibitor and transfusion-related or transmissible diseases such as hepatitis and HIV may be desirable.
Laboratory confirmation of a FIX inhibitor is clinically indicated when
- Bleeding is not controlled after adequate amounts of factor concentrate
- Failure of correction of aPTT measurement is repeated after incubating the patient’s plasma with normal plasma at 37°C for 1-2 hours.
By convention, more than 0.6 Bethesda units (BU) is considered a positive result for an inhibitor.
- > 5 BU is low titre of inhibitor
- > 10 BU is a high titre.
Carrier Testing and Fetal Testing
Factor X level is often normal in factor IX carriers. Genetic testing can be done by
- Direct genetic testing
- Linkage analysis by restriction fragment length polymorphism (RFLP)
- Direct mutation analysis
For fetal testing, test can be performed on chorionic villous or amniocentesis samples.
Imaging studies for acute bleeds
- Head CT scans without contrast are used to assess for spontaneous or traumatic intracranial hemorrhage.
- MRI is also useful in the evaluation of the CNS, cartilage, synovium, and joint space.
- Ultrasonography for acute or chronic effusions.
- X-rays – Evidence of chronic degenerative joint disease may be visible on radiographs in patients who are untreated or inadequately treated or in those with recurrent joint hemorrhages.
Treatment of Hemophilia B
The treatment of hemophilia may involve
- Management of hemostasis
- Management of bleeding episodes
- Use of factor replacement products and medications
- Treatment of patients with factor inhibitors
- Treatment and rehabilitation of patients with hemophilia synovitis.
Treatment of patients with hemophilia ideally should be provided through a comprehensive hemophilia care center.
Ambulatory replacement [home] therapy for bleeding episodes is essential for preventing chronic arthropathy and deformities.
Patients are treated with prophylaxis or intermittent, on-demand therapy for bleeding events. Prophylaxis prevents or at least reduces the progression of damage.
In most developed countries with access to recombinant product, prophylaxis is primary. The therapy is started in patients as young as 1 y and continues into adolescence.
Otherwise, secondary prophylaxis (after a target joint has been established to prevent worsening of the joint) is instituted for a defined period.
Emergency ABCs (airway, breathing, circulation) should be done and bleeding should be controlled by aggressive hemostatic techniques.
Correct coagulopathy immediately. Include a diagnostic workup for hemorrhage
Various factor IX concentrates especially recombinant factor IX products are available to treat hemophilia B. Fresh frozen plasma is no longer used in hemophilia because of the lack of safe viral elimination and concerns regarding volume overload.
Target levels by hemorrhage severity are as follows:
- Mild hemorrhages (ie, early hemarthrosis, epistaxis, gingival bleeding): Maintain a 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 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
For Musculoskeletal bleeding, immobilization of the affected limb and the application of ice packs are helpful.
Oral bleeding can be aided by an antifibrinolytic agent e-aminocaproic acid to neutralize the fibrinolytic activity in the oral cavity.
All head injuries must be managed with close observation and investigated by imaging such as CT scanning or MRI.
Treatment of Patients with Inhibitors
- High doses – In case of low titre inhibitors
- Activated prothrombin complex concentrate
- Recombinant activated FVIIa
- Large doses of factor IX along with steroids or intravenous immunoglobulin (IVIG) and cyclophosphamide.
- Success rates of 50-80% have been reported.
- Immune tolerance induction
- Rituximab – a monoclonal antibody
- Nonsteroidal anti-inflammatory
- Avoid aspirin [ antilplatelet]
Do not circumcise male infants born to mothers who are known or thought to be carriers of hemophilia until disease in the infant has been excluded.
Routine immunizations may be given by means of a deep subcutaneous route (rather than deep intramuscular route) with a fine-gauge needle.
In severe hemophilia, consider prophylaxis
Carrier testing may prevent births of individuals with major hemophilia.
Generally, individuals with severe hemophilia should avoid high-impact contact sports and other activities with a significant risk of trauma.
However, physical activity improves overall conditioning, reduces injury rate and severity.
Prognosis of Hemophilia B
With appropriate education and treatment, patients with hemophilia can live full and productive lives.
Intracranial hemorrhage is the second most common cause of death and the most common cause of death related to hemorrhage. Of
Overall, the mortality rate for patients with hemophilia is twice that of the healthy male population.
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