Hemophilia B 

Updated: Nov 14, 2019
Author: Robert A Zaiden, MD; Chief Editor: Srikanth Nagalla, MBBS, MS, FACP 

Overview

Practice Essentials

Hemophilia B, or Christmas disease, is an inherited, X-linked, recessive disorder that results in deficiency of functional plasma coagulation factor IX. Spontaneous mutation and acquired immunologic processes can result in this disorder as well. Hemophilia B constitutes about 20% of hemophilia cases, and about 50% of these cases have factor IX levels greater than 1%.

The role of the coagulation system is to produce a stable fibrin clot at sites of injury. See the image below.

Coagulation Cascade Coagulation Cascade

Signs and symptoms

The hallmark of hemophilia is hemorrhage into the joints. This bleeding is painful and leads to long-term inflammation and deterioration of the joint (typically the ankles in children, and the ankles, knees, and elbows in adolescents and adults), resulting in permanent deformities, misalignment, loss of mobility, and extremities of unequal lengths.

With mild hemophilia, hemorrhage is most likely to occur with trauma or surgery. A traumatic challenge relatively late in life may have to occur before mild or moderate hemophilia is suspected.

Signs and symptoms of moderate and severe hemophilia include the following:

  • 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

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

There may also be signs and symptoms of infectious disease related to HIV/AIDS or hepatitis.

See Presentation for more detail.

Diagnosis

Examination in patients with hemophilia B may reveal the following signs of hemorrhage:

  • Systemic: Tachycardia, tachypnea, hypotension, and/or orthostasis

  • Musculoskeletal: Joint tenderness, pain with movement, decreased range of motion, swelling, effusion, warmth

  • Neurologic: Abnormal findings, altered mental status, meningismus

  • Gastrointestinal: Can be painless or present with hepatic/splenic tenderness and peritoneal signs

  • Genitourinary: Bladder spasm/distention/pain, costovertebral angle pain

  • Other: Hematoma leading to location-specific signs (eg, airway obstruction, compartment syndrome)

Laboratory tests

Laboratory studies for suspected hemophilia B include the following:

  • Complete blood cell count: Normal or low hemoglobin/hematocrit levels; normal platelet count

  • Coagulation studies: Do not delay coagulation correction pending test results; normal bleeding and prothrombin times; normal or prolonged activated partial thromboplastin time

  • Factor IX (FIX) assay: Mild disease, result is over 5%; moderate, 1-5%; severe, below 1%

  • von Willebrand factor (vWF) and factor VIII levels: To exclude vWF deficiency as primary diagnosis (low vWF and low FVIII)

  • Screening tests for HIV and hepatitis

  • Genetic carrier and fetal testing

Imaging studies

After initiating coagulation therapy, perform early and aggressive imaging, even when there is a low suspicion for hemorrhage. Imaging choices are guided by clinical suspicion and the anatomic location of involvement, such as the following:

  • Head computed tomography scanning (without contrast): To assess for spontaneous or traumatic intracranial hemorrhage

  • Magnetic resonance imaging: To further evaluate spontaneous/traumatic hemorrhage in the head or spinal column; also to assess cartilage, synovia, and joint spaces

  • Ultrasonography: To assess joints affected by acute or chronic effusions

  • Joint radiography: Of limited value in acute hemarthrosis; to evaluate untreated or inadequately treated disease; in those with recurrent joint hemorrhages, chronic degenerative joint disease may be evident

See Workup for more detail.

Management

Factor IX is the treatment of choice for acute hemorrhage or presumed acute hemorrhage in patients with hemophilia B. Recombinant factor IX is the preferred source for replacement therapy. Ideally, patients with hemophilia should be treated at a comprehensive hemophilia care center.

Management of hemophilia B includes the following:

  • Control of hemostasis

  • Treatment of bleeding episodes

  • Administration of factor replacement products and medications

  • Use of factor inhibitors

  • Rehabilitation of patients with hemophilia synovitis

  • Primary and/or secondary prophylaxis

Treatment may also vary with site-specific locations (eg, joints, mouth, gastrointestinal region, head).

Pharmacotherapy

The following medications are used in the management of hemophilia B:

  • Factor IX-containing products (eg, factor IX, recombinant factor IX, factor IX complex)

  • Recombinant coagulation factor VIIa

  • Recombinant coagulation factor IX

  • Antifibrinolytics (eg, epsilon aminocaproic acid, tranexamic acid)

  • Antihemophilic agents (eg, desmopressin, anti-inhibitor coagulant complex, human antihemophilic factor, recombinant human antihemophilic factor, plasma-derived prothrombin complex concentrates/factor IX complex concentrates, plasma-derived coagulation factor IX concentrate)

  • Monoclonal antibodies (eg, rituximab)

  • Analgesics (eg, narcotic agents, NSAIDS, acetaminophen with codeine or synthetic codeine analogs)

See Treatment and Medication for more detail.

For related information, see Hemophilia A, Acquired Hemophilia, and Hemophilia C.

 

Background

Historical background

Hemophilia is one of the oldest described genetic diseases. An inherited bleeding disorder in males was recognized in Talmudic records of the second century. The modern history of hemophilia began in 1803 with the description of hemophilic kindred by John Otto, followed by the first review of hemophilia by Nasse in 1820. Wright demonstrated evidence of laboratory defects in blood clotting in 1893; however, FVIII was not identified until 1937 when Patek and Taylor isolated a clotting factor from the blood, which they called antihemophilia factor (AHF).

In 1952, Christmas disease was described and named after the surname of the first patient who was examined in detail. Mixing plasma from a patient with "true hemophilia" and with plasma from a patient with Christmas disease corrected the clotting time; thus, hemophilia A and B were differentiated.

In the early 1960s, cryoprecipitate was the first concentrate available for the treatment of patients with hemophilia. In the 1970s, lyophilized intermediate-purity concentrates were obtained from a large pool of blood donors. The introduction of concentrated lyophilized products that are easy to store and transport has dramatically improved the quality of life of patients with hemophilia and facilitated their preparation for surgery and home care.

In the 1980s, the risk of transmitting viral contaminants in commercial FVIII concentrates became increasingly recognized. By the mid 1980s, most patients with severe hemophilia had been exposed to hepatitis A, hepatitis B, and hepatitis C viruses and human immunodeficiency virus (HIV). New viricidal techniques have been effective in eliminating new HIV transmissions and virtually eliminating hepatitis B and hepatitis C exposures. The present standard of using recombinant products, especially those without exposure to animal proteins, in the treatment of hemophilia virtually eliminates the risk of viral exposure.

Severity classification

The classification of the severity of hemophilia has been based on either clinical bleeding symptoms or plasma procoagulant levels; the latter are the most widely used criteria. Persons with less than 1% normal factor (< 0.01 IU/mL) are considered to have severe hemophilia. Persons with 1-5% normal factor (0.01-0.05 IU/mL) are considered to have moderately severe hemophilia. Persons with more than 5% but less than 40% normal factor (> 0.05 to < 0.40 IU/mL) are considered to have mild hemophilia.

Clinical bleeding symptom criteria have been used because patients with factor IX levels of less than 1% occasionally have little or no spontaneous bleeding and appear to have clinically moderate or mild hemophilia. Furthermore, the reverse is true for patients with procoagulant activities of 1-5%, who may present with symptoms of clinically severe disease. A minority of patients have coexisting thrombophilic states such as factor V Leiden mutation, protein C or protein S deficiency, or prothrombin G20210A mutations, which counterbalance bleeding tendencies and therefore lessen or delay symptoms.

Pathophysiology

Factor IX deficiency, dysfunctional factor IX, or factor IX inhibitors lead to disruption of the normal intrinsic coagulation cascade, resulting in spontaneous hemorrhage and/or excessive hemorrhage in response to trauma. Hemorrhage sites include joints (eg, knee, elbow), muscles, central nervous system (CNS), GI system, genitourinary (GU) system, pulmonary system, and cardiovascular system. Patients who acquired HIV, hepatitis, or other viruses suffer from maladies associated with those infections.

Factor IX

Factor IX, a vitamin K–dependent single-chain glycoprotein, is synthesized first by the hepatocyte. The precursor protein undergoes extensive posttranslational modification before being secreted into the blood.

Factor IX is present in plasma in a concentration of 4-5 µg/mL, with a half-life of approximately 18-24 hours. A 3-fold variation in the activity of factor IX in plasma is normal. Since factor IX is smaller than albumin, it distributes in both the extravascular and intravascular compartments.

Coagulation system

The role of the coagulation system, as depicted in the image below, is to produce a stable fibrin clot at sites of injury. The clotting mechanism has two pathways: intrinsic and extrinsic.

Coagulation Cascade Coagulation Cascade

The intrinsic system is initiated when factor XII is activated by contact with damaged endothelium. The activation of factor XII can also initiate the extrinsic pathway, fibrinolysis, kinin generation, and complement activation.

In conjunction with high-molecular-weight kininogen (HMWK), factor XIIa converts prekallikrein (PK) to kallikrein and activates factor XI. Activated factor XI, in turn, activates factor IX in a calcium-dependent reaction. Factor IXa can bind phospholipids. Then, factor X is activated on the cell surface; activation of factor X involves a complex (tenase complex) of factor IXa, thrombin-activated FVIII, calcium ions, and phospholipid.

In the extrinsic system, the conversion of factor X to factor Xa involves tissue factor (TF), or thromboplastin; factor VII; and calcium ions. TF is released from the damaged cells. It is thought to be a lipoprotein complex that acts as a cell surface receptor for FVII, with its resultant activation. It also adsorbs factor X to enhance the reaction between factor VIIa, factor X, and calcium ions. Factor IXa and factor XII fragments can also activate factor VII.

In the common pathway, factor Xa (generated through the intrinsic or extrinsic pathways) forms a prothrombinase complex with phospholipids, calcium ions, and thrombin-activated factor Va. The complex cleaves prothrombin into thrombin and prothrombin fragments 1 and 2. Thrombin converts fibrinogen into fibrin and activates FVIII, factor V, and factor XIII.

Fibrinopeptides A and B, the results of the cleavage of peptides A and B by thrombin, cause fibrin monomers to form and then polymerize into a meshwork of fibrin; the resultant clot is stabilized by factor XIIIa and the cross-linking of adjacent fibrin strands. Because of the complex interactions of the intrinsic and extrinsic pathways (factor IXa activates factor VII), the existence of only one in vivo pathway with different mechanisms of activation has been suggested.

FVIII and FIX circulate in an inactive form. When activated, these 2 factors cooperate to cleave and activate factor X, a key enzyme that controls the conversion of fibrinogen to fibrin. Therefore, the lack of either of these factors may significantly impair clot formation and, as a consequence, result in clinical bleeding.

Genetics

The gene for factor IX—like the gene for factor VIII—is located on the long arm of chromosome X, within the Xq27 region. The factor IX gene (F9) has 34 kb and comprises eight exons and seven intervening sequences. The mature protein is composed of 415 amino acids. Point mutations and deletions in the factor IX gene are the most common causes of hemophilia B.

Clinical manifestations

The hallmark of hemophilia is hemorrhage into the joints. This bleeding is painful and leads to long-term inflammation and deterioration of the joint (typically the ankles in children and the ankles, knees, and elbows in adults and adolescents), resulting in permanent deformities, misalignment, loss of mobility, and extremities of unequal lengths.

Human synovial cells synthesize high levels of tissue factor pathway inhibitor, resulting in a higher degree of factor Xa inhibition, which predisposes hemophilic joints to bleed. Synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage progress, with eventual subchondral bone-cyst formation.

Inhibitors

Approximately 3-5% of patients with severe hemophilia B develop alloantibody inhibitors that can neutralize factor IX. These inhibitors are usually immunoglobulin G antibodies and appear after the first infusions of FIX concentrate.

Both genetic and environmental factors determine the frequency of inhibitor development. Specific molecular abnormalities (eg, gene deletions, stop codon mutations, frameshift mutations) and an absence or paucity of endogenous factor IX (severe disease) are associated with a higher incidence of inhibitor development. Inhibitors are more likely to develop in black children. In addition, purified products (some no longer marketed) have been associated with increased inhibitor development.

Etiology

Hemophilia B is an X-linked recessive disease caused by an inherited or acquired mutation in the factor IX gene or by an acquired factor IX inhibitor. The gene for factor IX is located on the long arm of the X chromosome in band q27. Factor IX contains 415 amino acids and has a molecular weight of 57,000 d. The gene that encodes this protein is 33 kb and contains 8 exons and 7 introns.

Several hundred mutations with different amino acid substitutes have been described in hemophilia B. These mutations include partial and total deletions, missense mutations, and others that result in the decreased or absent production of factor IX or the production of an abnormal protein. Evaluation and knowledge of the specific gene defect in families with severe hemophilia enables accurate gene tracking, carrier analysis, and prenatal diagnosis.

The defect results in the insufficient generation of thrombin by the factor IXa and factor VIIIa complex by means of the intrinsic pathway of the coagulation cascade. This mechanism, in combination with the effect of the tissue-factor pathway inhibitor, creates an extraordinary tendency for spontaneous bleeding.

Epidemiology

Hemophilia has a worldwide distribution. The incidence of hemophilia B is estimated to be approximately 1 case per 25,000-30,000 male births. The prevalence of hemophilia B is 5.3 cases per 100,000 male individuals, with 44% of those having severe disease.

Hemophilia B is much less common than hemophilia A. Of all hemophilia cases, 80-85% are hemophilia A, 14% are hemophilia B, and the remainder are various other clotting abnormalities.

Racial, sexual, and age-related differences in incidence

Hemophilia B occurs in all races and ethnic groups. In general, the demographics of hemophilia follow the racial distribution in a given population; for example, rates of hemophilia among whites, African Americans, and Hispanic males in the US are similar.

Because hemophilia is an X-linked, recessive condition, it occurs predominantly in males. Females usually are asymptomatic carriers. However, mild hemophilia may be more common in carriers than previously recognized. In one study, 5 of 55 patients with mild hemophilia (factor levels 5-50%) were girls.[1]

Females may have clinical bleeding due to hemophilia if one of the following conditions is present:

  • Extreme lyonization (ie, inactivation of the normal factor IX allele in one of the X chromosomes
  • Homozygosity for the hemophilia gene (ie, father with hemophilia and mother who is a carrier, two independent mutations, or some combination of inheritance and new mutations)
  • Turner syndrome (XO) associated with the affected hemophilia gene.

Significant deficiency in FIX may become evident in the neonatal period and continue through the life of the affected individual. The absence of hemorrhagic manifestations at birth does not exclude hemophilia. Excessive bleeding after normal trauma encountered during ambulation at the toddler stage may be the first indication of hemophilia.

The Leyden phenotype of hemophilia B manifests as severe childhood disease, which subsequently improves at the onset of puberty, likely due to androgen effect.

Prognosis

With appropriate education and treatment, patients with hemophilia can live full and productive lives. Prophylaxis and early treatment with factor concentrate that is safe from viral contamination have dramatically improved the prognosis of patients regarding morbidity and mortality due to severe hemophilia. Nevertheless, approximately one quarter of patients with severe hemophilia age d 6-18 years have below-normal motor skills and academic performance and have more emotional and behavioral problems than others.[2]

Factor concentrates have made home-replacement therapy possible, improving patients' quality of life. In addition, dramatic gains in life expectancy occurred during the era of replacement therapy. The life expectancy rose from 11 years or less for patients with severe hemophilia before the 1960s to almost 60 years prior to HIV epidemic in the 1980s.[3, 4]

Viral infection from contaminated factor concentrate became a problem during the replacement era. Most patients with hemophilia who received plasma-derived products that were not treated to eliminate potential contaminating viruses became infected with HIV or hepatitis A, hepatitis B, or hepatitis C viruses.

The most serious of these was HIV infection. The first deaths of people with hemophilia due to AIDS were observed in the early 1980s. Rates of seroconversion were more than 75% for severe disease, 46% for moderate disease, and 25% for mild disease.

In the United States, death rates of patients with hemophilia increased from 0.4 deaths per million population in 1979-1981 to 1.2 deaths per million population in 1987-1989; AIDS accounted for 55% of all hemophilia deaths. Causes of death shifted from intracranial and other bleeding to AIDS and cirrhosis from hepatitis. AIDS remains the most common cause of death in patients with severe hemophilia.[4] Indeed, HIV-infected individuals are likely to die of that disease rather than from hemophilia.

With improved screening of donors, new methods of factor concentrate purification, and recombinant concentrates, infectious complications now mostly of historical importance. However, even with these methods, some viruses (eg, parvovirus B19) cannot be removed and may be transmitted through plasma-derived products. Other potential infectious agents include those that cause Creutzfeldt-Jakob disease. With the development of animal protein–free products, the risk of contamination with these agents may be decreased.

Intracranial hemorrhage and hemorrhages into the soft tissue around vital areas, such as the airway or internal organs, remain the most important life-threatening complications. The lifetime risk of intracranial bleeding is 2-8% and accounts for one third of deaths due to hemorrhage, even in the era of factor replacement. Intracranial hemorrhage is the second most common cause of death and the most common cause of death related to hemorrhage. Of patients with severe hemophilia, 10% have intracranial bleeding, with a mortality rate of 30%.

Chronic debilitating joint disease results from repeated hemarthrosis; synovial membrane inflammation; hypertrophy; and, eventually, destructive arthritis. Early replacement of coagulation factors by means of infusion is essential to prevent functional disability. Thus, prophylactic therapy administered 2-3 times weekly, starting when patients are young, is considered the standard of care in most developed countries.

Before the widespread use of replacement therapy, patients with severe hemophilia had a shortened lifespan and diminished quality of life that was greatly affected by hemophilic arthropathy. Home therapy for hemarthroses became possible with factor concentrates. Prophylactic therapies with lyophilized concentrates that eliminate bleeding episodes help prevent joint deterioration, especially when instituted early in life (ie, at age 1-2 y).

Overall, the mortality rate for patients with hemophilia is twice that of the healthy male population. For severe hemophilia, the rate 4-6 times higher. If hepatitis and cirrhosis are excluded, the overall mortality rate of patients with severe hemophilia is 1.2 times that of the healthy male population.[4]

Patient Education

Starting in infancy, regular dental evaluation is recommended, along with instruction regarding proper oral hygiene, dental care, and adequate fluoridation.

Encourage the patient to engage in appropriate exercise. Advise the patient against participating in contact and collision sports.

Patient and family education about early recognition of hemorrhage signs and symptoms is important for instituting or increasing the intensity of replacement therapy. This treatment helps prevent the acute and chronic complications of the disease that may vary from life-threatening events to quality-of-life–impairing events.

In addition, educating patients or family members about factor replacement administration at home has greatly enhanced the quality of life of patients with severe hemophilia.

For patient education information, see the Blood and Lymphatic System Center, as well as Hemophilia.

 

Presentation

History

Hemophilia is suggested by a history of hemorrhage disproportionate to trauma or of spontaneous hemorrhage, or a family history of bleeding problems. Concomitant illness may include chronic inflammatory disorders, autoimmune diseases, hematologic malignancies (acquired form), and allergic drug reactions.

For individuals with documented hemophilia, inquire regarding the type of deficiency (eg, VIII, IX, von Willebrand), percent factor deficiency, known presence of inhibitors, and HIV/hepatitis status.

Approximately 30-50% of patients with severe hemophilia present with manifestations of neonatal bleeding (eg, after circumcision). Approximately 1-2% of neonates have intracranial hemorrhage. Other neonates may present with severe hematoma and prolonged bleeding from the cord or umbilical area or at sites of blood draws or immunizations.

After the immediate neonatal period, bleeding is uncommon in infants until they become toddlers, when trauma-related soft-tissue hemorrhage occurs. Young children may also have oral bleeding when their teeth are erupting. Bleeding from gum and tongue lacerations is often troublesome because the oozing of blood may continue for a long time despite local measures.

As physical activity increases in children, hemarthrosis and hematomas occur. Chronic arthropathy is a late complication of recurrent hemarthrosis in a target joint. Traumatic intracranial hemorrhage is a serious life-threatening complication that requires urgent diagnosis and intervention.

With mild disease, hemorrhage is most likely to occur with trauma or surgery. A traumatic challenge relatively late in life may have to occur before mild or moderate hemophilia is suspected.

Signs of hemorrhage include the following:

  • General - Weakness and orthostasis

  • Musculoskeletal (joints) - Tingling, cracking, warmth, pain, stiffness, and refusal to use joint (children)

  • CNS - Headache, stiff neck, vomiting, lethargy, irritability, and spinal cord syndromes

  • GI - Hematemesis, melena, frank red blood per rectum, and abdominal pain

  • Genitourinary - Hematuria, renal colic, and postcircumcision bleeding

  • Other - Epistaxis, oral mucosal hemorrhage, hemoptysis, dyspnea (hematoma leading to airway obstruction), compartment syndrome symptoms, and contusions

Joint and muscle hemorrhage are the most common manifestations of moderate and severe hemophilia. Petechiae usually do not occur in patients with hemophilia because they are manifestations of capillary blood leaking, which is typically the result of vasculitis or abnormalities in the number or function of platelets.

Signs of infectious disease include the following:

  • HIV/AIDS-related symptoms

  • Hepatitis-related symptoms

The principal sites of bleeding in patients with hemophilia are as follows. Bleeds affect weight-bearing joints and other joints. The muscles most commonly affected are the flexor groups of the arms and gastrocnemius of the legs. Iliopsoas bleeding is dangerous because of the large volumes of blood loss and because of compression of the femoral nerve.

In the genitourinary tract, gross hematuria may occur in as many as 90% of patients. In the GI tract, bleeding may complicate common GI disorders. Bleeding in the CNS is the leading cause of hemorrhagic death among patients with hemophilia.

Physical Examination

Systemic signs of hemorrhage include the following:

  • Tachycardia

  • Tachypnea

  • Hypotension

  • Orthostasis

Organ system–specific signs of hemorrhage include the following:

  • Musculoskeletal (joints) - Tenderness, pain with movement, decreased range of motion, swelling, effusion, and warmth

  • CNS - Abnormal neurologic exam findings, altered mental status, and meningismus

  • GI - Can be painless; hepatic/splenic tenderness and peritoneal signs

  • GU - Bladder spasm/distension/pain, costovertebral angle pain

  • Other - Hematoma leading to location-specific signs (eg, airway obstruction, compartment syndrome)

Signs of infectious disease include the following:

  • HIV/AIDS-related signs

  • Hepatitis-related signs

Direct the examination to identify signs related to bleeding in the joints, muscles, and other soft tissues that has occurred spontaneously or after minimal challenge. Observe the patient's stature. Examine the weight-bearing joints, especially the knees and ankles, and, in general, the large joints for deformities or ankylosis. Look for jaundice, other signs of liver failure (eg, cirrhosis from viral infection), and signs of opportunistic infections in patients who are HIV seroconverted.

Clinical Classification

Hemophilia is classified according to the clinical severity as mild, moderate, or severe (see Table 1, below). Patients with severe disease usually have less than 1% factor activity. It is characterized by spontaneous hemarthrosis and soft tissue bleeding in the absence of precipitating trauma. Patients with moderate disease have 1-5% factor activity and bleed with minimal trauma. Patients with mild hemophilia have more than 5% factor VIII (FVIII) activity and bleed only after significant trauma or surgery.

Table 1. Severity, Factor Activity, and Hemorrhage Type (Open Table in a new window)

Classification

Factor Activity, %

Cause of Hemorrhage

Mild

>5-40

Major trauma or surgery

Moderate

1-5

Mild-to-moderate trauma

Severe

< 1

Spontaneous, hemarthrosis

 

DDx

Diagnostic Considerations

Problems to be considered include vitamin K and other factor deficiencies, as well as acquired hemophilia. Other congenital bleeding disorders must be excluded. These may include the following:

  • von Willebrand disease (autosomal dominant transmission)

  • Platelet disorders (eg, Glanzmann thrombasthenia)

  • Deficiency of other coagulation factors (ie, factor V [FV], FVII, FX, FXI, or fibrinogen)

Differentiating between severe hemophilia A and hemophilia B is almost clinically impossible, but specific laboratory factor assays can help with the distinction. Conditions that can increase FVIII levels (eg, age, ABO blood type, stress, exercise) can obscure the diagnosis of hemophilia A. The diagnosis of hemophilia B may be delayed by physiologically low levels of all vitamin K–dependent coagulation factors. FIX Leyden, in which FIX levels progressively increase after puberty to nearly normal values, must also be considered when hemophilia B is diagnosed.

For related information, see Hemophilia A, Acquired Hemophilia, and Hemophilia C.

Differential Diagnoses

 

Workup

Approach Considerations

Laboratory studies for suspected hemophilia B include a complete blood cell count, coagulation studies, and a factor IX (FIX) assay. Never delay indicated coagulation correction pending diagnostic testing.

On the hemoglobin/hematocrit, expect normal or low values. Expect a normal platelet count. On coagulation studies, the bleeding time and prothrombin time (which assesses the extrinsic coagulation pathway) are normal.

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.

For FIX assays, levels are compared with a normal pooled-plasma standard, which is designated as having 100% activity or the equivalent of FIX U/mL. Normal values are 50-150%. Values in hemophilia are as follows:

  • Mild - Greater than 5%

  • Moderate - 1-5%

  • Severe - Less than 1%

Spontaneous bleeding complications are severe in individuals with undetectable activity (< 0.01 U/mL), moderate in individuals with activity (2-5% normal), and mild in individuals with factor levels greater than 5%.

Usually, von Willebrand factor (vWF) levels are also measured. The combination of low FVIII and low vWF may indicate vWF deficiency as the primary diagnosis.

Because FIX is a large molecule that does not cross the placenta, the diagnosis can be made at birth with quantitative assay of coagulation factors in the cord blood. However, early diagnosis of FIX deficiency is complicated by the physiologic reduction of vitamin K–dependent factors in young infants. In term and healthy premature neonates, FIX values are low (20-50% of the normal level), due to hepatic immaturity. levels rise to normal after 6 months of age. FVIII levels are normal during that period of life.

In patients with an established diagnosis of hemophilia B, laboratory evaluations include periodic screening for the presence of FIX inhibitor and screening for transfusion-related or transmissible diseases such as hepatitis and HIV. This may be less important in populations who receive only recombinant product.[#WorkupImagingStudies]

Imaging studies for acute bleeds

Early and aggressive imaging is indicated, even with low suspicion for hemorrhage, after coagulation therapy is initiated. Imaging choices are guided by clinical suspicion and anatomic location of involvement.

Head CT scans without contrast are used to assess for spontaneous or traumatic intracranial hemorrhage. Perform magnetic resonance imaging on the head and spinal column for further assessment of spontaneous or traumatic hemorrhage. MRI is also useful in the evaluation of the cartilage, synovium, and joint space.

Ultrasonography is useful in the evaluation of joints affected by acute or chronic effusions. This technique is not helpful for evaluating the bone or cartilage. Special studies such as angiography and nucleotide bleeding scan may be clinically indicated.

Testing for Inhibitors

Laboratory confirmation of a FIX inhibitor is clinically important when bleeding is not controlled after adequate amounts of factor concentrate are infused during a bleeding episode. For the assay, the aPTT measurement is repeated after incubating the patient's plasma with normal plasma at 37°C for 1-2 hours. If the prolonged aPTT is not corrected, the inhibitor concentration is titrated using the Bethesda method.

By convention, more than 0.6 Bethesda units (BU) is considered a positive result for an inhibitor. Less than 5 BU is considered a low titer of inhibitor, and more than 10 BU is a high titer. The distinction is clinically significant, as patients with low-titer inhibitors may respond to higher doses of FVIII concentrate.

Carrier Testing and Fetal Testing

FIX level is often normal in FIX carriers. When the specific FIX gene mutation is known, direct genetic testing provides accurate results. Linkage analysis by restriction fragment length polymorphism (RFLP) in multiple family members can be used. Direct mutation analysis is available in several laboratories for unknown FIX mutations.

For fetal testing, if the mutation is known, then RFLP can be performed on chorionic villous or amniocentesis samples. If the mutation is not known, gene sequencing can be performed.

Radiography

Radiography for joint assessment is of limited value in acute hemarthrosis. 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. In these patients, radiographs may show synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage that progresses with subchondral bone cyst formation. Hemophilic arthropathy evolves through 5 stages, starting as an intra-articular and periarticular edema due to acute hemorrhage and progressing to advanced erosion of the cartilage with loss of the joint space, joint fusion, and fibrosis of the joint capsules.[5] For discussion of the 5-stage Arnold-Hilgartner classification of hemophilic arthropathy, see Imaging in Musculoskeletal Complications of Hemophilia

 

Treatment

Approach Considerations

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, and treatment and rehabilitation of patients with hemophilia synovitis.

Treatment of patients with hemophilia ideally should be provided through a comprehensive hemophilia care center. These centers follow a multidisciplinary approach, with specialists in hematology, orthopedics, dentistry, and surgery; nurses; physiotherapists; social workers; and related allied health professionals. Patients treated at comprehensive care clinics have been shown to have better access to care, less morbidity, and better overall outcome.

Ambulatory replacement therapy for bleeding episodes is essential for preventing chronic arthropathy and deformities. Home treatment and infusion by the family or patient is possible in most cases. Prompt and appropriate treatment of hemorrhage is important to prevent long-term complications and disability.

Dose calculations are directed toward achieving a factor IX (FIX) activity level of 30% for most mild hemorrhages, of at least 50% for severe bleeds (eg, from trauma) or for prophylaxis of major dental surgery or major surgery, and 80-100% in life-threatening hemorrhage. Hospitalization is reserved for severe or life-threatening bleeds, such as large soft tissue bleeds; retroperitoneal hemorrhage; and hemorrhage related to head injury, surgery, or dental work.

Patients are treated with prophylaxis or intermittent, on-demand therapy for bleeding events. Prophylaxis has been shown in many studies to prevent or at least reduce the progression of damage to target sites, such as joints.[6, 7] According to a review of six randomized controlled trials, preventative therapy started early in childhood, as compared to on-demand treatment, is able to reduce total bleeds and bleeding into joints resulting in a decrease in overall joint deterioration and an improvement in patient quality of life.[8]

In most developed countries with access to recombinant product, prophylaxis is primary (ie, therapy is started in patients as young as 1 y and continues into adolescence). A cost-benefit analysis indicates that this approach reduces overall factor use and significantly reduces morbidity.[9] In situations in which this is not feasible, secondary prophylaxis (ie, therapy after a target joint has been established to prevent worsening of the joint) is instituted for a defined period.[10, 11]

Dosing is designed to maintain trough levels greater than 2%. With the development of FIX preparations that have extended half-lives, dosing for routine prophylaxis may be as infrequent as every 10 days.

In the future, oral administration of FIX for prophylaxis may become possible, through the use of hydrogel carriers that protect FIX from destruction in the stomach and release it in the intestines.[12] Gene therapy offers the potential for a definitive cure, and has shown promise in small trials in humans.[13]

For related information, see Hemophilia A, Acquired Hemophilia, and Hemophilia C.

Prehospital Care

Prehospital providers should address the emergency ABCs (airway, breathing, circulation) while rapidly transporting the patient to a definitive care facility. In the prehospital setting, providers should do the following:

  • Apply aggressive hemostatic techniques
  • Assist patients capable of self-administered factor therapy
  • Gather focused historical data if the patient is unable to communicate

Emergency Department Care

Before a patient with hemophilia is treated, the following information should be obtained:

  • The type and severity of factor deficiency
  • The nature of the hemorrhage or the planned procedure
  • The patient's previous treatments with blood products
  • Whether inhibitors are present and if so, their probable titer

Use aggressive hemostatic techniques. Correct coagulopathy immediately. Include a diagnostic workup for hemorrhage, but never delay indicated coagulation correction pending diagnostic testing. If possible, draw blood for the coagulation studies (see Workup), including 2 blue-top tubes to be spun and frozen for factor and inhibitor assays.

If admission is indicated, disposition (ICU vs floor) should be based on severity of hemorrhage and potential for morbidity and death. Choose attending service based on etiology of hemorrhage. Hematology/ blood bank/pathology consultation is mandatory.

Further outpatient care for patients with minor hemorrhage (not life threatening) consists of continued hemostatic measures (eg, brief joint immobilization, bandage). Hematologist or primary care physician follow-up care is indicated. The patient should continue factor replacement and monitoring.

If a patient has HIV seroconversion, arrange appropriate outpatient care at a specialty infectious disease clinic, monitor the patient's CD4 count, observe the patient for adverse effects of anti-HIV treatment, and monitor for and treat possible opportunistic infections.

Factor IX Concentrates

Various FIX concentrates 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. Cryoprecipitate contains no factor IX and is not appropriate for factor IX therapy.

Various purification techniques are used in plasma-based FIX concentrates to reduce or eliminate the risk of viral transmission, including heat treatment, cryoprecipitation, and chemical precipitation. These techniques inactivate viruses such as hepatitis B virus, hepatitis C virus, and HIV. However, the transmission of nonenveloped viruses (eg, parvovirus and hepatitis A virus) and poorly characterized agents (eg, prions) is still a potential problem.

Recombinant FIX products (eg, BeneFIX, Rixubis, Alprolix) are commercially available and have a lower risk of viral contamination. Each of the brands is FDA-approved for control and prevention of bleeding episodes, and for perioperative management in adults and children. Rixubis and Alprolix are also approved for routine prophylaxis in adults and children.

Idelvion, a long-acting recombinant FIX albumin fusion protein (rIX-FP, albutrepenonacog alfa) was approved in March 2016 for on-demand control and prevention of bleeding episodes, management of postoperative bleeding, and as prophylaxis to reduce the frequency of bleeding episodes. Approval was based on open-label trials in children and adults (n=90) with severe hemophilia B (FIX activity < 2%). Mean trough levels of FIX activity were 20 IU/dL on prophylaxis with rIX-FP 40 IU/kg weekly and 12 IU/dL FIX on prophylaxis with 75 IU/kg every 2 weeks.The switch from on-demand treatment to prophylaxis with rIX-FP resulted in a 100% reduction in median annualized spontaneous bleeding rate and 100% resolution of target joints (P < 0.0001).[14]

Rixubis approval for adults was based on a study demonstrating that twice-weekly prophylactic treatment for 6 months achieved a median annualized bleed rate of 2.0 with 43% of patients experiencing no bleeds.[15, 16]

Rebinyn (nonacog beta pegol) is a recombinant glycopegylated FIX with an extended half-life. Pegylation slows removal of FIX from the blood circulation. Rebinyn was approved by the FDA in June 2017 for control and prevention of bleeding episodes and for perioperative management in adults and children.[17]

Doses of FIX concentrate are calculated according to the severity and location of bleeding. Guidelines for dosing are provided in Table 2 below. As a rule, FIX 1 U/kg increases FIX plasma levels by 1%. The reaction half-time is 16 hours.

Target levels by hemorrhage severity are as follows:

  • 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

Table 2. General Guidelines for Factor Replacement for the Treatment of Bleeding in Hemophilia B (Open Table in a new window)

Indication or Site of Bleeding

Factor level Desired, %

FIX Dose, IU/kg*

Comment

Severe epistaxis; mouth, lip, tongue, or dental work

20-50

20-50

Consider aminocaproic acid (Amicar), 1-2 d

Joint (hip or groin)

40

40

Repeat transfusion in 24-48 h

Soft tissue or muscle

20-40

40

No therapy if site small and not enlarging (transfuse if enlarging)

Muscle (calf and forearm)

30-40

40

None

Muscle deep (thigh, hip, iliopsoas)

40-60

40-60

Transfuse, repeat at 24 h, then as needed

Neck or throat

50-80

50-80

None

Hematuria

40

40

Transfuse to 40% then rest and hydration

Laceration

40

40

Transfuse until wound healed

GI or retroperitoneal bleeding

60-80

60-80

None

Head trauma (no evidence of CNS bleeding)

50

50

None

Head trauma (probable or definite CNS bleeding, eg, headache, vomiting, neurologic signs)

100

100

Maintain peak and trough factor levels at 100% and 50% for 14 d if CNS bleeding documented†

Trauma with bleeding, surgery

80-100

100

10-14 d

Variations in responses related to patient or product parameters make determinations of factor levels important. These determinations are performed immediately after infusions and thereafter to ensure an adequate response and maintenance levels. Obtain factor assay levels daily before each infusion to establish a stable pattern of replacement regarding the dose and frequency of administration.

Management of Bleeding Episodes by Site

Musculoskeletal bleeding

The most common sites of clinically significant bleeding are joint spaces. Weight-bearing joints in the lower extremities are often target areas for recurrent bleeding. Joint hemorrhage is associated with pain and limitation in the range of motion, which is followed by progressive swelling in the involved joint.

Immobilization of the affected limb and the application of ice packs are helpful in diminishing swelling and pain.

Early infusion upon the recognition of pain may often eliminate the need for a second infusion by preventing the inflammatory reaction in the joint. Prompt and adequate replacement therapy is the key to preventing long-term complications. Cases in which treatment begins late or causes no response may require repeated infusions for 2-3 days.

Do not aspirate hemarthroses unless they are severe and involve significant pain and synovial tension. Some hemarthroses may pose particular problems because they interfere with the blood supply.

Hip joint hemorrhages can be complicated by aseptic necrosis of the femoral head. Administer adequate replacement therapy for at least 3 days.

Deep intramuscular hematomas are difficult to detect and may result in serious muscular contractions. Appropriate and timely replacement therapy is important to prevent such disabilities.

Iliopsoas muscle bleeding may be difficult to differentiate from hemarthrosis of the hip joint. Physical examination usually reveals normal hip rotation but significant limitation of extension.

Ultrasonography in the involved region may reveal a hematoma in the iliopsoas muscle. This condition requires adequate replacement therapy for 10-14 days and a physical therapy regimen that strengthens the supporting musculature.

Closed-compartment hemorrhages pose a significant risk of damaging the neurovascular bundle. These occur in the upper arm, forearm, wrist, and palm of the hand. They cause swelling, pain, tingling, numbness, and loss of distal arterial pulses. Infusion must be aimed at maintaining a normal level of FIX.

Other interventions include elevation of the affected part to enhance venous return and, rarely, surgical decompression.

Oral bleeding

Oral bleeding from the frenulum and bleeding after tooth extractions are not uncommon. Bleeding is aggravated by the increased fibrinolytic activity of the saliva.

Combine adequate replacement therapy with an antifibrinolytic agent (e-aminocaproic acid [EACA]) to neutralize the fibrinolytic activity in the oral cavity.

Topical agents such as fibrin sealant, bovine thrombin, and human recombinant thrombin can also be used.[18]

Hematoma in the pharynx or epiglottic regions frequently results in partial or complete airway obstruction; therefore, it should be treated with aggressive infusion therapy. Such bleeding may be precipitated by local infection or surgery.

Administer prophylactic factor infusion therapy before an oral surgical procedure to prevent the need for further treatment.

GI bleeding

GI bleeds are unusual compared with those associated with von Willebrand disease and, therefore, require an evaluation for an underlying cause. Depending on their location, they may be confused with acute abdomen or appendicitis. Manage GI hemorrhage with repeated or continuous infusions to maintain nearly normal circulating levels of FIX.

Intracranial bleeding

Intracranial hemorrhage is often trauma induced; in the pediatric population, spontaneous intracranial hemorrhages are more common than those related to trauma. If CNS hemorrhage is suspected, immediately begin an infusion prior to radiologic confirmation. Maintain the factor level in the normal range for 7-10 days until a permanent clot is established.

All head injuries must be managed with close observation and investigated by imaging such as CT scanning or MRI. If the patient is not hospitalized, instruct the patient and his or her family regarding the neurologic signs and symptoms of CNS bleeding so that the patient can know when to return for reinfusion.

Treatment of Patients with Inhibitors

Inhibitors are antibodies that neutralize FIX and can render replacement therapy ineffective. FIX inhibitors are less common than FVIII inhibitors; they occur found in only 1-3% of patients with severe hemophilia B. These inhibitors typically appear after the first infusions of FIX concentrate. Patients with FIX inhibitors can have anaphylactic reactions to FIX infusions, and may develop steroid-resistant nephrotic syndrome due to immune complex formation; this typically occurs in individuals with complete gene deletions.

The relatively low frequency of FIX inhibitors has lead to a dearth of experience in its treatment. Early hematology consultation for these patients is essential.

Low-titer inhibitors and, occasionally, high-titer inhibitors can be overcome with high doses of FIX concentrate. Recombinant human coagulation factor VIIa (rFVIIa) is indicated for the treatment of patients with bleeding episodes and for the prevention of bleeding in surgical interventions or invasive procedures in patients with inhibitors to FIX.[19]

Activated prothrombin complex concentrate (PCC) has shown promise, although it may trigger disseminated intravascular coagulopathy (DIC) at doses greater than 200 IU/kg/d. Desensitization and immune-tolerance strategies in those with identified inhibitors have been successful as well.

Recombinant activated FVIIa

Recombinant activated FVIIa (Eptacog Alfa, Novo Seven) is a vitamin K–dependent glycoprotein that is structurally similar to human plasma–derived FVIIa.[20] It is manufactured by using DNA biotechnology. Intravenous recombinant FVIIa has also been studied for treating bleeding episodes and for providing hemostasis during surgery in patients with particular bleeding diathesis.

Recombinant FVIIa is also effective and well tolerated in patients with acquired hemophilia and in those with Glanzmann thrombasthenia.

To date, recombinant activated FVIIa has proven to be relatively free of the risk of antigenicity, thrombogenicity, and viral transmission. However, the cost of this product has precluded its use as prophylaxis in patients with FIX inhibitors; when recombinant activated FVIIa has been used for this indication, select patients have had severe complications related to bleeding.

In pediatric patients, off-label treatment with recombinant FVIIa significantly reduced blood product administration, with 82% of patients subjectively classified as responders. Clinical context and pH values before administration were independently associated with response and 28-day mortality. Thromboembolic adverse events were reported in 5.4% of patients.[21]

Desensitization

Desensitization in nonemergency situations also may be feasible. This therapy includes large doses of FIX along with steroids or intravenous immunoglobulin (IVIG) and cyclophosphamide. Success rates of 50-80% have been reported. In life-threatening bleeding, methods to quickly remove the inhibiting antibody have been tried. Examples include vigorous plasmapheresis in conjunction with immunosuppression and infusion of FIX with or without antifibrinolytic therapy.

Immune tolerance induction

In immune tolerance induction (ITI), a person is rendered tolerant to FIX by means of daily exposure to FIX over several months to years.[22] The overall likelihood of success with ITI is 70% ± 10%. In patients with high-titer FIX inhibitors, ITI is less successful than it is in patients with FVIII inhibitors.

First described by Backmann in 1977, ITI has been used, with variations in the dosing schedule for FIX and with or without immunosuppressive therapy. This technique is well established in acquired hemophilia but not in congenital hemophilia.

Rituximab, a chimeric human-mouse monoclonal antibody against CD20, has been used with success in patients with hemophilia B and high titer inhibitors.[23] Reports describe durable complete responses with brief courses of rituximab and prednisone with or without cyclophosphamide in patients with autoimmune hemophilia and inhibitor titers of 5 to more than 200 BU.[24] Rituximab appears to be more effective in treating inhibitors in acquired hemophilia than in hereditary hemophilia.[25, 26]

In several small trials, a 4-week course of weekly rituximab has resulted in durable and complete responses. The addition of prednisone with or without cyclophosphamide has increased response rates.

An international immune tolerance study was started in 2002 to compare the efficiency, morbidity, and cost-effectiveness of low- versus high-dose ITI. For information, please see the study Web site Immune Tolerance Induction Study.

Concizumab

Concizumab is a subcutaneously administered monoclonal IgG4 antibody that promotes thrombin generation by binding to tissue factor pathway inhibitor (TFPI); TFPI is the primary inhibitor of the initiation of coagulation. In phase II trials, concizumab has demonstrated benefit for prophylaxis in patients with hemophilia B with inhibitors.[27]  The European Commission has granted orphan drug designation to concizumab for the treatment of hemophilia B.[28]

 

Prophylactic Factor Infusions

Most of the care for children with severe forms of hemophilia now takes place at home, in the community, and at school, allowing children with hemophilia to participate in normal activities that are otherwise impossible. This resulted from the development of prophylactic regimens of factor concentrate infusions that are administered at home, usually by a parent.

The main goal of prophylactic treatment is to prevent bleeding symptoms and organ damage, in particular to joints. Hemophilic arthropathy that results from recurrent or target joint bleeding can be prevented by this method.

Prophylaxis is not universally accepted, with only about one third of children with hemophilia B receiving this treatment modality in the United States. Reasons cited for the lack of acceptance of this modality include need for venous access, factor availability, repeated venipunctures, cost, and others.

Research questions that remain unanswered include when to initiate and stop infusions, dosing, and dose schedule. Tools have now been developed to assess long-treatment effects.

The long-acting recombinant FIX albumin fusion protein (Idelvion) was approved in March 2016. It is approved for prophylaxis to reduce the frequency of bleeding episodes. Adults who respond to once weekly prophylaxis may be switched to a slightly higher dose administered every 2 weeks. Clinical trial results demonstrated a 100% reduction in median annualized spontaneous bleeding rate (AsBR) and 100% resolution of target joints when subjects switched from on-demand to prophylaxis treatment with rIX-FP (P < 0.0001).[14]

In June 2013, the FDA approved the first recombinant coagulation factor IX (Rixubis) specifically indicated for the routine prevention of bleeding in patients with hemophilia B in children and adults.[29, 30] In addition to routine prophylaxis (prevention or reduction in frequency of bleeding episodes), Rixubis is indicated for the control of bleeding episodes and perioperative management in these patients. This purified protein is supplied in single-use vials of freeze-dried powder, and it is injected intravenously after reconstitution with sterile water. For routine prophylaxis, Rixubis is administered twice a week.[29, 30]

Approval of Rixubis was based on a multicenter study of 73 males (age range, 12-65 years) who received the drug for routine prophylaxis or as needed for hemostasis. Patients taking this agent prophylactically had a 75% lower annual rate of bleeding relative to those who had received on-demand therapy.[29, 30] The most common side effects associated with Rixubis in clinical studies included distorted taste, pain in an extremity, and atypical blood test results. Life-threatening anaphylaxis occurred less commonly.[29, 30]

In September 2014, Rixubis was approved for routine prophylactic treatment, control and prevention of bleeding episodes, and perioperative management in children with hemophilia B. Approval was based on the results of a clinical trial investigating the efficacy and safety of Rixubis among 23 previously-treated male patients aged < 12 years with severe or moderately severe hemophilia B. The patients were treated with a twice-weekly prophylaxis regimen (mean dose 56 IU/kg; mean treatment duration 6 months, mean of 54 exposure days). The median annualized bleeding rate (ABR) was 2.0 (0.0 for spontaneous bleeds and joint bleeds). Nine patients in the study (39.1%) experienced no bleeds and 23 bleeding episodes (88.5%) were treated with 1-2 infusions. There were no reports of inhibitor development, no severe allergic reactions, and no thrombotic or treatment-related adverse events among the study participants.[16]

The long-acting recombinant Fc fusion factor IX (rFIXFc), Alprolix, was approved by the FDA in March 2014 for patients with hemophilia B. It is the first treatment designed to require less frequent injections for routine prophylaxis. The safety and efficacy were evaluated in a multicenter clinical trial that compared each of 2 prophylactic treatment regimens with on-demand treatment. A total of 123 individuals with severe hemophilia B, aged 12-71 years, were followed for up to 18 months. The studies demonstrated effectiveness in preventing and treating bleeding episodes and during perioperative management of patients undergoing surgical procedures.[31, 32]

In December 2013, the FDA expanded the indication for anti-inhibitor coagulant complex (Feiba NF) to include routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B who have developed inhibitors. The approval was based on data from a pivotal Phase III study in which treatment with a prophylactic regimen showed a 72% reduction in median annual bleed rate (ABR) compared to treatment with an on-demand regimen.[33] An earlier study showed a 62% reduction in all bleeding episodes with anti-inhibitor coagulant complex prophylaxis compared with an on-demand regimen.[34]

Assessing adherence to prophylaxis

The Validated Hemophilia Regimen Treatment Adherence Scale–Prophylaxis (VERITAS-Pro) prophylaxis is a patient/parent questionnaire that uses 6 subscales (time, dose, plan, remember, skip, communicate), each containing 4 items, to assess patient adherence to prophylactic hemophilia treatment. In a study of 67 patients with hemophilia, including 53 with severe FVIII deficiency, Duncan et al found a strong correlation between VERITAS-Pro scores and adherence assessments (eg, infusion log entries).[35]

Pain Management

Pain management can be challenging in patients with severe hemophilia. Acute bleeding in joints and soft tissues can be extremely painful. This requires immediate analgesic relief.

Hemophilic chronic arthropathy is associated with pain. Narcotic agents have been used, but frequent use of these drugs may result in addiction. Nonsteroidal anti-inflammatory drugs may be used instead because their effects on platelet function are reversible and because these drugs can be effective in managing acute and chronic arthritic pain. Avoid aspirin because of its irreversible effect on platelet function.

Other analgesics may include acetaminophen in combination with small amounts of codeine or synthetic codeine analogs.

Complications

HIV-associated immune thrombocytic purpura is an exceedingly serious complication in patients with hemophilia because it may result in lethal intracranial bleeding. Correct platelet counts to more than 50,000/mL. Steroids are of limited effectiveness, and intravenous immunoglobulin or anti-Rh(D) generally induces transient remissions. Anti-HIV medications and splenectomies may result in long-term improvement of thrombocytopenia.

Allergic reactions are occasionally reported with the use of factor concentrates. Premedication or adjustment of the rate of infusion may resolve the problem.

Deterrence/Prevention

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 with appropriate laboratory testing. Perform blood assays of FIX with cord blood. When a cord blood sample is not available, obtain a sample from a superficial limb vein; avoid femoral and jugular sites.

Routine immunizations that require injection (eg, diphtheria, tetanus toxoids, and pertussis [DPT] or measles-mumps-rubella [MMR] vaccines) may be given by means of a deep subcutaneous route (rather than deep intramuscular route) with a fine-gauge needle.

Administer the hepatitis B vaccine (now routinely administered to all children) soon after birth to all infants with hemophilia. Administer the hepatitis A vaccine to those individuals with hemophilia and no hepatitis A virus antibody in their serum.

In severe hemophilia, consider prophylactic or scheduled FIX infusions. Prophylactic replacement is used to maintain a measurable FIX level at all times, with the goal of avoiding hemarthrosis and the vicious cycle of repetitive bleeding and inflammation that results in destructive arthritis.[36] This goal is achieved by administering factor 2-3 times a week. The National Hemophilia Foundation has recommended the administration of primary prophylaxis, beginning at age 1-2 years.

Carrier testing may prevent births of individuals with major hemophilia. This testing can be offered to women interested in childbearing who have a family history of hemophilia. Prenatal diagnosis is important even if termination of the pregnancy is not desired because a cesarean delivery may be planned or replacement therapy can be scheduled for the perinatal period.

Phenotypic and genotypic (ie, restriction fragment–length polymorphism) methods have advantages and disadvantages.

Preimplantation genetic diagnosis has been used as a possible alternative to prenatal diagnosis in combination with in vitro fertilization to help patients avoid having children with hemophilia or other serious inherited diseases.[37, 38, 39] The genetic diagnosis is made by using single cells obtained during biopsy from embryos before implantation. For this, fluorescence in situ hybridization is used. This technique circumvents pregnancy termination.

Activity

Generally, individuals with severe hemophilia should avoid high-impact contact sports and other activities with a significant risk of trauma. However, mounting evidence suggests that appropriate physical activity improves overall conditioning, reduces injury rate and severity, and improving psychosocial functioning.

Patients with severe hemophilia can bleed from any anatomic site after negligible or minor trauma, or they may even bleed spontaneously. Any physical activity may trigger bleeding in soft tissues. Prophylactic factor replacement early in life may help prevent bleeding during activity, as well as helping to prevent chronic arthritic and muscular damage and deformity.

Gene Therapy

With the cloning of FIX and advances in molecular technologies, the possibility of a cure for hemophilia with gene therapy was conceived. Substantial progress has been made in the development of gene therapy for hemophilia B.[40] This advancement reflects technical improvements of existing vector systems and the development of new delivery methods.

Preclinical studies in mice and dogs with hemophilia have resulted in long-term correction of the bleeding disorders and, in some cases, a permanent cure. However, the induction of neutralizing antibodies often precludes stable phenotypic correction.

In addition, the relatively high prevalence of antibodies against adeno-associated virus serotype 8 (AAV8), which is used as a vector, limits enrollment of clinical trial subjects.[41] Lentiviral vectors may offer an alternative to AAV8; Cantore and colleagues reported that gene therapy using lentiviral vectors was well tolerated and provided a stable long-term production of FIX in dogs with hemophilia B.[42]

Human trials have been performed in patients with hemophilia B. Nathwani and colleagues reported sustained long-term expression of therapeutic levels of FIX in 10 men with severe hemophilia B after a single intravenous infusion of an AAV8 vector expressing a codon-optimized factor IX transgene. In all 10 patients, the circulating factor IX rose to 1- 6% of the normal value over a median period of 3.2 years, with observation ongoing.[43]

In this study, four of the seven patients who had been receiving FIX prophylaxis were able to discontinue it.Three different vector doses were used, and responses were dose dependent: five of the six patients who received the highest vector dose had a greater than 90% reduction in their annual bleeding episodes.[43]

A proof-of-principle study by Morishige et al demonstrated that gene repair in hemophilia B can be accomplished with CRISPR (clustered regulatory interspaced short palindromic repeats) technology.  Using CRISPR/Cas9 on patient-derived induced pluripotent stem cells, these researchers repaired an in-frame deletion in exon 2 of the factor IX gene.[44]

Future prospects for RNA repair, use of gene-modified endothelial progenitors, and gene-modified stem-cell therapy are being investigated. Gene transfer for the treatment of hemophilia requires a combination of vector delivery systems, animal models, and clinical models and/or studies to prove its practical utility.

Consultations

Consultations may be indicated with a hematologist, blood bank, pathologist, or others as indicated by hemorrhagic complications. Early hematology consultation for management of inhibitors is essential. Annual dental evaluation is recommended.

A genetic counselor may be consulted. Genetic testing for hemophilia A is available and must be offered to potential carriers. Prenatal testing is performed by using amniocentesis or chorionic villus biopsy.

Before elective surgery is planned, a hematologist should be consulted to arrange adequate coverage with antihemophilic factors and to arrange close follow-up to ensure that factor levels are sufficient during the operation and in the recovery and healing period.

Consult an orthopedic surgeon in cases of permanent joint deformities resulting from recurrent hemarthrosis in relatively neglected cases or, occasionally, in cases of repetitive bleeding in a single joint despite intensive prophylactic replacement of factor and physiotherapy. Open surgical or arthroscopic synovectomy may decrease bleeding and pain in the affected joint.

Management should be provided in coordination with a comprehensive hemophilia care center.

 

Guidelines

Guidelines Summary

Guidelines for the management of acute joint bleeds and chronic synovitis in hemophilia from the United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) include recommendations for patients with and without inhibitors.[45]

Hemostatic management of patients with inhibitors to factor IX includes the following:

  • Patients with inhibitors should be encouraged to be on a home treatment program, and bleeds should be treated as early as possible.
  • Activated prothrombin complex (aPCC) 50–100 μg kg −1 or recombinant factor VIIa (rFVIIa) 270 μg kg −1 as a single dose (or 90 μg kg −1 2–3 hourly) are equally acceptable treatments for joint or soft tissue bleeds, with repeated doses as necessary. The frequency of infusion and duration of treatment should be determined by the clinical response.
  • The total daily dose of aPCC should not exceed 200 IU kg −1.
  • Tranexamic acid can be considered as adjunctive therapy to aPCC and rFVIIa.
  • Sequential alternating treatment of aPCC and rFVIIa can be considered for the management of limb/life-threatening bleeds.

Hemostatic management of patients without inhibitors includes the following:

  • All patients with severe hemophilia A and B and other patients at risk of joint bleeding should be offered home treatment.
  • The initial treatment of early and moderate bleeds should aim for a peak factor IX level of 50 to 60 IU dL −1. This is equivalent to 40 to 60 IU kg −1 for severe hemophilia B, with extended half-life factor IX being dosed at the lower end of the recommended range. Early bleeds often do not require a second infusion, and moderate bleeds often respond to a single infusion but may require up to 2 infusions.
  • Children may require more frequent or higher doses, as they have a shorter factor half-life than adults.
  • For joint-immobilizing bleeds, higher initial doses are recommended, which aim to raise the peak factor IX level to 60 to 80 IU dL −1. Doses should be administered every 24 hr until complete resolution of pain. For severe bleeds, more frequent administration may be required in the initial 48 hr with standard factor IX.
 

Medication

Medication Summary

Factor IX is the treatment of choice for acute hemorrhage or presumed acute hemorrhage. Recombinant factor IX is the preferred source for replacement therapy. The factor IX activity level should be corrected to 100% of normal for potentially serious hemorrhage (eg, CNS, trauma related, GI, GU, epistaxis) and to 30-50% of normal for minor hemorrhage (eg, hemarthrosis, oral mucosal, muscular).

One unit of factor IX is the amount of factor IX in 1 mL of plasma (1 U/mL or 1%). The volume of distribution of factor IX is approximately 100 mL/kg. To find the number of units of factor IX needed to correct the factor IX activity level, use the following:

Units factor IX = (weight in kg)(100 mL/kg)(1 U factor IX/mL)(desired factor IX level minus the native factor IX level)

The difference between the desired factor IX activity level and the patient's native factor IX activity level is expressed as a fraction. For example, if 100% activity is desired and the patient’s native activity is 5%, the calculation is as follows:

100% - 5% = 95% or 0.95

As an example, an 80-kg person with hemophilia with known 1% factor IX activity level presents to the emergency department with a serious upper GI bleed. The desired factor IX activity level is 100%. The dose of factor IX to administer to the patient would be calculated as follows:

Units factor IX = (80 kg)(100 mL/kg)(1 U factor IX/mL)(.99) = 7920

The next dose should be administered 24 hours after the first and is one half of the initial calculated dose.

Minor hemorrhage requires 1-3 doses of factor IX. Major hemorrhage requires many doses and continued factor IX activity monitoring with the goal of keeping the trough activity level at least 50%. Continuous infusions of factor IX may be considered for major hemorrhage.

Factor IX-containing Products

Class Summary

These agents are used to correct the patient's native deficiency, with the goals of achieving a normal hematologic response to hemorrhage or preventing hemorrhage. Fresh frozen plasma is no longer used in hemophilia because of the lack of safe viral elimination and concerns regarding volume overload.

Factor IX, recombinant (BeneFIX, Rixubis, Alprolix, Ixinity, Rebinyn)

Recombinant factor IX (rFIX) uses no human products for stabilization. Each of the brands is FDA-approved for control and prevention of bleeding episodes, and for perioperative management in adults and children. Rixubis and Alprolix are also approved for routine prophylaxis in adults and children. Alprolix is a long-acting product, it may be administered for routine prophylaxis once weekly or every 10 days. Rebinyn is a glycopegylated long-acting rFIX. Pegylation slows removal of FIX from the blood circulation.

Factor IX, recombinant/albumin fusion protein (Idelvion)

Recombinant protein that temporarily replaces missing coagulation Factor IX needed for effective hemostasis. Comprised of genetically fused recombinant coagulation Factor IX and recombinant albumin, which extends the half-life of Factor IX. It is indicated for on-demand control and prevention of bleeding episodes, management of postoperative bleeding, and as prophylaxis to reduce the frequency of bleeding episodes.

Factor IX (Mononine, AlphaNine SD)

Human blood-derived Factor IX indicated for control and prevention of bleeding episodes, and for perioperative management in adults and children.

Factor IX Complex (Bebulin, Bebulin VH, Profilnine SD)

Human plasma-derived prothrombin complex concentrates. These pooled plasma products (high purity) replace deficient FIX and other coagulation factors.

Coagulation Factor VIIa (Recombinant)

Class Summary

These agents can activate coagulation factor X to factor Xa as well as coagulation factor IX to IXa.

Factor VIIa, recombinant

This agent is indicated to treat bleeding episodes in patients with hemophilia A or B and inhibitors. It promotes hemostasis by activating the extrinsic pathway of the coagulation cascade, forming complexes with tissue factor, and promoting activation of factor X to factor Xa, factor IX to factor IXa, and factor II to factor IIa.

Antifibrinolytics

Class Summary

These agents are used in addition to factor IX replacement for oral mucosal hemorrhage and prophylaxis, as the oral mucosa is rich in native fibrinolytic activity. These agents are used in prophylaxis for oral surgery and in the treatment of excessive bleeding in the oral mucosa that results from local fibrinolytic activity. Their use is contraindicated as initial therapies for hemophilia-related hematuria originating from the upper urinary tract because they can cause obstructive uropathy or anuria. They should not be used in combination with prothrombin complex concentrate (PCC).

Epsilon aminocaproic acid (Amicar)

This is a lysine analog that binds to natively produced plasmin, reducing its fibrinolytic activity.

This agent inhibits fibrinolysis by inhibiting plasminogen activator substances and, to a lesser degree, antiplasmin activity. The principal drawbacks of this agent are that thrombi formed during treatment are not lysed, and its effectiveness is uncertain. It has been used to prevent recurrence of subarachnoid hemorrhage.

This agent is widely distributed. Its half-life is 1-2 hours. Peak effect occurs within 2 hours. Hepatic metabolism is minimal.

Tranexamic acid (Cyklokapron)

Tranexamic acid is an alternative to aminocaproic acid. It inhibits fibrinolysis by displacing plasminogen from fibrin.

Antihemophilic Agents

Class Summary

These agents are used to control bleeding in hemophilia B or FIX deficiency and to prevent and/or control bleeding in patients with hemophilia A and inhibitors to FVIII.

These are used to control bleeding in mild hemophilia and in some forms of von Willebrand disease.

These agents raise endogenous FVIII levels in mild hemophilia A. Increases as much as 3-fold from the baseline are observed, with peak responses at 30-60 minutes after infusion.[46]

These replace deficient FVIII in patients with hemophilia A. Recombinant products should be used initially and subsequently in all newly diagnosed cases of hemophilia that require factor replacement.

Desmopressin (DDAVP, Stimate)

The main effect of desmopressin is enhancement of water reabsorption in the kidney and smooth muscle constriction. It causes a dose-dependent increase in plasma FVIII and plasminogen activator.

This agent increases the cellular permeability of collecting ducts, resulting in renal reabsorption of water. Tachyphylaxis may occur, even after first dose, but the drug can be effective again after several days.

Anti-inhibitor coagulant complex (Feiba NF, Feiba VH Immuno)

This agent is a freeze-dried sterile human plasma fraction with factor VIII inhibitor bypassing activity. It contains factors II, IX, and X, mainly nonactivated; and factor VII, mainly in the activated form. It may shorten the activated partial thromboplastin time of plasma containing factor VIII inhibitors. Anti-inhibitor coagulant complex is indicated for prevention and control of spontaneous hemorrhage or bleeding during surgical interventions in hemophilia patients who have autoantibodies or alloantibodies to coagulation factors. It is also indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B who have developed inhibitors.

Human antihemophilic factor (Hemofil M, Koate-DVI)

FVIII is a protein in normal plasma that is necessary for clot formation and hemostasis. It activates factor X in conjunction with activated FIX; activated factor X converts prothrombin to thrombin, which converts fibrinogen to fibrin, which, with factor XIII, forms a stable clot.

Recombinant human antihemophilic factor (Recombinate, Kogenate, Helixate, Advate)

FVIII is a protein in normal plasma that is necessary for clot formation and hemostasis. It activates factor X in conjunction with activated FIX; activated factor X converts prothrombin to thrombin, which converts fibrinogen to fibrin, which, with factor XIII, forms a stable clot.

Plasma-derived prothrombin complex concentrates/Factor IX complex concentrates (Bebulin, Profilnine SD)

This agent replaces deficient FIX and other factors in the complex.

Plasma-derived coagulation factor IX concentrate (Alpha Nine SD, Mononine, BeneFIX)

This agent replaces deficient FIX and other factors in the complex. AlphaNine SD and Mononine contain only FIX. BeneFIX is a recombinant product.

Monoclonal Antibodies

Class Summary

These agents are monoclonal antibodies directed against the CD20 antigen on B cells. They are recommended as second-line therapy in the treatment of factor IX inhibitors, especially in cases with high inhibitor titers.

Rituximab (Rituxan)

Rituximab binds to, and mediates destruction of, B-cells, thereby decreasing production of inhibitors and autoimmunization.

 

Questions & Answers

Overview

What is hemophilia B?

What are the signs and symptoms of hemophilia B?

What are the signs of hemorrhage in hemophilia B?

Which lab tests are performed in the workup of hemophilia B?

Which imaging studies are performed in the workup of hemophilia B?

What is the treatment of choice for hemophilia B?

Which medications are used to treat hemophilia B?

When was hemophilia B first identified?

How is the severity of hemophilia B classified?

What is the pathophysiology of hemophilia B?

What is the role of factor IX in the pathophysiology of hemophilia B?

What is the role of the coagulation system in the pathophysiology of hemophilia B?

What is the role of genetics in the pathophysiology of hemophilia B?

What is the pathophysiology of hemorrhage in hemophilia B?

What is the pathophysiology of inhibitor development in hemophilia B?

What causes hemophilia B?

What is the prevalence of hemophilia B?

What are the racial predilections of hemophilia B?

What are the sexual predilections of hemophilia B?

At what age do the symptoms of hemophilia B initially appear?

What is the prognosis of hemophilia B?

What is included in patient education about hemophilia B?

Presentation

Which clinical history findings are characteristic of hemophilia B?

Which physical findings are characteristic of hemophilia B?

How is hemophilia B classified?

DDX

Which conditions are included in the differential diagnoses of hemophilia B?

How is hemophilia B differentiated from hemophilia A?

What are the differential diagnoses for Hemophilia B?

Workup

What is the role of lab testing in the workup of hemophilia B?

What is the role of imaging studies in the workup of hemophilia B?

When is testing for inhibitors indicated in the workup of hemophilia B?

What is the role of genetic testing in the workup of hemophilia B?

What is the role of radiography in the workups of hemophilia B?

Treatment

How is hemophilia B treated?

What is included in prehospital care for acute bleeding in patients with hemophilia B?

What is included in treatment of hemophilia B in the emergency department (ED)?

What types of factor IX concentrates are used in the treatment of hemophilia B?

What are the dosing guidelines for factor IX concentrates to treat hemophilia B?

How is hemophilia B musculoskeletal bleeding treated?

How is hemophilia B oral bleeding treated?

How is hemophilia B GI bleeding treated?

How is hemophilia B intracranial bleeding treated?

What is the role of concizumab in the treatment of hemophilia B?

How is hemophilia B treated in patients with inhibitors?

What is the role of recombinant activated FVIIa in the treatment of hemophilia B?

What is the role of desensitization in the treatment of hemophilia B?

What is the role of immune tolerance induction in the treatment of hemophilia B?

What is the role of prophylaxis in the treatment of hemophilia B?

How is prophylaxis adherence assessed in patients with hemophilia B?

How is pain managed in hemophilia B?

What are the possible complications of hemophilia B?

How are bleeding episodes prevented in hemophilia B?

Which activity modifications are used in the treatment of hemophilia B?

What is the role of gene therapy in the treatment of hemophilia B?

Which specialist consultations are beneficial to patients with hemophilia B?

Medications

What is the role of medications in the treatment of hemophilia B?

Which medications in the drug class Monoclonal Antibodies are used in the treatment of Hemophilia B?

Which medications in the drug class Antihemophilic Agents are used in the treatment of Hemophilia B?

Which medications in the drug class Antifibrinolytics are used in the treatment of Hemophilia B?

Which medications in the drug class Coagulation Factor VIIa (Recombinant) are used in the treatment of Hemophilia B?

Which medications in the drug class Factor IX-containing Products are used in the treatment of Hemophilia B?