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Factor Replacement Therapy in Hemophilia A and Hemophilia B

INTRODUCTION

Hemophilia is a hereditary, X-linked bleeding disorder that is caused by a deficiency in factor VIII (FVIII) and factor IX (FIX).1 Worldwide, more than 400,000 people are estimated to have hemophilia2; males typically present with the disorder while females are carriers.1 Hemophilia A, a deficiency in FVIII and the most common form of hemophilia, accounts for approximately 80% of cases.2 Hemophilia B is a deficiency in FIX and accounts for 15% to 20% of cases. Hemophilia A has an estimated incidence of 1 in 5000 male live births; hemophilia B has an incidence up to 1 in 30,000.3-6

DIAGNOSIS AND CLINICAL PRESENTATION

Family history can affect the timing of diagnosis.7,8 For example, if a family history of hemophilia exists, clinicians are more likely to diagnose the condition in utero or soon after birth. With no family history, the timing of the diagnosis depends on the disease’s severity; clinicians usually make the diagnosis in the first years of life for severe disease and in adulthood for mild disease.8 Hemophilia can be diagnosed phenotypically (based on measurements of FVIII or FIX in the plasma) or genetically (based on DNA analysis). To diagnose hemophilia before birth requires amniocentesis; diagnosis after birth requires laboratory confirmation. Several factor measurement methods exist.7,8

Hemophilia severity depends on the degree of deficiency in FVIII or FIX, for hemophilia A and hemophilia B, respectively.8 Severe hemophilia is defined as factor activity of less than 1% or a concentration of less than 0.01 international units of factor per mL of blood. Moderate hemophilia is defined as factor activity of greater than or equal to 1% but less than 5%, and mild hemophilia is defined as factor activity greater than 5% but less than 40%. Approximately 60% of hemophilia A cases are considered severe disease, 15% are moderate, and 25% are mild.9 An estimated 60% to 70% of hemophilia B cases are considered moderate or severe.3 A rare form of hemophilia B—Leyden phenotype— is characterized by FIX levels that begin increasing after puberty. By adulthood, the patient's severe disease converts to a much milder form.

Severe hemophilia most commonly manifests as spontaneous bleeding of the joints, which is the disease’s hallmark symptom.4,7,8 The knees, elbows, and ankles are often affected, and joint bleeding accounts for 75% of all bleeds. Hematomas and prolonged bleeding after surgery or trauma also suggest severe disease. Moderate hemophilia is associated with prolonged bleeding after trauma or surgery but spontaneous bleeding is less common than in severe disease. Mild hemophilia rarely manifests with spontaneous bleeding, but prolonged bleeding after minor trauma and surgery is possible. Sites of spontaneous and/or prolonged bleeding include hemarthrosis, deep muscle bleeds, and bleeding of mucous membranes such as the gums, nose, and genitourinary tract.7,8 Life-threatening bleeds (e.g., intracranial bleeds) occur in newborns with hemophilia at a rate of 3.5% to 4%, which is 40- to 80-fold higher than in the normal population.8 Intracranial hemorrhage in adults and children is associated with significant morbidity and is the leading, noninfectious cause of death.

CLINICAL USE OF REPLACEMENT FACTORS

Established in 1963, the World Federation of Hemophilia (WFH) provides leadership for hemophilia treatment globally.10 WFH first published guidelines for hemophilia management in 2005 and updated them in 2012. The guidelines apply to patients and health care providers in every country, regardless of factor concentrate availability. In accordance with the WFH’s mission to provide international access to the standard of care for hemophilia, WFH provides the guidelines at no cost.

Established in the U.S. in 1948, the National Hemophilia Foundation (NHF) is funded by three principal sources: (1) local chapters across the country; (2) donations from corporations and other organizations; and (3) a cooperative agreement with the U.S. Centers for Disease Control and Prevention (CDC).11 NHF convened the Medical and Scientific Advisory Council (MASAC) in 1954, which establishes the standards of care for hemophilia. Since its inception, the NHF MASAC has published more than 400 communications regarding all aspects of hemophilia care, including recommendations advising factor product use to treat bleeding disorders.12

Hemophilia treatment’s goals are twofold:

  • to prevent and treat acute bleeding by replacing the deficient clotting factor
  • to prevent recurrent joint bleeding complications, such as muscle contractures, pseudotumors, severe arthropathy and, ultimately, chronic pain and disability leading to orthopedic surgery.7

Hemophilia management requires complex care that is best guided by a comprehensive care team.7,8 This multidisciplinary team should include a physician with expertise in hemostasis, preferably a hematologist; a dedicated nurse coordinator; a musculoskeletal expert, such as a physiatrist, physical therapist or orthopedist; a laboratory specialist; and a social worker or psychologist.Coordinated care should be offered to select patients who may be eligible for home therapy, which requires administering factor concentrates and bypassing agents in the home. Home therapy patients have better outcomes than patients treated in clinical settings.13

The 2012 WFH guidelines provide recommendations for treatment and prophylaxis of bleeding episodes.7 In patients with active bleeding, treatment’s goal is hemostasis; the goal of prophylaxis depends on the type of bleeding it is intended to prevent.14 Primary and secondary prophylaxis aim to prevent joint disease before it starts, and tertiary prophylaxis aims to slow progression of joint disease and maintain joint mobility.

Episodic bleeding treatment, also called on-demand treatment, is initiated when clinically evident bleeding occurs. Prophylaxis can be given continuously, essentially year round, or intermittently, during certain high-risk periods of the year, to prevent bleeding episodes. Primary prophylaxis is initiated before the second clinically significant joint bleed and before 3 years of age in those without osteochondral joint disease. Secondary prophylaxis is also initiated before the onset of joint disease, but after the patient has experienced at least 2 bleeds into large joints. Tertiary prophylaxis is initiated after joint disease has been diagnosed. Intermittent or periodic prophylaxis is administered as needed for periods less than 45 weeks per year to prevent bleeding episodes.7

HISTORY OF FACTOR DEVELOPMENT

Before researchers discovered methods to store blood, the estimated life expectancy of people with hemophilia was 13 years.15 In the 1920s, blood transfusions were first used to replace missing clotting factors and in the 1930s, FVIII was identified. From the late 1950s to the early 1960s, fresh frozen plasma was administered to hospitalized patients with hemophilia. Scientists had yet to differentiate between hemophilia A and hemophilia B.8,15 At that time, individuals with severe hemophilia had a life expectancy of 20 years.15 In 1964, the clotting cascade was first described. By 1965, significant advances in hemophilia treatment had been made with the discovery that cryoprecipitate was rich in FVIII. In 1968, the first FVIII concentrate became available, and in the 1970s, FVIII and FIX were developed as freeze-dried powdered concentrates. The first inactivated factor concentrates were available in 1985.

The need for safer factor concentrate forms became obvious in the 1980s when human immunodeficiency virus (HIV) and hepatitis C virus (HCV) were transmitted through blood products; approximately half of all hemophilia patients in the U.S. were infected with these diseases and thousands died.15 Viral inactivation strategies during the manufacturing process were introduced, which nearly eradicated transmission of infections.1 In the 1990s, protein purification techniques were developed, making available high-purity, plasma-derived, factor concentrates with a greater concentration of factors per total protein content. In 1992, the first recombinant FVIII product (rFVIII) was approved by the U.S. Food and Drug Administration (FDA), followed by approval of recombinant FIX (rFIX) in 1997.15 With mass-produced, safe, recombinant products available in the United States, prophylaxis became the standard of care for hemophilia management. In the 2000s, recombinant factor products devoid of human or animal plasma derivatives were introduced.

FACTOR SAFETY

Viral transmission

Plasma-derived product contamination can occur at multiple phases, including during donor selection, plasma storage and transport, and production.16 Although donor selection and screening have reduced the incidence of blood-borne pathogen transmission, an inherent risk of infection transmission still exists because a plasma pool is used to manufacture the product. Donors now must meet certain selection criteria, and raw plasma material must be screened for HIV, HCV, and hepatitis B virus (HBV).

Since plasma-derived products still present a risk of infection despite steps to ensure safety, the manufacturing process must include viral reduction procedures.16 Viral inactivation is achieved by using several strategies1,8,17:

  • Chemical inactivation using solvent/detergent to disrupt the membrane
  • Heat inactivation by pasteurization, dry-heat, or steam heat
  • Nanofiltration to filter out the virus
  • Affinity chromatography with monoclonal antibodies

Many manufacturers use a 2-step process for viral inactivation.7 Regulatory agencies in the United States and the European Union enforce strict control of these manufacturing processes.16

Thrombosis and anaphylaxis/hypersensitivity reactions

Both plasma-derived and rFVIII and rFIX concentrates can induce immediate (type I) hypersensitivity reactions in people with hemophilia, but such reactions are rare. Hypersensitivity reactions occur more often with FIX than with FVIII products.8 Up to half of patients with hemophilia B and inhibitors (discussed below) may experience allergic reactions or anaphylaxis with FIX administration.7 For these patients, hydrocortisone may be given during FIX administration. Products that have a higher degree of purity (i.e., a higher percentage of the factor compared to other ingredients) are less likely to induce allergic reactions.7

Thromboembolism has been reported after administration of FIX products. Some thromboembolism cases have occurred in patients receiving a continuous infusion using a central venous catheter.18 Factor VIII products do not seem to carry this same risk.19 Prothrombin complex concentrates (PCCs) and rFVIIa carry boxed warnings describing possible thrombosis. Administering products that contain activated clotting factors increases the risk of thromboembolism development, especially at large doses.7 If possible, pure FIX concentrates should be administered for hemophilia B rather than PCCs to avoid thrombotic risk.

Inhibitor development

Development of antibodies to exogenously administered clotting factors is the major complication related to hemophilia treatment.20 In hemophilia, these antibodies are referred to as inhibitors. Inhibitors reduce factor efficacy and can cause a person with moderate hemophilia to progress to severe hemophilia.7 Worldwide, the estimated incidence of inhibitor development in patients with severe or moderate hemophilia A is 20% to 33%, and the incidence in patients with hemophilia B is 1% to 6%.21 Inhibitor development has a genetic component, and people with hemophilia A of African descent are more likely to develop FVIII inhibitors than Caucasian people. Inhibitors to factor replacement usually develop after an average of 9 to 12 treatments, which often corresponds an age of 1 to 2 years. The greatest risk of inhibitor development is within the first 50 exposures to rFVIII, and risk decreases after 200 days of treatment. However, a small risk remains into the sixth decade of life.

When inhibitors are suspected, titer measurements are required for diagnosis and treatment selection.20 Patients with inhibitor titers less than 5 Bethesda units (BU)/mL after factor concentrate exposure require as much as 2 to 3 times the typical replacement factor concentrate dose, administered at more frequent intervals than normal regimens, to overcome the inhibitors.1 However, it is impossible to administer an amount of factor replacement sufficient to overcome inhibitors to patients who have inhibitor titers greater than 5 BU/mL. These patients need bypassing agents such as PCCs, including activated PCC (aPCC), or recombinant factor VIIa (rFVIIa). Certain patients with persistent inhibitors may be eligible for immune tolerance induction, which combines FVIII concentrate with immunosuppressive agents, such as rituximab, cyclophosphamide, or corticosteroids, until the inhibitors are undetectable.22

FACTOR CHARACTERISTICS

Plasma-derived products

Compared to when they were first introduced on the market, plasma-derived factor products are much safer, which is attributed to improved donor screening, product testing, and viral reduction and inactivation.1,7 In fact, the WFH guidelines do not recommend the use of recombinant products over plasma-derived products. However, the NHF MASAC recommendations advise using recombinant factor products over plasma-derived products because of the lower risk of viral contamination with recombinant products.12 Table 1 lists the available plasma-derived FVIII and FIX products. There are no comparative data for plasma-derived factors’ efficacy, and no data suggest either is more effective. Most of the use data originates from small pharmacokinetic studies that determined half-life, recovery, and clearance.

Table 1. FDA-Approved Factor Concentrate Products  
Hemophilia Type Generic Drug Name and Features Brand Name (Generation)a FDA-Approved Indications
Hemophilia A Plasma-derived
Antihemophilic factor, plasma-derived Monoclate-P
Koate-DVIb
Hemofil M		 Monoclate-P/Koate DVI
  • Treatment of bleeding episodes in patients with hemophilia A, including perioperative management
Hemofil M
  • Prevention and control of bleeding episodes in patients with hemophilia A
Antihemophilic factor/von Willebrand factor complex, plasma-derived Humate-P
Alphanate
  • Treatment and prevention of bleeding episodes in patients with hemophilia A
  • Treatment of bleeding episodes in adults and children with von Willebrand disease, including spontaneous or trauma-induced bleeding
  • Prevention of excess bleeding during and after surgery when desmopressin is not effective or contraindicated
  • Alphanate is not indicated for severe von Willebrand disease
Recombinant
Antihemophilic factor, recombinant (full-length) Helixate FS (second)
Kogenate FS (second)
Advate (third)
Recombinate (first)
Novoeight (third)		 Kogenate FS/Helixate FS
  • Treatment and prevention of bleeding episodes in adults and children with hemophilia A
  • Perioperative management of hemophilia A
  • Prophylaxis to reduce bleeding episodes and reduce joint damage in patients with hemophilia A and no prior joint damage
Recombinate
  • Treatment and prevention of bleeding episodes in adults and children with hemophilia A
  • Perioperative management of hemophilia A
  • May be of use in the control of bleeding in the presence of low levels of FVIII inhibitors (<10 BU/mL) in hemophilia A
Advate/Novoeight
  • Treatment and prevention of bleeding episodes in adults and children with hemophilia A
  • Perioperative management of hemophilia A
  • Routine prophylaxis to prevent/reduce bleeding episodes in hemophilia A
Antihemophilic factor, recombinant (B-domain deleted) Xyntha (third)
  • Treatment and prevention of bleeding episodes in adults and children with hemophilia A
  • Surgical prophylaxis for hemophilia A
Antihemophilic factor, recombinant (B-domain deleted, Fc fusion protein) Eloctate (third)
  • Treatment and prevention of bleeding episodes in adults and children with hemophilia A
  • Perioperative management of hemophilia A
  • Routine prophylaxis to prevent/reduce bleeding episodes in patients with hemophilia A
Antihemophilic factor porcine, recombinant (B-domain truncated) Obizurc (second)
  • Treatment of bleeding episodes in adults with acquired hemophilia A
Hemophilia B Plasma-derived
Factor IX, plasma-derived Mononine
AlphaNine SD
  • Treatment and prevention of bleeding episodes in patients with hemophilia B
Factor IXd complex, plasma-derived Bebulin
Profilnine SD
  • Treatment and prevention of bleeding episodes in patients with hemophilia B
Recombinant
Factor IX, recombinant, Fc fusion protein Alprolix (third)
  • Treatment and prevention of bleeding episodes in adults and children with hemophilia B
  • Perioperative management of hemophilia B
  • Routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children with hemophilia B
Factor IX, recombinant BeneFIX (third)
Ixinity (third)
Rixubis (third)
  • Treatment and prevention of bleeding episodes in adults and children with hemophilia B, including perioperative management
Hemophilia A or B (inherited) with inhibitors Plasma-derived
Anti-inhibitor coagulant complex, plasma-derived FEIBA
  • Control of spontaneous bleeding episodes or for perioperative management of adults and children with hemophilia A or B and inhibitors
Recombinant
Factor VIIa, recombinant NovoSeven RT
  • Treatment of bleeding episodes and perioperative management in adults and children with hemophilia A or B and inhibitors or with acquired hemophilia
  • Treatment of bleeding episodes and perioperative management in adults and children with congenital factor VII deficiency
Source: 12,19

 aClassification by generation applies to recombinant products only.
bAlso contains von Willebrand factor, but this product has not been investigated for efficacy or approved by FDA for treatment of von Willebrand disease.
cNot indicated for the treatment of inherited hemophilia A.
dIn addition to FIX, also contains factors II and X and can be used off-label to treat these factor deficiencies.

Recombinant products

Recombinant technology has allowed for substantial improvement in factor product safety from an infectious standpoint.1 The recombinant process involves the use of recombinant DNA technology with Chinese hamster ovary cells (both FVIII and FIX), or baby hamster kidney cells (FVIII). First-generation FVIII products use human or animal proteins in the manufacturing process and the final product; second-generation FVIII products use human or animal proteins in the manufacturing process but not the final product; and third-generation FVIII products contain no human or animal proteins, nor are these proteins used in the manufacturing process.1,12 Also, albumin is used as a stabilizer in first-generation products; sugars are used as stabilizers in second- and third-generation products.

Nearly all recombinant factor trials are noncomparative, open-label trials. They often compare different regimens using 1 product, including various prophylaxis regimens and on-demand treatment. Outcomes commonly consist of annualized bleeding rate (ABR), number of infusions per total dosage needed to achieve hemostasis, and inhibitor development. The trials also usually assess pharmacokinetics in a subgroup of patients.

B domain deletion

Some recombinant FVIII products are manufactured with their B domain deleted or truncated. The removal of the B domain of FVIII increases yield during production without interfering with factor efficacy.23

A 3-way crossover study that compared 2 B domain–deleted rFVIII products (BDDrFVIII) and a plasma-derived, full-length FVIII product found that the BDDrFVIII products were bioequivalent to the FVIII product on the basis of maximum plasma concentration and area under the curve (AUC). However, FDA led a 2003 workshop that highlighted the concern that BDDrFVIII products might be more immunogenic than full-length FVIII products.24

In 2011, a meta-analysis of 29 prospective observational studies sought to confirm the reports made to FDA on BDDrFVIII-related inhibitor development.25 The analysis found that BDDrFVIII use in previously treated patients was associated with a 7-fold risk of new inhibitor development compared with full-length products and a nearly 11-fold increase in risk for high-titer (greater than 5 BU/mL) new inhibitor development. The meta-analysis’ major limitation was that the studies included were observational and lacked control groups.

A 2003 meta-analysis of 13 trials found that BDDrFVIII was associated with a higher risk of breakthrough bleeding with prophylaxis compared with full-length FVIII, which may be directly related to the shorter half-life of BDDrFVIII.26

Thus far, no clinical recommendations for use of full-length FVIII products have been made based on these findings. The WFH guidelines do not address this topic and state no preference for any specific factor product.7

Fusion protein technology

A recent strategy to extend factor products’ half-lives is the addition of an Fc fusion protein to the coagulation factor concentrates.27,28 This technology has already been applied to some drugs (e.g., romiplostin and etanercept).27 Two factor concentrate products currently employ Fc fusion protein technology: rFIX (rFIXFc; Alprolix), approved in March 2014, and rFVIII (rFVIIIFc; Eloctate), approved in June 2014.18,29

Fc fusion technology uses the Fc domain of immunoglobulin G to form fusions with factor concentrates. The complex interacts with the neonatal Fc receptor, which is expressed in endothelial cells in the vasculature, and epithelial cells in the intestine, lung, and kidneys.27,28 The complex avoids endosomal/lysosomal degradation, and the factor concentrate is recycled back into circulation. The Fc fusion protein technology does not extend the half-lives of rFVIII and rFVIX to the same extent.28 It is thought that the complexing of FVIII to von Willebrand factor (vWF) limits the ability to further extend the half-life, since vWF’s half-life is 18 hours. Other half-life prolongation methods such as polyethylene glycol and albumin are being studied, but there are no factor products on the U.S. market that use these technologies.

The major phase 3 trials that led to the approval of rFVIIIFc and rFIXFc were the A-LONG and B-LONG trials, which assessed the products in patients aged 12 years and older with severe hemophilia A and B, respectively.30,31 Both trials assessed pharmacokinetics, a primary efficacy ABR endpoint, and inhibitor development. In A-LONG, investigators found that the terminal half-life of rFVIIIFc was extended by a significant amount compared with rFVIII: 19 versus 12.4 hours, respectively.30 The median ABR was reduced by 92% in the individualized prophylaxis group compared with on-demand treatment, and it was reduced by 76% in the weekly prophylaxis group compared with on-demand treatment. Inhibitors were not detected in any patients. The treatment was well-tolerated. The authors concluded that rFVIIIFc allowed less frequent prophylaxis dosing of 1 to 2 times weekly and offered excellent control of bleeding. Additionally, the Fc fusion protein did not interfere with factor efficacy and was not associated with immunogenicity.

In the B-LONG trial, a pharmacokinetic analysis showed that rFIXFc had a significantly prolonged half-life compared with rFIX: 82.1 hours versus 33.8 hours, respectively.31 The ABR was significantly reduced by 83% in the weekly prophylaxis group compared with the on-demand group and by 87% in the interval-adjusted prophylaxis group compared with the on-demand group. There trial detected no inhibitors, and the rFIXFc was well-tolerated. The recently completed Kids A-LONG study showed similar efficacy and safety data for rFVIIIFc in a pediatric patient population (younger than 12 years old). The results of Kids B-LONG for rFIXFc for this same age group have not yet been published.32,33

PHARMACOKINETICS OF FACTOR PRODUCTS

Factor concentrate product dosing is based on body weight and tailored to individuals’ pharmacokinetic responses, which vary widely among patients.7 The half-lives of factor concentrates vary among patients.27 In general, the half-life of FVIII is between 8 and 12 hours, and the half-life of FIX is between 18 and 24 hours. More pharmacokinetic variability exists for FVIII than FIX because FVIII complexes with vWF, which has a half-life of approximately 18 hours.28 Some data show a correlation among body weight, age, and clearance of some of the factor products, but it is insufficiently reliable for use in pharmacokinetic estimations. Pharmacokinetic parameters within patients must be measured accurately using recommendations provided by the International Society on Thrombosis and Haemostasis.34,35

Trough levels are thought to be the most important indicator of effective bleeding prophylaxis, while peak levels should be used to achieve hemostasis.7,34 The importance of AUC and peak levels for prophylaxis have not been clearly established. The goal trough level for both FVIII and FIX for prophylaxis is 1 international unit/dL. Factor levels of greater than or equal to 1 international unit/dL have been shown to prevent bleeding and preserve joint function,7 and higher goal trough levels may be useful in patients who are highly physically active or in attempts to manage target joints.36 Administering factor products as a continuous IV infusion is a strategy for eliminating low trough levels, both for prophylaxis and treatment of hemophilia. A continuous infusion also results in a decreased factor clearance compared to slow IV injection, which helps to maintain target trough levels.37

Bleeding treatment

Patients with hemophilia must receive infusions of the deficient coagulation factor to achieve hemostasis.7 The desired factor level depends on the bleeding’s source. Table 2 outlines recommended factor levels and treatment duration durations based on the bleed source.

Calculate the FVIII dose as follows:

Units of factor VIII needed = [patient weight (kg) x (desired concentration – initial concentration)]/2

Dividing by 2 adjusts for the fact that for each unit of FVIII per kilogram of body weight, plasma FVIII levels are expected to increase by 2 international units/dL. Adult and pediatric patients receive the same dose.

Calculate the FIX dose as follows:

Units of factor IX needed = patient weight (kg) x (desired concentration – initial concentration)

FIX plasma levels are expected to increase by approximately 1 international unit/dL with each unit of FIX per kilogram of body weight administered. However, if an rFIX product is used, the increase will be less, so the calculated dose should be divided by 0.8 international unit/dL in adult patients and by 0.7 international unit/dL in pediatric patients. These calculations can vary slightly for each product, so clinicians must always consult the product labeling for specific dosing information and adjustments. Two examples are provided below.

Example 1

A peak level of 70 international units/dL of FVIII is required for management of bleeding in a 40 kg child with severe hemophilia A (factor VIII level less than 1%):

[40 kg x (70 international units/dL – 0 international units/dL)]/2 = 1400 international units of FVIII

Example 2

A peak level of 70 international units/dL of FIX is required for management of bleeding in a 60-kg child with a factor IX level less than 1%. Per the product labeling for a specific product, each product international unit increases the FIX circulating level by 0.98 international unit/dL:

[60 kg x (70 international units/dL – 0 international units/dL)]/0.98 = 4286 international units of FIX

Patients with hemophilia require additional consideration when undergoing elective or emergent surgery.7 When possible, patients should consult with their hemophilia care team before surgical procedures. Factor concentrate dosing and duration at target levels depends on the surgery type. Table 2 provides general factor level recommendations.

Table 2. Factor Level Goals for Treatment of Bleeding and Surgical Procedures
Site of Hemorrhage Desired Factor Level (international units/dL) Treatment Duration
Hemophilia A Hemophilia B
Joints 40 to 60 40 to 60 1 to 2 days
Superficial muscle 40 to 60 40 to 60 2 to 3 days
Large muscle 80 to 100 followed by maintenance of 30 to 60 60 to 80 followed by maintenance of 30 to 60 1 to 2 days initially with 3 to 5 days maintenance
Central nervous system/head/throat/neck 80 to 100 followed by maintenance of 50 60 to 80 followed by maintenance of 30 1 to 7 days initially with 8 to 21 days of maintenance
Surgery (major) 80 to 100 preoperatively followed by 60 to 80, 40 to 60, and then 30 to 50 postoperatively 60 to 80 preoperatively followed by 40 to 60, 30 to 50, and then 20 to 40 postoperatively Postoperative therapy for 1 to 3, 4 to 6, and 7 to 14 days for each dosage level, respectively
Surgery (minor) 50 to 80 preoperatively followed by 30 to 80 50 to 80 preoperatively followed by 30 to 80 Postoperative therapy for 1 to 5 days, depending on the type of procedure
Source: Reference 7

BLEEDING PROPHYLAXIS

Prophylaxis’ benefits include reduction in bleeding episodes and joint damage, especially when prophylaxis is initiated early in children with hemophilia.38,39 A systematic review found that in children with hemophilia A or B, prophylaxis with factor concentrates significantly reduced bleeding episodes and joint damage compared with on-demand bleeding treatment.40 However, the findings are inapplicable to prophylaxis use in patients who already have joint damage (i.e., tertiary prophylaxis).

Despite clear benefits of prophylaxis, there is no consensus on an ideal regimen.7 A commonly used prophylaxis strategy is the Malmo protocol: 25 to 50 international units/kg of factor are administered 3 times per week for hemophilia A and 2 times per week for hemophilia B. The Utrecht protocol follows the same schedule but uses lower doses: 15 to 30 international units/kg 3 times per week for hemophilia A and 2 times per week for hemophilia B.

Prophylaxis can be further categorized as “full dose,” “intermediate dose,” or “low dose.”27 Full dose is generally the administration of higher doses of factors (either FVIII or FIX), usually in the range of 15 international units/kg to 40 international units/kg. Low and intermediate dose strategies use doses lower than this. When a 3-times-weekly prophylaxis regimen is used for FVIII, it is common for dosing to occur on Monday, Wednesday, and Friday. However, low troughs on Sunday have sometimes led to alternate-day dosing or a higher dose administration on Friday. From a cost-effectiveness and pharmacokinetic standpoint, alternate-day dosing is ideal, because, while doubling the dose on a Friday leads to an extension of trough at goal for an extra half-life, increasing the dose to maintain adequate trough levels until Monday morning requires potentially harmful doses.34

When FVIII prophylaxis strategies are used daily, as opposed to every third day, pharmacokinetic simulations have demonstrated a 30-fold variation in dosages required to meet a goal trough level of 1 international units/dL to 1.5 international units/dL.34 Fewer FIX pharmacokinetic simulations have been conducted , but it is known that FIX displays a 2-compartment pharmacokinetic model. Also, clearance for FIX differs on the basis of whether it is plasma-derived or recombinant. Therefore, determination of prophylaxis dosing for FIX is more difficult than for FVIII, and dosing will be different depending on the product’s source. Prophylaxis dosing is also different between adults and children. An average adult requires a dose of 12 international units/kg of FVIII to meet the same trough goal as a child who requires a dose of 25 international units/kg of FVIII.

Factor concentrates’ half-lives necessitate frequent administrations when used for prophylaxis.27 In some cases, patients may need placement of central venous access devices, which increases risks for infection and thrombosis. Also, factor concentrate infusions can be painful and can disrupt a family’s schedule. The cost of factor products is also a major deterrent to care. Cost prevents prophylactic use in some parts of the world. Response variability further complicates widespread factor concentrate use: Intra-individual pharmacokinetic variation is high and interindividual variation exists as well, especially in growing children.34 The guidelines emphasize that prophylaxis should be tailored to the individual, with consideration for the availability of factor concentrates, venous access, age, and bleeding phenotype.7

FACTOR USE IN PATIENTS WITH INHIBITORS

For patients with low-responding inhibitors, factor concentrates at higher doses may be used to manage bleeding.7,41 However, patients with inhibitor levels greater than 5 BU/mL usually require treatment with rFVIIa (NovoSeven) or the aPCC, FVIII inhibitor bypassing activity (FEIBA or anti-inhibitor coagulant complex), to achieve hemostasis. Both effectively reduce bleeding in patients with hemophilia A or B and inhibitors, for on-demand treatment and prophylaxis.41 Two doses of rFVIIa (90 to 120 mcg/kg body weight x 2) and 1 dose of aPCC (75 to 100 international units/kg body weight) are similar in efficacy for achieving hemostasis during joint bleeds.7,42 These agents bypass the antibody (inhibitor) and provide hemostasis in the absence of FVIII and FIX.1 The aPCC contains vitamin K-dependent, nonactivated factors II, IX, and X and activated factor VII. The greatest concerns with the aPCC use include an anamnestic response (renewed rapid antibody production on a subsequent encounter with the same antigen) in patients with hemophilia A and B because of trace amounts of FVIII and FIX and possible viral contamination since it is plasma-derived. Thrombosis is also a concern with the administration of these products, as a boxed warning in the product labeling indicates. Recombinant FVIIa has a shorter half-life than aPCC (approximately 2 to 3 hours versus 8 to 12 hours); it must be dosed more frequently than aPCC (every 2 hours versus every 6 to 12 hours).1,41,43

A randomized comparison of rFVIIa and aPCC for controlling joint bleeds in children with severe hemophilia A reported better outcomes with rFVIIa than aPCC, and rFVIIa was associated with a higher percentage of response to bleeding.44 Another randomized trial—the FEIBA NovoSeven Comparative (FENOC) study—compared the efficacies of 1 dose of aPCC with 2 doses of rFVIIa administered within 4 hours of bleeding for achieving hemostasis in patients with hemophilia A and inhibitors.42 Six hours after administration, the hemostatic efficacy was 80.9% for aPCC and 78.7% for rFVIIa. The investigators concluded that the 2 agents were similar in efficacy, despite not reaching the predetermined statistical significance.

Leissinger and colleagues conducted a crossover trial comparing a 3-times-weekly prophylaxis regimen of aPCC with on-demand aPCC treatment in 34 patients with hemophilia A and inhibitors.45 They reported a 62% reduction in bleeding with prophylaxis compared with on-demand treatment. Similarly, Antunes and colleagues compared aPCC prophylaxis with on-demand treatment in patients with hemophilia A or hemophilia B and inhibitors.46 They reported a 72.5% reduction in bleeding with prophylaxis compared with on-demand treatment. After 1 year, patients receiving prophylaxis with aPCC experienced clinically meaningful improvements in health-related quality of life compared with patients receiving on-demand aPCC treatment.47

Both aPCC and rFVIIa are effective hemostatic agents, and they also effectively reduce bleeding in patients with hemophilia and inhibitors.41 Their use is shifting to a prophylactic strategy, but this is limited by cost and inconvenience. Another recombinant porcine FVIII product (Obizur) was recently approved for bleeding treatment in patients with acquired hemophilia A and inhibitors.48 Factor VIII inhibitors have poor activity against nonhuman FVIII, so FVIII is still effective within the clotting cascade.1 However, in clinical studies, 19 of 25 patients exposed to this product developed anti-porcine FVIII antibodies, which indicates it may become ineffective with increased use.48

STORAGE, STABILITY, AND ADMINISTRATION OF FACTOR CONCENTRATES

Factor products are available in single-use vials that contain 250 international units to 3000 international units or more, depending on the factor type and its source (recombinant or plasma-derived).49 Dosing is usually rounded up to the nearest vial size. Because overdose is unlikely, clinicians usually administer the entire vial. Factor products may be administered by slow IV injection or by continuous IV infusion.7 Slow IV injection rates vary based on the product, but in general, the rate of infusion should not exceed 3 mL/minute in adults and 100 international units/minute in children. Continuous IV infusion offers 3 advantages: avoidance of peaks and troughs, possible decreased factor use, and convenience.7,37 However, continuous infusions require catheter placement and, thus, increased infection risk, and use of an infusion pump, which may fail.7

Regardless of the factor product administration technique, clinicians should be concerned about the product’s stability.37,50 Factor products should be administered as soon as possible upon reconstitution, usually within 3 hours.49 When administering a continuous infusion, sterility is a concern because the product is infused over a time period that usually exceeds 3 hours.37 However, some data suggest that the products are stable for a longer periods of time after reconstitution. Some unreconstituted products are reported to be stable for up to 2 months at room temperature, and others are stable for up to 12 months.50 Patients need to consider temperature requirements and factor product storage when at work, at home, on travel, and in transit. Each product’s prescribing information contains specific administration information, including dosing, infusion rate, stability, and storage requirements.

THE PHARMACIST’S ROLE

Hemophilia is a chronic condition, and adherence to prescribed therapies is essential for optimal patient outcomes. Hospitals and specialty pharmacies typically dispense factor products. To educate health care professionals and counsel patients, pharmacists working in these settings must know about hemophilia and factor products. Specifically, pharmacists should be able to answer questions regarding dosing, storage, and factor products’ stability. Pharmacists have also helped lower costs associated with factor product use by helping create a blood factor stewardship program.51

One specific pharmacist-led program at a North Carolina medical center optimized product selection, dosing regimens, and infusion frequencies for an estimated cost savings of $4 million annually. These interventions also reduced bleeding-related readmissions in patients with hemophilia A.

Cost savings are important considering that on average, each factor unit costs $1.52 From Example 2 above, the dose for the 60 kg child would be approximately $4,300. For a 70-kg patient with hemophilia A on the Malmo protocol, 1 week’s worth of factor product could cost upwards of $10,500.

When educating patients, pharmacists should make sure they teach patients how to recognize bleeding’s signs and symptoms and how to discern when to go to the emergency department. Table 3 lists signs and symptoms of bleeding. Pharmacists can also educate patients on factor products’ potential adverse effects and review patients’ medication lists for agents that may cause bleeding (Table 4). Pharmacists can also direct patients to helpful websites, including the following:

Table 3. Bleeding Signs and Symptoms53,54
External bleeding
Bleeds in the mouth or from the gums
Severe and/or recurrent epistaxis
Common internal bleeding
Large bruises
An ache or "funny feeling" in muscles or joints (commonly knee, ankle, elbow, and hip joints)
Joint swelling
Joint stiffness
Difficulty using a joint or muscle
Joints or muscles that feel hot to the touch
Menorrhagia
Bleeding that requires an emergency department visit
Intracranial hemorrhage (severe headache, stiff neck, vomiting, sleepiness, weakness, behavioral changes, vision changes, seizure)
Eye
Throat
Gastrointestinal tract
Deep cuts or lacerations

Table 4. Drug Classes that May Increase Risk for Bleeding8,55
Anticoagulants (e.g., apixaban, dabigatran, rivaroxaban, warfarin)
Antidepressants – selective serotonin reuptake inhibitors (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline)
Antiplatelets (aspirin, clopidogrel)
COX-2 inhibitors (e.g., celecoxib)
NSAIDs (e.g., ibuprofen, naproxen)
Abbreviations: COX-2 = cyclooxygenase-2 inhibitors; NSAIDs = nonsteroidal anti-inflammatory agents

CONCLUSION

Hemophilia is a rare, inherited disorder that can cause frequent bleeding episodes in affected patients. Over the past 50 years, significant advances have been made in this disease’s treatment and prevention options, extending life expectancy and decreasing disability. Factor replacement therapy for hemophilia A and B has evolved to be safer and more preventive in nature. Patients with hemophilia can expect to enjoy near-normal life expectancies. However, the development of inhibitors remains a primary treatment concern with factor concentrates. Pharmacists should be equipped with a general knowledge of hemophilia and its treatment options to help improve patient outcomes.

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