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INTRODUCTION — Hemophilia A (factor VIII [factor 8] deficiency) and hemophilia B (factor IX [factor 9] deficiency) are X-linked inherited coagulation factor deficiencies that result in lifelong bleeding disorders. The availability of factor replacement products has dramatically improved care for individuals with these conditions. However, the severity and frequency of bleeding is variable, the optimal management is complex, new therapies are being introduced rapidly, and many challenging management decisions continue to arise.
This topic review discusses routine management of individuals with hemophilia A and B, including preventive and comprehensive care at various ages, and decisions regarding prophylactic factor infusion.
Separate topic reviews discuss diagnosis, treatment of bleeding, surgery, inhibitor eradication, age-related comorbidities and complications, and genetics of hemophilia.
●Diagnosis – (See "Clinical manifestations and diagnosis of hemophilia".)
●Surgery and treatment of bleeding – (See "Treatment of bleeding and perioperative management in hemophilia A and B".)
●Inhibitor eradication – (See "Factor VIII and factor IX inhibitors in patients with hemophilia".)
●Age-related comorbidities and complications – (See "Chronic complications and age-related comorbidities in people with hemophilia".)
●Genetics – (See "Genetics of the hemophilias".)
The evaluation and management of individuals with other inherited coagulation disorders and acquired factor deficiencies are also presented in detail separately. (See "Rare inherited coagulation disorders" and "Factor XI deficiency" and "Disorders of fibrinogen" and "Clinical presentation and diagnosis of von Willebrand disease" and "Acquired inhibitors of coagulation".)
ROUTINE/COMPREHENSIVE CARE — The optimal management of people with hemophilia is complex. Interventions directed at reducing complications of hemophilia and its treatment are paramount. At the same time, routine health maintenance and comprehensive care is critical to decrease other health risks that have the potential to become more complicated due to the underlying bleeding disorder.
Integrated care should be instituted as soon as the diagnosis of hemophilia is made . This includes decisions about use of factor prophylaxis, methods to minimize bleeding risk, modifications to facilitate routine comprehensive care, and counseling regarding psychosocial issues and disease inheritance. Education about the disease is important for families, especially those with newborns with a new hemophilia diagnosis, since the newborn will be the first family member with hemophilia in approximately one-third of families. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Epidemiology' and "Clinical manifestations and diagnosis of hemophilia", section on 'Initial presentation'.)
Hemophilia treatment centers — Designated hemophilia treatment centers (HTCs) have been established in many parts of the world to provide multidisciplinary care for individuals with hemophilia and other bleeding disorders. HTCs were established in the United States in the mid-1970s; there are approximately 140 active HTCs in the United States. HTCs are also present in most countries in the developed world .
Listings of HTCs are available online:
●United States – The Centers for Disease Control and Prevention lists United States HTCs on their website (www2a.cdc.gov/ncbddd/htcweb/Dir_Report/Dir_Search.asp)
●International – The World Federation of Hemophilia has a searchable directory of HTCs throughout the world (http://www.wfh.org/en/page.aspx?pid=1264)
The United States National Hemophilia Foundation (www.hemophilia.org) has additional resources.
Comprehensive HTCs provide a number of services, which may include testing for blood-borne viral infections and access to appropriate care and therapy. The multidisciplinary team provides coordinated chronic disease management and expert hemophilia care, risk reduction counseling, and ongoing education of patients and families. HTCs also manage home therapy and preventive services, and work closely with hemophilia consumer organizations.
The benefit of HTCs was demonstrated in a 2000 study that compared mortality in 2950 individuals with hemophilia (7575 person-years of observation) according to the site of care (HTC or non-HTC) . This study documented a significant improvement in life expectancy associated with HTC-based care (relative risk [RR] of death, 0.6; 95% CI 0.5-0.8) despite HTCs caring for a population with more severe disease and associated co-morbidities.
Newborn care — The majority of infants with hemophilia present with a known family history; advance noninvasive fetal sex determination is used to guide labor and delivery. However, a significant number of affected individuals have an unexpected diagnosis, likely due to a de novo mutation in the mother. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Initial presentation'.)
●For a male child born to a known female carrier, multidisciplinary planning is required to address maternal and fetal bleeding risks, method of delivery, and avoidance of interventions such as fetal scalp electrodes, fetal venous sampling, and operative vaginal delivery (eg, use of forceps, vacuum extraction). Intramuscular vitamin K and heel stick for standard neonatal screening tests should be performed by experienced staff with additional pressure held at the site. These issues are discussed in detail separately. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Method of delivery and anesthesia'.)
●Recommended neonatal immunizations (eg, hepatitis B vaccine) should be administered; the smallest gauge needle should be used, and pressure and ice applied to the site for three to five minutes post injection. (See 'Immunizations' below.)
●Invasive procedures such as circumcision should be deferred for any male child born to a hemophilia carrier or any newborn with unexplained bleeding until a diagnosis such as hemophilia is confirmed or excluded. Circumcision is a controversial and important decision for some families and is an important ritual for certain populations such as Muslims and Jews [4,5]. An approach to this and other invasive procedures if the patient is diagnosed with hemophilia is presented separately. (See "Treatment of bleeding and perioperative management in hemophilia A and B", section on 'Circumcision'.)
●Diagnostic testing for the relevant factor level (factor VIII  for hemophilia A or factor IX  for hemophilia B) is performed using cord blood (preferred) or a venous sample, with comparison to age-appropriate normal controls. In cases without a family history, von Willebrand factor antigen is also required in addition to the factor VIII level since von Willebrand disease (VWD) is also in the differential diagnosis. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Diagnostic evaluation'.)
Immunizations — Recommended immunizations should be given at age-appropriate intervals to individuals with hemophilia. Modifications to reduce the risk of bleeding include use of the smallest gauge needle and application of pressure and/or ice to the site for three to five minutes post injection.
Standard vaccination schedules and other issues such as avoidance of live vaccines when there is an immunocompromised member of the household, are presented separately. (See "Poliovirus vaccination" and "Standard immunizations for children and adolescents: Overview", section on 'Routine schedule'.)
Dental care — Appropriate oral hygiene and regular dental care is essential for individuals with hemophilia to prevent gum and tooth disease, which increase the risk of bleeding. Early infant dental intervention is recommended to teach proper brushing and ensure adequate household water fluoridation. The teeth should be cleaned routinely, and anticipated problem areas for causing bleeding should be discussed. An example is frenulum injury as a cause of bleeding in young children. Management of dental procedures is discussed separately. (See "Treatment of bleeding and perioperative management in hemophilia A and B".)
Exercise and athletic participation — An appropriate exercise regimen should be encouraged as a daily routine. Benefits include maintenance of a healthy weight, cardiovascular risk reduction, and positive effects on strength, flexibility, balance, and bone density, all of which contribute to decreased stress on joints. Exercise is also valuable for socialization and psychological health, which may be affected by a chronic condition such as hemophilia . Children with hemophilia are vulnerable to loss of physical conditioning, reduced bone density, and excessive weight gain/obesity due to activity restrictions [7,8]. The role of an exercise program is best discussed early to support positive lifelong habits and health.
The World Federation of Haemophilia Working Group on Physical Therapy and the National Hemophilia Foundation Physical Therapy Committee have developed patient educational materials that quantify some of the musculoskeletal benefits and risks of organized and individual physical exercise [9,10]. The best approach to defining individual athletic regimens involves consultation between the staff at a local HTC; the patient; and for minor children, the parents and caregivers.
Ideal activities are those that reflect the individual's preferences, abilities, and local resources, and include non-contact sports such as swimming, walking, golf, tennis, bicycling, archery, and table tennis, and supervised group activities . In one series of 37 children with severe hemophilia A or B who were receiving prophylactic factor infusions, the frequency of joint bleeding was low (<1 bleed or injury per season) and did not differ between high impact activities (eg, basketball, karate, skateboarding) and low impact activities (eg, cycling, swimming, hiking) . Examples of high and low impact sports are listed in the table (table 1).
Consultation with a specialist regarding protective gear, splints, and prophylactic factor infusions timed around the activities should be initiated early and as needed. Additional information about specific activities is provided in a publication from the National Hemophilia Foundation .
Medicines to avoid — Medicines that increase the risk of bleeding, including anticoagulants, aspirin, and other nonsteroidal anti-inflammatory drugs (NSAIDs) should generally be avoided in patients with hemophilia. Pain can be treated with local measures (eg, cold packs, immobilization, splinting), acetaminophen, propoxyphene, or codeine. Cardiovascular disease prevention should focus on diet, exercise, smoking avoidance, and control of hypertension and hypercholesterolemia.
Rare exceptions may include the following; consultation with a hemophilia expert or HTC is advised:
●Individuals with cardiovascular disease for whom the benefits are thought to outweigh the risks, with consideration given to institution of a replacement regimen that provides protection. (See "Chronic complications and age-related comorbidities in people with hemophilia", section on 'Cardiovascular disease'.)
●Some patients with arthropathy can use cyclooxygenase (COX)-2 inhibitors. (See "Overview of selective COX-2 inhibitors".)
It is also important to discuss herbal remedies and over-the-counter supplements such as fish oil, which may increase bleeding risk and are not always volunteered by the patient . These may not need to be strictly avoided, but the physician should be aware of their use and have a discussion about the possible impact on bleeding risk.
Planning for invasive procedures — For individuals with hemophilia who are undergoing elective surgery, collaboration between the surgeon, hematologist, and laboratory and transfusion medicine services should occur, with sufficient time to allow a smooth surgical course in which factor levels can be monitored and replacement therapy administered on time. The specific factor dosing schedule and appropriate target factor levels depend on the individual patient and procedure being performed; some individuals may be able to use products other than clotting factor (eg, DDAVP for mild hemophilia A). These issues are discussed in detail separately. (See "Treatment of bleeding and perioperative management in hemophilia A and B".)
DDAVP test dose for mild hemophilia A — DDAVP (desmopressin) is a synthetic analog of vasopressin (antidiuretic hormone) that promotes release of factor VIII and its carrier protein von Willebrand factor (VWF) from storage pools in platelet granules and endothelial cells. For individuals with mild hemophilia A (factor VIII activity level between 5 and 40 percent), a DDAVP test dose can be given to determine whether DDAVP is effective in that individual, and if so, whether it can be used to raise the factor VIII level in the setting of mild bleeding or minor invasive procedures. This should be done at least one week before a planned procedure, since tachyphylaxis occurs. Usually it is done as part of routine comprehensive care so that DDAVP can be used for a variety of mild bleeding scenarios, including surgical, traumatic, or spontaneous. (See "Treatment of bleeding and perioperative management in hemophilia A and B", section on 'Patient with mild hemophilia'.)
The DDAVP test dose should be performed when the individual is well. It involves a baseline measurement of factor VIII activity level, followed by administration of DDAVP, followed by measurement of a post-DDAVP factor VIII activity level. DDAVP can be administered intravenously, subcutaneously, or intranasally (with a nasal spray).
Dosing and post-DDAVP factor VIII level measurement is as follows:
●Intravenous or subcutaneous DDAVP – Give 0.3 mcg/kg (maximum dose, 20 mcg). The intravenous form is diluted in 50 mL of normal saline and infused over 20 to 30 minutes. Obtain the post-DDAVP factor VIII level approximately 60 minutes after DDAVP administration.
●Intranasal DDAVP – When using the nasal spray it is important to use the product intended for hemostatic therapy (Stimate) rather than the product for enuresis, since the dose is higher for bleeding disorders (1.5 mg/mL rather than 0.01 percent). Give one puff (150 mcg in one nostril) in patients weighing <50 kg and two puffs (150 mcg in both nostrils) in patients weighing ≥50 kg. Obtain the post-DDAVP factor VIII level approximately 90 minutes after DDAVP administration.
In individuals for whom this is effective, an approximately two- to fourfold increase in factor VIII activity level is expected at approximately 60 minutes after an infusion or 90 minutes after an intranasal dose, with the response persisting for 6 to 12 hours . Some individuals have a lower or greater increase. Additional doses may be given; however, tachyphylaxis may occur with repeated dosing, and dosing at intervals shorter than 24 hours may be associated with increased risk of water retention. One study of serial DDAVP doses found a 30 percent lower peak level in factor VIII increase between the first and second doses of DDAVP .
The likelihood of response to DDAVP has been assessed in several case series. As examples:
●In a review of intravenous DDAVP test doses given to 62 boys with mild hemophilia A at one institution, 29 (47 percent) had at least a twofold increase in factor VIII level one hour after administration of DDAVP . The likelihood of response was greatest in those with higher baseline factor levels and with increasing age; an additional seven boys who did not have an initial response and were retested approximately five years later did have a response upon retesting. Another report that included 20 patients with mild hemophilia A documented DDAVP responses in 75 percent .
●In a study of 22 individuals (11 with hemophilia A and 11 with von Willebrand disease [VWD]) who had a documented response to intravenous DDAVP at 60 minutes and were subsequently tested for the response to intranasal DDAVP (Stimate) at 90 minutes, all of the patients with hemophilia A had increases in factor VIII levels (median increment of 30 percent [from 17±11 percent to 50±25 percent]) . This was less than the median increment with intravenous DDAVP of 62 percent, but 9 of 11 had a final factor VIII level above 20 percent, which is minimally hemostatic in specific instances. A study in 10 volunteers without hemophilia documented that intravenous and intranasal DDAVP produced similar responses, supporting the usefulness of the intranasal route .
DDAVP is generally reserved for minor bleeding or minor invasive procedures in individuals with mild hemophilia A. Severe, life-threatening bleeding should be treated with factor infusion because the response to DDAVP is not immediate and may not raise the factor VIII level for optimal hemostasis. Individuals with moderate to severe hemophilia A (factor VIII level <5 percent) are unlikely to derive benefit because the incremental increase in factor VIII level would be insufficient for hemostasis. An exception might be an individual with a factor VIII level closer to 5 percent who wishes to use this therapy and testing may be performed to determine its utility. (See "Treatment of bleeding and perioperative management in hemophilia A and B".)
DDAVP is not used in hemophilia B because factor IX is not present in storage pools.
Obstetric care and preconception counseling — Obstetric care, including preconception counseling, prenatal evaluation, delivery, and neonatal diagnosis, are discussed in detail separately. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Obstetrical issues'.)
Travel — Appropriate planning for travel should occur in individuals with hemophilia regardless of level of severity. At a minimum, an emergency supply of hemostatic replacement therapy should be kept with the patient during travel. In addition, knowledge of the available HTC either along the route or at the final destination is needed. A letter from the primary HTC detailing the patient's diagnosis and treatment along with contact information for the treating hematologist is very useful. The use of a medic alert bracelet can be lifesaving in emergency situations. For air travel, a prescription listing medications can facilitate passage through airport security, especially if syringes and needles are carried.
ROUTINE FACTOR REPLACEMENT THERAPY (PROPHYLAXIS)
Overview of decision-making — A number of decisions need to be made regarding routine factor replacement therapy [19-21]:
●Should the individual receive prophylactic or on-demand therapy?
●Should prophylaxis be instituted at a very young age (before bleeding episodes occur) or deferred until a specific time?
●Should prophylaxis be continuous or intermittent?
●What is the best replacement product for the patient (plasma-derived, recombinant, long acting)?
●Does the individual require a central venous catheter?
●Can prophylaxis ever be discontinued?
Prophylaxis versus on-demand therapy — Prophylactic therapy (factor administration in the absence of bleeding) (table 2) is highly effective in reducing bleeding and long-term complications of bleeding such as chronic arthropathy in people with hemophilia, especially those with severe factor deficiency . Prophylactic therapy also reduces the incidence of intracerebral hemorrhage (ICH) which is less common than joint bleeding but potentially much more devastating . Additional advantages include reduced hospitalizations and reduced absenteeism from school or work .
However, the costs and burdens of prophylaxis are high, including the need for recurrent venous access that may require placement of a central venous catheter (which can result in an increased risk for infection and thrombosis), the need to adhere to recurrent intravenous factor infusions, the overall cost of care, and interference with family life and normal activities [25,26].
These benefits and risks, along with patient values and preferences, inform decisions regarding whether and when to start prophylaxis. Mild or moderate factor deficiency with a decreased clinical bleeding phenotype may be important decision-making points favoring on-demand therapy (ie, factor given only in the setting of acute bleeding or surgery, also called episodic therapy). Individuals may decide to change from on-demand to prophylactic therapy (or vice versa) based on the perceived burden and their health status.
The terminology for prophylaxis was revised in the 2012 World Federation of Hemophilia guideline to clarify whether prophylaxis is primary (before a bleeding event has occurred) or secondary, and continuous or intermittent (eg, for a few months at a time) (table 2).
●Primary prophylaxis – Individuals who have not had a bleeding episode but are at high risk of bleeding based on severe factor deficiency (eg, factor VIII or factor IX activity level <1 percent) are recommended to receive primary prophylaxis due to the high risk of spontaneous bleeding and efficacy of prophylaxis in preventing bleeding and its complications . Primary prophylaxis has been used extensively in parts of Europe, particularly in Sweden, and has been accepted by the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation (NHF) and the Pediatric Working Party of the United Kingdom Haemophilia Doctors' Organisation (UKHDO) as the optimal treatment modality for patients with severe hemophilia [27-29].
●Secondary prophylaxis – For individuals who have had more than one bleeding episode (eg, two or more bleeds into a target joint, evidence of joint disease by physical examination or radiography), secondary prophylaxis may be appropriate to prevent further morbidity, regardless of factor activity level. Those with severe disease (factor activity <1 percent) and more than one bleeding episode should receive secondary prophylaxis, whereas those with moderate or mild disease (factor activity 5 to 40 percent) and more than one bleeding episode may be able to use intermittent prophylaxis.
●Intermittent prophylaxis – For individuals with moderate or mild factor deficiency (eg, factor VIII or factor IX activity level >5 percent) and no prior bleeding, the need for prophylaxis is individualized based on the patient's factor level, which factor is deficient (factor VIII or factor IX), and the patient's physical activity level. Intermittent prophylaxis (also called "short-term prophylaxis"), which is administered for several weeks to months and then discontinued, may be used in specific circumstances such as high-impact physical activities, joint bleeding, or surgical procedures. We are more likely to use prophylaxis in those with lower baseline factor levels (eg, closer to 5 percent) and in those with moderate factor VIII deficiency than those with moderate factor IX deficiency.
Many individuals for whom prophylaxis is appropriate may not have access to factor infusions due to high costs and/or lack of resources. In resource-limited settings, options for those who cannot receive regular prophylaxis include intermittent prophylaxis and/or prophylaxis using lower doses. As an example, a 2016 study from India of patients with factor VIII deficiency found that prophylaxis using factor VIII at 10 units/kg (rather than the usual 25 to 40 units/kg) twice per week was cost-effective and significantly reduced joint bleeds and school absenteeism .
Evidence for the benefit of prophylaxis in reducing morbidity comes from randomized trials and observational studies, as well as experience with individuals who have factor activity levels above 1 to 2 percent and have significantly lower bleeding rates than those with factor levels <1 percent :
●A 2007 trial randomly assigned 65 boys with hemophilia A (factor VIII activity <2 percent) who were under 30 months of age to receive prophylaxis with recombinant factor VIII (25 units/kg every other day) or episodic therapy only at the time of joint bleeding . At six years of age, imaging studies of the ankles, knees, and elbows using magnetic resonance imaging (MRI) was performed. This showed a greater protection from joint damage (all six joints normal) in those assigned to prophylaxis (25 of 27 boys [93 percent]) compared with those assigned to episodic treatment (16 of 29 [55 percent]), with a relative risk (RR) of joint damage with episodic therapy of 6.1 (95% CI 1.5-24.4). Total bleeding events (joints and other sites) were also significantly less in the prophylaxis group (mean, 3.3 versus 17.7 per person per year). Adverse events included development of a factor VIII inhibitor in two boys in the prophylaxis arm (6 percent) and life-threatening hemorrhage in three boys in the episodic therapy group (9 percent).
●A 2011 trial (Evaluation Study on Prophylaxis: a Randomized Italian Trial [ESPRIT]) randomly assigned 45 children with severe hemophilia A (factor VIII activity <1 percent) who were one to seven years of age (median age, four years) to receive prophylaxis with recombinant factor VIII (25 units/kg three times per week) or episodic therapy at the time of bleeding . After a median period of approximately seven years of observation, joint bleeding was assessed by standard radiography. This showed a lower number of hemarthroses with regular prophylaxis than with episodic treatment (mean number of hemarthroses per patient 14.7 versus 40). Total bleeding events were significantly less in the prophylaxis arm (mean 38 versus 82 over the entire study period). Joint preservation was especially good in those who started prophylaxis at the age of three years or younger; none of the eight patients who began prophylaxis by age three had joint damage, compared with 3 of 10 (30 percent) of children of the same age assigned to episodic therapy.
●Trials in adults who were previously receiving on-demand therapy and converted to prophylaxis have all noted reductions in bleeding episodes [33-37]. As an example, in a series of 20 adults who converted from an on-demand schedule to routine prophylaxis, joint bleeds decreased from approximately two to four bleeds per month to approximately 0 to 0.5 bleeds per month .
●Several observational studies have also found that routine prophylaxis was associated with a reduction in joint bleeding and chronic arthropathy, especially when started early and targeted to individuals with severe disease [24,38-40].
Choice of replacement product — All of the available factor replacement products can produce satisfactory hemostasis. The choice among products thus is based on safety, purity, risk of inhibitor development, product half-life, individual product characteristics, patient response, and cost . We individualize the choice of replacement product based on the patient's circumstances and needs, following an open discussion with the patient regarding data on specific products. Once we determine which product is best for a patient, we make every effort to obtain this product, which may include providing the data and rationale to a third party payor.
●Inhibitor development – Inhibitor development (both low and high titer inhibitors) can greatly interfere with the ability to treat bleeding and achieve adequate hemostasis. High titer inhibitors bind to exogenously administered replacement factor and prevent it from achieving hemostasis. Inhibitor development is greatest in those with severe deficiency because it is most likely that the infused factor will be seen as a foreign protein in these individuals. Inhibitors are much more common in individuals with hemophilia A than those with hemophilia B.
Information on risks of inhibitor development with different types of factor concentrates and recombinant products is discussed in detail separately. (See "Factor VIII and factor IX inhibitors in patients with hemophilia", section on 'Replacement product'.)
●Safety from viral infections – Viral infections (eg, human immunodeficiency virus [HIV], hepatitis B and C viruses [HBV and HCV]) affected large numbers of people with hemophilia who received plasma-derived factor concentrates in the 1970s, 1980s, and early 1990s. Plasma-derived factor concentrates have been free of HIV, HBV, and HCV transmission since approximately 1993; however, concerns remain that potential transmission of blood borne diseases could occur, and this must be understood by patients and caregivers. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Infection from plasma-derived products'.)
We often use a recombinant product made in a human cell line with tighter binding to von Willebrand factor. Ultrapure products are also preferred for individuals who are infected with HIV, as they stabilize the CD4 cell count .
●Product half-life – A number of recombinant factor products with modifications to extend their half-lives have been produced. These products have the advantage of decreasing the dosing interval while maintaining adequate factor levels, especially for factor IX. These products are often more expensive per unit compared with other plasma-derived and recombinant products. However, the decreased dosing interval may reduce the need for a central venous catheter and the risk of catheter-associated complications in some patients. We often use these products for prophylaxis in children and individuals with factor IX deficiency who require prophylaxis.
Details of available longer half-life products, their mechanisms of action, dosing, and efficacy are presented below. (See 'Longer lasting recombinant factor VIII' below and 'Longer lasting recombinant factor IX' below.)
●Cost – Replacement products are expensive, especially longer lasting products. However, overall cost depends on how the product is used and the rate of breakthrough bleeding. Even the most expensive product may be cost-effective if it reduces the frequency of bleeding. Cost and third party coverage for factor products that takes into account the patient's clinical circumstances must be discussed. Countries and local institutions may have specific agreements in place that result in cost reductions. Enrollment in a clinical trial may also be an option for cost reduction .
All of the available factor replacement products are administered intravenously, with the majority requiring reconstitution. There is ongoing work in the development of therapies for subcutaneous administration. (See 'Prophylactic therapies under development' below.)
Age of initiation and dosing schedule — The goal of prophylaxis is to reduce (or, ideally, prevent) bleeding. Thus, it is generally initiated at as young an age as reasonably possible. Dosing is scheduled to maintain sustained, protective factor levels. However, both age at initiation and dosing frequency need to be balanced against the risks and burdens of therapy that is administered intravenously. In many cases, prophylaxis implies the need for a central venous access device, which must be maintained and used properly, and carries risks of infection and thrombosis. These risks, types of devices, and their proper care and use, are presented separately. (See "Overview of central venous access" and "Complications of central venous catheters and their prevention" and "Prevention of intravascular catheter-related infections".)
●Age – The benefit of starting prophylaxis at as young an age as possible is balanced against the burdens of regular (two to three times per week) intravenous therapy in an infant. We generally advise patients with severe hemophilia (factor activity level <1 percent) to start prophylaxis when they have significant bleeding such as a joint bleed or other bleeding that requires treatment with factor (but not for minor bruising or oral bleeding). This may be at approximately one year of age for some children and older for others. Some centers routinely start prophylaxis at 1 to 1.5 years of age .
Another option for patients or families who place a higher value on avoiding or delaying factor infusions (or venous access device insertion) is to wait until it becomes clear whether the patient is going to have frequent bleeding episodes. This has the advantage of potentially avoiding factor infusions in patients with infrequent or no bleeding. However, there is a potential risk of life-threatening bleeding if prophylaxis is not given. Neither of these risks are predictable.
The benefits of starting prophylaxis at a young age or soon after the first joint bleed have been shown in several studies:
•In a 2017 analysis from a United States hemophilia treatment center surveillance registry that included over 6000 patients followed for approximately 12 years, normal joint mobility was preserved in those who started prophylaxis before age 4 years . (See "Clinical manifestations and diagnosis of hemophilia", section on 'Hemophilic arthropathy'.)
•In a 2002 study involving 76 patients who started prophylaxis at different ages and were followed for two decades, the risk of long-term joint damage increased by 8 percent for every year after the first joint bleed that prophylaxis was delayed . The median age of first joint bleed in this study was 2.2 years, consistent with that seen in other studies. (See "Clinical manifestations and diagnosis of hemophilia", section on 'Age at first bleeding'.)
•In a 1999 series of 121 patients who started prophylaxis at different ages, the frequency of developing arthropathy was less in those who started prophylaxis at age 0 to 2 years compared with those who started between ages 3 and 10 years . The bleeding rate also decreased with shorter interval dosing (eg, less bleeding with dosing two times weekly [hemophilia B] or three time weekly [hemophilia A] compared with once weekly). In a subgroup of 55 patients who used a more intensive schedule (factor infusion three times weekly), there was no significant difference in bleeding rate between those who started prophylaxis before age 3 years or between 3 and 5 years.
Importantly, joint bleeding is not the only clinically important outcome. Studies to evaluate the benefit of prophylaxis in reducing other bleeding complications are ongoing.
●Dosing schedule – The goal of dosing is to maintain the factor level above 1 to 2 percent, essentially converting the patient from a severe to a moderate hemophilia phenotype. Larger doses given less frequently will produce higher peaks; smaller doses given more frequently will provide more uniform factor levels but involve more venipuncture and handling of factor.
The dosing and monitoring schedule are highly dependent on the patient and which factor is deficient. Very young children may be able to tolerate a lower trough level (eg, 1 to 2 percent) than older children who are more active and/or demonstrate a severe bleeding pattern. The dosing schedule can be adjusted according to the patient's trough factor level, bleeding rate, and intravenous access. The presence of a central venous access device facilitates more frequent monitoring of trough levels, but this may not be required in all patients.
The following are examples of typical starting schedules :
•Hemophilia A – Factor VIII, 25 to 40 units/kg of body weight, given three times per week (Malmo protocol) or 15 to 30 units/kg three times per week (Utrecht protocol). If a longer lasting product is used, small children may start with once or twice per week dosing and work up to the optimal dosing and trough level.
•Hemophilia B – Factor IX, 25 to 40 units/kg of body weight, given two times per week (Malmo protocol) or 15 to 30 units/kg two times per week (Utrecht protocol). Longer lasting products allow for once per week or once every two week dosing.
Other schedules such as every other day are also used; it is important to consult the product information for the specific product being administered, and the patient's individual pharmacokinetics. Management of product choice and dosing schedule is optimally done through a hemophilia treatment center. It is preferable to give the factor in the morning so that levels will be higher during periods of activity rather than during sleep. The vial size closest to the calculated dose should be used to limit the number of vials required.
For adults who have previously been receiving on-demand therapy and want to switch to prophylaxis, dosing is similar, although the typical amount of factor used during on-demand treatment and/or the circumstances in which bleeding was most likely to occur can also be incorporated into the dosing schedule (eg, dosing immediately before activities that previously were associated with bleeding, termed "activity-based prophylaxis"). Some adults with factor VIII deficiency may start with once weekly prophylaxis, which will significantly decrease bleeding and can acclimate them to the use of prophylaxis.
Flexibility in dosing schedules is supported by a 2012 trial that randomly assigned 66 patients with hemophilia A to receive standard dosing (20 to 40 units/kg every other day) or adjusted dosing based on pharmacokinetic data (20 to 80 units/kg every third day) and found that the two arms were comparable in annualized bleeding rates, total factor usage, and adverse event rates .
The importance of an adequate trough factor activity level in reducing "breakthrough" bleeding was demonstrated in a study involving 143 children and adults with severe hemophilia A who were receiving routine prophylaxis . The amount of time with trough factor VIII activity levels below 1, 2, and 5 percent were calculated from pharmacokinetic data and infusion records; this analysis showed that bleeding correlated strongly with lower trough levels, such that each hour spent with a factor VIII activity <1 percent was associated with a 2.2 percent increase in annualized bleeding rate.
Can prophylaxis be discontinued? — Once prophylaxis is started, a question may arise regarding whether or when the patient can or should be transitioned to on-demand treatment. The answer is highly patient-dependent, and we usually base our decisions on the symptoms being reported and the concerns of the patient. As an example, some adults may wish to switch to a less frequent regimen or have a trial off prophylaxis, with close observation of the effects on musculoskeletal symptoms and quality of life.
In a 2005 series that included 80 patients with severe hemophilia A or B who received prophylaxis during childhood, approximately one-third discontinued prophylaxis (median age of discontinuation, 21.5 years) . At a median follow up of 3.5 years, the individuals who stopped prophylaxis had a slightly higher rate of joint bleeds (3.2 versus 1.8 per year) but an equivalent clinical outcome based on clinical examination score that included inflammation, deformity, and instability; and a radiologic (Pettersson) score. However, these radiologic scores lag behind clinical bleeding events. We inform patients that the risk of development of joint disease continues when prophylaxis is discontinued, as does the risk of intracranial or other life-threatening bleeding events.
Available products — The tables list available products for factor VIII (table 3) and factor IX (table 4), which are described in the sections that follow. An updated table is also maintained by the of the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation (NHF) in the United States (www.hemophilia.org) [49,50].
Factor VIII products — Factor VIII products are used to treat hemophilia A (inherited deficiency of factor VIII [factor 8]). Factor VIII products can be derived from processed human plasma or produced from cell lines engineered to express large amounts of factor VIII (also called genetically engineered or recombinant factor VIII). The plasma-derived products are stratified based on purity, and the recombinant products are characterized by "generation"; both of these measures reflect decreasing exposure to human or animal proteins [51,52].
Available factor VIII products and their characteristics are listed in the table (table 3); an updated table is also maintained by the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation (NHF) in the United States (www.hemophilia.org) [49,50].
Plasma-derived concentrates — Plasma-derived factor VIII concentrates are prepared by commercial fractionation of carefully screened donor plasma. Viral inactivation procedures (pasteurization, solvent-detergent treatment, chemical disruption with sodium thiocyanate, or ultrafiltration) add another layer of protection against HIV and hepatitis viruses. Parvovirus B19, a non-lipid-enveloped virus, is an exception to elimination by heat inactivation and solvent/detergent methods, and parvovirus infection has been reported with a solvent/detergent treated, plasma-derived factor concentrate [53,54]. (See "Blood donor screening: Laboratory testing" and "Pathogen inactivation of blood products", section on 'Solvent/detergent treatment'.)
For the ultrahigh purity products, affinity chromatography using monoclonal antibodies provides an additional purification step . Preparation of factor VIII from Cryoprecipitate is no longer done.
Available products are characterized by their purity, which reflects the relative amounts of factor VIII and non-factor VIII protein in the product:
●Intermediate purity – These products typically contain 6 to 10 units of factor VIII/mg protein.
●High purity – These products contain at least 50 units of factor VIII/mg protein (range 50 to 150 units/mg protein), excluding albumin used for stabilization.
●Ultrahigh purity – These products are monoclonal antibody (mAb) affinity-purified and contain 3000 units of factor VIII/mg protein, excluding albumin used for stabilization [51,52]. This concentration is essentially identical to the purity of recombinant products [51,52].
Plasma-derived products include Hemofil-M, Monoclate-P, and Koate (previously called Koate DVI); Hemophil-M and Monoclate P are monoclonal antibody-purified (ie, ultrahigh purity) and Koate is chromatography-purified (ie, high purity).
Humate P is an intermediate purity product that contains factor VIII and von Willebrand factor (VWF); . It is mainly used for the treatment of von Willebrand disease (VWD) rather than hemophilia.
Products can also be classified by other properties such as half-life, as done in the table (table 3).
Recombinant human factor VIII — Recombinant factor VIII products include a number of genetically engineered proteins produced in either animal or human cell lines. For the most part, these are made using modified versions of the human factor VIII gene.
Available products are characterized by their "generation," which reflects the species of cell line in which they are produced and the addition of or exposure to human and/or animal protein in the final product:
●First generation – First generation products (eg, Recombinate) are produced from the cell culture supernatant of transfected animal cell lines. These products also have been exposed to bovine albumin or human albumin as a stabilizer, conferring a theoretical risk of viral exposure [56,57].
●Second generation – Second generation products (eg, Kogenate-FS, ReFacto) are produced from the cell culture supernatant of transfected animal cell lines, but they do not contain albumin in the final preparation. They are stabilized using sucrose [58-60].
●Third generation – Third generation products (eg, Advate, Kovaltry, Novoeight, Xyntha) are produced in animal cell lines; they have no added human or animal protein [61,62]. Viral inactivation steps are also used.
●Fourth generation – Fourth generation products (eg, Eloctate, Nuwiq) are produced in human cell lines; they have no added human or animal protein. In principle, production in a human cell line could make the protein more similar to endogenous factor VIII.
Additional modifications of the factor VIII gene can be made to enhance production and/or improve the pharmacokinetic profile of the product (see "Biology and normal function of factor VIII and factor IX", section on 'Structure'). These modifications include the following:
●B-domain deletion – "B-domain deleted" products have a genetic modification to remove part of the factor VIII gene; this improves production efficiency but does not alter the function of the protein. Examples include Xyntha, Novoeight, Nuwiq, and Eloctate. The portion of factor VIII encoded by the B-domain of the gene is not required for clotting activity [59,63]. B-domain deletion confers greater stability on the resultant smaller factor VIII molecule.
●Single chain – "Single chain" products have a genetic modification that creates a single molecule in which the heavy and light chains of factor VIII are fused, resulting in production of a single protein. This is intended to confer increased stability of the resultant factor VIII molecule . However, for the most part, single chain products have similar half-lives to other recombinant, standard half-life products. Nuwiq may have a slightly longer half-life in some adults, which is hypothesized to be related to tighter binding to VWF.
All of these products have been demonstrated to have excellent efficacy and safety profiles in clinical studies in which they reliably treated or reduced bleeding episodes [51,52,65-68]. Different recombinant products (or different generation products) have not been directly compared in randomized trials, with the exception of the SIPPET trial, which compared recombinant to plasma-derived products containing VWF. This trial is discussed in detail separately. (See "Factor VIII and factor IX inhibitors in patients with hemophilia", section on 'Recombinant versus plasma-derived products'.)
Additional recombinant products have been produced in which other molecules are added to factor VIII to extend its half-life. (See 'Longer lasting recombinant factor VIII' below.)
Longer lasting recombinant factor VIII — Factor VIII preparations with longer half-lives have the advantage of a longer dosing interval, enhancing the ease of administration for some patients.
The following strategies have been used for half-life extension for factor VIII:
●Factor VIII-Fc fusion – A recombinant product composed of factor VIII fused with a monomeric human immunoglobulin (IgG1) Fc domain (rFVIII-Fc; Eloctate) was approved by the US Food and Drug Administration (FDA) in 2014 for treatment of bleeding, prevention of bleeding, and perioperative management of patients with hemophilia A . This product binds to the neonatal Fc receptor (FcRn, present on many adult cell types) via its Fc domain, and this binding protects the factor from degradation, extending the half-life of factor VIII 1.5- to 1.7-fold.
In an open label pilot study (16 patients) and a subsequent dosing study (165 patients), this product was well tolerated and patients did not develop antibodies or inhibitors to the fusion protein during 28 days of observation and 50 exposure days, respectively [70,71]. Compared with recombinant factor VIII lacking the Fc fusion, rFVIII-Fc had a longer therapeutic duration as judged by several pharmacokinetic parameters. As an example, at the 65 international units/kg dose, the half-life of rFVIII was 11 hours, compared with 18.8 hours for the rFVIII-Fc, a 1.7-fold improvement . Twice weekly prophylactic dosing resulted in trough factor VIII levels of at least 1 to 3 units/dL in most patients . Pharmacokinetic studies have reported a shorter half-life in children younger than six years compared with adults; however, dosing in all patients is based on trough levels and bleeding symptoms rather than strictly calculated half-lives. Of note, there is wide variation in the pharmacokinetics of factor VIII among different individuals.
●Factor VIII-PEGylated – A recombinant product composed of factor VIII covalently fused to one or more polyethylene glycol (PEG) molecules (Adynovate) was approved by the FDA in 2015 for the treatment and prevention of bleeding in individuals 12 years of age and older with hemophilia A, which was expanded in 2016 to include children <12 years [72,73]. The PEG molecules extend the half-life by 1.4 to 1.5-fold . Studies in the setting of on-demand therapy or surgery have shown this product to be safe and hemostatically effective [74,75].
An earlier product manufactured by a different pharmaceutical company in which factor VIII was reconstituted in PEGylated liposomes was not pursued due to similar pharmacokinetics with other standard half-life factor VIII products.
●Single chain factor VIII – As noted above, single chain products may have a slightly increased half-life, although the prolongation is not as great as with Fc fusion or PEGylation. (See 'Recombinant human factor VIII' above.)
Additional factor VIII modifications designed to improve potency, stability, and other pharmacokinetic parameters are in development [70,71,76-83].
Decisions regarding the use of longer half-life products are individualized and balanced based upon the cost and benefit for each patient. For some patients, a modest decrease in the number of infusions may result in increased cost. In contrast, for some small children, a decrease in the frequency of infusion may allow avoidance of a central venous access device. Older individuals who use on-demand dosing of factor VIII may also benefit from weekly prophylaxis using a longer half-life product.
Recombinant porcine factor VIII — A recombinant, B domain-deleted porcine (pig) factor VIII (Obizur) is available for treating patients with autoantibodies to factor VIII (ie, patients with an acquired factor VIII inhibitor). This product is not licensed for use in patients with inherited hemophilia A. In principle, it might be effective for individuals with hemophilia A who have an inhibitor and serious bleeding, and whose porcine factor VIII inhibitor titre is low enough to allow a hemostatic porcine factor VIII level. The cross-reactivity of antibodies against human factor VIII with porcine factor VIII is approximately 30 to 50 percent . (See "Acquired inhibitors of coagulation", section on 'Treatment of factor VIII inhibitors' and "Treatment of bleeding and perioperative management in hemophilia A and B", section on 'Inhibitors'.)
A plasma-derived porcine factor VIII product manufactured from pigs (rather than the porcine DNA sequence) is no longer available.
Factor IX products — Factor IX products are used to treat hemophilia B (inherited deficiency of factor IX [factor 9]). Previously used sources of factor IX such as prothrombin complex concentrates (PCCs) are not considered first-line therapy for hemophilia B due to an increased risk of thrombosis as well as risks of plasma exposure. Available products are listed in the table (table 4). An updated table is also maintained by the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation (NHF) in the United States (www.hemophilia.org) [49,50].
Plasma-derived factor IX — Plasma-derived factor IX concentrates (eg, AlphaNine, Mononine) are prepared by commercial fractionation (chromatography, monoclonal antibody affinity) of carefully screened donor plasma . Viral inactivation procedures (pasteurization, solvent/detergent treatment, chemical disruption with sodium thiocyanate, or ultrafiltration) add another layer of protection against HIV and hepatitis viruses. (See "Blood donor screening: Laboratory testing" and "Pathogen inactivation of blood products", section on 'Solvent/detergent treatment'.)
These products provide excellent efficacy [85,86]. The product produced by chromatographic partitioning (AlphaNine) contains minor residual plasma proteins, whereas the monoclonal product (Mononine) is free of other plasma proteins. Viral attenuation to remove HIV and hepatitis is effective for both processes.
Recombinant factor IX — Recombinant human factor IX (eg, BeneFIX, Ixinity, Rixubis) has been genetically engineered by insertion of the human factor IX gene into a Chinese hamster ovary cell line. These products have been demonstrated to be safe and effective in the treatment of previously treated and previously untreated patients with hemophilia B [87-90]. The half-life of these products is 16 to 17 hours [86,91].
These products have no added albumin, giving them a theoretical safety advantage over plasma-derived concentrates . The volume of distribution of recombinant factor IX is larger than that for plasma-derived factor IX, with a more pronounced increase in infants and children; as a result, a greater of number of units are needed compared with plasma-derived factor IX to achieve the same factor activity level [93-95]. (See "Treatment of bleeding and perioperative management in hemophilia A and B", section on 'Elective surgery'.)
Longer lasting recombinant factor IX — Factor IX preparations with longer half-lives are available and confer a substantial prolongation of half-life, such that once weekly or every other week administration may be feasible.
The following strategies have been used for half-life extension for factor IX:
●Recombinant factor IX-Fc fusion – A recombinant product composed of factor IX fused with a monomeric human immunoglobulin Fc domain (FIX-Fc; Alprolix) was approved by the FDA in 2014 for prophylaxis and treatment of bleeding in individuals with hemophilia B, in both the routine and perioperative settings [96,97]. This product binds to the neonatal Fc receptor (FcRn, present on many adult cell types) via its Fc domain, and this binding protects rFIX-Fc from degradation, extending the half-life three- to fivefold compared with unmodified factor IX (eg, half-life of 54 to 90 hours, compared with 18 hours for native factor IX) [98,99].
In a study involving 123 previously treated patients with hemophilia B (age ≥12 years) who received once weekly prophylaxis (dose, 50 units/kg) or interval-adjusted prophylaxis (100 units/kg every 10 days, adjusted as needed), annualized bleeding rates were significantly lower than those for patients receiving on-demand therapy (3, 1.4, and 17.7, respectively) . Individuals who had previously received episodic treatment were able to substantially decrease their bleeding rates with weekly to every other week prophylactic dosing. In two additional open label studies involving 138 patients with severe hemophilia B, there were no instances of inhibitor formation, thrombosis, or anaphylactic reactions with this product [99,100].
●Recombinant factor IX-albumin fusion – A recombinant factor IX product composed of the factor IX gene fused to the gene for albumin via a cleavable linker sequence (Idelvion; rFIX-FP) was approved by the FDA in 2016 for prophylaxis or treatment of bleeding in individuals with hemophilia B, both in the routine and perioperative settings [101,102]. The protein circulates as a fusion protein, and the linker is cleaved upon factor IX activation, releasing activated factor IX (factor IXa). The half-life of this product is approximately 102 hours (approximately 5.6-fold prolongation) [102-104]. In addition to its efficacy in treating and preventing bleeding, this product also has the potential for higher trough levels, which may provide increased protection .
●Glyco-PEGylated recombinant factor IX – A recombinant factor IX product composed of factor IX with site-directed addition of polyethylene glycol (PEG) to the activation sequence of the factor IX protein (nonacog beta pegol [N9-GP]) is under development [105,106]. The PEG moiety is removed during factor IX activation . The half-life of this product is approximately 93 hours (approximately fivefold prolongation) .
In a study involving 74 patients with hemophilia B, annualized bleeding rates for individuals who received once weekly prophylaxis (dose, 40 units/kg or 10 units/kg) were significantly lower than that for patients receiving on-demand therapy (1.0, 2.9, and 15.6, respectively) . A fair number of patients receiving prophylaxis had no bleeding events (67 percent of those receiving 40 units/kg, and 8 percent of those receiving 10 units/kg). There were no inhibitors or other safety concerns during one year of therapy.
PROPHYLACTIC THERAPIES UNDER DEVELOPMENT — A number of additional approaches to reduce the risk of bleeding in people with hemophilia are under various stages of conceptualization or development [84,109,110]:
●Subcutaneous therapy – No subcutaneous factor replacement products are clinically available. Subcutaneous administration would avoid the need for intravenous access or central venous catheter placement. Other (non-factor) products under development may be administered subcutaneously, such as emicizumab and gene silencing therapies.
●Emicizumab – Emicizumab (previously designated ACE910) is a recombinant humanized antibody that binds to factors IXa and X simultaneously, bringing these two molecules together and essentially substituting for the role of factor VIIIa as a cofactor for factor IXa in activating factor X, as illustrated in the graphic (figure 1) [111-113]. Because the antibody binds to factor IXa, this therapy is expected to be effective for hemophilia A and not hemophilia B.
The efficacy of emicizumab has been tested in different populations of patients with hemophilia A:
•Prophylaxis in patients with an inhibitor – Emicizumab was tested as prophylaxis in 109 individuals age 12 years or older with hemophilia A who had an inhibitor in the 2017 open-label randomized HAVEN 1 trial . Participants were randomly assigned to once-weekly subcutaneous emicizumab or standard therapy without bypassing prophylaxis for 24 weeks, after which they could continue therapy at the same or increased dose of emicizumab if they experienced bleeding. Compared with controls, emicizumab-treated patients had a reduction in annualized bleeding rate (23.3 versus 2.9 events) as well as improvements in other measures of bleeding such as rate bleeding in specific sites or complete absence of bleeding during the study (63 versus 6 percent). In patients who had previously been receiving a bypassing agent, emicizumab reduced bleeding more effectively (annualized bleeding rate, 15.7 versus 3.3 events). Adverse events were mostly injection-site reactions, although three patients who were receiving an activated prothrombin complex concentrate (aPCC) along with emicizumab had a thrombotic microangiopathy, one had a cavernous sinus thrombosis, and one had skin necrosis; these resolved with discontinuation of the aPCC.
•Bleeding despite factor prophylaxis – Emicizumab was tested in an open-label study involving 18 individuals with severe hemophilia A who had bleeding episodes despite use of factor VIII prophylaxis, on-demand therapy, or bypassing therapy (in the 11 individuals with a factor VIII inhibitor) . Patients were treated for 12 weeks in three cohorts of weekly administration, at dose levels that were estimated to provide an equivalent trough FVIII level roughly equivalent to 3, 10, and 30 units/dL of factor VIII activity. Bleeding was remarkably decreased in 17 evaluable individuals, from a median annualized bleeding rate of 33 to a rate of 4 in the first cohort, from 18 to 0 in the second cohort, and from 15 to 0 in the third cohort. There were no serious adverse events, no thromboembolic complications, and no new anti-emicizumab antibodies. One patient stopped therapy early due to injection-site erythema, and one patient had a pre-existing antibody that reacted with emicizumab but did not interfere with the efficacy of the therapy.
Emicizumab can be administered subcutaneously and has a long half-life (four to five weeks in healthy volunteers) . Once-weekly dosing appears to be sufficient to maintain adequate plasma levels .
●Concizumab – Concizumab (previously called mAb2021) is a monoclonal antibody directed against tissue factor pathway inhibitor (TFPI), which inhibits the coagulation cascade by blocking the function of factor Xa and the activity of the tissue factor-factor VIIa complex (see "Overview of hemostasis", section on 'Tissue factor pathway inhibitor'). Inhibiting TFPI could lead to increasing procoagulant activity. Concizumab can be administered subcutaneously or intravenously. In an initial study involving 28 healthy volunteers and 24 people with hemophilia, concizumab was well-tolerated without serious adverse events . Efficacy in hemostasis has been suggested by preclinical models and in vitro testing [117,118]. Other approaches to blocking TFPI are also under development .
●Gene therapy – Gene therapy could lead to endogenous production of the deficient coagulation factor without the need for regular infusions of factor or other products. A variety of technologies may be used [120-123]. In ex vivo gene therapy, cells from the intended recipients are explanted, genetically modified to secrete factor VIII or IX, and then reimplanted.
Vectors encoding factor VIII or factor IX can also be injected directly into the recipient. Vectors incorporating factor VIIa, a protein to which factor VIII-deficient and factor IX-deficient subjects have immunologic tolerance, have also been employed [124,125].
Regardless of the methods used, the goal of gene therapy does not have to be restoration of normal factor levels; conversion from a severe to a mild hemophilia phenotype would be sufficient to produce significant improvement.
Early studies in small numbers of patients have demonstrated the feasibility of these approaches:
•Hemophilia A – In one study, six patients were treated using a non-viral gene therapy system in which patient dermal fibroblasts were transfected with a plasmid for factor VIII expression and injected into the omentum . There were no serious adverse effects or inhibitors, and plasma levels of factor VIII activity rose in four of the six patients, resulting in less bleeding and/or less factor requirement for up to 10 months of observation.
In a second study, 13 patients received intravenous infusion of a retroviral vector for expression of a B-domain-deleted human factor VIII . There were no major adverse events or inhibitors, although one patient had transient detection of the retrovirus in semen by polymerase chain reaction (PCR). During one year of observation, factor VIII requirement decreased in five patients, increased in three, and stayed the same in two.
•Hemophilia B – A series of studies has evaluated adenoviral gene transduction of factor IX constructs [128-132]. In one study, 10 patients treated with three dose levels of an adeno-associated virus serotype 8 (AAV8) vector expressing a codon-optimized factor IX had dose-dependent increases in factor IX levels (range, 1 to 6 percent, versus pre-study levels of <1 percent) [131,132]. A follow-up study demonstrated that these increases persisted over a median of 3.2 years. Annualized bleeding rates decreased from 16 to 2, and four of seven patients were able to discontinue factor IX prophylaxis. Transient, asymptomatic elevations in alanine aminotransferase levels with corresponding reductions in factor IX activity and increased numbers of AAV8-reactive T lymphocytes were seen in four individuals, suggesting a loss of transduced hepatocytes. These reactions responded to administration of a short course of prednisolone. There were no other major adverse events or factor IX inhibitors.
Despite these results, issues of sustained levels of factor delivery, neutralizing antibody response, T cell response to the viral vector, safety, and cost remain to be resolved [128,133-139]. Additional studies are ongoing .
●Cellular therapy – Cellular therapy involves introducing intact cells into the patient rather than manipulation of coagulation factor genes. Foreign cells capable of surviving in the host may be enclosed in immunoprotective devices before implantation to prevent rejection. In a mouse model of hemophilia A, transplantation of liver sinusoidal endothelial cells from non-hemophilic donor animals resulted in increased factor levels and correction of the bleeding phenotype .
●Reducing endogenous anticoagulant proteins – Some individuals with hemophilia who co-inherit a prothrombotic mutation such as the factor V Leiden mutation or antithrombin deficiency are observed to have less frequent bleeding or an altered disease phenotype with apparent decreased severity of symptoms (see "Clinical manifestations and diagnosis of hemophilia", section on 'Clinical manifestations'). This observation has led to the development of approaches that target endogenous anticoagulant proteins.
One such strategy is using gene silencing with antisense oligonucleotides (ASOs) that reduce the expression of antithrombin (encoded by the SERPINC1 gene). Reducing antithrombin levels has the potential to increase thrombin generation and clot formation when levels of factor VIII or factor IX are low. This approach initially appeared promising in a study in which patients with moderate to severe hemophilia A or B were treated with the investigational antithrombin ASO fitusiran; patients had fewer bleeding events when receiving the drug compared with the period before the drug was administered (mean annualized bleeding rate, 0 versus 3); this correlated with reduced antithrombin levels and the effect appeared to be dose-dependent . In September 2017, in the open-label extension study, a patient with hemophilia A without inhibitors developed a fatal thrombotic event, and dosing was suspended in all ongoing studies pending further safety review and development of a mitigation strategy .
Prior pharmacokinetic analysis showed that the drug had a short half-life in the plasma (three to five hours), but the reduction of antithrombin levels persisted for several weeks . The monthly regimen used in the study induced a dose-dependent reduction of antithrombin (mean maximum reduction, 70 to 89 percent from baseline). A reduction in the antithrombin level of more than 75 percent from baseline resulted in mean peak thrombin values at the lower end of the range seen in individuals without hemophilia. Prior to the recent fatal thrombotic event, there were no other significant adverse events related to the drug and no other patients have experienced thromboembolic complications, with the possible exception of one episode of noncardiac chest pain for which there was no evidence of deep vein thrombosis or pulmonary embolism by Doppler ultrasonography of the legs and computed tomography (CT)-angiography, respectively.
SOCIETY GUIDELINES — Guidelines for the management of hemophilia are published by the World Federation of Hemophilia (WFH) and the National Hemophilia Foundation:
●World Federation of Hemophilia (WFH) 2012 guideline – https://www1.wfh.org/publication/files/pdf-1472.pdf
These guidelines are largely consistent with the recommendations in UpToDate.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Hemophilia (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Comprehensive health care is crucial for people with hemophilia because it minimizes other health risks that have the potential to become more serious due to an increased bleeding risk. Designated hemophilia treatment centers (HTCs) have been established in many parts of the world; United States HTCs are listed by the Centers for Disease Control and Prevention and international HTCs are listed by the World Federation of Hemophilia. HTCs provide integrated multidisciplinary care for individuals with hemophilia, and their involvement has been demonstrated to reduce morbidities. (See 'Routine/comprehensive care' above.)
•Routine procedures (eg, heel stick, vitamin K administration, neonatal immunizations) should be performed by experienced personnel. Procedures such as circumcision should be deferred until a hemophilia diagnosis is confirmed or excluded. (See 'Newborn care' above and 'Immunizations' above.)
•Appropriate oral hygiene and regular dental care is essential. An appropriate exercise regimen should be encouraged for maintenance of a healthy weight, cardiovascular risk reduction, and positive effects on strength, flexibility, balance, joint stabilization, bone density, socialization, and psychological health. Medicines that increase the risk of bleeding should be avoided. (See 'Dental care' above and 'Exercise and athletic participation' above and 'Medicines to avoid' above.)
•Advance detailed planning is required for invasive procedures, pregnancy, and travel. (See 'Planning for invasive procedures' above and 'Obstetric care and preconception counseling' above and 'Travel' above.)
●Prophylactic therapy is highly effective in reducing bleeding and long-term complications; however, the costs and burdens remain high. Individuals at high risk of bleeding should receive primary prophylaxis (table 2). Secondary prophylaxis may be appropriate for those who have had more than one bleeding episode. For individuals with moderate or mild hemophilia and no prior bleeding, prophylaxis is individualized. Intermittent (short term, episodic) prophylaxis may be used in specific circumstances such as high-impact physical activities, joint bleeding, or surgical procedures. (See 'Prophylaxis versus on-demand therapy' above.)
●A large number replacement factor products are now available that can produce satisfactory hemostasis for hemophilia A (table 3) and hemophilia B (table 4). These include plasma-derived proteins, recombinant proteins, and recombinant proteins with modifications to extend half-life. The choice among products is individualized and takes into account safety, purity, risk of inhibitor development, half-life, individual pharmacokinetics, and cost. We make every effort to obtain the best product for each patient, which may include providing the data and rationale to a third party payor. (See 'Choice of replacement product' above and 'Available products' above.)
●For patients with severe hemophilia, we advise starting prophylaxis either prior to or when there is significant bleeding, which may be at around one year of age for some children and older for others. Dosing is scheduled to maintain sustained, protective factor levels (eg, above 1 to 2 percent). Typical dosing schedules are listed above. (See 'Age of initiation and dosing schedule' above.)
●A number of prophylactic therapies other than replacement factor are under development, including a monoclonal antibody that substitutes for the function of activated factor VIII, and therapies that block the function of coagulation inhibitors. Development of gene therapy approaches also continues. (See 'Prophylactic therapies under development' above.)
●Separate topic reviews discuss hemophilia A and B diagnosis, treatment of bleeding, perioperative management, management of age-related morbidities, inhibitor eradication, and genetics. (See "Clinical manifestations and diagnosis of hemophilia" and "Treatment of bleeding and perioperative management in hemophilia A and B" and "Factor VIII and factor IX inhibitors in patients with hemophilia" and "Genetics of the hemophilias".)
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