Hemophilia A (Factor VIII Deficiency) Treatment & Management

The treatment of hemophilia may involve prophylaxis, management of bleeding episodes, treatment of factor VIII (FVIII) inhibitors, and treatment and rehabilitation of hemophilia synovitis. Use of factor replacement products and other medications, including pain medications, is typically required.

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

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

Dose calculations are directed toward achieving an FVIII activity level of 30-40% for most mild hemorrhages, of at least 50% for severe bleeds (eg, from trauma) or prophylaxis of major dental surgery or major surgery, and 80-100% for life-threatening hemorrhage. Hospitalization is reserved for severe or life-threatening bleeds, such as large soft tissue bleeds; retroperitoneal hemorrhage or other internal bleeding; and hemorrhage related to head injury, surgery, or dental work.

Patients can be treated with prophylaxis or with intermittent, on-demand therapy for bleeding events. Prophylaxis has been shown in many studies to prevent or at least reduce the progression of damage to target sites, such as joints. ^{[30, 31]} According to a review of six randomized, controlled trials, preventive therapy started early in childhood, as compared with on-demand treatment, can reduce total bleeds and bleeding into joints, resulting in decreased overall joint deterioration and improved quality of life. ^[32]

In most developed countries with access to recombinant product, prophylaxis is primary (ie, therapy is started in patients as young as 1 y and continues into adolescence). A cost-benefit analysis indicates that this approach reduces overall factor use and significantly reduces morbidity. ^[33] In situations in which this is not feasible, secondary prophylaxis (ie, therapy after a target joint has developed, to prevent worsening of the joint) is instituted for a defined period.

For prophylaxis, dosing is designed to maintain trough levels of 2% or higher. This usually requires the administration of FVIII three times per week. Individualized therapy (ie, tailored prophylaxis) has been also used with success; the best approach has yet to be determined. Monoclonal antibodies (ie, emicizumab, marstacimab) may also be used for prophylaxis.

The treatment of patients with inhibitors of FVIII is difficult. Bleeding episodes in patients with low-titer inhibitors (ie, concentrations below 5 Bethesda units [BU]) occasionally can be overcome with high doses of factor VIII. ^[34] Options in other cases include a variety of agents that bypass FVIII, such as activated FVII and emicizumab; desensitization; and immune tolerance induction.

In patients who develop synovitis from joint bleeds, injection of radioisotopes into the joint to ablate the synovium (radiosynovectomy) can be used to decrease bleeding, slow progression of cartilage and bone damage, and prevent arthropathy. Unresponsive cases may require arthroscopic synovectomy or arthroplasty. ^[35]

Increasing evidence associates hemophilia with low bone mineral density; consequently, careful assessment and management of fracture risk are recommended. Regular exercise, fall prevention strategies, and optimization of calcium and vitamin D intake are recommended, along with prophylactic factor replacement therapy in severe hemophilia. ^[22]

Please see the following for more information:

• Acquired Hemophilia
• Hemophilia B (Factor IX Deficiency)
• Hemophilia C

Rapid transport to definitive care is the mainstay of prehospital care. Prehospital care providers should do the following:

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

Before treating a patient with hemophilia, obtain the following information:

• The type and severity of factor deficiency
• The nature of the hemorrhage or the planned procedure
• The patient's previous treatments with blood products
• Whether inhibitors are present and if so, their probable titer
• Any previous history of desmopressin acetate (DDAVP) use (mild hemophilia A only), with the degree of response and clinical outcome.

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

Minor bleeding, as from cuts and abrasions, may respond to conservative measures, such as pressure and ice. Mild hematuria may subside spontaneously. Do not aspirate hematomas or joints or cauterize bleeding sites unless specifically indicated, because these procedures may aggravate the bleeding.

Epistaxis and moderately severe hematuria may be adequately treated by achieving and maintaining FVIII levels in the range of 30-50%. Use a higher dose initially, followed by a gradual lowering of the dose after the bleeding is under control, and then continue FVIII replacement until clinical and objective evidence indicates resolution of the bleeding.

Acute joint bleeding and expanding, large hematomas require adequate factor replacement for a prolonged period until the bleed begins to resolve, as evidenced by clinical and/or objective methods. Relief of the intense pain with joint bleeds frequently requires the use of narcotic analgesics; relief of pain also accompanies cessation of bleeding after adequate factor replacement.

Life-threatening bleeding episodes are generally initially treated with FVIII levels of approximately 100%, until the clinical situation warrants a gradual reduction in dosage. Continuous intravenous infusions avoid the low troughs and excesses of intermittent bolus dosing, maintain adequate levels at all times, and reduce usage of expensive factor replacement product by approximately 30%.

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

Patients whose condition and bleeding are stabilized should be transferred to a comprehensive hemophilia care center for further treatment and monitoring. These centers offer a multidisciplinary approach by specialists experienced in hemophilia.

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

If a patient has HIV seroconversion, arrange appropriate outpatient care at a specialty infectious disease clinic. These patients require monitoring of their CD4 count, observation for adverse effects of anti-HIV treatment, and monitoring for and treatment of possible opportunistic infections.

Various FVIII concentrates are available to treat hemophilia A. Fresh frozen plasma and cryoprecipitate are no longer used in hemophilia because of the lack of safe viral elimination and concerns regarding volume overload.

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

Many recombinant FVIII concentrates are currently available. The advantage of such products is the elimination of viral contamination. Third-generation products with no exposure to animal proteins further decrease this risk. The effectiveness of these products appears comparable to that of plasma-derived concentrates. Concerns regarding higher incidences of inhibitor development remains a complex problem, and selection of products, particularly with previously untreated or minimally treated patients, should ideally be done in conjunction with a provider with experience in hemophilia following a discussion of risks and benefits with the patient/caregiver.

With wider availability of improved products (ie, better stability, purity), use of continuous infusion for administration has incrementally increased. Continuous infusion of antihemophilic factors prevents the peaks and valleys in factor concentrations that occur with intermittent infusion; this benefit is particularly important when treatment is required for prolonged periods.

Besides improved hemostasis, continuous infusion decreases the amount of factor used, which can result in significant savings. The indications for this approach include the following:

• Intracranial hemorrhage
• Vascular compromise
• Iliopsoas bleeding
• Preparation for surgery

In most minor-to-moderate bleeding episodes, intermittent boluses are adequate. Intermittent boluses can also be used prophylactically, especially in the treatment of recurrent bleeding in target joints.

Doses of FVIII concentrate are calculated according to the severity and location of bleeding. Guidelines for dosing are provided in Table 2 below. As a rule, FVIII 1 U/kg increases FVIII plasma levels by 2%. The half life of infused factor is usually 8-12 hours. Incremental recovery (ie, the amount increase of factor activity per unit per kg) and half life vary from patient to patient and ideally should be individualized based on that patient's experience.

Target levels by hemorrhage severity are as follows:

• Mild hemorrhages (ie, early hemarthrosis, epistaxis, gingival bleeding) - Maintain an FVIII level of 30%

• Major hemorrhages (ie, hemarthrosis or muscle bleeds with pain and swelling, prophylaxis after head trauma with negative findings on examination) - Maintain an FVIII level of 50%

• Life-threatening bleeding episodes (ie, major trauma or surgery, advanced or recurrent hemarthrosis) - Maintain an FVIII level of 80-90% until stabilization; after stabilization, maintain levels above 40-50% for a minimum of 7-10 days

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

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

Desmopressin vasopressin analog, or 1-deamino-8-D-arginine vasopressin (DDAVP), is considered the treatment of choice for mild and moderate hemophilia A. It is not effective in the treatment of severe hemophilia. DDAVP stimulates a transient increase in plasma FVIII levels. Other possible mechanisms of action are noted.

DDAVP may result in sufficient hemostasis to stop a bleeding episode or to prepare patients for dental and minor surgical procedures. A test dose should be performed before prophylactic use. It can be intravenously administered at a dose of 0.3 mcg/kg of body weight in the inpatient setting. Its peak effect is observed in 30-60 minutes.

If the test dose produces an appropriate rise in the FVIII level, at least 1 week should elapse before performance of any procedures. This allows time for replenishment of endogenous stores of FVIII so that an adequate DDAVP-induced rise in FVIII is obtained for the procedure.

A concentrated DDAVP intranasal spray (1.5 mg/mL) is available for outpatient use. Its effectiveness is similar to that of the intravenous preparation, although its peak effect is observed later, at 60-90 minutes after administration.

Hyponatremia due to water retention is a potentially serious adverse effect. Patients should be advised to limit water intake for approximately 12-18 hours after the administration of DDAVP, until the antidiuretic effect passes, and should avoid three consecutive daily doses. Due to risk of hyponatremia, any use of IV fluids should be reviewed carefully and sodium levels may need to be monitored. In addition, patients should be alerted to the distinct drop in urine output they will experience after DDAVP administration, and the subsequent increase when the antidiuretic effect of DDAVP wanes.

Tachyphylaxis may occur even after first dose, but the drug can be effective again after several days. A minor adverse effect of DDAVP is facial flushing.

Musculoskeletal bleeding

The most common sites of clinically significant bleeding are joint spaces. Weight-bearing joints in the lower extremities are often target areas for recurrent bleeding. Joint hemorrhage is associated with pain and limitation in the range of motion, which is followed by progressive swelling in the involved joint.  Many patients report a prodrome of warmth or tingling of the joint prior to symptoms of frank hemorrhage.

Immobilization of the affected limb and the application of ice packs are helpful in diminishing swelling and pain. Early infusion upon the recognition of initial symptoms of a joint bleed may often eliminate the need for a second infusion by preventing the inflammatory reaction in the joint. Prompt and adequate replacement therapy is the key to preventing long-term complications. Cases in which treatment begins late or causes no response may require repeated infusions for 2-3 days.

Do not aspirate hemarthroses unless they are severe and involve significant pain and synovial tension. Some hemarthroses may pose particular problems because they interfere with the blood supply. Arthrocentesis is indicated if septic arthritis is suspected.

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

Guidelines on the management of acute joint bleeds and chronic synovitis in hemophilia were issued by the United Kingdom Haemophilia Centre Doctors' Organisation in 2017. Recommendations on hemostatic management of patients with hemophilia A without inhibitors were as follows ^[36] :

• All patients with severe hemophilia A and other patients at risk of joint bleeding should be offered home treatment
• The initial treatment of early and moderate bleeds should aim for a peak FVIII of 50 to 60 IU/dL; this is equivalent to 25 to 30 IU/kg for severe hemophilia A for standard and extended half-life products
• Early bleeds often do not require a second infusion, and moderate bleeds often respond to a single infusion but may require up to 2 infusions
• Children may require more frequent or higher doses, as they have a shorter factor half-life than adults
• For joint-immobilizing bleeds, higher initial doses are recommended, which aim to raise the peak FVIII level to 60 to 80 IU/dL; doses should be administered every 24 hr until complete resolution of pain; for severe bleeds, more frequent administration may be required in the initial 48 hr with standard FVIII

Recommendations for hemostatic management of patients with inhibitors to FVIII were as follows ^[36] :

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

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

Iliopsoas muscle bleeding may be difficult to differentiate from hemarthrosis of the hip joint. Physical examination usually reveals normal hip rotation but significant limitation of extension. Ultrasonography in the involved region may reveal a hematoma in the iliopsoas muscle. This condition requires adequate replacement therapy for 10-14 days and a physical therapy regimen that strengthens the supporting musculature.

Closed-compartment hemorrhages pose a significant risk of damaging the neurovascular bundle. These can occur in any area where fascial planes restrict the expanding hematoma and can cause neurovascular compression and compromise. They cause swelling, pain, tingling, numbness, and loss of distal arterial pulses. Infusion must be aimed at maintaining a normal level of FVIII. Other interventions include elevation of the affected part to enhance venous return and, rarely, surgical decompression.

Oral bleeding

Oral bleeding from the frenulum and bleeding after tooth extractions are not uncommon. Bleeding is aggravated by the increased fibrinolytic activity of saliva. If not treated appropriately, dental bleeding can persist and expand to sublingual, pharyngeal, facial, or dissecting neck hematomas or other serious bleeding.

Combine adequate replacement therapy with an antifibrinolytic agent (epsilon-aminocaproic acid [EACA] or tranexamic acid [TA]) to neutralize the fibrinolytic activity in the oral cavity. Topical agents such as fibrin sealant, bovine thrombin, and human recombinant thrombin can also be used. ^[37]

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

Dental extractions or mucosal procedures can be handled with a single preprocedure dose of FVIII, to achieve a peak level of approximately 30%, along with a single 20 mg/kg dose of EACA. ^[38] Routine practice is to continue antifibrinolytic therapy in an outpatient setting for several days after the dental extraction.

Gastrointestinal bleeding

GI bleeds are much less common in persons with hemophilia than in those with von Willebrand disease and, therefore, require an evaluation for an underlying cause. Manage GI hemorrhage with repeated or continuous infusions to maintain nearly normal circulating levels of FVIII.

Intracranial bleeding

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

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

Inhibitors are antibodies that neutralize factor VIII (FVIII) and can render replacement therapy ineffective. They are found more commonly in patients with moderate to severe hemophilia (up to 30% of those with severe disease) who have received significant amounts of replacement therapy. Inhibitors develop in relatively young children, usually within their first 50 exposures to FVIII.

Rarely, inhibitors can develop in individuals without genetic hemophilia (eg, elderly persons, pregnant women). These occasionally are responsive to immunosuppressive therapy (eg, prednisone).

The treatment of patients with inhibitors of FVIII is difficult. Assuming no anamnestic response, low-titer inhibitors (ie, concentrations below 5 Bethesda units [BU]) occasionally can be overcome with high doses of factor VIII. ^[34] There is no established treatment for bleeding episodes in patients with high-titer inhibitors.

Other approaches to treating patients with FVIII inhibitors include the following:

• Porcine FVIII, which has low cross-reactivity with human FVIII antibody
• Activated prothrombin complex concentrate (aPCC)
• Activated recombinant FVII (rFVIIa)
• Desensitization
• Immune tolerance induction (ITI)
• Monoclonal antibodies that bridge FIXa and FX (eg, emicizumab)

Emicizumab

Emicizumab is a first-in-class bispecific monoclonal antibody that performs the function of activated FVIII, bridging activated FIX and FX to restore the coagulation cascade, but is unaffected by FVIII inhibitors. In November 2017, following a priority review, the US Food and Drug Administration (FDA) approved emicizumab for routine prophylaxis of bleeding episodes in adult and pediatric patients (including newborns) with hemophilia A who have FVIII inhibitors. Approval was based on the HAVEN 1 and 2 clinical trials. In 2018, the FDA extended approval for use of emicizumab to patients without FVIII inhibitors, based on the HAVEN 3 trial results. ^[39]

The HAVEN 1 trial included 109 adult and adolescent males aged 12 years or older who had hemophilia A with inhibitors. Patients taking emicizumab experienced about 2.9 treated bleeding episodes per year, compared with about 23.3 treated bleeding episodes per year for patients who did not receive prophylactic treatment, representing an 87% reduction in the rate of treated bleeding episodes (P < 0.001). Emicizumab-treated patients also reported an improvement in hemophilia-related symptoms (painful swellings and joint pain) and physical functioning (pain with movement and difficulty walking). ^[40]

Interim results from the single-arm HAVEN 2 study in children aged younger than 12 years with hemophilia A with inhibitors who received emicizumab prophylaxis are consistent with the positive results from the HAVEN 1 study. After a median observation time of 12 weeks, only 1 of the 19 study patients receiving emicizumab reported a treated bleed. ^[41]

Three patients in the HAVEN 1 trial who experienced breakthrough bleeding despite emicizumab prophylaxis and were treated with aPCC developed thrombotic microangiopathy (TMA). Episodes of TMA occurred only in patients who received, on average, cumulative doses of aPCC of more than 100 U/kg daily for 24 hours or more. This complication appears to represent a unique interaction between emicizumab and aPCC, as no cases of TMA had previously been reported in patients receiving aPCC alone. Strategies for treating breakthrough bleeding in patients receiving emicizumab may include the use of recombinant FVIIa, FVIII in patients with a low inhibitor titer, and lower doses of aPCC. ^[42]

Recombinant activated factor VII

Recombinant activated FVII (rFVIIa) has become the first choice of bypassing agents. ^[43] Recombinant FVIIa is a vitamin K–dependent glycoprotein that is structurally similar to human plasma–derived FVIIa. ^[44] It is manufactured by using DNA biotechnology.

Intravenous recombinant FVIIa has been studied for the treatment of bleeding episodes and for providing hemostasis during surgery in patients with a particular bleeding diathesis. ^[43] Recombinant FVIIa is also effective and well tolerated in patients with acquired hemophilia and in those with Glanzmann thrombasthenia.

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

In pediatric patients, off-label treatment with recombinant FVIIa significantly reduced blood product administration, with 82% of patients subjectively classified as responders. Clinical context and pH values before administration were independently associated with response and 28-day mortality. Thromboembolic adverse events were reported in 5.4% of patients. ^[45]

Desensitization

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

Immune tolerance induction

In ITI, tolerance to FVIII is induced by means of regular exposure to FVIII over several months to years. ^{[34, 46]} The overall likelihood of success with ITI is 70% ± 10%.

Factors associated with successful outcome of ITI include the following ^[47] :

• Historical inhibitor titers < 200 BU and immediate pre-ITI titers < 10 BU
• Younger age at ITI initiation
• An interval of < 5 years between inhibitor diagnosis and ITI start
• ITI interruption < 2 weeks in duration

First described by Backmann in 1977, ITI has been used with variations in the dosing schedule for FVIII and with or without immunosuppressive therapy (eg, cyclophosphamide, prednisone). Most of the recent protocols that use FVIII alone have avoided use of immunosuppression because of the toxicity risk. This technique is well established in persons with congenital hemophilia with allo-antibodies but does not have a role in persons with acquired hemophilia A with auto-antibodies.

Rituximab, a chimeric human-mouse monoclonal antibody against CD20 that rapidly and specifically depletes B cells, has been used with success in ITI. ^{[48, 49]} A 4-week course of weekly rituximab, with or without prednisone and/or cyclophosphamide, has shown durable and complete responses in several small trials in patients with autoimmune hemophilia and inhibitor titers of 5 to more than 200 BU. ^[50] Rituximab appears to be more effective in treating inhibitors in acquired hemophilia than in hereditary hemophilia. ^{[51, 52]}

The choice of FVIII dosing regimen for ITI has ranged from 50 IU/kg 3 times weekly to 300 IU/kg/d. An international study in patients with severe hemophilia and high-titer inhibitors found no significant difference between low-dose and high-dose ITI in terms of the percentage of subjects achieving tolerance (70%) or in the time taken to achieve tolerance. However, the study was stopped early because of safety considerations involving bleeding (significantly more common early on in the low-dose arm) and lack of statistical power. ^[47]

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

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

Prophylaxis is not universally accepted, with only about half the children with hemophilia A receiving this treatment modality in the United States. Reasons cited for the lack of acceptance include need for venous access, factor availability, repeated venipunctures, and cost, among others. Research questions that remain unanswered include when to initiate and stop infusions, dosing, and dose schedule.

Factor VIII prophylaxis

In 2014 the FDA approved a long-acting recombinant FVIII–Fc fusion protein (rFVIIIFc) product (Eloctate) for control of bleeding episodes, management of perioperative bleeding, and routine prophylaxis in patients with hemophilia A. For routine prophylaxis, rFVIIIFc is infused every 4 days, whereas other available recombinant FVIII products are administered every 2-3 days. ^{[53, 54]}

The rFVIIIFc product was developed by fusing rFVIII to the Fc portion of IgG₁, which allows a naturally occurring pathway to prolong the product's duration of action. FDA approval was based on a study in 164 patients with hemophilia A in which the median rate of bleeding episodes with prophylactic use of rFVIIIFc was 1.6 per year, compared with 33.6 per year in patients receiving on-demand treatment. ^{[53, 54]} In an open-label extension study of rFVIIIFc in 211 patients, which included up to 5 years of follow-up, no inhibitors were observed, annualized bleed rates remained low in patients on individualized prophylaxis, and most patients maintained extended-dosing intervals (median of 3.5 days). ^[55]

Other rFVIII products are also approved by the FDA for routine prophylaxis (eg, NovoEight, Kogenate, Nuwiq, Adynovate, Kovaltry, Afstyla, Jivi). Adynovate and Jivi are pegylated rFVIII products that allow less frequent administration. For prophylaxis, Jivi is administered every 5 days and Adynovate is administered 2 times per week.

In the phase III PROPEL trial, which studied pharmacokinetic-guided prophylaxis with Adynovate, targeting FVIII trough levels of 1-3% or 8-12% both proved effective. ^[56] Patients with higher trough levels were more likely to be completely free of bleeds; in the second 6 months of the trial, rates with 1-3% vs 8-12% trough levels were as follows:

• Zero total bleeds - 42% vs 62% ( P = 0.055)
• Zero spontaneous bleeds - 60% vs 76% (P = 0.101)
• Zero spontaneous joint bleeds - 65% vs 85% (P = 0.026)

FVIII consumption varied widely in each treatment group, with overlapping ranges, emphasizing the need for personalized treatment. However, most patients in the 1-3% arm were able to achieve their target FVIII trough with approximately twice-weekly dosing, whereas most of those in the 8-12% arm needed to infuse every other day, or even daily. ^[56]

Anti-inhibitor coagulant complex prophylaxis

In 2013, the US Food and Drug Administration (FDA) expanded the indication for anti-inhibitor coagulant complex (Feiba NF) to include routine prophylaxis in patients with hemophilia A or B who have developed inhibitors. Approval was based on data from a pivotal phase III study in which a prophylactic regimen resulted in a 72% reduction in median annual bleed rate compared with on-demand treatment. ^[57] An earlier study showed a 62% reduction in all bleeding episodes with prophylaxis versus an on-demand regimen. ^[58]

Emicizumab

The bispecific monoclonal antibody emicizumab is approved for prophylaxis in adults and children (including newborns) who have hemophilia A with or without FVIII inhibitors. The HAVEN 3 trial demonstrated that emicizumab prophylaxis is also effective in patients without inhibitors. ^[39]

In this phase III trial, 152 patients 12 years of age or older who had been receiving episodic treatment with FVIII were randomized to emicizumab prophylaxis once weekly or every 2 weeks, or no prophylaxis. The annualized bleeding rate was 1.5 in patients receiving weekly dosing and 1.3 with biweekly dosing, versus 38.2 events in patients receiving no prophylaxis. More than half of the study patients who received prophylaxis had no treated bleeding events. Those patients who had previously received FVIII prophylaxis had significantly lower bleeding rates with emicizumab prophylaxis. ^[39]

Marstacimab

In October 2024 the FDA approved marstacimab (Hympavzi) for routine prophylaxis in congenital hemophilia A without factor VIII inhibitors, in patients aged 12 years or older. Approval was based on an open-label, multicenter study in 116 adult and pediatric patients with severe hemophilia A or  B, without inhibitors, in which marstacimab proved superior to on-demand factor replacement for bleeds and equivalent to prophylactic factor replacement. (Marstacimab is also approved for use in hemophilia B). ^{[59, 60]}

Marstacimab is a human monoclonal IgG1 antibody directed against the Kunitz domain 2 (K2) of the tissue factor pathway inhibitor (TFPI). TFPI is the primary inhibitor of the extrinsic coagulation pathway; neutralization of TFPI activity enhances coagulation by inactivating factor Xa/factor VIIa/tissue factor complex protease functions. Marstacimab is administered weekly by subcutaneous injection.

Concizumab

In December 2024, the US Food and Drug Administration (FDA) approved the TFPI antagonist concizumab (Alhemo) for routine prophylactic use in adults and pediatric patients aged 12 years or older with hemophilia A with factor VIII inhibitors or hemophilia B with factor IX inhibitors; treatment is aimed at preventing bleeding episodes or decreasing their frequency. Approval was based on a multi-national, multi-center, randomized, open-label, phase 3 trial in patients with hemophilia A or B, with inhibitors. Compared with patients who received no prophylaxis, those who underwent treatment with concizumab achieved an 86% reduction in annualized bleeding rates. ^{[61, 62]}

Assessing adherence to prophylaxis

The Validated Hemophilia Regimen Treatment Adherence Scale–Prophylaxis (VERITAS-Pro) prophylaxis is a patient/parent questionnaire that uses six subscales (time, dose, plan, remember, skip, communicate), each containing four items, to assess patient adherence to prophylactic hemophilia treatment. In a study of 67 patients with hemophilia, including 53 with severe FVIII deficiency, Duncan et al found a strong correlation between VERITAS-Pro scores and adherence assessments (eg, infusion log entries). ^[63]

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

Hemophilic chronic arthropathy is painful. Narcotic agents have been used, but their benefit for long-term therapy is limited by side effects, the development of tolerance, and the risk of addiction.

Nonsteroidal anti-inflammatory drugs (NSAIDs) can be effective in managing acute and chronic arthritic pain, but significant caution must be used in dose and frequency due to concerns for increased risk of bleeding. Although they pose a risk of GI bleeding, their effects on platelet function are reversible. Avoid aspirin because of its irreversible effect on platelet function. Other analgesics may include acetaminophen in combination with small amounts of codeine or synthetic codeine analogs.

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

Allergic reactions are occasionally reported with the use of factor concentrates, and these can be severe. Premedication or adjustment of the rate of infusion may resolve the problem. It is quite possible that residual cell line proteins (from mouse or hamster cell lines) may contribute to this, and change of product to different source cell line can be considered.

Do not circumcise boys born to mothers who are known or thought to be carriers of hemophilia unless disease in the infant has been excluded with appropriate laboratory testing. Perform blood assays of FVIII with cord blood. When a cord blood sample is not available, obtain a sample from a superficial limb vein; avoid femoral and jugular sites.

Routine immunizations that require injection (eg, diphtheria, tetanus toxoids, and pertussis [DPT] or measles-mumps-rubella [MMR] vaccines) may be given by means of a deep subcutaneous (rather than deep intramuscular) injection with a fine-gauge needle. Administer the hepatitis B vaccine (now routinely administered to all children) soon after birth to all infants with hemophilia. Administer the hepatitis A vaccine to those individuals with hemophilia and no hepatitis A virus antibody in their serum.

The Italian hemophilia and vaccinations (HEVA) project notes that most experts agree that individuals with hemophilia should be vaccinated according to the schedule for the general population, and that in addition, these patients should be vaccinated against hepatitis A virus and hepatitis B virus infection, particularly if they are candidates for plasma‐derived FVIII products. The HEVA project also provides the following general recommendations on vaccination in patients with hemophilia ^[64] :

• Children and adults with hemophilia should receive mandatory and recommended vaccinations as per the institutional vaccination schedule, regardless of their baseline factor VIII level
• Subcutaneous administration of vaccines is preferred over intramuscular administration, regardless of disease severity, to reduce the risk of bleeding
• With vaccines that require intramuscular administration, providing factor replacement prior to vaccination is advisable
• Apply ice to the injection site before and after vaccine administration
• Avoid rubbing the injection site after vaccination; instead, provide compression
• Use the thinnest possible needle for vaccine injection

The HEVA project included the following recommendations on vaccination of hemophilia patient subgroups ^[64] :

• Use of live attenuated vaccines is contraindicated in immunocompromised patients
• Immunocompromised patients should be vaccinated against pneumococcal infection and influenza
• Patients aged ≥65 years should be vaccinated against pneumococcus and influenza as per the institutional vaccination schedule
• Patients travelling to areas where yellow fever and/or typhus are endemic should be vaccinated against those diseases

The World Federation of Hemophilia (WFH), in collaboration with the European Association for Haemophilia and Allied Disorders, European Haemophilia Consortium, and US National Bleeding Disorders Foundation, has issued the following recommendations on COVID-19 vaccination for people with bleeding disorders ^[65] :

• People with bleeding disorders are not at greater risk of contracting COVID-19 or developing a severe form of the disease, so they are not considered a priority group for vaccination
• Administer the vaccine intramuscularly, using the smallest-gauge needle available (25-27 gauge); however, some vaccines must be administered using the accompanying needle-syringe combination, in which case the use of an alternative needle may not be possible or desirable
• Apply pressure to the injection site for at least 10 minutes afterwards, to reduce bleeding and swelling. Additionally, patients should inspect/palpate the injection area several minutes and 2-4 hours later to assess for delayed hematoma
• Discomfort in the arm for 1-2 days after injection should not be alarming unless it worsens and is accompanied by swelling. Any adverse events (eg, hematoma, allergic reaction) should be reported to a hemophilia treatment center
• Patients should immediately contact their physician or go to the nearest hospital emergency department if they experience an allergic reaction, as it can be life-threatening; patients with a history of allergic reactions to extended half-life clotting factor concentrates containing polyethylene glycol (PEG) should discuss vaccine choice with their physician because some vaccines contain PEG as an excipient
• In patients with severe/moderate hemophilia, administer the vaccine after a factor VIII injection. For patients with a basal FVIII above 10%, no hemostatic precautions are required
• Patients on emicizumab (with or without an inhibitor) can be vaccinated by intramuscular injection at any time, without hemostatic precautions and without receiving a dose of FVIII

In severe hemophilia, consider prophylactic or scheduled factor VIII. Prophylactic replacement of FVIII is used to maintain a measurable level at all times, with the goal of avoiding hemarthrosis and the vicious cycle of repetitive bleeding and inflammation that results in destructive arthritis. ^[66] This goal is achieved by administering factor 2-3 times a week. The National Bleeding Disorders Foundation has recommended the administration of primary prophylaxis, beginning at the age of 1-2 years.

Carrier testing is valuable for women who are related to obligate carrier females or males with hemophilia. Carrier testing may prevent births of individuals with major hemophilia. This testing can be offered to women interested in childbearing who have a family history of hemophilia. Prenatal diagnosis is important even if termination of the pregnancy is not desired, because plans for delivery and neonatal management can be made.

Preimplantation genetic diagnosis has been used as a possible alternative to prenatal diagnosis in combination with in vitro fertilization to help patients avoid having children with hemophilia or other serious inherited diseases. ^{[67, 68, 69]} The genetic diagnosis is made by using single cells obtained during biopsy from embryos before implantation. For this, fluorescence in situ hybridization is used. This technique circumvents pregnancy termination. However, it is expensive and has limited success rates, with a 22% chance for a live birth. ^[29]

Generally, individuals with severe hemophilia should avoid high-impact contact sports and other activities with a significant risk of trauma. However, mounting evidence suggests that appropriate physical activity improves overall conditioning, reduces injury rate and severity, and improves psychosocial functioning. Kumar et al reported that aerobic exercise on a stationary cycle resulted in significant improvement in hemostatic indices in post-adolescent patients with mild-to-moderate hemophilia A. ^[70]

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

With the cloning of FVIII and advances in molecular technologies, the possibility of a cure for hemophilia A with gene therapy was conceived. ^[71] Although the development of gene therapy for hemophilia A faced several complications, including the large size of the FVIII gene, preclinical studies in mice and dogs with hemophilia resulted in long-term correction of the bleeding disorders and, in some cases, a permanent cure. ^[72] Possible approaches to gene therapy for hemophilia A include the following ^[73] :

• Ex vivo gene therapy, in which cells to be transplanted are genetically modified to secrete factor VIII and then are reimplanted into the recipient

• In vivo gene therapy, in which a vector (typically a virus altered to include FVIII DNA) is directly injected into the patient ^[74]

• Nonautologous gene therapy, in which cells modified to secrete FVIII are packaged in immunoprotected devices and implanted into recipients

The FDA approved the first gene therapy for hemophilia A, valoctocogene roxaparvovec (Roctavian), in June 2023. It is a one-time, single-dose IV adeno-associated virus vector–based gene therapy indicated for severe hemophilia A (congenital FVIII deficiency with FVIII activity < 1 IU/dL) in adults without preexisting antibodies to adeno-associated virus serotype 5 (AAV5) detected by an FDA-approved test. 

Approval was based on the phase 3, open-label, single-group GENEr8-1 trial (n=134). Among the 132 HIV-negative participants, the mean FVIII activity level at weeks 49 through 52 increased by 41.9 IU/dL (P < 0.001; median change, 22.9 IU/dL). After week 4 following infusion, the 112 participants enrolled from a prospective noninterventional study decreased their annualized rates of FVIII concentrate use by 98.6%, and their rates of treated bleeds decreased by 83.8% (P < 0.001 for both comparisons). ^[75]  

The usefulness of AAV-based gene therapy such as valoctocogene roxaparvovec is limited by the fact that approximately one third of patients with hemophilia A have antibodies to AAV5. Ex vivo gene therapy offers a potential alternative in such cases. ^[76] Gao et al reported that this approach can result in stable, long-term engraftment of FVIII-producing cells. These researchers transduced endothelial colony-forming cells (ECFCs) and placenta-derived mesenchymal stromal cells (PMSCs) with a lentiviral vector that expressed FVIII, and administered the cells by intramuscular injection. Use of ECFCs and PMSCs together produced better results than either cell type separately, and engraftment rates were higher in neonatal mice than in adult mice. ^[77]

Implantation of liver-derived stem cells that have been expanded in vitro is under consideration, as these could theoretically induce a steady-state production of quantities of factor sufficient to prevent spontaneous bleeding.

Management should be provided in coordination with a comprehensive hemophilia care center. Specific consultations may be indicated with a hematologist, blood bank, pathologist, or others, as indicated by hemorrhagic complications. Early hematology consultation for management of inhibitors is essential. Annual dental evaluation is recommended.

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

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

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

In patients who develop synovitis from joint bleeds, intra-articular injection of radioisotopes to ablate the synovium (radiosynovectomy) can be used to decrease bleeding, slow progression of cartilage and bone damage, and prevent arthropathy. Yttrium-90 and rhenium-186 have proved equally effective for radiosynovectomy. ^[78] A review by Rodriguez-Merchan et al concluded that radiosynovectomy is effective, safe, and well tolerated. ^[78]

The review by Rodriguez-Merchan included 500 synovectomies in 443 joints of 345 patients with chronic hemophilic synovitis. One to three injections were administered, with a 6-month interval between injections. On average, the number of hemarthroses decreased by 64.1%, articular pain decreased by 69.4%, the degree of synovitis decreased by 31.3%, and the World Federation of Haemophilia score improved by 19%. Only four complications (0.9%) occurred. In 28 joints (6.3%), arthroscopic synovectomy or total knee replacement was eventually required. ^[35]