4 Prophylaxis
1 Introduction
Today, prophylactic treatment is the standard of care for patients with severe hemophilia and moderate hemophilia with severe phenotype and should be continued lifelong (global WFH recommendation). In mild hemophilia, the clinical phenotype must be considered, and prophylaxis can be offered to patients with joint bleeds or other significant bleeding episodes.
The goal of prophylactic treatment in hemophilia is to prevent bleedings, while enabling people with hemophilia (PWH) to live active lives and achieve a quality of life comparable to that of individuals without hemophilia. Prophylaxis protects against joint bleeds and subsequent development of arthropathy, as well as other serious bleeds such as intracranial bleeds, muscle bleeds and intra-abdominal hemorrhages. Prophylaxis provides good protection against intracranial hemorrhage (ICH) [1].
ICH and other serious bleeds during the first year of life remain a threat; therefore, early prophylaxis is recommended for infants with severe hemophilia, ideally before 3 months of age [2].
Long-term prophylaxis has been shown in multiple studies to be superior to on-demand therapy and short-term prophylaxis [3–6]. Initially, prophylaxis aimed to shift the phenotype from severe to moderate hemophilia, targeting a trough factor activity of 0.01 KIU/L. However, this level proved insufficient to prevent arthropathy and other bleeding events. Today, clinicians aim for trough levels of at least 3-5 IU/dL or higher [7].
The emergence of extended half-life (EHL) and ultra-long half-life (UHL) factor products, as well as FVIII mimetics such as emicizumab for hemophilia A, allows for improved bleed protection, potentially shifting the phenotype toward mild hemophilia while reducing treatment burden through longer dosing intervals. Other subcutaneous therapies, such as marstacimab and concizumab, provide additional options, particularly for patients with hemophilia B.
Recent data suggest a shift toward targeting higher levels. Emicizumab is associated with low annual bleeding rates and is thought to correspond to a continuous factor level of approximately 15-20 IU/dL [8]. Additional studies indicate reduced bleeding and arthropathy at endogenous factor levels above 10 IU/dL [9].
However, even higher levels may be required for complete protection, as patients with mild hemophilia (factor levels 20–30 IU/dL) may still experience joint bleeds [10–12]. Arthropathy has also been reported in patients without documented bleeds [12] and the risk remains significantly higher compared to the general population [13]. PK-based approaches suggest that factor levels of 35–50 IU/dL may be needed to prevent all bleeding events [14,15].
In summary, multiple lines of evidence indicate that targeting higher factor levels than previously recommended (3–5 IU/dL) is beneficial. In addition to bleeding rates and pharmacokinetics, factors such as bleeding severity, joint health (HJHS), imaging findings, and quality of life should be considered when tailoring treatment.
1.1 RECOMMENDATIONS
- Primary prophylaxis is recommended for all patients with severe hemophilia A and B and should be initiated as early as possible, with the aim of achieving trough levels within the mild hemophilia range to prevent all bleeding events, including subclinical bleeds.
- In moderate hemophilia A and B, prophylaxis is generally recommended as for patients with severe phenotype, particularly for those with baseline factor levels below 3 IU/dL.
- In mild hemophilia with a clinically significant bleeding phenotype, e.g. joint bleeds, prophylaxis should be considered.
- Prophylaxis should be continued lifelong.
2 Choice of prophylactic treatment
- The choice of prophylactic treatment should be made through a shared decision-making process, balancing the benefits and risks of available options. Factor concentrates have the advantage of long-term clinical experience and allow for individualized dosing based on pharmacokinetics and clinical response. However, they require intravenous administration and are associated with a risk of inhibitor development.
- In contrast, FVIII mimetics and rebalancing therapies offer subcutaneous administration and more stable steady-state hemostasis, which may reduce treatment burden. Their limitations include less extensive long-term safety data, potential adverse events, the need for additional intravenous FVIII/FIX in cases of breakthrough bleeding or surgery, and challenges in laboratory monitoring.
2.1 Factor products
- Recombinant rather than plasma derived FVIII and IX products are preferred when available due to the potential risk of transmission of infectious agents. Although one randomized study reported a higher inhibitor rate with recombinant standard half-life (SHL) FVIII products [16]; the European Medicines Agency (EMA) has concluded that current evidence is insufficient to demonstrate clinically meaningful differences between product classes.
2.2 Extended half-life factor products
Extended half-life (EHL) and ultra-long half-life (UHL) recombinant factor concentrates are available in the Nordic countries and are generally preferred over SHL products, as they allow for higher trough levels and reduced injection frequency.
For FVIII, modifications of the manufacturing process including the use of single chain FVIII, human cell lines and optimized glycosylation and sulfation, have increased half-life to approximately 14 hours. Further prolongation can be achieved through pegylation or fusion of to the Fc domain of IgG1 Fc-domain, enabling dosing intervals of 3–7 days in selected patients [17].
Efanestocog alfa is an ultra-long half-life product with a half-life of 37-41 hours, allowing for once weekly dosing [18,19]. It provides higher trough levels than other FVIII products and represents an important option for improving bleed protection. Monitoring requires specific reagents for the OSA-assay (see chapter Coagulation factor activity assays for monitoring treatment with replacement therapy with focus on Extended half-life products) and data in previously untreated patients.
For FIX, half-life extension through pegylation or fusion with the human IgG1 Fc-domain or albumin results in half-lives of 85-105 hours, allowing dosing every 7-14 days [17]. EHL FIX products enable higher trough levels with fewer injections and have demonstrated good efficacy and tolerability, including in previously untreated patients [20]. As with EHL FVIII, specific assays may be required for accurate monitoring.
2.3 FVIII mimetics
Emicizumab is a bispecific monoclonal antibody that mimics the function of FVIII by bridging FIX and FX in the coagulation cascade. It is approved for prophylaxis in patients of all ages with moderate to severe hemophilia A, with or without inhibitors.
Emicizumab is administered subcutaneously on a weekly, biweekly, or four-weekly schedule after an initial loading phase, achieving steady-state concentrations within approximately one month. It has been associated with low bleeding rates and a reduced treatment burden.
However, emicizumab does not replace FVIII in situations such as trauma or surgery, and supplemental treatment with FVIII is required.
Its effect cannot be reliably measured using standard coagulation assays, and modified assays are necessary for monitoring.
Rare adverse events, including thrombosis, thrombotic microangiopathy, and anti-drug antibody development, have been reported [21,22].
Questions remain regarding the maintenance of FVIII tolerance and prevention of inhibitor development in previously untreated patients.
In Nordic clinical practice, routine FVIII exposure is not generally continued after switching to emicizumab in patients without inhibitors.
Emicizumab is reimbursed for patients with hemophilia A with inhibitors in all Nordic countries, while reimbursement for non-inhibitor patients varies.
Dosing intervals should be adjusted to allow the use of whole vials when possible.
2.4 Rebalancing agents
Rebalancing therapies, such as marstacimab and concizumab, are monoclonal antibodies targeting the Kunitz domain 2 of tissue factor pathway inhibitor (TFPI), thereby enhancing the extrinsic coagulation pathway and restoring hemostatic balance.
Marstacimab is approved for prophylaxis in patients aged 12 years or older with severe hemophilia A or B without inhibitors. Concizumab is approved for patients aged 12 years or older with moderate or severe hemophilia A or B, regardless of inhibitor status.
These agents are administered subcutaneously and represent an alternative to factor-based therapies. However, clinical experience remains limited, and their long-term safety profile is not yet fully established.
Like FVIII mimetics, their effect cannot be assessed using standard coagulation assays, and specialized laboratory methods are required.
Both marstacimab and concizumab should be discontinued several days prior to elective surgery, and experience in acute surgical settings is limited.
Reimbursement policies vary across the Nordic countries.
2.5 RECOMMENDATIONS
Both factor concentrates and non-factor therapies (e.g. FVIII mimetics, anti-TFPI) should be considered in patients without inhibitors, with the aim of achieving optimal bleed prevention and the most cost-effective treatment, taking indications, availability and reimbursement into account.
Treatment choice should be based on shared decision-making, including patient preferences and clinical characteristics (e.g. venous access and adherence challenges).
Recombinant products are preferred over plasma-derived products.
Factor concentrates with extended and ultralong half-lives are preferred over standard half-life products in both hemophilia A and B.
Emicizumab is recommended for patients with hemophilia A with inhibitors (see chapter Inhibitors).
Anti-TFPI is recommended for patients ≥12 years with hemophilia B and inhibitors (see chapter Inhibitors).
3 Initiating prophylaxis with factor products
The aim of prophylactic treatment is to prevent not only arthropathy but also serious bleeding events such as intracranial hemorrhage (ICH). Prophylaxis provides effective protection against ICH [1].
However, since prophylaxis with factor concentrates has traditionally been initiated around one year of age, and full-scale prophylaxis may take several months to establish - often requiring a central venous access device - ICH and other serious bleeding events remain a significant risk during the first year of life. Infants are particularly vulnerable due to a high risk of head trauma, and ICH may also occur spontaneously in severe hemophilia, sometimes with life-threatening consequences.
The introduction of emicizumab enables earlier initiation of prophylaxis in patients with severe and moderate-to-severe hemophilia A. Historically, prophylaxis with FVIII or FIX concentrates has been initiated at approximately one year of age, when venous access is easier to establish.
In children with severe or moderate hemophilia B, prophylaxis should be initiated as early as possible, preferably using extended half-life (EHL) FIX products to reduce the burden of intravenous administration.
3.1 Initiating prophylaxis with FVIII mimetics and rebalancing agents
- Currently, no rebalancing agents are approved for initiating prophylaxis in young children. For children with hemophilia A, emicizumab has been used from birth with good bleeding protection (HAVEN 7). After the loading phase, dosing once weekly or every two weeks is recommended in infants. When possible, dosing intervals may be adjusted to allow the use of whole vials of emicizumab.
3.2 Initiating prophylaxis with factor products
In young children without a central venous access device (CVAD), EHL factor concentrates are preferred over SHL products.
Treatment may be initiated once weekly via a peripheral vein, with the aim of increasing dosing frequency if needed and feasible. Topical anesthetic cream is commonly used to reduce discomfort during venipuncture.
The goal is full prophylaxis, depending on the product used.
Dosing and frequency should be individualized based on the patient, preferably using whole vials.
To reduce the risk of inhibitor development, particularly in hemophilia A, intensive treatment with factor concentrates should be avoided during the first 20 exposure days (EDs), as treatment exceeding 5 consecutive days is associated with an increased inhibitor risk [23–25]. There is no strong evidence that port implantation increases inhibitor risk [23,25,26]. In the RODIN study [25], central venous access surgery during the first 75 EDs did not increase inhibitor risk.
In infants with hemophilia A initiating prophylaxis with emicizumab, switching to factor prophylaxis may be considered on an individual basis, considering patient preferences, bleeding phenotype, and local reimbursement policies
3.3 CVAD for administration of factor concentrates
Peripheral venous access is successful in approximately 50% of young children, while the remaining patients experience ongoing difficulties. In such cases, for patients with severe or moderate hemophilia A, emicizumab should be considered. For other groups (e.g., hemophilia B or where emicizumab is not reimbursed), a CVAD - typically a fully implanted subcutaneous port - may be required.
Most children can be treated at home by their parents, and from around 10–12 years of age, many can begin self-administration.
A port provides reliable venous access, facilitates early home treatment by parents and helps prevent major bleeding episodes, particularly when access to the hemophilia center is limited.
The decision to use a central venous port is often a compromise between the medical goal, the bleeding tendency and familiarity with the devices at the hemophilia center.
The most frequent complications with CVADs are infections, mechanical problems and catheter related thromboses (usually clinically silent).
Most ports can remain in use for several years without complications [27,28].
3.4 RECOMMENDATIONS
- Prophylaxis should be considered before 3 months of age in infants with severe and moderate hemophilia A, particularly in those with baseline factor levels below 3 IU/dL.
- Prophylaxis should be started as soon as possible and before age 1.5 years and the onset of hemophilia-related bleeds in children with severe and moderate hemophilia B, particularly in those with baseline factor levels below 3 IU/dL.
- Emicizumab is recommended for infants with severe hemophilia A to enable very early prophylaxis.
- Emicizumab and efanestocog alfa are both options for individualized therapy in PTPs.
- CVADs should be used when necessary, however, emicizumab and efanestocog alfa are preferred over CVADs in hemophilia A.
3.5 Pharmakokinetics of factor treatment
- Both the dose and the dosing interval should be individualized based on the patient’s bleeding phenotype, level of physical activity and interindividual pharmacokinetic variability. PK assessment using a Bayesian approach is recommended to characterize and optimize treatment. The Canadian WAPPS HEMO website offer PK calculations free of charge.
3.6 Assessment of rebalancing agents and FVIII mimetics
- Assessment of rebalancing agents should be performed as recommended in the product information. For emicizumab, concentrations can be measured in many centers in the Nordic countries to support treatment individualization.
3.7 Bleeding frequency
- The patients should be instructed to document bleedings and home treatment in a prospective diary, either on paper or electronically. To motivate patients, the reports should be actively used during consultations with the hemophilia center and taken into consideration when planning dosing schedules.
3.8 Quality of life
- To evaluate quality life standardized quality of life formulas can be used where the simplest is EQ-5D-5L but also SF-36 is used in many centers. The EQ-5D-5L assess pain and mobility. Hemo-QoL is a validated, disease specific QoL instrument useful in children which exist in different versions depending on the need. As generic instruments, SF-36 may be used.
3.9 Physical score
Physical score is performed mainly by physiotherapist (see chapter Physiotherapy) and the recommended score is HJHS (hemophilia joint health score) which takes into consideration function, pain and signs of arthropathy.
HJHS was developed to study early joint disease in hemophilia and has been validated in children up to the age of 18 years [29]. The HJHS assesses structural changes. HJHS has been widely implemented as an assessment tool in clinical studies, also in adults.
Other scores such as the Gilbert score are not sensitive enough in patient with no or just minimal joint damage but are still used in some clinical trials.
3.10 Imaging technique scores
- Different imaging techniques exist, and MRI is the most sensitive method to detect early signs of joint damage. MRI is also used in clinical studies. Due to the high cost MRI cannot be recommended for routine assessment of joint damage. The method of choice when physical signs of joint damage occur is X-ray of the joint, and in selected cases subsequently MRI. Validated scoring systems exist for plain X-ray (Pettersson score), MRI (IPSG score and several others) and are being developed for US [30–32].
3.11 Ultra-sound
- Evaluation with a ultrasound-based scoring system, Hemophilia Early Arthropathy Detection with UltraSound (HEAD-US) performed by non-imaging specialists, such as physiotherapist, hemophilia nurse or doctor, has recently emerged as a complement to the clinical score and seems to correlate well with HJHS. HEAD-US may be more sensitive in detecting early signs of hemophilia arthropathy than HJHS but longer follow-up studies are required to show the relevance of findings by HEAD-US and the need for intervention.
3.12 RECOMMENDATIONS
- Treatment should be individualized using pharmacokinetic (PK) analysis in patients on replacement therapy and concentrations in patients on non-factor therapies.
- Bleeding frequency should be documented prospectively. In the event of breakthrough bleeding, the current treatment regimen should be re-evaluated.
- Quality of life should be assessed using validated tools such as the EQ-5D, SF-36, or Hemo-QoL.
- Joint health should be evaluated using HJHS version 2.1 and imaging techniques. MRI is the most sensitive method but is not recommended for routine use due to cost; X-ray and ultrasound (HEAD-US) are practical alternatives.
- Ultrasound (HEAD-US) is recommended as a supplement to regular clinical joint assessment.