Last updated March 15, 2022

Management of Hemophilia, 3rd edition

RECOMMENDATIONS

Comprehensive Care of Hemophilia

Recommendation 2.2.1: • For people with hemophilia, the WFH recommends coordinated delivery of comprehensive care by a multidisciplinary team of healthcare professionals with expertise and experience in hemophilia. • Remark: The core members of the comprehensive care team should consist of a medical director, nurse coordinator, musculoskeletal specialists, medical laboratory specialist, psychosocial specialist, and the patient and family caregivers. The roles assumed by the core team members may differ at different centres depending on the availability and expertise of trained staff and the organization of services within the centre. (Consensus Based)

Recommendation 2.2.2: • For people with hemophilia, the WFH recommends availability of and access to: ◦ appropriate emergency care at all times;  a coagulation laboratory capable of performing clotting factor assays and inhibitor testing; ◦ appropriate clotting factor concentrates (CFCs), either plasma-derived or recombinant, as well as other hemostatic agents such as desmopressin (DDAVP), emicizumab, and antifibrinolytics; ◦ safe blood components such as fresh frozen plasma (FFP) and cryoprecipitate that have been adequately screened, tested, and/or virus-inactivated if CFCs are not available; ◦ casting and/or splinting for immobilization and mobility/support aids, as needed; ◦ other specialists to address specific medical and health-related issues that some individuals may encounter, as needed.  (Consensus Based)

Recommendation 2.2.3: • For all patients with hemophilia, the WFH suggests the preparation of written clinical management protocols to ensure continuity of care in the event of changes in clinic personnel.  (Consensus Based)

Recommendation 2.2.4: • For people with hemophilia, the WFH recommends a multidisciplinary checkup including hematologic, musculoskeletal, and quality-of-life assessments by the core comprehensive care team members at least yearly (every 6 months for children). • Remark: Smaller centres and family physicians can provide primary care and management of some complications of hemophilia, in frequent consultation with the hemophilia comprehensive care centre, especially for patients who live a long distance from the nearest hemophilia treatment centre.

Recommendation 2.2.5: • For all patients with hemophilia, the WFH recommends systematic data collection in patient registries, where possible, to inform allocation of resources, support improvement of care delivery services, and promote collaboration among centres in sharing data and conducting research.  (Consensus Based)

Recommendation 2.2.6: • The WFH recommends that adequate education be provided to people with hemophilia, their family members, and other caregivers to enable self-management and sufficient understanding of the disease for prevention of bleeds and related complications and for life planning.  (Consensus Based)

Recommendation 2.2.7: • For people with hemophilia and their families, the WFH recommends promotion and/or facilitation of educational and recreational activities in collaboration with patient organizations, to provide them with opportunities to discover new interests and capabilities and build a support network with diverse members of the hemophilia community.  (Consensus Based)

Recommendation 2.3.1:• For people with hemophilia, the WFH recommends promotion of regular physical activity and fitness, with special attention on bone health maintenance, muscle strengthening, coordination, physical functioning, healthy body weight, and positive self-esteem.  (Consensus Based)

Recommendation 2.3.2: • For people with hemophilia, the WFH recommends promotion of non-contact sports. High-contact and collision sports and high-velocity activities should be avoided unless the individual is on a prophylactic regimen that is adequate to cover such activities and is properly educated on the potential risks and other required protective measures. • Remark: The choice of sports activities should take into consideration the individual's physical condition and ability, preferences and interests, local customs, and available resources.  (Consensus Based)

Recommendation 2.3.3: • For people with hemophilia, the WFH recommends consultation with a physical therapist or other musculoskeletal specialist before engaging in sports and physical activities to discuss their appropriateness specific to the individual's condition and their requirement for particular physical skills and/or protective gear.  (Consensus Based)

Recommendation 2.4.1: • For people with hemophilia with a muscle or joint bleed, the WFH recommends following the PRICE principles (protection, rest, ice, compression, and elevation) in addition to increasing factor level.  (Consensus Based)

Recommendation 2.4.2: • For people with hemophilia recovering from a joint or muscle bleed, the WFH recommends gradual re-initiation of physical activities under the supervision of a physical therapist with experience in hemophilia to assess resumption of normal motor development and coordination. • Remark: For children with hemophilia recovering from a joint or muscle bleed, the physical therapist and family caregiver should remain in close contact to discuss and decide on the appropriate sports and activities for the child's progressive rehabilitation.  (Consensus Based)

Recommendation 2.4.3: • For people with hemophilia with established hemophilic arthropathy or after recovery from musculoskeletal bleeding, the WFH recommends physical therapy and rehabilitation activities.  (Consensus Based)

Recommendation 2.4.4: • For people with hemophilia, the WFH recommends the use of antifibrinolytic drugs (e.g., tranexamic acid, epsilon aminocaproic acid [EACA]) alone or as adjuvant treatment, particularly in controlling mucosal bleeds and for invasive dental procedures.  (Consensus Based)

Recommendation 2.5.2: • For patients with hemophilia, a detailed record of all treatments administered (reason, batch number, number of units, etc.) should be documented and used to personalize treatment plans.  (Consensus Based)

Recommendation 2.5.3: • For children with hemophilia, central venous access devices could be considered to facilitate early access to bleed treatment and prophylaxis.  (Consensus Based)

Recommendation 2.6.1: • For people with hemophilia with acute or chronic pain, the WFH recommends the use of age-appropriate pain assessment tools to determine the cause and guide appropriate management.  (Consensus Based)

Recommendation 2.6.2: • For people with hemophilia with venous access pain, discomfort or anxiety, the WFH recommends the application of a local anesthetic spray or cream at the site of venous access.  (Consensus Based)

Recommendation 2.6.3: • For people with hemophilia with acute pain due to a joint or muscle bleed, the WFH recommends immediate administration of clotting factor concentrates to stop bleeding, pain medication, and adjunctive measures such as immobilization, compression, and splinting to minimize pain, if appropriate.  (Consensus Based)

Recommendation 2.6.4: • For patients with hemophilia and postoperative pain, the WFH advises proportionate management of postoperative pain in coordination with the anesthesiologist or pain specialist.  (Consensus Based)

Recommendation 2.6.5: • For patients with hemophilia and postoperative pain, the WFH recommends analgesia similar to that used in patients without hemophilia including, as appropriate, the use of intravenous morphine or other narcotic analgesics, followed by an oral opioid (e.g., tramadol, codeine, hydrocodone, etc.) and paracetamol/acetaminophen as pain decreases. • Remark: With the exception of selective COX-2 inhibitors, NSAIDs should not be used in patients with hemophilia. • Remark: The intramuscular route for administration of analgesia is not advised.  (Consensus Based)

Recommendation 2.6.6: • For people with hemophilia and chronic hemophilic arthropathy in need of pain management, the WFH recommends functional training and adaptations alongside appropriate analgesics.  (Consensus Based)

Recommendation 2.6.7: • For people with hemophilia and chronic hemophilic arthropathy, the WFH recommends education on pain management including the use of complementary pain management techniques (e.g., meditation, distraction, mindfulness, or music therapy).  (Consensus Based)

Recommendation 2.6.8: • For children and adults with hemophilia with pain due to chronic hemophilic arthropathy, the WFH recommends the use of paracetamol/acetaminophen, selective COX-2 inhibitors, tramadol, or morphine, and avoidance of other NSAIDs. Codeine may be used for children over 12 years of age but is contraindicated in younger children. • Remark: Prolonged use of these medications may have risks of dependence or addiction, as well as organ damage, and must be carefully monitored. • Remark: People with persistent pain should be referred to a specialized pain management team.  (Consensus Based)

Recommendation 2.6.9: • For patients with hemophilia with disabling pain from chronic hemophilic arthropathy, the WFH recommends referral to an orthopedic specialist for consideration of orthopedic surgery.  (Consensus Based)

Recommendation 2.6.10: • For children and adults with hemophilia, the WFH recommends interim management of dental or orofacial pain according to a proportionate approach for pain relief and referral to a dental care professional for assessment.  (Consensus Based)

Recommendation 2.7.1: • For children and adults with hemophilia, the WFH recommends provisions for access to regular preventive dental and oral health care as part of comprehensive hemophilia care.  (Consensus Based)

Recommendation 2.7.2: • For children with hemophilia, the WFH recommends referral to a designated dental care centre at the time of the first tooth eruption (around 6 months of age) or by age 1 in order to reduce the complications, morbidity, costs, and health and psychosocial impacts associated with oral diseases in people with hemophilia.  (Consensus Based)

Recommendation 2.7.3: • For adults with hemophilia, the WFH recommends facilitating access to appropriate adult dental services and procedures, with regular dental assessments throughout their lives to monitor and safeguard oral health using evidence-based and personalized preventive dental protocols.  (Consensus Based)

Recommendation 2.7.4: • For people with hemophilia, the WFH recommends preventive dental and oral care as a priority to ensure optimal oral health and hygiene to prevent periodontal disease and dental caries, which predispose to gum bleeding, dental pain, tooth loss, chewing difficulties, and social impacts.  (Consensus Based)

Recommendation 2.7.5: • For all people with hemophilia, the WFH recommends education on the importance of good oral hygiene to prevent dental problems and complications, including instructions for twice-daily brushing of the teeth using a soft- or medium-texture toothbrush and fluoridated toothpaste to remove plaque deposits; the toothpaste should not be rinsed away but rather retained (“spit, but don't rinse”) after brushing to maximize fluoride benefit. • Remark: The use of dental floss or interdental brushes should be encouraged to ensure complete plaque removal. aids.  (Consensus Based)

Recommendation 2.7.6: • For children with hemophilia 6 years of age and younger, the WFH recommends parental/caregiver supervision of toothbrushing.  (Consensus Based)

Recommendation 2.7.7: • For patients with hemophilia, the WFH recommends that dental extraction or other invasive procedures within the oral cavity (e.g., dental implantation, periodontal surgery, or gum biopsy) be performed only with a personalized plan for hemostasis management in consultation with a hematologist.  (Consensus Based)

Recommendation 2.7.8: • For patients with hemophilia, the WFH recommends the use of systemic or topical tranexamic acid or epsilon aminocaproic acid (EACA) as adjunct treatment in the management of dental interventions pre- and postoperatively, to reduce the need for factor replacement therapy.  (Consensus Based)

Recommendation 2.7.9: • For patients with hemophilia requiring dental extractions, the WFH recommends local hemostatic measures. Typical procedures include wound suture, topical use of antifibrinolytics, oxidized cellulose, and fibrin sealant, applied as appropriate. • Remark: Patients should be advised to maintain a soft diet and undertake careful brushing around the wound site for a minimum of 3-5 days postoperatively to avoid disturbing the clot and wound healing within the tooth socket.  (Consensus Based)

Recommendation 2.7.10: • For patients with hemophilia, the WFH recommends appropriate local anesthesia for dental treatments as an essential part of pain and anxiety management. Most dental injections pose a low risk for patients with hemophilia when delivered by a dental care professional using local anesthesia with a vasoconstrictor, and when the agent is delivered slowly with a single-use fine-gauge needle.  (Consensus Based)

Recommendation 2.7.11: • For patients with hemophilia requiring higher-risk intramuscular oral injections commonly associated with the provision of surgical dentistry (such as inferior alveolar dental block [IDB], superior alveolar nerve block, or injections in the floor of the mouth or vascular lingual tissues), the WFH recommends systemic hemostatic measures preoperatively to avoid the risk of hematoma. These measures should be established in consultation with the hematologist. • Remark: The availability and effectiveness of alternative low-risk routes of local anesthetic delivery (such as intraligamentary single-tooth anesthesia, or buccal infiltration injections with 4% articaine) are effective alternatives to IDB and permit dental procedures in primary and permanent mandibular molar teeth.  (Consensus Based)

Recommendation 2.7.12: • For patients with hemophilia, the WFH recommends the use of antifibrinolytic agents as effective adjunct treatment in the management of dental hygiene therapies that facilitates access to regular dental care delivered by a dental hygienist.  (Consensus Based)

Recommendation 2.7.13: • In patients with hemophilia, the WFH asserts that the presence of blood-borne infections does not affect the safety of dental treatment as stringent universal cross-infection procedures are now mandatory across all disciplines of dentistry and recommends the provision of full dental services regardless of infectivity or immunological status.  (Consensus Based)

Recommendation 2.8.1: • Children and adolescents with hemophilia should be supported with ongoing education and skills development, including the ability to self-infuse and other self-efficacy skills, to gain necessary hemophilia knowledge for self-management of their condition before they make the transition from pediatric to adult care. • Remark: The comprehensive care team should support young patients and their families through the transition period. When possible, the first visit should be performed by both the pediatric and adult hematologists.  (Consensus Based)

Recommendation 2.8.2: • For adolescents with hemophilia on prophylaxis, the WFH recommends individual education and training, ideally from a hemophilia nurse coordinator, to ensure adequate knowledge of hemophilia, and to support prophylaxis adherence and self-care management. This should include understanding measurements of adherence, as well as factors and risks that can lead to changes in bleeding rates.  (Consensus Based)

Recommendation 2.8.3: • For adolescents 12-18 years of age with hemophilia, the WFH recommends age-specific hemophilia camps to foster peer group support and develop their self-infusion skills and understanding of the importance of adherence to treatment.  (Consensus Based)
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Laboratory Diagnosis and Monitoring

Recommendation 3.1.1: • The WFH recommends that testing for diagnosis and monitoring of hemophilia must be carried out by staff with knowledge and experience in coagulation laboratory testing using equipment and reagents that have been validated for this specific purpose. • Remark: Details of laboratory tests for the diagnosis and monitoring of hemophilia are described in the WFH laboratory manual.  (Consensus Based)

Recommendation 3.2.1: • In preparation for collection of a blood sample for determination of prothrombin time (PT), activated partial thromboplastin time (APTT), or FVIII/FIX activity, the WFH advises that patients with hemophilia may maintain their regular diet—overnight fasting is not necessary prior to blood draw. • Remark: High levels of lipid in the plasma may affect the determination of clotting times when using coagulometers with optical systems.  (Consensus Based)

Recommendation 3.2.2: • In preparation for collection of a blood sample for determination of APTT or FVIII/FIX activity, the WFH recommends that patients with hemophilia avoid strenuous exercise prior to blood draw. • Remark: Strenuous exercise or stress can temporarily elevate FVIII activity of patients with mild hemophilia A into the reference range; therefore, patients should be rested for a few minutes prior to venipuncture.  (Consensus Based)

Recommendation 3.2.3: • For the diagnosis and monitoring of hemophilia A and B, the WFH recommends that blood samples be labelled immediately with the patient's first and last name, an identification number or date of birth, and the date and time of specimen collection. This should be done before leaving the side of the patient. • Remark: There is no consensus on whether the tube should be labeled immediately before or immediately after blood collection.  (Consensus Based)

Recommendation 3.2.4: • The WFH recommends that blood samples for determination of PT, APTT, or FVIII/FIX activity be collected in citrate tubes containing 0.105-0.109M (around 3.2%) aqueous trisodium citrate dihydrate, capped during processing, and kept at 18-25°C during transport and storage. Blood samples should be centrifuged at ambient temperature for a minimum of 1700 g for at least 10 minutes, and either be analyzed within 8 hours of collection (4 hours for FVIII:C) or stored deep frozen at −35°C or lower. • Remark: Storage of citrated whole blood samples at 2-8°C should be avoided as this may result in loss of FVIII activity. • Remark: Platelet poor plasma (PPP) samples can be stored at −35°C for up to 3 months and at −70°C for up to 6 months prior to determination of FVIII/FIX activity. Storage of PPP at −20°C is usually inadequate. Freezers with auto-defrost should not be used to store PPP prior to determination of PT, APTT, or FVIII/FIX activity.  (Consensus Based)

Recommendation 3.2.5: • The WFH recommends that blood samples for determination of PT, APTT, or FVIII/FIX activity should be rejected and replaced if the collection tube contains less than 80% of the target fill volume. • Remark: If the collection tube contains between 80% and 90% of its target fill volume, the results obtained using certain methods may have minor artefactual prolongation of PT and APTT and minor artefactual reduction in FVIII/FIX activity.  (Consensus Based)

Recommendation 3.2.6:• The WFH recommends that blood samples for determination of APTT or FVIII/FIX activity should be rejected and replaced if in vitro hemolysis or clotting have occurred during the collection and processing of the sample. • Remark: The impact of in vitro hemolysis on PT is insufficient to affect patient management. • Remark: Samples from patients with in vivo hemolysis that have been collected for determination of PT, APTT, or FVIII/FIX activity can be accepted and tested.  (Consensus Based)


Recommendation 3.2.7: • For laboratory investigation of patients being assessed due to clinical suspicion of hemophilia A, the WFH recommends that prothrombin time testing also be performed using a laboratory reagent containing human tissue factor. • Remark: Hemophilia A is sometimes excluded despite clinical suspicion of its presence. Such cases may have other factor deficiencies. Some patients with certain FVII defects may have symptoms similar to mild hemophilia but may display normal PT and FVII activity if the laboratory reagent contains non-human tissue factor so that the diagnosis would be missed. (Consensus Based)

Recommendation 3.2.8: • For laboratory investigation of patients being assessed due to clinical suspicion of hemophilia, the WFH recommends that an APTT result within the reference range not be used to rule out the presence of mild hemophilia A or B. • Remark: In some cases of mild hemophilia A or B, APTT may be within the normal range. (Consensus Based)

Recommendation 3.2.9: • The WFH recommends that an APTT result within the normal range obtained in a sample containing an equal volume mixture of patient and pooled normal plasma that was analyzed immediately after preparation of that mixture should not be used to rule out the possible presence of an FVIII inhibitor. • Remark: The APTT of an equal volume mixture of patient and pooled normal plasma becomes substantially prolonged over a period of 1 to 2 hours of incubation at 37°C if the patient sample contains a neutralizing anti-FVIII inhibitor. (Consensus Based)

Recommendation 3.2.10: • For laboratory investigation of patients being assessed due to clinical suspicion of hemophilia A, the WFH recommends the use of both the one-stage FVIII assay and the chromogenic FVIII:C assay in the initial diagnostic workup. • Remark: Both assays should be performed even if the result of one of the two assays shows FVIII activity within the normal range. • Remark: The one-stage FVIII assay requires the use of FVIII-deficient plasma containing less than 1 IU/dL (<1%) FVIII activity and normal levels of other clotting factors that can influence APTT (fibrinogen, FII, FV, FIX, FX, FXI, FXII, prekallikrein, and HMWK). (Consensus Based)

Recommendation 3.2.11: • For laboratory investigation of patients being assessed due to clinical suspicion of hemophilia B, the WFH recommends the use of the one-stage FIX assay in the initial diagnostic workup. • Remark: Data are currently insufficient to make recommendations on the role of the chromogenic FIX assay in the initial diagnostic workup of hemophilia B. • Remark: The one-stage FIX assay requires the use of FIX-deficient plasma containing less than 1 IU/dL (<1%) FIX activity and normal levels of other clotting factors that can influence APTT (fibrinogen, FII, FV, FVIII, FX, FXI, FXII, prekallikrein, and HMWK). (Consensus Based)

Recommendation 3.2.12: • For one-stage or chromogenic FVIII/FIX assays, the reference/standard plasma used for calibration, whether commercially or locally prepared, must be traceable to a WHO international standard, and results should be reported in international units (IUs). • Remark: Results should be reported as IU/mL or IU/dL. • Remark: In principle, percentage is the appropriate unit of activity only when the assay is performed using pooled normal plasma as the reference plasma whose activity is not traceable back to a WHO international standard. (Consensus Based)

Recommendation 3.2.13: • For laboratory investigation due to clinical suspicion of hemophilia using one-stage FVIII/FIX assays, the WFH recommends analysis using 3 different dilutions of test plasma samples. • Remark: The results of the test and standard plasma dilutions should be compared by parallel-line analysis. One way to assess this is to calculate the coefficient of variation (CV) of the 3 results using the equation CV = ([standard deviation/mean] × 100). If the CV of the 3 results is less than 15%, then the average of the 3 results should be reported. If the CV is greater than 15%, the results should be scrutinized. Presence of pathological inhibitors against specific clotting factors or lupus anticoagulants can interfere with some one-stage FVIII and FIX assays. Some therapeutic anticoagulants can also show this interference effect. In all of these settings, factor activity increases in the assay as the plasma is increasingly diluted. Factor activity is underestimated when the plasma is diluted less, and a more accurate activity result is obtained when the test plasma is diluted more. (Consensus Based)

Recommendation 3.2.14: • In populations where lupus anticoagulant occurs, the WFH recommends the use of an APTT reagent insensitive to lupus anticoagulant to perform one-stage FVIII/FIX assays. (Consensus Based)

Recommendation 3.2.15: • For all one-stage FVIII/FIX assays, only the clotting times of test sample dilutions that are within the range covered by the calibration curve should be used to calculate FVIII/FIX activity in the test sample. • Remark: When assaying test samples from patients with moderate or severe hemophilia A or B, an extended or additional calibration curve may be needed. It is not acceptable to extend the calibration curve by extrapolation without analyzing additional dilutions of the reference/calibration plasma. (Consensus Based)

Recommendation 3.2.16: • For all types of FVIII and FIX assays, an internal quality control (IQC) sample should be included with each batch of test samples analyzed. Results should only be released for patient management purposes after confirmation that the IQC result is within the target range for that material. • Remark: A description of how to set target ranges for IQC materials and handle out-of-range IQC results is available in the WFH laboratory manual. (Consensus Based)

Recommendation 3.2.17: • For internal quality control samples with FVIII/FIX activity in the range of 50-150 IU/dL, the between-assay coefficient of variation should be less than 10%. • Remark: Some studies have shown use of a stored calibration curve to be associated with higher between-assay CVs than use of a new calibration curve generated alongside patient samples. (Consensus Based)

Recommendation 3.2.18: • For monitoring replacement therapy with FVIII or FIX concentrates, the WFH recommends that laboratories use a FVIII/FIX assay that has been validated for use with the specific concentrate used for treatment. • Remark: This recommendation is particularly important for modified molecular forms of FVIII and FIX. (Consensus Based)

Recommendation 3.2.19: • For monitoring replacement therapy with plasma-derived FVIII concentrates, the WFH recommends use of a one-stage or chromogenic FVIII assay calibrated with a plasma standard traceable to a WHO international standard. (Consensus Based)

Recommendation 3.2.20: • For monitoring replacement therapy with clotting factor concentrates containing full-length recombinant FVIII, the WFH recommends use of a one-stage or chromogenic FVIII assay calibrated with a plasma standard traceable to a WHO international standard. (Consensus Based)

Recommendation 3.2.21: • For monitoring replacement therapy with efmoroctocog alfa (recombinant FVIII fused with human immunoglobulin G1 [rFVIIIFc]; Elocta®/Eloctate®), the WFH recommends use of a one-stage or chromogenic FVIII assay calibrated with a plasma standard traceable to a WHO international standard. Recommendation 3.2.22: • For monitoring replacement therapy with turoctocog alfa pegol (recombinant B-domain-truncated FVIII with a site-specific 40-kDa polyethylene glycol group [N8-GP]; Esperoct®), the WFH recommends use of a chromogenic FVIII assay or APTT-based one-stage FVIII assay with validated reagents, including some ellagic acid activator reagents (Actin®, Actin®FS, SynthAFax, DG Synth) and some silica activator reagents (Pathromtin®SL, SynthASil), calibrated with a plasma standard traceable to a WHO international standard. • Remark: One-stage FVIII assays with APTT-SP, STA®-PTT Automate, or TriniCLOTAPTT HS reagents significantly underestimate true FVIII activity of N8-GP and should not be used.

Recommendation 3.2.23: • For monitoring replacement therapy with damoctocog alfa pegol (recombinant B-domain-deleted FVIII with a site-specific 60 kDa branched polyethylene glycol group [BDD-rFVIII]; Jivi®), the WFH recommends use of a chromogenic FVIII assay or APTT-based one-stage FVIII assay with validated reagents, including the ellagic acid activator reagent Actin®FSL and some silica activator reagents (Pathromtin®SL, SynthASil), calibrated with a plasma standard traceable to a WHO international standard. • Remark: One-stage FVIII assays with the ellagic acid activator reagent Actin®FS or the kaolin activator reagent C.K. Prest®significantly overestimate true FVIII activity and should not be used. One-stage FVIII assays with APTT-SPand STA®-PTT Automate reagents significantly underestimate true FVIII activity and should not be used. (Consensus Based)

Recommendation 3.2.24: • For monitoring replacement therapy with rurioctocog alfa pegol (full-length recombinant FVIII with non-site-specific 20-kDa polyethylene glycol; Adynovate®/Adynovi®), the WFH advises that more laboratory assay studies are required to inform recommendations about laboratory monitoring. • Remark: There are conflicting findings in the literature assessing the use of one-stage and chromogenic FVIII assays in samples containing rurioctocog alfa pegol. (Consensus Based)

Recommendation 3.2.25: • For monitoring replacement therapy with lonoctocog alfa (single-chain recombinant FVIII [rVIII-SingleChain]; Afstyla®), the WFH recommends use of a chromogenic FVIII assay calibrated with a plasma standard traceable to a WHO international standard. • Remark: The summary of product characteristics recommends chromogenic assays. It also states that the one-stage FVIII assay result underestimates the FVIII activity level by approximately 45% compared to the chromogenic assay result, and suggests that if the one-stage assay is used, the result should be multiplied by a factor of 2. (Consensus Based)

Recommendation 3.2.26: • For monitoring replacement therapy with plasma-derived FIX concentrates, the WFH recommends use of a one-stage or chromogenic FIX assay calibrated with a plasma standard traceable to a WHO international standard. (Consensus Based)

Recommendation 3.2.27: • For monitoring replacement therapy with clotting factor concentrates containing unmodified recombinant FIX, the WFH recommends use of a one-stage FIX assay calibrated with a plasma standard traceable to a WHO international standard. • Remark: Chromogenic FIX assays have been reported to underestimate the FIX activity of recombinant FIX concentrate.

Recommendation 3.2.28: • For monitoring replacement therapy with eftrenonacog alfa (recombinant FIX fused with human immunoglobulin G1 [rFIXFc]; Alprolix®), the WFH recommends use of a chromogenic FIX assay or APTT-based one-stage FIX assay with validated reagents, including some ellagic acid activator reagents (Actin®, Actin®FS, Actin®FSL), some silica activator reagents (Pathromtin®SL, SynthASil), and a polyphenol activator reagent (Cephascreen®), calibrated with a plasma standard traceable to a WHO international standard. • Remark: One-stage FIX assays with STA®-PTT Automate or kaolin activator (C.K. Prest®) reagents significantly underestimate true rFIXFc (Alprolix®) activity and should not be used. (Consensus Based)

Recommendation 3.2.29: • For monitoring replacement therapy with albutrepenonacog alfa (recombinant FIX fused with recombinant human albumin [rFIX-RFP]; Idelvion®), the WFH recommends use of an APTT-based one-stage FIX assay with validated reagents, including some silica activator reagents (Pathromtin®SL, SynthASil), calibrated with a plasma standard traceable to a WHO international standard. • Remark: One-stage FIX assays with the ellagic acid activator reagent Actin®FS or the kaolin activator reagent C.K. Prest®significantly underestimate true rFIX-RFP (Idelvion®) activity and should not be used. One-stage assays with the ellagic acid activator SynthAFaxreagent or chromogenic FIX assays significantly overestimate true rFIX-RFP (Idelvion®) activity and should not be used. (Consensus Based)

Recommendation 3.2.30: • For monitoring replacement therapy with nonacog beta pegol (recombinant FIX with a 40-kDa polyethylene glycol moiety [N9-GP]; Refixia®/Rebinyn®), the WFH recommends use of a chromogenic FIX assay or APTT-based one-stage FIX assay with validated reagents, including the ellagic acid activator reagent SynthAFaxor the polyphenol activator Cephascreen®, calibrated with a plasma standard traceable to a WHO international standard. • Remark: Most one-stage FIX assays significantly overestimate or underestimate true FIX activity of N9-GP and should not be used. One-stage assays using the ellagic acid activator reagent SynthAFaxor the polyphenol activator reagent Cephascreen®, are suitable for monitoring therapy with N9-GP. (Consensus Based)

Recommendation 3.2.31: • For patients receiving emicizumab in whom confirmation of expected emicizumab levels is required, the WFH recommends use of a modified one-stage assay including an additional pre-dilution step of test plasma and assay calibration with specific emicizumab calibrators. • Remark: Even at subtherapeutic levels of emicizumab, APTT may be normal or subnormal in patients with severe hemophilia A with or without inhibitors. (Consensus Based)

Recommendation 3.2.32: • For determination of FVIII activity in patients with hemophilia A receiving emicizumab, the WFH recommends use of a chromogenic FVIII assay containing bovine FX. • Remark: At therapeutic levels, emicizumab affects any chromogenic FVIII assay containing FX of human origin. Emicizumab may also affect chromogenic FVIII assays containing FIXa of human and FX of bovine origin but only at emicizumab levels higher than those expected in patients receiving recommended doses. (Consensus Based)

Recommendation 3.2.33: • For determination of FVIII inhibitor levels in patients receiving emicizumab, the WFH recommends use of a chromogenic FVIII assay containing bovine FX. (Consensus Based)

Recommendation 3.2.34: • For patients with a suspected neutralizing anti-emicizumab antibody, the WFH recommends measuring emicizumab levels using a modified one-stage assay including an additional pre-dilution step of test plasma and assay calibration with specific emicizumab calibrators. • Remark: Validated anti-drug antibody assays may also be used for this purpose, if available. (Consensus Based)

Recommendation 3.2.35: • For determination of anti-FVIII inhibitors in a sample containing greater than 5 IU/dL FVIII activity, the WFH recommends that prior to testing, the sample be heated to 56°C for 30 minutes and centrifuged at ambient temperature for a minimum of 1700 g for at least 5 minutes. • Remark: The quantification limit of the Nijmegen-Bethesda FVIII inhibitor assay is around 0.6 BU/mL. • Remark: The Nijmegen-Bethesda FVIII inhibitor assay requires use of buffered pooled normal plasma as a source of FVIII, which is then mixed with an equal volume of FVIII-deficient plasma to prepare the control mixture. (Consensus Based)

Recommendation 3.2.36: • For determination of anti-FIX inhibitors in a sample containing greater than 5 IU/dL FIX activity, the WFH recommends that prior to testing, the sample be heated at 56°C for 30 minutes and centrifuged at ambient temperature for a minimum of 1700 g for at least 5 minutes. (Consensus Based)

Recommendation 3.2.37: • For quantification of anti-FVIII inhibitors, the WFH recommends that the Nijmegen-Bethesda assay be used. • Remark: Bethesda assays detect neutralizing antibodies. A small proportion of anti-FVIII antibodies are non-neutralizing, shorten the half-life of infused FVIII, and are not detected by Bethesda assays. • Remark: The Nijmegen modification describes a specific method for buffering pooled normal plasma; other buffering methods may be suitable.

Recommendation 3.2.38: • For quantification of FVIII and FIX inhibitors, the WFH recommends that only residual FVIII/FIX activity between 25% and 75% of the FVIII/FIX in the control mixture be used to calculate inhibitor concentrations. • Remark: The most accurate inhibitor results are obtained when the residual FVIII/FIX activity is close to 50% of the level in the control mixture. (Consensus Based)

Recommendation 3.2.39: • For quantification of low-titer anti-FVIII inhibitors (<2 BU/mL), the WFH recommends use of a chromogenic Nijmegen-Bethesda FVIII assay to measure residual FVIII activity. • Remark: Use of a chromogenic Nijmegen-Bethesda FVIII assay instead of a one-stage FVIII assay provides greater specificity and reduces possible variability in measurement of residual FVIII leading to underestimation to the extent that a false positive inhibitor is reported when no inhibitor is present.

Recommendation 3.2.40: • For quantification of FVIII activity in recipients of gene transfer, the WFH advises that more research is necessary to determine the relative accuracy of chromogenic and one-stage assays in predicting hemostatic protection. • Remark: The one-stage assay appears to consistently produce FVIII activity results that are approximately 1.6-fold greater than those obtained with the chromogenic assay for multiple FVIII transgene products. Correlation with both plasma and recombinant FVIII-specific activity and clinical response may be needed for accurate determination of FVIII activity in recipients. (Consensus Based)

Recommendation 3.2.41: • For quantification of FIX activity in recipients of gene transfer, the WFH advises that more research is necessary to determine the relative accuracy of chromogenic and one-stage assays in predicting hemostatic protection. • Remark: FIX Padua (R338L) has been utilized for FIX gene therapy because it has a higher specific activity than native FIX. The one-stage assay appears to consistently produce FIX Padua activity results that are approximately 1.6-fold greater than those obtained with the chromogenic assay. Correlation with both plasma and recombinant FIX-specific activity is needed for accurate determination of FIX Padua activity in recipients. (Consensus Based)

Recommendation 3.4.1: • The WFH strongly recommends that coagulation laboratories implement quality assurance programs for all laboratory systems to ensure quality adherence and the reliability of laboratory blood testing procedures and reporting for the diagnosis and treatment of hemophilia. (Consensus Based)

Recommendation 3.4.2: • For hemostasis screening tests, the WFH recommends performing internal quality controls with at least two levels of internal quality control samples (normal and abnormal plasma samples) for all test batches at least daily. (Consensus Based)

Recommendation 3.4.3: • The WFH strongly recommends that clinical laboratories routinely participate in external quality assessment for each assay used for the diagnosis and treatment of hemophilia. • Remark: Participation in the WFH International External Quality Assessment Scheme (IEQAS) enables laboratories to improve and standardize laboratory testing for hemophilia. (Consensus Based)

6731

Genetic Assessment

Recommendation 4.1.1: • For people with hemophilia, the WFH recommends that genetic testing be offered to identify the specific underlying genetic variant associated with their disorder.  (Consensus Based)

Recommendation 4.1.2: • For obligate carriers of hemophilia and “at-risk” female relatives of people with hemophilia or potential carriers of hemophilia, the WFH recommends that genetic testing be offered for the previously identified genetic variant in theF8orF9gene.  (Consensus Based)

Recommendation 4.1.3: • For females with low phenotypic coagulation FVIII or FIX levels, the WFH recommends that investigation of the genetic/epigenetic basis of the phenotype be offered.  (Consensus Based)

Recommendation 4.1.4:• For obligate carriers of hemophilia and “at-risk” female relatives of people with hemophilia or potential carriers of hemophilia, the WFH recommends the inclusion of a detailed family pedigree to support the genetic testing referral.  (Consensus Based)

Recommendation 4.1.5: • For individuals with suspected hemophilia and potential carriers of hemophilia, the WFH strongly recommends that phenotypic screening for FVIII or FIX levels, von Willebrand factor (VWF) antigen, and VWF activity testing be performed prior to referral for genetic testing.  (Consensus Based)

Recommendation 4.1.6: • For people with hemophilia, obligate carriers of hemophilia, “at-risk” female relatives, or individuals with low coagulation factor levels, the WFH strongly recommends detailed genetic counselling prior to offering genetic testing. • Remark: Genetic counselling should include a discussion of the experimental limits of the molecular results according to the availability of practical approaches. • Remark: Genetic counselling should include a discussion of the possibility of incidental findings in genes other thanF8orF9, if the methodology used by the investigating laboratory (e.g., next generation sequencing [NGS]) may detect such genetic variations. • Remark: Genetic counselling should be performed by a genetic counsellor when available. If no genetic counsellor is available, a medical professional with knowledge of genetics in hemophilia can provide genetic counselling.

Recommendation 4.1.7: • For all patients referred for genetic testing, the WFH strongly recommends that informed consent be obtained from the patient, parent, or legal guardian. This requires both permission to carry out testing and education to ensure that they fully understand the testing procedure, the benefits and limitations of the test, and possible consequences of the test results. • Remark: Written informed consent may need to be obtained and documented by the clinician or genetic counsellor in compliance with local policies and practices.  (Consensus Based)

Recommendation 4.2.1: • For people with suspected or established hemophilia undergoing genetic testing, the WFH recommends that the index case (proband) be genotyped to identify the underlying genetic variant.  (Consensus Based)

Recommendation 4.2.2: • For obligate carriers of hemophilia and “at-risk” female relatives of the affected proband or potential carrier of hemophilia, the WFH recommends genetic counselling about their risk of being a carrier.  (Consensus Based)

Recommendation 4.2.3: • For all obligate carriers of hemophilia and “at-risk” female relatives of people with hemophilia or potential carriers of hemophilia, the WFH recommends that phenotypic coagulation factor levels be measured.  (Consensus Based)

Recommendation 4.2.4: • For all obligate carriers of hemophilia and “at-risk” female relatives of people with hemophilia, the WFH recommends that genetic testing be offered for the previously identified genetic variant in theF8orF9gene.  (Consensus Based)

Recommendation 4.2.5: • For females with low phenotypic coagulation FVIII or FIX levels, the WFH recommends that investigation of the genetic/epigenetic basis of the phenotype be offered.  (Consensus Based)

Recommendation 4.2.6: • For pregnant females who are carriers of anF8orF9variant and are carrying a male fetus, the WFH recommends that prenatal diagnosis (PND) be offered to determine the hemophilia status of the fetus. • Remark: Genetic counselling should include a discussion of the risk of the PND procedure to the pregnancy. • Remark: It is important to be aware of and follow the relevant laws governing such procedures in the country where the service is being provided.  (Consensus Based)

Recommendation 4.2.7: • For families who wish to be prepared for a child with hemophilia before birth or who wish to terminate an affected fetus, the WFH recommends that prenatal diagnosis (PND) by chorionic villus sampling or amniocentesis be offered. • Remark: It is important to be aware of and follow the relevant laws governing such procedures in the country where the service is being provided. • Remark: PND may be offered in early pregnancy or in late pregnancy by late-gestation amniocentesis in order to guide the management of the delivery of an affected child.  (Consensus Based)

Recommendation 4.2.8: • For people with suspected or established hemophilia, the WFH recommends that genetic testing be performed; knowledge of the genetic variant may help predict the risk of inhibitor development, response to immune tolerance induction (ITI), and depth of phenotype severity, as well as determine the availability of gene manipulation techniques.  (Consensus Based)

Recommendation 4.3.1: • For male probands, the WFH recommends that genetic testing be directed by the proband's baseline phenotypic coagulation factor level, which indicates the severity of the disorder. ◦ In patients with severe hemophilia A (FVIII:C <1 IU/dL) or moderate hemophilia A with lower-borderline factor activity levels (FVIII:C 1-3 IU/dL), analysis of theF8intron 22 inversion and theF8intron 1 inversion should be performed first. ◦ Patients with severe hemophilia A in whom recurrent inversions (i.e.,F8intron 22 and intron 1 inversions) cannot be detected should undergo screening and characterization of small variants, including single nucleotide variants (SNV) and small insertion, duplication, or deletion variants covering the essential regions ofF8including the 26 exons, exon/intron boundaries, and 5′ and 3′ untranslated regions. If these tests are still uninformative, patients should be screened for copy number variants (CNV) including largeF8deletions, duplications, or complex rearrangements. ◦ In patients with moderate (FVIII:C 1-5 IU/dL) or mild (FVIII:C 5-40 IU/dL) hemophilia A, screening and characterization of small variants (i.e., SNV and small insertions, duplications, or deletions) covering the essential regions ofF8including the 26 exons, exon/intron boundaries, and 5′ and 3′ untranslated regions should be performed first. If these tests are still uninformative, patients should be screened forF8CNV. ◦ In all patients with hemophilia B (i.e., patients with severe [FIX:C <1 IU/dL], moderate [FIX:C 1-5 IU/dL], and mild [FIX:C 5-40 IU/dL] hemophilia B), screening and characterization of small variants (i.e., SNV and small insertions, duplications, or deletions) covering the essential regions ofF9including the 8 exons, exon/intron boundaries, and 5′ and 3′ untranslated regions should be performed first. If these tests are still uninformative, patients should be screened forF9CNV.  (Consensus Based)

Recommendation 4.4.1: • For people with severe hemophilia A, or moderate hemophilia A with lower-borderline factor activity levels (FVIII:C 1-3 IU/dL), the WFH recommends testing for theF8intron 22 inversion andF8intron 1 inversion in the first line of genetic testing. • Remark: Different techniques can be used for detection of theF8intron 22 inversion and intron 1 inversion depending on the available technical expertise and resources. • Remark: All results should be confirmed by independent analytical testing of the DNA sample.  (Consensus Based)

Recommendation 4.4.2: • For people with severe hemophilia A who are negative for the commonF8intron 22 inversion andF8intron 1 inversion variants, the WFH recommends full gene screening of the essential regions ofF8, including the 26 exons, splice boundaries, promoter, and 5′ and 3′ untranslated regions. • Remark: For example, depending on the availability of resources, fullF8gene screening may take the form of polymerase chain reaction (PCR) and Sanger sequencing or next generation sequencing (NGS). Where resources are limited, laboratories may choose a cost-effective screening approach prior to Sanger sequencing. • Remark: When choosing an analytical technique, laboratories must be aware of the sensitivity and specificity of the approach used and the turn-around time for producing an interpretive report. • Remark: The presence of a variant should be confirmed in both 5′ (forward) and 3′ (reverse) directions, specifically in heterozygous carriers, when analyzing variants detected using Sanger sequencing. • Remark: All results should be confirmed by independent analytical testing of the DNA sample.  (Consensus Based)

Recommendation 4.4.3: • For people with hemophilia B, the WFH recommends full gene screening of the essential regions ofF9, including the 8 exons, splice boundaries, promoter, and 5′ and 3′ untranslated regions. • Remark: For example, depending on the availability of resources, fullF9gene screening may take the form of polymerase chain reaction (PCR) and Sanger sequencing or next generation sequencing (NGS). Where resources are limited, laboratories may choose a cost-effective screening approach prior to Sanger sequencing. • Remark: When choosing an analytical technique, laboratories must be aware of the sensitivity and specificity of the approach used and the turn-around time for producing an interpretive report. • Remark: The presence of a variant should be confirmed in both 5′ (forward) and 3′ (reverse) directions, specifically in heterozygous carriers, when analyzing variants detected using Sanger sequencing. • Remark: All results should be confirmed by independent analytical testing of the DNA sample.  (Consensus Based)

Recommendation 4.4.4: • For people with hemophilia A or B in whom no variant is detectable on inversion analysis or full gene sequencing, the WFH recommends that a large deletion or duplication event be investigated. • Remark: Copy number variation (CNV) analysis may be performed using various validated techniques dependent on the resources available to the laboratory. According to the practical limitations of the technique, results should be provided with an estimation of error, if applicable. • Remark: All results should be confirmed by independent analytical testing of the DNA sample.  (Consensus Based)

Recommendation 4.4.5 • For prenatal testing, the WFH recommends maternal cell contamination testing of the fetal sample. • Remark: Different techniques can be used for maternal cell contamination testing depending on the available technical expertise and resources. For example, multiple autosomal short tandem repeat (STR) markers may be used. • Remark: When choosing an analytical technique, laboratories must be aware of the sensitivity and specificity of the approach used and the turn-around time for producing an interpretive report.  (Consensus Based)

Recommendation 4.5.1: • The WFH recommends that variants be classified per the American College of Medical Genetics and Genomics (ACMG) guidelines. • Remark: ClinGen, a U.S. National Institutes of Health-funded resource dedicated to building a central resource that defines the clinical relevance of genes and variants, has assembled an international expert committee to apply ACMG recommendations toF8andF9variants, which should produce more hemophilia-specific recommendations.  (Consensus Based)

Recommendation 4.5.2: • The WFH recommends that variants be described using the Human Genome Variation Society (HGVS) nomenclature.  (Consensus Based)

Recommendation 4.6.1: • The WFH recommends that interpretive reports contain: ◦ patient information including patient name, date of birth, ordering clinician, date of specimen collection, diagnosis, baseline factor level, and family pedigree; ◦ description of the assay(s), references to the literature (if applicable), limitations of the test, and the genome reference sequence used for analysis; ◦ results including DNA variant(s) in Human Genome Variation Society (HGVS) nomenclature and American College of Medical Genetic and Genomics (ACMG) variant classification; and ◦ interpretation of test results in a format useful to the ordering clinician, including recommendations for follow-up testing if indicated, implications of test results for patients and family members, and the role of genetic counselling.  (Consensus Based)

Recommendation 4.6.2: • For all interpretive reports for all individuals undergoing genetic testing for hemophilia, the WFH recommends that the ordering clinician and reporting scientist be available to discuss the potential phenotypic consequences of the reported genotype, as required.  (Consensus Based)

Recommendation 4.7.1: • For people in whom a strong diagnosis of hemophilia is certain but noF8orF9variant is detected using current diagnostic genetic testing, the WFH recommends that other genetic causes be considered (e.g., deep intronic variants). • Remark: Current testing techniques are expected to evolve in the near future to include next generation sequencing (NGS) and whole genome sequencing (WGS). • Remark: NGS and WGS techniques should only be used after it is established that structural variants can be detected by the technique.  (Consensus Based)

Recommendation 4.7.2: • For “at-risk” female relatives of people with hemophilia in whom the familial variant is not detected using standard diagnostic genetic testing, particularly in females with one affected child, the WFH recommends that the possibility of mosaicism be considered and discussed during genetic counselling.  (Consensus Based)

Recommendation 4.7.3: • For people with hemophilia A in whom the mode of inheritance is not conclusive, and in whom no inversion or variant is detected by current diagnostic testing, the WFH recommends that other potential diagnoses be investigated, including type 2N von Willebrand disease (VWD), combined FV and FVIII deficiency, or other types of VWD.  (Consensus Based)

Recommendation 4.7.4: • For symptomatic females with low phenotypic coagulation FVIII or FIX levels in whom just one pathogenic variant is found, the WFH recommends performing investigative tests for an X-chromosome inactivation pattern, if locally available.  (Consensus Based)

Recommendation 4.8.1: • The WFH recommends that genetic diagnostic laboratories should undergo periodic accreditation, if available, by an approved body.  (Consensus Based)

Recommendation 4.8.2: • The WFH recommends that internal quality control (IQC) of genetic tests be performed and recorded routinely within the laboratory.  (Consensus Based)

Recommendation 4.8.3: • The WFH recommends that laboratories participate in external quality assessment schemes (EQAS) for the genetic tests they provide. • Remark: Participation in an EQAS ensures the provision of a test that is robust and reliable. This may be through participation in a formal EQAS or an informal sample exchange between laboratories.  (Consensus Based)
6731

Hemostatic Agents

Recommendation 5.1.1: • For patients with hemophilia, the WFH does not express a preference for recombinant over plasma-derived clotting factor concentrates. • Remark: The choice between these classes of product must be made according to local criteria including availability, cost, and patient preferences.  (Consensus Based)

Recommendation 5.2.1: • For people with hemophilia, the WFH recommends the use of products that have been accepted by the official regulatory agencies responsible for protecting and promoting public health with consideration given to the plasma quality (i.e., purity of the product) and the manufacturing process (i.e., viral inactivation/elimination). • Remark: A plasma-derived product created by a process that incorporates two viral reduction steps should not automatically be considered better than one that only has one specific viral inactivation step. If only one step is used, this step should preferably inactivate viruses with and without lipid envelopes. Most recently, licensed products use two orthogonal viral inactivation/elimination steps. • Remark: Current prothrombin complex concentrates should be considered safer than earlier products due to the inclusion of coagulation inhibitors such as heparin, antithrombin, and proteins C, S, and Z.  (Consensus Based)

Recommendation 5.3.1: • For people with hemophilia receiving FVIII concentrates who would benefit from optimization of prophylaxis, the WFH recommends individualized pharmacokinetic monitoring. • Remark: Peak factor level should be measured 15-30 minutes after the infusion to verify calculated dose. Plasma half-life can be determined via full PK (10-11 blood samplings taken over a period of 32-96 hours), or with limited sampling in combination with population PK estimates.  (Consensus Based)

Recommendation 5.3.2: • For patients with hemophilia receiving FVIII concentrates where steady-state hemostatic correction is necessary for a prolonged period of time (e.g., perioperative management or in the case of a severe bleeding episode in a patient with a low-responding inhibitor), the WFH recommends consideration for use of continuous infusion. • Remark: Continuous infusion may lead to a reduction in the total quantity of clotting factor concentrates used and can be more cost-effective in patients with severe hemophilia. However, this cost-effectiveness comparison can depend on the doses used for continuous and intermittent bolus infusions. • Remark: Continuous infusion requires the use of specifically designated pumps and knowledge of the stability of the particular clotting factor concentrate after reconstitution within the infusion device, and patients must be monitored frequently for pump failure.  (Consensus Based)

Recommendation 5.3.3: • For treatment of FIX deficiency in patients with hemophilia B, the WFH recommends a product containing only FIX rather than prothrombin complex concentrates (PCCs), which also contain other clotting factors, such as factors II, VII, and X, some of which may become activated during manufacture and may predispose the patient to thromboembolism. • Remark: Pure FIX products have reduced risk of thrombosis or disseminated intravascular coagulation, compared to what was observed with large doses of older-generation PCCs. • Remark: Current PCCs are considered safer than earlier products due to the inclusion of coagulation inhibitors such as heparin, antithrombin, and proteins C, S, and Z. Nevertheless, in cases of intensive treatment (e.g., perioperative management), prothrombotic clotting factors may accumulate in plasma and may increase the risk for thromboembolic complications. When PCCs are used in high doses in order to normalize FIX levels, thromboprophylaxis should be considered.  (Consensus Based)

Recommendation 5.3.4: • For hemophilia B patients requiring prolonged therapy at high doses, the use of pure FIX concentrates is recommended over prothrombin complex concentrates.  (Consensus Based)

Recommendation 5.3.5: • For hemophilia B patients undergoing surgery, the use of pure FIX concentrates is recommended over prothrombin complex concentrates.  (Consensus Based)

Recommendation 5.3.6: • For hemophilia B patients with liver disease, the use of pure FIX concentrates is recommended over prothrombin complex concentrates.  (Consensus Based)

Recommendation 5.3.7: • For hemophilia B patients with previous thrombosis or known thrombotic tendency, the use of pure FIX concentrates is recommended over prothrombin complex concentrates.  (Consensus Based)

Recommendation 5.3.8: • For hemophilia B patients concomitantly using drugs known to have thrombogenic potential, including antifibrinolytic agents, the use of pure FIX concentrates is recommended over prothrombin complex concentrates.  (Consensus Based)

Recommendation 5.3.9: • For patients with hemophilia B receiving FIX concentrates who would benefit from optimization of prophylaxis, the WFH recommends pharmacokinetic monitoring. • Remark: Peak factor level should be measured 15-30 minutes after the infusion to verify calculated dose. Plasma half-life can be determined via full PK (10-11 blood samplings taken over a period of 1-2 weeks), or with limited sampling in combination with population PK estimates.  (Consensus Based)

Recommendation 5.3.10: • For patients with hemophilia A or B, there is no evidence for any clinical safety issues in persons with hemophilia to recommend a preference among the various mechanisms of action (e.g., PEGylation, Fc-fusion, albumin-fusion) used to extend the half-life of clotting factor concentrates.  (Consensus Based)

Recommendation 5.3.11: • Patients with hemophilia who are transitioning from standard half-life clotting factor concentrates to extended half-life clotting factor concentrates would typically require decreased dose frequencies, but EHL products may also be used to maintain higher trough levels to optimize prophylaxis. • Remark: Pharmacokinetic-guided dosing as per Recommendations 5.3.1 and 5.3.9 provides for more individualized prophylaxis.  (Consensus Based)

Recommendation 5.4.1: • For people with hemophilia A with an inhibitor requiring treatment for acute bleeding complications or surgery, the WFH recommends that a bypassing agent be used. • Remark: Bypassing agents include recombinant activated factor VIIa or activated prothrombin complex concentrate.  (Consensus Based)

Recommendation 5.4.2: • For patients with hemophilia B and an inhibitor with a history of anaphylaxis to FIX-containing clotting factor concentrates, recombinant activated factor VIIa must be administered as activated prothrombin complex concentrate cannot be used.  (Consensus Based)

Recommendation 5.4.3: • The WFH recommends that patients with hemophilia with an inhibitor should be considered for regular prophylaxis to prevent bleeding events.  (Consensus Based)

Recommendation 5.5.1: • For patients with hemophilia, the WFH strongly recommends the use of viral-inactivated plasma-derived or recombinant clotting factor concentrates in preference to cryoprecipitate or fresh frozen plasma. • Remark: The WFH supports the use of CFCs in preference to cryoprecipitate or FFP due to concerns about quality, safety, and efficacy. However, the WFH recognizes the reality that they are still widely used in countries around the world where they are the only available or affordable treatment options.  (Consensus Based)

Recommendation 5.5.2: • For patients with hemophilia, fresh frozen plasma is not recommended due to concerns about the safety and quality. • Remark: However, the WFH recognizes the as yet unavoidable reality of their continued use in some parts of the world where it is the only available or affordable treatment option.  (Consensus Based)

Recommendation 5.5.3: • For patients with hemophilia, cryoprecipitate is not recommended due to concerns about the safety and quality. • Remark: The use of cryoprecipitate can only be justified in situations where clotting factor concentrates are not available as there is no proven advantage for their use over CFCs. It is strongly encouraged that viral-inactivation procedures be used, if available.  (Consensus Based)

Recommendation 5.6.1: • For patients with mild or moderate hemophilia A and carriers of hemophilia A, the WFH recommends considering desmopressin (DDAVP) as an option for treatment. • Remark: The WFH recommends testing DDAVP prior to therapeutic use to evaluate the individual FVIII response. The decision to use DDAVP must be based on the patient's baseline FVIII activity, the increment achieved, and the duration of treatment required. • Remark: In general, the most common adverse events observed are tachycardia, flushing, tremor, abdominal discomfort, and headache, especially during rapid infusion, and are mostly mild and transient. However, hypotension and/or severe hyponatremia can also occur. • Remark: For pregnant women during labour and delivery, the WFH recommends caution in the use of DDAVP, and it should be avoided in pre-eclampsia and eclampsia. • Remark: With more than 3 consecutive days of dosing, the therapeutic response may decrease (tachyphylaxis) and the risk of complications rises; thus, clotting factor concentrates may be needed when higher factor levels are required for a prolonged period.  (Consensus Based)

Recommendation 5.6.2: • For adults, the WFH recommends DDAVP not be used for more than 3 consecutive days and only under close supervision. If DDAVP is administered twice in a single day, subsequent daily dosing should be limited to once per day. • Remark: In general, the most common adverse events observed are tachycardia, flushing, tremor, abdominal discomfort, and headache, especially during rapid infusion. However, hypotension and/or hyponatremia can also occur. • Remark: With more than 3 consecutive days of dosing, the therapeutic response may decrease (tachyphylaxis) and the risk of complications rises; thus, clotting factor concentrates may be needed when higher factor levels are required for a prolonged period.  (Consensus Based)

Recommendation 5.6.3: • For children, the WFH recommends using no more than 1 dose of DDAVP per day for no more than 3 consecutive days. • Remark: In general, the most common adverse events observed are tachycardia, flushing, tremor, abdominal discomfort, and headache, especially during rapid infusion. However, hypotension and/or hyponatremia can also occur. • Remark: With more than 3 consecutive days of dosing, the therapeutic response may decrease (tachyphylaxis) and the risk of complications rises; thus, clotting factor concentrates may be needed when higher factor levels are required for a prolonged period.  (Consensus Based)

Recommendation 5.6.4: • For children under 2 years of age, the WFH alerts that DDAVP is contraindicated due to increased risk of seizures as consequences of water retention and hyponatremia.  (Consensus Based)

Recommendation 5.6.5: • For patients at risk of cardiovascular disease or thrombosis, the WFH recommends that DDAVP should be used with caution due to the risk of thromboembolism and myocardial infarction.  (Consensus Based)

Recommendation 5.6.6: • For patients with hemophilia, the WFH recommends that antifibrinolytics are a valuable alternative to use alone or as adjuvant treatment, particularly in controlling mucocutaneous bleeding (e.g., epistaxis, oral and gastrointestinal bleeding, and menorrhagia) and for dental surgery and eruption or shedding of teeth. • Remark: Antifibrinolytics can be used with standard doses of clotting factor concentrates, including bypassing agents. However, they should not be used with prothrombin complex concentrates due to the increased risk of thromboembolism.  (Consensus Based)

Recommendation 5.6.7: • For patients with hematuria, the WFH recommends against the use of antifibrinolytics, as it is contraindicated in these patients due to increased risk of obstructive uropathy.  (Consensus Based)

Recommendation 5.6.8: • For patients with renal impairment, the WFH recommends reduced dosing of antifibrinolytics and close monitoring.  (Consensus Based)

Recommendation 5.7.1: • For patients with hemophilia A with an inhibitor, the WFH recommends that emicizumab should be used for regular prophylaxis. • Remark: For patients with hemophilia A with no inhibitor, the WFH recommends that emicizumab can be used for regular prophylaxis.  (Consensus Based)
6731

Prophylaxis in Hemophilia

Recommendation 6.1.1: • For patients with hemophilia A or B with a severe phenotype (note that this may include patients with moderate hemophilia with a severe phenotype), the WFH strongly recommends that such patients be on prophylaxis sufficient to prevent bleeds at all times, but that prophylaxis should be individualized, taking into consideration patient bleeding phenotype, joint status, individual pharmacokinetics, and patient self-assessment and preference. • Remark: Individualizing prophylaxis means that if patients continue to experience bleeds, their prophylaxis regimen should be escalated (in dose/frequency or both) to prevent bleeding. • Remark: In countries with significant healthcare constraints, the WFH still advocates for the use of prophylaxis over episodic therapy but recognizes that less intensive prophylaxis may be used.  (Consensus Based)

Recommendation 6.1.2: • For pediatric patients with severe hemophilia A or B, the WFH recommends early initiation of prophylaxis with clotting factor concentrates (standard or extended half-life FVIII/FIX) or other hemostatic agent(s) prior to the onset of joint disease and ideally before age 3, in order to prevent spontaneous and breakthrough bleeding including hemarthroses which can lead to joint disease.  (Consensus Based)

Recommendation 6.1.3: • For adolescents and adults with hemophilia who show evidence of joint damage and have not as yet been on prophylaxis, the WFH recommends commencing tertiary prophylaxis in order to reduce the number of hemarthroses, spontaneous and breakthrough bleeding, and slow down the progression of hemophilic arthropathy.  (Consensus Based)

Recommendation 6.2.1: • For patients with severe phenotype hemophilia A or B, especially children, the WFH recommends regular long-term prophylaxis as the standard of care to prevent hemarthrosis and other spontaneous and breakthrough bleeding, maintain musculoskeletal health, and promote quality of life. When prophylaxis is not feasible, episodic therapy is essential treatment for acute hemorrhages, but it will not prevent long-term joint damage. • Remark: In the long term, early and regular prophylaxis for children reduces hemarthrosis and other hemophilic bleeding, produces better health and joint outcomes, reduces the number of hospital visits and admissions, and may avert the need for orthopedic interventions, including surgery, in the future.  (Consensus Based)

Recommendation 6.3.1: • For patients with severe phenotype hemophilia A or B, prophylaxis with clotting factor concentrates (either standard or extended half-life) is recommended at a dose and dosing interval (dependent on the pharmacokinetic [PK] properties of the clotting factor concentrate) that allow them to at all times have sufficient circulating factor to prevent hemarthrosis, and spontaneous and breakthrough bleeding, based on their individual needs and lifestyles and preserve musculoskeletal function. • Remark: In the past, a trough factor level of 1 IU/dL (1%) was deemed an adequate goal. Now recognizing that with a 1% trough level, patients remain at risk of bleeding, most clinicians would prefer to target higher trough levels (>3%-5%, or higher). Recent studies show that such trough levels achieve less bleeding. However, the trade-off is that higher trough levels may require higher doses or more frequent infusions of clotting factor concentrates. This should therefore be personalized based on the individual's activities, lifestyle, and PK handling of factor.  (Consensus Based)

Recommendation 6.3.2: • For patients who are adherent to their prescribed prophylaxis regimen but still experience breakthrough bleeds, the WFH recommends escalation of prophylaxis with measurement of trough levels and, if required, orthopedic interventions as appropriate. • Remark: Any patient who fails to respond to adequate factor replacement therapy after past responsiveness should be tested for inhibitor development prior to escalation of therapy.  (Consensus Based)

Recommendation 6.4.1: • For patients with severe phenotype hemophilia A or B using EHL FVIII or FIX concentrates, the WFH recommends prophylaxis with EHL clotting factor concentrates at sufficient doses and dosing intervals to prevent hemarthroses and spontaneous and breakthrough bleeding and preserve joint function.  (Consensus Based)

Recommendation 6.5.1: • For patients with severe phenotype hemophilia A without inhibitors, prophylaxis with emicizumab will prevent hemarthrosis, spontaneous, and breakthrough bleeding. • Remark: The WFH however notes that there are very little long-term data on patient outcomes with such an approach and recommends that such data be obtained.  (Consensus Based)

Recommendation 6.6.1: • For patients with moderate/severe hemophilia A or B, especially those who have experienced a life-threatening bleed (e.g., intracranial hemorrhage [ICH]), the WFH recommends prophylaxis with FVIII or FIX concentrates or with a non-factor therapy (e.g., emicizumab for hemophilia A) in order to prevent a recurrent life-threatening bleed. This is particularly important during the first 3-6 months following an ICH as the risk of recurrence is highest during this period. • Remark: As inhibitor development is associated with intense exposure as would occur in the setting of an ICH, such patients require good clinical monitoring of treatment response and frequent laboratory testing for inhibitors.  (Consensus Based)

Recommendation 6.6.2: • For patients with hemophilia and venous access difficulties that impede regular clotting factor concentrate infusions, the WFH recommends insertion of a central venous access device (CVAD) to facilitate prophylactic clotting factor concentrate infusions. Another currently available option is the use of emicizumab while in the future there may be other subcutaneous non-factor therapies that become available.  (Consensus Based)

Recommendation 6.8.1: • For patients with severe phenotype hemophilia A or B on prophylaxis, the WFH recommends that patients/caregivers be taught to maintain timely and accurate records of bleeding episodes and treatment and be followed in hemophilia treatment centres.

Recommendation 6.10.1: • For patients with severe phenotype hemophilia A or B in countries with healthcare constraints, the WFH still strongly recommends prophylaxis (even when the only option is using lower factor doses) over episodic factor therapy to reduce hemarthroses and other spontaneous and breakthrough bleeding and better preserve joint function.
 
6731

Treatment of Specific Hemorrhages

Recommendation 7.2.1: • Hemophilia patients with severe hemarthrosis should be treated immediately with intravenous clotting factor concentrate replacement infusion(s) until there is bleed resolution. (Consensus Based)

Recommendation 7.2.2: • Hemophilia patients with moderate or mild joint bleeding should be given 1 intravenous infusion of clotting factor concentrate, repeated if clinically indicated, depending on the resolution of the bleed.  (Consensus Based)

Recommendation 7.2.3: • In hemophilia patients with hemarthrosis, severity of pain should be graded and monitored according to the World Health Organization (WHO) pain scale.  (Consensus Based)

Recommendation 7.2.4: • Hemophilia patients with pain due to hemarthrosis should be given analgesic medication according to the severity of the pain.  (Consensus Based)

Recommendation 7.2.5: • In hemophilia patients with severe pain, management of such pain should include opioids based on clinical symptoms to an extent that the patient is comfortable to weight bear or use the joint as much as possible without any pain.  (Consensus Based)

Recommendation 7.2.6: • Hemophilia patients with hemarthrosis should be managed using the RICE approach (Rest, Ice, Compression, and Elevation) in addition to clotting factor concentrate replacement. • Remark: The WFH recognizes that in some regions of the world, RICE may be the only initial treatment available or the best treatment available in the absence of an adequate supply of CFCs or other hemostatic agents..  (Consensus Based)

Recommendation 7.2.7: • In hemophilia patients with hemarthrosis, weight-bearing should be avoided until the symptoms improve to an extent that the patient is comfortable to weight bear without significant pain.  (Consensus Based)

Recommendation 7.2.8: • In hemophilia patients, use of opioid analgesia in managing pain should be limited in duration, as much as possible.  (Consensus Based)

Recommendation 7.2.9: • In hemophilia patients with hemarthrosis, physical therapy exercises performed under clotting factor coverage should begin as soon as the pain symptoms stop.  (Consensus Based)

Recommendation 7.2.10: • In hemophilia patients with hemarthrosis, the aim of physical therapy should be to return joint function to the pre-bleed state.  (Consensus Based)

Recommendation 7.2.11: • For hemophilia patients without inhibitors on factor replacement therapy presenting with joint hemorrhage and persistent pain, arthrocentesis is recommended only if there is a tense, painful hemarthrosis or suspicion of infection. Routine arthrocentesis is not advised. • Remark: In many healthcare settings, arthrocentesis is not common practice because of fear of introducing intra-articular infection.  (Consensus Based)

Recommendation 7.3.1: • In hemophilia patients presenting with suspected central nervous system bleeds or bleed-related symptoms, clotting factor replacement therapy should be administered immediately before investigations are performed.  (Consensus Based)

Recommendation 7.3.2: • In patients with hemophilia presenting with suspected central nervous system bleeding that could be life-threatening, clotting factor replacement therapy should be administered immediately before investigations are performed and continued until the bleed resolves. • Remark: In patients with hemophilia who have been treated for central nervous system bleeding, secondary prophylaxis is recommended to prevent bleed recurrence.  (Consensus Based)

Recommendation 7.4.1: • In hemophilia patients with throat and neck bleeding, clotting factor replacement therapy should be administered immediately and critical care evaluation sought.  (Consensus Based)

Recommendation 7.4.2: • In hemophilia patients with throat and neck bleeding, including injury of the tongue, clotting factor replacement therapy should continue until the bleeding symptoms have resolved.  (Consensus Based)

Recommendation 7.4.3: • In hemophilia patients with throat and neck bleeding and local infection, antifibrinolytics should be started to treat the bleed and antibiotics to treat the infection.  (Consensus Based)

Recommendation 7.5.1: • In hemophilia patients with gastrointestinal bleeding, factor levels should be raised immediately and the underlying etiology of the bleed identified and treated.  (Consensus Based)

Recommendation 7.5.2: • Hemophilia patients with gastrointestinal bleeding should be prescribed antifibrinolytics.  (Consensus Based)

Recommendation 7.5.3: • In hemophilia patients with gastrointestinal bleeding, endoscopic and radiologic imaging should be performed to identify all sites of bleeding.  (Consensus Based)

Recommendation 7.5.4: • In hemophilia patients with gastrointestinal bleeding, hemoglobin levels should be monitored regularly.  (Consensus Based)

Recommendation 7.6.1: • For hemophilia patients with urinary tract hemorrhage, the site of bleeding should be identified and clotting factor replacement therapy should be administered immediately.  (Consensus Based)

Recommendation 7.6.2: • Hemophilia patients with renal bleeding should be given adequate hydration and prescribed bed rest until bleeding stops.  (Consensus Based)

Recommendation 7.6.3: • In hemophilia patients with renal bleeding, antifibrinolytics should not be administered.  (Consensus Based)

Recommendation 7.6.4: • In hemophilia patients with renal bleeding, clotting factor replacement therapy should continue until the bleeding is resolved.  (Consensus Based)

Recommendation 7.7.1: • In hemophilia patients with ophthalmic bleeding, clotting factor levels should be raised immediately and the patient evaluated by an ophthalmologist.  (Consensus Based)

Recommendation 7.7.2: • In hemophilia patients with ophthalmic bleeding, regular physical examination should be carried out every 6-8 hours for the duration of the ophthalmic bleed. • Remark: Imaging may be included as clinically indicated..  (Consensus Based)

Recommendation 7.7.3: • In hemophilia patients with ophthalmic bleeding, treatment and monitoring should be continued until the bleeding is resolved.  (Consensus Based)

Recommendation 7.8.1: • In hemophilia patients with oral bleeding, the site of bleeding should be identified and direct pressure and/or sutures applied, if possible.  (Consensus Based)

Recommendation 7.8.2: • In hemophilia patients with oral bleeding, antifibrinolytics should be prescribed and administered at appropriate dosages.  (Consensus Based)

Recommendation 7.8.3: • In hemophilia patients with persistent oral bleeding, clotting factor replacement therapy should be administered along with local measures such as sutures and topical adrenaline application to stop the bleeding.  (Consensus Based)

Recommendation 7.9.1: • In hemophilia patients with epistaxis, the head should be elevated and cold compression applied to the Little's area of the nose.  (Consensus Based)

Recommendation 7.9.2: • In hemophilia patients with epistaxis, nasal packing should be avoided as it can cause bleeding when removed. However, in practice, nasal packing is used extensively.  (Consensus Based)

Recommendation 7.9.3: • In hemophilia patients with epistaxis, gauze soaked in an antifibrinolytic agent may be used in addition to clotting factor replacement therapy.  (Consensus Based)

Recommendation 7.9.4: • In hemophilia patients with persistent epistaxis, vital signs and hemoglobin levels should be monitored until the bleeding stops (usually within 24-48 hours).  (Consensus Based)

Recommendation 7.9.5: • In hemophilia patients with recurrent epistaxis, the underlying pathology should be identified immediately and treated. Decongestants and antihistamines should help if bleeding is related to allergy, and antibiotics should be administered if bleeding is related to infection.  (Consensus Based)

Recommendation 7.10.1: • In hemophilia patients with lacerations and abrasions, clotting factor replacement therapy should be administered and the wound sutured immediately, if appropriate, in consultation with appropriate surgeons.  (Consensus Based)
6731

Inhibitors to Clotting Factor

Recommendation 8.2.1: • For patients with newly diagnosed hemophilia A, the WFH recommends regular inhibitor screening at least every 6-12 months, and then annually. • Remark: In general, more frequent screening should be considered for recurrent bleeds or target joints that occur despite standard factor replacement. • Remark: This recommendation places greater value on early inhibitor diagnosis in patients with severe hemophilia and late diagnosis in adulthood in patients with less severe disease, such as after intensive exposure to clotting factor concentrate, for example after surgery. • Remark: The requirement for frequent blood draws was considered in relationship to the potential morbidity of uncontrolled or life-threatening bleeds.  (Consensus Based)

Recommendation 8.2.2: • For patients with hemophilia A who receive clotting factor concentrate for more than 5 consecutive days, the WFH suggests inhibitor screening within 4 weeks of the last infusion.  (Consensus Based)

Recommendation 8.2.3: • For patients with hemophilia A who have poor or no response to adequate clotting factor replacement therapy, or who have lower than expected factor recovery or half-life, the WFH suggests inhibitor screening.  (Consensus Based)

Recommendation 8.2.4: • For patients with hemophilia A who undergo surgery, the WFH suggests inhibitor screening preoperatively in order to determine if an inhibitor is present which, if present, may require non-FVIII-containing therapy.  (Consensus Based)

Recommendation 8.2.5: • For patients with newly diagnosed hemophilia B, the WFH recommends regular inhibitor screening at least every 6-12 months, and then annually. • Remark: In general, more frequent inhibitor screening should be considered when recurrent bleeds or target joints occur despite adequate factor replacement. • Remark: Because inhibitor incidence is much lower in hemophilia B than in hemophilia A, experience and evidence are limited. • Remark: This recommendation places greater value on early inhibitor diagnosis to avoid uncontrolled bleeds and bleeding complications. The requirement for frequent blood draws was considered in relationship to the potential morbidity of uncontrolled or life-threatening bleeds.  (Consensus Based)

Recommendation 8.2.6: • For patients with hemophilia B who are treated with clotting factor concentrate for more than 5 consecutive days, the WFH suggests inhibitor screening within 4 weeks of the last infusion.  (Consensus Based)

Recommendation 8.2.7: • For patients with hemophilia B who fail to respond to adequate clotting factor replacement therapy or who have lower than expected factor recovery or half-life, the WFH suggests inhibitor screening.  (Consensus Based)

Recommendation 8.2.8: • For patients with hemophilia B who develop an allergic reaction to FIX therapy, including anaphylaxis or nephrotic syndrome, the WFH suggests inhibitor screening to determine if an inhibitor is present.  (Consensus Based)

Recommendation 8.2.9: • For patients with severe hemophilia B who undergo major surgery, the WFH suggests preoperative inhibitor screening.  (Consensus Based)

Recommendation 8.3.1: • For patients with hemophilia A and FVIII inhibitors who develop an acute bleed, the WFH recommends that treatment be based on whether the inhibitor is low-responding or high-responding.  (Consensus Based)

Recommendation 8.3.2: • For patients with hemophilia A and inhibitors who have acute bleeds, the WFH recommends FVIII concentrate for those with low-responding inhibitors, and a bypassing agent (recombinant factor VIIa [rFVIIa] or activated prothrombin complex concentrate [aPCC]) for those with high-responding inhibitors. • Remark: In those receiving non-factor therapy for prophylaxis (e.g., emicizumab), the WFH prefers rFVIIa over aPCC because of the risk of thrombotic microangiopathy when aPCC is used with emicizumab. • Remark: In patients receiving emicizumab who receive FVIII concentrate, the WFH recommends bovine reagent chromogenic FVIII assays (bovine FX in kit reagent) to measure plasma FVIII:C activity and inhibitor titer levels. • Remark: Caution is urged when rFVIIa is used in patients receiving emicizumab who have risk factors for thrombosis (e.g., past venous thromboembolism, obesity, smoking, chronic infection, inflammation) due to the risk of acute non-ST segment elevation myocardial infarction (non-STEMI) and pulmonary embolism.  (Consensus Based)

Recommendation 8.3.3: • For patients with hemophilia A and low-responding inhibitors who develop an acute bleed, the WFH recommends a FVIII-containing product or, if the hemostatic response is poor, the WFH recommends rFVIIa or aPCC. For those receiving emicizumab prophylaxis who develop an acute bleed, the WFH prefers rFVIIa over aPCC to avoid the risk of thrombotic microangiopathy. • Remark: Caution is urged when rFVIIa is used in patients receiving emicizumab who have risk factors for thrombosis (e.g., past venous thromboembolism, obesity, smoking, chronic infection, inflammation) due to the risk of acute non-STEMI and pulmonary embolism. • Remark: The WFH recommends bovine reagent-based chromogenic FVIII assays (bovine FX in kit reagent) to measure plasma FVIII:C activity and inhibitor titer levels.  (Consensus Based)

Recommendation 8.3.4: • For patients with hemophilia A and high-responding FVIII inhibitors receiving emicizumab who develop an acute bleed, the WFH prefers rFVIIa over aPCC to avoid the risk of thrombotic microangiopathy. • Remark: Caution is urged when rFVIIa is used in patients receiving emicizumab who have risk factors for thrombosis (e.g., past venous thromboembolism, obesity, smoking, chronic infection, inflammation) due to the risk of arterial thromboembolism, e.g., acute non-STEMI and pulmonary embolism. • Remark: The WFH recommends bovine reagent-based chromogenic FVIII assays (bovine FX in kit reagent) to measure plasma FVIII:C activity and inhibitor titer levels.  (Consensus Based)

Recommendation 8.3.5: • For patients with hemophilia A and inhibitors who receive emicizumab, the WFH recommends bovine chromogenic assays (bovine FX in kit reagent) to monitor inhibitor levels.  (Consensus Based)

Recommendation 8.3.6: • For patients with hemophilia A and inhibitors receiving emicizumab, the WFH recommends close clinical monitoring for thrombosis, adverse reactions, and thrombotic microangiopathy. • Remark: Caution is urged when rFVIIa is used in patients receiving emicizumab who have risk factors for thrombosis (e.g., past venous thromboembolism, obesity, smoking, chronic infection, inflammation) due to the risk of acute non-STEMI and pulmonary embolism.  (Consensus Based)

Recommendation 8.3.7: • As emicizumab is used to prevent, but not treat, acute bleeds in patients with hemophilia A and inhibitors, the WFH recommends clotting factor replacement therapy for acute bleeds.  (Consensus Based)

Recommendation 8.3.8: • For patients with hemophilia A and inhibitors receiving emicizumab who have an acute bleed, the WFH recommends clotting factor replacement therapy including FVIII for those with low-responding inhibitors; the WFH prefers rFVIIa over aPCC for those with high-responding FVIII inhibitors due to the risk of thrombotic microangiopathy. • Remark: Caution is urged when rFVIIa is used in patients receiving emicizumab who have risk factors for thrombosis (e.g., past venous thromboembolism, obesity, smoking, chronic infection, inflammation) due to the risk of acute non-STEMI and pulmonary embolism.  (Consensus Based)

Recommendation 8.3.9: • For patients with hemophilia A and inhibitors receiving emicizumab who have an acute bleed, the WFH prefers rFVIIa over aPCC, because of the risk of thrombotic microangiopathy. • Remark: The WFH suggests following black box warnings for emicizumab and maintaining vigilance as new evidence develops. • Remark: Caution is urged when rFVIIa is used in patients receiving emicizumab who have risk factors for thrombosis (e.g., past venous thromboembolism, obesity, smoking, chronic infection, inflammation) due to the risk of acute non-STEMI and pulmonary embolism. Thrombotic risks may last for up to 6 months during which plasma levels of emicizumab may persist.  (Consensus Based)

Recommendation 8.3.10: • For patients with hemophilia A and low-responding FVIII inhibitors who undergo surgery or an invasive procedure, the WFH suggests higher, more frequent FVIII product dosing than usual due to the short half-life of FVIII. • Remark: The WFH also recognizes adjusted-dose FVIII continuous infusion as an option.  (Consensus Based)

Recommendation 8.3.11: • For patients with hemophilia A and high-responding FVIII inhibitors who undergo surgery or an invasive procedure, the WFH recommends bypass agent therapy (rFVIIa or aPCC) at the discretion of the clinician. If single-agent bypass fails, sequential bypass agent treatment, i.e., rFVIIa alternating with aPCC, is another therapeutic approach. The WFH also recommends close clinical monitoring for thrombosis.  (Consensus Based)

Recommendation 8.3.12: • For patients with hemophilia A and inhibitors receiving emicizumab who undergo major surgery or an invasive procedure, the WFH recommends a FVIII-containing product for those with low-responding inhibitors. The WFH prefers rFVIIa over aPCC for those with high-responding inhibitors due to the risk of thrombotic microangiopathy. The WFH makes no recommendations on specific dose, frequency, or duration as there are insufficient data. • Remark: Caution is urged when rFVIIa is used in patients receiving emicizumab who have risk factors for thrombosis (e.g., past venous thromboembolism, obesity, smoking, chronic infection, inflammation) due to the risk of acute non-STEMI and pulmonary embolism.  (Consensus Based)

Recommendation 8.3.13: • For patients with hemophilia A and inhibitors receiving emicizumab who undergo minor surgery or an invasive procedure, the WFH recommends either low-dose or no clotting factor replacement therapy. • Remark: Caution is urged when rFVIIa is used in patients receiving emicizumab who have risk factors for thrombosis (e.g., past venous thromboembolism, obesity, smoking, chronic infection, inflammation) due to the risk of acute non-STEMI and pulmonary embolism.  (Consensus Based)

Recommendation 8.3.14: • For patients with hemophilia A and inhibitors receiving emicizumab who undergo major surgery or an invasive procedure, the WFH recommends close clinical monitoring for thrombosis, consumptive coagulopathy, or thrombotic microangiopathy.  (Consensus Based)

Recommendation 8.3.15: • For patients with hemophilia A and inhibitors who use bypass agent therapy, the WFH recommends clinical monitoring and consideration for laboratory monitoring with thrombin generation and other coagulation tests, but more data are needed to recommend the latter.  (Consensus Based)

Recommendation 8.3.16: • For patients with hemophilia A who develop persistent low-responding inhibitors, the WFH suggests that immune tolerance induction (ITI) be considered.  (Consensus Based)

Recommendation 8.3.17: • For patients with hemophilia A and persistent inhibitors who fail immune tolerance induction (ITI) or never underwent ITI, the WFH recommends emicizumab prophylaxis over bypass agent prophylaxis (rFVIIa or aPCC), as emicizumab is more effective in bleed prevention and simpler to administer, as it is given weekly and subcutaneously.  (Consensus Based)

Recommendation 8.3.18: • For patients with hemophilia A who switch to another type or brand of factor product, the WFH has no preference for the choice of specific type of therapy, as current evidence indicates product switching does not increase risk of inhibitor development. • Remark: The WFH encourages product choice based on potential advantages, such as simpler administration, safety, efficacy, and personal preferences. • Remark: The WFH supports prospective data collection on inhibitor formation by product, particularly before and after switching products.  (Consensus Based)

Recommendation 8.3.19: • For patients with severe hemophilia A and inhibitors, the WFH recommends emicizumab over bypass agent prophylaxis to reduce bleeding episodes, as emicizumab appears to be superior to bypass prophylaxis.  (Consensus Based)

Recommendation 8.4.1: • For patients with hemophilia B who develop anaphylaxis to FIX therapy, the WFH recommends screening for an inhibitor to FIX, as an allergic reaction may be the first sign of inhibitor development.  (Consensus Based)

Recommendation 8.4.2: • For patients with hemophilia B and a family history of inhibitors or risk factors for inhibitor development, the WFH recommends monitoring initial infusions in a clinic or hospital setting capable of managing severe allergic reactions.  (Consensus Based)

Recommendation 8.4.3: • For patients with hemophilia B who develop anaphylaxis to FIX therapy, the WFH recommends screening for nephrotic syndrome, as it is more common in FIX inhibitor patients with allergic reactions to FIX.  (Consensus Based)

Recommendation 8.4.4: • For patients with hemophilia B and inhibitors and an allergic reaction/anaphylaxis to FIX therapy, the WFH recommends rFVIIa to treat acute bleeds but is against use of aPCC as it contains FIX and may cause or worsen an allergic reaction. • Remark: For patients with hemophilia B and inhibitors and allergic reaction to FIX therapy, the WFH indicates there are insufficient data to recommend desensitization by small, repeated doses of FIX, intravenously or subcutaneously, and recognizes that in some, this approach may worsen an allergic reaction or cause anaphylaxis. If undertaken, FIX desensitization should be performed with caution and under close supervision by experts only.  (Consensus Based)

Recommendation 8.4.5: • For patients with hemophilia B and inhibitors who develop anaphylaxis to FIX therapy, the WFH recommends bypass therapy with rFVIIa over aPCC, as aPCC contains FIX and may cause or worsen an allergic reaction.  (Consensus Based)

Recommendation 8.4.6: • For patients with hemophilia B and inhibitors who develop an acute bleed, the WFH recommends treatment based on whether the inhibitor is low-responding or high-responding and whether there is a history of allergic reactions.  (Consensus Based)

Recommendation 8.4.7: • For patients with hemophilia B and low-responding FIX inhibitors, the WFH recommends use of a FIX-containing product to treat acute bleeds, as long as there is no allergic reaction to FIX.  (Consensus Based)

Recommendation 8.4.8: • For patients with hemophilia B and high-responding FIX inhibitors, the WFH prefers rFVIIa over aPCC to treat acute bleeds, as aPCC contains FIX and may cause or worsen an allergic reaction.  (Consensus Based)

Recommendation 8.4.9: • For patients with hemophilia B and inhibitors who use bypass agent therapy, the WFH recommends clinical monitoring and consideration for laboratory monitoring with thrombin generation and other coagulation tests, although more data are needed to recommend the latter.  (Consensus Based)

Recommendation 8.4.10: • For patients with hemophilia B and inhibitors, the WFH is unable to make a recommendation on the use of immune tolerance induction, as experience with ITI in hemophilia B is limited. • Remark: In patients with hemophilia B and inhibitors in whom ITI is attempted, high-dose factor replacement protocols should be followed similar to what is recommended for hemophilia A, with strong consideration for the use of immunosuppression. It should be noted the risk of nephrotic syndrome may increase with high-dose ITI.  (Consensus Based)

Recommendation 8.4.11: • For patients with hemophilia B and low-responding FIX inhibitors who undergo surgery, the WFH has no preference for type of FIX products, but recommends more frequent dosing due to the short FIX half-life.  (Consensus Based)

Recommendation 8.4.12: • For patients with hemophilia B and FIX inhibitors who undergo surgery, the WFH recommends rFVIIa over aPCC, as aPCC contains FIX and may cause or worsen an allergic reaction.  (Consensus Based)

Recommendation 8.4.13: • For patients with hemophilia B and inhibitors and an allergic reaction to FIX who undergo surgery, the WFH prefers rFVIIa over aPCC as aPCC contains FIX and may cause or worsen an allergic reaction.  (Consensus Based)

Recommendation 8.4.14: • For patients with hemophilia B and inhibitors who undergo surgery or an invasive procedure, the WFH recommends close clinical monitoring for thrombosis or consumptive coagulopathy.  (Consensus Based)

Recommendation 8.4.15: • For patients with hemophilia B who switch to another type or brand of factor product, the WFH has no preference in the choice of specific type of therapy, as current evidence indicates product switching does not increase the risk of inhibitor development, but rigorous controlled trials are lacking.  (Consensus Based)
6731

Specific Management Issues

Recommendation 9.2.1: • Carriers of hemophilia, irrespective of factor level, should be registered at a hemophilia treatment centre. 

Recommendation 9.2.2: • Carriers of hemophilia with low factor levels should be treated and managed the same as males with hemophilia.  (Consensus Based)

Recommendation 9.2.3: • All potential and obligate carriers of hemophilia should have their FVIII/FIX levels measured to establish their baseline levels prior to major procedures, surgery, or pregnancy.  (Consensus Based)

Recommendation 9.2.4: • Carriers of hemophilia should be offered counselling that includes reproductive implications and choices.  (Consensus Based)

Recommendation 9.2.5: • Pregnant carriers of hemophilia should have their FVIII/FIX levels assayed in the third trimester of pregnancy to assess their bleeding risk during delivery and in the postpartum period.  (Consensus Based)

Recommendation 9.2.6: • For pregnant carriers of hemophilia, delivery should be in a hospital with access to hemophilia specialists where complications during labour and delivery can be dealt with promptly to maintain the safety of mother and child.  (Consensus Based)

Recommendation 9.2.7: • For pregnant carriers of hemophilia, the WFH recommends against instrumental delivery.  (Consensus Based)

Recommendation 9.2.8: • Carriers of hemophilia should be monitored for both primary and secondary postpartum hemorrhage, which should be treated with appropriate hemostatic measures.  (Consensus Based)

Recommendation 9.2.9: • Male babies born to known or potential carriers of hemophilia should have cord blood testing of activated partial thromboplastin time (APTT) or factor levels.  (Consensus Based)

Recommendation 9.3.1: • In patients with hemophilia, the circumcision procedure should be performed electively by an experienced surgeon and hematology team in a resourced hematology treatment centre with access to clotting factor concentrates.  (Consensus Based)

Recommendation 9.3.2: • In patients with hemophilia, the plasma factor level should be raised to 80-100 IU/dL just prior to the procedure.  (Consensus Based)

Recommendation 9.3.3: • In patients with hemophilia undergoing circumcision, intraoperative care should be taken to cauterize all bleeding vessels.  (Consensus Based)
Recommendation 9.3.4: • For patients with hemophilia undergoing circumcision, the WFH suggests use of topical fibrin sealant as an adjunctive therapy, using a product manufactured with robust viral reduction/inactivation processes if available, to minimize the risk of bloodborne pathogen transmission.  (Consensus Based)

Recommendation 9.3.5 • For patients with hemophilia undergoing circumcision, the WFH recommends adjusting clotting factor replacement to the clinical course of the procedure. If continued clotting factor replacement is required, the goal would be to maintain factor levels above 50 IU/dL for the first 3 days, and above 30 IU/dL for the subsequent 4-8 days.  (Consensus Based)

Recommendation 9.3.6: • In patients with hemophilia post-circumcision, inhibitor measurement should be repeated if there is intractable bleeding that is poorly responsive to replacement therapy and local hemostatic measures.  (Consensus Based)

Recommendation 9.3.7: • In patients with hemophilia post-circumcision, non-dissolvable stitches (if used) should be removed 10-14 days postsurgery; the inevitable bleeding should be managed with clotting factor replacement.  (Consensus Based)

Recommendation 9.3.8: • In hemophilia patients with intractable bleeding post-circumcision, all angles should be considered, including blood vessel bleeding, clotting factor deficiency, and platelet abnormalities.  (Consensus Based)

Recommendation 9.3.9: • In hemophilia patients with intractable bleeding post-circumcision, adjunct and supportive therapy should be used; this includes transfusion and local hemostatic measures, such as the application of topical agents.  (Consensus Based)

Recommendation 9.4.1: • Children and adults with hemophilia should be administered the same routine vaccines as the general population; however, they should preferably receive the vaccines subcutaneously rather than intramuscularly or intradermally, as it is as safe and effective as the latter and does not require clotting factor infusion. • Remark: If intramuscular injection must be the route of administration, a dose of clotting factor concentrate should be given, and the smallest gauge needle available (25-27 gauge) should be used. • Remark: Additionally, an ice pack should be applied to the injection site for 5 minutes before injection of the vaccine, and pressure should be applied to the site for at least 10 minutes to reduce bleeding and swelling.  (Consensus Based)

Recommendation 9.4.2: • In children and adults with hemophilia and human immunodeficiency virus (HIV) infection, the WFH recommends standard immunizations, including pneumococcal and influenza vaccines and hepatitis A and B immunization.  (Consensus Based)

Recommendation 9.4.3: • In children and adults with hemophilia and HIV infection, the WFH recommends that live virus vaccines (such as chickenpox, yellow fever, rotavirus, oral polio, and combined measles, mumps, and rubella [MMR] vaccines) should be avoided.  (Consensus Based)

Recommendation 9.5.1: • Patients with hemophilia A and B should have ready access to and be evaluated for acute and elective surgical procedures that could enhance their well-being or quality of life.  (Consensus Based)

Recommendation 9.5.2: • The WFH recommends patients with hemophilia requiring surgery should be managed at or in consultation with a comprehensive hemophilia treatment centre.  (Consensus Based)

Recommendation 9.5.3: • For patients with hemophilia requiring surgery, sufficient quantities of clotting factor concentrates must be available for the surgery itself and to maintain adequate coverage postoperatively for the duration required for recovery and/or rehabilitation.  (Consensus Based)

Recommendation 9.5.4: • The WFH recommends centres providing surgery for patients with hemophilia should have adequate laboratory support for reliable monitoring of clotting factor levels in the perioperative period.  (Consensus Based)

Recommendation 9.5.5: • For patients with mild hemophilia A undergoing surgery, the WFH recommends the use of DDAVP for hemostasis if the patient shows good therapeutic response to DDAVP in pre-surgery testing. • Remark: DDAVP is not recommended for surgical hemostasis in those patients with mild hemophilia A in whom the response to DDAVP (increase of plasma FVIII activity levels) is unsatisfactory or in whom DDAVP is contraindicated (e.g., in those with significant cardiovascular disease). • Remark: Due to the risk of tachyphylaxis, DDAVP should not be given for more than 3-5 days unless the patient can be monitored closely and switched to clotting factor concentrate if this occurs. Therefore, if the anticipated treatment duration will be longer than 3-5 days (e.g., after major surgery), providers may choose to avoid the use of DDAVP from the outset. • Remark: DDAVP is the first choice for patients with mild hemophilia A to avoid the cost of CFCs and exposure to FVIII concentrates and the potential risk of inhibitor development, which increases with the number of exposures. • Remark: Given the need for close monitoring, an experienced hematology team should manage these patients.  (Consensus Based)

Recommendation 9.5.6: • For patients with hemophilia undergoing surgery, antifibrinolytics and topical hemostatic agents should be considered if ancillary therapies are required beyond factor replacement.  (Consensus Based)

Recommendation 9.5.7: • Pre- and postoperative assessment of all patients with hemophilia A and B should include inhibitor screening and inhibitor assay.  (Consensus Based)

Recommendation 9.5.8: • For patients with hemophilia undergoing surgery, the WFH advises against neuraxial anesthesia. If neuraxial anesthesia is required, it should be performed only under adequate clotting factor coverage as the safety of neuraxial procedures has not been established in patients with hemophilia. • Remark: It is recognized that in some centres, neuraxial anesthesia is acceptable after restoring hemostasis in patients with hemophilia, whereas in other centres this procedure is discouraged and general anesthesia is preferred.  (Consensus Based)

Recommendation 9.5.9: • Patients with mild hemophilia A and all patients with hemophilia receiving intensive factor replacement for the first time are at particular risk of inhibitor development, and therefore should be rescreened for inhibitor presence 4-12 weeks postoperatively.  (Consensus Based)

Recommendation 9.5.10: • In surgical patients with hemophilia B requiring intensive replacement therapy, the WFH recommends against use of prothrombin complex concentrate (PCC) due to risk of accumulation of clotting factors II, VII, and X, which can be associated with higher risk of thrombotic complications.  (Consensus Based)

Recommendation 9.5.11: • The WFH recommends replacement therapy for a duration of at least 3 days for minor surgical procedures, and at least 7-10 days for major surgical procedures.  (Consensus Based)

Recommendation 9.5.12: • For patients with hemophilia A and B undergoing major surgery, the WFH recommends against routine use of pharmacologic thromboprophylaxis.  (Consensus Based)

Recommendation 9.6.1: • Adult patients with hemophilia should be assessed for sexual health issues as part of routine care to address possible impacts related to age, joint bleeding, joint pain and stiffness, and muscle bleeding (e.g., iliopsoas), which can sometimes arise during sexual activity.  (Consensus Based)

Recommendation 9.6.2: • For patients with hemophilia with comorbidities who may experience complications of hemophilia accompanied by sexual dysfunction, the WFH recommends that healthcare providers at hemophilia treatment centres provide a multipronged psychosocial approach that includes communicating openly about sexual activity and quality of life in a consistent and comprehensive manner.  (Consensus Based)

Recommendation 9.7.1: • For patients with severe hemophilia, the WFH recommends the provision of psychological and social support as part of comprehensive hemophilia care, with enlistment of assistance from local healthcare organizations wherever psychologists or social workers are unavailable.  (Consensus Based)

Recommendation 9.7.2: • For patients with hemophilia, the WFH recommends that hemophilia treatment centres assist patients and families in forming and joining support groups or networks, and encourage participation in their patient organizations.  (Consensus Based)

Recommendation 9.7.3: • For patients with hemophilia, the WFH recommends appropriate programming at hemophilia treatment centres and patient organizations to assist in successful aging through assessment of their developmental progression, assessment and prevention of comorbidities and functional impairments, assessment of cognitive and emotional function, identification of depression and referral for treatment, and reinforcement of social connectedness.  (Consensus Based)

Recommendation 9.8.1: • In patients with hemophilia, the WFH recommends age-appropriate cancer screening.  (Consensus Based)

Recommendation 9.8.2: • For diagnosis and treatment of malignancy in patients with hemophilia, the WFH recommends the provision of adequate factor replacement as necessary to minimize bleeding risk.  (Consensus Based)

Recommendation 9.8.3: • In patients with hemophilia, if chemotherapy or radiotherapy is accompanied by severe long-lasting thrombocytopenia, the WFH recommends continuous prophylactic replacement therapy.  (Consensus Based)

Recommendation 9.8.4: • Antineoplastic treatments for patients with hemophilia diagnosed with cancer should be the same as recommended for the general population.  (Consensus Based)

Recommendation 9.8.5: • For hemophilia patients without inhibitors diagnosed with cancer, the WFH advises that venous thromboembolism prophylaxis management decisions should be based on evaluation of the individual patient's bleeding and thrombotic risk. If used in patients receiving factor concentrates, it must be carefully managed to maintain factor levels below the risk range for VTE. • Remark: If pharmacologic thromboprophylaxis for hemophilia patients without inhibitors diagnosed with cancer is used, it should mimic what is recommended for the general population, provided that appropriate factor replacement therapy is administered, taking into account that factor replacement to high factor levels above normal is a potential risk factor for VTE.  (Consensus Based)

Recommendation 9.8.6: • Patients with hemophilia and non-valvular atrial fibrillation should be treated by medical teams composed of experienced hematologists and cardiologists.  (Consensus Based)

Recommendation 9.8.7: • For patients with severe or moderate hemophilia and atrial fibrillation, the WFH recommends clinical management based on basal FVIII/FIX levels and stroke risk by weighing the patient's stroke risk as calculated by the CHA2DS2-VASc score against an estimated bleeding risk occurring as a consequence of anticoagulation therapy, and withholding anticoagulation if stroke risk is deemed to be lower than bleeding risk.  (Consensus Based)

Recommendation 9.8.8: • For patients with hemophilia and atrial fibrillation at high risk of bleeding and thromboembolism, the WFH recommends left atrial appendage occlusion, particularly if long-term replacement therapy with deficient clotting factor is not feasible. • Remark: Left atrial appendage occlusion for patients with hemophilia and atrial fibrillation should be preceded by assessments of the individual's risk of bleeding and thromboembolism and implemented under the advisement of a cardiologist.  (Consensus Based)

Recommendation 9.8.9: • For patients with hemophilia in whom the risk of non-valvular atrial fibrillation-associated stroke is high or outweighs the risk of bleeding complications, the WFH recommends careful consideration of the use of anticoagulants. • Remark: The choice between direct oral anticoagulants and vitamin K antagonists depends on the local protocols, availability of antidotes for reversal of anticoagulant activity, and feasibility of maintaining adequate trough levels of the deficient clotting factor. • Remark: Despite the scarcity of evidence-based data for this indication in patients with hemophilia, most experts suggest maintaining trough levels of the deficient clotting factor in the individual patient at ≥15-30 IU/dL while on anticoagulant therapy for atrial fibrillation. • Remark: Because treatment responses to DOACs and VKAs may vary, decisions on anticoagulant therapy should be based on the individual patient in consultation with a cardiologist.  (Consensus Based)

Recommendation 9.8.10: • In hemophilia patients with inhibitors, antithrombotic therapy is generally contraindicated.  (Consensus Based)

Recommendation 9.8.11: • In patients with hemophilia undergoing surgical procedures who carry a high risk of developing venous thromboembolism (e.g., in cases of major orthopedic surgery, major abdominal surgery for cancer, or long post-surgery immobilization), the WFH recommends an assessment of individual risk of VTE.  (Consensus Based)

Recommendation 9.8.12: • For patients with hemophilia undergoing surgery associated with a high risk of venous thromboembolism and bleeding complications, the WFH recommends consideration of the use of mechanical methods for thromboprophylaxis. • Remark: In contrast to pharmacological thromboprophylaxis, mechanical methods of thromboprophylaxis are not associated with the risk of bleeding complications.  (Consensus Based)

Recommendation 9.8.13: • For patients with hemophilia in whom the balance of the risk of bleeding compared to the risk of developing venous thromboembolism favours pharmacological thromboprophylaxis, the WFH recommends the same practice as that applied in the general population, provided that adequate replacement therapy is administered. • Remark: Decisions on anticoagulant therapy in a patient with hemophilia should always be preceded by assessments of the individual's bleeding and thrombotic risk. In some patients with hemophilia, the risk of uncontrolled bleeding may outweigh the benefit of anticoagulation.  (Consensus Based)

Recommendation 9.8.14: • For patients with hemophilia without inhibitors, the WFH recommends the use of prophylactic doses of anticoagulants only after ensuring hemostatic control with adequate replacement therapy. • Remark: If the risk of uncontrolled bleeding outweighs the benefit of anticoagulation, anticoagulants should not be used. • Remark: This recommendation does not apply to patients with hemophilia and inhibitors in whom anticoagulants are generally contraindicated.  (Consensus Based)

Recommendation 9.8.15: • In hemophilia patients without inhibitors who experience an acute episode of venous thromboembolism, the WFH recommends the use of high-intensity anticoagulation for the minimal duration and under clotting factor replacement protection and close clinical and laboratory monitoring. • Remark: This recommendation does not apply to hemophilia patients with inhibitors in whom anticoagulants are generally contraindicated.  (Consensus Based)

Recommendation 9.8.16: • Patients with hemophilia should have regular height and weight measurements to monitor body mass index.  (Consensus Based)

Recommendation 9.8.17: • Patients with hemophilia who are overweight or obese should be referred for dietary advice and/or weight management.  (Consensus Based)

Recommendation 9.8.18: • Patients with hemophilia who are obese should have FVIII/FIX replacement therapy based on lean body weight after individual pharmacokinetic assessments.  (Consensus Based)

Recommendation 9.8.19: • Patients with hemophilia should have the same screening for diabetes as the general population.  (Consensus Based)

Recommendation 9.8.20: • Patients with hemophilia and diabetes should have the same management strategies to control their diabetes as the general population; if treatment with insulin is indicated, subcutaneous injections can be administered without bleeding and without the need for factor replacement.  (Consensus Based)

Recommendation 9.8.21: • All patients with hemophilia should be encouraged to engage in regular physical activity and to have adequate calcium and vitamin D intake. • Remark: Hemophilia patients with musculoskeletal conditions and injuries should have physical therapy and rehabilitation supervised by a physical therapist with hemophilia experience.  (Consensus Based)

Recommendation 9.8.22: • Hemophilia patients with osteoporosis, fragility fractures, or who are at increased fracture risk should be treated with individually adjusted anti-osteoporotic medications.  (Consensus Based)

Recommendation 9.9.1: • The WFH recommends that aging patients with hemophilia be granted the same access to health education and preventive strategies to reduce the risks or impacts of age-related morbidities as the general population.  (Consensus Based)

Recommendation 9.9.2: • The WFH recommends the hemophilia team should be closely involved in managing aspects and complications of care related to aging and ensure close consultation and agreement on treatment plans.  (Consensus Based)

Recommendation 9.9.3: • For all patients with hemophilia, the WFH recommends regular blood pressure measurements as part of their standard care. • Remark: This recommendation is based on data indicating a higher prevalence of arterial hypertension among patients with hemophilia irrespective of age as compared with males in the general population.  (Consensus Based)

Recommendation 9.9.4: • For patients with hemophilia, the WFH recommends the same management of arterial hypertension as that applied in the general population. • Remark: Patients with hemophilia diagnosed with hypertension may be treated in a hemophilia treatment centre or referred to primary care providers depending on the local healthcare system and practices.  (Consensus Based)

Recommendation 9.9.5: • Patients with hemophilia should receive the same screening and management for individual cardiovascular disease risk factors as the general population.  (Consensus Based)

Recommendation 9.9.6: • Patients with hemophilia and cardiovascular disease should receive routine care adapted to their individual situation in consultation with a cardiologist.  (Consensus Based)

Recommendation 9.9.7: • For patients with hemophilia without inhibitors who have been diagnosed with cardiovascular disease, the WFH recommends similar management as that applied to the general population, except for the necessary additional correction of impaired hemostasis with clotting factor concentrates. • Remark: Decisions on cardiovascular treatment strategy for patients with hemophilia should always be preceded by assessments of the individual's bleeding and thrombotic risks and cardiac disease severity and implemented under the advisement of a cardiologist.  (Consensus Based)

Recommendation 9.9.8: • Among patients with hemophilia and high-responding inhibitors, the WFH recommends limiting the use of antithrombotics to those patients in whom the risk of untreated thrombosis outweighs the risk of bleeding complications. • Remark: This recommendation is based on the observation that hemostatic response to bypassing agents is often unpredictable. • Remark: More research is needed to better understand the safety of antithrombotic therapy in patients treated with emicizumab.  (Consensus Based)

Recommendation 9.9.9: • Given the scarcity of published data on antiplatelet therapy in patients with hemophilia, the WFH recommends careful evaluation of an individual's bleeding and thrombotic risk. • Remark: It has been suggested that the trough level of the deficient clotting factor be maintained at ≥15-30 IU/dL during dual antiplatelet therapy and at ≥1-5 IU/dL during single-agent antiplatelet therapy; however, treatment strategy should be tailored to the individual. • Remark: The decision on use of antiplatelet therapy in a patient with hemophilia should always be made in consultation with a cardiologist.  (Consensus Based)

Recommendation 9.9.10: • Given the scarcity of published data on patients with hemophilia undergoing percutaneous coronary intervention, the WFH recommends careful evaluation of an individual's bleeding and thrombotic risk.  (Consensus Based)
• Remark: It has been suggested that in patients with hemophilia without inhibitors who are undergoing PCI, the deficient clotting factor be maintained at the peak level of 80-100 IU/dL for as long as therapeutic doses of antithrombotics are used; however, treatment strategy should be tailored to the individual. • Remark: The decision on use of antithrombotic therapy for this indication should always be made in consultation with a cardiologist.  (Consensus Based)

Recommendation 9.9.11: • Given the scarcity of published data on patients with hemophilia undergoing coronary artery bypass grafting, the WFH recommends careful evaluation of an individual's bleeding and thrombotic risk. • Remark: It has been suggested that in patients with hemophilia without inhibitors who are undergoing CABG, similarly to other major surgical procedures, the deficient clotting factor be maintained at the peak level of 80-100 IU/dL before, during, and after CABG until sufficient wound healing has taken place; however, treatment strategy should be tailored to the individual. • Remark: The decision on use of antithrombotic therapy for this indication should always be made in consultation with a cardiologist.  (Consensus Based)

Recommendation 9.9.12: • Given the scarcity of published data on patients with hemophilia and ST-elevation myocardial infarction in whom early percutaneous coronary intervention is not available, the WFH recommends careful evaluation of an individual's bleeding risk and cardiac disease severity. • Remark: Use of fibrinolytic therapy may only be considered after complete correction of hemostasis with deficient clotting factor replacement. • Remark: The decision on use of fibrinolytic therapy for this indication should always be made in consultation with a cardiologist.  (Consensus Based)

Recommendation 9.9.13: • When heart valve replacement is indicated in patients with hemophilia, a bioprosthetic valve should be the first choice to avoid the need for indefinite anticoagulation.  (Consensus Based)

Recommendation 9.9.14: • In patients with hemophilia, the management of hypercholesterolemia should be the same as for the general population.  (Consensus Based)

Recommendation 9.9.15: • As adults with hemophilia experience many personal and social changes with aging, the WFH recommends active psychosocial assessments and support for their changing needs.  (Consensus Based)
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Musculoskeletal Complications

Recommendation 10.2.1: >• For people with hemophilia, the WFH recommends regular physical assessment of the synovial condition after every bleed, preferably using suitable imaging techniques such as ultrasound (when feasible) until the situation is controlled, as clinical assessment alone is inadequate to detect early synovitis.  (Consensus Based)

Recommendation 10.2.2: • For patients with hemophilia who have chronic synovitis and no access to regular prophylaxis, the WFH recommends nonsurgical treatment, including short-term prophylaxis for 6-8 weeks to control bleeding; physical therapy to improve muscle strength and joint function; and selective COX-2 inhibitors to reduce pain and inflammation. • Remark: Physical therapy with individualized goals and exercises based on the patient's functional level should start slowly with increasing progression of weight-bearing activities. • Remark: For patients with acute pain and recurrent bleeding, bracing may stabilize the affected joint and limit motion, but caution is advised as prolonged immobilization leads to muscle weakness, so isometric exercises even within bracing are advised. • Remark: If unresponsive to nonsurgical interventions, treatment should be escalated to treat the synovitis directly, by the treatment intervention of the local expert.  (Consensus Based)

Recommendation 10.2.3: • For patients with hemophilia who have chronic synovitis (characterized only by minimal pain and loss of range of motion) the WFH recommends consultation with an experienced musculoskeletal specialist in a hemophilia treatment centre.  (Consensus Based)

Recommendation 10.2.4: • For patients with hemophilia who have unresolved chronic synovitis, the WFH recommends nonsurgical synovectomy as a first-line treatment option using radioisotope synovectomy with a pure beta emitter (phosphorus-32, yttrium-90, rhenium-186, or rhenium-188). One dose of CFC per dose of isotope should be used. • Remark: Choice of isotope depends on the joint being injected and isotope availability. • Remark: The joint should be immobilized for at least 24 hours, followed by progressive rehabilitation for restoration of strength and function. • Remark: When radioisotopes are not available, chemical synoviorthesis with either rifampicin or oxytetracycline chlorhydrate (once weekly injection for 5-6 weeks) is an alternative, accompanied by one dose of CFC per treatment, a local anesthetic, and oral analgesics.  (Consensus Based)

Recommendation 10.2.5: • For patients with hemophilia who have chronic synovitis that no longer responds to nonoperative interventions, the WFH recommends surgical synovectomy (preferably arthroscopic, not open) only by an experienced team in a hemophilia treatment centre.  (Consensus Based)

Recommendation 10.3.1: • For the prevention and treatment of chronic hemophilic arthropathy in people with hemophilia, the WFH recommends a combination of regular replacement therapy to reduce frequency of bleeding and physical therapy aimed at preserving muscle strength and functional ability. Physical therapy may be done with or without factor coverage, depending on availability and the patient's response to therapy.  (Consensus Based)

Recommendation 10.3.2: • For the prevention and treatment of the sequelae of joint arthropathy in people with hemophilia, the WFH recommends nonsurgical measures such as bracing, orthotics, mobility aids, and serial casting and traction devices to aid in the correction of flexion contractures. This may be done with or without factor coverage.  (Consensus Based)

Recommendation 10.3.3: • For patients with hemophilia with chronic hemophilic arthropathy for whom nonsurgical measures have failed to provide satisfactory pain relief and improved function, the WFH recommends consultation with an orthopedic specialist on surgical intervention options which may include: ◦ synovectomy and joint debridement; ◦ arthroscopy to release intra-articular adhesions and correct impingement; ◦ extra-articular soft tissue release to treat contractures; ◦ osteotomy to correct angular deformity;  arthrodesis (of the ankle); ◦ joint replacement in end-stage arthritis. • Remark: Adequate resources including a sufficient supply of CFCs or other appropriate hemostatic agents (e.g., bypassing agents for patients with inhibitors) and postoperative rehabilitation services must be available to increase the likelihood of success for any surgical procedure.  (Consensus Based)

Recommendation 10.4.1: • All hemophilia patients with muscle bleeds should be given clotting factor replacement therapy immediately and, where applicable, be observed for neurovascular complications associated with the bleed.  (Consensus Based)

Recommendation 10.4.2: • For all hemophilia patients with muscle bleeds, the WFH recommends detailed clinical assessment, grading, and monitoring of pain according to the WHO pain scale, as muscle bleed pain may be an early indicator of reversible neurovascular and tissue damage. • Remark: While many pain assessment scales exist, use of the WHO pain scale is preferred because it is a simple and universal tool that permits uniform measurement of pain in people with hemophilia and generates comparable population-level outcome data important to advancing hemophilia treatment and research.

Recommendation 10.4.3: • In hemophilia patients with muscle bleeds with evidence of compartment syndrome and neurovascular compromise, a fasciotomy is required within 12 hours from the time of onset of symptoms before irreversible damage sets in due to tissue necrosis.  (Consensus Based)

Recommendation 10.5.1: • For hemophilia patients with soft tissue bleeding and signs of a possible pseudotumour, the WFH recommends clinical assessment and radiological confirmation using X-ray, ultrasound, and magnetic resonance imaging, as appropriate. • Remark: While ultrasound is useful for serial assessment of a soft tissue pseudotumour, MRI provides more detailed information prior to surgical intervention. • Remark: A CT scan or CT angiogram may be indicated, especially for a large pseudotumour and/or pre-operative planning.  (Consensus Based)

Recommendation 10.5.2: • For patients with hemophilia who have developed small early pseudotumours (prior to acquiring a pseudocapsule) and have no access to regular prophylaxis, the WFH recommends a short course (6-8 weeks) of clotting factor replacement therapy with possible continuation of therapy if serial ultrasound evaluations indicate that the pseudotumour is shrinking, with repeat evaluation after 4-6 months.  (Consensus Based)

Recommendation 10.5.3: • For patients with hemophilia who have developed large pseudotumours, the WFH recommends surgical excision of the pseudotumour with the pseudocapsule, performed only by a surgical team with experience in hemophilia, in a hemophilia treatment centre wherever possible, followed by close monitoring and long-term prophylaxis to prevent recurrence of bleeding. • Remark: Fluctuations in factor levels during the first postoperative year may increase the likelihood of bleed recurrence. Therefore, close monitoring and optimal correction of factor levels are of paramount importance.  (Consensus Based)

Recommendation 10.6.1: • For people with hemophilia who incur fractures, the WFH recommends immediate treatment with clotting factor concentrates or other hemostatic agents, and continued treatment to maintain sufficiently high factor levels for bleed control for a week or longer, depending on the likelihood of bleeding due to fracture site or stability. Subsequently, lower factor levels may be maintained for 10-14 days to prevent soft tissue bleeding while the fracture becomes stabilized. Clinical monitoring is paramount due to the risk of compartment syndrome.  (Consensus Based)

Recommendation 10.6.2: • For people with hemophilia who incur fractures, the WFH recommends splints over full casts to avoid compartment syndrome (especially in the early stages), and external fixators for open or infected fractures.  (Consensus Based)

Recommendation 10.6.3: • For people with hemophilia who incur fractures, the WFH recommends avoiding prolonged immobilization and advises supervised physical therapy and rehabilitation as soon as the fracture is stabilized to restore range of motion, muscle strength, and function.  (Consensus Based)

Recommendation 10.7.1: • For patients with hemophilia requiring orthopedic surgery, especially in cases where oozing is present at closure as well as dead space or cavities, the WFH suggests the use of local coagulation enhancers and wound infiltration with local anesthetic agents (lignocaine/lidocaine and/or bupivacaine) with an adrenaline and fibrin sealant or spray to control blood oozing when operating in extensive surgical fields.  (Consensus Based)

Recommendation 10.7.2 • For patients with hemophilia requiring orthopedic surgery, the WFH recommends factor replacement therapy and close pain control and monitoring, with higher doses of analgesics in the immediate postoperative period.  (Consensus Based)

Recommendation 10.7.3: • For patients with hemophilia in the postoperative period following orthopedic surgery, the WFH recommends gradual rehabilitation by a physical therapist experienced in hemophilia management.  (Consensus Based)

Recommendation 10.8.1: • For patients with hemophilia, the WFH recommends joint replacement only in cases of established hemophilic arthropathy that is not responsive to nonsurgical or other surgical treatments, and that is accompanied by associated pain, functional impairment, and loss of participation in activities of daily living. • Remark: Perioperatively, tranexamic acid and fibrin sealants may be used to reduce blood loss. • Remark: Physical therapy should ideally start on the day of surgery with early mobilization and appropriately progressive exercises to regain motion and muscle strength.  (Consensus Based)

Recommendation 10.9.1: • For patients with hemophilia who have chronic musculoskeletal pain or functional limitations, the WFH recommends psychosocial interventions tailored to meet the specific needs of each individual based on their physical, emotional, social, educational, and cultural circumstances.  (Consensus Based)

Recommendation 10.9.2: • For patients with hemophilia who have chronic musculoskeletal pain or functional limitations, the WFH recommends specific individualized psychosocial assessments and intervention strategies aimed at achieving better quality of life, including psychosocial counselling, educational and employment counselling, and financial planning.  (Consensus Based)

Recommendation 10.9.3: • For patients with hemophilia who have chronic musculoskeletal pain or functional limitations, the WFH recommends the promotion of support networks, peer mentoring, and group educational opportunities to support their ability to cope with musculoskeletal complications, reduce social isolation, and strengthen resilience.  (Consensus Based)
6731

Outcome Assessment

Recommendation 11.2.1: • For providers of care for people with hemophilia, the WFH recommends ensuring that the frequency of all bleeds is documented in real time by patients/caregivers and reviewed together at least annually, with particular reference to intra-articular, intramuscular, and central nervous system bleeds, including their recovery status. Standard criteria defined by the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis should be used.

Recommendation 11.7.1: • The WFH recommends assessing and documenting the musculoskeletal and overall health of each patient at least annually. This should include an assessment of body structure and function, activity levels, participation and health-related quality of life as per the World Health Organization's International Classification of Functioning, Disability and Health (WHO ICF), as much as possible, in the right clinical context. • Remark: Standard definitions and validated tools should be used as much as possible, including the following: ◦ For body structure and function, clinical assessment of joints is (most) commonly done using the Hemophilia Joint Health Score (HJHS) in both children and adolescents. ◦ Under the same domain, early structural changes in joints are best assessed using ultrasound (US) or magnetic resonance imaging (MRI). Late osteochondral changes may be assessed on plain radiographs. ◦ Functional activity levels should be assessed using the most appropriate option available for that individual, including the Haemophilia Activities List (HAL), the Haemophilia Activities List for children (PedHAL), or the Functional Independence Score in Hemophilia (FISH). ◦ HRQoL is an important aspect of outcome measurement that may be assessed using either generic or disease-specific tools, but only in combination with the other domains of the WHO ICF. (Consensus Based)
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All statements identified as recommendations are consensus based, as denoted by image

Recommendation Grading

Overview

Title

Management of Hemophilia, 3rd edition

Authoring Organization

Publication Month/Year

August 3, 2020

Document Type

Guideline

External Publication Status

Published

Country of Publication

CA

Inclusion Criteria

Female, Male, Adult, Older adult

Health Care Settings

Ambulatory, Emergency care, Hospital

Intended Users

Genetics, nurse, nurse practitioner, physician, physician assistant

Scope

Assessment and screening, Management, Treatment

Diseases/Conditions (MeSH)

D006467 - Hemophilia A, D002836 - Hemophilia B

Keywords

hemophilia, bleeding disorders, hemostasis