Hemophilia A and B, the most common severe hereditary bleeding disorders, arise from deficiencies in factor VIII and factor IX, respectively. These conditions result in prolonged bleeding episodes, which can occur spontaneously or with minimal trauma, depending on the level of factor activity. Apart from treating acute bleeding, prophylaxis is a key strategy in hemophilia management. Prophylactic treatment significantly reduces the frequency of hemarthroses, thereby mitigating hemophilic arthropathy and the need for corrective joint surgeries. It also lowers the incidence of cerebral and muscle bleeds, decreases hospitalizations, and enhances patients’ quality of life by reducing time off work and less frequent monitoring.
To support this practice, this Guidelines Side-By-Side article will take a deep dive into hemophilia management recommendations by making a side-by-side comparison of the current clinical practice guidelines from the International Society on Thrombosis and Haemostasis (ISTH) and the World Federation of Hemophilia (WFH). In examining these recommendations and analyzing the recommendations from leading medical societies, the article can help to equip healthcare providers with critical insights and best practices to enhance the management of hemophilia and ensure comprehensive, interprofessional care for affected individuals and their families.
Titles of Comparison:
- Treatment of Congenital Hemophilia A and B
- Society: International Society on Thrombosis and Haemostasis (ISTH)
- Publication Date: June 2024
- Objective: This clinical practice guideline from the International Society on Thrombosis and Haemostasis aims to provide an evidence-based hemophilia treatment approach based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to support patients, caregivers, hematologists, pediatricians, other clinicians, researchers, and stakeholders in treatment decisions about congenital hemophilia A and B.
- Target Population: Adults and children with hemophilia
- Methodology: GRADE
- Graded Strength of Recommendations: Yes
- Graded Level of Evidence: Yes
- Systematic Review Conducted: Yes
- Literature Review Conducted: Yes
- COIs & Funding Source(s) Disclosed: Yes
- Management of Hemophilia, 3rd edition
- Society: World Federation of Hemophilia (WFH)
- Publication Date: August 2020
- Objective: This new edition provides principles of care that aims to provide a framework for development of a comprehensive healthcare system for hemophilia including advocacy and empowerment for people with hemophilia (PWH). The recommendations in this edition were all developed through a formal evidence-informed and consensus-based methodology involving multidisciplinary healthcare professionals (HCPs) and well-informed PWH. While directed primarily at HCPs, these guidelines should also be very useful for PWH as well as advocacy organizations.
- Target Population: Adults and children with hemophilia
- Methodology: Incorporated the Trustworthy Consensus-Based Statement (TCBS) approaches with a modified Delphi approach for guideline recommendations
- Graded Strength of Recommendations: WFH guideline recommendations recommendations were not graded as the vast majority of the evidence base in the field, given the barriers to clinical research and data collection in rare diseases, is insufficient to support meta-analyses, but were clearly marked “CB” for consensus-based.
- Graded Level of Evidence: No
- Systematic Review Conducted: Yes
- Literature Review Conducted: Yes
- COIs & Funding Source(s) Disclosed: Yes
- Summary | Patient Summary | Full Text
Comparison Content:
| WFH (2020) Management of Hemophilia, 3rd Edition | ISTH (2024) Treatment of Congenital Hemophilia A and B |
|---|---|
| Prophylaxis for Severe, Moderately-Severe, and Moderate Hemophilia with a Severe Phenotype: | |
• For patients with hemophilia A or B with a severe phenotype (can include patients with moderate hemophilia with a severe phenotype): – Strongly recommend patients be on prophylaxis sufficient to prevent bleeds at all times in an individualized approachIndividualization includes possible escalation of the prophylaxis regimen (in dose/frequency or both) if patients continue to experience bleeds. • For patients in resource-limited settings: – Still advocate for the use of prophylaxis over episodic therapy, even if less intensive prophylaxis needs to be used. • For patients in countries with healthcare constraints:Still strongly recommend prophylaxis (even when the only option is using lower factor doses) over episodic factor therapy to reduce hemarthroses, spontaneous and breakthrough bleeding, and support joint function preservation. • For patients with severe phenotype hemophilia A or B, especially children: – Recommend 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. • For adolescents and adults with hemophilia who show evidence of joint damage and have not as yet been on prophylaxis: – Recommend commencing tertiary prophylaxis in order to reduce the number of hemarthroses, spontaneous and breakthrough bleeding, and slow down the progression of hemophilic arthropathy. • For patients who are adherent to their prescribed prophylaxis regimen but still experience breakthrough bleeds: – Recommends escalation of prophylaxis with measurement of trough levels and, if required, orthopedic interventions as appropriate. • For patients with severe phenotype hemophilia A or B on prophylaxis: – Recommend patients & caregivers be taught to maintain timely and accurate records of bleeding episodes and treatment and be followed in hemophilia treatment centers. | • For patients with severe and moderately-severe hemophilia A without inhibitors: – Recommend prophylaxis over episodic treatment of bleeding events. • For patients with severe hemophilia A with inhibitors: – Suggest prophylaxis over episodic treatment of bleeding events. • For patients with severe and moderately-severe hemophilia B without inhibitors: – Recommend prophylaxis over episodic treatment of bleeding events. • In resource-limited settings in which the use of standard-dose prophylaxis for severe hemophilia A without inhibitors is not possible: – Conditionally suggest prophylaxis with low-dose FVIII concentrates over episodic treatment of bleeding events. |
| Prophylaxis With Factor VIII Clotting Factor Concentrates: | |
• For patients with hemophilia and venous access difficulties that impede regular clotting factor concentrate infusions: – Recommend 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. | • For individuals with severe and moderately severe hemophilia A without inhibitors undergoing a major invasive procedure: – Conditionally suggest either continuous or bolus infusion of plasma-derived or standard half-life recombinant FVIII concentrates. • For patients with severe and moderately severe hemophilia A without inhibitors: – Conditionally suggest prophylaxis with either standard or extended half-life recombinant FVIII concentrates. • In resource-limited settings in which the use of standard-dose prophylaxis for severe hemophilia A without inhibitors is not possible: – Conditionally suggest prophylaxis with low-dose FVIII concentrates over episodic treatment of bleeding events. • For previously untreated individuals with severe hemophilia A who will start prophylaxis with a plasma-derived or standard half-life recombinant FVIII concentrate: – Conditionally suggest initial prophylaxis with plasma-derived FVIII over standard half-life recombinant FVIII concentrate. • For patients with severe hemophilia A with high-responding inhibitors who will start immune tolerance induction: – Conditionally suggest immune tolerance induction with either low- or high-dose FVIII concentrates. |
| Prophylaxis With Factor VII Clotting Factor Concentrates: | |
Not specifically detailed in prophylaxis discussions section. | • For individuals with severe hemophilia A with inhibitors undergoing invasive procedures requiring treatment with bypassing agents: – Conditionally suggest either recombinant FVII activated (FVIIa; eptacog alfa) or activated prothrombin complex concentrate. • For individuals with severe hemophilia A with inhibitors who present with joint bleeding and will be treated with recombinant FVIIa (eptacog alfa): – Conditionally suggest treatment with either 3 doses of 90 μg/kg at 3-hour intervals or a single dose of 270 μg/kg. |
| Prophylaxis With Factor IX (FIX) Clotting Factor Concentrates: | |
| • For pediatric patients with severe hemophilia A or B: – Recommend 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 diseaseIdeally before age 3 in order to prevent spontaneous and breakthrough bleeding including hemarthroses which can lead to joint disease. • For patients with severe phenotype hemophilia A or B using EHL FVIII or FIX concentrates: – Recommend prophylaxis with EHL clotting factor concentrates at sufficient doses and dosing intervals to prevent hemarthroses and spontaneous and breakthrough bleeding and preserve joint function. | • For patients with severe and moderately-severe hemophilia B without inhibitors: – Conditionally suggest prophylaxis with purified plasma-derived FIX or standard or extended half-life recombinant FIX concentrates. |
| Prophylaxis With Emicizumab (monoclonal antibody that mimics activated Factor VIII) | |
| • For patients with severe phenotype hemophilia A without inhibitors: – Recommend prophylaxis with emicizumab to prevent hemarthrosis, spontaneous, and breakthrough bleeding. • For patients with moderate/severe hemophilia A or B, especially those who have experienced a life-threatening bleed (e.g., intracranial hemorrhage): – Recommend 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. – Particularly important during the first 3-6 months following an ICH as the risk of recurrence is highest during this period. | • For patients with severe hemophilia A with inhibitors: – Conditionally suggest prophylaxis with emicizumab over bypassing agents. • For patients with severe and moderately severe hemophilia A without inhibitors: – Conditionally suggest either prophylaxis with emicizumab or prophylaxis with FVIII concentrates. |
Key Takeaways:
Prophylaxis Recommendations:
- Severe Hemophilia (A & B)
- WFH: Strongly recommend individualized prophylaxis to prevent bleeding in patients with severe phenotype hemophilia A or B, including those in resource-limited settings.
- Prophylaxis is advised to be continued even if lower doses are required due to constraints.
- ISTH: Recommends prophylaxis over episodic treatment for severe and moderately severe hemophilia A and B, including those with inhibitors.
- In resource-limited settings, low-dose FVIII prophylaxis is suggested if standard dosing isn’t feasible.
- WFH: Strongly recommend individualized prophylaxis to prevent bleeding in patients with severe phenotype hemophilia A or B, including those in resource-limited settings.
Prophylaxis with Factor VIII Concentrates:
- WFH: Supports the use of standard or extended half-life FVIII concentrates for prophylaxis.
- For patients with venous access difficulties, suggests using a central venous access device (CVAD) or emicizumab.
- ISTH: Recommends prophylaxis with standard or extended half-life FVIII concentrates.
- For major invasive procedures, continuous or bolus infusion of FVIII concentrates is conditionally suggested.
- In resource-limited settings, low-dose FVIII prophylaxis is recommended if standard dosing is not possible.
Prophylaxis with Factor IX Concentrates:
- WFH: Recommends early initiation of prophylaxis with FVIII or FIX concentrates for pediatric patients and use of extended half-life products to prevent joint disease and bleeding.
- ISTH: Suggests prophylaxis with purified plasma-derived FIX or standard/extended half-life recombinant FIX concentrates for severe and moderately severe hemophilia B.
Prophylaxis with Emicizumab:
- WFH: Strongly recommends emicizumab for patients with severe phenotype hemophilia A, especially those with a history of life-threatening bleeds. Emicizumab is also recommended to prevent bleeding in patients with severe hemophilia A without inhibitors.
- ISTH: Conditionally suggests emicizumab for severe hemophilia A with inhibitors over bypassing agents.
- For severe and moderately severe hemophilia A without inhibitors, emicizumab or FVIII concentrates may be used.
Additional Prophylaxis Considerations:
- WFH: Emphasizes the importance of adhering to prophylaxis regimens, including escalation if breakthrough bleeding occurs.
- Also encourage timely and accurate record-keeping by patients and caregivers.
- ISTH: Provides conditional recommendations for various scenarios, such as starting prophylaxis with plasma-derived FVIII or addressing inhibitors with immune tolerance induction using either low- or high-dose FVIII concentrates.
Comparing hemophilia management recommendations from ISTH and WFH side-by-side highlights the depth and commitment of these leading organizations to improving care for individuals with bleeding disorders and underscores the importance of staying up to date on evidence-based recommendations from leading organizations to advance care for individuals with bleeding disorders. Utilizing these guidelines, healthcare providers are better equipped to deliver targeted, evidence-based care that leverages the latest developments in hemophilia prophylactic management in a way that ensures patient care is optimized and aligned with best practices, ultimately enhancing treatment outcomes and quality of life for individuals with hemophilia!
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