Hemophilia, a rare congenital bleeding disorder, is caused by pathogenic variants in the encoding genes, leading to the complete or partial deficiency of clotting factors VIII (Hemophilia A) or IX (Hemophilia B). Treating hemophilia involves certain complexities, and until now, no evidence-based clinical practice guidelines based on the GRADE methodology have been established to guide treatment. The International Society on Thrombosis and Haemostasis (ISTH) has developed evidence-based clinical practice guidelines aimed at systematically reviewing the relevant evidence to provide a scientific basis for treatment decisions in Hemophilia A and B, thereby supporting healthcare providers in their clinical practice. To this end, ISTH formed a globally representative, multidisciplinary guideline panel that prioritized clinical questions based on their urgency and the importance of outcomes to patients and clinicians.

The expert panel ultimately identified 13 key topics, 11 of which focus on treatment strategies for Hemophilia A, while the remaining two address treatment approaches for Hemophilia B. Specifically, the team delved into the use of FVIII concentrates in prophylactic and episodic treatments, the efficacy of bypassing agents, non-factor therapies for Hemophilia A (with or without inhibitors), and immune tolerance induction in Hemophilia A. For Hemophilia B, the discussion also covered the role of FIX concentrates in prophylactic and episodic treatment of bleeding events. These 13 recommendations received consensus from the expert panel, with 7 (54%) based on evidence from randomized clinical trials, 3 (23%) relying on observational studies, and the remaining 3 (23%) based on indirect comparative analysis. The panel strongly recommends adopting prophylactic treatment strategies over episodic treatment for patients with severe and moderate Hemophilia A and B. Looking ahead, research in this field should focus on direct comparisons of treatment strategies and studies on therapies for Hemophilia B (with or without inhibitors). Future updates of these guidelines will be informed by the latest comprehensive evidence, with a particular focus on novel FVIII and FIX concentrates, innovative non-factor therapies, and gene therapy for severe/non-severe hemophilia, aiming to provide more precise and effective treatment strategies.

Summary of the 13 Practice Recommendations

Hemophilia A Without Inhibitors

Recommendation 1:

For patients with severe and moderate Hemophilia A without inhibitors, the ISTH Hemophilia Guideline Panel recommends prophylactic treatment over on-demand treatment for bleeding events (strong recommendation, based on moderate-certainty evidence ★★★☆).

Commentary

Prophylactic treatment offers substantial benefits in reducing bleeding risk while minimizing adverse events.

The cost and availability of prophylactic concentrates remain significant barriers to implementing this recommendation.

Increasing the acceptance and adherence to prophylactic treatment among vulnerable populations may help reduce current health equity gaps.

This recommendation may also apply to Hemophilia A patients with a severe bleeding phenotype, even if their FVIII plasma levels are ≥2 IU/dL.

Recommendation 2:

For patients with severe and moderate Hemophilia A without inhibitors, the ISTH Hemophilia Guideline Panel suggests using Emicizumab or FVIII concentrates for prophylactic treatment (conditional recommendation, based on very low-certainty evidence ★☆☆☆).

Commentary

Given its administration schedule—weekly, biweekly, or every four weeks—and subcutaneous administration, Emicizumab may offer a lower treatment burden for patients. There remains uncertainty about the long-term safety and efficacy of Emicizumab in infants with Hemophilia A.

This recommendation may also apply to Hemophilia A patients with a severe bleeding phenotype, even if their FVIII plasma levels are ≥2 IU/dL.

Recommendation 3:

For patients with severe and moderate Hemophilia A without inhibitors, the ISTH Hemophilia Guideline Panel suggests using standard half-life or extended half-life recombinant FVIII concentrates for prophylactic treatment (conditional recommendation, based on very low-certainty evidence ★☆☆☆).

Commentary

Extended half-life recombinant FVIII concentrates may offer a lower treatment burden due to less frequent injections and potentially higher trough levels.

This recommendation may also apply to Hemophilia A patients with a severe bleeding phenotype, even if their FVIII plasma levels are ≥2 IU/dL.

Recommendation 4:

In resource-limited settings, for patients with severe Hemophilia A without inhibitors who cannot access standard-dose prophylactic treatment, the ISTH Hemophilia Guideline Panel suggests using low-dose FVIII concentrates for prophylactic treatment rather than on-demand treatment for bleeding events (conditional recommendation, based on very low-certainty evidence ★☆☆☆).

Commentary

In environments where FVIII concentrates are adequately accessible, standard prophylactic treatment is the optimal choice.

However, compared to no prophylaxis, low-dose FVIII prophylaxis reduces the risk of bleeding, making it preferable to on-demand treatment.

This recommendation may also apply to Hemophilia A patients with a severe bleeding phenotype, even if their FVIII plasma levels are ≥2 IU/dL.

Recommendation 5:

For previously untreated patients with severe Hemophilia A who are about to start prophylactic treatment, the ISTH Hemophilia Guideline Panel suggests choosing plasma-derived FVIII over standard half-life recombinant FVIII for initial prophylactic treatment (conditional recommendation, based on very low-certainty evidence ★☆☆☆).

Commentary

Initial prophylactic treatment refers to the first 50 exposure days to FVIII. Current evidence suggests that in previously untreated patients, using standard half-life recombinant FVIII may be associated with a higher risk of inhibitor development compared to plasma-derived FVIII. However, different recombinant and plasma-derived FVIII concentrates may vary in their risk of inhibitor formation.

Although the risk of transmitting blood-borne pathogens with plasma-derived FVIII has been minimized, some patients or healthcare providers may still prefer to avoid using plasma-derived FVIII.

The supporting studies for this recommendation did not evaluate extended half-life FVIII concentrates, and thus this recommendation does not cover them.

All plasma-derived FVIII concentrates should meet current safety standards.

Recommendation 6:

For patients with severe and moderate Hemophilia A without inhibitors who are about to undergo major invasive surgery, the ISTH Hemophilia Guideline Panel suggests using continuous or intermittent infusions of plasma-derived or standard half-life recombinant FVIII concentrates (conditional recommendation, based on very low-certainty evidence ★☆☆☆).

Commentary

For patients with severe Hemophilia A, there may be no significant difference in efficacy between continuous or intermittent infusion of plasma-derived or standard half-life recombinant FVIII concentrates before, during, or after invasive surgery.

This recommendation applies to patients undergoing major general and orthopedic surgeries. Continuous infusion tends to use less FVIII, which may be relevant in resource-limited settings. Given the lack of comparative studies for extended half-life recombinant FVIII concentrates, this recommendation does not apply to them.

Hemophilia A With Inhibitors

Recommendation 7:

For patients with severe Hemophilia A with inhibitors, the ISTH Hemophilia Guideline Panel suggests prophylactic treatment over on-demand treatment for bleeding events (conditional recommendation, based on low-certainty evidence ★★☆☆).

Recommendation 8:

For patients with severe Hemophilia A with inhibitors, the ISTH Hemophilia Guideline Panel suggests using Emicizumab for prophylactic treatment rather than bypassing agents (conditional recommendation, based on very low-certainty evidence ★☆☆☆).

Commentary

Emicizumab may be more effective in preventing bleeding events compared to bypassing agents and may also be more cost-effective. Additionally, Emicizumab’s administration schedule—weekly, biweekly, or every four weeks—and subcutaneous administration may offer a lower treatment burden for patients.

Recommendation 9:

For patients with severe Hemophilia A with high-responding inhibitors who are about to begin immune tolerance induction (ITI), the ISTH Hemophilia Guideline Panel suggests using low-dose or high-dose FVIII concentrates for ITI (conditional recommendation, based on very low-certainty evidence ★☆☆☆).

Commentary

Both dosing regimens may be similarly effective in achieving immune tolerance, but in settings where FVIII is limited, the low-dose regimen may be preferred.

The low-dose regimen may be associated with a higher risk of bleeding compared to the high-dose regimen.

This recommendation applies to both plasma-derived and standard half-life recombinant FVIII concentrates, as no randomized controlled trials have evaluated the use of extended half-life recombinant FVIII concentrates for ITI.

The studies supporting this recommendation were conducted before the advent of Emicizumab.

Recommendation 10:

For patients with severe Hemophilia A with inhibitors who require bypassing agents and are about to undergo invasive surgery, the ISTH Hemophilia Guideline Panel suggests using recombinant factor VIIa (eptacog alfa) or activated prothrombin complex concentrates (APCC) (conditional recommendation, based on very low-certainty evidence ★☆☆☆).

Commentary

For patients receiving Emicizumab prophylaxis, recombinant factor VIIa is recommended as the first choice, as the combination of Emicizumab and APCC may carry a risk of thrombotic complications.

Most patients in the studies informing this recommendation had high-responding inhibitors. The evidence comparing recombinant factor VIIa and APCC is limited to small cohort studies involving different types of surgeries. At this stage, it is not possible to determine whether one option is more effective than the other.

Recombinant factor VIIa requires more frequent administration and is generally more expensive than APCC, which may limit its feasibility in some settings.

Eptacog beta (a specific form of recombinant factor VIIa) was not evaluated in the studies informing this recommendation, so it is not included in this recommendation.

Patients with low-titer inhibitors (typically less than 2 BU) may have adequate FVIII recovery after receiving higher-than-usual doses of FVIII, and thus, FVIII concentrates may be used for their treatment.

Recommendation 11:

For patients with severe Hemophilia A with inhibitors experiencing joint bleeding and being treated with recombinant factor VIIa (eptacog alfa), the ISTH Hemophilia Guideline Panel suggests using one of two dosing regimens: either 90 μg/kg every 3 hours for a total of three doses, or a single dose of 270 μg/kg (conditional recommendation, based on very low-certainty evidence ★☆☆☆).

Commentary

Limited available evidence does not indicate a clear advantage of one dosing option over the other in treating joint, muscle, and mucocutaneous bleeding events.

The single-dose regimen may offer a lower treatment burden for patients and healthcare providers. However, with the three-dose regimen, if bleeding stops quickly, some patients may not need to complete all three doses, potentially saving resources.

The studies supporting this recommendation were conducted before the advent of Emicizumab.

Hemophilia B Without Inhibitors

Recommendation 12:

For patients with severe and moderate Hemophilia B without inhibitors, the ISTH Hemophilia Guideline Panel recommends prophylactic treatment over on-demand treatment for bleeding events (strong recommendation, based on moderate-certainty evidence ★★★☆).

Commentary

Prophylactic treatment offers significant benefits in reducing bleeding risk while minimizing adverse events.

The cost and availability of prophylactic concentrates remain significant barriers to implementing this recommendation.

Promoting the acceptance and adherence to prophylactic treatment among vulnerable populations may help reduce current health equity gaps.

This recommendation may also apply to Hemophilia B patients with a severe bleeding phenotype, even if their FIX plasma levels are ≥2 IU/dL.

No studies were found comparing the effectiveness of prophylactic treatment versus on-demand treatment for bleeding in untreated patients with Hemophilia B.

Recommendation 13:

For patients with severe and moderate Hemophilia B without inhibitors, the ISTH Hemophilia Guideline Panel suggests using purified plasma-derived FIX or standard or extended half-life recombinant FIX concentrates for prophylactic treatment (conditional recommendation, based on very low-certainty evidence ★☆☆☆).

Commentary

Extended half-life recombinant FIX concentrates may offer a lower treatment burden due to less frequent injections.

Although the risk of transmitting blood-borne pathogens with plasma-derived FIX has been minimized, some patients or healthcare providers may still prefer to avoid using plasma-derived FIX. This recommendation does not include the use of prothrombin complex concentrates, as their use may increase the risk of thrombosis.

This recommendation may also apply to Hemophilia B patients with a severe bleeding phenotype, even if their FIX plasma levels are ≥2 IU/dL.

All plasma-derived FIX concentrates should meet current safety standards.