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The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.

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The ISTH has published clinical guidelines for the treatment of Congenital Hemophilia A and B. Guidelines are available from the World Federation of Hemophilia, UKHCDO Guidelines and the American Society of Hematology, to mention a few and sure there are several more local guidelines. So what makes this one notable? To date, there is no evidence-based clinical practice guideline on hemophilia treatment. This document is also based on the GRADE approach. This will look at the importance of guidelines as well as using this GRADE approach.

HEMOPHILIA:

The most common forms of hemophilia are hemophilia A which presents with a deficiency in factor VIII and hemophilia B which is a factor IX deficiency. This is an X-linked inheritance pattern which affects almost 20,000 individuals in the US. It primarily affects males, but females are carriers. The diagnosis and management is complex in that it requires preventative prophylaxis to avoid bleeding and complications as well as the use of replacement therapy during acute bleeding episodes. This requires a comprehensive approach.¹

Patients who present with severe hemophilia phenotypes produce less than 1% of FVIII or FIX activity. This results in patients experiencing recurrent musculoskeletal, soft tissue and intracranial hemorrhages (ICH) which can be life threatening. Patients classified as moderate hemophiliacs have factor levels in the range of 1-5% with rare spontaneous bleeding events but they still have a risk of bleeding as a result of trauma. Mild hemophiliacs have levels above 6% and bleeding occurs due to trauma, but still have a higher risk of ICH mortality compared to normal individuals.²

Standard of care is to maintain levels in severe hemophiliacs above 1% using prophylactic factor concentrates to prevent arthropathy. Extended half-life is also used to reduce the use of concentrated factors. Therapies such as emicizumab has transformed the clinical management of hemophilia in particular in patients with inhibitors. Gene replacement therapy is the new development in treatment of these patients.²

PURPOSE OF CLINICAL GUIDELINES:

Clinical guidelines are recommendations that are intended to optimize patient care. These are determined by a review of evidence and an assessment of benefits and harms of alternative care options. They help to standardize practices, implement research efforts and most importantly improve quality and safety of care. Their goal is to provide best practice recommendations.³

This evidence-based clinical practice guideline from the International Society on Thrombosis and Haemostasis (ISTH) aims to provide an overview of evidence and support patients, caregivers, hematologists, pediatricians and other clinicians, researchers and stakeholders in treatment decisions about congenital hemophilia A and B.⁴ A panel of experts formulated recommendations that guide the retrieval of evidence used to inform the recommendations. Helpful recommendations are clear and actionable and should specify if they are strong or weak, applicable for all patients or for use in certain circumstances. Since judgements are involved in interpretations useful guidelines consider all relevant factors that have a bearing on clinical decisions. These should not be influenced by conflicts of interest.⁵

The ISTH formed a multidisciplinary guideline panel of physicians and patients with global representation, balanced to minimize potential bias from conflicts of interest. The panel prioritized a set of clinical questions and outcomes according to their importance for clinicians and patients. A methodological team supported the guideline development process, including searching of the evidence and performing systematic reviews.⁴

GRADING SYSTEM APPROACH:

The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used, including GRADE Evidence-to-Decision frameworks. This provides a systematic and transparent framework for clarifying questions and summarizing the evidence. It helps to determine outcomes of interest and move the evidence to a recommendation or a decision.⁶

It also rates the certainty of evidence for each outcome as high, moderate, low or very low which include the effects of interventions, prognostic estimates, values and preferences, test accuracy, resource utilization and other health questions. The assessment includes assessing the possible impact of risk of bias, imprecision, inconsistency, indirectness, and publication bias, the magnitude of effects, dose-response relations and residual plausible bias on effects or associations.⁷

There were 13 questions that were selected and that addressed the treatment of hemophilia A (11) and hemophilia B⁽²⁾. It looked at questions on prophylactic treatment with FVIII concentrates, bypassing agents, use of emicizumab in patients with or without inhibitors and immune tolerance induction. The questions for hemophilia B also addressed questions on prophylactic and episodic treatment of bleeding events with factor IX concentrates. The evidence was based on randomized clinical trials (54%), observational studies (23%) and indirect comparisons (23%). The recommendations are clear, and each provides its corresponding strength. A strong recommendation points to what is superior, conditional recommendations highlight what is needed to be considered individually as well as the circumstances in which the decision is being made to implement the recommendation.⁴

Below is a summary of the recommendations taken from the guidelines. To read the entire guideline it can be accessed at: https://www.jthjournal.org/article/S1538-7836(24)00318-0/fulltext

SUMMARY OF RECOMMENSATIONS:

Hemophilia A without inhibitors
Recommendation 1:
In individuals with severe and moderately-severe hemophilia A without inhibitors, the ISTH Hemophilia Guideline Panel recommends prophylaxis over episodic treatment of bleeding events (strong recommendation, based on moderate certainty evidence).⁴

Recommendation 2:
In individuals with severe and moderately-severe hemophilia A without inhibitors, the ISTH Hemophilia Guideline Panel suggests either prophylaxis with emicizumab or prophylaxis with factor VIII concentrates (conditional recommendation, based on very-low certainty evidence).⁴

Recommendation 3:
In individuals with severe and moderately-severe hemophilia A without inhibitors, the ISTH Hemophilia Guideline Panel suggests prophylaxis with either standard or extended half-life recombinant factor VIII concentrates (conditional recommendation, based on very-low certainty evidence).⁴

Recommendation 4:
In resource-limited settings in which the use of standard-dose prophylaxis for severe hemophilia A without inhibitors is not possible, the ISTH Hemophilia Guideline Panel suggests prophylaxis with low-dose factor VIII concentrates over episodic treatment of bleeding events (conditional recommendation, based on very-low certainty evidence).⁴

Recommendation 5:
In previously untreated individuals with severe hemophilia A who will start prophylaxis with a plasma-derived or standard half-life recombinant factor VIII concentrate, the ISTH Hemophilia Guideline Panel suggests initial prophylaxis with plasma-derived factor VIII over standard half-life recombinant factor VIII concentrate (conditional recommendation, based on very-low certainty evidence).⁴

Recommendation 6:
In individuals with severe and moderately-severe hemophilia A without inhibitors undergoing a major invasive procedure, the ISTH Hemophilia Guideline Panel suggests either continuous or bolus infusion of plasma-derived or standard half-life recombinant factor VIII concentrates (conditional recommendation, based on very-low certainty evidence).⁴

Hemophilia A with inhibitors
Recommendation 7:
In individuals with severe hemophilia A with inhibitors, the ISTH Hemophilia Guideline Panel suggests prophylaxis over episodic treatment of bleeding events (conditional recommendation, based on low certainty evidence).⁴

Recommendation 8:
In individuals with severe hemophilia A with inhibitors, the ISTH Hemophilia Guideline Panel suggests prophylaxis with emicizumab over bypassing agents (conditional recommendation, based on very-low certainty evidence).⁴

Recommendation 9:
In individuals with severe hemophilia A with high-responding inhibitors who will start immune tolerance induction, the ISTH Hemophilia Guideline Panel suggests immune tolerance induction with either low- or high-dose factor VIII concentrates (conditional recommendation, based on very-low certainty evidence ).⁴

Recommendation 10:
In individuals with severe hemophilia A with inhibitors undergoing invasive procedures requiring treatment with bypassing agents, the ISTH Hemophilia Guideline Panel suggests either recombinant factor VIIa (eptacog alfa) or activated prothrombin complex concentrate (conditional recommendation, based on very-low certainty evidence).⁴

Recommendation 11:
In individuals with severe hemophilia A with inhibitors who present with joint bleeding and will be treated with recombinant factor VIIa (eptacog alfa), the ISTH Hemophilia Guideline Panel suggests treatment with either three doses of 90 μg per kg at 3-hour intervals or a single dose of 270 μg per kg (conditional recommendation, based on very-low certainty evidence).⁴

Hemophilia B without inhibitors
Recommendation 12:
In individuals with severe and moderately-severe hemophilia B without inhibitors, the ISTH Hemophilia Guideline Panel recommends prophylaxis over episodic treatment of bleeding events (strong recommendation, based on moderate certainty evidence).⁴

Recommendation 13:
In individuals with severe and moderately-severe hemophilia B without inhibitors, the ISTH Hemophilia Guideline Panel suggests prophylaxis with purified plasma-derived factor IX or standard or extended half-life recombinant factor IX concentrates (conditional recommendation, based on very-low certainty evidence).4

CONCLUSIONS:

It is important for laboratories to understand and be aware of treatments for hemophilia A and B and how they can impact coagulation testing. Many treatments can be difficult to monitor since they are reagent dependent. Being aware of the limitations of your testing is important for your clinicians to be aware of. Any guideline can only aid in improving the quality and safety for these patients.

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REFERENCES:

1. Kenneth A Bauer, Current challenges in the management of hemophilia, Am J Manag Care. 2015 Mar;21(6 Suppl):S112-22.
2. Shosaku Nomura, Current Status and Challenges in Delivering Comprehensive Care for Patients with Hemophilia, J Blood Med. 2023; 14: 629–637
3. Dimitra Panteli, Helena Legido-Quigley, Christoph Reichebner, Günter Ollenschläger, Corinna Schäfer, and Reinhard Busse. Clinical Practice Guidelines as a quality strateg https://www.ncbi.nlm.nih.gov/books/NBK549283/
4. Rezende SM, Neumann I, Angchaisuksiri P, Awodu O, Boban A, Cuker A,
Curtin JA, Fijnvandraat K, Gouw SC, Gualtierotti R, Makris M, Nahuelhual P, O’Connell N, Saxena R, Shima M, Wu R, Rosendaal FR, International Society on Thrombosis and Haemostasis Clinical Practice Guideline for Treatment of Congenital Hemophilia A and B based on the GRADE methodology, Journal of Thrombosis and Haemostasis (2024),
5. Romina Brignardello-Petersen, DDS, MSc, PhD1; Alonso Carrasco-Labra, DDS, MSc, PhD2,3; Gordon H. Guyatt, MD, MSc1, How to Interpret and Use a Clinical Practice Guideline or Recommendation Users’ Guides to the Medical Literature, JAMA. 2021;326(15):1516-1523
6. Gordon H Guyatt 1, Andrew D Oxman, Holger J Schünemann, Peter Tugwell, Andre Knottnerus, GRADE guidelines: a new series of articles in the Journal of Clinical Epidemiology, J Clin Epidemiol 2011 Apr;64(4):380-2.
7. Schünemann, H.J., Reinap, M. (2023). GRADE: A Transparent Approach for Evidence-Based Recommendations and Decisions in Health. In: Raviglione, M.C.B., Tediosi, F., Villa, S., Casamitjana, N., Plasència, A. (eds) Global Health Essentials. Sustainable Development Goals Series. Springer, Cham. https://doi.org/10.1007/978-3-031-33851-9_84

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