Hemophilia

Hemophilia is a rare bleeding disorder resulting from a deficiency of coagulation factor VIII (FVIII, hemophilia A) or factor IX (FIX, hemophilia B). The deficiency is due to pathogenic mutations in the F8 and F9 genes that code for the factor proteins.¹ Hemophilia A and B are linked to the X chromosome; therefore, the disease affects primarily males who inherit a defective maternal X chromosome. The disease is characterized by hemorrhages that can be life-threatening and damage skeletal muscles and joints. The diagnostic process includes the patient’s family history and history of bleeding, in addition to a factor assay to identify a deficiency of any of the coagulation factors.

The World Federation of Hemophilia (WFH) has been actively developing guidelines for the management of hemophilia.² The guidelines have been endorsed by the International Society on Thrombosis and Haemostasis (ISTH) and accepted by the National Guideline Clearinghouse (NGC). With improvements in diagnosis and treatment, the guidelines have been revised. The third edition of the WFH Guidelines for the Management of Hemophilia is a comprehensive collection of recommendations focused on the diagnosis and management of hemophilia.³ The guidelines were prepared following a consideration of the available evidence for the latest advances in genetic studies, laboratory findings, and therapeutic approaches. New recommendations on outcome assessments are also included. 

The latest WFH guidelines have been endorsed by the Asian-Pacific Society on Thrombosis and Hemostasis, the European Haemophilia Consortium, and the National Hemophilia Foundation (USA) and are available through the WFH website (http://www.wfh.org). All recommendations have been reached by consensus according to the “Trustworthy Consensus-Based Statements” process.⁴

Recommendations for Genetic Assessment

Identifying the genetic defect of a patient with  hemophilia can be particularly useful when the diagnosis proves difficult. It can also aid in establishing the risk for inhibitor development. The WFH therefore recommends that genetic testing be performed to identify the genetic variant causing the disease. Genetic screening can be performed by polymerase chain reaction (PCR) and Sanger sequencing, or by next-generation sequencing.³

Because other genetic defects may be discovered incidentally during the assessment, patients should first discuss their genetic evaluation with a genetic counselor.

Recommendations for Prophylaxis Therapy

For patients with severe hemophilia, the WFH recommends a prophylactic treatment that can prevent bleeding at all times. Prophylaxis should be adapted to each individual; however, the goal of treatment is to increase the level of FVIII or FIX to a constant value that should be higher than 1 IU/dL (1%).⁵ When the target levels are above 3% to 5%, less bleeding will occur. To achieve these percentages, however, higher doses of clotting factors or an increase in infusion frequency is needed.³

An early start to prophylactic treatment will reduce the risk for intracranial hemorrhage. The initiation of regular prophylaxis at a young age should be the standard of care for patients with hemophilia until an alternate therapeutic approach is available. The WHF also recommends that prophylaxis be initiated for adult patients with a severe phenotype if they are not already being treated.³

For patients with moderate to severe hemophilia A or B who may have experienced a life-threatening bleed, the WHF recommends that prophylaxis consist of FVIII or FIX concentrate or a non-factor therapy. In the latter case, emicizumab (Hemlibra®) is the only non-factor replacement product approved by the Food and Drug Administration for the treatment of hemophilia A.³

Recommendations for the Treatment of Joint Hemorrhages

Prolonged spontaneous or traumatic hemorrhaging occurs in patients with hemophilia, particularly in synovial joints such as the ankles, knees, and elbows. Patients with hemarthrosis should be treated immediately with intravenous infusions of replacement clotting factor concentrate to avoid complications. Pain should be managed with paracetamol/acetaminophen, cyclooxygenase (COX)-2-selective inhibitors, tramadol, or opioids. Additionally, a RICE approach (rest, ice, compression, and elevation) should be followed. Patients should receive physical therapy guidance as soon as their pain subsides with the goal of restoring joint function.

Patients who have hemophilic arthropathy that is not relieved by nonsurgical strategies should consult an orthopedic specialist. Specialist recommendations may include synovectomy and joint debridement, arthroscopy, or joint replacement.³

Recommendations for Inhibitor Screening

Immunoglobulin G antibodies that develop in response to the administration of FVIII or FIX can neutralize infused clotting factors. It is recommended that patients with a recent diagnosis of hemophilia A and B undergo inhibitor screening at least every 6 to 12 months, and then annually. Screening is also recommended if a clotting factor concentrate has been administered for more than 5 days consecutively. Screening should be performed within 4 weeks after the last infusion.³

The treatment of bleeding in a patient who has hemophilia A with low-responding inhibitors is FVIII replacement. The amount of FVIII needed to neutralize the antibodies should be determined, and an additional 50 IU/kg should be added. When a patient has high-responding inhibitors, therapy with a bypassing agent, such as recombinant activated factor VIIa (rFVIIa), activated prothrombin complex concentrate (aPCC), or porcine FVIII, should be administered. For patients who have hemophilia B with low-responding inhibitors, FIX should be infused as long as an allergic reaction can be avoided. For patients who have high-responding inhibitors and an allergic reaction to FIX infusion, rFVIIa is recommended for the treatment of acute bleeds. The administration of aPCC is not recommended because it contains FIX and may induce or exacerbate an allergic reaction.³

References

1. Peters R, Harris T. Advances and innovations in haemophilia treatment. Nat Rev Drug Discov. 2018;17(7):493-508. doi:10.1038/nrd.2018.70

2. Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al, Treatment Guidelines Working Group on Behalf of The World Federation of Hemophilia. Guidelines for the management of hemophilia. Haemophilia. 2013;19(1):e1-47. doi:10.1111/j.1365-2516.2012.02909.x

3. Srivastava A, Santagostino E, Dougall A, et al. WFH guidelines for the management of hemophilia, 3rd ed. Haemophilia. 2020;26(Suppl 6):1-158. doi:10.1111/hae.14046

4.  WHF guidelines for the management of hemophilia, 3rd ed. World Federation of Hemophilia. Accessed August 3 , 2021.

5.  Nilsson IM, Berntorp E, Löfqvist T, Pettersson H. Twenty-five years’ experience of prophylactic treatment in severe haemophilia A and B. J Intern Med. 1992;232(1):25-32. doi:10.1111/j.1365-2796.1992.tb00546.x

Reviewed by Debjyoti Talukdar, MD, on 8/11/2021.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.