Hemophilia A and hemophilia B are congenital, X-linked, hemorrhagic disorders caused by a deficiency or dysfunction of coagulation factors VIII (FVIII) and IX (IX), respectively.1 Both FVIII and FIX are glycoproteins necessary for the coagulation cascade to generate thrombin. Perturbation of FVIII and IX levels or activity can result in delayed thrombin generation and consequently defective clot formation.2

Hemophilia is a rare disease, with a prevalence of 1 in 5000 male births (hemophilia A) and 1 in 25,000 male births (hemophilia B).1 The disease can be diagnosed through the family history or after episodes of bleeding.3 In the diagnostic process, measurement of FVIII or FIX clotting activity is important.4

The clinical manifestations of hemophilia A and B are similar. The hallmark of the disease is spontaneous bleeding, which typically occurs in the joints, especially the ankles, elbows, and knees.4 Patients with hemophilia can also lose significant amounts of blood as a result of trauma or surgery.1

One of the major bleeding complications associated with hemophilia is intracranial hemorrhage.4 The risk for intracranial hemorrhage in the neonatal period has been estimated to be 1% to 4%; the probability is higher during the first week of life.3 Other complications associated with the disease itself or with available treatments have been described.

Hemophilic Arthropathy

Recurrent bleeding into the joints leads to joint and tissue damage, which increases the likelihood of further bleeding.1,5 Inflammatory synovitis can develop as the hemoglobin released from erythrocytes is deposited into the joint spaces. The synovium gradually thickens during repeated episodes of joint hemorrhage, and the progressive destruction of bone and cartilage ultimately results in the development of hemophilic arthropathy.5 This condition significantly reduces joint mobility, causing joint deformity, muscle atrophy, and chronic pain. The activity of patients with hemophilic arthropathy is limited, and their quality of life is typically severely diminished.1,5 

Arthropathy can be prevented by prophylactic treatment with coagulation factors. Bleeding into the joints can be managed with splinting and physical therapy as well as factor replacement. When arthropathy stabilizes, surgery is often the best treatment option; the surgical procedure may consist of synovectomy, joint debridement, joint fusion, and arthroplasty.5

Infectious Diseases

Before the 1980s, donor blood was pooled to prepare factor concentrates. Viral contamination of large plasma pools, which was not uncommon,3,5 put patients at risk for hepatitis B or C, or even infection with the human immunodeficiency virus.5 Hepatitis C had a strongly negative effect on patients with hemophilia, leading to chronic infections with the development of cirrhosis. In a few cases, malignancies developed.6 

Viral contamination was later reduced by improving the methods of preparing pooled factors.5 However, although the risk of transmitting enveloped viruses no longer exists, the risk of transmitting non-enveloped viruses, such as the hepatitis A virus and parvoviruses, has not been completely eliminated.7 Patients with hemophilia should be vaccinated against hepatitis A and B.3

Development of Inhibitors

The standard treatment for bleeding in hemophilia is factor replacement. This can be done as needed or prophylactically.5 Prophylactic treatment is appropriate for patients with severe hemophilia, and it has been reported that it may help to prevent joint damage and hemarthroses.8 The development of neutralizing antibodies (inhibitors), however, is a major complication of such treatment.4 Specific antibodies (immunoglobulin G) against FVIII and FIX preparations develop that neutralize the factor being administered,5 and this complication significantly interferes with successful treatment.9 Even though inhibitor development does not affect the location or frequency of bleeding, it can exacerbate the disease because other treatments may not be as effective.9

Inhibitor development is more frequent in hemophilia A; this complication develops in nearly 30% of patients with hemophilia A. Antibodies may develop in up to 5% of patients with hemophilia B. Inhibitors are more likely to develop in patients who present with severe disease or who have been treated soon after their disease has been diagnosed. The first 50 exposures to coagulation factor are the ones most likely to lead to this complication.5 

Patients are classified as high or low responders according to their antibody titers. Preventing or treating bleeding in a patient with a low antibody titer requires the infusion of high doses of FVIII or FIX concentrates. For patients presenting with high antibody titers, bypassing agents such as activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa) can be used, but they are less effective than standard treatment.9

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. Peyvandi F, Garagiola I, Young G. The past and future of haemophilia: diagnosis, treatments, and its complications. Lancet. 2016;388(10040):187-197. doi:10.1016/S0140-6736(15)01123-X

3. Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet. 2003;361(9371):1801-1809. doi:10.1016/S0140-6736(03)13405-8

4. Kizilocak H, Young G. Diagnosis and treatment of hemophilia. Clin Adv Hematol Oncol. 2019;17(6):344-351. PMID:31437138

5. Zimmerman B, Valentino LA. Hemophilia: in review. Pediatr Rev. 2013;34(7):289-294; quiz 295. doi:10.1542/pir.34-7-289

6. Lee C, Dusheiko G. The natural history and antiviral treatment of hepatitis C in haemophilia. Haemophilia. 2002;8(3):322-329. doi:10.1046/j.1365-2516.2002.00620.x

7. Evatt BL, Farrugia A, Shapiro AD, Wilde JT. Haemophilia 2002: emerging risks of treatment. Haemophilia. 2002;8(3):221-229. doi:10.1046/j.1365-2516.2002.00612.x

8. Manco-Johnson MJ, Abshire TC, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357(6):535-544. doi:10.1056/NEJMoa0676599. Haya S. Prophylactic treatment in hemophilic patients with inhibitors. Blood Coagul Fibrinolysis. 2019;30(1S Suppl 1):S14-S18. doi:10.1097/MBC.0000000000000823

Reviewed by Harshi Dhingra, MD, on 8/10/2021.