Loading...
Hemophilia A is the second most common inherited bleeding disorder, after von Willebrand disease (vWD), with a worldwide incidence of approximately 1 case per 5000 males.[1] Hemophilia A is caused by a deficiency or abnormality of the plasma coagulation protein factor VIII (FVIII). In its severe form, this condition can cause significant morbidity from recurrent spontaneous bleeding into joints, muscles, and the brain. In its milder form, hemophilia A can lead to prolonged oozing of blood after injuries, tooth extractions, or surgery. The age at diagnosis, the frequency of bleeding, and the severity of bleeding episodes are related to the level of FVIII clotting activity.
Image courtesy of Crystl / Wikimedia Commons.
A few days into the postnatal period, a male infant is found to have excessive bleeding after circumcision. Laboratory results reveal a prolonged partial thromboplastin time (PTT) that corrects after the addition of normal pooled plasma in a 1:1 ratio, which is indicative of a factor deficiency in the intrinsic pathway. FVIII coagulation activity is less than 1% (<0.01 IU/mL). The platelet count, factor IX (FIX) activity, factor XI (FXI) activity, and von Willebrand factor (vWF) antigen and activity levels are normal. There is no history of a bleeding disorder in his family.
What is the most likely diagnosis in this male infant?
Diagram courtesy of Elizabeth DelGiacco, DO.
Answer: Hemophilia A.
Hemophilia A is the most common X-linked recessive bleeding disorder; therefore, it usually affects boys—as illustrated in the 18th-century obituary shown. However, some carrier females can also be affected, depending on the degree of Barr body inactivation of the affected gene. Hemophilia A is distinguished from hemophilia B by a normal FIX activity level. Subtype 2N of vWD (vWD 2N) can also manifest with low FVIII levels owing to a mutation of the FVIII binding site, which leads to increased clearance.[2] Both vWD 2N and hemophilia A are marked by a low FVIII:vWF activity ratio. The only way to distinguish between the two conditions is by testing with an FVIII binding assay.
Image courtesy of Salem Gazette (Massachusetts).
Hemophilia A is a classic example of X-linked recessive inheritance. It was first described in the second century CE.[3] The image displays a classic X-linked recessive inheritance pattern, with females in most cases acting as "silent" carriers of the disease. In approximately 25% of cases, no family history is identified. These cases presumably represent de-novo mutations arising either in the affected individual or, more commonly, in the maternal grandfather's germ cell during meiosis when there is an absence of homologous X chromosome pairing.[4]
Image adapted from Flickr / Morgan TH. Heredity and Sex. New York: Columbia University Press; 1913:253.
The FVIII gene (F8) is located on the long arm of the X chromosome. It is approximately 186 kb long, with 26 exons and 25 introns. Approximately 50% of severe hemophilia A cases are due to an inversion at intron 22. Within intron 22 are two small genes, F8A and F8B. In addition, there are two F8A genes telomeric to F8, making this a vulnerable breakpoint site. An intrachromosomal recombination event occurs on the single X chromosome, resulting in an inversion with one of two homologous extragenic F8A genes. A wide range of mutations of F8 result in hemophilia. Different types of mutations have been characterized (deletion, inversion, missense, and nonsense), and these can affect the severity of disease.[5,6]
Image courtesy of Elizabeth DelGiacco, DO.
The infant male patient with severe hemophilia A presented earlier is now 9 months old. He has been appropriately referred to a hemophilia treatment center and is receiving regular care and preventive measures. He has had no further bleeding episodes since undergoing circumcision. You would like to prevent future bleeding episodes.
What is the most appropriate next step for preventing spontaneous bleeding in this patient?
Image courtesy of Andylim / Dreamstime.
Answer: Primary prophylaxis with FVIII concentrate.
Many FVIII concentrates (recombinant or highly purified pooled plasma products) are commercially available. Each can be infused for prevention or therapy.[8] Patients with severe disease can be treated with routine prophylactic factor infusion to prevent or suppress bleeding. Other individuals are taught to infuse at the earliest sign of bleeding; this is termed an on-demand approach.[9] Parents often can learn to infuse children as young as 2 years. By age 12 years, most children with hemophilia can learn to self-infuse.[10]
Emicizumab, a bispecific antibody that mimics FVIII, was granted a breakthrough therapy designation from the FDA for prophylaxis with once-weekly subcutaneous injections. A study by Shima et al found that it led to less episodic treatment of bleeding and less inhibitor formation.[11]
Image courtesy of Wikimedia Commons.
Randomized studies in young boys (age <30 months) with severe hemophilia A have shown that primary prophylaxis with regular infusion of recombinant FVIII can prevent joint damage, as well as decrease the frequency of spontaneous hemorrhages.[8] The affected individual is eventually trained to self-administer prophylactic infusions three times per week, or every other day, to maintain FVIII clotting activity greater than 1%. The half-life of FVIII is approximately 10-12 hours. One IU of FVIII is the amount of clotting activity found in 1 mL of fresh normal pooled plasma. Thus, 1 IU of FVIII per kilogram of body weight will raise a patient's plasma level by approximately 2%.[12]
Image courtesy of Medscape.
The most common cause of morbidity in patients with hemophilia is hemarthrosis.[4] The photograph on the left (A) is from a teenage boy and shows bleeding into both knees and ankles, as well as into the right thigh. The radiograph on the right (B) is from a different patient and reveals typical severe hemarthrosis with widening of the intercondylar notch, accentuation of the trabeculae, and enlargement of the medial epicondyle.
Acutely, bleeding into the joint space causes severe pain and immobility. Absorption of the blood then promotes synovial inflammation, thickening, and blood vessel formation.[13] This can result in the development of a "target joint" that incurs repeated bleeding. Target joints are most commonly the hinged joints, including ankles, knees, and elbows. Multiaxial joints, including the shoulders, wrists, and hips, are less likely to become target joints.
Images courtesy of Medscape.
Without treatment, joints with repeated intra-articular bleeding develop a characteristic synovitis, which leads to debilitating joint damage and consequent muscle wasting.
The photograph on the left (A) shows a chronically fused, extended knee in a patient with hemophilia. The radiograph on the right (B) depicts advanced hemophilic arthropathy of the knee joint, with fusion, loss of cartilage, and joint-space deformity.
Images courtesy of (left) Medscape and (right) learningradiology / William Herring, MD, FACR.
Despite primary prophylaxis with FVIII concentrates and appropriate counseling about activity, your patient sustains a fall from a ladder. He presents to the emergency department 2 hours later. On physical examination, there is faint ecchymosis on his left forehead. Neurologic examination does not reveal any abnormalities.
What is the most appropriate next step?
Image courtesy of Mike2focus / Dreamstime.
Answer: Urgent evaluation of the head trauma for intracranial bleeding and treatment.
Every reported instance of head trauma in a patient with hemophilia A should be treated on an emergency basis, even in the absence of any neurologic symptoms or signs of external bruising. The prevalence of intracranial bleeding is less than 5%,[14] but this remains a major cause of mortality. Infusion of 40-50 IU/kg to result in 100% FVIII replacement should be completed, even before computed tomography (CT) of the head is performed. If there is no sign of bleeding, trough levels of FVIII should be maintained above 80% for at least 2-3 days. If there is evidence of head injury, as in this case, then 100% replacement must be continued for at least 2 weeks.[14]
Image courtesy of Medscape.
Your patient with severe disease presents to your office and is found to have two new large spontaneous intramuscular bleeds in his right posterior thigh. He denies having sustained trauma. He reports self-infusing appropriate doses of product at home and has not missed any doses in the past month. Laboratory studies reveal FVIII activity of less than 1%. A prolonged PTT does not correct with the incubation of a 1:1 mix of normal plasma.
What is your diagnosis?
Image courtesy of Elizabeth DelGiacco, DO.
Answer: Immunoglobulin (Ig) G alloantibody or inhibitor to FVIII epitopes.
Hemophilia A patients are at high risk for developing an IgG alloantibody or inhibitor, specifically to FVIII epitopes. The prevalence is 25% in patients with severe hemophilia A (10% overall). Inhibitors are more common in patients with mutations that completely disrupt the formation of FVIII, including inversions (40%), large deletions (32%), and nonsense mutations that create stop codons (37%).[15] The likelihood of developing an inhibitor also depends on the concentrate used for replacement therapy; those patients who receive plasma-derived FVIII containing vWF have the lowest incidence.[16] Inhibitors are measured in Bethesda units (BU), with 1 BU defined as the volume of plasma that inactivates 50% of FVIII activity in normal plasma. Your patient has a Bethesda titer of 50 BU.
What treatment would you consider starting to prevent the patient's bleeding from worsening?
Image courtesy of Elizabeth DelGiacco, DO.
Patients with inhibitors are categorized either as low responders, if their inhibitor level does not exceed 5 BU, or as high responders, if their inhibitor level rises briskly above 5 BU in response to the presence of FVIII antigen.[17] High responders cannot be treated with FVIII infusion alone, because of the large amount of FVIII that would be required to neutralize the antibody. Other acute and chronic treatment strategies have been developed for this situation and are outlined in the table (shown).[18]
Table courtesy of Elizabeth DelGiacco, DO.
It is recommended that individuals with hemophilia A receive routine follow-up and care through one of the 150 government-funded hemophilia treatment centers (HTCs). For individuals with severe or moderate hemophilia A, assessments are recommended every 6-12 months. For those with mild disease, assessments are recommended at least every 2-3 years.[19]
Special attention should be given to monitoring joint disease and transfusion-transmitted infections. In the final decades of the 20th century, high rates of infection with HIV—and, to a lesser extent, hepatitis B virus (HBV) and hepatitis C virus (HCV)—from contaminated factor concentrates derived from pooled plasma devastated the hemophilia population and spurred development of the recombinant and purified FVIII products currently available.[9]
Image courtesy of Medscape / Sam Shlomo Spaeth.
Previous
Next 
