ESSENTIALS OF DIAGNOSIS
Hemophilia A: congenital deficiency of coagulation factor VIII.
Hemophilia B: congenital deficiency of coagulation factor IX.
Recurrent hemarthroses and arthropathy.
Risk of development of inhibitory antibodies to factor VIII or factor IX.
Many older patients received blood products contaminated with HIV or hepatitis C virus.
The frequency of hemophilia A is ~1 per 5000 live male births, whereas hemophilia B occurs in ~1 in 25,000 live male births. Inheritance is X-linked recessive, leading to affected males and carrier (affected) females with variable bleeding tendencies. Daughters of all affected males are obligate carriers. There is no race predilection. Factor activity testing is indicated for male infants with a hemophilic maternal pedigree who are asymptomatic or who experience excessive bleeding, for all daughters of affected males (100% chance of being affected) and carrier mothers (50% chance of being affected), and for otherwise asymptomatic adolescents or adults who experience unexpected excessive bleeding with trauma or invasive procedures.
Inhibitors to factor VIII will develop in approximately 20–25% of patients with severe hemophilia A, and inhibitors to factor IX will develop in less than 5% of patients with severe hemophilia B. The risk of development of an inhibitor to factor VIII or factor IX is highest in patients with severe hemophilia who have a sibling in whom inhibitor formation occurred; the characteristics of initiation of administration of factor replacement in childhood, as well as mutation type, also may be influential. Recent data suggest that recombinant products may have an increased risk of inhibitor formation than products made from pooled plasma.
A substantial proportion of older patients with hemophilia acquired infection with HIV or HCV or both in the 1980s due to exposure to contaminated factor concentrates and blood products.
Severe hemophilia (factor VIII activity less than 1%) presents in infant males or in early childhood with spontaneous bleeding into joints, soft tissues, or other locations. Spontaneous bleeding is not common in patients with mild hemophilia (factor VIII activity greater than 5%), but bleeding is common with a significant hemostatic challenge (eg, surgery, trauma). Intermediate clinical symptoms are seen in patients with moderate hemophilia (factor VIII activity 1–5%). Female carriers of hemophilia can have a wide range of factor VIII activity and therefore have variable bleeding tendencies.
Significant hemophilic arthropathy is usually avoided in patients who have received long-term prophylaxis with factor concentrate starting in early childhood, whereas joint disease is common in adults who have experienced recurrent hemarthroses. Patients tend to have one or two “target” joints into which they bleed most often.
Inhibitor development to factor VIII or factor IX is characterized by bleeding episodes that are resistant to treatment with clotting factor VIII or IX concentrate, and by new or atypical bleeding.
Hemophilia A or B is diagnosed by demonstration of an isolated reproducibly low factor VIII or factor IX activity level, in the absence of other conditions. If the aPTT is prolonged, it typically corrects upon mixing with normal plasma. A variety of mutations, including inversions, large and small deletions, insertions, missense mutations, and nonsense mutations may be causative. Depending on the level of residual factor VIII or factor IX activity and the sensitivity of the thromboplastin used in the aPTT coagulation reaction, the aPTT may or may not be prolonged, although it typically is markedly prolonged in severe hemophilia. Hemophilia is classified according to the level of factor activity in the plasma. Severe hemophilia is characterized by less than 1% factor activity, moderate hemophilia features 1–5% factor activity and mild hemophilia features greater than 5% factor activity. Female carriers may become symptomatic if significant lyonization has occurred favoring the defective factor VIII or factor IX gene, leading to factor VIII or factor IX activity level markedly less than 50%. Typically, a clinical bleeding diathesis occurs once the factor activity is less than 20%, but this appears to be patient-specific, and bleeding can occur in trauma, surgery, and delivery if the factor activity is less than 50%.
In the presence of an inhibitor to factor VIII or factor IX, there is accelerated clearance of and suboptimal or absent rise in measured activity of infused factor, and the aPTT does not correct on mixing. The Bethesda assay measures the potency of the inhibitor.
A. Factor VIII or IX Products
Plasma-derived or recombinant factor VIII or IX products are the mainstay of treatment. The standard of care for most individuals with severe hemophilia is primary prophylaxis: by the age of 4 years, most children with severe hemophilia have begun twice- or thrice-weekly infusions of factor to prevent the recurrent joint bleeding that otherwise would characterize the disorder and lead to severe musculoskeletal morbidity. In selected cases of less severe hemophilia, or as an adjunct to prophylaxis in severe hemophilia, treatment with factor products is given periprocedurally, prior to high-risk activities (such as sports), or as needed for bleeding episodes (Table 14–8). Recombinant factor VIII and factor IX molecules that are bioengineered to have an extended half-life may allow for extended dosing intervals in patients who are treated prophylactically. The decision to switch to a long-acting product is patient specific. The long-acting factor IX products have clear added value in reducing frequency of factor injections. This is not so clear with the long-acting factor VIII products. Patients with mild hemophilia A may respond to as-needed (on demand) intravenous or intranasal treatment with DDAVP. Antifibrinolytic agents may be useful in cases of mucosal bleeding and are commonly used adjunctively, such as following dental procedures.
Table 14–8.Treatment of bleeding in selected inherited disorders of hemostasis. ||Download (.pdf) Table 14–8. Treatment of bleeding in selected inherited disorders of hemostasis.
|Disorder ||Subtype ||Treatment for Minor Bleeding ||Treatment for Major Bleeding ||Comment |
|Hemophilia A ||Mild ||DDAVP1 ||DDAVP1 or factor VIII product ||Treat for 3–10 days for major bleeding or following surgery, keeping factor activity level 50–80% initially. Adjunctive aminocaproic acid (EACA) may be useful for mucosal bleeding or procedures |
| ||Moderate or severe ||Factor VIII product ||Factor VIII product |
|Hemophilia B ||Mild, moderate, or severe ||Factor IX product ||Factor IX product |
|von Willebrand disease ||Type 1 ||DDAVP1 ||DDAVP1, vWF product |
| ||Type 2 ||DDAVP,1 vWF product ||vWF product |
| ||Type 3 ||vWF product ||vWF product |
|Factor XI deficiency ||— ||FFP or EACA ||FFP ||Adjunctive EACA should be used for mucosal bleeding or procedures |
B. Factor VIII or IX Inhibitors
Factor inhibitors (antibodies that interfere with activity or half-life) are a major clinical problem for patients with hemophilia. It may be possible to overcome low-titer inhibitors (less than 5 Bethesda units [BU]) by giving larger doses of factor, whereas treatment of bleeding in the presence of a high-titer inhibitor (more than 5 BU) requires infusion of an activated prothrombin complex concentrate (such as FEIBA [factor eight inhibitor bypassing activity]) or recombinant activated factor VII. Recombinant porcine factor VIII is also an option but is reserved for selective circumstances because of its cost. Inhibitor tolerance induction, achieved by giving large doses (50–300 units/kg intravenously of factor VIII daily) for 6–18 months, succeeds in eradicating the inhibitor in 70% of patients with hemophilia A and in 30% of patients with hemophilia B. Patients with hemophilia B who receive inhibitor tolerance induction, however, are at risk for development of nephrotic syndrome and anaphylactic reactions, making eradication of their inhibitors more problematic. Additional immunomodulation may allow for eradication in selected inhibitor tolerance induction–refractory patients. Emicizumab is a novel bi-specific antibody that brings activated factor IX and factor X together, effectively replacing the cofactor function of factor VIII in the clotting cascade, providing a real therapeutic advance for patients with inhibitors. Emicizumab has also been demonstrated to be an effective option for patients without inhibitors.
Phase I/II gene therapy trials for hemophilia A and B have shown great promise for patients with severe hemophilia A and B. For many, gene therapy has eliminated the need to use any factor replacement, and most patients no longer have spontaneous bleeding. While phase III clinical trials have been restricted to patients 18 years of age and older, the results look extremely promising. It is not known when this potentially life-changing gene therapy will become an approved treatment outside of clinical trials.
D. Antiretroviral Therapy
Antiretroviral treatment should be administered to hemophilia patients with HIV infection. Patients with hepatitis C infection should be referred for treatment to eradicate the virus.
The cyclooxygenase (COX)-2 selective nonsteroidal anti-inflammatory drug, celecoxib, may be used to treat arthritis symptoms; generally, other NSAIDs and aspirin should be avoided due to the increased risk of bleeding from inhibition of platelet function. Oral opioid medications are commonly used to control pain, including joint pain and surgical pain from the often-needed total joint replacements.
All patients with hemophilia should be seen regularly in a comprehensive hemophilia treatment center.
et al. Treatment for preventing bleeding in people with haemophilia or other congenital bleeding disorders undergoing surgery. Cochrane Database Syst Rev. 2015 Feb 9;2:CD009961.
et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N Engl J Med. 2017 Dec 7;377(23):2215–27.
et al. Emicizumab
prophylaxis in patients who have hemophilia A without inhibitors. N Engl J Med. 2018 Aug 30;379(9):811–22.
et al; Joint Outcomes Committee of the Universal Data Collection, US Hemophilia Treatment Center Network. Prophylaxis usage, bleeding rates, and joint outcomes of hemophilia, 1999 to 2010: a surveillance project. Blood. 2017 Apr 27;129(17):2368–74.
et al; US Hemophilia Treatment Center Network. Men with severe hemophilia in the United States: birth cohort analysis of a large national database. Blood. 2016 Jun 16;127(24):3073–81.
et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014 Nov 20;371(21):1994–2004.
et al. Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. N Engl J Med. 2020 Jan 2;382(1):29–40.