(See also Overview of Coagulation Disorders.)
Hemophilia A (factor VIII deficiency), which affects about 80% of patients with hemophilia, and hemophilia B (factor IX deficiency) have identical clinical manifestations and screening test abnormalities. Both are X-linked genetic disorders. Specific factor assays are required to distinguish the two.
Hemophilia is an inherited disorder that results from mutations, deletions, or inversions affecting the factor VIII or factor IX gene. Because these genes are located on the X chromosome, hemophilia affects males almost exclusively. Daughters of men with hemophilia are obligate carriers, but sons are normal. Each son of a carrier has a 50% chance of having hemophilia, and each daughter has a 50% chance of being a carrier.
Normal hemostasis (see figure Pathways in blood coagulation) requires > 30% of normal factor VIII and IX levels. Most patients with hemophilia have levels < 5%; severely affected patients have extremely low levels (< 1%). The functional level (activity) of factor VIII or IX in hemophilia A and B, and thus bleeding severity, varies depending on the specific mutation in the factor VIII or IX gene.
Carriers usually have levels of about 50%; rarely, random inactivation of the normal X chromosome in early embryonic life results in a carrier having factor VIII or IX levels of < 30%.
Most patients with hemophilia who were treated in the early 1980s were infected with HIV as a result of contaminated plasma or factor VIII or IX concentrates (before the development of effective viral inactivators). Occasional patients developed immune thrombocytopenia secondary to HIV infection, which exacerbated bleeding.
Patients with hemophilia bleed into tissues (eg, hemarthroses, muscle hematomas, retroperitoneal hemorrhage). The bleeding may be immediate or occur slowly, depending on the extent of trauma and plasma level of factor VIII or IX. Pain often occurs as bleeding commences, sometimes before other signs of bleeding develop. Chronic or recurrent hemarthroses can lead to synovitis and arthropathy. Even a trivial blow to the head can cause intracranial bleeding. Bleeding into the base of the tongue can cause life-threatening airway compression.
In mild hemophilia (factor levels 5 to 25% of normal), excessive bleeding may occur after surgery or dental extraction.
Moderate hemophilia (factor levels 1 to 5% of normal) usually causes bleeding after minimal trauma.
Severe hemophilia (factor VIII or IX level < 1% of normal) causes severe bleeding throughout life, usually beginning soon after birth (eg, scalp hematoma after delivery or excessive bleeding after circumcision).
Hemophilia is suspected in patients with recurrent bleeding, unexplained hemarthroses, or a prolongation of the PTT. If hemophilia is suspected, PTT, PT, platelet count, and factor VIII and IX assays are obtained. In hemophilia, the PTT is prolonged, but the PT and platelet count are normal.
Factor VIII and IX assays determine the type and severity of the hemophilia. Because factor VIII levels may also be reduced in von Willebrand disease (VWD), von Willebrand factor (VWF) activity, antigen, and multimer composition are measured in patients with newly diagnosed hemophilia A, particularly if the disorder is mild and a family history indicates that both male and female family members are affected. Determining if a female is a true carrier of hemophilia A is sometimes possible by measuring the factor VIII level. Similarly, measuring the factor IX level often identifies a carrier of hemophilia B.
Polymerase chain reaction (PCR) analysis of DNA that comprises the factor VIII gene, available at specialized centers, can be used for diagnosis of the hemophilia A carrier state and for prenatal diagnosis of hemophilia A by chorionic villus sampling at 12 weeks or amniocentesis at 16 weeks. These procedures carry a 0.5 to 1% risk of miscarriage.
After repeated exposure to factor VIII or IX replacement, about 30% of patients with severe hemophilia A and 3% with hemophilia B develop factor VIII or factor IX isoantibodies (alloantibodies) that inhibit the coagulant activity of any additional factor VIII or factor IX infused. Thus, patients should be screened for isoantibodies (eg, by measuring the degree of PTT shortening immediately after mixing the patient’s plasma with an equal volume of normal plasma, and then by repeating the measurement after incubation for 1 hour), especially before an elective procedure that requires replacement therapy. If isoantibodies are present, their titers can be measured by determining the extent of factor VIII inhibition by serial dilutions of patient plasma.
Family members who are carriers should be identified so that they may be offered genetic counseling.
To prevent bleeding, patients should avoid aspirin and nonsteroidal anti-inflammatory drugs (both inhibit platelet function). Regular dental care is essential so that tooth extractions and other dental surgery can be avoided. Drugs should be given orally or IV; IM injections can cause hematomas.
Patients with hemophilia should be vaccinated against hepatitis B.
If symptoms suggest bleeding, treatment should begin immediately, even before diagnostic tests are completed. For example, treatment for headache that might indicate intracranial hemorrhage should begin before CT is completed.
Replacement of the deficient factor is the primary treatment.
In hemophilia A, the factor VIII level should be raised transiently to
Repeated infusions at 50% of the initial calculated dose should then be given every 8 to 12 hours to keep trough levels > 50% for 7 to 10 days after major surgery or life-threatening hemorrhage. Each unit/kg of factor VIII increases the factor VIII level by about 2%. Thus, to increase the level from 0% to 50%, about 25 units/kg are required.
Factor VIII can be given as purified factor VIII concentrate, which is derived from multiple donors. It undergoes viral inactivation, but inactivation may not eliminate parvovirus or hepatitis A virus. Recombinant factor VIII is free of viruses and is usually preferred unless patients are already seropositive for HIV or for hepatitis B or C virus.
In hemophilia B, factor IX can be given as a purified or recombinant viral-inactivated product every 24 hours. The target levels of factor correction are the same as in hemophilia A. However, to achieve these levels, the dose must be higher than in hemophilia A because factor IX is smaller than factor VIII and, in contrast to VIII, has an extensive extravascular distribution.
Fresh frozen plasma contains factors VIII and IX. However, unless plasma exchange is done, sufficient whole plasma usually cannot be given to patients with severe hemophilia to raise factor VIII or IX to levels that prevent or control bleeding. Fresh frozen plasma should, therefore, be used only if rapid replacement therapy is necessary and factor concentrate is unavailable or the patient has a coagulopathy that is not yet defined precisely.
A recombinant factor VIII-Fc fusion protein (1), a recombinant factor IX-Fc fusion protein (2), a polyethylene glycol (PEG)-linked recombinant factor VIII (3), and a PEGylated factor IX (4) all have longer in vivo survival times and have been reported to control bleeding in hemophilia A and B.
For hemophilia A, emicizumab is a recombinant humanized bispecific monoclonal antibody that binds to both factor IX and factor X, links them into a factor Xase-like active complex that obviates the need for factor VIII, and may be an effective treatment for hemophilia A (5).
Newer therapeutic agents in clinical trials for both hemophilia A or B include fitusiran and concizumab (6, 7). Fitusiran is a small inhibitory RNA that knocks down the production of the natural anticoagulant protein, antithrombin. Concizumab is a humanized monoclonal antibody that blocks tissue factor pathway inhibitor (TFPI), another natural anticoagulant protein, and increases thrombin production in hemophilia A and B.
Gene therapy using adenovirus-associated delivery of either the factor VIII or IX gene is also in clinical trials for the treatment of hemophilia A or B (8).
Both VWF and factor VIII are stored in the Weibel-Palade bodies of endothelial cells, and secreted in response to endothelial cell stimulation (9). Adjunctive therapy for mild or moderate hemophilia A may, therefore, include in vivo stimulation of patient endothelial cells with the synthetic vasopressin analogue DDAVP (deamino-D- arginine vasopressin, also known as desmopressin). As described for VWD, desmopressin may temporarily raise factor VIII levels. The patient’s response should be tested before desmopressin is used therapeutically. Its use after minor trauma or before elective dental surgery may obviate replacement therapy. Desmopressin should be used only for patients with mild hemophilia A (basal factor VIII levels ≥ 5%) who have demonstrated responsiveness.
An antifibrinolytic agent (aminocaproic acid 2.5 to 4 g orally 4 times a day for 1 week or tranexamic acid 1.0 to 1.5 g orally3 or 4 times a day for 1 week) may also be used as adjunctive therapy in hemophilia A or B to prevent late bleeding after dental extraction or other oropharyngeal mucosal trauma (eg, tongue laceration).
1. Mahlangu J, Powell JS, Ragni MV, et al: Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood 123:317–325, 2014.
2. Powell JS, Pasi KJ, Ragni MV, et al: Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. N Engl J Med 369:2313–2323, 2013.
3. Konkle BA, Stasyshyn O, Chowdary P, et al: Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood 126:1078–1085, 2015.
4. Collins PW, Young G, Knobe K, et al. Recombinant long-acting glycoPEGylated factor IX in hemophilia B: A multinational randomized phase 3 trial. Blood 124:3880–3886, 2014.
5. Nuto A, Yoshihashi K, Takeda M, et al: Anti-factor IXa/X bispecific antibody (ACE910): Hemostatic potency against ongoing bleeds in a hemophilia A model and the possibility of routine supplementation. J Thromb Haemost 12:206–213, 2014.
6. Sehgal A, Barros S, Ivanciu L, et al: An RNAi therapeutic targeting antithrombin to rebalance the coagulation system and promote hemostasis in hemophilia. Nat Med 21:492–497, 2015.
7. Chowdary P, Lethagen S, Friedrich U, et al: Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: A randomized first human dose trial. J Thromb Haemost 13:743–754, 2015.
8. George LA: Hemophilia gene therapy comes of age. Blood Adv 1:2591–2599, 2017.
9. Turner NA and Moake JL: Factor VIII is synthesized in human endothelial cells, packaged in Weibel-Palade bodies and secreted bound to ULVWF strings. PLoS ONE 10(10): e0140740, 2015.
Hemophilias are X-linked recessive disorders of coagulation.
Hemophilia A (about 80% of patients) involves factor VIII deficiency, and hemophilia B involves factor IX deficiency.
Patients bleed into tissues (eg, hemarthroses, muscle hematomas, retroperitoneal hemorrhage) following minimal trauma; fatal intracranial hemorrhage may occur.
The partial thromboplastin time is prolonged but the prothrombin time and platelet count are normal; factor VIII and IX assays determine the type and severity of the hemophilia.
Patients with bleeding or in whom bleeding is anticipated (eg, before surgery or dental extraction) are given replacement factor, preferably using a recombinant product; dose depends on the circumstances.
About 30% of patients with severe hemophilia A who require repeated factor VIII infusions develop antibodies to factor VIII.