(See also Overview of Coagulation Disorders.)
Hemophilias are common hereditary bleeding disorders caused by deficiencies of either clotting factor VIII or IX. The extent of factor deficiency determines the probability and severity of bleeding. Bleeding into deep tissues or joints usually develops within hours of trauma. The diagnosis is suspected in a patient with an elevated PTT and normal PT and platelet count; it is confirmed by specific factor assays. Treatment includes replacement of the deficient factor if acute bleeding is suspected, confirmed, or likely to develop (eg, before surgery).
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%; some 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 their 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 due to contaminated factor concentrates. 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.
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). Moderate hemophilia (factor levels 1 to 5% of normal) usually causes bleeding after minimal trauma. In mild hemophilia (factor levels 5 to 25% of normal), excessive bleeding may occur after surgery or dental extraction.
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. 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 wk or amniocentesis at 16 wk. These procedures carry a 0.5 to 1% risk of miscarriage.
After repeated exposure to factor VIII replacement, about 15 to 35% of patients with hemophilia A develop factor VIII isoantibodies (alloantibodies) that inhibit the coagulant activity of any additional factor VIII infused. 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 h), 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.
Patients should avoid aspirin and NSAIDs (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 h 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 h. 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), as well as a recombinant factor IX-Fc fusion protein (2) and a pegylated recombinant factor IX (3), with longer in vivo survival times have recently been reported to successfully control bleeding in hemophilia A and B.
In patients with hemophilia who develop a factor VIII inhibitor, treatment is best accomplished using recombinant activated factor VII (VIIa) in repeated high doses (eg, 90 mcg/kg).
Both VWF and factor VIII are stored in the Weibel-Palade bodies of endothelial cells, and secreted in response to endothelial cell stimulation (4). Adjunctive therapy for hemophilia A thus includes 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 po qid for 1 wk or tranexamic acid 1.0 to 1.5 g po tid or qid for 1 wk) 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. 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.
4. 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 PTT is prolonged but the PT 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 15 to 35% of patients with hemophilia A who require repeated factor VIII infusions develop antibodies to factor VIII.