Approach Considerations
Laboratory studies for suspected hemophilia B include a complete blood cell count, coagulation studies, and a factor IX (FIX) assay. Never delay indicated coagulation correction pending diagnostic testing. The United Kingdom Haemophilia Centre Doctors' Organization (UKHCDO) recommends that in the emergency setting, clinical assessment should be performed no more than 15 minutes after the patient arrives, and if treatment is required it should be initiated no longer than 30 minutes after arrival. [19]
On the hemoglobin/hematocrit, expect normal or low values. Expect a normal platelet count. On coagulation studies, the bleeding time and prothrombin time (which assesses the extrinsic coagulation pathway) are typically normal.
Usually, the activated partial thromboplastin time (aPTT) is prolonged; however, a normal aPTT does not exclude mild or even moderate hemophilia because of the relative insensitivity of the test, especially with factor levels greater than 15%. [20] The aPTT is significantly prolonged in severe hemophilia.
For FIX assays, levels are compared with a normal pooled-plasma standard, which is designated as having 100% activity or the equivalent of FIX U/mL. Normal values are 50-150%. Values in hemophilia are as follows:
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Mild - Greater than 5% to 40%
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Moderate - 1-5%
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Severe - Less than 1%
Spontaneous bleeding complications are severe in individuals with undetectable activity (< 0.01 U/mL), moderate in individuals with activity (2-5% normal), and mild in individuals with factor levels greater than 5%.
Usually, von Willebrand factor (vWF) levels are also measured. The combination of low FVIII and low vWF may indicate vWF deficiency as the primary diagnosis.
Because FIX is a large molecule that does not cross the placenta, the diagnosis can be made at birth with quantitative assay of coagulation factors in the cord blood. However, early diagnosis of FIX deficiency is complicated by the physiologic reduction of vitamin K–dependent factors in young infants. In term and healthy premature neonates, FIX values are low (20-50% of the normal level), due to hepatic immaturity. Levels rise to normal after 6 months of age. FVIII levels are normal during that period of life.
In patients with an established diagnosis of hemophilia B, laboratory evaluations include periodic screening for the presence of FIX inhibitor and screening for transfusion-related or transmissible diseases such as hepatitis and HIV. Screening for infectious disease may be less important in patients who have received only recombinant product.
Imaging studies for acute bleeds
Early and aggressive imaging is indicated, even with low suspicion for hemorrhage, after coagulation therapy is initiated. Imaging choices are guided by clinical suspicion and anatomic location of involvement.
Head computed tomography (CT) scans without contrast are used to assess for spontaneous or traumatic intracranial hemorrhage. Perform magnetic resonance imaging on the head and spinal column for further assessment of spontaneous or traumatic hemorrhage. Magnetic resonance imaging (MRI) is also useful in the evaluation of the cartilage, synovium, and joint space.
Ultrasonography is useful in the evaluation of joints affected by acute or chronic effusions. This technique is not helpful for evaluating the bone or cartilage. Special studies such as angiography and nucleotide bleeding scan may be clinically indicated.
Testing for Inhibitors
Laboratory confirmation of a FIX inhibitor is clinically important when infusion of adequate amounts of factor concentrate fails to control a bleeding episode. For the assay, the aPTT measurement is repeated after incubating the patient's plasma with normal plasma at 37°C for 1-2 hours. If the prolonged aPTT is not corrected, the inhibitor concentration is titrated using the Nijmegen modification of the Bethesda inhibitor assay. Specific antibodies to FIX usually are IgG subclass 4 or a mixture of IgG subclasses 1 and 4. An experienced laboratory must perform these tests.
By convention, more than 0.6 Bethesda units (BU) is considered a positive result for an inhibitor. Less than 5 BU is considered a low titer of inhibitor, and more than 10 BU is a high titer. The distinction is clinically significant, as patients with low-titer inhibitors may respond to higher doses of factor concentrate.
Carrier Testing and Fetal Testing
Plasma FIX levels are normal in approximately a third of FIX carriers. If the specific FIX gene mutation is known, direct genetic testing provides accurate results. Linkage analysis by restriction fragment length polymorphism (RFLP) in multiple family members can be used. Direct mutation analysis is available in several laboratories for unknown FIX mutations.
For fetal testing, if the mutation is known, then RFLP can be performed on chorionic villus or amniocentesis samples. If the mutation is not known, gene sequencing can be performed.
Radiography
Radiography for joint assessment is of limited value in acute hemarthrosis. Evidence of chronic degenerative joint disease may be visible on radiographs in patients who are untreated or inadequately treated or in those with recurrent joint hemorrhages. In these patients, radiographs may show synovial hypertrophy, hemosiderin deposition, fibrosis, and damage to cartilage that progresses with subchondral bone cyst formation.
Hemophilic arthropathy evolves through 5 stages, starting as an intra-articular and periarticular edema due to acute hemorrhage and progressing to advanced erosion of the cartilage with loss of the joint space, joint fusion, and fibrosis of the joint capsules. [4] See the image below. For discussion of the 5-stage Arnold-Hilgartner classification of hemophilic arthropathy, see Imaging in Musculoskeletal Complications of Hemophilia
Knee radiographs in a patient with advanced hemophilic arthropathy demonstrate chronic severe arthritis, fusion, and loss of cartilage and joint space.
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Coagulation Cascade
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Obituary in the Salem Gazette (Massachusetts) of a 19-year-old man, March 22, 1796.
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The hemostatic pathway: role of factor IX.
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Activation of factor IX and function of the intrinsic tenase complex. Activation of factor IX is followed by formation of the intrinsic tenase complex, which activates factor X to activated factor X, leading to a second and larger burst of thrombin production during activation of hemostasis.
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Vitamin K–dependent carboxylation of precursor factor IX to procoagulant factor IX. Carboxylation of glutamate (Glu) to gamma-carboxyglutamate (Gla) residues in the precursor protein of the vitamin K–dependent factors occurs in the endoplasmic reticulum of the hepatocyte. Reduced vitamin K is oxidized in this process. Warfarin prevents the reduction and recycling of oxidized vitamin K.
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Cell surfaced-directed hemostasis. Initially, a small amount of thrombin is generated on the surface of the tissue factor (TF)–bearing cell. Following amplification, the second burst generates a larger amount of thrombin, leading to fibrin (clot) formation. (Adapted from Hoffman and Monroe, Thromb Haemost 2001, 85(6): 958-65.)
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Knee radiographs in a patient with advanced hemophilic arthropathy demonstrate chronic severe arthritis, fusion, and loss of cartilage and joint space.
Tables
Classification |
Factor Activity, % |
Cause of Hemorrhage |
Mild |
>5-40 |
Major trauma or surgery |
Moderate |
1-5 |
Minor trauma or surgery; occasional spontaneous hemarthrosis |
Severe |
< 1 |
Lifelong spontaneous hemorrhages and hemarthroses starting in infancy |
Indication or Site of Bleeding |
Factor level Desired, % |
FIX Dose, IU/kg* |
Comment |
Severe epistaxis; mouth, lip, tongue, or dental work |
20-50 |
20-50 |
Consider aminocaproic acid (Amicar), 1-2 d |
Joint (hip or groin) |
40 |
40 |
Repeat transfusion in 24-48 h |
Soft tissue or muscle |
20-40 |
40 |
No therapy if site small and not enlarging (transfuse if enlarging) |
Muscle (calf and forearm) |
30-40 |
40 |
None |
Muscle deep (thigh, hip, iliopsoas) |
40-60 |
40-60 |
Transfuse, repeat at 24 h, then as needed |
Neck or throat |
50-80 |
50-80 |
None |
Hematuria |
40 |
40 |
Transfuse to 40% then rest and hydration |
Laceration |
40 |
40 |
Transfuse until wound healed |
GI or retroperitoneal bleeding |
60-80 |
60-80 |
None |
Head trauma (no evidence of CNS bleeding) |
50 |
50 |
None |
Head trauma (probable or definite CNS bleeding, eg, headache, vomiting, neurologic signs) |
100 |
100 |
Maintain peak and trough factor levels at 100% and 50% for 14 d if CNS bleeding documented† |
Trauma with bleeding, surgery |
80-100 |
100 |
10-14 d |
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- Overview
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- Approach Considerations
- Prehospital Care
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- Factor IX Concentrates
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