Diagnostic Considerations
Problems to be considered include vitamin K deficiency and other factor deficiencies. Other congenital bleeding disorders must be excluded. These may include the following:
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von Willebrand disease (autosomal dominant transmission)
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Platelet disorders (eg, Glanzmann thrombasthenia)
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Deficiency of other coagulation factors (ie, factor II, V, VII, X, or XI; or fibrinogen)
Clinical differentiation of severe hemophilia A from severe hemophilia B is almost impossible, but specific factor assays can help with the distinction. Conditions that can increase factor VIII levels (eg, age, ABO blood type, stress, exercise) can obscure the diagnosis of hemophilia A.
Please see the following for more information:
Combined factor V and factor VIII deficiency
In rare cases a true hemophilic factor VIII deficiency may be associated with hereditary factor V deficiency. Treatment of bleeding episodes in these patients requires use of fresh-frozen plasma (FFP) to replace factor V, and replacement of factor VIII by FFP and desmopressin or FVIII concentrates. [19]
Combined deficiency of factor VIII and factor V has been traced to mutations in the lectin mannose binding protein 1 (LMAN1) or multiple coagulation factor deficiency 2 (MCFD2) genes, which encode proteins involved in the intracellular transport of FV and FVIII. [19] A similarly reduced level of factor V and factor VIII clotting activities in plasma, and finding other members in the same family with combined factor V and factor VIII deficiency, are all clues to the disorder.
Most difficult to detect on the basis of the history alone is the presence or absence of consanguinity (a feature of recessive disorders requiring 2 doses of the gene for clinical manifestations). In families with known mutations, allele-specific hybridization studies show the difference between homozygotes and heterozygotes.
Acquired multiple-factor coagulopathies due to liver disease, diffuse intravascular coagulation (DIC), warfarin excess, or coagulopathy of dysproteinemias should also be considered.
Differential Diagnoses
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Hemophilia, Type B
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Coagulation pathway.
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The hemostatic pathway. APC = activated protein C (APC); AT-III = antithrombin III; FDP = fibrin degradation products; HC-II = heparin cofactor II; HMWK = high-molecular-weight kininogen; PAI = plasminogen activator inhibitor; sc-uPA = single-chain urokinase plasminogen activator; tc-uPA = two-chain urokinase plasminogen activator; TFPI = tissue factor pathway inhibitor; tPA = tissue plasminogen activator
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Structural domains of human factor VIII. Adapted from: Stoilova-McPhie S, Villoutreix BO, Mertens K, Kemball-Cook G, Holzenburg A. 3-Dimensional structure of membrane-bound coagulation factor VIII: modeling of the factor VIII heterodimer within a 3-dimensional density map derived by electron crystallography. Blood. Feb 15 2002;99(4):1215-23; Roberts HR, Hoffman M. Hemophilia A and B. In: Beutler E, Lichtman MA, Coller BS, et al, eds. Williams Hematology. 6th ed. NY: McGraw-Hill; 2001:1639-57; and Roberts HR. Thoughts on the mechanism of action of FVIIa. Presented at: Second Symposium on New Aspects of Haemophilia Treatment; 1991; Copenhagen, Denmark.
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Possible genetic outcomes in individuals carrying the hemophilic gene.
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Photograph of a teenage boy with bleeding into his right thigh as well as both knees and ankles.
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Photograph of the right knee in an older man with a chronically fused, extended knee following open drainage of knee bleeding that occurred many years previously.
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Photograph depicting severe bilateral hemophilic arthropathy and muscle wasting. The 3 punctures made into the left knee joint were performed in an attempt to aspirate recent aggravated bleeding.
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Radiograph depicting advanced hemophilic arthropathy of the knee joint. These images show chronic severe arthritis, fusion, loss of cartilage, and joint space deformities.
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Radiograph depicting advanced hemophilic arthropathy of the elbow. This image shows chronic severe arthritis, fusion, loss of cartilage, and joint space deformities.
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Photograph of a hemophilic knee at surgery, with synovial proliferation caused by repeated bleeding; synovectomy was required.
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Large amount of vascular synovium removed at surgery.
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Microscopic appearance of synovial proliferation and high vascularity. If stained with iron, diffuse deposits would be demonstrated; iron-laden macrophages are present.
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Large pseudocyst involving the left proximal femur.
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Transected pseudocyst (following disarticulation of the left lower extremity due to vascular compromise, nerve damage, loss of bone, and nonfunctional limb). This photo shows black-brown old blood, residual muscle, and bone.
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Dissection of a pseudocyst.
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Transected pseudocyst with chocolate brown-black old blood.
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Photograph of a patient who presented with a slowly expanding abdominal and flank mass, as well as increasing pain, inability to eat, weight loss, and weakness of his lower extremity.
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Plain radiograph of the pelvis showing a large lytic area.
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Intravenous pyelogram showing extreme displacement of the left kidney and ureter by a pseudocyst.
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Photograph depicting extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acquired factor VIII inhibitor.
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Magnetic resonance image of an extensive spontaneous abdominal wall hematoma and thigh hemorrhage in an older, previously unaffected man with an acquired factor VIII inhibitor.
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Coagulation Cascade
Tables
Classification |
Factor Activity, % |
Cause of Hemorrhage |
Mild |
>5-40 |
Major trauma or surgery |
Moderate |
1-5 |
Mild-to-moderate trauma |
Severe |
< 1 |
Spontaneous |
Indication or Site of Bleeding |
Factor level Desired, % |
FVIII Dose, IU/kg |
Comment |
Severe epistaxis; mouth, lip, tongue, or dental work |
20-50 |
10-25 |
Consider aminocaproic acid (Amicar), 1-2 d |
Joint (hip or groin) |
40 |
20 |
Repeat transfusion in 24-48 h |
Soft tissue or muscle |
20-40 |
10-20 |
No therapy if site small and not enlarging (transfuse if enlarging) |
Muscle (calf and forearm) |
30-40 |
15-20 |
None |
Muscle deep (thigh, hip, iliopsoas) |
40-60 |
20-30 |
Transfuse, repeat at 24 h, then as needed |
Neck or throat |
50-80 |
25-40 |
None |
Hematuria |
40 |
20 |
Transfuse to 40% then rest and hydration |
Laceration |
40 |
20 |
Transfuse until wound healed |
GI or retroperitoneal bleeding |
60-80 |
30-40 |
None |
Head trauma (no evidence of CNS bleeding) |
50 |
25 |
None |
Head trauma (probable or definite CNS bleeding, eg, headache, vomiting, neurologic signs) |
100 |
50 |
Maintain peak and trough factor levels at 100% and 50% for 14 d if CNS bleeding documented† |
Trauma with bleeding, surgery |
80-100 |
50 |
10-14 d |
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