This case highlights the importance of confirming the diagnosis when first seeing a patient with reportedly known hemophilia. If original laboratory reports are not available, repeat testing is suggested. First, it is important to be certain about which factor (VIII, IX, or XI) is low. There was a case at another facility where a new hemophilia patient received factor VIII concentrate for a bleeding event, but actually had hemophilia B (factor IX deficiency). Second, laboratories must test factors at multiple dilutions to rule out an inhibitor (e.g., lupus anticoagulant, heparin, or direct thrombin inhibitor). For example, a patient with a diagnosis of hemophilia C (factor XI deficiency), who had moved from another state, was seen at my institution. Our testing revealed, however, that only the 1:10 dilution (1 volume of sample in 9 volumes of diluent) revealed a low factor XI activity, and the factor XI activity increased with dilution, such that a 1:40 dilution (1 volume sample in 39 volumes diluent) had normal factor XI activity. We found that the patient had a lupus anticoagulant interfering in the factor XI assay, which cause a false reduction in factor XI activity. For the 20 years before these tests, he had received unnecessary fresh frozen plasma preoperatively, and the lupus anticoagulant's thrombotic risk had not been realized.
If factor VIII is low, other entities need to be considered before diagnosing hemophilia A. Factor VIII is labile and can be falsely low if the sample has clotted, has been kept as whole blood on ice, or has undergone repeated freeze/thaw cycles. Disseminated intravascular coagulation can consume factor VIII. von Willebrand disease, when severe enough, causes low factor VIII. mportantly, normal von Willebrand factor results do not exclude type 2N von Willebrand disease, which is characterized by a factor VIII activity 5%–40% of normal, owing to a von Willebrand factor mutation that impairs its ability to bind and protect factor VIII. Type 2N von Willebrand disease can be distinguished from hemophilia A by the inheritance pattern (autosomal vs X-linked, respectively) or, if necessary, by a factor VIII–binding assay or genetic tests at a reference laboratory. As shown in this case, it is important that the prothrombin and activated partial thromboplastin times also be assessed to screen for other causes of low factor VIII activity, such as combined deficiencies of factors V and VIII, clotted sample, or disseminated intravascular coagulation.
The most efficient approach is to start with measuring the prothrombin and activated partial thromboplastin times in a laboratory that reflexively performs mixing studies, factor assays, and/or lupus anticoagulant testing, as indicated.
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Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.
- Received for publication September 7, 2011.
- Accepted for publication September 8, 2011.
- © 2012 The American Association for Clinical Chemistry