This month, Caroline Berube, MD, discusses treatment for a patient with a prolonged PTT and antiphospholipid antibodies.
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I just saw a 78-year-old female patient with a prolonged partial thromboplastin time (PTT) for a second opinion. She was first noted to have a prolonged PTT in early adulthood. Subsequent testing disclosed a positive lupus anticoagulant and anticardiolipin antibodies. She has had no bleeding or clotting problems over the years. She recently saw another hematologist for the prolonged PTT. The following blood tests were obtained: Factor IX (FIX) activity less than 1, FIX inhibitor of 3.3 Bethesda units, factor VIII (FVIII) activity of 63, a negative von Willebrand panel, thrombin clotting time of 16 seconds, fibrinogen of 365, prothrombin time of 14.3 seconds, and PTT of 107 seconds. Three weeks ago, she was initiated on prednisone 70 mg daily. She denies any history of deep vein thrombosis, pulmonary embolism, transient ischemic attack, myocardial infarction, or cerebrovascular accident. In my opinion, the prolonged PTT is secondary to the antiphospholipid antibodies, which were not reassessed. These are likely also interfering with the FIX inhibitor test. I would like to get her off the prednisone as soon as possible. How would you treat this patient?
This case illustrates the challenge that clinical laboratories face in differentiating specific FVIII/FIX inhibitors from the presence of a lupus anticoagulant (LA) in a plasma sample. In this case, LA can interfere with the FIX activity assay; conversely, the presence of a FIX inhibitor may also interfere with the LA assay. The finding of LA is relatively frequent compared with the rare occurrence of a specific factor inhibitor in individuals without hemophilia.
In general, coagulation inhibitors are identified following the finding of a prolonged clotting time and confirmed by a mixing study using a 1:1 mix of patient plasma with normal plasma. In the absence of correction of the PTT with mixing studies, the laboratory must determine whether it is secondary to a nonspecific factor inhibitor (LA, heparin, or other anticoagulant), a specific factor inhibitor or, rarely, both. Here, a normal thrombin time rules out heparin as a cause. In the case of a PTT inhibitor, further testing for LA and specific factor assays are usually performed.
In this case, the finding of a markedly prolonged PTT along with a prior positive LA and anticardiolipin antibody result is suggestive of a persistent LA. The diagnosis of LA can be further supported if other clot-based assays such as dRVVT are positive. The issue here is whether the patient has a concurrent “true” de novo specific FIX inhibitor to guide therapy. Clinically, the absence of bleeding complications argues against a specific FIX inhibitor or acquired hemophilia B. Most reported cases of specific factor inhibitor development are due to an autoantibody to FVIII (acquired hemophilia A), whereas specific FIX antibody occurrence is rare. In both instances, affected individuals usually present with significant spontaneous bleeding involving the mucosa, skin, and muscle, which can be life threatening. This is not the case in this patient without bleeding manifestations.
From a laboratory perspective, here are some considerations to distinguish LA from a specific FVIII/FIX inhibitor:
- Factor assays should be run by using at least three dilutions. This is critical, especially when there is a nonspecific inhibitor effect such as a LA. The pattern of factor activity across dilutions can provide important clues to the nature of the inhibitor. In the presence of LA, measured factor activities by one stage assay may show a falsely low factor activity due to nonspecific inhibitor interference, resulting in an apparent rising factor activity with increasing dilutions (nonparallelism). Still, high dilutions may not be sufficient to get rid of the interference from a strong LA. In contrast, if a specific factor inhibitor is present, the measured factor activity would be consistently low across plasma dilutions.
- When performing the Bethesda assay to determine the specific factor inhibitor titer, this PTT-based test can also be affected by a strong LA
- Plasma containing FVIII specific inhibitors shows a time dependency for inhibition; this is not the case with other factor inhibitors or LA
- Determination of FVIII/FIX activity by chromogenic assay would be optimal, chromogenic assays being insensitive to LA (commercially available). ELISA assays may be useful, although not readily available.
To summarize, the patient has a history of a strong LA. The report of a specific FIX inhibitor of 3.3 Bethesda units is unanticipated in this elderly woman without bleeding complications, raising the possibility of misidentification in the setting of LA. Determination of FIX by chromogenic assay would be valuable information to clarify the diagnosis. This highlights the importance of good communication between the clinician and the laboratory staff in such cases.
- Moser, K, Funk Dorothy. AJH Educational material Chromogenic factor VIII activity assay. Am J Hematol. 2014;89:781-4.
- Kershaw, G. Favaloro, EJ. Laboratory identification of factor inhibitors: an update. Pathology. 2012;44:293-302.
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NEXT MONTH'S CLINICAL DILEMMA
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