From Dr. Samir Patel: George, I was wondering if I could get some input from you or any of the other readers regarding a patient in my clinic. This is a 52 year old woman with history of multiple surgeries (dental, orthopedic) and with mixed history of intraoperative bleeding, late bleeding, and no bleeding. She was sent due to history and a prolonged aPTT (PTT). I have performed an extensive workup but have not been able to identify the cause of the prolongation and am not sure what to recommend regarding further workup and future surgery.
- PT/INR, normal
- PTT 46.2s; mixing studies: 1:1 mix 38.1s; 1:1 at 60 minutes 39.0s
- Lupus AC profile: PTT 45.8s, PTT–LA 51.5s, hexagonal phase phospholipid, 7.2s, DRVVT 28.2s. Comment: no lupus anticoagulant was detected. Results are consistent with presence of one or more factor specific inhibitors. Since DRVVT was within the normal limits, the factors in question are VIII, IX, XI, XII and the contact factors.
- Thrombin time, 14.3s
- Fibrinogen, 342 mg/dL
- Factor II, 102%; factor V, 109%; factor VIII, 193%; factor IX, 487%, 436%; factor X, 112%; factor XI, 94%; factor XII, 90%, prekallikrien 141%, 76%; high molecular weight kininogen, 75%
- Euglobulin lysis, normal
- Reptilase time, 17.7s
- Antiphosphatidyl serine antibodies negative, anticardiolipin antibodies negative
Unless I’m misinterpreting these results, lupus anticoagulant testing is negative but none of the factor assays show any abnormalities or presence of an inhibitor that would explain the prolongation of the PTT. Please help, thanks. Samir
Hello, Dr. Patel, and thank you for your interesting case. Though your PTT mixing studies appear to indicate an inhibitor, the results are somewhat borderline positive, and may bear repeating. While we await comments from our participants, may I suggest you also consider a factor XIII assay, as factor XIII deficiency associates with intermittent and delayed bleeding? Also, though perhaps less likely, you may wish to check on platelet function. Looking forward to additional comments!
From Dr. Dorothy Adcock:
From Dr. Dorothy Adcock:
Perhaps it is factor IX Padua.
From Dave McGlasson:
From Dave McGlasson:
Platelet function work up and factor XIII seems like the logical step. I also would like to know what reagent was used for the PTT: was it ellagic acid or particulate-activated? This can make A huge difference in the result. If anything that huge FIX assay would shorten the PTT, not prolong it. I would repeat the factor assay with another test reagent. Are there any lipid issues with the subject? Was the tests performed on photo-optic or mechanical instruments? This can affect the results.
From Bob Gosselin:
From Bob Gosselin:
I find it really really odd that the factor IX is soooooooooo high. What’s up with that? Was there any parallelism issues with the factors?
Also odd, they are looking at APA for w/u, as well as contact factors for a bleeding patient.
XIII, as suggested seems like the way to go, especially since there is delayed bleeding, but that IX of >400% is a cunumdrum.
We had a similar patient with bleeding, prolonged APTT, non-corrected, no LA, and factors within NL limits–she had an underlying monoclonal gammopathy. Sent the sample to DAF (?) to see if they could tease something out, but alas, they could not find anything either. Prolonged APTT may be a red herring and unrelated to the bleeding, so assessing platelet seems reasonable, if delayed, then perhaps the Canadian defect (?)… BG
Mild APTT prolongation only
Mild APTT prolongation only and mild bleeding phenotype might be caused by endogenous circulating heparinoids (heparin-like anticoagulant), usually they should interfere with thrombin time, but if they have rather short length as LMWH, it could express only anti-Xa activity. Anti-Xa test or hepzyme-PTT could help. For example, a recent case report where INTEM/HEPTEM (NATEM+/-heparinase) were utilized to detect endogenous heparinoids:
Miroslav D, et al. Endogenous heparinoids may cause bleeding in mucor infection and can be detected by nonactivated thromboelastometry and treated by recombinant activated factor VII. Medicine (Baltimore). 2016; 95: e2933 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779038/
A diagnostic conundrum!
A diagnostic conundrum! Several possibilities. As already noted, perhaps (acquired) FXIII deficiency or a platelet dysfunction–even the ‘Quebec’ disorder, which are both associated with delayed bleeding, and which would be unrelated with the raised APTT. The APTT may be associated with the cause of bleeding, or may be a red herring (an incidental finding unrelated to the cause). The mixing studies are unclear, since the normal value was not given, but may be consistent with some sort of “inhibitor.” Is there a history of prolonged APTT, or is this just recent? Could be related to an acquired event, perhaps even a paraprotein? I would ask for this (paraprotein) and perhaps also D-dimer. LA is not likely, but we have seen several cases of LA that only became apparent at high sample dilutions, as the LA swamped the phospholipid in the test system, but here the screen was positive, and other assays such as anticardiolipin also positive. The high level of FIX is unusual, and should be further evaluated.