From “Balasubm” at Einstein Healthcare in Philadelphia: Hi George, I have a 74 year old female renal dialysis patient who is asymptomatic with prolonged prothrombin time (PT) of 38 seconds and activated partial thromboplastin time (APTT, PTT) of 116 seconds, with a normal thrombin time. Mixing performed immediately reveals PT of 30.3 seconds (N 9.5-13.5) and APTT of 84.3 seconds (N 22-38). After incubation the PT went to 31.6 seconds and APTT to 86.6 seconds. The specimen was drawn from the dialysis catheter, however, these lines do not use heparin. Could you please tell us what you think these results mean?
Hello, and thank you for your question. Yes, given that there was no correction upon immediate mixing, you have presumptive lab evidence for a lupus anticoagulant (LA). The normal thrombin time supports the absence of heparin, and additionally, the absence of either of the new oral anticoagulants, dabigatran or rivaroxaban. I recommend you perform an LA profile on the specimen, typically one that uses a dilute Russell viper venom time kit and Sta-Clot LA kit for confirmation.
I know of no other therapeutic used in renal dialysis that could account for the prolonged PT and PTT and the lack of correction, however the patient’s physician will want to order a confirmatory LA profile 12 weeks or more from this positive sample, and it may be possible to collect the new specimen at a time between dialysis treatments to eliminate the possibility of interference.
Dear Herb,
Thank you for your response to my comment regard
Dear Herb,
Thank you for your response to my comment regarding the Factor FV inhibitor. We also used Dade (Siemens) Thrombin, diluted to the concentration mentioned by you). Although bovine thrombin thrombin is no longer in use clinically, there are still are other causes for their formation eg malignancies and exposure to various antibiotics. The patient mentioned in my previous comment had been administered many different antibitoics including ceftriaxone (known association with FV inhibitors)
Oops, I forgot to address “jlow”s question concerning the di
Oops, I forgot to address “jlow”s question concerning the differences between Bovine Thrombin Time and Human Thrombin Time. We use as our default Thrombin time the Stago reagent which has a concentration of 1.5NIH unit/ml. To perform the Bovine Thrombin time, we prepare Dade Thrombin Reagent which has a much higher concentration of Thrombin (100 NIH units/ml) and dilute it to 3.0 NIH units/ml. This dilution makes the assay sensitive to the Bovine antibodies if they are present.
Regards,
Herb Crown
St. Louis University Hospital Coagulation Reference Laboratory
(Herb, thanks for the additional information, very helpful and informative. Geo)
Hi jlow, George and readers. This is a really interesti
Hi jlow, George and readers. This is a really interesting case and certainly raises some questions.
The problems associated with bovine prepared fibrin glue are well documented, to the extent that there are many current products available and in use that are either recombinant such as RECOTHROM (www.recothrom.com) or human derived product such as EVICEL (http://www.ethicon360.com/products/evicel-fibrin-sealant-human) and Tisseel (http://tisseel.com).
The problem with bovine derived products is not the production of antibodies to the bovine thrombin even though they may occur. This is a very interesting publication concerning bovine thrombin glue and subsequent Factor V antibody production: http://bloodjournal.hematologylibrary.org/content/76/10/2011.long .
The major problem in bovine thrombin glue is the contamination of small amounts of bovine Factor V and the subsequently developed antibodies to bovine Factor V which are cross reactive to the patients Factor V resulting in measurable titers and significant bleeding in some cases. Here is another publication that may be of help: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1421171/
This case does present an interesting question and that is this, why does this patient exhibit an antibody to Factor V? It has been a couple of years since bovine derived thrombin glue has been used. This question prompted me to consult Dr Google and I found this poster presented by Dr. Duane Randleman, et al, at the American College of Clinical Pharmacy Annual meeting in October 2009: http://www.lotuscr.com/lotus-pdf/Zymogenetics-BovineThrombin-ACCP2009-Poster.pdf
The conclusion is as follows, Clinicians should be aware that antibodies to bovine thrombin products may persist for years following exposure. The case that Balasubm presents is a reminder of the veracity of these antibodies and their ability to sneak up on us.
Regards,
Herb Crown
St. Louis University Hospital Reference Laboratory
Dear George,
I would like to comment on Herb’s comment rega
Dear George,
I would like to comment on Herb’s comment regarding FV inhibitors and a prolonged thrombin time when tested with bovine thrombin but not human thrombin. I dont quite understand the reason for this difference. I understand that the FV inhibitor may have been precipitated by the use of bovine thrombin on the patient but i thought that the inhibitor was directed against FV and not at the fibrinogen to fibrin conversion. A paper by Favaloro Blood Coag Fibrinolysis 2004, 15 637 in which case histories of 14 acquired FV inhibitors was presented, the TT was normal in all 5 cases where it was mentioned (although whether bovine or human thrombin was used in the test) but I do know that the TT from the case contributed by our lab (case 8)was definitely performed with bovine thrombin.
Hi Balasubm and George. This is an example of something I h
Hi Balasubm and George. This is an example of something I have only seen twice in my career….a PT mixing study that did not correct pre and post incubation, and both times the patient had exposure to fibrin glue.
The Thrombin Time reagent we use (and probably most everyone else) is a human derived product and will be normal in this situation. If you had a bovine derived preparation of thrombin for the thrombin time you would have seen a prolonged thrombin time.
Regards
Herb Crown
St. Louis University Coagulation Reference Lab
Yes, definitely, with bleeding, these results could be consi
Yes, definitely, with bleeding, these results could be consistent with a factor V inhibitor, which often is triggered by the surgical use of fibrin glue that uses bovine thrombin. Thanks for this interesting case. Geo.
Thanks George for your answer. Follow up: I later found out
Thanks George for your answer. Follow up: I later found out that this patient did have some bleeding. Her lupus anticoagulant testing was negative. Her factor V was low, other factors normal, could this be an acquired FV deficiency with an inhibitor?
Hello, and thank you for your comment. There is an error in
Hello, and thank you for your comment. There is an error in my answer! Rivaroxaban and apixaban, the direct anti-Xa inhibitors do not prolong the thrombin time, which measures only the final stage of the coagulation pathway, the conversion of fibrinogen to fibrin. These direct anti-Xa antithrombotics act higher in the coagulation pathway, at the level of factor X. Their effect can be measured using an anti-Xa assay or the Pefakit PiCT assay. Thus a normal thrombin time does not rule out rivaroxaban. The direct thrombin inhibitors argatroban, bivalirudin, and the new oral DTI, dabigatran, prolong the thrombin time. So does heparin, which possesses both anti-Xa and antithrombin activity. Thank you for helping me clarify this answer. Geo.
Why does a normal thrombn time exclude a DXAI effects, e.g.
Why does a normal thrombn time exclude a DXAI effects, e.g. rivaroxaban?