From Karen Dallas, MD, Saskatoon Health Region: I have searched the internet and cannot find a direct connection between thromboembolism prophylaxis with direct thrombin inhibitors and the induction of a prothrombotic state once discontinued. We have observed a few cases which seem to exhibit this phenomenon at my institution. Can you guide me towards any information on this occurrence?
Hi, Dr. Dallas, it is nice to “hear” from you. I had the pleasure of meeting you in 2012 at the Thrombosis and Hemostasis Summit of North America in Chicago, and again at ISTH in Amsterdam last summer. I hope you will be attending this year’s Summit.
I presume you are referring to dabigatran (Pradaxa®), the oral direct thrombin inhibitor. In the US, dabigatran is cleared only for stroke prophylaxis in non-valvular atrial fibrillation, whereas the direct anti-Xa inhibitor rivaroxaban (Xarelto®) is the only direct oral anticoagulant cleared for thromboembolism prophylaxis in total knee and total hip replacement surgery. I believe dabigatran is cleared for that purpose in Canada, however.
Dabigatran and rivaroxaban package inserts (and TV ads) encourage patients to take their pills on schedule and to never skip a dosage. The warning is based on the consideration that, unlike warfarin, the antithrombotic property is immediately lost because both have half-lives of 12–17 hours. Given that prothrombin has a 60-hour half-life and factor X a 30–hour half-life, it may be there is a slightly longer safety margin than 12 hours, however the distributors are compelled to err on the safe side.
I found this comment in Cove CL, Hylek EM, An updated review of target‐specific oral anticoagulants used in stroke prevention in atrial fibrillation, venous thromboembolic disease, and acute coronary syndromes. J Am Heart Assoc 2013; 2(5): e000136 (linked below). “Although concern has been raised about excessive thrombotic risk with cessation of these agents, there is no evidence to support a drug‐specific rebound phenomenon. As with warfarin, periods off of drug should be minimized to the extent that is safely possible given the underlying hypercoagulable states present with AF and VTE.”
Given the package insert warnings, the statement in the Cove article, and your clinical experience in Saskatoon, I’d like to see some data from your experience and also learn what other Fritsma Factor participants have experienced in “real life.” Is there really an increased risk of thrombosis when DOACs are discontinued?
Here’s the article: Cove Review Oct 2014 JAHA.
Jan 28 2014
Comments (8)
Anticoagulant Therapy
Hello, you may find documentation on coagulation factor half
Hello, you may find documentation on coagulation factor half-lives in Gallani D, Neff AT, Chapter 139, Rare Coagulation Factor Deficiencies, in Hoffman R, Benz EJ, Silberstein LE, et al. Hematology, Basic Principles and Practice, 6th Edition, Elsevier, 2014. Geo.
Some information is available in table 24.2:
http://www.ess
Some information is available in table 24.2:
http://www.essentialhaematology6.com/tables/chapter24.pdf
Half-life as ranges for vitamin K factors is in table 24-1:
http://www.ashp.org/DocLibrary/Bookstore/P2548/Sample-Chapter-24.pdf
Hello George, I am confused. I thought that prothrombin has
Hello George, I am confused. I thought that prothrombin has a 100 hour half-life and factor X a 65 hour half-life.. I would appreciate if you could give me some documentation on that. Thank you
Many thanks to Dr. Vadim Kostousov for his facility in findi
Many thanks to Dr. Vadim Kostousov for his facility in finding pertinent references. And by the way, Dr. Dallas, Birmingham is experiencing a rare cold spell (well, 20 degrees F) and snowstorm that, because we don’t maintain a fleet of salt spreaders and plows, has totally paralyzed the city.
Added Wednesday AM: Birmingham and Atlanta remain completely shut down, though the sun may begin to thaw the roads at about 1 PM. Many who were out at noon yesterday had to abandon their vehicles and seek shelter. They are still there, waiting for the thaw.
Thanks guys. That letter in BMJ sounds suspiciously like our
Thanks guys. That letter in BMJ sounds suspiciously like our experience. We have some clinical and lab data as well. We may try to publish a lit review and case series seeing as there is not much out there. But I like the rebound or resumption question. I guess that really is the question! 🙂
And yes, guys good to “see” you here as well! It is -35C in Saskatoon so I’m trying to escape for any reason at all!
Why direct thrombin (but not factor Xa) inhibitors could con
Why direct thrombin (but not factor Xa) inhibitors could contribute to rebound thrombosis is suggested here:
Antithrombin-independent thrombin inhibitors, but not direct factor Xa inhibitors, enhance thrombin generation in plasma through inhibition of thrombin-thrombomodulin-protein C system.
http://www.ncbi.nlm.nih.gov/pubmed/22012070
and recently confirmed here:
Effect Of dabigatran and rivaroxiban on thrombomodulin mediated activation Of protein C and thrombin activated fibrinolysis inhibitor (TAFI). Potential clinical implications
http://bloodjournal.hematologylibrary.org/content/122/21/3641
a letter published in BMJ: Thrombotic events after discontin
a letter published in BMJ: Thrombotic events after discontinuing dabigatran: rebound or resumption?
http://www.bmj.com/content/345/bmj.e4469
Dr Dallas, nice to see your post on Fritsma Factor. We are c
Dr Dallas, nice to see your post on Fritsma Factor. We are conducting a protocol at our institution comparing methods to measure dabigatran levels in a co-hort of 100 subjects. We had one subject that took themself off of dabigatran due to heavy bleeding of the gums for 72 hours without consulting his provider. The subject had a mild stroke during the time they ceased taking the medication. This was the only subject who we know voluntarily took themselves off of their meds without consulting their physician and had an event. This was the only patient that accomplished this in our study group.