Dabigatran Toxicity: The Top 10 Questions

September 11, 2011, 4:02 pm

As I mentioned in yesterday’s post, my Emergency Medicine News column on “Dabigatran Toxicity: The Top 10 Questions” has just been posted online. Test yourself on these questions — just click on the question to reveal the answer:

1)

Pradaxa is actually not dabigatran, but rather the inactive pro-drug dabigatran etexilate. After ingestion, Pradaxa is rapidly converted to dabigatran, a direct inhibitor of thrombin. Dabigatran blocks the last stages of the coagulation cascade: cleavage of fibrinogen into fibrin, activation of platelets, and stabilization of forming clots. Unlike heparin, which inhibits only free thrombin, dabigatran also impairs fibrin- and clot-bound thrombin.

2)

Elimination is primarily through the kidneys. Since metabolism does not involve — and does not induce — hepatic cytochrome P450 enzymes, dabigatran has few interactions with other drugs.

3)

Peak anticoagulant effect occurs 1 -3 hours after ingestion. Assuming normal renal function, the half-life is 12-14 hours. With significant renal impairment, half-life may be greater than 24 hours, and drug levels can increase if the dose is not adjusted or discontinued. It is not known how, or if, the kinetics of dabigatran change in massive overdose.

4)

The manufacturer advises that rifampin decreases blood levels and should generally be avoided.

5)

Unlike the situation with heparin and warfarin, no really good test exists for determining dabigatran anticoagulant activity. In addition, there is no antidote with proven efficacy for reversing dabigatran-induced anticoagulation.

6)

The activated partial thromboplastin time (aPTT) can indicate qualitatively the presence of dabigatran, but does not allow for quantitative estimate of how much or to what effect. Thombin clotting time (TT) has similar limitations.

7)

Recombinant activated factor VII (rFVIIa) improves laboratory measures of clotting in a rat-tail model. Unfortunately, this factor can promote thrombosis since it directly activates thrombin on the surface of platelets even if tissue factor is not present.

Prothrombin complex concentrates (PCCs) contain some thrombin that theoretically — and I emphasize theoretically — might overwhelm dabigatran inhibition. This has only be studied in rat models and in vitro, with mixed results. PCCs also can cause thrombosis. At this point there is not enough evidence to allow informed clinical risk-benefit analysis regarding use of rFVIIa or PCCs in this setting.

8)

Possibly. Dabigatran is a small molecule with low binding to plasma proteins and a moderate volume of distribution, making it ideal for enhanced elimination by hemodialysis (HD). With an overdose patient who is not bleeding, HD would seem unnecessary. Patients on dabigatran who present with life-threatening bleeding that can not be controlled with local measures and replacement of blood — for instance bleeding into a closed space such as the cranium, spinal cord, or pericardium — might benefit from hemodialysis.

9)

Dabigatran exetilate is adsorbed to activated charcoal (AC). Administering a single dose of AC within one or two hours after ingestion would be reasonable if there are no contraindications. Measuring aPTT or TT might indicate an anticoagulation effect, but would not reflect how serious this is. Some authors suggest that in the absence of renal impairment, drug effect will resolve within one day.  If this is true, 24 hours of observation would be appropriate.

10)

Given the limitations of testing and lack of proven antidote, this situation will be real challenge. The knowledge that would allow us to answer this question is still incomplete and evolving. Key measures would include: supportive care with attention to airway, breathing, and circulation; local control of the bleeding site(s) if possible; and replacement of blood as indicated.  If further measures are needed– especially if there is significant bleeding into a closed space — consultation with a local poison center and a hematology/coagulation specialist if available — would be indicated.

Related posts:

Review: the bleeding patient on dabigatran

Dabigatran and the elderly

Dabigatran exetilate: a new challenge for emergency physicians and toxicologists

 

 

 

 

3 Comments:

  1. Nickel Says:

    Hey Leon –

    Love the site; LOTS of useful stuff… just a comment on this, and I admit it’s hair-splitting:

    In regards to #9, technically dagibitran is adsorbed (not absorbed) to activated charcoal. =)

    Cheers!

  2. Leon Says:

    Nickel:

    Thanks so much for the nice comment. I’m delighted you’re finding the posts on TPR useful!

    You are absolutely correct that I should have said that dabigatran is “adsorbed” to AC. I have made the change in the post.

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