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Chapter 1

Massive GI Bleed on Anticoagulants

Rob Orman, MD and Thomas Deloughery, MD
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28:53

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Rob and Tom Deloughery discuss management of actively bleeding patients who have been prescribed anticoagulation medications.

  • Case 1:  A patient presents to the ED with gastrointestinal bleeding. This patient is on warfarin with an INR of 10. Blood pressure is 70 systolic.

    • What is the best approach to reversal of the warfarin effect?

      • Most sources recommend 4-factor PCC if there is life or limb threatening bleeding. There are 2 methods to dose it.

        • Based on the INR (per the package insert).  

          • INR 2- <4: 25 units/kg. Not to exceed 2500 units.

          • INR 4-6: 35 units/g. Not to exceed 3500 units.

          • INR >6: 50 units/kg. Not to exceed 5000 units.

        • Fixed dosing

          • DeLoughery’s hospital has been using a flat dose of 1500 units.

          • Other’s feel that 25 units/kg is sufficient for warfarin reversal.

          • Cohen, Jessica, et al. "Comparison of Two Fixed Doses of Four Factor Prothrombin Complex Concentrate for Rapid Warfarin Reversal." Journal of the American College of Surgeons 225.4 (2017): e20. Abstract

          • Astrup, Greta, Preeyaporn Sarangarm, and Allison Burnett. "Fixed dose 4-factor prothrombin complex concentrate for the emergent reversal of warfarin: a retrospective analysis." Journal of thrombosis and thrombolysis 45.2 (2018): 300-305. PMID: 29164374

          • Klein, Lauren, et al. "Evaluation of fixed dose 4-factor prothrombin complex concentrate for emergent warfarin reversal." The American journal of emergency medicine 33.9 (2015): 1213-1218. PMID: 26143315

      • Vitamin K must be given also, since factor replacement has a short half-life (12-24 hours).

        • Intravenous vitamin K should be given slowly.

          • DeLoughery gives 10 mg mixed in a small bag of saline over 15 minutes. Others give the same dose over an hour.

          • While 10 mg will fully reverse warfarin anticoagulation, some give only 2.5 or 5.0 mg.  These smaller doses are likely adequate.

        • Old formulations of vitamin K had a higher incidence of anaphylactic reactions (1:3000-4000). Current rates are less than 1:100,000.

      • If fresh frozen plasma (FFP) necessary when PCC is used? Usually.

        • Though PCC lacks factors V and VIII, these are supplied by the vascular endothelium (factor VIII) and transfused platelets (factor V).

        • The big gap is that PCC lacks fibrinogen. In a massive transfusion, maintaining fibrinogen levels is critical.  This can be done by giving either FFP or cryoprecipitate.

    • Massive transfusion protocol.  This unstable patient will require multiple blood products. After PCC and the first round of red blood cells have been given, what are DeLoughery’s next steps?  

      • FFP is given first to stay ahead of the coagulopathy.

      • Platelets are given when the platelet count is under 50,000 or after the patient has received 6 units of pRBCs.

      • The 1:1:1 protocol applies (6 units RBCs : 6 units of FFP : 1 unit of single donor apheresis platelets - the old method of platelet transfusion was called the ‘6 pack’. The old 6 pack and single unit of apheresis have about the same amount of platelets. You could make the argument to change the phrasing of 1:1:1 to 6:6:1. Six units red cells, 6 units FFP, 1 unit single donor apheresis platelets).

    • When do you stop the massive transfusion?  DeLoughery views massive transfusion in two phases.

      • Phase 1: Storm the fort and get in the blood. This phase ends when the patient is hemodynamically stable, bleeding has stopped, and mental status (if assessable) has improved.

      • Phase 2: Mopping up. When no longer hypotensive and hemoglobin is above 7, he switches to lab based monitoring of anticoagulation.

  • Case 2:  Same patient presents hypotensive with a massive GI bleed, but medication history is notable for dabigatran rather than warfarin.

    • How do we reverse direct oral anticoagulants (DOACs)?

      • Stop the bleeding directly if you can.

      • 4-factor PCC may help. The data is very weak that PCCs improve outcomes in patients taking DOACs who are bleeding. There is decent lab reversal data on healthy volunteers and retrospective studies which suggest that PCC may be useful for dabigatran and Xa blocker reversal. Dose is 50 units/kg.

        • Almegren, Mosaad. "Reversal of direct oral anticoagulants." Vascular health and risk management 13 (2017): 287. PMID: 28769570

        • Xu, Yan, et al. "Direct Oral Anticoagulant-or Warfarin-Related Major Bleeding: Characteristics, Reversal Strategies, and Outcomes From a Multicenter Observational Study." Chest152.1 (2017): 81-91. PMID: 28219635

      • Idarucizumab (which is not readily available in many institutions) is a dabigatran direct reversal agent and will rapidly improve labs, but bleeding may take many hours to stop. This is an antibody that tightly binds dabigatran, effectively removing it from the circulation. 5 grams are given as two 2.5 gram boluses.

      • The scientific rigor that went into the phase III  idarucizumab trial has come under fire from GFOP Justin Morgenstern. An excellent read on why this data may be more marketing tha high quality data.

        • Grottke, Oliver, et al. "Prothrombin complex concentrates and a specific antidote to dabigatran are effective ex-vivo in reversing the effects of dabigatran in an anticoagulation/liver trauma experimental model." Critical Care 18.1 (2014): R27. PMCID: PMC4059479

        • Justin Morgenstern, "Idarucizumab: Plenty of optimism, not enough science", First10EM blog, January 15, 2018. Available at: https://first10em.com/idarucizumab/.

        • EM Lit of Note critical analysis of the NEJM Idarucizumab study

      • Andexanet alfa is a Xa reversal agent but is still under FDA review.

        • Pollack Jr, Charles V., et al. "Idarucizumab for dabigatran reversal—full cohort analysis." New England Journal of Medicine 377.5 (2017): 431-441. PMID: 28693366

      • Vitamin K is not needed for DOAC reversal

 

  • What is the target hemoglobin in the setting of massive blood loss?  It depends on the stability of the patient.

    • An unstable, hypotensive patient with massive hemorrhage needs volume. If the bleeding is acute, you cannot rely on the hemoglobin to reflect the actual amount of blood in the body. Transfuse until stable.

      • It takes approximately 24 hours for the hemoglobin to fully equilibrate after acute blood loss. This is due to the movement of extracellular/interstitial fluid into the intravascular spaces.

      • Though full equilibration can take 24 hours, within 30 minutes you should see hemoglobin start to drop and in an hour some sources state that a liter of interstitial fluid can be shifted into the intravascular compartment in this time.

        • Bruns, Brandon, et al. "Hemoglobin drops within minutes of injuries and predicts need for an intervention to stop hemorrhage." Journal of Trauma and Acute Care Surgery 63.2 (2007): 312-315. PMID:17693829

      • Detailed and concise description of the physiology of acute hemorrhage from Deranged Physiology.

    • A landmark study published in the NEJM demonstrated that using a hemoglobin cutoff of 7 g/dL in GI bleed patients  led to better outcomes compared to a hemoglobin target of 9 g/dL.

      • If the patient is stable, using a target of 7 g/dL aligns with the date.

      • If the patient is unstable, you may under-resuscitate if you use a target of 7. Resuscitate to improving the shock state.

      • Villanueva, Càndid, et al. "Transfusion strategies for acute upper gastrointestinal bleeding." New England Journal of Medicine 368.1 (2013): 11-21. PMID: 23281973

  • Should I give tranexamic acid (TXA) to my non-traumatic massively bleeding patient?

    • Whether TXA is effective in a GI bleed is still being studied.  DeLoughery will not give TXA in this instance unless there is evidence of coagulopathy and/or the patient has cirrhosis (as these patients have excess fibrinolysis).

    • There is evidence that TXA improves bleeding-related mortality for women with postpartum hemorrhage.

      • The WOMAN trial evaluated TXA use in approximately 20,000 women with postpartum hemorrhage. This study showed that if TXA was given within 3 hours of delivery, death was 1.2% versus 1.7% with placebo.

      • The WHO has updated its position to strongly recommend intravenous TXA within 3 hours of birth with clinically diagnosed postpartum hemorrhage.

      • Shakur, Haleema, et al. "Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial." The Lancet 389.10084 (2017): 2105-2116. PMCID: PMC5446563

Vogel, Joshua P., et al. "Updated WHO recommendation on intravenous tranexamic acid for the treatment of post-partum haemorrhage." The Lancet Global Health 6.1 (2018): e18-e19. PMID: 29100880 Full Text

jotham g. -

A great dive dive down on GI bleeding thank you TOM

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