In the second part of this epic 2-part authoritative episode, Anticoagulants, PCCs & Platelets, we have Dr. Walter Himmel (also known as ‘The walking encyclopedia of EM’) along with Dr. Katerina Pavenski (Head of Transfusion Medicine at St. Michael’s Hospital) & Dr. Jeannie Callum (Head of Transfusion Medicine at Sunnybrook Hospital) who will discuss the latest on comparative efficacy and reversal of Warfarin vs Dabigatran vs Rivaroxiban vs Abixaban, the use of prothrombin complex concentrates (PCCs), the ins and outs of thrombocytopenia & platelet transfusions, ITP, TTP, anti-platelet associated intracranial bleeds, indications for Tranexamic Acid & more…
Written Summary and blog post by Claire Heslop, Edited by Anton Helman, October 2013
Summary of New Oral Anticoagulants
Direct Thrombin (IIa) Inhibitor
- Dabigitran (Pradax)
Factor Xa inhibitors
- Rivaroxaban (Xarelto)
- Apixaben (Eliquis)
- Oral (vs. LMWH)
- No monitoring of INR
- Fast onset (within hours)
- Standard dose (no weight adjustment)
- Minimal drug/dietary interaction
- No antidote (i.e Vit K, PCC, plasma with warfarin)
- No means to determine compliance, anticoagulation effect
- Renal failure prolongs half life (with CrCl
New oral anticoagulants have short half life (~12 hours), therefore, if miss 2-3 doses, treat as uncoagulated patient.
INR tends to be increased with Rivaroxaban/Apixaban, PTT tends to be increased with Dabigitran. Therefore, INR/PTT may give a clue to compliance.
Atrial fibrillation; DVT/PE
**NOT mechanical heart valve
Newer Anticoagulants in DVT & PE
Factors to consider when deciding to use a newer anticoagulant in DVT/PE:
- Renal failure (contraindication to new anticoagulants)
- Dehydration & acute renal failure increases half life of new anticoagulants (especially Dabigitran & Rivaroxiban)
- Liver impairment (new anticoagulants partailly hepatically cleared)
- Pregnancy (new anticoagulants contraindicated)
- Absoloute contraindication: mechanical heart valve
Starting Newer Anticoagulants in the ED for DVT
- Rivaroxaban (approval in Canada):
- 15 mg po bid x 3 week (please note that Dr. Helman made an error on the podcast stating with the dose by stating ‘Dabigitran’ instead of ‘Rivaroxiban’ – thanks to Dr. Dan Honsinger from Barrie for picking this up!)
- Then step down dose
- 10 mg po bid x 7 days
- Then step down dose
- Important to emphasize compliance! These medications have a short half life, therefore, missing 2-3 doses could mean becoming uncoagulated and at higher risk of thromboembolism.
MANAGING LIFE THREATENING BLEEDING IN THE ANTICOAGULATED PATIENT
A) Warfarin Reversal in Life-threatening Bleeding
Vitamin K: 10 mg IV over 30 minutes (starts to work in 2-3 hours, INR reversed within 24 hrs with adequate production of coagulation factors). Administer in 50 cc of Normal Saline over 30 min.
* anaphylaxis with IV Vitamin K is very rare – do not withhold IV Vit K because of fear of anaphylaxis!
Plasma (FFP): 4-6 units typically required, large volume, need time for thawing, ABO compatibility, risks of transfusion – infection, TRALI, TACO, etc.)
Prothrombin Complex Concentrate (PCC, e.g. Octaplex, Beriplex – 4 factor PCC in Canada, with factors 2,7,9,10)
- Works almost immediately
- Factor 7 has short half life, so, PCC stops working effectively after 4-8hrs. Thus, vitamin K must be given with PCC.
- Contraindicated in HIT, liver disease, recent thrombosis, MI, ischemic stroke, DIC
- Check INR immediately (within 15 min) and in 6 hrs
- Dosing may be INR or weight based. Check product monographs or institutional guidelines.
- Current Canadian recommendations:
- INR 1.6-3: 1000 U PCC + Vit K
- INR 3-5: 2000 U PCC+Vit K
- INR >5: 3000 U PCC+Vit K
- Dose may vary with extremes of weight
- Mix powder with provided solvent and administer as per manufacturer’s monograph (slow push or minibag) or institutional guidelines.
B) Use of Recombinant Factor 7a (rFVlla) in Bleeding Patients
No benefit from using rFVIIa in bleeding patients, and clear harm (increased risk of thromboembolic events) in prophylactic or therapeutic use. Might be beneficial in a bleeding hemophiliac patient who has developed inhibitors.
C) Risk of Thrombosis with PCC vs. Plasma
Unclear. There may be a small increased risk of thrombosis in patients receiving PCC.
D) High Probability of Intracranial Bleed
What to do when there is a high clinical suspicion of intracranial bleed, with a suggestive history, and patient on warfarin while waiting coagulation studies and imaging?
In select scenarios where there is high likelihood of intracranial bleed based on history and physical exam, and delay to bloodwork/imaging, our experts have used 1000 units of PCC while waiting for these results.
E) Bleeding with New Oral Anticoagulants
Dabigitran/Rivaroxaban: overall bleeding risk approximately equal to warfarin. Increased risk of GI bleed, but decreased risk of intracranial bleed.
Apixaban: less major and clinically significant non-major bleeding vs. warfarin in one study.
Reversal Strategies [Heidbuchel, 2013]
- Supportive management, hydration, local control.
- Ongoing life threatening bleed, PCC, APCC (FEIBA), rFVIIa may be considered. No human studies available..
- Case reports: PCC may be helpful if no alternative and patient declining: 40-50 units/kg. Then monitor 30 minutes. If no improvement and continued bleed, try FEIBA (50-80 units/kg). rFVIIa as last resort.
- Dialysis may be helpful: less drug bound to protein
- No change in laboratory abnormalities with PCC (vs. change with Rivaroxaban)
Bleeding in Patients on Antiplatelet Agents
No prospective studies. In life threatening bleed, consider 1 pool of platelets. If worsening clinically or progression of bleed, consider 2nd pool of platelets.
DDAVP may counteract ASA and clopidogrel effect. No studies have evaluated effectiveness of this.
Risk of Anaphylaxis with IV Vitamin K
Anaphylaxis risk with IV Vitamin K is approximately 3/10,000
Anaphylactoid reactions are more common. To prevent, give slowly. For example, to give 10mg of Vitamin K, put in 50cc of Normal Saline, and give at a rate < 1 mg/min (i.e. over 30 minutes is appropriate).
DDx: ITP, TTP, bone marrow failure, myelodysplastic syndrome…
TTP: most life threatening condition. Diagnosis should be entertained in all patients with low plts and low Hb. If fragments or shistocytes on blood film and elevated LDH assume TTP. These patients need transfer to a facility where plasmapheresis is available. Consider starting FFP infusion while awaiting transfer. Once patient develops classic pentad, often too late.
UPDATE 2015: A clinical practice guideline for platelet transfusion from the AABB.
When and How to Transfuse Platelets
Transfuse if platelet count < 10, as increased risk of spontaneous ICH. Consider transfusion if known coagulopathy, sepsis or high fever and platelet count < 20.
Transfuse 1 pool of platelets (equivalent to 4 units of platelets in older terminology) over 1 hour.
Measure platelet count after transfusion (15-60 min post transfusion). Expect increase in platelet count of 20-40. Variability due to how brisk the bleed, how quickly platelets are consumed.
Group & Screen for Platelets
Platelets should ideally be ABO identical.
Very few RBCs in platelets, however, enough to cause alloimmunization. Therefore, Rh neg females with child bearing potential should receive Rh neg platelets. If such a patient receives Rh pos platelets, consider giving Rh immunoglobulin.
Risks of Platelet Transfusion
- Sepsis 1/10,000
- Death from sepsis 1/60,000
- TRALI/TACO (see part 1)
Thrombocytopenia in Patients Requiring Invasive Procedures
Dependent on skill level. General guidelines recommend platelet counts as follows for common ED procedures:
- Central line: plt count > 20-25
- LP: plt count >50-100
- Paracentesis/Thoracentesis >10
Thrombocytopenia and Platelet Transfusions in Special Circumstances:
- ITP: Life Threatening Bleed:
- Corticosteroids, IVIG, platelets transfusions
- 40-60% of patients with ITP will respond to platelets
- ITP: Non-bleeding Patients:
- No platelet transfusion
- Reserve platelet transfusions for life threatening bleeding, as increased thrombotic risk
Effective in reducing bleeding in heavy menstrual bleeding, consder in intracranial hemorrhage, oral bleeding, epistaxis and major trauma.
Oral dosing: 1g tid x 4-5 days
In oral bleeding consider using 5% tranexamic acid dissolved in tap water and swishing in mouth for 2 minutes then spitting out. Repeat if necessary.
Thrombosis Risk with Tranexamic Acid
No increased risk of thrombosis in cardiac and non-cardiac surgery. CRASH-2 study – trend toward decreased thrombotic events if given within 3 hours.
IV dosing 1g over 10 min then 1 g over 8 h
Dr. Helman, Dr. Himmel, Dr. Pavenski and Dr. Callum have no conflicts of interest to declare.
Agnelli et al. 2013. NJEM: 369; 799-808. www.nejm.org/doi/full/10.1056/NEJMoa1302507
Prins et al. 2013. Thromb J: 11: 21. www.ncbi.nlm.nih.gov/pubmed/24053656
American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis. Chest. 2012;141 (2suppl):e152S-e184s. www.ncbi.nlm.nih.gov/pubmed/23953342
Heidbuchel et al. 2013. Europace:15; 625-51. www.ncbi.nlm.nih.gov/pubmed/?term=Heidbuchel+et+…
CRASH-2 Investigators. 2010. Lancet: 376; 23-32. www.ncbi.nlm.nih.gov/pubmed/?term=CRASH-2+Invest…