Approach of Management of bleeding in patients receiving direct oral anticoagulant with a brief overview of classes of anticoagulant and medications

1. Management Of Bleeding In
Patients Receiving Direct Oral
Anticoagulants
Zeinab Noormonavar
PharmD Candidate
11/27/2021
1

2. 2
Craven, J. (2019, February 19). Preferred treatment to reduce GI bleeding risk with NSAIDS in Oa, RA. Rheumatology Advisor. Retrieved
November 26, 2021, from https://www.rheumatologyadvisor.com/home/topics/pain-management/preferred-treatment-to-reduce-gi-bleeding-
risk-with-nsaids-in-oa-ra/.
Jun, L., Vareldzis, R., & Anonymous. (2018, September 13). Dialyzing a patient with an intracranial hemorrhage.
Renal Fellow Network. Retrieved November 26, 2021, from https://www.renalfellow.org/2017/03/02/dialyzing-
hd-patient-with-intracrania/.

3. At the end of presentation we’ll be able to:
• Approach to managing bleeding in patients receiving DOACs.
• Identify the classification and pharmacological treatment modalities.
• Learn the different drugs used.
3
Outline

4. Introduction
4
Elsevier. (n.d.). Guide for authors. Guide for authors - JACC: Advances - ISSN 2772-963X. Retrieved November 27, 2021, from https://www.elsevier.com/journals/jacc-
advances/2772-963X/guide-for-authors.
Anticoagulation is the cornerstone of treatment for thrombosis
and thromboembolic complications of a variety of disorders.
The use of any anticoagulant is associated with an increased risk
of bleeding, and bleeding complications can be life-threatening.
A rapid onset and offset of anticoagulant effect, fixed dosing,
fewer drug and dietary interactions and no monitoring
requirement; these make attractive options for DOACs over VKAs

5. Definition
• Direct oral anticoagulants (DOACs; also called non-vitamin K oral anticoagulants
[NOACs]) are oral medications that directly inhibit a specific enzyme in the
coagulation cascade.
5
Abdou, D. M. (2020, October 13). New oral anticoagulants - ask hematologist: Understand hematology. Ask Hematologist | Understand Hematology. Retrieved November
27, 2021, from https://askhematologist.com/new-oral-anticoagulants/.

6. Definition (Cont’d)
Drugs MOA Dose SE
Dabigatran Factor IIa inhibitor
75 – 150 mg BID
110 mg Qd/BID
Dyspepsia & Gastritis
Any bleeding
Rivaroxaban
Factor Xa inhibitor
10 – 20 mg Qd
2.5 – 15 mg BID
Major bleeding
Hematoma
Back & abdominal pain
Wound secretion
Apixaban 2.5 – 5 mg BID
Major bleeding
Thrombocytopenia
Hypotension
Edoxaban 15 – 30 – 60 mg Qd
Abnormal LFTs
Rash
Non major bleeding
6
News November 26, 2021, Medscape Medical News November 26, 2021, Medscape Medical News November 25, 2021, Medscape Medical News November 24, 2021, Medscape Medical News November 26, 2021, FDA Approvals November 24,
2021, Medscape Reader Polls November 24, 2021, Associated Press November 24, 2021, Article July 24, 2020, Commentary September 30, 2021, Commentary September 13, 2021, Commentary August 23, 2021, European Heart Journal November
26, 2021, Emerging Infectious Diseases November 25, 2021, American Journal of Cardiovascular Drugs November 24, 2021, American Journal of Clinical Dermatology November 24, 2021, Critical Care November 23, 2021, Headache November 22,
2021, Fast Five Quiz November 23, 2021, … Medscape Medical News November 23, 2021. (n.d.). Pharmacists. Medscape. Retrieved November 27, 2021, from https://www.medscape.com/pharmacists.

7. Bleeding Severity
Bleeding in critical site Hemodynamic instability
Overt bleeding in Hgb drop ≥2g/dL
OR
Administration ≥2 units of packed
RBCs
Imaging study
(Endoscopy / CT scan)
7
If ≥ 1 of the following factors applies, the bleed is classified as Major
Elsevier. (n.d.). Guide for authors. Guide for authors - JACC: Advances - ISSN 2772-963X. Retrieved November 28, 2021, from https://www.elsevier.com/journals/jacc-
advances/2772-963X/guide-for-authors.

8. Critical Site Bleeding
8
Elsevier. (n.d.). Guide for authors. Guide for authors - JACC: Advances - ISSN 2772-963X. Retrieved November 28, 2021, from https://www.elsevier.com/journals/jacc-advances/2772-
963X/guide-for-authors.

9. Laboratory Measurement
• In the anticoagulated patient who presents with clinically relevant bleeding or
needs an urgent unplanned procedure, measurement of anticoagulant activity is
a key step in the evaluation.
9
Helen HaileSelassie, P. D. (2018, November 20). Management of bleeding in patients treated with direct oral anticoagulants. U.S. Pharmacist – The Leading Journal in Pharmacy. Retrieved November
28, 2021, from https://www.uspharmacist.com/article/management-of-bleeding-in-patients-treated-with-direct-oral-anticoagulants.

10. Other Limited Laboratory Testing
• No additional laboratory testing is absolutely required beyond coagulation
testing outlined in the previous slide.
10
Hemoglobin Platelet
Renal
Function
Hepatic
Function
DIC
UpToDate. (n.d.). Retrieved November 28, 2021, from https://www.uptodate.com/contents/management-of-bleeding-in-patients-receiving-direct-oral-
anticoagulants?source=history_widget#H3430371.

11. General Management
Immediate
discontinuation of all
anticoagulant
Establishment of an
effective airway and
large-bore
intravenous access
Body temperature,
blood pH, and
electrolyte balance,
including calcium
Transfusions if
required
Use of reversal
agent
Volume
resuscitation
Continuous
hemodynamic
assessment
Early administration
of Tranexamic Acid
11
UpToDate. (n.d.). Retrieved November 28, 2021, from https://www.uptodate.com/contents/management-of-bleeding-in-patients-receiving-direct-oral-
anticoagulants?source=history_widget#H3430371.

12. 12
Elsevier. (n.d.). Guide for authors. Guide for authors - JACC: Advances - ISSN 2772-963X. Retrieved November 28, 2021, from https://www.elsevier.com/journals/jacc-advances/2772-963X/guide-for-authors.

13. Anticoagulant Reversal Strategy
The International Society on Thrombosis and Hemostasis recommends
consideration of anticoagulant reversal for patients with:
1. Serious bleeding
2. DOAC level >50 ng/mL
3. For patients requiring an invasive procedure with high bleeding risk and a DOAC
level >30 ng/mL
13
Specific
antidote
Prothrombin
complex
concentrates
(PCCs)
Anti
fibrinolytic
agent
Desmopressin
(DDAVP)
Circulation/ GIT
drug removal
Helen HaileSelassie, P. D. (2018, November 20). Management of bleeding in patients treated with direct oral anticoagulants. U.S. Pharmacist – The Leading Journal in Pharmacy. Retrieved November 28, 2021, from
https://www.uspharmacist.com/article/management-of-bleeding-in-patients-treated-with-direct-oral-anticoagulants.

14. Drugs MOA Dose SE
Idarucizumab
Humanized
monoclonal antibody
fragment
(Dabigatran antidote)
5 g IV
Either 2 consecutive
infusion or as bolus
injection
Hypokalemia
Delirium
Constipation
Andexanet alpha
Factor Xa Inhibitor
Antidotes
Low dose:
Initial IV bolus: 400 mg IV;
target infusion rate of 30
mg/min
Follow-on IV infusion: 4
mg/min IV for up to 120 min
High dose:
Initial IV bolus: 800 mg IV;
target infusion rate of 30
mg/min
Follow-on IV infusion: 8
mg/min IV for up to 120 min
Infusion related rxn
Thromboembolic
event
Sudden death
14
Anticoagulant Reversal (Cont’d)
News November 26, 2021, Medscape Medical News November 26, 2021, Medscape Medical News November 25, 2021, Medscape Medical News November 24, 2021, Medscape Medical News November 26, 2021, FDA Approvals November 24, 2021, Medscape Reader Polls November 24, 2021, Associated Press November 24, 2021,
Article July 24, 2020, Commentary September 30, 2021, Commentary September 13, 2021, Commentary August 23, 2021, European Heart Journal November 26, 2021, Emerging Infectious Diseases November 25, 2021, American Journal of Cardiovascular Drugs November 24, 2021, American Journal of Clinical Dermatology November
24, 2021, Critical Care November 23, 2021, Headache November 22, 2021, Fast Five Quiz November 23, 2021, … Medscape Medical News November 23, 2021. (n.d.). Pharmacists. Medscape. Retrieved November 27, 2021, from https://www.medscape.com/pharmacists.

15. Drugs MOA Dose SE
FEIBA
Activated PCCs
(aPCCs)
50 – 80 units/kg
Headache
Lethargy
Nausea
Thromboembolic event
3 – factor
4 – factor
Inactivated PCCs
(PCCs)
Fixed dose:
2000 units
Weight based dose:
25 – 50 units/kg
Allergic rxn
Headache
Nausea
Sleepiness
DVT (Lesser extends)
15
Anticoagulant Reversal (Cont’d)
News November 26, 2021, Medscape Medical News November 26, 2021, Medscape Medical News November 25, 2021, Medscape Medical News November 24, 2021, Medscape Medical News November 26, 2021, FDA Approvals November 24, 2021, Medscape Reader Polls
November 24, 2021, Associated Press November 24, 2021, Article July 24, 2020, Commentary September 30, 2021, Commentary September 13, 2021, Commentary August 23, 2021, European Heart Journal November 26, 2021, Emerging Infectious Diseases November 25,
2021, American Journal of Cardiovascular Drugs November 24, 2021, American Journal of Clinical Dermatology November 24, 2021, Critical Care November 23, 2021, Headache November 22, 2021, Fast Five Quiz November 23, 2021, … Medscape Medical News November
23, 2021. (n.d.). Pharmacists. Medscape. Retrieved November 27, 2021, from https://www.medscape.com/pharmacists.

16. Drugs MOA Dose SE
Tranxamic
acid
Anti fibrinolytic
agent
PO:
1 – 1.5 g BID/TID
IV:
10 – 20 mg/kg
bolus then 10
mg/kg infusion
TID/QID
Nasal and sinus symptoms
Headache
Back pain
Abdominal pain
Musculoskeletal pain
Visual abnormalities
Hypotension (rapid injection)
N/V/D
Desmopressin
Vasopressin-
related
0.3 mcg/kg
SC or IV
Dry mouth
Headache
Hyponatremia
16
Anticoagulant Reversal (Cont’d)
News November 26, 2021, Medscape Medical News November 26, 2021, Medscape Medical News November 25, 2021, Medscape Medical News November 24, 2021, Medscape Medical News November 26, 2021, FDA Approvals November 24,
2021, Medscape Reader Polls November 24, 2021, Associated Press November 24, 2021, Article July 24, 2020, Commentary September 30, 2021, Commentary September 13, 2021, Commentary August 23, 2021, European Heart Journal November
26, 2021, Emerging Infectious Diseases November 25, 2021, American Journal of Cardiovascular Drugs November 24, 2021, American Journal of Clinical Dermatology November 24, 2021, Critical Care November 23, 2021, Headache November 22,
2021, Fast Five Quiz November 23, 2021, … Medscape Medical News November 23, 2021. (n.d.). Pharmacists. Medscape. Retrieved November 27, 2021, from https://www.medscape.com/pharmacists.

17. Algorithm
17
Elsevier. (n.d.). Guide for authors. Guide for authors - JACC: Advances - ISSN 2772-963X. Retrieved November 28, 2021, from https://www.elsevier.com/journals/jacc-advances/2772-
963X/guide-for-authors.
Unimplemented action. Ovid. (n.d.). Retrieved November 29, 2021, from https://ovidsp.dc2.ovid.com/ovid-
a/ovidweb.cgi?&S=LBBIFPBELAEBLFOFIPOJPEEHHLCFAA00&size=full&WebLinkReturn=Full%2BText%3DL%7CS.sh.24.45%7C0%7C00132577-201909000-00007&View%2BImage=00132577-
201909000-00007%7CFF10.

18. 18
Algorithm (Cont’d)
Elsevier. (n.d.). Guide for authors. Guide for authors - JACC: Advances - ISSN 2772-963X. Retrieved November 28, 2021, from https://www.elsevier.com/journals/jacc-advances/2772-963X/guide-for-authors.

19. Surgery/Invasive Procedure
• It is often possible to delay a procedure long enough to allow most or
all of the anticoagulant effect to dissipate spontaneously in patients
with normal renal or hepatic function.
Short half-lives of the DOACs
• If urgent or emergent surgery is required and there is insufficient time
to allow the anticoagulant effect to dissipate.
Appropriate reversal strategies
19
Spyropoulos, A. C. (2020). JavaScript disabled. Scientific and Standardization Committee Communication: Guidance document on the periprocedural management of patients on chronic oral
anticoagulant therapy: Recommendations for standardized reporting of procedural/surgical bleed risk and patient‐specific thromboembolic risk. Retrieved November 29, 2021, from
https://onlinelibrary.wiley.com/doi/epdf/10.1111/jth.14598.

20. Antidotes Under Development
Ciraparantag
(PER977)
• Binds directly and specifically to direct thrombin inhibitors, factor Xa inhibitors, and heparins.
• For Edoxaban, required the lowest dose for full reversal of effect.
• Normalized the whole blood clotting time within 10 minutes.
FXaI16L
• It is a mutant form of factor Xa.
• Circulates in a zymogen-like (inactive) state.
• Becomes activated when it encounters activated factor V (factor Va) on damaged cellular surfaces.
• reverse the effect of Rivaroxaban or Dabigatran in vitro in human plasma.
20
Ansell JE;Bakhru SH;Laulicht BE;Steiner SS;Grosso M;Brown K;Dishy V;Noveck RJ;Costin JC;, jack e. (2021). Use of per977 to reverse the anticoagulant effect of Edoxaban. The New England
journal of medicine. Retrieved November 29, 2021, from https://pubmed.ncbi.nlm.nih.gov/25371966/.
Thalji NK;Ivanciu L;Davidson R;Gimotty PA;Krishnaswamy S;Camire RM; (n.d.). A rapid pro-hemostatic approach to overcome direct oral anticoagulants. Nature medicine. Retrieved November
29, 2021, from https://pubmed.ncbi.nlm.nih.gov/27455511/.

21. Take Home Message
Direct oral
anticoagulants
(DOACs) reversibly
inhibit coagulation
factors and have a
shorter half-life
than warfarin.
We assess the
severity of bleeding
and the degree of
anticoagulation
through the patient
history and physical
examination.
In most cases of
DOAC-associated
bleeding, including
major bleeding, we
discontinue the drug;
transfuse blood
products if necessary.
Agent specific
intervention is first
line therapy in life-
threatening
conditions.
Minor bleeding can
usually be managed
conservatively using
local hemostatic
measures.
Most patients can
resume
anticoagulation after
a bleed, with
accumulating
evidence that
restarting the
anticoagulant results
in improved
outcomes with lower
risks of thrombosis.
21

22. Case Study
• A 42 year-old woman who was told by
her internist that she would be on a
DOAC for life after being diagnosed
with a pulmonary embolism six
months prior comes into your ED with
a one day history of hematochezia,
shortness of breath, hypoxia and
abdominal pain (pain scale: 9/10).
Her vitals are abnormal (Hypotension
90/70, hyperthermia 39), her
hemoglobin comes back 4 g/dl (5g/dl).
Elevated aPTT and TT.
• Would you stop DOACs?
A. Yes
B. No
• What is the next step in management?
22

23. • Which agent most likely patient was on it?
A. Rivaroxaban
B. Warfarin
C. Dabigatran
23
Case Study (Cont’d)
• A 42 year-old woman who was told by
her internist that she would be on a
DOAC for life after being diagnosed
with a pulmonary embolism six
months prior comes into your ED with
a one day history of hematochezia,
shortness of breath, hypoxia and
abdominal pain (pain scale: 9/10).
Her vitals are abnormal (Hypotension
90/70, hyperthermia 39), her
hemoglobin comes back 4 g/dl (5g/dl).
Elevated aPTT and TT.

24. • Do we need to use Antidote? If yes,
specify.
A. Andrexanet alpha
B. Idarizumab
C. Tranexamic acid / desmopressin
D. No need to use antidote
24
Case Study (Cont’d)
• A 42 year-old woman who was told by
her internist that she would be on a
DOAC (Dabigatran 150mg BID) for life
after being diagnosed with a
pulmonary embolism six months prior
comes into your ED with a one day
history of hematochezia, shortness of
breath, hypoxia and abdominal pain
(pain scale: 9/10).
Her vitals are abnormal (Hypotension
90/70, hyperthermia 39), her
hemoglobin comes back 4 g/dl (5g/dl).
Elevated aPTT and TT.

25. References
25
1. Elsevier. (n.d.). Guide for authors. Guide for authors - JACC: Advances - ISSN 2772-963X. Retrieved November 27, 2021, from
https://www.elsevier.com/journals/jacc-advances/2772-963X/guide-for-authors.
2. Abdou, D. M. (2020, October 13). New oral anticoagulants - ask hematologist: Understand hematology. Ask Hematologist | Understand Hematology. Retrieved
November 27, 2021, from https://askhematologist.com/new-oral-anticoagulants/.
3. News November 26, 2021, Medscape Medical News November 26, 2021, Medscape Medical News November 25, 2021, Medscape Medical News November 24,
2021, Medscape Medical News November 26, 2021, FDA Approvals November 24, 2021, Medscape Reader Polls November 24, 2021, Associated Press November
24, 2021, Article July 24, 2020, Commentary September 30, 2021, Commentary September 13, 2021, Commentary August 23, 2021, European Heart Journal
November 26, 2021, Emerging Infectious Diseases November 25, 2021, American Journal of Cardiovascular Drugs November 24, 2021, American Journal of Clinical
Dermatology November 24, 2021, Critical Care November 23, 2021, Headache November 22, 2021, Fast Five Quiz November 23, 2021, … Medscape Medical News
November 23, 2021. (n.d.). Pharmacists. Medscape. Retrieved November 27, 2021, from https://www.medscape.com/pharmacists.
4. Helen HaileSelassie, P. D. (2018, November 20). Management of bleeding in patients treated with direct oral anticoagulants. U.S. Pharmacist – The Leading Journal
in Pharmacy. Retrieved November 28, 2021, from https://www.uspharmacist.com/article/management-of-bleeding-in-patients-treated-with-direct-oral-
anticoagulants.
5. UpToDate. (n.d.). Retrieved November 28, 2021, from https://www.uptodate.com/contents/management-of-bleeding-in-patients-receiving-direct-oral-
anticoagulants?source=history_widget#H3430371
6. Unimplemented action. Ovid. (n.d.). Retrieved November 29, 2021, from https://ovidsp.dc2.ovid.com/ovid-
a/ovidweb.cgi?&S=LBBIFPBELAEBLFOFIPOJPEEHHLCFAA00&size=full&WebLinkReturn=Full%2BText%3DL%7CS.sh.24.45%7C0%7C00132577-
201909000-00007&View%2BImage=00132577-201909000-00007%7CFF10
7. Spyropoulos, A. C. (2020). JavaScript disabled. Scientific and Standardization Committee Communication: Guidance document on the periprocedural management
of patients on chronic oral anticoagulant therapy: Recommendations for standardized reporting of procedural/surgical bleed risk and patient‐specific
thromboembolic risk. Retrieved November 29, 2021, from https://onlinelibrary.wiley.com/doi/epdf/10.1111/jth.14598
8. Ansell JE;Bakhru SH;Laulicht BE;Steiner SS;Grosso M;Brown K;Dishy V;Noveck RJ;Costin JC;, jack e. (2021). Use of per977 to reverse the anticoagulant effect of
Edoxaban. The New England journal of medicine. Retrieved November 29, 2021, from https://pubmed.ncbi.nlm.nih.gov/25371966/.
9. Thalji NK;Ivanciu L;Davidson R;Gimotty PA;Krishnaswamy S;Camire RM; (n.d.). A rapid pro-hemostatic approach to overcome direct oral anticoagulants. Nature
medicine. Retrieved November 29, 2021, from https://pubmed.ncbi.nlm.nih.gov/27455511/.

26. 26
For further information don’t hesitate to
contact me by Zeinab.nm1163@gmail.com