1. AUB:Iatrogent Coagulopathy
Tavoosi, A
Assistant Professor of Cardiology
Imam Khomeini Hospital

2. Abnormal uterine bleeding affects ≥20% of women taking anticoagulants

4. Oral Anticoagulants VKA: Warfarin NOAC or DOAC
Anti Xa: Rivaroxaban, Apixaban, Edoxaban
Direct thrombin(IIa) Inhibitor: Dabigatran
Oral Anticoagulants

5. All DOACs have been indiscriminately shown to have a lower risk of intracranial bleeding in comparison to VKA
Rivaroxaban, edoxaban and the 150 mg dose of dabigatran increase this risk of gastrointestinal bleeding compared to VKA
Apixaban and the 110 mg dose of dabigatran are not associated with a higher risk of gastrointestinal bleeding compared to VKA

6. HMB Is often overlooked
A recent meta-analysis of published clinical trials evaluating bleeding observed with rivaroxaban therapy has no specific mention of HMB
HMB Is often overlooked
Wasserlauf G et al. (2013) Meta-analysis of rivaroxaban.American Journal of Cardiology, 112,454–460.

7. International Society on Thrombosis and Haemostasis (ISTH)
Definition of clinically relevant non-major bleeding does not specify HMB as a sub- category of bleeding to report.
International Society on Thrombosis and Haemostasis (ISTH)

8. This lack of formal recognition
Perpetuates the absence of specific information in the literature on this important area
and
HMB has an overall negative impact on women’s quality of life, incurring significant direct and indirect costs
This lack of formal recognition

9. Anticoagulation & Abnormal Uterine Bleeding
Measured menstrual blood loss and vitamin K antagonist therapy (VKA)
Anticoagulation & Abnormal Uterine Bleeding

10. Sjalander A et al. J Thromb Thrombolysis. 2007;24:39-41

11. Huq FY et al. Contraception. 2011; 84:128-132

12. 1. Ferreira M et al. Br J Haematol. 2015 July 27. doi:10. 1111/bjh
1. Ferreira M et al. Br J Haematol July 27.doi: /bjh Myers B et al. Br J Haematol Mar 11.doi:10.111/bjh Marten S et al. Blood (abstract 1131)

13. Rivaroxaban vs. VKA
De Crem N et al. Thromb Res. 2015;136:

14. Hazard Ratio: 0.56 (95% CI, )

15. AUB appears more frequent with rivaroxaban than with VKA
Data for other DOACs limited

16. Medical treatment is first line therapy once malignancy and significant pelvic pathology are excluded
Tranexamic acid, Hormone Therapy

17. warfarin-associated coagulopathy
The degree of INR elevation
The presence of clinically significant bleeding
Underlying thrombotic risk/indication for anticoagulation
warfarin-associated coagulopathy

18. Serious or life-threatening bleeding: require rapid, full reversal of any warfarin effect
No bleeding or minor bleeding: may be best served by holding warfarin without administration of a reversal agent, especially if the underlying thrombotic risk is particularly high

20. Serious/life-threatening bleeding
Discontinue warfarin
Serious/life-threatening bleeding 

21. Administer 10 mg vitamin K by slow intravenous infusion (eg, over 20 to 60 minutes)
Vitamin K can be administered without waiting for laboratory tests or imaging studies
If the patient requires re-initiation of anticoagulation while refractory to warfarin, another agent such as heparin can be used
Vitamin K may be repeated at 12-hour intervals if the INR remains elevated.
Vitamin K

22. A 4-factor prothrombin complex concentrate (PCC, unactivated) rather than Fresh Frozen Plasma (FFP) for rapid reversal, due to the similar efficacy and lower risk of adverse events with PCC
Dosing depends on patient weight and the INR at presentation; a typical dose for INR >6 is 50 units/kg 
Pcc

24. Recheck the prothrombin time (PT)/INR at approximately 30 minutes following PCC administration, and periodically thereafter, with the frequency determined by the severity of bleeding
monitoring

25. Antifibrinolytic agents such as tranexamic acid or epsilon-aminocaproic acid may be used in some settings (eg, oral/mucosal bleeding)
Desmopressin (DDAVP) may be used for platelet dysfunction
Other agents

26. Recombinant activated factor VII (rFVIIa)
Generally is not used to treat warfarin- associated bleeding, because it does not supply the other vitamin K-dependent factors affected by warfarin
Recombinant activated factor VII (rFVIIa)

27. Transfusions Platelets
If a patient is bleeding in the setting of thrombocytopenia or
if a patient is taking concomitant antiplatelet therapy (eg, ASA, clopidogrel)
Some experts use a target platelet count of >50,000/microL and others use a target platelet count of >100,000/microL, especially for life- threatening bleeding
Transfusions

28. FFP If no PCC is available (initial dose 15 to 30 mL/kg) or
If the patient is receiving massive transfusions for severe ongoing bleeding
FFP

29. INR >9 without bleeding
Without bleeding, warfarin therapy should be held and 2.5 to 5 mg of vitamin K administered orally
Nonbleeding patients should not be given PCC or FFP solely to correct a supratherapeutic INR, as these products have associated risks
INR >9 without bleeding

30. INR 5 to 9 without bleeding
Without bleeding, warfarin is held temporarily (eg, one or two doses) with or without administration of a small dose of oral vitamin K (eg, 1 to 2.5 mg)
INR 5 to 9 without bleeding

31. INR <5 without bleeding
 Without bleeding, one or more doses of warfarin may be omitted and/or the dose is reduced slightly
INR <5 without bleeding

32. Measurement of Anticoagulant Effects of DOACs
Test
Dabigatran
Rivaroxaban
Apixaban
Specific
Assay
Hemoclot
Anti-Xa
Non-specific assays
aPTT
↑↑↑ ↑ PT ↑↑ TT
↑↑↑↑
No effect
Measurement of Anticoagulant Effects of DOACs

33. Management of NOAC Bleeding
Hold drug(s)
No Vit K
Resuscitation (i.v. access, fluid administration, blood product transfusion)
Maintain diuresis to clear drug
Mechanical compression and surgical methods to stop bleeding
Management of NOAC Bleeding

34. Bleeding while using a DOAC
Bleeding Management
Inquire about last DOAC intake
Determine Creatinine ,Hb and WBC
Inquire Lab for possibility of rapid coagulation assessment
Life –treatening bleeding
Moderate to severe bleeding
Minor bleeding

35. Rivaroxaban and apixaban are highly bound to plasma proteins
Dialysis is ineffective in clearing these drugs

36. MANAGEMENT OF LIFE-THREATENING BLEEDING
Basic resuscitation
Airway, breathing, and circulation with attempts to control hemorrhage
Immediate resuscitation and stabilization with intravenous fluids, packed red blood cells and plasma may be required in the unstable patient
NOAC reversal should be considered
MANAGEMENT OF LIFE-THREATENING BLEEDING

37. Short Half Life
Mild Bleeding

38. Moderate to Severe Bleeding

39. Life –threatening bleeding

40. Prothrombin complex concentrates (PCCs)
4-Factor PCC (Beriplex) or (Kanokad)
(Factors II, VII, IX, X , proteins C and S)
3-Factor PCC
(factors II, IX, X)
Activated PCC (FEIBA)
(Factors II, IX, X, and activated VII)
Prothrombin complex concentrates (PCCs)

41. Thank you!