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

Abnormal uterine bleeding affects ≥20% of women taking anticoagulants

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

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

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.

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)

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

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

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

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

1. Ferreira M et al. Br J Haematol. 2015 July 27. doi:10. 1111/bjh 1. Ferreira M et al. Br J Haematol. 2015 July 27.doi:10.1111/bjh.13583 2. Myers B et al. Br J Haematol. 2016 Mar 11.doi:10.111/bjh.14003 3. Marten S et al. Blood. 2015 (abstract 1131)

Rivaroxaban vs. VKA De Crem N et al. Thromb Res. 2015;136:749-753

Hazard Ratio: 0.56 (95% CI, 0.23-1.39)

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

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

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

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

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

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

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

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

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

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)

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

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

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

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

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

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

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

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

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

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

Short Half Life Mild Bleeding

Moderate to Severe Bleeding

Life –threatening bleeding

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)

Thank you!