Reversal of Anticoagulants induce bleeding including Antiplatelets, Anticoagulants and Thrombolytics

1. Reversal Of Antithrombotic Agents
DR ANKIT GAJJAR
MD,IDCCM,IFCCM,EDIC
Consultant Intensivist at INS Hospital, Surat

2. Antithrombotic Agents
• Anti platelet drugs…. Aspirin, Clopidogrel
• Anti coagulants
Parenteral
UFH
LMWH…. Enoxaparin, Dalteparin
Fondaparinux
Oral
Warfarin
NOAC
• Thrombolysis

3. Vascular Injury
Exposure of collagen and vWF Tissue factor exposure
Platelet adhesion and release Activation of coagulation
Platelet recruitment and activation Thrombin generation
Fibrin formationPlatelet aggregation
Platelet – fibrin thrombus

4. • Drugs used in thrombosis
• Anticoagulants: drugs which prevent clotting by inhibiting clotting factors
(coagulation process) (used in prevention and treatment of thrombosis).
• Antiplatelets: drugs which prevent and inhibit platelet activation and
aggression (used as prophylactic therapy in high risk patients).
• Thrombolytics or Fibrinolytics: act by dissolving existing or already formed
thrombi or emboli and used in the acute treatment of thrombosis.
•

5. Anti platelet drugs

6. The role of platelets

7. The role of platelets

8. The role of platelets

9. The role of platelets

10. Plaque Disruption
Collagen vWF
Platelet adhesion and secretion
Aspirin
Ticlopidine
Clopidogrel
Abciximab
Eptifibatide
Tirofiban
Platelet aggregation
Platelet recruitment and activation
COX-1
ADP
GPllb / llla activation
X
Mechanisms of action of
antiplatelet drugs
X
TXA2

13. Antiplatelet Agents
• Aspirin
Irreversibly inhibit COX 1 enzyme
Rapid onset <1 hr
Half life 15- 30 minutes
5-7 days for platelet recovery

14. Antiplatelet Agents
• Clopidogrel
• Irreversibly inhibit ADP receptor subtype P2Y12 receptor,
required for platelet activation
• Half life 8 hrs
• 5 days for platelet recovery

15. Antiplatelet Agents
• Mixing of Aspirin treated platelets ex-vivo, with 30-50 %
untreated donor platelets, restored abnormal platelets
aggregation response. So, infusion of 2-3 adult dose of donor
platelets are effective in emergency reversal of aspirin in
adults.
Vilahur et al 2007
Li et al 2012
British journal of Haematology 2012, 160, 35-46

16. Antiplatelet Agents
• Reversal
Elective surgery wait for 5-7 days
For emergency surgery, replacement with platelet transfusion
should be consider
For conservative management, platelet transfusion is not
recommended (risk/benefit ratio)
Desmopressin (0.4 micrg/kg) can be consider spcifically in patient
with Uremia
No role of FFP and Protamine
Dastur CK, Stroke and Vascular Neurology 2017

17. Anti coagulants

22. UFH
• Acts on intrinsic pathway
• Inactivates IX, X, XI and XII and thrombin and inhibit conversion of
fibrinogen to fibrin
• Metabolized in liver and reticulo endothelial system
• No Renal adjustment
• Dose : 60-80 Unit/kg bolus f/b 12-18 Unit/kg/hr
Px - 5000 Unit Bd / Tid
• Monitoring by aPTT level
• Does not affect Prothrombin Time

23. UFH
• Shorter half life 30-90 minutes
• Reversal
If stopped before 4 hours, no need of any reversal
If infusion is going on, calculate last 2-2.5 hours of heparin and give
protamine sulphate 1 mg/100 unit of heparin (maximum 50 mg)
If dose unknown, give 50 mg of protamine
100 % reversal effect
Mesure aPTT before OT
No role of FFP or Vitamin K

24. LMWH
• Enoxaparin and Dalteparin
• Inhibit factor X>II
• Does not affect aPTT and PT level
• Renal clearance, so dose adjustment in renal failure
• Dose: Therapeutic - I mg/kg bid or 1.5 mg/kg od
(1 mg/kg od in renal failure)
Prophylactic – 40 mg sc od
• No need of monitoring (factor Anti Xa level can be monitored
in special case)

25. LMWH
• Reversal
For elective surgery, stop before 24 hours
For immediate reversal,
- last dose < 8 hours – 1 mg protamine / 1 mg enoxaparin
(additional 0.5 mg protamine / 1 mg enoxaparin can be used)
- last dose 8-12 hours – 0.5 mg protamine / 1 mg enoxaparin
60 % reversal
No use of FFP or Vitamin K

26. Fondaparinux
• Indirect Factor Xa inhibitor
• Does not affect aPTT and PT
• No need of monitoring
• Renal clearance (C/I if CrCl < 30 ml/min)
• Dose : Prophylactic : 2.5 mg sc od
Therapeutic : < 50 kg 5 mg sc od
50-100 kg 7.5 mg sc od
> 100 kg 10 mg sc od

27. Fondaparinux
• Reversal
Elective surgery stop before 24 hours
No agent for immediate reversal
Factor VIIa can be try

28. Warfarin
• Inhibit Vitamin K dependent factor II, VII, IX and X
• Mesure PT for dose adjustment
• Half life 36 hrs.
• 5 days for INR to become normal
• Target INR 2-3

29. Warfarin
• For immediate reversal of INR
• Inj vit K 10 mg iv with PCC or FFP
• PCC – 4 factor or 3 factor PCC 1500-2000 IU
 Cost and availability
 Rapid and specific reversal
• FFP – 15 – 20 ml/kg (6-8 units of FFP)
 Shorter duration of action
 large volume infusion and more complication
 Slow reversal than PCC
Target INR <1.5

30. Warfarin
• Factor VIIa can be used
• No role of protamine sulphate

31. Warfarin
• Supratherapeutic INR without bleeding
• INR 5-9 – omit 1-2 dose+- 1.25 -5 mg PO vitamin K
• INR >9 ( no bleed )- omit 1-2 dose +/- 2.5 - 5 mg PO vitamin K
• Surgery Reversal
INR > 1.5-2.5 hrs.
• Sx <24 hrs – 0.5 -1 mg IV vit.K x1 +/- 5-8 ml/kg FFP
• Sx 24-96 hrs- 0.5 -1 mg PO vitamin K
INR > 2.5 – 5
• Sx <24 hrs – 1-2.5 IV Vitamin K +/- 5-8ml /kg FFP
• Sx 24-96 hrs – 1-2.5 mg PO vitamin K

32. Warfarin
• For elective surgery
• Stop warfarin before 5 days
• Switch over to UFH / LMWH
• Stop UFH / LMWH before surgery

33. Dabigatran
• NOAC
• Direct thrombin inhibitor (Argatroban, bivalirudin)
• Dose : 150 mg PO bd
if CrCl 15-30 ml/min – 75 mg PO bd
• No need of monitoring for therapeutic effect but Thrombin
time will be elevated
• No use of FFP or Protamine
• Indication : Stroke prevention in non valvular AF

34. Dabigatran
• Reversal
• For elective surgery, stop before 24 hours
• For emergency reversal, Idarucizumab (Praxbind®)
Infuse two 2.5 gram/50 mL vials undiluted over 5-10 minutes each
- Second vial should be infused within 15 minutes of first vial
• Activated Charcoal – within 1 hr. of Dabigatran
• Dialysis – Last resort, removes 60% of dabigatran(mainly in renal failure)
• 4 factor PCC (50 unit/kg) if Praxibind is not available
• Factor VIIa can be tried
• A normal aPTT and TT rules out clinically relavent Dabigatran effect.

35. Factor Xa inhibitors
• Rivaroxaban, Apixaban, Edoxaban
• Elective surgery – stop before 24 hours
• Emergency reversal
• If presenting within 2 hours of intake – activated charcoal
• 4 factor PCC – 50 units / kg
• Laboratory testing not helpful
• Not dialysable

36. Thrombolytic agents

37. Thrombolytic agents
• Cryoprecipitate 10 units
• If fibrinogen <150 mg/dl post cryoprecipitate, consider
additional cryoprecipitate
• 6-8 unit of platelet concentrate
• If cryoprecipitate not available, FFP can be given
• If not available, than tranexamic acid 15-20 ml/kg

38. Protamine Sulphate
• Protamine is basic in nature and combine with acidic heparin
• Calculate dose
• Maximum dose 50 mg (1 ampoule)
• Severe Allergic reaction
• Administration
Dilute in 5 ml of sterile water
Inject over 10 minutes

39. TAKE HOME MESSAGE
DRUG Elective Emergency Not indicated Monitoring
Aspirin
Clopidogrel
Stop before 5-7 days Platelet concentrate
Desmopressin
(Uremia)
FFP
Vitamin K
Protamine
None
UFH Stop before 4-6
hours
Protamine Sulphate
(100%)
FFP
Vitamin K
aPTT
LMWH Stop before 24 hours Protamine Sulphate
(60 %)
FFP
Vitamin K
Anti Xa level
Fondaperinux Stop before 24 hours FVIIa FFP
Vitamin K
Protamine
Anti Xa level
Warfarin Stop before 5-7 days Vitamin K
4 PCC 50 Unit/kg
FFP 15-20 ml/kg
Protamine PT

40. Drug Elective Emergency Not indicated Monitoring
Dabigatran Stop before 24 hours Activated Charcoal
Praxbind 5 gm
4 factor PCC
Dialysis
FFP
Vitamin K
Protamine
TT
aPTT
Rivaroxaban Stop before 24 hours Activated Charcoal
4 factor PCC
FFP
Vitamin K
Protamine
Dialysis
None
Thrombolytics --- 10 Cryoprecipitate
6-8 RDP
FFP
---- Fibrinogen

41. Thank you