reversal protocol for various anticoagulant specially for neurological disease

1. Reversal of Anticoagulants
with special reference to
Neurological disorder
DR BHAVIN J PATEL
SR NEUROLOGY
GMC, KOTA

2. Introduction
Coagulation occurs through the action of discrete enzyme
complexes, which are composed of a vitamin K–dependent enzyme
and a nonenzyme cofactor.
Anticoagulant medication act at various stage of coagulation
cascade and prevent thrombosis

3. Classification

4. Mechanism of action

5. Parenteral anticoagulant

6. Oral anticoagulants
Vitamin K antagonist:-
1) Warfarin:-
Bioavailabily nearly complete; absorption dampened by food
Can cross placental barrier
Half-life: 25 - 60 hr; Excreted in urine and stool
Toxicities: bleeding, fetal bone abnormalities, skin necrosis

7. Oral anticoagulants
Acenocoumarol(acitrom):-
Same as warfarin with following differences:
 Shorter half life 10-16 hrs
 More rapid onset of action on PT
 Shorter duration of action (2 days)
Causes GI disturbances, oral ulcerations and dermatitis

8. Oral anticoagulants
Alok Dabi et al Reversal Strategies for Intracranial Hemorrhage Related to Direct Oral Anticoagulant
Medications Hindawi Critical Care Research and Practice Volume 2018

9. Indications of anticoagulants
Acute ischemic stroke
Cerebral venous sinus thrombosis
Venous thromboembolism
Spinal cord injury

10. Monitoring
Routine monitoring is required in unfractioned Heparin and vitamin
K antagonist only.

11. Warfarin Monitoring
INR daily until it is in therapeutic range
3 times weekly for 2 weeks
Once stable and warfarin dose is known
INR every 3-4 week or more frequently if new
medication started

12. Monitoring
Indications:-
During long term therapy for LMWH and fondaparinoux.
Patient with bleeding
Required emergency invasive procedure or surgery
Impaired renal function

13. Monitoring
Anticoagulant Laboratory investigation
LMWH & fondaperinoux Anti Factor Xa Assay
Rivaroxaban ,Edoxaban, Apixaban
Dabigatran TCT, dTCT, ECT
Indicatons:-
Extreme of body weight
Assessing for medical compliance

14. Side Effects
MC side effect:- BLEEDING (all anticoagulant)
Osteoporosis and thrombocytopenia(heparin)
Hypersinsitivity reaction (enoxaparin and warfarin)
Skin necrosis (warfarin)
Hepatitis and ARF(warfarin)
Gastrointestinal dysfunction (warfarin and dabigatran)

15. Why reversal of anticoagulation?
Incidence of ICH:-
Spontaneous ICH :- 25-30 /lakh ( mortality 30%)
On warfarin:- 2000-3000/lakh (50%)
On DOAC:-520/lakh ( 45 % of all death after major bleed)
Alok Dabi et al Reversal Strategies for Intracranial Hemorrhage Related to Direct Oral Anticoagulant
Medications Hindawi Critical Care Research and Practice Volume 2018

16. Management of Bleeding due to
anticoagulation
Assessment of bleeding
Assessment of anticoagulation status
Baseline laboratory testing
Basic therapeutic measures
Specific reversal for individual anticoagulant
Surgical intervention
Reinitiation of anticoagulant

17. Assessment of bleeding
Site of bleeding
Rate of hemorrhage
Amount of blood loss
Current state of bleed:- active or stopped?
Thorough physical examination with vitals
Imaging study ( Ct head or abdomen)
Endoscopy

18. Classification of bleeding
Major bleeding:-
Intracranial bleed
Retroperitoneal bleed
Massive gastrointestinal bleed
Compartment syndrome
Active bleed with hemodynamic
instability
 Minor bleed:-
 Epistaxis
 Uncomplicated soft tissue bleed
 Minor Gastrointestinal bleed
 Superficial Skin bleeding

19. Poor Prognostic factor
Presence of coma (GCS<8)
Neck stiffness
Focal neurological deficit with seizure
DBP>110mmhg
ICH volume above 60 ml
Presence of IVH ( Increase by 2 ml in 24hr)
Lobar haemorrhage
>33% rise in hematoma volume
Alok Dabi et al Reversal Strategies for Intracranial Hemorrhage Related to Direct Oral Anticoagulant
Medications Hindawi Critical Care Research and Practice Volume 2018

20. Assessment of anticoagulation status
Which anticoagulant was taken by patient? Other aggravating medicine?
Interval since last dose:-
Anticoagulation resolved fully after 5 half lives period.
Anticoagulant Elimination half life Five half lives
Warfarin 25 -60 Hr 5-10 days
Acitrom 10-16 hr 2-3.5 days
Dabigatran 12-17 hr 2-3.5 days
Rivaroxaban 5-9 hr 1-2 days
Apixaban 8-15 hr 1.5-3 days
Edoxaban 6-11 hr 1.3-2 days
Matthew M et al,Contemporary Reversal of Oral Anticoagulation in Intracerebral Hemorrhage , Stroke.
2019;50:529-536

21. Assessment of anticoagulation status
Renal and Hepatic function:-
Half lies of anticoagulant is depend on patient renal or hepatic
function
Anticoagulant Route of elimination
Warfarin And Acitrom Hepatic metabolism
Dabigatran Renal excretion 80%
Rivaroxaban and Apixaban Hepatic 70% renal 30%
Edoxaban Hepatic 60% Renal 40%
Betrixaban Hepatic 90%
Matthew M et al,Contemporary Reversal of Oral Anticoagulation in Intracerebral Hemorrhage , Stroke.
2019;50:529-536

22. Assessment of anticoagulation status
Coagulation testing:-
In routine PT-INR is used for warfarin and APTT is for heparin anticoagulation
status.
Routine coagulation study should not used for DOAC.
Patient with normal coagulation study and persistent bleeding are treated as if
they are anticoagulated.
Anticoagulant Coagulation test
Heparin APTT
Warfarin PT-INR
Dabigatran TCT,ECT
Factor Xa inhibitor Anti Xa assay
Matthew M et al,Contemporary Reversal of Oral Anticoagulation in Intracerebral Hemorrhage , Stroke.
2019;50:529-536

23. Assessment of anticoagulation status
Other laboratory testing:-
Hemoglobin level with Hct
Platelet count
Fibrinogen and D-dimer level

24. Basic therapeutic intervention
ABC:- Airway protection and maintenance of normal oxygenation
GCS<8)
Hemodynamic resuscitation
BP control (SBP< 140 mmhg to be achieved within 1 hr)
Adequate fluid resuscitation
Activated charcoal if last dose <2 hr.

25. Basic therapeutic intervention
Maintain normothermia and normoglycemia
Stop anticoagulants and antiplatelet
VTE prevention:- SCD use.
Evaluate for the need of REVERSAL.

26. Specific reversal therapy
All patients with major bleeding should be treated with specific
antidote if available.
High quality randomized trials are lacking for particular strategies.
Treatment option available as reversal agents are:-
Specific reversal antidote
Pro-hemostatic therapies
Prothrombin complex concentrate
FFP,cryoprecipitate and Recombinant factor 7

27. Unfractioned Heparin and LMWH
 Specific antidote:- protamine I.V for both
 Onset of action:- 5 min
 Duration of action:- 2 hour
 It has 100% reversal effect on heparin and 60 % for LMWH.
 HD has partial reversal effect.
 Degree of reversal can be assessed by
 Heparin:- APTT or factor Xa activity for heparin.
 LMWH:- Anti factor Xa assay

28. Unfractioned Heparin and LMWH
Alok Dabi et al Reversal Strategies for Intracranial Hemorrhage Related to Direct Oral Anticoagulant
Medications Hindawi Critical Care Research and Practice Volume 2018

29. Fondaperinux
 No specific antidote available for fondaperinux.
 Factor 7a or aPCC(90 mcg/kg) can be used.
 Andexanet alfa and aripazine are newer drugs under trial which
may be effective.
 Degree of reversal can be assessed by anti factor Xa assay for
both.

30. Warfarin
Specific antidote :- Vitamin K
Route of administration:- oral, subcutaneous or Intravenous
For major bleeding Intravenous infusion is given as it is more
effective.
Reversal of anticoagulant effect can take up to 24 to 48 hour.
In case of serious bleeding alone vitamin K is not sufficient.

31. Warfarin
Fresh frozen plasma(FFP):-
Provides non specific coagulation factors.
10-20 ml/ kg IV FFP required for 15-25% increase in plasma
coagulation factor.
It also takes few hours for complete reversal of anticoagulation
effect.
Disadvantage:-
Risk of transmission of HIV,HCV and HBV
Requires large volume of transfusion

32. Warfarin
Prothrombin complex concentrate (PCC):-
Contain vitamin K dependent factors.
Available in 3 factor and 4 factor PCC.
4 factor PCC also available in activated form.
25 % more concentration then FFP.
Dose :- 25-50 IU/kg.

33. Warfarin
Prothrombin complex concentrate (PCC):-
Advantage:-
 Smaller volume
 Less immunologic reaction
Disadvantage:-
Availability
 Cost.

35. Warfarin
Recombinant Factor 7:-
Reported to normalize INR in 10 minutes.
Dose:- 10-40 mcg/kg
Half life :-2-3 hr
Used along with vitamin K or FFP.
Cost:- 18000 Rs/ pack of 1 mg.

37. Dabigatran
Specific antidote:-idareucizumab
Human monoclonal antibody against dabigatran
Dose:- 5 gm IV once.
Onset of action :-10-30 minutes
Half life:-1 hr
Indication:-
Emergency surgery
Major or life threatening bleed
Prajwal Dhakal et al Reversal of Anticoagulation and Management of Bleeding in Patients on Anticoagulants
Clinical and Applied Thrombosis/Hemostasis 1-6

39. Dabigatran
Advantage:-
No pro thrombotic effect
Not affected by renal or hepatic dysfunction
Rapid reversal 100% within 4 hour
No evidence of immunogenicity
Can be used multiple times.
Disadvantage:-
Availabilty
cost
Prajwal Dhakal et al Reversal of Anticoagulation and Management of Bleeding in Patients on Anticoagulants
Clinical and Applied Thrombosis/Hemostasis 1-6

40. Recently

41. Factor Xa inhibitor
Specific antidote:- andexanet alfa
Its catalytically inactive form of factor Xa
Used for life threatening bleed.
It can be also effective against LMWH and fondaperinux.
Half life :- 6 hours
Dose:-
Prajwal Dhakal et al Reversal of Anticoagulation and Management of Bleeding in Patients on Anticoagulants
Clinical and Applied Thrombosis/Hemostasis 1-6

43. Ciraparantag
Prevent anticoagulant from binding to endogenous targets.
It has potential for universal antidote as it is effective against all
class of anticoagulant
Elimination through kidney.
Effect of reversal within 5-20 minutes.
Reversal can be assessed by whole blood clotting time.
Side effect:- facial flushing , headache, altered taste
In phase 2 trial
Prajwal Dhakal et al Reversal of Anticoagulation and Management of Bleeding in Patients on Anticoagulants
Clinical and Applied Thrombosis/Hemostasis 1-6

44. DOACs
Prothrombin complex concentrate (PCC):-
Indication:- life threatening bleed only
Very limited data on its efficacy in reversal
Recommanded dose:- 25-50 IU/kg.
Unactivated PCC has less risk of thrombosis
For factor Xa inhibitor:- Unactivated> activated
For dabigatran:- activated> unactivated

45. DOACs
Antifibrinolytic agent:-
Tranexamic acid and epsilon aminocaproic acid
Used for major and minor bleed
Dose:- 1.5 gm iv every 8 hrly for tranexamic acid
2 gm iv every 6 hourly for EACA
Tranexamic acid excretion is dependent on renal function
Till bleeding occurs

46. DOAC
FFP and Recombinant factor 7:-
Both of them not shown ant benefit in DOAC related bleed.
FFP can be transfused as a massive transfusion protocol in hemodynamic
unstable patient.
Desmopressin:-
Used to improve platelet function especially in setting of uremia and antiplatelet
medication.
Dose:- 0.3 mcg/kg subcutaneous or IV.
Disadvantage:- early tachyphylaxis and hyponatremia

47. Transfusion:-
RBC transfusion may be required for severe bleeding.
Platelet transfusion can be used in case of severe thrombocytopenia
and patient taking antiplatelet require neurosurgical intervention.
Hemodialysis is useful for reversal of dabigatran in renal
dysfunction patient.

48. Surgical intervention
Infratentorial ICH:-
ICH >3 cm size
Brainstem compression
Hydrocephalus
Supratentorial ICH:-
Clinical detoriation
Accessible ICH with high risk of
herniation
Medically refractory raised ICP

49. Reintiation of Anticoagulation
Risk of thromboembolic event is more in absences of OAC than risk of major
bleed with OAC.
For E.g.:-
Risk of bleed in mechanical heart valve & AF on OAC:- major bleed 2-3%, ICH
0.3-0.5%
Risk of thromboembolic event in Mechanical heart valve & AF pt not on OAC:-12-
22% & 6-18%

50. Bleeding predictability scores

51. Jacques Donzé et al Scores to Predict Major Bleeding Risk During Oral Anticoagulation Therapy: A Prospective
Validation Study The American Journal of Medicine (2012) 125, 1095-1102

52. Factors affecting Reintiation of
Anticoagulation

53. Factors affecting Reintiation of
Anticoagulation

54. Factors affecting Reintiation of
Anticoagulation

55. Factors affecting Reintiation of
Anticoagulation

56. Factors affecting Reintiation of
Anticoagulation

57. Factors affecting Reintiation of
Anticoagulation

58. Reintiation of Anticoagulation
Timing of restarting of OAC:-
Higher risk of stroke/VTE with minor bleed:- Restarted within 1-2
week
Higher risk of stroke/VTE with major bleed:- restart upto 4 week
DOAC reach therapeutic level within few hours compare to VKA
which takes few days.

59. Conclusion
Anticoagulant therapy is associated with significant increase in incidence of major
bleeding.
NOAC has less chance of ICH compare to VKA.
Specific antidotes are available for NOAC but availability and cost is major
drawback.
PCC is comparable in efficacy and easily available alternative for specific antidote.
Reintiation of anticoagulant mainly depends on
1) indication of OAC 2) predicted risk of stroke/VTE versus bleeding
In high risk patient OAC should be started as early as possible.

60. References
Matthew M et al,Contemporary Reversal of Oral Anticoagulation in Intracerebral Hemorrhage ,
Stroke. 2019;50:529-536.
Alok Dabi et al Reversal Strategies for Intracranial Hemorrhage Related to Direct Oral
Anticoagulant Medications Hindawi Critical Care Research and Practice Volume 2018
Ariela L. Marshall et alAnticoagulation for Noncardiac Indications in Neurologic Patients:
Comparative Use of Non-Vitamin K Oral Anticoagulants, Low-Molecular-Weight Heparins, and
Warfarin Curr Treat Options Neurol (2014) 16:309
Prajwal Dhakal et al Reversal of Anticoagulation and Management of Bleeding in Patients on
Anticoagulants Clinical and Applied Thrombosis/Hemostasis 1-6
Up To Date.com