Table 3 Anticoagulants and reversal strategies

 Warfarin

Factors II, VII, IX, X; proteins C, S

Hepatic metabolism

0.3–1.1 % [90]

Good linear correlation PT/INR

Vitamin K

Not dialyzable

Withhold VKA + intravenous vitamin K + replace vitamin K–dependent factors (three- or four-factor PCC IV or FFP if PCCs are not available), and correct the INR (keep INR < 1.4) (Class I; Level of Evidence C) [9]

92 % renal elimination

Vitamin K 10 mg IV associated with 4-FPCC 20 IU/kg (or FFP = 10–15 ml/kg, if PCC is not available)

PCCs might be considered over FFP (Class IIb; Level of Evidence B) [9]

20–60

Goal: INR < 1.4 [90]

rFVIIa is not recommended for VKA reversal in ICH (Class III; Level of Evidence C) [9]

 UFH

Binds and activates antithrombin (which blocks coagulation factors Xa and IIa). By inactivating thrombin, heparin prevents fibrin formation

Renal

0.1 to 0.2 % [90, 151]

Good linear correlation aPTT

Protamine sulfate 1 mg of protamine per 100 units of UFH infused over the preceding 3 hours

Not dialyzable

Protamine sulfate—1 mg for every 100 units of heparin given in the previous 2–3 hours with a maximum single dose of 50 mg (Strong recommendation, moderate quality evidence) [90]

0.5–2.5 (dose dependent)

If aPTT is still elevated, repeat administration of protamine at a dose of 0.5 mg protamine per 100 units of UFH (Conditional recommendation, low quality of evidence) [90]

Reversal of prophylactic SC heparin only if aPTT is significantly prolonged (Good Practice statement) [90]

 Enoxaparin

LMWH

Binds and activates antithrombin (which blocks coagulation factors Xa and IIa)

40 % renal

0.2–0.5 % [98] Enoxaparin 1 mg/kg BID; bridging warfarin with target INR 2–3

Anti-factor Xa

Protamine sulfate partially reverses (60 %) LMWH effect. One mg protamine for every 1 mg enoxaparin

Not dialyzable

Strong recommendation, moderate quality evidence [90]

4.5 hours

Protamine sulfate 1 mg per 1 mg of enoxaparin (maximum single dose of 50 mg—if enoxaparin was given within 8 hours)

Protamine sulfate 0.5 mg of protamine per 1 mg of enoxaparin (if enoxaparin was given within 8–12 hours)

After 12 hours, protamine is not needed

 Dalteparin

LMWH

Binds and activates antithrombin (which blocks coagulation factors Xa and IIa)

Renal

Not established

Anti-factor Xa

Protamine sulfate partially reverses (60 %) LMWH effect. One mg protamine for every 100 anti-Xa IU dalteparin

Not dialyzable

Protamine sulfate 1 mg per 100 IU of dalteparin administered in the past 3–5 half-lives (maximum 50 mg) (Strong recommendation, moderate quality evidence) [90]

2.5 hours

3.7–7.7 hours with RF

 Nadroparin

LMWH

Binds and activates antithrombin (which blocks coagulation factors Xa and IIa)

Renal

Not established

Anti-factor Xa

Protamine sulfate partially reverses (60 %) LMWH effect. One mg protamine for every 100 anti-Xa IU nadroparin

Not dialyzable

Protamine sulfate 1 mg per 100 IU of nadroparin administered in the past 3–5 half-lives (maximum 50 mg) (Strong recommendation, moderate quality evidence) [90]

3.5 hours

 Fondaparinux

 (Aristra®)

Binds with antithrombin and potentiates inhibition of free factor Xa, preventing formation of the prothrombinase complex

50–77 % renal

Not established

Anti-factor Xa

None

Activated PCC (FEIBA 20 units/kg)

aPCC 20 IU/kg (Conditional recommendation, low-quality evidence) [90]

17–21 hours

Dialyzable (clearance increased by 20 %)

rFVIIa (90 μg/kg) if aPCC is not available (Conditional recommendation, low-quality evidence) [90]

Prolonged in older patients and in RF

Protamine sulfate is not recommended (Strong recommendation, low-quality evidence) [90]

 Argatroban

 (Acova®)

Competitive direct inhibition of thrombin (factor IIa) including thrombin-mediated platelet activation and aggregation

No renal excretion

0.75 hours (prolonged in hepatic dysfunction)

Not established

aPTT, ACT

None

Activated PCC (FEIBA 50–80 units/kg)

Antifibrinolytic agent (e.g., tranexamic acid, epsilon-aminocaproic acid)

Hemodialysis (approximately 20 % over 4 hours)

aPCC (50 units/kg) or four-factor PCC (50 units/kg) (Conditional recommendation, low-quality evidence) [90]

rFVIIa or FFP are not recommended in direct thrombin inhibitor-related ICH (Strong recommendation, low-quality evidence) [90]

 Bivalirudin

Reversible direct inhibition of thrombin (factor IIa) including thrombin-mediated platelet activation and aggregation

20 % renal

0.1 % [151]

ECT (PT, aPTT, ACT has nonlinear prolongation)

None

Activated PCC (FEIBA 50–80 units/kg)

0.5 (prolonged in renal impairment)

Antifibrinolytic agent (e.g., tranexamic acid, epsilon-aminocaproic acid)

aPCC (50 units/kg) or four-factor PCC (50 units/kg) (Conditional recommendation, low-quality evidence)

GFR 30–59, 34 minutes

Hemodialysis (approximately 25 % over 4 hours)

rFVIIa or FFP are not recommended in direct thrombin inhibitor-related ICH (Strong recommendation, low-quality evidence)

GFR 10–29, 57 minutes

 Dabigatran

 (Pradaxa®)

Reversible direct inhibition of thrombin (factor IIa) including thrombin-mediated platelet activation and aggregation

>80 % renal

0.30 % (150 mg) [98]

Modified TT/ECT/prolongs PT linearly with increasing serum levels, while aPTT is affected in a nonlinear way

Idarucizumab or Praxbind® (humanized antibody fragment against dabigatran), in two doses of 2.5 g IV 15 minutes apart

Activated PCC (FEIBA 50–80 units/kg)

Idarucizumab 5 g IV in two divided doses if dabigatran was administered within 3–5 half-lives and no RF (Strong recommendation, moderate quality of evidence) or in the presence of RF leading to continued drug exposure beyond the normal 3–5 half-lives (Strong recommendation, moderate quality of evidence)

12–17 hours

0.23 % (110mg) [98]

Activated charcoal if last dose was taken < 2 hours

Hemodialysis (approximately 57 % over 4 hours)

Antifibrinolytic agent (e.g., tranexamic acid, epsilon-aminocaproic acid)

Hemodialysis if idarucizumab is not available (Conditional recommendation, low-quality data)

16.6 hours in mild RF

ICH distribution: 46 % intraparenchymal, 45 % SDH, and 8 % SAH [90]

18.7 hours in moderate RF

27.5 hours in severe RF

34.1 hours in patients on hemodialysis

 Desirudin

Irreversible direct inhibition of thrombin (factor IIa) including thrombin-mediated platelet activation and aggregation

40–50 % renal

2 hours (12 hours with renal impairment)

Not established

aPTT

None

Dialyzable

aPCC (50 units/kg) or four-factor PCC (50 units/kg) (Conditional recommendation, low-quality evidence) [90]

rFVIIa or FFP are not recommended in direct thrombin inhibitor-related ICH (Strong recommendation, low-quality evidence) [90]

 Apixaban

 (Eliquis®)

Prevents factor Xa-mediated conversion of prothrombin to thrombin

Mainly fecal

27 % renal

8–14 hours

Apixaban 5 mg twice daily

0.33 %/year [98]

Anti-factor Xa

There are scant data regarding the effect of apixaban on traditional coagulation tests

Currently, there is no FDA-approved specific antidote for this class of anticoagulants

Antidotes under investigation:

– Aripazine (PER977—synthetic small molecule)

– Andexanet (PRT064445—recombinant modified factor Xa protein)

Unactivated four-factor PCC (50 units/kg). If not available, a three-factor PCC can be used.

Activated charcoal if last dose was taken < 2 hours

Antifibrinolytic agent (e.g., tranexamic acid, epsilon-aminocaproic acid)

Minimal removal with dialysis (decreased by 14 % over 4 hours)

Activated charcoal (50 g) within 2 hours of ingestion (Conditional recommendation, very low-quality evidence) [90]

aPCC (50 units/kg) or Four-factor PCC (50 U/kg) or activated PCC (50 U/kg) if ICH happened within 3–5 half-lives of drug or if liver failure (Conditional recommendation, low-quality evidence) [90]

Four-factor PCC or activated PCC over rFVIIa (Conditional recommendation, low-quality evidence) [90]

 Rivaroxaban

 (Xarelto®)

Prevents factor Xa-mediated conversion of prothrombin to thrombin

66 % renal

28 % fecal

7 to 11 hours

Rivaroxaban 20 mg daily

- < 0.5 % /year

Anti-factor Xa

Rivaroxaban levels linearly increase PT and aPTT levels

Currently, there is no FDA-approved specific antidote for this class of anticoagulants

Antidotes under investigation:

– Aripazine (PER977—synthetic small molecule)

– Andexanet (PRT064445—recombinant modified factor Xa protein)

Unactivated four-factor PCC (50 units/kg). If not available, a three-factor PCC can be used.

Activated charcoal if last dose was taken < 2 hours

Antifibrinolytic agent (e.g., tranexamic acid, epsilon-aminocaproic acid)

Not dialyzable (rivaroxaban is highly protein bound)

Activated charcoal (50 g) within 2 hours of ingestion (Conditional recommendation, very low-quality evidence) [90]

Four-factor PCC (50 U/kg) or activated PCC (50 U/kg) if ICH happened within 3–5 half-lives of drug or if liver failure (Conditional recommendation, low-quality evidence) [90]

Four-factor PCC or activated PCC over rFVIIa (Conditional recommendation, low-quality evidence) [90]

 Edoxaban

Prevents factor Xa-mediated conversion of prothrombin to thrombin

50 % renal

10–14 hours

Edoxaban 60 mg daily compared with warfarin (HR 0.54, 95 % CI 0.38–0.77) [90]

There are scant data regarding the effect of edoxaban on traditional coagulation tests

Currently, there is no FDA-approved specific antidote for this class of anticoagulants

Antidotes under investigation:

– Aripazine (PER977—synthetic small molecule)

– Andexanet (PRT064445—recombinant modified factor Xa protein)

Unactivated four-factor PCC (50 units/kg). If not available, a three-factor PCC can be used.

Activated charcoal if last dose was taken < 2 hours

Antifibrinolytic agent (e.g., tranexamic acid, epsilon-aminocaproic acid)

Not dialyzable (edoxaban is highly protein bound)

Activated charcoal (50 g) within 2 hours of ingestion (Conditional recommendation, very low-quality evidence) [90]

Four-factor PCC (50 U/kg) or activated PCC (50 U/kg) if ICH happened within 3–5 half-lives of drug or if liver failure (Conditional recommendation, low-quality evidence) [90]

Four-factor PCC or activated PCC over rFVIIa (Conditional recommendation, low-quality evidence) [90]

 Aspirin

Irreversible COX-1 and 2 enzyme inhibitor (inhibits thromboxane A2)

5.6–35.6 % renal

0.3 hours

It is unclear if antiplatelet therapy increases the incidence of ICH

Light Transmission Platelet Aggregation with or without Secretion

None

The usefulness of platelet transfusions in ICH patients with a history of antiplatelet use is uncertain

Dialyzable

DDAVP 0.4 μg/kg

DDAVP 0.4 μg/kg IV (Conditional recommendation, low-quality evidence) [90]

Platelet transfusion is not recommended (Conditional recommendation, low-quality evidence) [90]

Platelet transfusion for patients who will undergo a neurosurgical procedure (Conditional recommendation, moderate quality of evidence) [90]

DDAVP can be used in addition to platelet transfusion in patients who will undergo neurosurgical procedure (Conditional recommendation, low-quality evidence) [90]

 Clopidogrel

Irreversible inhibition of P2Y12 ADP receptor

50 % renal

46 % fecal

6–8 hours

It is unclear if anti platelet therapy increases the incidence of ICH

Light Transmission Platelet Aggregation with or without Secretion

None

The usefulness of platelet transfusions in ICH patients with a history of antiplatelet use is uncertain

Not dialyzable

DDAVP 0.4 μg/kg

DDAVP 0.4 μg/kg IV (Conditional recommendation, low-quality evidence) [90]

Platelet transfusion is not recommended (Conditional recommendation, low-quality evidence) [90]

Platelet transfusion for patients who will undergo a neurosurgical procedure (Conditional recommendation, moderate quality of evidence) [90]

DDAVP can be used in addition to platelet transfusion in patients who will undergo neurosurgical procedure (Conditional recommendation, low-quality evidence) [90]

 Prasugrel

Irreversible inhibition of P2Y12 ADP receptor

68 % renal

27 % fecal

2–15 hours

It is unclear if anti platelet therapy increases the incidence of ICH

Light Transmission Platelet Aggregation with or without Secretion

None

The usefulness of platelet transfusions in ICH patients with a history of antiplatelet use is uncertain

Not dialyzable

DDAVP 0.4 μg/kg

DDAVP 0.4 μg/kg IV (Conditional recommendation, low-quality evidence) [90]

Platelet transfusion is not recommended (Conditional recommendation, low-quality evidence) [90]

Platelet transfusion for patients who will undergo a neurosurgical procedure (Conditional recommendation, moderate quality of evidence) [90]

DDAVP can be used in addition to platelet transfusion in patients who will undergo neurosurgical procedure (Conditional recommendation, low-quality evidence) [90]

 Ticlopidine

Irreversible inhibition of P2Y12 ADP receptor

60 % renal

23 % fecal

12 hours (increases with RF to 4–5 days after repeated doses)

It is unclear if anti platelet therapy increases the incidence of ICH

Light Transmission Platelet Aggregation with or without Secretion

None

The usefulness of platelet transfusions in ICH patients with a history of antiplatelet use is uncertain

Not dialyzable

DDAVP 0.4 μg/kg

DDAVP 0.4 μg/kg IV (Conditional recommendation, low-quality evidence) [90]

Platelet transfusion is not recommended (Conditional recommendation, low-quality evidence) [90]

Platelet transfusion for patients who will undergo a neurosurgical. procedure (Conditional recommendation, moderate quality of evidence) [90]

DDAVP can be used in addition to platelet transfusion in patients who will undergo neurosurgical procedure (Conditional recommendation, low-quality evidence) [90]

 Dipyridamole

Reversible adenosine reuptake inhibitor

Fecal

10 hours

It is unclear if anti platelet therapy increases the incidence of ICH

Light Transmission Platelet Aggregation with or without Secretion

None

The usefulness of platelet transfusions in ICH patients with a history of antiplatelet use is uncertain

Not dialyzable

DDAVP 0.4 μg/kg

DDAVP 0.4 mcg/kg IV (Conditional recommendation, low-quality evidence) [90]

Platelet transfusion is not recommended (Conditional recommendation, low-quality evidence) [90]

Platelet transfusion for patients who will undergo a neurosurgical procedure (Conditional recommendation, moderate quality of evidence) [90]

DDAVP can be used in addition to platelet transfusion in patients who will undergo neurosurgical procedure (Conditional recommendation, low-quality evidence) [90]

 Ticagrelor

Reversible inhibition of P2Y12 ADP receptor

26 % renal

58 % fecal

7 hours (metabolite = 9 hours)

It is unclear if anti platelet therapy increases the incidence of ICH

Light Transmission Platelet Aggregation with or without Secretion

None

The usefulness of platelet transfusions in ICH patients with a history of antiplatelet use is uncertain

Not dialyzable

DDAVP 0.4 μg/kg

DDAVP 0.4 mcg/kg IV (Conditional recommendation, low-quality evidence) [90]

Platelet transfusion is not recommended (Conditional recommendation, low-quality evidence) [90]

Platelet transfusion for patients who will undergo a neurosurgical procedure (Conditional recommendation, moderate quality of evidence) [90]

DDAVP can be used in addition to platelet transfusion in patients who will undergo neurosurgical procedure (Conditional recommendation, low-quality evidence) [90]

 Cilostazol

Reversible phosphodiesterase III inhibitor, increases cAMP, inhibits ADP-induced platelet aggregation, and causes vasodilation

74 % renal

20 % fecal

10 hours

It is unclear if anti platelet therapy increases the incidence of ICH

Light Transmission Platelet Aggregation with or without Secretion

None

The usefulness of platelet transfusions in ICH patients with a history of antiplatelet use is uncertain

Not dialyzable

DDAVP 0.4 μg/kg

The usefulness of platelet transfusions in ICH patients with a history of antiplatelet use is uncertain

DDAVP 0.4 μg/kg IV (Conditional recommendation, low-quality evidence) [90]

Platelet transfusion is not recommended (Conditional recommendation, low-quality evidence) [90]

Platelet transfusion for patients who will undergo a neurosurgical procedure (Conditional recommendation, moderate quality of evidence) [90]

DDAVP can be used in addition to platelet transfusion in patients who will undergo neurosurgical procedure (Conditional recommendation, low-quality evidence) [90]