Skip to main content

Advertisement

Table 3 Anticoagulants and reversal strategies

From: The critical care management of spontaneous intracranial hemorrhage: a contemporary review

Drug Target Elimination and half-life (hours) Rate of ICH Monitoring coagulation tests Antidote and reversal Possible intervention Guidelines
Vitamin K antagonist
 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]
Unfractionated heparin, LMWHs, and heparinoids
 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
Pentasaccharides
 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]
Direct thrombin (factor IIa) inhibitors
 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]
Direct factor Xa inhibitors
 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]
Antiplatelets
 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]
  1. aPTT activated partial thromboplastin time, ECT ecarin clotting time, ICH intracerebral hemorrhage, INR International Normalized Ratio, PCC prothrombin complex concentrate, PT prothrombin time, TT thrombin time, LMWH low-molecular-weight heparin, UFH unfractionated heparin, RF renal failure, GFR glomerular filtration rate, BID two times a day, SDH subdural hematoma, SAH subarachnoid hemorrhage, HR heartrate, ACT activated clotting time, FFP Fresh frozen plasma, IV intravenous, VKA vitamin K antagonist, rFVIIa recombinant activated factor VII, SC subcutaneous, DDAVP Desmopressin