Anti-Coagulant Reversal for Pediatric Population

Original Date: 09/2023
Purpose: To provide guidance of choice and dosing of reversal agents and strategies in the setting of traumatic bleeding in pediatric patients taking anticoagulants and antiplatelet therapy.

Class	Drug	MOA	Measurement	Half Life	Excretion	Reversal
Vitamin K antagonists	Warfarin (Coumadin)	Warfarin function as anticoagulants by reducing the functional plasma concentration of vitamin K-dependent factors (i.e. factors II, VII, IX and X).	PT/INR TEG	2-5 days	Urine: 92%, primarily as metabolites	IV Vitamin K:30 microgram/kg³ In the presence of significant bleeding, immediate reversal using FFP or prothrombin complex concentrates (PCC) Adult dosage for PCC based on INR level for reference: INR < 4 – 25 units/kg INR 4-6 – 35 units/kg INR > 6 – 50 units/kg Recheck INR 15-30 minutes after administration.
Heparin	Heparin	Potentiates the action of antithrombin III and thereby inactivates thrombin (factors IXa, Xa, XIa, XIIa) and prevents the conversion of fibrinogen to fibrin	aPTT TEG	Premature neonates: 35.5 – 41.6 minutes Range: 1-2 hours	Urine	Protamine dose based on time since last heparin dose³ <30 mins – 1 mg/100 units heparin received 30-60 mins – 0.5-0.75 mg/100 units heparin received 60-120 mins – 0.375-0.5 mg/100 units heparin received >120 mins: 0.25 – 0.375 mg/100 units heparin received
	LMWH enoxaparin	Enoxaparin has a higher ratio of anti-factor Xa to anti-factor IIa activity than unfractionated heparin	Anti-Xa level TEG	Anti-factor Xa activity: 4.5-7 hours	Urine: 40% Clearance decreased by 30% in patients with CrCl < 30 mL/min	Dosed within 8 hours: administer protamine 1 mg IV per 1 mg enoxaparin (max: 50 mg)³ Dosed within 8-12 hours: administer 0.5 mg IV per 1 mg enoxaparin (max: 50 mg)³
Direct thrombin inhibitors	Argatroban	A direct, highly selective thrombin inhibitor.	aPTT TEG	Normal: 39-51 minutes Hepatic impairment: 181 minutes	Feces: ~65% Urine: ~22%	Stop the infusion Definitive reversal therapy: renal replacement therapy.⁴ Limited data to use PCC.
Direct thrombin inhibitors	Bivalirudin	Specific and reversible direct thrombin	aPTT TEG	Normal: 25 minutes Moderate renal impairment: 34 minutes Severe renal impairment: 57 minutes	Urine: 20%	Stop the infusion Definitive reversal therapy: renal replacement therapy.⁴ Limited data to use PCC.
Factor Xa Inhibitors	Rivaroxaban (Xarelto™)	Inhibits platelet activations and fibrin clot formation via direct, selective and reversible inhibition of factor Xa in both the intrinsic and extrinsic coagulation pathways.	Chromogenic anti-FXa assay	Infants <6 months: 1.6 hours Infant > 6 months and children < 2 years: 1.9 hours Children > 2 years: 3 hours Adolescents: 4.2 hours Adult: 5-9 hours	Urine: 66% Feces: 28%	Consider PCC Kcentra dose as below: <4 months old = 40 units/kg 4 months to 5 years = 30 units/kg >5 years old = 20 units/kg
Factor Xa Inhibitors	Apxiban (Eliquis™)	Inhibits platelet activation and fibrin clot formation via direct, selective and reversible inhibition of free and clot-bound factor Xa (FXa)	Chromogenic anti-FXa assay	Adult: ~ 12 hours	Urine: 27% as parent drug	Consider PCC Kcentra dose as below: <4 months old = 40 units/kg 4 months to 5 years = 30 units/kg >5 years old = 20 units/kg
Antiplatelet	Aspirin	Irreversibly inhibits cyclooxygenase-1 and 2 (COX-1 and 2) enzymes, via acetylation, which results in decreased formation of prostaglandin precursors; irreversibly inhibits formation of prostaglandin derivative, thromboxane A₂, via acetylation of platelet cyclooxygenase, thus inhibiting platelet aggregation	Aspirin effect platelet Goal of < 550 Aspirin Reaction Units (ARU) TEG	Half life: 15-20 minutes Adult data: Parent drug: Plasma concentration: 15 to 20 minutes; Salicylates (dose dependent): 3 hours at lower doses (300 to 600 mg), 5 to 6 hours (after 1 gram), 10 hours with higher doses	Urine: 75% as salicylic acid, 10% as salicylic acid Clearance of aspirin is slower in neonates, potentially placing them at risk of bleeding for longer periods of time	No reversal agent available.⁴ Type and cross pheresis Platelets (4-20 U/kg) may be given to counteract the platelet aggregation inhibition of aspirin
Antiplatelet	Clopidogrel (Plavix™)	The active metabolite irreversibly blocks the P2Y₁₂ component of ADP receptors on the platelet surface, which prevents activation of the GPIIb/IIIa receptor complex, thereby reducing platelet aggregation.	Clopidogrel (Plavix) effect platelet TEG	Parent drug: 6 hours; active metabolite (thiol): about 30 minutes, inactive metabolite (carboxylic acid): about 8 hours.	Urine: 50% Feces: 40%	No reversal agent available.⁴ Type and cross pheresis Platelets (4-20 U/kg) may be given to counteract the platelet aggregation inhibition of aspirin
Antiplatelet	Dipyridamole	Inhibits the activity of adenosine deaminase and phosphodiesterase, which causes an accumulation of adenosine, adenine nucleotides and cyclic AMP, which inhibit platelet aggregation.	Platelet aggregation TEG	Peak serum concentration are reached around 75 minutes, and half-life is 10-12 hours	Feces	No reversal agent available.⁴ Type and cross pheresis Platelets (4-20 U/kg) may be given to counteract the platelet aggregation inhibition of aspirin
Thrombolytics	Alteplase	Initiates local fibrinolysis by binding to fibrin in a thrombus (clot) and converts entrapped plasminogen to plasmin	Fibrinogen TEG	More than 50% present in plasma cleared approximately 5 minutes after infusion terminated.	Hepatic: 50%	The choice and doses of blood products can be guided by appropriate hemostatic monitoring. Transfusion Cryoprecipitate (5-10 mL/kg) Fibrinogen concentrate: limited data**
Pentasaccharides	Fondaparinux (Arixtra™)	Fondaparinux is a synthetic pentasaccharide that causes an thrombin III-mediated selective inhibition of factor Xa. Neutralization of factor Xa interrupts the blood coagulation cascade and inhibits thrombin formation and thrombus development	Fondaparinux based anti-factor Xa	17-21 hours, prolonged with renal impairment	Urine: 77%	No known reversal agent

*PCC: prothrombin complex concentrate

** Limited literature for Pediatric dosage of fibrinogen concentrate.

Clinical Implications/Special considerations

Aspirin: this effect is irreversible for the life of the platelets exposed (7-10 days in healthy persons, may be shorter in children with inflammation and exposure to extracorporeal circuits due to inflammation-induced COX-2 activation resulting in high on-aspirin platelet reactivity).
Clopidogrel: platelets blocked by clopidogrel are affected for the remainder of their lifespan.
Bleeding events/supratherapeutic on Clopidogrel: consider pharmacogenomics testing for CYP2C19 hypermetabolizer
Alteplase: duration – more than 50% present in plasma cleared approximately 5 minutes after infusion terminated, approximately 80% cleared within 10 minutes; fibrinolytic activity persists for up to 1 hour after infusion terminated.
There is limited literature of using fibrinogen concentrate in pediatric population. For reference only: for reversal of thrombolytics, the adult recommendation for fibrinogen concentrate as following:For adult sized population:
- Fibrinogen level unknown= 2 gm IV (most common)
- Fibrinogen level <100 = 2 gm IV
- Fibrinogen level 100-200 = 1 gm IV
- Fibrinogen level > 200 = repeat level q8h

References:

Dabbous MK, Sakr FR and Malaeb DN. Anticoagulant therapy in pediatrics. J Basic Clin Pharm, 5(2):27-33March 2014-May 2014. doi: 4103/0976-0105.134947
Chen A, Stecker E and Warden BA. Direct oral anticoagulant use: a practical guide to common clinical challenges. Journal of the American Heart Association, 2020,9(13): e017559. DOI: 10.1161/JAHA.120.017559.
Monagle P, Chan AKC, Goldenberg NA, Ichord RN, et al. Antithrombin therapy in neonates and children. Antithrombotic therapy and prevention of thrombosis, 9^th edition: American College of Chest Physicians Evidence-Based Clinical Guidelines. CHEST, 2012; 14(2)(suppl):e737S-e801S.
Giglia TM, Witmer C, Procaccini DR and Byrnes JW. Pediatric Cardiac Intensive Care Society 2014 Consensus statement: pharmacotherapies in cardiac critical care anticoagulation and thrombolysis. Pediatric Critical Care Med, 2016;17:S77-S88.
Monagle P, Chan AK, Massicotte P, Chalmers E and Michelson AD. Antithrombin therapy in Children: the seventh ACCP conference on antithrombotic and thrombolytic therapy. 2004, 126:645S-687S.