Anticoagulation with direct thrombin inhibitors during extracorporeal membrane oxygenation

Table 1 Pharmacology of direct thrombin inhibitors

	Valence	Thrombin binding	Onset of action	Half-life	Protein binding	Metabolism	Special considerations
Bivalirudin	Bivalent	Reversible	2-4 min	25 min	None	Serum proteases	Avoid during low-flow states Removed by non-diffusive dialysis modalities Dose reductions necessary in renal dysfunction
Argatroban	Univalent	Reversible	30 min	45 min	20% albumin 34% alpha-acid glycoprotein	Hepatic (hydroxylation, aromatization)	Dose reductions necessary in hepatic dysfunction

Table 2 Summary of studies reporting on argatroban in adult patients supported with extracorporeal membrane oxygenation

First author, Year	Study type	Population	Circuit (VA/VV)	CRRT	Bolus dose (mg/kg)	Initial infusion (mg/kg/min)	Monitoring	Duration	Major bleeding	Thrombosis	Other adverse events	Outcome
Jyoti et al[21], 2013	Case report	54M ARDS, HIT	VV	No	NA	0.6	ACT 200-220 s aPTT 60-80 s	552 h (23 d)	NA	NA	NA
Pappalardo et al[23], 2009	Case report	71F post-cardiotomy, HIT	VA	No	0.5	0.5	ACT 180-220 s	6 d	NA	Ventricular fibrillation due to LA thrombus, suspected to be due to heparin in tubing with residual HIT. BIV dosing increased	NA	Decannulated and discharged in stable condition
Pieri et al[24], 2013	Case control	n = 10 (4 HIT)	VV (n = 5) VA (n = 5)	n = 7 (70%)	N/A	0.025	aPTT 45-60 s	8 d (range 6-23)	n = 3 (30%)	n = 1 (10%)	No difference in bleeding or thrombosis compared to UFH patients Less dose corrections than UFH Less supra-therapeutic aPTTs than UFH	n = 4 (40%) died
Berei et al[20], 2018	Retrospective	n = 44 CS (n = 37) Sepsis (n = 11) Respiratory (n = 3) Mixed (n = 4)	VA (n = 26) VV (n = 2)	n = 17 (39%)	UFH 80 units/kg at cannulation No BIV bolus	0.04	aPTT 45-65 s (low intensity) or 60-80 s (high intensity)	156.9 h (mean)	n = 20 (45.5%)	n = 10 (22.7%)	Increased flow rates during first 96 h High intensity BIV had more TTR with no difference in outcomes	No difference in death at 30 d between BIV and UFH (36% vs 32%)
Netley et al[22], 2017	Retrospective	n = 11 ARDS (n = 8) ECLS (n = 3)	VA (n = 4) VV (n = 7)	n = 4 (36%)	NA	2.5	aPTT 40-60 s, 50-70 s, or 60-80 s	Mean 9.9 d (range 4-22)	n = 8 (72.7%)	n = 2 (18.2%), both after hospital discharge	NA	n = 5 (45%) died after withdrawal of care n = 6 (55%) discharged from hospital
Ranucci et al[25], 2011	Retrospective	n = 8, post-cardiotomy	VA	NA	NA	0.03-0.05 ½ dose if reduced CrCl	ACT 160-180 s or aPTT 50-80 s or TEG r 12-30 min	39-262 h	NA	None	Bleeding not reported, but less average blood loss (mL/kg/d) in BIV patients	n = 2 (25%) survived n = 2 (25%) dead on ECMO n = 4 (50%) weaned but died
Walker et al[26], 2019	Retrospective	n = 14 ARDS (n = 12) Post-cardiotomy (n =2) HIT (n = 11/13)	VV (n = 11) VA (n = 3)	n = 6 (43%)	0.2 (n = 1, others NA)	0.04-0.26	aPTT 1.5-2.5 × baseline	Median 5.2 d (range 0.9-28.4 d)	n = 4 (29%)	Circuit clotting (n = 5, 36%)	Infusion held during major bleeding episodes with no need for correction Higher infusion rates noted with CRRT	n = 9 (64%) decannulated n = 7 (50%) survived to discharge

ACT: Activated clotting time; aPTT: Activated partial thromboplastin time; ARDS: Acute respiratory distress syndrome; BIV: Bivalirudin; CRRT: Continuous renal replacement therapy; CS: Cardiogenic shock; ECLS: Extra-corporeal life support; HIT: Heparin-induced thrombocytopenia; NA: Not available; TEG: Thromboeslastography; UFH: Unfractionated heparin; VA: Veno-arterial; VV: Veno-venous.

Table 3 Summary of studies reporting on argatroban in adult patients supported with extracorporeal membrane oxygenation

First author, Year	Study type	Population	Circuit (VA/VV)	CRRT	Bolus dose	Initial infusion	Monitoring	Duration	Majorbleeding	Thrombosis	Other adverse events	Outcome
Sin et al[37], 2017	Case report	27M ARDS, HIT	VV	Yes	NA	0.2 µg/kg/min	aPTT 50-60 s	60 d	Hemothorax developed while on heparin, resolved on ARGA day 27	None	Transient elevations in liver enzymes, no clinical consequence	Patient transferred for lung transplantation
Ratzlaff et al[35], 2016	Case report	58M ARDS, HIT	VV	No	NA	0.1-0.3 µg/kg/min	aPTT 60-90 s	11 d	None	None	NA	Withdrawal of care after 28 d of ECMO support
Johnston et al[34], 2002	Case report	32M CS, HIT	VA	No	10 mg	2 µg/kg/h	ACT 200-400 s aPTT 80-90 s	7 d	None	NA	NA	Decannulated on ECMO day 10
Dolch et al[32], 2010	Case report	40M ARDS, HIT	VV	No	NA	0.35 µg/kg/min	aPTT 45-60 s	108 d	Major bleeding after lung transplant (ECMO day 114) – ARGA held	NA	Hepatic failure post-transplant Infusion reduced to 0.02 µg/kg/min	Patient underwent lung transplant on ECMO day 114, complicated by graft failure Died on post-operative day 17 (multi-organ failure)
Fernandes et al[33], 2019	Case report	44M CS, HIT	VA	Yes	NA	1.5 mg/h	aPTT 60-70 s	20 d	Mediastinal bleeding due to pulmonary edema Massive intraoperative hemorrhage during LVAD insertion, DIC	LV and RV thrombus during intraoperative DIC	NA	Survived to discharge
Cornell et al[31], 2007	Case series	n = 4 with HIT ARDS (n = 3) CS (n = 1)	VA (n = 2) VV (n = 2)	No	NA	0.2-2.0 µg/kg/min	ACT 210-230 s	88-184 h	Major bleeding (n = 2)	NA	NA	Survival to discharge (n = 2, 50%) Death (n = 2, 50%)
Beiderlinden et al[30], 2007	Case series	n = 9 with ARDS, HIT	VV	n = 8	NA	2.0 µg/kg/min (n = 1) 0.2 µg/kg/min (n = 8)	aPTT 50-60 s	4 ± 1 d (mean)	Major bleeding (n = 1) in patient who received higher initial infusion dose	None	NA	Survived (n = 6) Died (n = 3)
Rougé et al[36], 2017	Case series	49M CS, HIT 69M ARDS, HIT	VA	n = 1	NA	0.2 µg/kg/min 1 µg/kg/min	aPTT 1.5-3.0 × baseline	10 d 8 d	NA	Circuit clotting (n = 1)	ALF requiring dose reduction	Survived (n = 1) Decannulated, but died prior to discharge (n = 1)
Menk et al[38], 2017	Retrospective	n = 34 ARDS, HIT or heparin resistance	VV (n = 24) pECLA (n = 9)	NA	NA	0.3 µg/kg/min	aPTT 50-75 s	265 h (131-460)	n = 11—no differences compared to matched UFH cohort	n = 6—no differences compared to matched UFH cohort	NA	n = 21 (54%) died

ACT: Activated clotting time; aPTT: Activated partial thromboplastin time; ARDS: Acute respiratory distress syndrome; ARGA: Argatroban; CRRT: Continuous renal replacement therapy; CS: Cardiogenic shock; DIC: Disseminated intravascular coagulation; ECLS: Extra-corporeal life support; HIT: Heparin-induced thrombocytopenia; LVAD: Left ventricular assist device; NA: Not available; TEG: Thromboeslastography; UFH: Unfractionated heparin; VA: Veno-arterial; VV: Veno-venous.