**5. Direct thrombin inhibitors**

#### **5.1 Bivalirudin**

Alternative agents, such as direct thrombin inhibitors (DTI), have been increasingly used in ECMO centers worldwide. Bivalirudin is a DTI that binds to both circulating and clot-bound thrombin [35]. The basic structure of thrombin consists of the active site, exosite 1, and exosite 2. Exosite 1 is the location where specific substrates, such as fibrin, can bind and orient peptide bonds toward the active site of thrombin [36]. Bivalirudin is a bivalent DTI that blocks thrombin at the active site and exosite 1 [36, 37]. Bivalirudin is primarily metabolized by proteolytic enzymes with 20% renally excreted [36]. With limited evidence to support the safety and therapeutic profile of bivalirudin in patients undergoing ECMO, bivalirudin has primarily been used in patients unresponsive to unfractionated heparin or those who developed heparin-induced thrombocytopenia [38]. In *in vitro* studies, bivalirudin inhibits both soluble and clot-bound thrombin, a unique mechanism of action not known to occur with unfractionated heparin [35]. Two prospective studies assessing clot resolution found that patients anticoagulated with bivalirudin for the treatment of deep vein thrombosis (DVT) had complete or partial clot resolution within 48 hours [39, 40].

#### **5.2 Argatroban**

Argatroban is a L-arginine derivative that reversibly binds and inhibits thrombin. Argatroban is a univalent DTI that binds solely to the active site of thrombin. It is metabolized by hepatic CYP3A4/5 oxidases and is excreted primarily in the feces [36, 41, 42]. Menk and colleagues retrospectively reviewed 78 adult patients with acute respiratory distress syndrome (ARDS) on ECMO. The single center study supported that patients anticoagulated with argatroban had no difference in major or minor bleeding and had more goal aPTT values compared to UFH controls [43]. Multiple studies have shown that doses vary widely between adult and pediatric patients anticoagulated with argatroban on ECMO, thus careful monitoring is imperative to ensure optimal anticoagulation [43–45]. A literature analysis reviewed nine articles describing 34 patients anticoagulated with argatroban. Pediatric patients were administered a dose ranging from 0.1 to 12 mcg/kg/min to achieve therapeutic anticoagulation. There was no correlation between the dose of argatroban and the age of the patient [45].

Bivalirudin and argatroban remain the most commonly utilized direct thrombin inhibitors for anticoagulation during ECMO, but small case studies have evaluated the efficacy of lepirudin [46, 47]. Unfortunately, the product is no longer available due to production discontinuation by the manufacturer.

#### **5.3 Direct thrombin inhibitor use in ECMO**

Disadvantages of DTIs include limited availability of laboratory monitoring specific to DTIs and lack of antidote. Currently, most centers that use DTIs follow aPTT for monitoring, which as mentioned previously can be affected by several patient variables. Ecarin chromogenic assay and dilute thrombin time are possible superior tests for monitoring, but are currently not widely available [36]. Unlike heparin, which can be reversed with protamine, no antidote exists for DTIs, but recombinant factor VIIa has been shown to be an effective reversal agent [48]. Plasmapheresis has also been shown to be effective in clearing bivalirudin, but limited evidence has been published supporting its use. An advantage of bivalirudin over argatroban is that it can be quickly removed by continuous renal replacement therapy [49].

**225**

provided the original work is properly cited.

*Anticoagulation in Pediatric Extracorporeal Membrane Oxygenation*

Evidence of DTIs for ECMO patients is limited to case series or retrospective analyses. To confirm the safety and efficacy of DTIs and superiority (or at least noninferiority) to heparin, prospective randomized trials of pediatric and adult patients are needed. Two randomized studies are currently enrolling to compare bivalirudin to UFH for pediatric and adult ECMO patients (NCT03318393 and NCT03707418).

At present, systemic anticoagulation is the primary method to prevent thrombus

In summary, while the goal for ECMO anticoagulation is to prevent clinically significant bleeding and clotting, the morbidity and mortality for these complications remain high for pediatric patients. Unfractionated heparin continues to be the most commonly used anticoagulant for ECMO patients in spite of its many disadvantages including altered pharmacokinetics in children and difficulty in lab monitoring. While there is a large variation between lab monitoring of heparin among ECMO centers, combination testing with anti-factor Xa and/or aPTT with viscoelastic tests is potentially superior. DTIs such as bivalirudin and argatroban remain promising alternatives to heparin, but prospective studies are needed to confirm their safety

formation during ECMO, but the use of nitric oxide within the extracorporeal circuit may be used to inhibit platelet adhesion. Nitric oxide (NO) is an endogenous substance released by the endothelial cells. NO temporarily inactivates platelets resulting in decreased function and aggregation [50, 51]. However, the effect of NO only temporarily inhibits platelets and after rapid degradation of NO by hemoproteins, platelets will regain normal function [52]. The utility of NO within ECMO circuits to limit or negate the requirement of systemic anticoagulation remains a promising area of research, but further studies to evaluate the long-term risks of

*DOI: http://dx.doi.org/10.5772/intechopen.85104*

**6. Nitric oxide**

thrombosis are warranted.

**7. Conclusion**

and efficacy.

**Author details**

Texas, United States of America

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Pediatric Critical Care, University of Texas Southwestern Medical Center, Dallas,

Jamie Weller\*, Lakshmi Raman, Ayesha Zia and Ali McMichael

\*Address all correspondence to: jamie.weller@utsouthwestern.edu

Evidence of DTIs for ECMO patients is limited to case series or retrospective analyses. To confirm the safety and efficacy of DTIs and superiority (or at least noninferiority) to heparin, prospective randomized trials of pediatric and adult patients are needed. Two randomized studies are currently enrolling to compare bivalirudin to UFH for pediatric and adult ECMO patients (NCT03318393 and NCT03707418).
