The indications for ECMO have been widely expanded recently due to the improvement of technology. According to our data analyzed in autopsy cases, 97% patients were noted to have bleeding in at least one organ system and 57% patients were found to have thrombosis (Otterness, C, Soundar, E, Eldin, K, Teruya, J.). This highlights the importance and urgency of gaining more understanding about the pathophysiology of bleeding and thrombosis in ECMO since it is multifactorial, results in increased mortality, and is poorly understood. We may discuss the following in the setting of ECMO: •	Acquired von Willebrand syndrome •	Coagulation and inflammation in ECMO and potential novel anticoagulant drug targets •	Hemolysis and von Willebrand factor •	Definitionfor bleeding and clotting •	Neonatal ECMO •	Anticoagulant monitoring tests

Texas Children's Hospital

University of Alberta

Department of Pediatric Hematology and Oncology, University Hospital Freiburg

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Frontiers in Medicine

Hematology

Hemostasis in ECMO and VAD

The indication for extracorporeal membrane oxygenation (ECMO) has been expanded in the recent years. The new indication includes ECMO cardiopulmonary resuscitation, known as ECPR, and sepsis. Since patients on ECMO are usually critically ill, coagulation derangement such as disseminated intravascular coagulation (DIC) is not uncommon. Hemostasis in ECMO is extremely complex; however it provides us a great model to understand the mechanism of overall hemostasis and anticoagulation in the presence of an artificial surface. How can we improve survival and decrease the incidence of bleeding and thrombosis? In this research topic, Hemostasis in ECMO and ventricular assist device (VAD), we included topics of activation mechanism of hemostasis, acquired von Willebrand syndrome (AVWS), neonatal ECMO, novel surface of tubes to prevent clot formation, and hemolysis.<a href="https://doi.org/10.3389/fmed.2018.00352">Doyle and Hunt</a> described the overall activation mechanism of hemostasis in ECMO. It involves not only coagulation factors and platelets, but also neutrophil adhesion, release of tissue factor and cytokines from monocytes, fibrinolysis and complement activation. They discuss cell-based coagulation activation which involves the extrinsic pathway and contact activation pathway (= intrinsic pathway) separately.<a href="https://doi.org/10.3389/fmed.2018.00289">Van Ommen et al.</a> discussed neonatal ECMO from developmental hemostasis. The overall hemostasis among neonates is different from older infants. They clearly explain the challenges of anticoagulation due to the immature hemostatic system and prevention and management of hemorrhage and thrombosis in neonatal ECMO. Unfractionated heparin is most commonly used as anticoagulant; however, the “best” monitoring technique of its anticoagulant effect remains to be determined.<a href="https://doi.org/10.3389/fmed.2018.00361">Hensch et al.</a> described different scenarios of ECMO. Some ECMO cases are unique and informative from a coagulation standpoint. They presented 4 cases; persistently high antithrombin levels throughout the course and the requirement for less heparin dose and no circuit change for 72 days; pulmonary hemorrhage managed by nebulizer with tranexamic acid or recombinant activated factor VII; sepsis induced DIC and purpura fulminans successfully managed by therapeutic plasma exchange; and a patient with respiratory failure resistant to heparin anticoagulation managed by bivalirudin.<a href="https://doi.org/10.3389/fmed.2019.00007">Rauch et al.</a> discussed that AVWS occurs in patients with continuous flow (CF)-VADs and ECMO. Characteristically for AVWS is the loss of the high molecular weight (HMW)-multimers which leads to reduced von Willebrand factor (VWF) collagen binding activity (VWF:CB), ristocetin cofactor activity (VWF:RCo), and VWF:Activity (VWF:Ac), respectively. This causes a decrease of the VWF:CB/VWF-Antigen (VWF:CB/VWF:Ag)-ratio, VWF:RCo/VWF-Antigen (VWF:RCo/VWF:Ag)-ratio, and VWF:Ac/VWF-Antigen (VWF:Ac/VWF:Ag)-ratio, respectively. Clinical implications of AVWS in VAD- and ECMO patients were reported and possible therapy was described. In addition, they discussed the data collected from a swine CF-VAD model which demonstrated that changes in pulsatility regimen can be pivotal to modulate VWF multimerization in plasma in high shear condition. Acute changes of pulse pressure induced a release of new VWF HMW-multimers from Weibel Palade Bodies.<a href="https://doi.org/10.3389/fmed.2018.00228">Valladolid et al.</a> described VWF, free hemoglobin, and thrombosis in ECMO. It is known that intravascular hemolysis causes increased levels of plasma free hemoglobin. It is associated with renal damage, hemostatic derangement, and higher mortality rate. They untangled the mechanism of thrombotic tendency due to VWF mediated platelet adhesion and thrombus formation on a surface-adsorbed fibrin(ogen) under high shear stress.<a href="https://doi.org/10.3389/fmed.2018.00321">Ontaneda and Annich</a> reviewed the development of both present and future novel surface in ECMO circuits. Systemic anticoagulation alone causes high risk for bleeding if excessive doses are administered and thrombosis if not enough anticoagulation is used. Circuits may be coated by biomimetic surfaces such as heparin and nitric oxide, and biopassive surfaces such as phosphorylcholine, poly-2-methoxyethlacrylate, and fluid-repellent surfaces. Lastly in vitro and in vivo endothelialization is discussed. However, all coating materials have advantages and disadvantages. Authors conclude that in order to achieve ultimate goal, i.e., less bleeding and thrombotic complications during ECMO, clinicians, basic scientists, and industry need to work together.JT and BZ wrote the text. MM reviewed and edited the text.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Editorial: Hemostasis in ECMO and VAD

During the last decade the use of ventricular assist devices (VADs) for patients with severe heart failure has increased tremendously. However, flow disturbances, mainly high shear induced by the device is associated with bleeding complications. Shear stress-induced changes in VWF conformation are associated with a loss of high molecular weight multimers (HMW) of VWF and an increased risk of bleeding. This phenomenon and its cause will be elaborated and reviewed in the following.

During the last decade the use of ventricular assist devices (VADs) for patients with severe heart failure has increased tremendously. However, flow disturbances, mainly high shear induced by the device is associated with bleeding complications. Shear stress-induced changes in VWF conformation are associated with a loss of high molecular weight multimers (HMW) of VWF and an increased risk of bleeding. This phenomenon and its cause will be elaborated and reviewed in the following.

Acquired von Willebrand Syndrome in Patients With Ventricular Assist Device

Extracorporeal membrane oxygenation (ECMO) is a life-saving procedure that requires careful coagulation management. Indications for ECMO continue to expand, leading to more complicated patients treated by ECMO teams. At our pediatric institution, we utilize a Coagulation Team to guide anticoagulation, transfusion and hemostasis management in an effort to avoid the all-to-common complications of bleeding and thrombosis. This team formulates a coagulation plan in conjunction with a multidisciplinary ECMO team after careful review of all available laboratory data as well as the patient's clinical status. Here, we present our general strategies for ECMO management in various clinical scenarios and a review of the literature pertaining to coagulation management in the pediatric ECMO setting.

Extracorporeal membrane oxygenation (ECMO) is a life-saving procedure that requires careful coagulation management. Indications for ECMO continue to expand, leading to more complicated patients treated by ECMO teams. At our pediatric institution, we utilize a Coagulation Team to guide anticoagulation, transfusion and hemostasis management in an effort to avoid the all-to-common complications of bleeding and thrombosis. This team formulates a coagulation plan in conjunction with a multidisciplinary ECMO team after careful review of all available laboratory data as well as the patient&apos;s clinical status. Here, we present our general strategies for ECMO management in various clinical scenarios and a review of the literature pertaining to coagulation management in the pediatric ECMO setting.

Coagulation and Bleeding Management in Pediatric Extracorporeal Membrane Oxygenation: Clinical Scenarios and Review

Extracorporeal membrane oxygenators are used in critical care for the management of severe respiratory and cardiac failure. Activation of the coagulation system is initiated by the exposure of blood to synthetic surfaces and the shear stresses of the circuit, especially from device pumps. Initial fibrinogen deposition and subsequent activation of coagulation factors and complement allow platelets and leucocytes to adhere to oxygenator surfaces and enhance thrombin generation. These changes and others contribute to higher rates of thrombosis seen in these patients. In addition, bleeding rates are also high. Primary haemostasis is impaired by platelet dysfunction and loss of their key adhesive molecules and shear stress causes an acquired von Willebrand defect. In addition, there is also altered fibrinolysis and lastly, administration of systemic anticoagulation is required to maintain circuit patency. Further research is required to fulyl establish the complexities of the haemostatic changes with these devices, and to elucidate the mechanistic changes that are mainly responsible so that plans can be made to reduce their complications and improve management.

Extracorporeal membrane oxygenators are used in critical care for the management of severe respiratory and cardiac failure. Activation of the coagulation system is initiated by the exposure of blood to synthetic surfaces and the shear stresses of the circuit, especially from device pumps. Initial fibrinogen deposition and subsequent activation of coagulation factors and complement allow platelets and leucocytes to adhere to oxygenator surfaces and enhance thrombin generation. These changes and others contribute to higher rates of thrombosis seen in these patients. In addition, bleeding rates are also high. Primary haemostasis is impaired by platelet dysfunction and loss of their key adhesive molecules and shear stress causes an acquired von Willebrand defect. In addition, there is also altered fibrinolysis and lastly, administration of systemic anticoagulation is required to maintain circuit patency. Further research is required to fulyl establish the complexities of the haemostatic changes with these devices, and to elucidate the mechanistic changes that are mainly responsible so that plans can be made to reduce their complications and improve management.

Current Understanding of How Extracorporeal Membrane Oxygenators Activate Haemostasis and Other Blood Components

The balance between systemic anticoagulation and clotting is challenging. In normal hemostasis, the endothelium regulates the balance between anticoagulant and prothrombotic systems. It becomes particularly more challenging to maintain this physiologic hemostasis when we are faced with extracorporeal life support therapies, where blood is continuously in contact with a foreign extracorporeal circuit surface predisposing a prothrombotic state. The blood-surface interaction during extracorporeal life support therapies requires the use of systemic anticoagulation to decrease the risk of clotting. Unfractionated heparin is the most common anticoagulant agent widely used in this setting. New trends include the use of direct thrombin inhibitor agents for systemic anticoagulation; and surface modifications that aim to overcome the blood-biomaterial surface interaction by modifying the hydrophilicity or hydrophobicity of the polymer surface; and coating the circuit with substances that will mimic the endothelium or anti-thrombotic agents. To improve hemocompatibility in an extracorporeal circuit, replication of the anti-thrombotic and anti-inflammatory properties of the endothelium is ideal. Surface modifications can be classified into three major groups: biomimetic surfaces (heparin, nitric oxide, and direct thrombin inhibitors); biopassive surfaces [phosphorylcholine, albumin, and poly- 2-methoxyethylacrylate]; and endothelialization of blood contacting surface. The focus of this paper will be to review both present and future novel surface modifications that can obviate the need for systemic anticoagulation during extracorporeal life support therapies.

The balance between systemic anticoagulation and clotting is challenging. In normal hemostasis, the endothelium regulates the balance between anticoagulant and prothrombotic systems. It becomes particularly more challenging to maintain this physiologic hemostasis when we are faced with extracorporeal life support therapies, where blood is continuously in contact with a foreign extracorporeal circuit surface predisposing a prothrombotic state. The blood-surface interaction during extracorporeal life support therapies requires the use of systemic anticoagulation to decrease the risk of clotting. Unfractionated heparin is the most common anticoagulant agent widely used in this setting. New trends include the use of direct thrombin inhibitor agents for systemic anticoagulation; and surface modifications that aim to overcome the blood-biomaterial surface interaction by modifying the hydrophilicity or hydrophobicity of the polymer surface; and coating the circuit with substances that will mimic the endothelium or anti-thrombotic agents. To improve hemocompatibility in an extracorporeal circuit, replication of the anti-thrombotic and anti-inflammatory properties of the endothelium is ideal. Surface modifications can be classified into three major groups: biomimetic surfaces (heparin, nitric oxide, and direct thrombin inhibitors); biopassive surfaces [phosphorylcholine, albumin, and poly- 2-methoxyethylacrylate]; and endothelialization of blood contacting surface. The focus of this paper will be to review both present and future novel surface modifications that can obviate the need for systemic anticoagulation during extracorporeal life support therapies.

Novel Surfaces in Extracorporeal Membrane Oxygenation Circuits

Extracorporeal membrane oxygenation (ECMO) is becoming increasingly utilized to manage neonates with cardiac and respiratory failure. The procedure involves extensive anticoagulation in a sick neonate with underlying disease pathology. In addition, the immature hemostatic system in the neonate adds to the complexity of titrating the necessary anticoagulation. This places the infant at greater risk for life threatening hemorrhage and thrombosis. Managing anticoagulation in these infants is extremely challenging and needs the expertise of a physician with a thorough knowledge of the intricacies of developmental hemostasis and limitations of the current laboratory techniques available to manage anticoagulation. This article provides a brief overview of the developing hemostatic system of the neonate and the challenges associated with managing anticoagulation in this vulnerable population of patients.

Extracorporeal membrane oxygenation (ECMO) is becoming increasingly utilized to manage neonates with cardiac and respiratory failure. The procedure involves extensive anticoagulation in a sick neonate with underlying disease pathology. In addition, the immature hemostatic system in the neonate adds to the complexity of titrating the necessary anticoagulation. This places the infant at greater risk for life threatening hemorrhage and thrombosis. Managing anticoagulation in these infants is extremely challenging and needs the expertise of a physician with a thorough knowledge of the intricacies of developmental hemostasis and limitations of the current laboratory techniques available to manage anticoagulation. This article provides a brief overview of the developing hemostatic system of the neonate and the challenges associated with managing anticoagulation in this vulnerable population of patients.

Neonatal ECMO

Though extracorporeal membrane oxygenation (ECMO) provides life-saving support, this intervention exposes patients to certain risks. Circulating free hemoglobin (fHb) resulting from mechanically induced hemolysis and insufficient haptoglobin/hemopexin may promote thrombosis within the ECMO circuit. Thrombi in the circuit can result in thromboembolic complications in these patients. Prevention of thrombus formation and propagation in the ECMO circuit may improve clinical outcome. fHb released during hemolysis has been shown to have multiple adverse effects, including thrombosis, but the mechanism by which fHb contributes to thrombosis in an ECMO circuit remains elusive. It is well established that (1) high shear stress generated in the circuit may cause hemolysis, and (2) plasma fibrinogen is adsorbed onto the inner tubing of the ECMO circuit over time. Plasma von Willebrand factor (pVWF) mediates platelet deposition at sites of vascular injury under high shear stress by sensing alterations in the hemodynamic environment. This biophysical property of pVWF that enables hemostasis may also contribute to the pathogenesis of ECMO-induced thrombosis. pVWF contains binding sites for both adsorbed fibrin(ogen) and fHb. High concentrations of fHb increase pVWF-mediated platelet adhesion and thrombus formation on a surface-adsorbed fibrin(ogen) under high shear stress. The molecular mechanism(s) by which fHb drives the conformation of pVWF into a prothrombotic state is currently unknown. Reduction of thrombotic risks during ECMO intervention warrants further investigations into the interaction between pVWF and fHb.

Though extracorporeal membrane oxygenation (ECMO) provides life-saving support, this intervention exposes patients to certain risks. Circulating free hemoglobin (fHb) resulting from mechanically induced hemolysis and insufficient haptoglobin/hemopexin may promote thrombosis within the ECMO circuit. Thrombi in the circuit can result in thromboembolic complications in these patients. Prevention of thrombus formation and propagation in the ECMO circuit may improve clinical outcome. fHb released during hemolysis has been shown to have multiple adverse effects, including thrombosis, but the mechanism by which fHb contributes to thrombosis in an ECMO circuit remains elusive. It is well established that (1) high shear stress generated in the circuit may cause hemolysis, and (2) plasma fibrinogen is adsorbed onto the inner tubing of the ECMO circuit over time. Plasma von Willebrand factor (pVWF) mediates platelet deposition at sites of vascular injury under high shear stress by sensing alterations in the hemodynamic environment. This biophysical property of pVWF that enables hemostasis may also contribute to the pathogenesis of ECMO-induced thrombosis. pVWF contains binding sites for both adsorbed fibrin(ogen) and fHb. High concentrations of fHb increase pVWF-mediated platelet adhesion and thrombus formation on a surface-adsorbed fibrin(ogen) under high shear stress. The molecular mechanism(s) by which fHb drives the conformation of pVWF into a prothrombotic state is currently unknown. Reduction of thrombotic risks during ECMO intervention warrants further investigations into the interaction between pVWF and fHb.