**2. Overview of hemostasis**

In order to discuss the intricacies of anticoagulation during ECMO, a basic understanding of the mechanisms required for hemostasis and the coagulation cascade is necessary (**Figure 1**). Hemostasis occurs by vascular constriction, platelet plug creation, and clot formation through fibrin [3]. The vasculature surrounding the damaged tissue constricts limiting blood flow to the area. Platelets adhere to the exposed endothelium

#### **Figure 1.**

*In vivo concept of coagulation. The clotting system is classified into the initiation, amplification, and propagation phase. TF, tissue factor (thromboplastin); II, prothrombin; I, fibrinogen.*

via von Willebrand factor creating a platelet plug to temporize the bleeding. Finally, the clotting cascade is activated by the presence of tissue factor released when blood vessels are damaged [3]. The clotting cascade has been traditionally described as the intrinsic and extrinsic pathways merging to initiate the common pathway, and resulting in the activation of fibrinogen to fibrin to form a stable clot. This classification is pertinent for understanding *in vitro* coagulation tests, but fails to account for the *in vivo* coagulation process [4, 5]. Current evidence suggests that the initial cascade augments the formation of thrombin through multiple feedback loops. The initiation phase is activated with exposure of tissue factor from damaged blood vessels. The initial amount of thrombin produced is insufficient to achieve adequate hemostasis, thus a series of feedback loops prompted by thrombin act to catalyze the factor (F) V and FVIII, eventually accelerating the activity of FXa and FIXa. This second phase is classified as the amplification phase [4]. The propagation phase ensures continued production of thrombin and thus fibrin, by forming sufficient prothrombinase complexes [4].

The hemostatic processes are counterbalanced by antithrombotic factors such as protein C, protein S, thrombomodulin, antithrombin, and tissue factor pathway inhibitor. Clot degradation is initiated by the fibrinolytic factors such as tissue plasminogen activator (tPA), plasminogen, and urokinase plasminogen activator [3]. The extracorporeal circuit interferes with the described mechanisms designed to achieve adequate hemostasis. Immediately upon contact with the foreign ECMO circuit, the coagulation cascade is activated and a complex inflammatory response occurs [6]. Platelets, neutrophils, and leukocytes are activated along with thrombin and plasmin. Platelets adhere to the foreign surface leading to both platelet and factor consumption. Activated neutrophils contribute to the inflammatory response by producing cytokines. In addition, thrombin, FXa, and FVIIa cause complement activation further causing an inflammatory state. The end result is a consumptive state with disequilibrium of coagulation [7–10].

#### **3. Anticoagulation with unfractionated heparin in ECMO**

Although anticoagulation during ECMO is necessary to prevent circuit thrombosis and subsequent thromboembolic events in the patient, it continues to be a

**221**

*Anticoagulation in Pediatric Extracorporeal Membrane Oxygenation*

**ICH N(%)**

significant risk factor for complications in ECMO patients. The most common bleeding complications during ECMO include intracranial hemorrhage (ICH), surgical site bleeding, and gastrointestinal hemorrhage (**Table 1**). Surgical site bleeding is the most frequent complication and occurs in up to 25% of pediatric cardiac and respiratory ECMO patients [1]. Bleeding events are associated with increased mortality [2]. For example, while ICH is not a frequent complication, the effect is significant with a survival rate of 17–40% compared to 45–68% for those who do not have an ICH [1]. In addition to hemorrhage, thrombotic complications can occur. While not as common as bleeding complications, cerebral infarcts accounted for 3–7% of complications described in the ELSO registry report [1]. Unfractionated heparin continues to be the most widely studied and used anticoagulant for anticoagulation in ECMO, but alternative agents are increasingly being used in pediatric and adult ECMO patients.

*Patient-related hemorrhagic and thrombotic complications extrapolated from the ELSO registry, 2009–2015 [1].* 

**Surgical site bleeding N(%)**

Neonatal cardiac 326(11) 739(26) 35(1) 93(3) Neonatal respiratory 643(11) 386(7) 89(2) 180(3) Pediatric cardiac 251(6) 974(25) 79(2) 231(6) Pediatric respiratory 243(5) 332(10) 135(4) 158(7)

**GI hemorrhage N(%)**

**Cerebral infarct N(%)**

Unfractionated heparin (UFH) is the gold standard anticoagulant during ECMO

and is commonly used in ECMO centers worldwide. Heparin acts as a catalyst to potentiate the action of antithrombin III, inhibiting thrombin and activated coagulation factor X, thus inhibiting the conversion of fibrinogen to fibrin [11]. The half-life of heparin is approximately 1–2 hours in healthy adults, but can vary significantly in pediatric patients. Heparin is metabolized by the reticuloendothelial system in the liver and spleen, and is excreted in the urine [11]. In the pediatric population, developmental hemostasis and the patient's age may affect the pharmacokinetics of heparin [12]. For example, the neonatal population frequently requires additional monitoring and higher bolus and infusion rates to obtain effective anticoagulation [6, 12–14]. Another complication due to unfractionated heparin use is heparin-induced thrombocytopenia that is seen in 1–2% of pediatric patients [11]. For patients with preexisting conditions that preclude them from safe anticoagulation, such as trauma patients with intracranial hemorrhage or patients that develop hemorrhagic complications while on ECMO, successful use of heparin-free ECMO management with or without heparin-bonded circuits has been documented [15–17]. However, the published literature is limited primarily to specific popula-

Close monitoring to ensure anticoagulation is therapeutic is necessary to decrease the risk of hemorrhage or thrombosis during ECMO. The common tests used to monitor heparin during ECMO are activated clotting time (ACT), activated partial thromboplastin time (aPTT), and anti-factor Xa. No single test has been

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

*ICH, intracranial hemorrhage; GI, gastrointestinal.*

**3.1 Unfractionated heparin**

**Table 1.**

tions and for a limited duration of time.

**4. Monitoring during heparin anticoagulation**


*Anticoagulation in Pediatric Extracorporeal Membrane Oxygenation DOI: http://dx.doi.org/10.5772/intechopen.85104*

#### **Table 1.**

*Advances in Extracorporeal Membrane Oxygenation - Volume 3*

via von Willebrand factor creating a platelet plug to temporize the bleeding. Finally, the clotting cascade is activated by the presence of tissue factor released when blood vessels are damaged [3]. The clotting cascade has been traditionally described as the intrinsic and extrinsic pathways merging to initiate the common pathway, and resulting in the activation of fibrinogen to fibrin to form a stable clot. This classification is pertinent for understanding *in vitro* coagulation tests, but fails to account for the *in vivo* coagulation process [4, 5]. Current evidence suggests that the initial cascade augments the formation of thrombin through multiple feedback loops. The initiation phase is activated with exposure of tissue factor from damaged blood vessels. The initial amount of thrombin produced is insufficient to achieve adequate hemostasis, thus a series of feedback loops prompted by thrombin act to catalyze the factor (F) V and FVIII, eventually accelerating the activity of FXa and FIXa. This second phase is classified as the amplification phase [4]. The propagation phase ensures continued production of thrombin and thus

*In vivo concept of coagulation. The clotting system is classified into the initiation, amplification, and propagation* 

The hemostatic processes are counterbalanced by antithrombotic factors such as protein C, protein S, thrombomodulin, antithrombin, and tissue factor pathway inhibitor. Clot degradation is initiated by the fibrinolytic factors such as tissue plasminogen activator (tPA), plasminogen, and urokinase plasminogen activator [3]. The extracorporeal circuit interferes with the described mechanisms designed to achieve adequate hemostasis. Immediately upon contact with the foreign ECMO circuit, the coagulation cascade is activated and a complex inflammatory response occurs [6]. Platelets, neutrophils, and leukocytes are activated along with thrombin and plasmin. Platelets adhere to the foreign surface leading to both platelet and factor consumption. Activated neutrophils contribute to the inflammatory response by producing cytokines. In addition, thrombin, FXa, and FVIIa cause complement activation further causing an inflammatory state. The end

fibrin, by forming sufficient prothrombinase complexes [4].

*phase. TF, tissue factor (thromboplastin); II, prothrombin; I, fibrinogen.*

result is a consumptive state with disequilibrium of coagulation [7–10].

**3. Anticoagulation with unfractionated heparin in ECMO**

Although anticoagulation during ECMO is necessary to prevent circuit thrombosis and subsequent thromboembolic events in the patient, it continues to be a

**220**

**Figure 1.**

*Patient-related hemorrhagic and thrombotic complications extrapolated from the ELSO registry, 2009–2015 [1]. ICH, intracranial hemorrhage; GI, gastrointestinal.*

significant risk factor for complications in ECMO patients. The most common bleeding complications during ECMO include intracranial hemorrhage (ICH), surgical site bleeding, and gastrointestinal hemorrhage (**Table 1**). Surgical site bleeding is the most frequent complication and occurs in up to 25% of pediatric cardiac and respiratory ECMO patients [1]. Bleeding events are associated with increased mortality [2]. For example, while ICH is not a frequent complication, the effect is significant with a survival rate of 17–40% compared to 45–68% for those who do not have an ICH [1]. In addition to hemorrhage, thrombotic complications can occur. While not as common as bleeding complications, cerebral infarcts accounted for 3–7% of complications described in the ELSO registry report [1]. Unfractionated heparin continues to be the most widely studied and used anticoagulant for anticoagulation in ECMO, but alternative agents are increasingly being used in pediatric and adult ECMO patients.

#### **3.1 Unfractionated heparin**

Unfractionated heparin (UFH) is the gold standard anticoagulant during ECMO and is commonly used in ECMO centers worldwide. Heparin acts as a catalyst to potentiate the action of antithrombin III, inhibiting thrombin and activated coagulation factor X, thus inhibiting the conversion of fibrinogen to fibrin [11]. The half-life of heparin is approximately 1–2 hours in healthy adults, but can vary significantly in pediatric patients. Heparin is metabolized by the reticuloendothelial system in the liver and spleen, and is excreted in the urine [11]. In the pediatric population, developmental hemostasis and the patient's age may affect the pharmacokinetics of heparin [12]. For example, the neonatal population frequently requires additional monitoring and higher bolus and infusion rates to obtain effective anticoagulation [6, 12–14]. Another complication due to unfractionated heparin use is heparin-induced thrombocytopenia that is seen in 1–2% of pediatric patients [11].

For patients with preexisting conditions that preclude them from safe anticoagulation, such as trauma patients with intracranial hemorrhage or patients that develop hemorrhagic complications while on ECMO, successful use of heparin-free ECMO management with or without heparin-bonded circuits has been documented [15–17]. However, the published literature is limited primarily to specific populations and for a limited duration of time.

#### **4. Monitoring during heparin anticoagulation**

Close monitoring to ensure anticoagulation is therapeutic is necessary to decrease the risk of hemorrhage or thrombosis during ECMO. The common tests used to monitor heparin during ECMO are activated clotting time (ACT), activated partial thromboplastin time (aPTT), and anti-factor Xa. No single test has been

found to be superior to monitor heparin during ECMO. ECMO centers worldwide vary in their practices on the type of test or combination of tests used to monitor heparin [2, 18].
