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DOI: 10.1177/1089253209347384

2009 13: 154SEMIN CARDIOTHORAC VASC ANESTHWilliam C. Oliver

Anticoagulation and Coagulation Management for ECMO

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154

Anticoagulation and Coagulation Management for ECMO

William C. Oliver, MD

From the Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota.

Address correspondence to: William C. Oliver, Department of Anesthesiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; e-mail: [email protected].

Seminars in Cardiothoracic and Vascular Anesthesia

Volume 13 Number 3September 2009 154-175

© 2009 The Author(s)10.1177/1089253209347384

http://scv.sagepub.com

Since the inception of extracorporeal mem-brane oxygenation (ECMO) in 1971,1 thou-sands of adults and pediatric patients have

been saved. Advances in ECMO have reduced mor-bidity and mortality compared with early experi-ences. However, mortality is still high with survival rates of 77% for neonatal respiratory failure, 53% for adult respiratory failure, 45% for pediatric cardiac failure, and 32% for adult cardiac failure.2 The prin-cipal causes of mortality and morbidity remain bleeding and thrombosis.3,4 Bleeding and thrombo-sis are related to contact of blood and its cellular components with the nonbiologic surface of the extracorporeal circuit (EC) used during ECMO that results in a massive inflammatory and clotting response. Consequently, anticoagulation is neces-sary to prevent thrombosis but it also increases the risk of excessive bleeding especially as the duration of ECMO increases. Excessive bleeding is the most common reason for premature separation from ECMO that may rob the cardiac and respiratory

systems of an opportunity to rest and improve. The aim of this article is to review the management of anticoagulation and transfusion in pediatric and adult patients that require ECMO.

Normal Coagulation

To successfully manage anticoagulation and transfu-sion in a patient on ECMO, a thorough knowledge of the normal coagulation process for pediatric and adult patients is essential. Knowledge of the coagula-tion system continues to evolve from early concepts of zymogen clotting factors and cofactors activating in sequence through two separate pathways, intrinsic and extrinsic to generate fibrin for clotting, to a more encompassing process that includes the vascular endothelium, blood coagulation, prevention of clot-ting, and fibrinolysis. The fundamental principle that governs the coagulation system is the unremit-ting drive to balance procoagulant and anticoagu-lant forces.

Normal coagulation consists of interactions between the vascular endothelium and plasma pro-teins and platelets. A major advancement in the understanding of coagulation is the enhanced appre-ciation for the role of the endothelium (Figure 1). It is instrumental in maintaining the balance between

Advances in extracorporeal membrane oxygenation (ECMO) management have helped to reduce compli-cations compared with its inception but they remain high. The principal causes of mortality and morbidity are bleeding and thrombosis. The nonbiologic surface of an extracorporeal circuit provokes a massive inflam-matory response leading to consumption and activation of procoagulant and anticoagulant components. The vast differences in neonatal and adult anticoagula-tion and transfusion requirements demands tremendous

clinical knowledge to provide the best care. Increased use of thrombelastogram will complement other meth-ods currently being used to improved care. Methods to recognize the level of thrombin formation at the bed-side could help reduce neurologic complications. ECMO requires a multidisciplinary team approach to achieve the best outcomes.

Keywords: anticoagulation; transfusion; extracorpo-real circuit; thromboelastogram; thrombosis



Anticoagulation and Coagulation Management for ECMO / Oliver 155

procoagulant and anticoagulant activity. Its proper functioning is better appreciated today than at any time in the past.5

The negatively charged membranes of the endothelium usually limit clotting unless an injury or disruption occurs. At the site of endothelial injury, blood contacts the subendothelium that contains collagen, thromboxane, von Willebrand factor (vWF), and other platelet attractants produced by the endothelial cells exposing them to procoagulant pro-teins and nonactivated platelets. The platelet recep-tors attach to the subendothelial molecules, especially vWF, causing platelet adhesion and formation of a platelet plug. Continued recruitment of platelet ago-nists is necessary to achieve sufficient platelet acti-vation to cause irreversible platelet aggregation, thereby sustaining the platelet plug.

For the platelet plug to become a clot, it must be reinforced by fibrin (Figure 2). The surfaces of acti-vated platelets possess unique properties of the plate-let membrane that strongly enhances activation of blood coagulation to play a major role in thrombin generation and fibrin production. With increasing thrombin generation, platelet aggregation will con-tinue to accelerate that not only strengthens the platelet plug but also releases the platelets’ alpha and

dense granules. These granules contain compounds necessary for clotting such as vWF, platelet factor 4, factor V, fibrinogen, and a number of other platelet agonists. The fibrin that changes the platelet plug to clot is formed from the cleavage of the 4 peptide bonds of fibrinogen, referred to as fibrinopeptides A and B, by thrombin. The removal of the bonds allows polymerization and subsequent clot forma-tion. Thrombin also strengthens the clot by cleaving factor XIII that establishes covalent bonds between fibrin molecules.

Besides the endothelium, an integral membrane protein called tissue factor (TF) is now more recog-nized as a major part of fibrin formation through the blood coagulation pathways. Previously, the intrinsic and extrinsic pathways of the blood coagulation sys-tem were believed to work separately to activate fac-tor X, initiating the common pathway to thrombin formation (Figure 3), but they are not independent of one another because deficiencies of one pathway are not compensated by the other pathway. Current understanding suggests that TF complexes with trace amounts of factor VII in the blood to activate factor VII, but only in conjunction with a phospholipid surface of a monocyte, platelet, or microparticles. This forms the TF:VIIa complex6 so that VIIa acti-vates factor X to reach the common coagulation path-way7 and factor IX of the intrinsic pathway to generate thrombin and fibrin formation (Figure 1). Early in

Figure 1. The endothelial cell membrane is involved in a vari-ety of procoagulant activities. The extrinsic pathway is activated by the expression of tissue factor (TF) at the endothelial cell surface. TF complexed with factor VIIa stabilizes the VIIa site. This results in the conversion of factor IX to factor IXa and ultimately catalyzes the activation of factor X. With help of an activated cell membrane and calcium (Ca2+), factor Xa catalyzes the conversion of factor V to factor Va to convert prothrombin (II) to thrombin (IIa).

Figure 2. GAG with AT inhibit excess thrombin.Factors Va and VIIIa with slashes have been inactivated by APC represented. Va and VIIIa with slashes indicate Va and VIIIa inactivated by APC. Activated platelets and fibrin form a hemo-static plug.NOTES: APC, activated protein C; AT antithrombin; GAG, Glycosaminoglycans; PC, protein C; S, the cofactor of protein C; T, thrombin; TF, tissue factor; TM, thrombomodulin.Source: Reprinted with permission from Roberts HR, Monroe DM, Escobar MA. Current concepts of hemostasis: implications for therapy. Anesthesiology. 2004;100:722-730, figure 3. Copyright 2004 American Society of Anesthesiologists, Lippincott Williams & Wilkins.



156 Seminars in Cardiothoracic and Vascular Anesthesia / Vol. 13, No. 3, September 2009

thrombin generation, it is the TF:VIIa complex that actually primes thrombin generation but eventually thrombin formation becomes independent of this TF:VIIa complex.8 Despite beginning with the extrin-sic pathway, thrombin formation is 50 times faster via the intrinsic pathway activation.6

Unopposed clotting would be catastrophic, so mechanisms exist to inhibit perpetual clot formation as well as dissolve existing clot. Inhibition of sus-tained clot formation is primarily accomplished by antithrombin (AT) by limiting activity once a com-plex is formed with the clotting protein. Produced in the liver, AT can inhibit all serine proteases, not only thrombin and factor X. AT is consumed once it forms the complex with the serine protease. Adequate AT concentration is very important to main-tain the balance between procoagulant and antico-agulant activity, especially with exposure to an EC. AT reaches adult levels in about 6 months after birth.9 Excess thrombin that is not complexed with AT is bound by thrombomodulin derived from endothe-lial cells. This thrombin–thrombomodulin complex also activates protein C and in conjunction with its cofactor, protein S inactivates factors Va and VIIIa.7

Finally, the endothelium produces tissue factor path-way inhibitor to stop clotting by complexing not only with TF but also with factors VIIa and Xa.

The fibrinolytic system’s function is to limit the extent of clot growth and ultimately dissolve it. Plasmin, a serine protease, is the primary effector molecule. It not only dissolves clot by lysing fibrin but also hydrolyzes fibrinogen, factors V, VIII, IX, and XI to stop clotting. Plasmin is activated by clot formation that stimulates the endothelium to pro-duce tissue type plasminogen activator (tPA). To prevent excessive fibrinolysis, α-2-antiplasmin effi-ciently inactivates plasmin and thrombomodulin. Plasmin formation generates plasminogen activating inhibitor that inhibits plasmin completing the feed-back loop.

The coagulation system for neonates, infants, and children contains all the necessary components for clotting but only in different concentrations com-pared with adults.10 Newborn clotting factors VII, IX, X, XI, XII, prothrombin, prekallikrein, and high molecular weight kininogen are approximately 50% of adult levels whereas factors VIII, XIII, V, fibrino-gen, and vWF approach or even exceed adult values (Table 1).11 Clotting factor levels are not only a function of the postnatal but also of gestational age. A weakness in thrombin generation in the preterm and term infant may reduce clotting capability when combined with lower clotting factor and contact pro-tein levels in this age range.12 Infant prothrombin levels lag behind adult concentrations by 20% and a weaker capacity to generate thrombin persists even into childhood.9 Newborn platelets are hyporeactive compared with adult platelets but achieve adult reac-tivity rapidly in 10 to 14 days. A majority of inhibitors of clotting, AT and proteins C and S are also 50% of adult levels at birth.9

The newborn coagulation system overall matures over 6 months to adult levels and function even if premature birth temporarily depresses its capabili-ties; however, maturation does not insure normal concentrations of all clotting factors. Similarly, lower concentrations may not indicate poor clotting capa-bility. Miller et al13 demonstrated functional integrity of the coagulation system of neonates and infants with the thrombelastogram (TEG) even though mat-uration was not complete. In fact, a “more coagula-ble state” was reported based on TEG values in those individuals 1 to 3 months of age compared with adults despite the low clotting factor concentrations normally present in this age range.11 In essence, it is

Figure 3. Coagulation cascade consisting of the extrinsic, intrinsic, and common pathways.NOTES: PL, phospholipids; Ca2+ = calcium.Source: Reprinted with permission from Hartmann M, Sucker C, Boehm O, Koch A, Loer S, Zacharowski K. Effects of cardiac surgery on hemostasis. Transfus Med Rev. 2006;20:230-241, figure 3. Copyright 2006 Elsevier.




difficult to reliably estimate the clotting capability of pediatric patients based solely on the concentration of clotting factors and platelets, so functional mea-sures of clotting such as the TEG may provide important information to guide diagnosis and treat-ment. However, the rarity of spontaneous hemor-rhage and thrombosis in neonates and infants suggests a balance between clotting and anticoagu-lation in normal circumstances.

Extracorporeal Circuit and Hemostatic Activation

The inflammatory response and coagulation are closely connected and readily return to equilibrium at the local level. In contrast, exposure of the blood and cellular components to a nonbiologic surface of an EC provokes a massive inflammatory and thrombotic response exceeding any contact activation experi-enced at a local level. The inflammatory response activates cellular and enzymatic components that interact with the activated coagulation system (Figure 4). A highly procoagulant state mediated primarily by

thrombin is counterbalanced by an excessive fibrin-olytic response mediated by plasmin. The result is consumption and activation causing clotting factor deficiencies, impaired platelet function, thrombocy-topenia, and fibrinolysis (Figure 5). To complete the feedback loop, thrombin, factors Xa and VIIa also activate the inflammatory responses directly or indi-rectly by complement activation.14 The ongoing nature of the procoagulant (thrombin) and anticoagulant (fibrinolysis) actions in concert with the elevated inflammatory response that occurs during ECMO creates opportunities for imbalance that heightens the chance of thrombosis or more commonly exces-sive bleeding.15 Reduced postoperative bleeding asso-ciated with cardiopulmonary bypass (CPB) and cardiac surgery was accomplished by efforts to block the final complement pathway and therefore the inflammatory response.16 However, the many arms of the inflammatory response have limited the benefits of targeted therapies. Furthermore, the inflammatory response of neonates and infants is far greater than adults exposed to EC17 and associated with greater morbidity,18 so even stronger measures would be nec-essary to show any clinically significant benefit.

Table 1. Reference Values for Coagulation Tests in Healthy Full-term Infant During the First 6 Monthsa

Tests Day 1 (n) Day 5 (n) Day 30 (n) Day 90 (n) Day 180 (n) Adult (n)

PT (s) 13.0 ± 1.43 (61)* 12.4 ± 1.46 (77)*† 11.8 ± 1.25 (67)*† 11.9 ± 1.15 (62)* 12.3 ± 0.79 (47)* 12.4 ± 0.78 (29)APTT (s) 42.9 ± 5.80 (61) 42.6 ± 8.62 (76) 40.4 ± 7.42 (67) 37.1 ± 6.52 (62)* 35.5 ± 3.71 (47)* 33.5 ± 3.44 (29)TCT (s) 23.5 ± 2.38 (58)* 23.1 ± 3.07 (64)† 24.3 ± 2.44 (53)* 25.1 ± 2.32 (52)* 25.5 ± 2.86 (41)* 25.0 ± 2.66 (19)Fibrinogen (g/L) 1.83 ± 0.58 (61)* 3.12 ± 0.75 (77)* 2.70 ± 0.54 (67)* 2.43 ± 0.68 (60)*† 2.51 ± 0.68 (47)*† 2.78 ± 0.61 (29)II (U/mL) 0.48 ± 0.11 (61) 0.63 ± 0.15 (76) 0.68 ± 0.17 (67) 0.75 ± 0.15 (62) 0.88 ± 0.14 (47) 1.08 ± 0.19 (29)V (U/mL) 0.72 ± 0.18 (61) 0.95 ± 0.25 (76) 0.98 ± 0.18 (67) 0.90 ± 0.21 (62) 0.91 ± 0.18 (47) 1.06 ± 0.22 (29)VII (U/mL) 0.66 ± 0.19 (60) 0.89 ± 0.27 (75) 0.90 ± 0.24 (67) 0.91 ± 0.26 (62) 0.87 ± 0.20 (47) 1.05 ± 0.19 (29)VIII (U/mL) 1.00 ± 0.39 (60)*† 0.88 ± 0.33 (75)*† 0.91 ± 0.33 (67)*† 0.79 ± 0.23 (62)*† 0.73 ± 0.18 (47)† 0.99 ± 0.25 (29)vWF (U/mL) 1.53 ± 0.67 (40)† 1.40 ± 0.57 (43)† 1.28 ± 0.59 (40)† 1.18 ± 0.44 (40)† 1.07 ± 0.45 (46)† 0.92 ± 0.33 (29)†

IX (U/mL) 0.53 ± 0.19 (59) 0.53 ± 0.19 (75) 0.51 ± 0.15 (67) 0.67 ± 0.23 (62) 0.86 ± 0.25 (47) 1.09 ± 0.27 (29)X (U/mL) 0.40 ± 0.14 (60) 0.49 ± 0.15 (76) 0.59 ± 0.14 (67) 0.71 ± 0.18 (62) 0.78 ± 0.20 (47) 1.06 ± 0.23 (29)XI (U/mL) 0.38 ± 0.14 (60) 0.55 ± 0.16 (74) 0.53 ± 0.13 (67) 0.69 ± 0.14 (62) 0.86 ± 0.24 (47) 0.97 ± 0.15 (29)XII (U/mL) 0.53 ± 0.20 (60) 0.47 ± 0.18 (75) 0.49 ± 0.16 (67) 0.67 ± 0.21 (62) 0.77 ± 0.19 (47) 1.08 ± 0.28 (29)PK (U/mL) 0.37 ± 0.16 (45)† 0.48 ± 0.14 (51) 0.57 ± 0.17 (48) 0.73 ± 0.16 (46) 0.86 ± 0.15 (43) 1.12 ± 0.25 (29)HMW-K (U/mL) 0.54 ± 0.24 (47) 0.74 ± 0.28 (63) 0.77 ± 0.22 (50)* 0.82 ± 0.32 (46)* 0.82 ± 0.23 (48)* 0.92 ± 0.22 (29)XIIIa (U/mL) 0.79 ± 0.26 (44) 0.94 ± 0.25 (49)* 0.93 ± 0.27 (44)* 1.04 ± 0.34 (44)* 1.04 ± 0.29 (41)* 1.05 ± 0.25 (29)XIIIb (U/mL) 0.76 ± 0.23 (44) 1.06 ± 0.37 (47)* 1.11 ± 0.36 (45)* 1.16 ± 0.37 (44)* 1.10 ± 0.40 (41)* 0.97 ± 0.20 (29)Plasminogen 1.95 ± 0.35 (44) 2.17 ± 0.38 (60) 1.98 ± 0.36 (52) 2.48 ± 0.37 (44) 3.01 ± 0.40 (47) 3.36 ± 0.44 (29) (CTA, U/mL)

NOTES: PT, prothrombin time; APTT, activated partial thromboplastin time; TCT, thrombin clotting time; vWF, von Willebrand factor; PK, prekal-likrein; HMW-K, high molecular weight kininogen.aAll factors except fibrinogen and plasminogen are expressed as units per milliliter (U/mL) where pooled plasma contains 1.0 U/mL. Plasminogen units are those recommended by the Committee on Thrombolytic Agents (CTA). All values are expressed as mean ± standard deviation.*Values that do not differ statistically from the adult values.†These measurements are skewed because of a disproportionate number of high values. The lower limit that excludes the lower 2.5th percentile of the population has been given in the respective figures. The lower limit for factor VIII was 0.50 U/mL at all time points for the infant.Source: Reprinted with permission from Andrew M, Paes B, Milner R, et al. Development of the human coagulation system in the full-term infant. Blood. 1997;70:165-172, table 2. Copyright 1997 American Society of Hematology (ASH).




Contact between blood and a nonbiologic sur-face of an EC activates high molecular weight kini-nogen, plasma kallikrein, and factor XII to begin the process of clotting. Within seconds of the blood’s contact with the surface of the EC, a layer of fibrin-ogen, vWF, and fibronectin is adsorbed that contains the protein sequence responsible for strongly attract-ing platelet adhesive receptors such as GPIIa-IIIb and GPIb (GP = glycoprotein). Platelets will initially adhere to such a site but only with repeated platelet stimulation, will they progress from a reversible state of platelet adhesion to an irreversible state of aggregation and platelet recruitment. This change is reflected in pediatric patients after CPB when pre-CPB platelet aggregation fell as much as 77% by end of surgery.19 Besides attracting platelets, surface pro-teins such as fibrinogen and factor XII affect other cellular processes and interactions that promote a procoagulant environment.

For infants during the first two hours of ECMO, activated platelets catalyze increased thrombin forma-tion, evidenced by rapid increases in concentration of prothrombin fragments 1 + 2 (F1+2), thrombin–anti-thrombin (TAT) complexes, and fibrin split products, to generate fibrin to stabilize the platelet plug (Figure

6).20 Activated platelets are far more attracted to the surface of the oxygenator and endothelium than resting ones but contact activation eventually slows over the ensuing 48 hours as markers of thrombin formation subside. The reason for less contact acti-vation at this point may be a surface replete with proteins and cellular components.20 Ongoing sur-face activation not only forms clot from thrombin and factor XII formation, but also stimulates tPA to generate plasmin to dissolve clot. Activated endothe-lial cells and platelets control the amounts of tPA to try to maintain that balance between procoagulant and anticoagulant forces.

Activation of the coagulation system occurs not only on the surface of the EC but also within the patient’s vasculature leading to either overt throm-bosis or disseminated intravascular coagulation.21 Vascular endothelial cells in contact with activated platelets and other procoagulant agonists, will pro-duce thrombin, but resting endothelial cells express little TF so that there is minimal thrombin and clot.17 The role of the EC is not only to activate the

Figure 4. Cellular and plasmatic systems involved in the inflammatory response induced by cardiopulmonary bypass–in-duced contact activation.Source: Reprinted with permission from Mössinger H, Dietrich W. Activation of hemostasis during cardiopulmonary bypass and pediatric aprotinin dosage. Ann Thorac Surg. 1998;65(6 suppl): S45-S51. Copyright 1998 The Society of Thoracic Surgeons, Elsevier.

Figure 5. Pathophysiology of hemostatic abnormalities with extracorporeal circulation. Contact activation via extracorporeal circulation (ECC) refers to contact activation related to inter-face of blood with nonendothelial surface of the ECC. Pericardial activation refers to activation of the hemostatic system via the tissue factor pathway mediated by transfusion pericardial blood containing tissue thromboplastin. Mechanical ECC refers to shear forces imposed by some of the components of the ECC circuit as listed (tPA = tissue plasminogen activator).Source: Modified and reprinted with permission from Despotis GJ, Gravlee G, Filos K, Levy J. Anticoagulation monitoring dur-ing cardiac surgery: a review of current and emerging tech-niques. Anesthesiology. 1999;91:1122-1151. Copyright 1999 Lippincott Williams & Wilkins.




endothelium to express TF, but it also causes a change to occur in the endothelial membrane to support the TF:VIIa complex, also known as the prothrombinase complex (Figure 1). The importance of the endothelium in clotting and anticoagulation in patients undergoing ECMO is just now begun to

be appreciated but future findings may hold some answers to better management of ECMO.

Anticoagulation

The goal of anticoagulation for ECMO is to prevent life-threatening thrombosis and excessive bleeding. Discerning the degree of anticoagulation to attenu-ate platelet and thrombin activation but provide suf-ficient clotting to prevent excessive bleeding is difficult. It is made more difficult because the tech-nology to accurately assess the degree of anticoagu-lation is not clinically available or developed currently. Unidentified macroscopic clots cause a variety of thromboembolic events in patients considered ade-quately anticoagulated.22 It appears that the effec-tiveness of anticoagulation worsens with the duration of ECMO. A recent autopsy series of ECMO patients reported unexpectedly high rates of systemic throm-boemobolic events approaching 50% with an almost linear increase with duration of ECMO (Figure 7).23 However, the study identified a median time of 6 days with freedom from these events. Current management of anticoagulation for ECMO partially derived from the experiences of CPB.24 Advancements of anticoagulation in ECMO will likely remain lim-ited because of the difficulty of conducting random-ized trials compared with CPB. The ensuing paragraphs will discuss the monitoring and dosing for anticoagulation for ECMO.

Monitoring for Anticoagulation

Identification of the level of anticoagulation is the heartbeat of ECMO management. In the initial years of cardiac surgery with CPB, a fixed dose of heparin was administered without monitoring for level of anticoagulation. The advent of anticoagula-tion monitoring was a great advancement to improve care in cardiac surgery.

The earliest and most popular test to monitor anticoagulation for EC was the activated clotting time (ACT). It measures the integrity of the intrinsic coagulation and common pathways. To perform an ACT, whole blood is placed in a test tube with 1 of 2 activators of the contact pathway, celite (diatoma-ceous earth) or kaolin (clay). The celite ACT forms clot that will disrupt the magnetic field of the mag-netic detector by pulling iron away from it, thereby halting the timer. The kaolin ACT has a plunger that

Figure 6. A, Course of F1+2 (in nanomoles per liter). B, TAT (in micrograms per liter). C, d-dimer (in nanograms per liter). A steep increase of values is seen within the first 2 hours of ECMO. Thereafter F1+2 and TAT values decrease, whereas d-di-mer levels remain high. Values represent mean ± SEM. preEC, Before start of ECMO (n = 6, asterisk; otherwise n = 7).NOTES: F1+2, prothrombin fragments; TAT, thrombin–anti-thrombin complexes; ECMO, extracorporeal membrane oxygen-ation; SEM, standard error of the mean.Source: Reprinted with permission from Urlesberger B, Zobel G, Zenz W, et al. Activation of the clotting system during extracor-poreal membrane oxygenation in term newborn infants. J Pediatr. 1996;129:264-268, figure 1. Copyright 1996 Mosby.




actively rises and falls in whole blood until the rate of the falling plunger is slowed by clot formation and an optical sensor detects the change halting the timer. The ACT is a functional test of anticoagula-tion. Bull et al25 were the first to explore the possibil-ity of evaluating the degree of anticoagulation during CPB with the ACT. To achieve good results, they recognized that a dose response method was neces-sary to dose heparin during CPB because of the great variability associated with the amount of hepa-rin and the resulting ACT values among patients. Bull et al25 obtained ACT values for numerous time points generating a curve predicting the heparin required to achieve “adequate anticoagulation.” ACT management of anticoagulation was proclaimed suc-cessful without “visible” clots in the EC. The ACTs that provided such conditions varied between 300 and 600 seconds. Soon after, Young et al26 chal-lenged the accepted range of ACTs for adequate anticoagulation. In a study of monkeys undergoing CPB, significantly higher fibrin monomer levels were found in animals below an ACT of 400 seconds despite the absence of visible clot in the EC. This not only changed the minimal “acceptable” ACT for heparinization with EC, but more important, it dis-pelled the idea that the absence of overt clotting

indicated adequate anticoagulation. Subsequently, more sensitive tests were developed and employed to evaluate “adequate anticoagulation” during EC.

ACT remains the predominant test to manage heparin anticoagulation during ECMO.27 However, the ACT’s capability to correctly measure the level of anticoagulation has been questioned.28 Concern about the ACT’s ability to provide adequate antico-agulation is because the test results are affected by patient characteristics, such as coagulopathy, imma-ture coagulation system, platelet dysfunction, hypo-thermia, AT level, age, and hemodilution,29 as well as technical factors, such as sample size, venous or arte-rial blood, and temperature.27 Even changes in the use of a specific ACT device may result in unrecog-nized inadequate anticoagulation.30

A concern with the ACT for management of anticoagulation with EC is its limited range of accu-racy. The correlation coefficient of a laboratory-derived heparin concentration (anti-Xa level) to kaolin ACT (r = .93) and celite ACT (r = .91) before initia-tion of EC is excellent,31 but deteriorates on EC (r = .38) especially with neonates or infants (Figure 8). Heparin levels < 2 u/mL have been reported despite prolonged ACT values indicative of adequate anti-coagulation.32 Ongoing thrombin generation is evi-dent in adults, and especially children, undergoing cardiac surgery and CPB despite “acceptable” ACT

Figure 7. Time-dependent incidence of systemic thromboem-bolisms in ECMO patients based on autopsy findings.NOTES: ECMO, extracorporeal membrane oxygenation; d, days.Source: Reprinted with permission from Rastan AJ, Lachmann N, Walther T, et al. Autopsy findings in patients on postcardiotomy extracorporeal membrane oxygenation (ECMO). Int J Artif Organs. 2006;29:1121-1131. Copyright 2006 Wichtig Editore.

Figure 8. Activated clotting time (ACT) versus heparin levels (anti-factor Xa activity). The correlation of the ACT values and plasma heparin levels was r = .38.Source: Reprinted with permission from Chan AK, Leaker M, Burrows FA, et al. Coagulation and fibrinolytic profile of paediat-ric patients undergoing cardiopulmonary bypass. Thromb Haemost. 1997;77:270-277, figure 12. Copyright 1997 International Society on Thrombostasis and Haemostasis.




values supporting inadequate anticoagulation.29,33-35 Such poor correlations with the ACT and heparin levels may be improved with more normal clotting factor levels in the patient. The correlation of ACT with anti-Xa derived heparin concentrations was poor with crystalloid only hemodilution (Figure 9A) but improved with same degree of hemodilution (75%) as crystalloid but substituting fresh frozen plasma (FFP; Figure 9b).36 Koster et al37 also found poor correlation of the ACT with saline hemodilu-tion, which improved by adding plasma during CPB

but besides a better correlation of the ACT with heparin levels there was evidence of reduced throm-bin generation, fewer d-dimers, and less neutrophil activation. This suggests that ACT management with ECMO may be improved if adequate clotting factor levels are maintained. Unfortunately, increas-ing complexities associated with ECMO patients also worsen the correlation of ACT to heparin dosing causing more uncertainty for the clinician with this form of monitoring.

The popular range for the ACT with heparin dur-ing ECMO has been 180 to 220 seconds.38 Recently, a retrospective review of 604 consecutive pediatric ECMO patients at a single institution were analyzed for factors that affected outcome.27 The mean ACT for all patients was 227 ± 50 seconds but the range of 158 to 620 seconds was very broad. Using regres-sion analysis to determine the correlation of survival with heparin dosing and ACT values, it was higher heparin dosing and not the ACT that was predictive of survival independent of other variables (P < .0001). Figure 10 shows a moderate correlation coefficient (r = .48) between ACT and heparin dosing (units/kg/h) but when survival was plotted, the greatest survival was in the right upper quadrant of the graph with the higher heparin dosing. All the data suggest increased survival with increasing heparin dosing.27 Furthermore, higher heparin dosing was also associ-ated with increased survival in patients who had prior surgery and required ECMO. Survivors had significantly shorter ECMO times but significantly greater heparin doses adjusted for body weight per hour. ACTs were not different between survivors and nonsurvivors.

Although the celite and kaolin ACT tests are the most popular types of anticoagulation monitoring tests, there are other types of ACT tests such as the i-STAT (Abbott Laboratories, Abbott Park, IL) ACT. Although the results are shorter compared with tra-ditional ACT there may be some value in its use during ECMO where rapid ACT is often required.39

There are also efforts to replace the traditional ACT with an ACT derived from point-of-care (POC) instruments such as the sonoclot,40 and the TEG with TF activation41 but they have not become popu-lar at this time.

Despite the continued use of the ACT, it alone may be too insensitive to achieve consistent ade-quate anticoagulation during ECMO so the addition of other coagulation tests may prove beneficial. The measurement of heparin concentration is an option

Figure 9. A, Correlation of the kaolin activated clotting time (ACT) to the chromogenically measured plasma anti-Xa activity. B, Correlation of the plasma added modified kaolin ACT to the chromogenically measured plasma anti-Xa activity.Source: Reprinted with permission from Koster A, Despotis G, Gruendel M, et al. The plasma supplemented modified activated clotting time for monitoring of heparinization during cardiopul-monary bypass: a pilot investigation. Anesth Analg. 2002;95:26-30, figure 1. Copyright 2002 International Anesthesia Research Society, Lippincott Williams & Wilkins.




to manage anticoagulation. Laboratory derived hep-arin concentration is the gold standard but is not easily or quickly obtained for patients on ECMO. A relatively accurate point-of-care heparin concen-tration is obtained with the technique of heparin/protamine titration. The Hepcon (Medtronic Perfusion Systems, Minneapolis, MN) is able to pro-vide heparin concentrations that have relatively good correlation to the laboratory-derived anti-Xa plasma heparin measurements.31 These tests do not however, actually measure the anticoagulant proper-ties of heparin, so they are not functional tests, such as the ACT, but still depend on clotting to determine the concentration.

Heparin concentration monitoring for anticoagu-lation is more frequent in cardiac surgery with CPB especially when severe hemodilution or hypothermia is anticipated. Heparin concentration monitoring with the Hepcon has demonstrated superior capabil-ity to achieve adequate anticoagulation in adults and especially children undergoing cardiac surgery and

CPB compared with the ACT.33,34 Codispoti and Mankad35 compared heparin concentration man-agement for pediatric and adult CPB finding not only more adequate anticoagulation but also increased heparin dosing and reduced bleeding and transfusion requirements compared with ACT man-agement. Better platelet preservation with higher than lower heparin concentrations in patients undergoing CPB28 may be advantageous with ECMO as bleeding due to thrombocytopenia and poor plate-let function is a major problem. More important, unlike the ACT, use of heparin concentrations have the benefit of being less sensitive to changes in the patient’s platelet and clotting factor levels so better management of anticoagulation is possible.

Studies of heparin concentration monitoring for anticoagulation during ECMO are few compared to the ACT so target heparin levels have not been deter-mined. In 1990, a study of heparin clearance during ECMO unintentionally discovered heparin concen-trations of 0.1 to 0.3 u/mL associated with ACTs of 110 to 220 seconds.42,43 Urlesberger et al20 noted that the heparin concentrations remained surprisingly steady in term newborn infants requiring ECMO compared with the ACT with heparin dosing during a 48-hour period (Figure 11). Similar to the studies by Green et al,42,43 this study shows a similar range of heparin concentration of 0.2 to 0.4 u/mL during ECMO, but unfortunately there are no other studies to confirm the findings. Uncertainty regarding the target heparin concentration during ECMO has lim-ited its use.

The use of viscoelastic tests for anticoagulation is not totally new. Several centers have incorporated the TEG into their management of ECMO.44 It is a major part of anticoagulation and transfusion ther-apy in our institution. The TEG is a device that measures the viscoelastic properties of the blood to examine the whole clotting system instead of iso-lated parts.45 It provides ongoing coagulation pro-files looking at not only the initiation of clotting but also the strength and dissolution of the clot as in the case of fibrinolysis. Figure 12 shows the parameters of the TEG.

To manage anticoagulation with the TEG, the reaction time, r, is the most important value because it represents the time for initial fibrin formation. It is affected by severe hypofibrinogemia, hypercoagu-lability, and heparin. In fact, the TEG is so sensitive to the effects of heparin that as little as 0.3 u/mL will prolong the r time and 1 u/mL will greatly suppress

Figure 10. Scatterplot shows the moderate positive linear cor-relation between heparin dose and ACT (r = .48, P < .001). Similar moderate correlations were observed in both survivors (open triangles; r = .52, P < .001) and nonsurvivors (filled tri-angles; r = .43, P < .001). Regression line (solid line) based on all patients is drawn according to the derived linear equation for estimating ACT from heparin dose: y = 0.95x + 180.NOTES: ACT, activated clotting time; ECMO, extracorporeal membrane oxygenation.Source: Reprinted with permission from Baird CW, Zurakowski D, Robinson B, et al. Anticoagulation and pediatric extracorpo-real membrane oxygenation: impact of activated clotting time and heparin dose on survival. Ann Thorac Surg. 2007;83:912-919, figure 1. Copyright 2007 The Society of Thoracic Surgeons, Elsevier.




clotting so that only a flat line occurs. This makes it impractical for management of anticoagulation dur-ing CPB, but not ECMO because heparin levels usually do not exceed 1 u/mL.

The value of the TEG for ECMO and CPB has become more recognized over the last decade with the application of additives such as heparinase, TF, and kaolin to expand its capabilities. The addition of kaolin to the TEG (kTEG) sample gives a more rapid result. The addition of heparinase to the TEG (hTEG) permits a fully formed tracing to be gener-ated and so allows a view of hemostatic capability

even with a heparin infusion (Figure 13). Because the TEG r is sensitive to certain many factors, the best diagnostic option is to perform a hTEG and kTEG simultaneously46 especially during ECMO. Simulta-neous TEGs will provide a measure of the degree of anticoagulation. If the kTEG r time and the hTEG r time are similar in length, then very little systemic heparin is present. We like to maintain a kTEG r of more than 20 minutes as a baseline for anticoagula-tion. If the kTEG r time exceeds 90 minute, then anticoagulation may be too great possibly increasing bleeding.

Figure 11. A, Heparin concentration (in international units per milliliter). B, Activated clotting time (ACT; in seconds). The ACT values increased at the start of ECMO, whereas heparin concentration has a stable course. Values represent mean ± SEM. preEC, Before the start of ECMO (n = 6, asterisk; other-wise n = 7).NOTES: ACT = activated clotting time; ECMO, extracorporeal membrane oxygenation; SEM, standard error of the mean.Source: Reprinted with permission from Urlesberger B, Zobel G, Zenz W, et al. Activation of the clotting system during extracor-poreal membrane oxygenation in term newborn infants. J Pediatr. 1996;129:264-268, figure 2. Copyright 1996 Mosby.

Figure 12. Quantification of native thromboelastogram (TEG) variables. Analysis of the thrombelastograph. r = reaction time (time from sample placement in the cuvette until TEG tracing amplitude reaches 2 mm; normal range, 6-8 min). This repre-sents the rate of initial fibrin formation and is related function-ally to plasma clotting factor and circulating inhibitor activity (intrinsic coagulation). Prolongation of the r time may be a result of coagulation factor deficiencies, anticoagulation (hepa-rin), or severe hypofibrinogenemia. A small r value may be pres-ent in hypercoagulability syndromes. K = clot formation time (normal range, 3-6 min); measured from r time to the point where the amplitude of the tracing reaches 20 mm. The coagu-lation time represents the time taken for a fixed degree of vis-coelasticity to be achieved by the forming clot, as a result of fibrin build up and cross linking. It is affected by the activity of the intrinsic clotting factors, fibrinogen and platelets. Angle α° (normal range, 50-60°) = greatest amplitude on the TEG trace and is a reflection of the absolute strength of the fibrin clot. It is a direct function of the maximum dynamic properties of fibrin and platelets. Platelet abnormalities, whether qualitative or quantitative, substantially disturb the maximum amplitude (MA). A60 (normal range, MA-5 mm) = amplitude of the tracing 60 min after MA is achieved. It is a measure of clot lysis or retraction. The clot lysis index (CLI; normal range >85%) is derived as A60/MA × 100 (%). It measures the amplitude as a function of the time and reflects loss of clot integrity as a result of lysis.Source: Reprinted with permission from Mallett SV, Cox DJ. Thrombelastography. Br J Anaesth. 1992;69:307-313, figure 2. Copyright 1992 Oxford University Press.




The TEG is not only useful for determining anticoagulation but is also able to characterize hyper-coagulability. This information is relevant when man-aging the anticoagulation from birth to adulthood. The concentration of procoagulant and anticoagu-lant compounds vary in amount from birth to adult-hood; however, the ability to assess this functionally with a POC test is beneficial. Miller et al13 found that most coagulable infants are 1 to 3 months of age whereas neonates are similar to infants 6 months of age in terms of coagulability with the TEG. The TEG of infants demonstrates that even with lower plasma levels than adults they clot effectively. Kinetics may explain the low levels despite functional equivalency compared with adults.

A new type of TEG, the rotational TEG (RoTEG) may be helpful in the future in ECMO patients and is gaining rapid popularity in Europe because of its simplicity compared with the native TEG (Figure 14). The device still evaluates whole blood viscoelastic properties but is mechanistically different from the TEG and the parameters are defined differently. The RoTEG is not yet available in the United States.

Activated Partial Thromboplastin Time

The activated partial thromboplastin time (APTT) is universally recognized as a standard monitor for heparin therapy except when high heparin dosing is required as in CPB. The APTT is performed on

recalcified citrated plasma and represents the intrin-sic and common pathways.47 Its reagent contains phospholipids that act as platelets for clotting to occur. The wide variety of reagents results in some occasional sensitivity to various clotting factor defi-ciencies. The activator for the APTT influences the clotting time as well so that APTT results between institutions may not be comparable.

In situations that do not require high heparin dosing, such as ECMO, the APTT is a valuable tool to assess anticoagulation. Although both ACT and APTT are prolonged with heparin, there is poor cor-relation between the ACT and the APTT. In a com-parison between laboratory APTT and five bedside devices for monitoring heparin therapy, including the celite and kaolin ACT, the ACT was found to corre-late poorly with the APTT.48 Furthermore, in very ill patients requiring continuous infusions of hepa-rin the ACT could not delineate between low and moderate levels of anticoagulation compared with the APTT (Figure 15).49

The APTT that will prevent thrombus extension with heparin has been reported as 1.5 times baseline APTT. This APTT corresponds to a heparin level of 0.2 to 0.3 u/mL and does correlate moderately well with heparin concentrations.50 The APTT is sensitive

Figure 13. Thromboelastogram with heparinase and native whole blood samples. The difference in the r time and angles are especially notable.Source: Reprinted with permission from Agati S, Ciccarello G, Salvo D, Turla G, Undar A, Mignosa C. Use of a novel antico-agulation strategy during ECMO in a pediatric population: single-center experience. ASAIO J. 2006;52:513-516, figure 2. Copyright 2006 Lippincott Williams & Wilkins.

Figure 14. Typical tracings of viscoelastic point-of-care coag-ulation devices. Top, Thrombelastograph (TEG) tracing: r = reaction time; K = kinetics; α = slope between r and K; MA = maximum amplitude; CL = clot lysis. Bottom, Rotation throm-belastography (ROTEM) tracing: CT = clotting time; CFT = clot formation time; α = slope of tangent at 2 mm amplitude; MCF = maximal clot firmness; LY = lysis.Source: Reprinted with permission from Ganter MT, Hofer CK. Coagulation monitoring: current techniques and clinical use of viscoelastic point-of-care coagulation devices. Anesth Analg. 2008;106:1366-1375, figure 3A. Copyright 2008 International Anesthesia Research Society, Lippincott Williams & Wilkins.




over a heparin range of 0.1 to 1.0 u/mL. When the heparin level gets much more than 1 u/mL, the APTT becomes markedly prolonged. For ECMO anticoagu-lation, the APTT is another measure to manage anti-coagulation, not only to prevent thrombus formation but also to avoid excessive hemorrhage. In general, we have found that an APTT of 50 to 80 seconds complements the kTEG r time for anticoagulation. Because of the APTT sensitivity, it will take priority over the ACT when there is a discrepancy between the two measurements. For infants and children, the APTT may be prolonged in response to hemodilution without any measurable heparin. This is demonstrated in a trial looking at the use of FFP in infants that underwent CPB.51 The APTT of control infants before CPB was 35.2 ± 6.8 seconds compared with 117 ± 42.3 seconds after CPB and heparin neutralization.

Infants who received FFP as a prime had lower post-CPB APTT values of 99.2 ± 41.7 seconds, which did not quite reach statistical significance but demon-strated the impact of hemodilution on the APTT. Significant hemodilution may occur with the early stages of ECMO or during circuit changes, so it is important to be aware of this problem. The ACT, although affected by hemodilution, is less susceptible to it than the APTT.

Anticoagulation Therapy

Heparin continues to dominate anticoagulation ther-apy for ECMO because it is rapidly acting, easily reversible, inexpensive, widely available, and well tolerated by pediatric and adult patients. It is a gly-cosaminoglycan composed of chains of alternating residues of d-glucosamine and an uronic acid. Its unique pentasaccharide present in only one third of the molecule has a strong affinity to bind with AT. This binding causes a conformational change at the lysine site of AT that converts a slow inhibitor of ser-ine proteases, to one up to 10 000 times faster than normal depending on the enzyme. Serine proteases such as kallikrein and factors Xa, IXa, XIa, and XIIa are inhibited to a much weaker degree than factor Xa and thrombin, the most sensitive to AT. Thrombin bound to clot or surfaces of the circuit is not capable of being inhibited by the AT–heparin complex.6 As a result, bound thrombin will further activate clotting and thrombin generation resulting in greater hepa-rin needs. The action of heparin is not solely limited to thrombin but also to TF inhibition by stimulating tissue factor pathway inhibitor.

Once heparin is injected, it immediately binds to plasma proteins such as platelet factor 4, fibronec-tin, vWF, and others, which reduces its bioavailability especially at low doses.50 Heparin also binds to mac-rophages and the endothelium further complicat-ing its pharmacokinetics. Its anticoagulant activity is heterogeneous because of its variant size, clearance, and molecular format. Biologic activity varies between 30 minutes and 6 hours depending on the systemic heparin concentration. The half-life is affected so much by the dose that the anticoagulant response is not linear. It is metabolized in the reticuloendothe-lial system as well as the liver and 50% will be excreted unchanged by the kidneys.50 Clearance of heparin is greater for children with congenital heart disease than for adults.52

Figure 15. ACT at different levels of heparin anticoagulation. Group 1 APTT < 60 seconds; group 2 APTT 60 to 90 seconds; group 3 APTT > 90 seconds. All 3 groups differed statistically from one another (P < .001). Only Group 3 was the mean ACT (192 ± 39.1 seconds) significantly higher than the other mean ACT values for groups 1 and 2.NOTES: ACT, activated clotting time; APTT, activated partial thromboplastin time.Source: Reprinted with permission from De Waele JJ, Van Cauwenberghe S, Hoste E, Benoit D, Colardyn F. The use of the activated clotting time for monitoring heparin therapy in critically ill patients. Intensive Care Med. 2003;29:325-328, figure 2. Copyright 2003 Springer-Verlag.




Anticoagulation for ECMO is based on the need to prevent thrombus formation in the EC and patient; however, complete inhibition of thrombin would cause excessive bleeding. Depending on the history of the patient prior to ECMO, profound coagulation abnormalities may exist as with cardiac surgery. If a patient is bleeding or is likely to bleed after place-ment on ECMO, anticoagulation may be held and coagulation abnormalities corrected until the bleed-ing is controlled. The use of a heparin-coated circuit and good cardiac outputs are recommended. Once bleeding has been controlled to a degree, heparin will be given.

Heparin dosing for adults and pediatric patients is different for several reasons. The larger blood volume/weight ratios in neonates compared with adults require greater heparin dosing. The more rapid metabolic rates with neonates and infants may allow greater excretion by the kidneys and therefore affects heparin dosing. Heparin elimination half-life is also dependent on the initial dose as well as the tempera-ture. However, there is evidence that heparin clearance in infants is less after ECMO than before initia-tion.42 Therefore, the actual heparin clearance after initiation of ECMO is only speculation, hence hepa-rin dosing must depend on laboratory tests.

Differences in heparin dosing for adults and pedi-atric patients may also derive from differences in thrombin generation. There is evidence that neo-nates have greater thrombin generation even before the start of CPB compared with older children.53 However, even with higher heparin dosing during CPB, neonates had more evidence of thrombin gen-eration than younger children based on increased F 1 + 2 and fibrinopeptide A concentrations. The idea of heparin resistance or sensitivity in neonates has been debated. Dietrich et al54 suggested that the neonate is sensitive to heparin even though AT levels are below adult for at least 6 months. On the con-trary, however, Guzzetta et al53 have shown that the study by Dietrich et al was focused on the wrong endpoint, to reach such a conclusion. The research seems to point to neonates are more resistant to heparin and require greater amounts of heparin to inhibit thrombin that has implications for ECMO management. Additionally, neonates from cardiac surgery may have increased heparin needs as there is increased circulating thrombin because of greater clot-bound thrombin that is caused by the catheters and other nonbiologic items often placed in these neonates prior to initiation of ECMO.

Traditionally, heparin dosing ranges between 20 and 70 u/kg/h for ECMO. The difference in heparin anticoagulant responsiveness between individuals is evident by the wide range of heparin dosing response slopes in both normal (median 92, 95% confidence interval [CI] 77-117 s/u/mL) and cardiac patients (median 79, 95% CI 58-114 s/u/mL).55 Heparin dos-ing for ECMO for adults and pediatric patients may differ but is often derived from the guidelines for patients with thromboembolic disease.21 Most agree that the APTT should be 1.5 to 2.5 times the control. The most recent studies of heparin concentration suggest a value of 0.3 to 0.7 u/mL.21 The use of APTT in neonates on ECMO must be considered for prolongations because of hemodilution and not hep-arin. However, even in adults the APTT is prolonged without circulating heparin, because of hemodilu-tion.56 It is in this situation of hemodilution that the ACT may be more accurate with respect to circulat-ing heparin than the APTT. Otherwise, the APTT should provide excellent heparin monitoring. It is not unusual to see heparin dosing change during the ECMO duration in a patient. When monitoring anti-Xa levels, heparin concentration increases with time on ECMO.57 The cause may be a decrease in AT or maybe ECMO bound heparin is removed from the surface to increase the amount of circulating heparin.

Heparin dosing and effective anticoagulation are closely connected with AT concentration. Reduced heparin responsiveness is called heparin resistance. As mentioned earlier, for effective inhibition of throm-bin, adequate levels of AT are required with heparin. The major cause of heparin resistance is acquired deficiency of AT often associated with severe hemodi-lution, liver abnormalities, preoperative heparin use, or consumption during EC. Heparin infusions will continue to deplete the AT level. However, the man-agement of AT during ECMO is undecided. Arnold et al58 found a mean AT level of 27% in neonates under-going ECMO with some levels as low as 19%. This level of AT was also associated with a 30% incidence of neurologic bleeding. With the continuous adminis-tration of AT to normalize the AT level to 100% in another study of neonates, reduced bleeding was demonstrated during ECMO.44 From a cardiac surgi-cal bleeding aspect, Hashimoto et al59 demonstrated that supplementation with AT in pediatric patients to maintain preoperative levels suppressed activation of the coagulation system based on the extent of fibrin formation. Because complete suppression of




thrombin is not the goal of ECMO anticoagulation, it is difficult to make recommendations regarding the proper practice. It is clear that prolonged durations of ECMO will lead to consumption of AT and the patient may not be capable of maintaining the level. It is our practice to monitor AT daily during ECMO but replacement is an individual preference.

Transfusion and ECMO

The morbidity and mortality associated with hem-orrhage during ECMO is known. Stronger antico-agulation to lessen thrombotic complications will inevitably lead to greater bleeding and transfusion of blood products.60 Unlike in the past, the morbidity associated with blood transfusion is currently related to immunomodulation and increased inflammatory response that occurs with excessive blood transfu-sion rather than infectious transmission. Repeated transfusions compounded by a profound inflam-matory response associated with EC greatly increase the risk of sepsis. Therefore, efficient and appropri-ate transfusion to minimize bleeding and transfu-sion requirements may contribute greatly to reducing morbidity and mortality associated with ECMO.

Bleeding and transfusion with ECMO usually take 2 different forms. Serious hemorrhage in the neonate with respiratory distress syndrome who needs ECMO is primarily related to injury of the central nervous system at the intracranial level.60 Intracranial hemorrhage may occur in 15% of neo-nates61 and lead to premature discontinuation of ECMO or serious morbidity after separation. The risk of bleeding for neonates on ECMO is height-ened by the knowledge that up to 70% of neonates and infants have preexisting coagulation abnormali-ties prior to initiation of ECMO.61 However, it is not apparent that coagulopathy is the major cause for bleeding as other factors such as prolonged hypoxia, ischemia, acidosis, carotid ligation, and changes in the cerebral blood flow may play a role. In contrast, hemorrhage in other group of patients that require ECMO, especially postcardiac surgical patients, is about massive blood loss and transfusion that may continue indefinitely and also require premature sepa-ration from ECMO. A prospective study of autopsies of ECMO patients found a mean of 45 u of packed red blood cells (PRBCs) per patient, massive transfu-sion of non–red cell blood products and reex-ploration rates in the range of 40% to 80% in adult

postcardiotomy patients.23 Caring for patients on ECMO entails the ability to manage both types of vastly different hemorrhagic conditions.

In general, the approach to transfusion in ECMO patients includes assessment and maintenance of coagulation mechanisms that may prevent or reduce catastrophic bleeding and its complications.44,58 Some of the key factors that may contribute to hemorrhage and merit examination for management of ECMO are clotting factor and platelet production, endothe-lial injury, consumption, fibrinolysis, systemic illness, and multisystem organ dysfunction. Full correction of coagulation abnormalities may be unwarranted depending on the risk of thrombosis and the amount ongoing hemorrhage. Unfortunately, the partial degree of anticoagulation maintained during ECMO causes consumption of clotting factors and platelet activation that will necessitate repeated transfusions until separation from the EC.

Optimal transfusion management during ECMO requires an array of scheduled tests that repeatedly assess hemostatic capability such as platelet count (PC) AT, prothrombin time (PT), APTT, and TEG, and hemoglobin requirements. Additional tests that influence transfusion decisions include liver function tests, inflammatory markers, and measures of cell disruption.

Profound reduction in coagulation components of neonates and infants occur with initiation of ECMO compared with adults (Table 2).58 Table 2 illustrates the low coagulation concentrations pro-duced from priming the EC with PRBC and albumin. These levels persist over the next 24 hours despite transfusion of blood products to correct the deficien-cies. Factors V, VII, and VIII start to recover the fast-est after initiation of ECMO. Factor V concentration is lower than predicted based on hemodilution dur-ing the initiation of ECMO58 similar to neonates on CPB.62 In contrast, McManus et al61 found that the addition of 20% of the prime with FFP attenuated some of the major factor deficiencies associated with ECMO but not all. An FFP prime is especially important if excessive bleeding is ongoing prior to initiation of ECMO. With excessive bleeding, falls in coagulation levels will likely exceed those in Table 3 with initiation of ECMO. Although it has been rec-ommended to reach normal coagulation status at least once during the early period of ECMO,58 opti-mal factor levels to maintain during the entire dura-tion of ECMO are indeterminate but depend strongly on the amount of bleeding.




It is generally necessary to administer platelet and clotting factor products to obtain the hemo-stasis needed to remain on ECMO. For bleeding in pediatric63,64 and adult56 patients after separation from CPB, routine coagulation tests (RCTs) have been beneficial to appropriately treat bleeding and are recommended for ECMO management. The PC is readily measured with other RCT.

To determine clotting factor needs, specific fac-tor levels are not clinically available during ECMO; however, the PT may arguably be the best test.58 PT assesses the extrinsic and common pathway integ-rity by measuring clotting of recalcified plasma in the presence of tissue thromboplastin.47 PT’s sensi-tivity for clotting factor deficiencies depends on the choice of thromboplastin. The fibrinogen level is

Table 2. Median and Range at 4 Time Periods for Each of 6 Clotting Factors and ATIII (rel, Relative to Normal Adult Plasma Levels of 100%) and for Fibrinogen and Platelets (Normal Those Described for a Healthy 1-Day-Old

Term Neonate With Values Encompassing 95% of the Population)

Immediately Prior to ECMO on ECMO 6 h 24 h “Normal”

Median Range Median Range Median Range Median Range Mean 95% Range

ATIII (rel) 30* 18-85 19* 3-49 28* 17-46 33.5* 15-51 63 39-87Fibrinogen (g/L) 1.85* 1.05-4 0.5* 0.1-1.8 1.45* 1.05-2.9 2.3 1.2-3 2.83 2.167-3.99Factor II (rel) 22* 7-71 14* 3-39 24.5* 12-46 29* 16-64 48 26-70Factor V (rel) 28* 10-74 8* 3-30 20* 9-32 32* 17-52 72 34-108Factor VII (rel) 39.5* 13-82 16* 10-38 30.5* 12-49 42.5* 16-70 66 28-104Factor VIII (rel) 82.5 43-176 24.5* 9-78 39.5* 23-76 68.5 39-174 100 50-178Factor IX (rel) 30* 12-109 16.5* 10-51 26.5 12-62 30.5 18-137 53 15-91Factor X (rel) 30.5 7-112 14.5* 4-48 29 16-55 31 13-63 40 12-68Platelets (109/L) 141* 26-291 39* 16-105 94* 52-148 126* 106-137 >150 —ACT (s)a 125* 87-175 999* 284-999 216* 128-331 214* 196-263 80-120 —PT (s)b 24* 14-45 43* 21-170 27* 20-40 21* 17-37 13 10-16APPT (s)c 54* 31-250 250* 210-250 250* 170-250 250* 224-250 43 31-55

NOTES: ECMO, extracorporeal membrane oxygenation; ACT, activated clotting time; PT, prothrombin time; APTT, activated par-tial thromboplastin.*Significant number of values outside the “normal” range (P < .05).aPopulation data for platelets or ACT is not adequate to make this comparison.bPT values greater than 170 recorded at 170.cAPTT values greater than 250 recorded at 250.Source: Reprinted with permission from Arnold P, Jackson S, Wallis J, Smith J, Bolton D, Haynes S. Coagulation factor activity during neonatal extra-corporeal membrane oxygenation. Intensive Care Med. 2001;27:1395-1400, table 2. Copyright 2001 Springer.

Table 3. Kaolin-Activated Thrombelastograph Reference Valuesa

<1 yr 1-5 yr 6-10 yr 11-16 yr Adults n = 24 n = 24 n = 26 n = 26 n = 25 13M/11F 12M/12F 12M/14F 13M/13F 12M/13F

R (min) 7.7 (4.5-11.6) 8.3 (5.7-10.9) 7.8 (5.3-11.0) 6.9 (3.8-11.1) 7.5 (5.3-9.3)K (min) 1.8 (1.2-2.3) 2.0 (1.4-3.3) 2.0 (1.4-2.8) 1.9 (1.2-2.9) 2.0 (1.4-3.5)α (°) 66.5 (58.8-73.4) 63.6 (53.8-70.3) 63.9 (54.3-70.7) 65.1 (54.9-73.2) 64.3 (48.8-72.2)MA (mm) 67.2 (60.7-73.2) 65.2 (57.6-71.3) 65.0 (57.3-72.8) 66.5 (56.8-74.4) 63.0 (55.3-69.3)LY30 (%) 3.8 (0.3-8.4) 3.0 (0.2-7.8) 3.3 (0.2-6.2) 3.7 (0.5-8.0) 4.3 (0.8-8.6)

NOTES: M, males; F, females; R, reaction time; K, coagulation time; α, measure of the rate of clot formation; MA, maximum ampli-tude; LY30, percentage lysis 30 min post-MA.aResults are expressed as the mean and boundary encompassing 95% of the population.Source: Reprinted with permission from Chan K-L, Summerhayes RG, Ignjatovic V, Horton SB, Monagle PT. Reference values for kaolin-activated thromboelastography in healthy children. Anesth Analg. 2007;105:1610-1613, table 1. Copyright 2007 International Anesthesia Research Society, Lippincott Williams & Wilkins.




also important with its role to reinforce the platelet plug but often requires time to obtain the result. POC fibrinogen levels have yet to provide the accu-racy to substitute for the laboratory-derived fibrin-ogen levels. Because the APTT is affected by both heparin and hemodilution, it is the least useful of the RCTs to determine clotting factor levels and so guide transfusion.

The TEG complements the use of RCT in the management of transfusion during ECMO because it examines not only the initiation but also the strength of clotting. It is valuable because it simultaneously examines three critical parts of the coagulation sys-tem, platelet function, clotting factors, and fibrin-olysis. This is possible because the TEG is conducted in whole blood, not plasma. The endpoint for the plasma-based RCTs is the start of fibrin strand for-mation, but the TEG runs until clot formation and dissolution occur.

The TEG has greatly expanded its capabilities as a POC coagulation test with previously described changes. The activated TEG has enabled clinicians to make more rapid decisions about transfusion resulting in more timely administration of blood products. Although TEG studies have been con-ducted with three activators, kaolin, celite, and TF, kaolin is the only commercially available activator. The kTEG produces a result 20 to 30 minutes sooner than the 1 hour necessary for a native TEG. TF added to the TEG can produce clot in 6.5 minutes.65

It is very important to realize that the normal ranges of the native TEG are changed with activators but the patterns remain similar. Typically, the r and K values are most affected and shorten significantly with activation compared with the native TEG. Clot strength is increased so the maximum amplitude (MA) and angle are appreciably bigger. However, each activator may change the normal range of the native TEG slightly different from one another. Miller et al65 looked at neonates and infants under-going CPB with the celite- and TF-activated TEG to identify any correlation between a faster TEG with activators and RCT. These activators shortened time to clotting but did not change the MA and angle much. It is important to recognize the differences in the TEG ranges with activation, but a working knowledge of the native TEG values and patterns45 is just as important to manage transfusion during ECMO. Many times TEG pattern recognition of the traces will aid in determination of fibrinolysis or plate-let dysfunction before values are known.

Age also affects the normal range of both native and activated TEG values. In individuals younger than 12 months of age, all the normal ranges for the TEG differ from adult values.13 In fact, differences exist between birth and 12 months. Miller et al66 reported differences in the normal ranges during these ages <30 days, 1 to 3 months, 3 to 6 months, 6 to 12 months, and 1 to 2 years in a study of pedi-atric patients undergoing cardiac surgery. Recently, the reference values of the kTEG were reported in 100 healthy children from 1 month to 16 years and 25 adults (Table 3).67 Even with studies that report TEG values, each hospital may have slightly differ-ent normal ranges for the TEG. It is important to verify the normal ranges with the hospital’s refer-ence laboratory to published values to insure accurate interpretation of the TEG.65,66

In 1994, Tuman et al68 used the hTEG to provide a fully formed tracing during CPB and demonstrated the impact of heparin on not only the r but also the K, MA, and angle of the TEG. Heparinase cannot completely restore the TEG to its original form if large systemic doses of heparin are present.68 The lower systemic amounts of heparin favor the use of the hTEG in management of transfusion during ECMO.

Another benefit of the TEG for ECMO manage-ment relates to its sensitivity to detect fibrinolysis compared with RCT. The RCT, such as d-dimer levels are not specific for fibrinolysis during EC, but its detection is very important because excessive bleeding has been highly correlated with it in car-diac patients with CPB.65 More compelling was the difference in the incidence of fibrinolysis in pediat-ric and adult patients of 14% and 1%, respectively, with the hTEG.

Transfusion requirements associated with ECMO may be very high.3,23 Improvements in perioperative transfusion management of both adults and children undergoing cardiac surgery with CPB have resulted in less bleeding and lower transfusions with utiliza-tion of algorithm-based transfusion practice.56,65,69 Unfortunately, there is no evidence for algorithm-based transfusion during ECMO in part because anticoagulation is maintained instead of reversed and potential subjects are few compared with cardiac surgery and CPB. The following recommendations for transfusion with ECMO will be a compilation of opinion, anecdotal information and generalization from experience with CPB.

Platelet transfusion represents a major part of management of ECMO patients. The effect of EC




on platelet function and number has been well documented.32,62,70-73 Severe thrombocytopenia con-sistently occurs with the onset of ECMO especially in neonates and infants but often increases after 24 hours on ECMO.58 Moreover, many patients are placed on ECMO after cardiac surgery so that plate-let function and number are poor prior to ECMO. If bleeding is excessive on ECMO, platelet transfusion is largely based on PC. The degree of thrombocy-topenia that triggers platelet transfusion varies among institutions and physicians. The more criti-cally ill the patient, the more likely platelets have been given. In our institution, the PC is maintained in a range of 45 to 65 109/L in concert with minimal to mild bleeding. The PC is important as reported by Muntean,21 who found a significant relationship between PC and bleeding complications on ECMO especially in neonates.

Following CPB, platelets are no longer exposed to the effects of surface activation and heparin acti-vation so that indications to guide platelet trans-fusions have developed.56 In contrast with ECMO, platelets are constantly exposed to activation from the EC and heparin resulting in recurrent platelet dysfunction. This is expressed during ECMO by fre-quent platelet transfusions even with “normal” PC.74 Although PC may largely direct platelet transfusion, determination of platelet function may be beneficial. The measurement of platelet function during CPB and ECMO is imperfect because the gold standard of platelet function, a platelet aggregation study, is not clinically available. Consequently, the TEG has been incorporated as a POC measure of platelet function. It has been recognized by The Society of Thoracic Surgeons and Society of Cardiovascular Anesthesiologists as an important test to obtain in post-CPB patients prior to platelet transfusion to improve care.75

The value of TEG for transfusion of platelets is its ability to measure the integrity of platelet activity and number and the beginning of the fibrin–platelet interactions. The TEG angle also measures the rate of clot formation that reflects platelet and fibrinogen interaction. Finally, the MA of the TEG represents the summation of fibrinogen and platelets interact-ing with factors XIII and VIII.13

To evaluate platelet function during ECMO, both the kTEG and hTEG are run simultaneously in a scheduled fashion throughout its duration. A fully formed kTEG will be generated in contrast to CPB with higher heparin dosing. The hTEG will generate

a TEG unaffected by heparin. Depending on the MAs, angles and current PC and PT values, differences between the values are attributed to some degree of platelet dysfunction. Differences between tracing with respect to clotting factors is more difficult to discern, so a PT is used to estimate the role of factor deficiency.56 We would refrain from transfusion of platelets with a PC of 45 to 65 109/L if the angle of the hTEG was >25° or MA of the hTEG >40 mm. The combination of TEG, PC, and PT may minimize platelet transfusions based on PC alone and there-fore extend the life of the oxygenator.

Transfusion of clotting factors is more frequently based on PT and fibrinogen levels than the TEG. Although the level of factors to achieve clotting in general has been acknowledged to be 25% to 30%, it may not apply during ECMO. We use the interna-tional normalized ratio (INR) to guide the transfu-sion of clotting factors attempting to maintain it at ≤1.3. Although FFP contains most of the clot-ting factors, it is not concentrated in any of them. This is nicely demonstrated by the finding of signifi-cantly greater bleeding after CPB with FFP than cryoprecipitate in infants randomize to FFP or cryo-precipitate for excessive bleeding.63 The inability of FFP to raise factor levels during ECMO without large volumes was similarly demonstrated.21 However, if bleeding is minimal, FFP may play a role during ECMO as it provides enough volume to maintain adequate flow with the EC and maintain good osmo-lality to minimize edema. However, it should not be used as volume replacement if the coagulation tests are normal.

Fibrinogen, although one of the clotting factors, is discussed separately because it is intimately con-nected to clot formation with platelets and so is very critical to clot formations. Its importance compared with other clotting factors was nicely demonstrated in an animal model where 65% of the blood volume was replaced with a gelatin solution.76 Normalization of the RoTEG values, representing the integrity of the coagulation, was achieved rapidly with 50% less bleeding by the addition of fibrinogen alone despite the reduced levels of other factors.

Laboratory determination of fibrinogen is impor-tant for management of transfusion during ECMO. Levels of fibrinogen < 50 mg/dL commonly occur in neonates and infants during CPB62 and ECMO.58 Muntean21 has recommended maintaining a fibrinogen level of 100 mg/dL during ECMO. A higher concentration may be needed depending on




prior cardiac surgery or refractory bleeding. These low fibrinogen levels may carry even greater signifi-cance in those younger than 12 months of age because there is a functional immaturity compared with adults.77 This is supported by the significantly reduced bleeding after CPB in infants that received cryoprecipitate instead of FFP.63 The donated cryo-precipitate contained mature fibrinogen to replace the immature fibrinogen of infants.

Apart from the laboratory fibrinogen test, the TEG is useful test to determine fibrinogen require-ments. A prolonged r with the kTEG cannot distin-guish between low fibrinogen and heparin, but a prolonged r with hTEG is consistent with low fibrin-ogen. Recently, TEG abnormalities in infants follow-ing CPB have shown a tendency to correlate better with fibrinogen level than PC.77 Soon, availability of the RoTEG, may greatly improve the ability to separate out effects on the TEG tracing between low fibrinogen and platelets with a special technique unique to the RoTEG.69

It is important to be cognizant with transfusion of blood products during ECMO, administration of cryoprecipitate with platelet concentrates may greatly increase the risk of thrombus and thromboembolic complications so should be given separately at differ-ent times.

If bleeding during ECMO is refractory to admin-istration of blood products, other forms of therapy may be cautiously considered. Fibrinolysis is a known risk factor for excessive bleeding. Antifibrinolytics have been used successfully following CPB with the onset of fibrinolysis and excessive bleeding to sig-nificantly reduce bleeding compared with control.78 There are not studies that evaluate antifibrinolytic treatment for new onset of fibrinolysis during ECMO. It is essential that one use the TEG for diagnosis, as RCTs are not specific. The initiation of an antifibrinolytic during ECMO is risky and has resulted in massive thrombosis and death.79 Prothrombin complex concentrates have not only been effective with excessive bleeding in cardiac surgery but have also resulted in fatal thrombosis during ECMO.80 We do not recommend prothrom-bin complex concentrates even if the levels of vita-min K factors are low. Finally, recombinant activated factor VII (rVIIa) (Novoseven; NovoNordisk, Copenhagen, Denmark) has recently been used off label to control refractory bleeding following cardiac surgery.81 Although the mechanism of action is inde-terminate, it appears to enhance hemostasis at the

site of injury without activating systemic coagula-tion. It may bind to TF on cells at the site of injury that then stimulate thrombin generation at the bleeding sites. Recombinant activated factor VII can initiate thrombin generation without TF on the sur-face of platelets, which also arrive at sites of injury.

The efficacy of rVIIa for intractable bleeding dur-ing CPB has been mixed.81-83 Agarwal et al81 studied 46 neonates and infants, who had cardiac surgery and severe bleeding, over a period of 5 years. A total of 96% of the patients responded with signifi-cantly reduced mediastinal chest tube drainage and transfusion requirements. Chest tube drainage was reduced by 60% after rVIIa and the PT fell from 19.9 ± 1.6 to 13.5 ± 1.9 seconds (P < .001) and PRBCs were significantly reduced. Others have found no reduction in transfusion or reduced time to close the chest.82 The administration of rVII during ECMO has been successful in anecdotal and case series to control refractory bleeding.84,85

Dosing of rVIIa for cardiac surgery has been established at 90 µg/kg whereas for ECMO it is 50 to 60 µg/kg, in part to reduce the risk of widespread thrombosis.81 Unlike CPB patients, 70% of pediat-ric and ECMO patients were treated successfully with one dose. The overall dosing was almost half of the conventional dosing especially lower doses were given in the ECMO patients. The authors suggested 30 to 50 µg/kg for each dose every 2 to 4 hours to control serious refractory bleeding.

The concern for massive clotting with the use of rVIIa and ECMO is great as the risk of thrombosis is high for ECMO even without administration of rVIIa. The occurrence of fatal thrombosis with rVIIa during ECMO is well described.86 However, in a recent retrospective study looking specifically at con-genital heart surgical patients that required ECMO,83 rVIIa was well tolerated and significantly affected persistent hemorrhage without evidence of throm-bosis. Another retrospective unmatched case control study with 46 neonates and infants over a period of 5 years that had cardiac surgery with severe bleeding reported 10% of the patients developed serious thrombosis compared with controls.81 One can pos-tulate that the availability of TF and platelets during ECMO may be very high and continue to rise such that there may be a high circulating level of TF beyond the TF primarily located on the ECMO sur-face. Therefore, with the administration of rVIIa, both the intravascular space and the surface of cir-cuit clot instantaneously.




The risk of thrombosis with rVIIa during ECMO must be evaluated in the context of other procoagu-lant factors. The risk may greatly increase if other procoagulant treatments are combined with it such as antifibrinolytics or prothrombin complex concen-trates.80 If rVIIa is given during ECMO, the circuit before and after administration must be examined to detect any new clots that may predispose to a more serious thrombosis. High pressures in the circuit after rVIIa should immediately cause alert for major clotting in the oxygenator. Recently, there is evidence that the RoTEG may be used to monitor rVIIa in these situations providing some ability to monitor the situation before it becomes life threatening.40

Finally, the transfusion or PRBC is a compli-cated topic that requires a definition for the critical hemoglobin. The critical hemoglobin for transfu-sion of PRBC during ECMO is influenced by the level of bleeding, congenital heart disease, myocar-dial function, preoperative hemoglobin, ECMO flow, neurologic status, and a host of other factors. The management of PRBC transfusion is beyond the scope of this article but is an important part of transfusion management.

Future of ECMO

Management of anticoagulation and transfusion for ECMO continues to evolve but very slowly. Randomized trials and studies to find the best prac-tice are unlikely for the reasons given earlier. New technology is being used increasingly but again stud-ies to confirm efficacy are difficult. Unfortunately, treatment for bleeding is easier to diagnose and treat compared with thromboembolic events. Improved methods to recognize the level of thrombin forma-tion at the bedside would improve the care of these patients and possibly prevent neurologic injury. ECMO is a major commitment of resources to a patient com-plicated by a number of problems that require a multidisciplinary team approach to achieve the best outcomes.

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