Platelet dysfunction during pediatric cardiac ECMO

Platelet dysfunction during pediatric cardiac ECMO

Journal Pre-proof Platelet dysfunction during pediatric cardiac ECMO Katherine Cashen, Amarilis Martin PII: S1058-9813(19)30098-0 DOI: https://doi...

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Journal Pre-proof Platelet dysfunction during pediatric cardiac ECMO

Katherine Cashen, Amarilis Martin PII:

S1058-9813(19)30098-0

DOI:

https://doi.org/10.1016/j.ppedcard.2019.101187

Reference:

PPC 101187

To appear in:

Progress in Pediatric Cardiology

Received date:

21 October 2019

Revised date:

11 December 2019

Accepted date:

16 December 2019

Please cite this article as: K. Cashen and A. Martin, Platelet dysfunction during pediatric cardiac ECMO, Progress in Pediatric Cardiology(2019), https://doi.org/10.1016/ j.ppedcard.2019.101187

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

© 2019 Published by Elsevier.

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Platelet Dysfunction during Pediatric Cardiac ECMO Katherine Cashen DOa, Amarilis Martin MDa

Affiliations: aDivision of Critical Care, Department of Pediatrics, Children's Hospital of

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Michigan/Wayne State University School of Medicine, Detroit, MI

Corresponding Author: aKatherine Cashen DO, Division of Critical Care Medicine,

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Children’s Hospital of Michigan, 3901 Beaubien Carl’s Building Suite 4105, Detroit, MI

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48201. Phone (313)745-5629 Fax (313) 966-0105. [email protected]

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Contact Information: Amarilis Martin MD, Division of Critical Care Medicine, Children’s Hospital of Michigan, 3901 Beaubien, Detroit, MI 48201. Phone (313) 966-

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7579 Fax (313) 966-0105. [email protected]

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Abstract Pediatric extracorporeal membrane oxygenation (ECMO) is used for respiratory and cardiac failure refractory to conventional treatment. ECMO has been increasingly utilized for pediatric cardiac patients. Despite improved mortality, complications during and after ECMO are high and bleeding may be life threatening. Pediatric cardiac patients are at high

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risk for bleeding due to anticoagulation, surgery, and acquired platelet dysfunction. In this review, we focus on the many mechanisms contributing to platelet dysfunction, available

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monitoring of platelet function, what is known about platelet count and transfusion,

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treatment of bleeding, and future steps needed to improve our care for this patient

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population.

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Key Words: extracorporeal membrane oxygenation, congenital heart disease, platelet dysfunction, cardiopulmonary bypass Introduction Pediatric cardiac extracorporeal membrane oxygenation (ECMO) has been used for children with cardiac failure since the 1970s(1). In July 2019, the Extracorporeal Life

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Support Organization (ELSO) Registry reported between 1990 and 2019, 8,498 neonatal cardiac patients (<30 days of age) underwent ECMO with 43% survival to discharge. An

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additional 1,923 neonates underwent Extracorporeal Cardiopulmonary Resuscitation

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(ECPR) with 42% survival to discharge. An even larger number of pediatric cardiac

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patients, 11,839 children (30 days of age up to 19 years of age) were placed on ECMO with

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52% survival. Pediatric ECPR had a 42% survival rate for the 4,608 patients supported (2). Most pediatric cardiac patients are placed on ECMO during the peri-operative period

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surrounding palliative or corrective surgery for congenital cardiac defects (3). Indications

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for veno-arterial (VA) ECMO continue to increase but despite growing experience and improved technology mortality has remained unchanged and morbidity is high.(4).

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Pediatric cardiac ECMO patients are at high risk for bleeding. In a large multicenter prospective study, (the Bleeding and Thrombosis during ECMO (BATE) study), performed by the Collaborative Pediatric Critical Care Research Network 70% of children had a bleeding event during ECMO(5). Of these bleeding events 16% consisted of intracranial hemorrhages. The BATE cohort included 207 patients placed on ECMO for cardiac indications and 70 patients placed on ECPR. Children placed on ECMO for a cardiac indication and children placed on for ECPR had higher risk of bleeding than the

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respiratory cohort. Irrespective of the indication, bleeding events during ECMO were associated with increased mortality(5). Bleeding during ECMO is caused by a multitude of factors. Anticoagulation during ECMO, hemostatic alterations due to the underlying disease process, patient related factors, and the ECMO circuit all contribute to bleeding risk. Acquired platelet dysfunction, both

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quantitative and qualitative contributes to risk of bleeding. Pediatric cardiac ECMO patients are even more susceptible to platelet dysfunction and bleeding than respiratory ECMO

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patients (4,6). In this review, we describe hemostatic alterations during cardiac critical

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illness and ECMO. We then review what is known about platelet dysfunction in the

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pediatric cardiac population, platelet dysfunction during and after cardiopulmonary bypass,

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ECMO, platelet transfusion thresholds, and functional assays used to measure platelet activity. Finally, we discuss potential treatments for bleeding and next steps to improve our

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care for this patient population.

Hemostatic Alterations During Critical Illness and ECMO

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The balance between procoagulant and anticoagulant factors is altered during critical illness. Primary hemostasis due to platelet activation followed by aggregation and platelet plug formation (7) and secondary hemostasis which includes the coagulation pathway and fibrin generation (8-9) may be affected. Critical illness and inflammation are associated with simultaneous increased risk of thrombosis and bleeding (9) The ECMO circuit is made up of a mechanical blood pump, gas exchange device, heat exchange device, tubing and cannulas. In venoarterial (VA) ECMO blood is drained from the venous circulation, pumped through the circuit where gas exchange (oxygenation 4

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and carbon dioxide clearance) is performed then returned to the arterial circulation. Figure 1 depicts a neonate on VA ECMO. Cannulation can be performed peripherally via cervical or femoral vessels or centrally with central cannulation carrying the highest bleeding risk. Activation of the coagulation and inflammatory pathways occur when blood is exposed to the non-endothelial surface of the ECMO tubing.(11-13).

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This activation consists of activation of platelets, factor XII, tissue factor, von Willebrand factor (VWF) and fibrinolysis (14-18). Cellular damage from shear stress from the pump,

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hemolysis, thrombosis and acquired VWD contribute to ongoing hemostatic alterations.

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Children placed on ECMO after cardiac surgery are at even higher risk of bleeding than

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children with other indications for ECMO (5). These children may have underlying platelet

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dysfunction, acquired platelet dysfunction from cardiopulmonary bypass and ECMO. In

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addition, they must undergo systemic anticoagulation for ECMO.

Platelet Dysfunction in Cardiac Patients

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Platelets are small anucleated cells that are critical for hemostasis. Specific differences exist

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between neonatal and adult platelets (9). Other contributions to platelet dysfunction in pediatric cardiac patients include genetic conditions, medication effects and cardiopulmonary bypass (Table 1.) Neonates Neonatal platelets are hyporeactive when exposed to physiologic agonists (19-21). But, despite hyporeactivity the bleeding time and platelet closure time (markers of platelet function which includes the contribution of VWF activity) are shortened (22). These findings suggest that the higher levels of VWF and larger VWF multimers increase the

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adhesive ability of platelets and compensate for the hyporeactivity (19-21). Thus, although there are developmental changes in platelet function and concentration of VWF in a healthy neonate hemostasis is maintained. But, in critical illness seen in cardiac neonates this equilibrium will be disrupted and bleeding or thrombosis may occur. Genetics

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Children with congenital heart disease (CHD) are more likely than the general population to have inherited and acquired thrombocytopenia. Numerous genes have been implicated in

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the development of CHD and thrombocytopenia. Amegakaryocytic thrombocytopenia with

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radio-ulnar synostosis, thrombocytopenia-absent radius syndrome, Noonan syndrome, and

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Jacobsen syndrome are associated with CHD and thrombocytopenia (23). In addition,

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Trisomy 21 is associated with thrombocytopenia and CHD (24). In Trisomy 21, the thrombocytopenia is generally mild and not associated with increased risk of bleeding (24).

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Overall many children with genetic syndromes and chromosomal disorders have both CHD

Medications

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and disorders of platelet production or function.

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Many children with CHD are treated with anti-platelet agents. Aspirin is used most commonly followed by clopidogrel and dipyridamole. In addition, commonly employed medications for cardiac patients including nitric oxide, milrinone, nonsteroidal antiinflammatory drugs, and certain antibiotics which can all cause platelet dysfunction (25). These medication exposures in addition to the systemic anticoagulation during ECMO contribute to bleeding complications. Cardiopulmonary Bypass

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Cardiopulmonary bypass (CPB) causes widespread activation of the hemostatic system. This activation occurs due to several mechanisms including the contact system, fibrinolysis, inflammation, and platelet activation (26). Platelets bind to fibrinogen that is already bound to the CPB circuit and become activated releasing granules and microparticles (27-28). Microparticles, or microvesicles, are small circulating fragments of platelet plasma

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membranes that participate in thrombus formation. Evidence shows that CPB increases levels of β-thrombogloblin, platelet factor 4, platelet P-selectin, GMP140, which are all

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markers of platelet activation (29-32). In addition, leukocytes may stimulate tissue factor

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release from platelets (27). At the onset of CPB, initial exposure of platelets to the circuit

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causes platelet activation and a decrease in platelet count. and Shear stress from the CPB

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tubing and pump causes platelets to bind VWF, release microparticles and lead to thrombus formation. Eventually, this continuous activation may lead to platelet exhaustion and

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decreased function. Platelets are diluted and decreased platelet aggregation has been

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reported after CPB (33). Thrombocytopenia from platelet consumption and qualitative platelet dysfunction occurs during CPB due to alteration in platelet receptors critical for

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adhesion (34). Longer duration of CPB is associated with a larger decrease in platelet count and decreased platelet function (35). In summary, CPB leads to initial platelet activation followed by both quantitative and qualitative platelet dysfunction.

Platelet Dysfunction during ECMO Circuit Activation The ECMO circuit is similar to the CPB circuit. Platelets adhere and are activated by the non-endothelial tubing of the ECMO circuit (36). Similar to CPB, increased markers of 7

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platelet activation and degranulation have been reported during ECMO (37-39). Saini and colleagues reported severe qualitative platelet dysfunction in children during ECMO measured by thromboelastography (TEG)-platelet mapping (PM) (40). Others have reported persistently decreased platelet aggregation during ECMO even after platelet transfusion (38,41). In these studies, platelet function took 8-24 hours after decannulation

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to normalize suggesting that it cannot be easily reversed by transfusion or decannulation (38,41).

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Von Willebrand Factor

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Von Willebrand Factor (VWF) plays an important role in clot formation. This

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plasma glycoprotein binds to FVIII, platelet surface glycoproteins and collagen and forms a

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complex with FVIII that protects it from degradation by activated protein C and aids in platelet plug and clot formation (42). During ECMO, shear stress results in loss of high

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molecular weight VWF multimers which may result in acquired VWD and increased

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bleeding complications (43-44). Platelet Count and Transfusion

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Decreased platelet count (<150 x109/L) has been reported in up to 30% of children in the Pediatric Intensive Care unit (45-46). The neonatal population similarly reports rates of 18-35% in Neonatal Intensive Care units (47-48). The incidence in the neonatal and pediatric cardiac population is not well described. Multiple studies describe a decrease in platelet count soon after initiation of ECMO (38). In a large multicenter study performed by the Collaborative Pediatric Critical Care Research Network (CPCCRN), neonates had a larger decline in median platelet count than pediatric patients after ECMO initiation (49). Neonates received higher average daily 8

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platelet transfusion volume than pediatric patients and certain patient characteristics, location of ECMO care, mode of ECMO and acute and chronic diagnoses were associated with increased average daily platelet transfusion volume. In this study, average daily platelet count was not independently associated with mortality but platelet transfusion volume was. The authors hypothesized that the absolute platelet count was less important

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than the transfused volume of platelets suggesting that ongoing platelet consumption, harmful effects of transfused platelets, or other unmeasured variables were associated with

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mortality (49). An association with platelet transfusion volume and bleeding and

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thrombotic complications was reported (49). While bleeding and platelet transfusion

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volume are highly correlated, average daily platelet transfusion volume was the strongest

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predictor of mortality in the multivariable model. While platelet transfusion during pediatric ECMO is common practice, it is important to recognize it may be adversely

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Platelet Function Assays

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associated with complications and mortality.

Measurements of platelet function are challenging in the pediatric population due to

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the relatively large volume of blood required to perform these assays and technical expertise required. Aggregometry, thromboelastography (TEG®) or TEG-PM, and rotational thromboelastometry (ROTEM®) have been utilized and a study utilizing platelet function analysis (PFA-100/200) is also currently underway in the pediatric population (ClinicalTrials.gov Identifier: NCT00748878). Table 2 details a few of these tests and their benefits and limitations. A recent review of platelet function during pediatric ECMO found only three studies that assessed platelet function in pediatric ECMO patients (50). Of these three studies, only one included patients with cardiac disease (pulmonary hypertension, 9

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myocarditis, and post-operative CHD) (50). This study reported increased mortality and severe bleeding in patients with significant platelet dysfunction (40). Multiple gaps in our knowledge exist regarding platelet function and pediatric ECMO and even more gaps exist in the pediatric cardiac population. Additional considerations

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Other factors that may contribute to platelet dysfunction during pediatric cardiac ECMO are uremia from renal failure, need for continuous renal replacement therapy

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(CRRT), and hemolysis.

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Bleeding during Cardiac ECMO

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Bleeding occurs commonly during pediatric ECMO and risk factors include cardiac ECMO and ECPR and direct transition from CPB to ECMO (5). In a large single center

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study, a diagnosis of CHD was associated with a significantly higher odds ratio of daily

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bleeding compared to a respiratory or other cardiac diagnosis (6). Central cannulation, older age, and lower platelets were associated with increased bleeding days and these patients

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had increased mortality (6).

The management of bleeding depends on the site and cause. Pulmonary hemorrhage, gastrointestinal bleeding, and genitourinary bleeding occur rarely (4,5). Cannula and surgical site bleeding occur most commonly in post-operative cardiac patients (5). Chest tube bleeding is also common in the cardiac population. Typically local site bleeding is treated with direct pressure followed by surgical intervention if local measures are ineffective. Decreasing anticoagulant dose and transfusion of blood products to correct deficiencies may be indicated. Increasing target thresholds for platelet count and fibrinogen 10

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is often employed but the efficacy of this practice is unclear. Consideration of acquired VWD, FXIII deficiency, and heparin induced thrombocytopenia should be considered when bleeding does not respond to decreased anticoagulation and replacement of deficient blood products. In a recent review of the Pediatric Cardiac Critical Care Consortium Registry

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(PC4), the most frequent complication during ECMO in post-surgical cardiac patients was bleeding requiring re-operation (25.2%) and unplanned re-operation (22.5%) (51). In the

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medical cardiac patients, stroke (15%), need for CRRT (15%), and intracranial hemorrhage

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(11.7%) were the most common complications (51). Thus, surgical and medical cardiac

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patients have different complications but the severity of these complications is similar.

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Others report using antifibrinolytic agents like aminocaproic acid and tranexamic acid intravenously to manage surgical site bleeding. These medications have been reported

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more commonly in the congenital diaphragmatic hernia population. Reports of recombinant

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factor VII (rVIIa) and Prothrombin Complex Concentrate (PCC) have been associated with thrombosis, and suggest that these agents should only be used in severe refractory bleeding

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during ECMO (52-53).

Next Steps Circuit modifications including heparin-coated circuits, nitric oxide embedded surfaces and newer oxygenators that cause less platelet and leukocyte activation are under development (54). Optimal transfusion thresholds, anticoagulants, and monitoring are unknown. Additional studies focused on platelet function and transfusion thresholds are needed. In 2019, a group of experts from the Pediatric Cardiac Intensive Care Society (PCICS) 11

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developed a two part roadmap to identify management and research goals to address bleeding and thrombosis during pediatric ECMO (55-56). This group of experts proposes standardizing definitions of bleeding and thrombosis, standardizing ECMO equipment and anticoagulation practice as much as possible. The hope would then be to identify a “best

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practice” based on practice at centers with the best clinical outcome (56).

Conclusion

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Platelet dysfunction both quantitative and qualitative is common during pediatric

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ECMO. Cardiac ECMO patients are at high risk of platelet dysfunction which contributes

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to their risk of bleeding. Other factors contribute to this bleeding risk including need for

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anticoagulation during ECMO, hemostatic alterations due to the underlying diagnosis, exposure to CPB, surgical sites, and acquired platelet dysfunction from the ECMO circuit.

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Bleeding requiring re-operation was common in a large multicenter cohort of postoperative

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pediatric cardiac surgical patients and intracranial hemorrhage was high in the medical cardiac patients (51). While many risk factors for bleeding have been identified, the optimal

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platelet count, transfusion threshold, anticoagulation strategy, and laboratory monitoring to mitigate the risk of bleeding is unknown. Circuit modifications and additional research focused on these knowledge gaps are sorely needed to combat the acquired platelet dysfunction and risk of bleeding seen in pediatric cardiac ECMO patients.

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55. Penk JS, Reddy S, Polito A, et al. Bleeding and thrombosis with pediatric extracorporeal life support: a roadmap for management, research and the future from the Pediatric Cardiac Intensive Care Society (Part 1). Pediatr Crit Care Med 2019; epub ahead of print 56. Penk JS, Reddy S, Polito A, et al. Bleeding and thrombosis with pediatric extracorporeal life support: a roadmap for management, research and the future from the Pediatric Cardiac Intensive Care Society (Part Two). Pediatr Crit Care Med 2019; epub ahead of print

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Figure 1. Neonatal venoarterial ECMO Schematic

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ECMO Circuit o Activation from circuit contact o Inflammation o Thrombin generation o Endothelial dysfunction o Platelet activation and consumption leading to thrombus generation o Acquired factor XIII deficiency o Acquired von Willebrand deficiency

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Antiplatelet Agents o Aspirin o Clopidogrel o Dipyridamole o GP IIb/IIIa antagonists

Complications o Bleeding o Hemolysis o Organ dysfunction o Thrombosis

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Genomics o Hematologic disorders o Genetic syndromes (e.g., Trisomy 21)

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Table 1. Factors Contributing to Platelet Dysfunction in Pediatric Cardiac Patients Inherent Medications Mechanical Other Age Anticoagulants Surgery Transfusion o Immature o UFH (e.g., o Bleeding o Thresholds vary coagulation variable patient o Inflammatory o Transfusion system in the response, HIT) state reactions neonatal period o LMWH o Changes in o Direct thrombin hematological inhibitors characteristics o Warfarin throughout development

Critical Illness o Sepsis o Systemic inflammatory state o Immune and hematologic system crosstalk

Other Medications o Histamine-2 receptor antagonists o Milrinone o Nitric oxide

Other Mechanical Devices o CPB o CVVHD o Plasmapheresis

CPB (cardiopulmonary bypass), CVVHD (continuous veno-venous hemodiafiltration), HIT (heparin-induced thrombocytopenia), LMWH (low molecular weight heparin), UFH (unfractionated heparin) 18

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Measures Platelet Aggregation

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Advanced, widely employed

Platelet Activation: thrombopoiesis, and effects of antiplatelet therapy

Screening test

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Platelet enzyme-linked immunosorbent assay (ELISA)

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Flow cytometry

Limitation LTA-Large blood volumes, special expertise in interpretation, time consuming WBIsmaller volume of blood required than LTA, faster time but operator variability is still a concern Expensive, requires highly specialized instrument

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Table 2. Platelet function tests Test Benefit Aggregometry (Light LTA-Gold transmission (LTA), standard whole blood impedance aggregometry (WBI))

Thromboelastography (TEG®), TEG®-Platelet mapping and ROTEM Platelet Test

Visoelastic changes of the entire clotting process

Platelet function analyzer-100/200

Most widely used, simple, rapid technique, small amount of whole blood

Needs further validation

Platelet Adhesion/Activation

Insensitive to changes in platelet function but with platelet mapping may add more information Depends on concentrations of vWF and hematocrit (both are variable during ECMO) lack of specificity

Hemostatic potential and risk of bleeding, information about platelet function and aggregation Platelet function

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Highlights

Pediatric cardiac ECMO has a 52% survival rate.



Bleeding during ECMO is common and associated with acquired platelet dysfunction.



Optimal platelet count, transfusion threshold, and monitoring during pediatric cardiac ECMO is not known.



Of the three studies that measured platelet function during pediatric ECMO, only one included cardiac ECMO patients.



Platelet transfusion volume and platelet dysfunction have been associated with increased mortality in pediatric ECMO patients.



Additional studies are needed to improve our care of this complex patient population.

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