1073 90 Thrombosis in Pediatric Critical Care SALLY CAMPBELL AND PAUL MONAGLE • Vascular access devices are the most common cause of throm boembolic disease in children; thus, every attempt should be[.]
90 Thrombosis in Pediatric Critical Care SA LLY CAMPBELL AND PAUL MONAGLE PEARLS • • • Vascular access devices are the most common cause of thromboembolic disease in children; thus, every attempt should be made to limit their use based on real clinical need Thrombophilia is rarely the major cause of thrombosis in critically ill children; multiple tests to identify thrombophilic states are rarely useful for patient management For reasons that remain uncertain, heparin-induced thrombocytopenia is rarely seen in children Dramatic improvements in pediatric intensive care have led to the improved survival of critically ill children and to the emergence of previously rare complications In order to achieve this improved survival, there has been a dramatic increase in the invasiveness of supportive care The use of central venous access, invasive arterial monitoring, and circulatory support, including ventricular assist devices (VADs) and extracorporeal membrane oxygenation (ECMO), as well as processes such as hemofiltration and hemodialysis, which are performed through large-bore vascular access devices, increases the likelihood of vascular endothelial damage or direct vascular obstruction Thrombosis may develop within these artificial circuits that can subsequently embolize into the systemic circulation These insults to the vascular system are often combined with prolonged hypotension, systemic inflammatory states, and infection, all of which may alter endothelial and vascular responsiveness Finally, there are a multitude of drugs and fluids administered during the periods of critical illness that can impact directly on plasma proteins and endothelial function or that may lead to dilution of critical plasma proteins involved in the coagulation system Not surprisingly, therefore, thromboembolism is an increasingly common problem faced in the pediatric intensive care setting, contributing significantly to morbidity and mortality This chapter describes key issues related to thrombosis in the pediatric intensive care unit (PICU) Developmental hemostasis is a crucial concept both to the understanding of the etiology of thrombosis in children and to the application of diagnostic and therapeutic strategies The etiology, epidemiology, clinical features, diagnosis, and management of the major types of thrombosis encountered in children in the intensive care unit (ICU) are discussed However, thrombosis of the central nervous system (CNS), including arterial ischemic stroke and cerebral sinovenous thrombosis, are beyond the scope of this chapter (see Chapter 66) • • Care must be taken in the diagnosis of thrombosis in children, as assumptions made in adult diagnostic strategies may not be true in children Unfractionated heparin is the most useful anticoagulant in critically ill children However, dosing errors are common, and pediatric intensive care units should spend considerable resources on training and systems to ensure safe management of heparin As in many areas of pediatrics, high-level evidence is often lacking; however, best available evidence is cited when possible Extrapolation from adult studies resulting in suboptimal treatment outcomes in children highlights the need for pediatricspecific trials and guidelines Developmental Hemostasis The hemostatic system is a dynamic, evolving entity that not only affects the frequency and natural history of thromboembolic disease in children but also the response to therapeutic agents.1–5 The global functioning of the coagulation system in neonates and children is different from adults, as are the plasma levels of many coagulation proteins.6 Overall, the levels of most coagulation proteins increase with age; neonates compared with adults have significantly lower levels of these proteins The exceptions to this are FV, FVIII, FXIII, and vWF, which are elevated at birth compared with adults In addition to quantitative differences, there is evidence of qualitative differences in many coagulation proteins, especially in neonates.7 This is in the context of the entire plasma proteome being dramatically different in children compared with adults.8 More recently, differences in platelets and cellular interactions have been described that may be of clinical significance.9,10 Although ongoing research in this area is desperately needed, current knowledge regarding the differences between adults and children in plasma proteins most likely to impact on anticoagulation therapy is as follows Plasma concentrations of antithrombin (AT) are physiologically low at birth (,0.50 U/mL) and not increase to adult values until months of age.3 Sick premature neonates frequently have plasma levels of AT of less than 0.30 U/mL This likely has an effect on the action of heparin, whose antithrombotic activity 1073 1074 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology is dependent on catalysis of AT to inactivate specific coagulation enzymes—in particular, thrombin Some studies suggest that children in PICUs have markedly reduced AT levels compared with age-matched controls, potentially further enhancing this effect (eFig 90.1) The capacity of plasmas from neonates to generate thrombin is both delayed and decreased compared with adults and is similar to plasma from adults receiving therapeutic amounts of heparin.11 Both an increased sensitivity and an increased resistance to unfractionated heparin’s anticoagulant activities have been reported in vitro in plasma from neonates Increased sensitivity to unfractionated heparin is observed in systems based on assays dependent on thrombin generation (e.g., activated partial thromboplastin time [aPTT]) The in vitro effects of unfractionated heparin (0.25 U/mL) on neonates, children, and adults were compared recently Thrombin generation was delayed and reduced in children compared with adults and virtually absent in neonates.12 Resistance to unfractionated heparin is observed in systems based on assays that measure the inhibition of exogenously added factor Xa or thrombin and that are dependent on plasma concentrations of AT In vitro, thrombin generation is similar in adults and children at the same concentration of low-molecular-weight heparin (LMWH) However, at 0.25 U/mL LMWH, thrombin generation was delayed and reduced by approximately half in newborns compared with adults These differences were matched by reductions in rates of prothrombin consumption.12 The vitamin K–dependent clotting factors are the most extensively studied group of factors in infants Factors II, VII, IX, and X have been demonstrated to be one-half to one-third that of adults despite receiving vitamin K prophylaxis at birth The levels of the vitamin K–dependent factors and the contact factors (factors XI and XII, prekallikrein, and high-molecular-weight kininogen) gradually increase to values approaching adult levels by months of life For children receiving vitamin K antagonists, the capacity of their plasmas to generate thrombin is delayed and decreased by 25% compared with plasmas from adults with similar international normalized ratios.13 Whether the overall activity of the protein C/protein S system varies with age is unknown However, at birth, plasma concentrations of protein C are very low, and they remain decreased during the first months of life Although total amounts of protein S are decreased at birth, functional activity is similar to that in the adult because protein S is completely present in the free, active form owing to the absence of C4-binding protein.14,15 a2-Macroglobulin appears to play a substantially increased role in thrombin regulation in children compared with adults.16 Plasma concentrations of thrombomodulin are increased in early childhood and decrease to adult values by late teenage years However, the influence of age on endothelial cell expression of thrombomodulin has not been determined.17 Total tissue factor pathway inhibitor (TFPI) levels in newborns are reported as being similar to levels in older children or adults Free TFPI is reported as being significantly lower in newborns.18 Despite the changes in individual protein levels and in global tests of coagulation, the hemostatic system in neonates and children does not seem disadvantageous compared with the “normal” coagulation system as measured in adults There are no data to support either an increased bleeding or thrombotic risk during infancy and childhood for any given stimulus; on the contrary, one could argue that the hemostatic system in neonates and children is protective against bleeding and thrombotic complications compared with adults This is despite the fact that, when considering individual proteins, many proteins exist at levels during stages of infancy that would be associated with disease in adults There clearly remains much to be learned about the evolution of the coagulation system with age, and this is an area in which there is much ongoing active research As a better understanding of the neonatal and child coagulation system is achieved over the coming years, thinking may change regarding many aspects of thrombosis development and management in this patient population Etiology and Epidemiology Unlike adults, 95% of venous thromboembolisms (VTEs) in children are secondary to an identifiable risk factor.19 While there are a variety of risk factors to consider, perhaps the most useful concept for the clinician to understand remains Virchow's triad Virchow's triad recognizes that three factors are involved in the development of thrombosis: the blood vessel wall, blood constituents, and blood flow20 (Fig 90.2) Patients in the PICU often demonstrate abnormalities in one, two, or all of these factors; the recognition of this can be a useful guide to therapy For example, in a patient with a cardiac lesion, either primary or postsurgical, where there is extremely poor blood flow in one part of the cardiovascular system, the optimal management is to improve the blood flow While anticoagulation may have an important role, progressively increasing the intensity of anticoagulation will significantly increase the risk of bleeding and yet may not substantially further reduce the risk of thrombosis, which is being driven primarily by flow Alternatively, patients with disseminated intravascular coagulation (DIC) have a marked perturbation of function of the vascular endothelium Therefore, anticoagulation alone is unlikely to prevent thrombotic complications, which will be avoided only by treatment of the primary illness and subsequent resolution of the DIC Combinations of these factors are important in many instances For example, central venous access is a common precipitant of thrombosis most often through interruption to flow (especially in small infants in whom the catheter-to-vein diameter ratio is close to 1:1) and through disruption of the vessel wall at the insertion site However, thrombosis is seen more commonly when there is an additional abnormality in the blood constituents as well, for example, in protein-losing states such as nephrotic syndrome or enteropathy, or through inflammatory or septic conditions, or via drugs such as oral contraceptives Consideration of the etiologic factors in this way often enables clinicians to make Vessel wall Thrombosis Blood composition Blood flow • Fig 90.2 Virchow's triad, highlighting the importance of each factor in contributing to thrombosis formation 1074.e1 180 PICU patients Healthy children 160 Antithrombin (%) 140 120 100 80 60 40 20