Andersons pediatric cardiology 1914

including factors II, V, VII, and X, and coagulant inhibitors, such as protein C, protein S, plasminogen, and antithrombin III.138–141 An elevated level of factor VIII is a strong risk f

including factors II, V, VII, and X, and coagulant inhibitors, such as protein C, protein S, plasminogen, and antithrombin III.138–141 An elevated level of factor VIII is a strong risk factor for venous thromboembolism in the normal adult population, with a predicted incidence of recurrent thrombosis of more than 10% per year in those with increased serum levels.142 Longitudinal studies monitoring serum factor VIII levels in patients with a functionally univentricular heart have demonstrated a conversion from low serum levels early in the course of staged reconstruction, to significantly raised levels after Fontan completion.143

Increased factor VIII activity correlates with higher superior vena cava pressure

in the Fontan circulation.143 As such, it is hypothesized that increased pressure transmitted to the liver sinusoidal endothelium leads to the upregulation of factor VIII synthesis.144 Thrombocytopenia may also contribute, particularly if related

to heparin treatment, in which it may be associated with a high risk of

thrombosis,145 or when associated with portal hypertension and failure of the Fontan circulation (see Fontan Failure) Lastly, progressive endothelial

dysfunction develops with prolonged exposure to the Fontan circulation Even well-functioning adult patients may have underlying endothelial dysfunction, indicated by increased plasma concentrations of endothelin-1146 and abnormal digital pulse amplitude tonometry.147 This multitude of factors leads to the high incidence of thromboembolic events that contribute to significant morbidity and mortality early and late after Fontan surgery

FIG 73.18 Coronal plane magnetic resonance imaging in a patient with a

large thrombus within the extracardiac Fontan pathway The red dots show

the location of the thrombus (From Kutty S, Rathod RH, Danford DA, Celermajer DS Role of imaging in the evaluation of single ventricle with the

Fontan palliation Heart 2016;102[3]:174–183.)

Immunologic Abnormalities

Many children with a functionally univentricular heart have immunologic

anomalies on routine laboratory investigations, the most common being

lymphopenia that predominantly involves CD4 T cells Absolute lymphocyte counts decrease with time after the Fontan operation Patients who are more than

10 years post-Fontan surgery have been found to be four times as likely to have significant lymphopenia as compared with patients in the first decade post

Fontan.148 However, the clinical significance of these findings is unclear because there does not appear to be an increase in opportunistic infections even in the setting of significant lymphopenia Increased lymphatic recirculation may be a compensatory mechanism, allowing for preservation of normal tissue-level T-cell function even in the setting of low cell counts Nevertheless, there is an abnormally high incidence of atopy (approximately 60%), suggesting abnormal

The most significant deficiencies were noted in patients with PLE (see later), although lymphopenia occurs even in the absence of PLE All patients with PLE are lymphopenic, with preferential loss of T cells (CD4 more than CD8) but preservation of normal levels of B and natural killer cells.149,150

Hypogammaglobulinemia is common, mainly affecting immunoglobulin G (IgG) and IgA levels.147,148

Patients with PLE have higher rates of nonresponsiveness to vaccination, particularly to hepatitis B and measles, mumps, and rubella,150,151 and may require repeated vaccinations and avoidance of live vaccines Some advocate for

antibiotic prophylaxis against opportunistic infections such as Pneumocystis jirovecii and Mycobacterium avium, although supporting clinical evidence is

lacking.150 In assessing the immunocompromised state of patients with PLE, confounding factors such as malnutrition and the side effects of

immunosuppressive therapies should also be considered

Renal Dysfunction

Late survivors of the Fontan surgery invariably experience multiorgan sequelae including progressive liver dysfunction and PLE; however, the long-term

progression of their renal function is poorly understood The early occurrence of acute kidney injury is currently well recognized following complex surgical reconstruction in the neonate, with increasing evidence of late renal dysfunction

in these patients (see Chapter 78) In addition, in the Fontan circulation, there is reduced renal perfusion as the chronic elevation of CVP increases efferent

arteriolar pressure Glomerular filtration pressure is also increased, leading to a high incidence of microalbuminuria In a small retrospective cohort study of 21 patients at mean 11 years post-Fontan completion, almost half the group had an increased urine microalbumin/creatinine ratio.152 A strong correlation between urine microalbumin/ creatinine ratio and superior vena cava mean pressure was also demonstrated

Microalbuminuria may be a more sensitive indicator of early renal disease than the estimated glomerular filtration rate (eGFR) In a review of 68 patients a decade after Fontan completion, 90% had a normal eGFR (eGFR >90 mL/min per 1.73 m2) but more than 40% had microalbuminuria.153 Furthermore, serum creatinine may not be a reliable indicator of kidney function in this population Fontan patients often have a lower muscle mass and are relatively malnourished,