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............................................................................................................................................................................. eventually Eisenmenger syndrome (see sections 3.4.3 and 4.15). They may present with or without prior palliative intervention. Cyanotic patients are complex and must be followed by an ACHD specialist.

3.4.8.1 Adaptive mechanisms Cyanosis induces adaptive mechanisms to improve oxygen transport and delivery to the tissue: secondary erythrocytosis, rightward shift of the oxyhaemoglobin dissociation curve, and increase in cardiac output.82,83 Erythrocytosis secondary to erythropoietin stimulus is the physiological response to chronic hypoxaemia. Compensated erythrocytosis reflects an equilibrium and decompensated erythrocytosis indicates failure of an equilibrium (excessive red blood cell/haemoglobin increase and unstable, rising haematocrit with major hyperviscosity symptoms).82,84

3.4.8.2 Multisystem disorder Cyanosis and secondary erythrocytosis imply profound consequences for the entire organ system:82,84,85 • Blood viscosity is increased and is directly related to red blood cell mass.84 • Haemostatic abnormalities are common and complex and are attributed to abnormalities in platelets (thrombocytopaenia and thrombasthenia), coagulation pathways, and other abnormal coagulation mechanisms. Vitamin K-dependent clotting factors and factor V are reduced, fibrinolytic activity is increased, and the largest von Willebrand multimers are depleted. • Increased turnover of red blood cells/haemoglobin and impaired urate filtration lead to hyperuricaemia.86 The increased concentration of unconjugated bilirubin puts cyanotic patients at risk for calcium bilirubinate gallstones. • Severe endothelial dysfunction is evident by the striking impairment of endothelium-dependent vasodilation.85 • Chronic hypoxaemia, increased blood viscosity, and endothelial dysfunction affect microcirculation, myocardial function, and the function of other organ systems.

3.4.8.3 Clinical presentation and natural history Clinical presentation includes central cyanosis, a result of an increased quantity of reduced haemoglobin (>5 g/100 mL blood), clubbing, and frequently scoliosis. The underlying anatomy/pathophysiology characterizes cardiac findings. Mortality is significantly higher in cyanotic patients than in acyanotic patients.87 Outcome is determined by the underlying anatomy, pathophysiology, palliative procedures, complications of cyanosis, and preventive measures.88,89 Low platelet count, severe hypoxia, cardiomegaly, and elevated haematocrit during childhood are parameters to predict premature death and adverse events in patients with and without PVD.90 Iron deficiency is associated with adverse late outcome;91,92 BNP can predict outcome in Eisenmenger patients.93,94 However, in a multicentre study,89 only age, pre-tricuspid shunt, absence of sinus rhythm, lower oxygen saturation at rest, and presence of pericardial effusion, but not BNP, were the strongest predictors for death.

3.4.8.4 Late complications

• Hyperviscosity symptoms include headache, faintness, dizziness, fatigue, tinnitus, blurred vision, paraesthesia of fingers, toes, and lips, muscle pain, and weakness (classified moderate when they interfere with some activities, severe when they interfere with most activities).82,83 Hyperviscosity symptoms are unlikely in an iron-replete patient with haematocrit <65%. • Bleeding and thrombotic diathesis occur; both cause a therapeutic dilemma (risks of thrombosis and bleeding). Spontaneous bleeding is usually minor, self-limiting (dental bleeding, epistaxis, easy bruising, menorrhagia). Haemoptysis is the most common major bleeding event and is an external manifestation of an intrapulmonary haemorrhage not reflecting the extent of parenchymal bleeding (reported in up to 100% of Eisenmenger patients).95,96 Thrombosis is caused by coagulation abnormalities, stasis of blood in dilated chambers and vessels, atherosclerosis and/or endothelial dysfunction, the presence of thrombogenic material (e.g. conduits), and arrhythmias. The haemostatic abnormalities do not protect against thrombotic complications. Laminated thrombi in large, partially calcified and aneurysmal PAs are common (up to 30%).97100 Female sex, low oxygen saturation, older age, biventricular dysfunction, and dilated PAs have been identified as risk factors.97,100,101

• Cerebrovascular infarctions are common, but underreported.97

They may be caused by thromboembolic events (paradoxical embolism, supraventricular arrhythmia), rheological factors (microcytosis), endothelial dysfunction, and traditional atherosclerotic risk factors. The severity of secondary erythrocytosis is not in itself a risk factor.102 Microcytosis caused by iron deficiency, due to inappropriate phlebotomies, was the strongest independent predictor for cerebrovascular events in one study.91 Severity of cyanosis and CHD complexity are other risk factors.97 • Paradoxical emboli may be caused by transvenous leads or catheters. • Iron deficiency is frequently caused by, and may be exacerbated by, inappropriate phlebotomies or heavy menstruation in female patients. • Arrhythmias  supraventricular and ventricular. • Infectious complications include endocarditis, cerebral abscess, and pneumonia. Fever, associated with a new or different headache, raises suspicion of a brain abscess. • Renal dysfunction is common and is due to functional and structural abnormalities of the kidneys. • Cholelithiasis is common and can be complicated by cholecystitis/choledocholithiasis. • Rheumatological complications include gouty arthritis, hypertrophic osteoarthropathy, and kyphoscoliosis.83 3.4.8.5 Diagnostic aspects Particular attention must be paid to hyperviscosity symptoms and bleeding/ischaemic complications. Oxygen saturation must be obtained with pulse oximetry at rest for at least 5 min, and exercise capacity should be assessed on a regular basis, preferably with a 6MWT. Blood work must include cellular blood count, mean corpuscular volume (MCV), serum ferritin (serum iron, iron saturation, transferrin, and transferrin saturation may be required for earlier detection of iron deficiency), creatinine, serum uric acid, clotting profile, BNP/ NT-pro-BNP, folic acid, and vitamin B12 in the presence of elevated MCV or normal MCV and low serum ferritin. Downloaded from academic.oup.com/eurheartj/article/42/6/563/5898606 by guest on 07 October 2026