Abstract
Objectives: thromboembolic complications are a major cause of morbidity and mortality following Fontan (FO) surgery. It is also well established that altered FO circulation results in systemic complications, including liver and endothelium damage. We sought to evaluate whether dysfunctions of these sources of hemostatic factors may result in changes of fibrin clot properties. Methods: a permeation coefficient (Ks) and clot lysis time (CLT) were assessed in 66 FO patients, aged 23.0 years [IQR 19.3–27.0], and 59 controls, aged 24.0 years [IQR 19.0–29.0]. Ks was determined using a pressure-driven system. CLT value was measured according to assay described by Pieters et al. Endothelium and liver-derived hemostatic factors along with liver function parameters were evaluated. The median time between FO operation and investigation was 20.5 years [IQR 16.3–22.0]. Results: FO patients had lower Ks (p = 0.005) and prolonged CLT (p < 0.001) compared to that of controls. Ks correlated with CLT (r = −0.28), FVIII (r = −0.30), FIX (r = −0.38), fibrinogen (r = −0.41), ALT (r = −0.25), AST (r = −0.26), GGTP (r = −0.27) and vWF antigen (r = −0.30), (all p < 0.05). CLT correlated with the time between FO operation and investigation (r = 0.29) and FIX (r = 0.25), (all p < 0.05). After adjustment for potential cofounders, TAFI antigen and GGTP were independent predictors of reduced Ks (OR 1.041 per 1% increase, 95% CI 1.009–1.081, p = 0.011 and OR 1.025 per 1 U/L increase, 95% CI 1.005–1.053, p = 0.033, respectively). Protein C and LDL cholesterol predicted prolonged CLT (OR 1.078 per 1% increase, 95% CI 1.027–1.153, p = 0.001 and OR 6.360 per 1 μmol/L increase, 95% CI 1.492–39.894, p = 0.011, respectively). Whereas elevated tPA was associated with lower risk of prolonged CLT (OR 0.550 per 1 ng/mL, 95% CI 0.314–0.854, p = 0.004). GGTP correlated positively with time between FO surgery and investigation (r = 0.25, p = 0.045) and patients with abnormal elevated GGTP activity (n = 28, 42.4%) had decreased Ks, compared to that of the others (5.9 × 10−9 cm2 vs. 6.8 × 10−9 cm2, p = 0.042). Conclusion: our study shows that cellular liver damage and endothelial injury were associated with prothrombotic clot phenotype reflected by Ks and CLT.
Highlights
The Fontan (FO) procedure is the end-stage palliation for patients with univentricular physiology and it considerably improved survival rates [1,2]
Our study revealed that cellular liver damage, reflected by noninvasive liver function tests and endothelial injury were associated with prothrombotic clot phenotype in adults following FO surgery
Hepatic disorders, which are common in FO patients, are caused by hemodynamic disturbances and systemic venous congestion following FO surgery
Summary
The Fontan (FO) procedure is the end-stage palliation for patients with univentricular physiology and it considerably improved survival rates [1,2]. It was speculated that impaired function of endothelium as well as cellular liver damage, commonly observed in adults with FO physiology, might at least partly explain these unfortunate events [6,7,8,9,10]. Several factors, including the geometry of the fibrin network define fibrin clot architecture, which is a key determinant of the efficiency of clot lysis [13,14]. Permeability of the clot, reflected by fibrin porosity and its structural design, might be determined by the permeation coefficient (Ks ). Reduced Ks is a typical feature of the prothrombotic fibrin clot phenotype, which is associated with faster formation of denser fibrin mesh, relatively resistant to lysis [13,15]. Increased CLT value is a manifestation of hypofibrinolysis and might predispose to both venous and arterial thrombosis [16,17]
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