Properties of Plasma Clots in Adult Patients Following Fontan Procedure: Relation to Clot Permeability and Lysis Time—Multicenter Study

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.

Role of red blood cells in hemostasis and whole blood clot contraction in adults after Fontan procedure

“…Almost all patients after the Fontan procedure develop chronic liver disease, which progress over time [9,10,13]. Hepatic dysfunction in our study was reflected by higher levels of GGT and AST with subsequent deficiency of coagulation factors synthesized in the liver [1,2,9,10,13]. In the current study we showed that hepatic dysfunction contributes to reduced clot contraction and polyhedrocytes formation.…”

“…Results of our study may support the concept that liver dysfunction may play a major role in abnormal clot function in Fontan patients. Almost all patients after the Fontan procedure develop chronic liver disease, which progress over time [9,10,13]. Hepatic dysfunction in our study was reflected by higher levels of GGT and AST with subsequent deficiency of coagulation factors synthesized in the liver [1,2,9,10,13].…”

“…However, the clinical relevance of polyhedrocytes is currently investigated. Taking into account high incidence of polyglobulia and a nonpulsatile flow in the Fontan circulation (FC) further research is highly encouraged [1,2,[9][10][11].…”

Fibrin clot permeability (Ks) in patients on left ventricular assist device

“…Patients with Fontan circulation had lower Ks values than controls, and a low Ks value was associated with lower levels of protein C, protein S, and albumin. As in the group of LVAD patients the Ks correlated negatively with brinogen concentration and factor VIII activity 23 .…”

Thromboembolic Complications in Adult Patients Following Fontan Procedure—A Multicenter Study

“…Well-known risk factors for the development of TEC include chronic venous congestion, high prevalence of supraventricular arrhythmias, the presence of prosthetic material, residual intracardiac shunt, or protein-losing enteropathy [6,7]. We have already shown that adult FO patients are also characterized by hepatic dysfunction as well as enhanced platelet activation, endothelial injury, and impaired fibrinolysis [8,9].…”