Patients with cirrhosis have profound alterations of hemostasis that include thrombocytopenia and increased level of Von Willebrand factor, reduced levels of most procoagulant factors and inhibitors, and complex changes in fibrinolysis. Current theory posits that these changes result in a rebalanced hemostatic state that is maintained by a simultaneous decline in both pro and anti-hemostatic drivers. This equilibrium, however, becomes susceptible to perturbations and easily shifts towards either hypo-coagulability (increased risk of bleeding) or hyper-coagulability (increased risk of thrombosis). Understanding the hemostatic alterations associated with cirrhosis and its complications would improve the management of bleeding and thrombosis in these patients. In this two-part project, we extensively investigated alterations of hemostasis driven by two common complications observed in patients with cirrhosis, that is acute kidney injury (AKI) and hepatocellular carcinoma (HCC). In study part #1, we demonstrated that AKI is associated with complex hemostatic changes including both prohemorrhagic and prothrombotic features. On one hand, AKI was associated with platelet dysfunction, low FXIII, and hyper-fibrinolytic alterations (increased bleeding tendency), while on the other hand AKI was associated with increased FVIII, reduced anticoagulants, and hypo-fibrinolytic defects (increased thrombotic tendency). These data support the association between AKI and post-paracentesis hemoperitoneum seen in patients with decompensated cirrhosis, and reinforce the importance of treating AKI in these patients. In fact, optimization of renal function may help to restore the hemostatic balance and mitigate bleeding and thrombotic risks. In study part #2, we demonstrated that HCC in cirrhosis is associated with a more pronounced hypercoagulable profile due to increased platelet aggregation, activation of coagulation and plasmatic hypercoagulability, and reduced activation of fibrinolysis. These hypercoagulable changes provide explanation for the increased risk of portal vein thrombosis in patients with cirrhosis and HCC, and reinforce the need for studies on prophylactic anticoagulation for the prevention of thrombotic complications in these patients.
I pazienti con cirrosi hanno profonde alterazioni dell’emostasi. Queste alterazioni includono ridotta conta piastrinica ed incremento del fattore di Von Willebrand, ridotti livelli di fattori pro ed anticoagulanti, e alterazioni della fibrinolisi. Ne deriva che l’equilibrio emostatico nei pazienti con cirrosi è fragile e suscettibile a perturbazioni esterne che possono spingerlo verso l’ipo-coagulabilità (aumentato rischio di emorragia) o l’iper-coagulabilità (aumentato rischio di trombosi). Valutare le alterazioni dell’emostasi associate alla cirrosi e alle sue complicanze potrebbe migliorare la gestione delle complicanze emorragiche e trombotiche in questi pazienti. In questa studio, abbiamo valutato le alterazioni emostatiche indotte da due frequenti complicazioni associate alla cirrosi: l’insufficienza renale acuta e l'epatocarcinoma. Nella prima parte dello studio, abbiamo dimostrato che l’insufficienza renale acuta è associata a complesse alterazioni emostatiche sia in senso pro-emorragico (disfunzione piastrinica, ridotto livello di FXIII, e iper-fibrinolisi) sia pro-trombotiche (aumentato livello di FVIII, ridotti anticoagulanti, e ipo-fibrinolisi). Questi dati supportano l’associazione fra insufficienza renale acuta e rischio di emoperitoneo post-paracentesi nei pazienti con cirrosi scompensata, e rinforzano la necessità di trattamento proattivo dell’insufficienza renale acuta nei pazienti con cirrosi sottoposti a procedure invasive. Infatti, il miglioramento della funzione renale potrebbe ridurre i rischi di emorragia e trombosi. Nella seconda parte della tesi, abbiamo dimostrato che l’epatocarcinoma nei pazienti con cirrosi è associato ad un più significativo stato iper-coagulabile dovuto ad aumentata aggregazione piastrinica, attivazione della coagulazione e iper-coagulabilità plasmatica, e ridotta attivazione della fibrinolisi. Questi cambiamenti iper-coagulabili supportano l’associazione tra epatocarcinoma e aumentato rischio di trombosi venosa portale nei pazienti con cirrosi ed epatocarcinoma, e rinforzano la necessità di studi clinici per valutare l'eventuale utilizzo di terapia anticoagulante profilattica per prevenire la comparsa di complicanze trombotiche in questi pazienti.
Squilibrio emostatico nei pazienti con cirrosi: il ruolo di insufficienza renale acuta ed epatocarcinoma
ZANETTO, ALBERTO
2022
Abstract
Patients with cirrhosis have profound alterations of hemostasis that include thrombocytopenia and increased level of Von Willebrand factor, reduced levels of most procoagulant factors and inhibitors, and complex changes in fibrinolysis. Current theory posits that these changes result in a rebalanced hemostatic state that is maintained by a simultaneous decline in both pro and anti-hemostatic drivers. This equilibrium, however, becomes susceptible to perturbations and easily shifts towards either hypo-coagulability (increased risk of bleeding) or hyper-coagulability (increased risk of thrombosis). Understanding the hemostatic alterations associated with cirrhosis and its complications would improve the management of bleeding and thrombosis in these patients. In this two-part project, we extensively investigated alterations of hemostasis driven by two common complications observed in patients with cirrhosis, that is acute kidney injury (AKI) and hepatocellular carcinoma (HCC). In study part #1, we demonstrated that AKI is associated with complex hemostatic changes including both prohemorrhagic and prothrombotic features. On one hand, AKI was associated with platelet dysfunction, low FXIII, and hyper-fibrinolytic alterations (increased bleeding tendency), while on the other hand AKI was associated with increased FVIII, reduced anticoagulants, and hypo-fibrinolytic defects (increased thrombotic tendency). These data support the association between AKI and post-paracentesis hemoperitoneum seen in patients with decompensated cirrhosis, and reinforce the importance of treating AKI in these patients. In fact, optimization of renal function may help to restore the hemostatic balance and mitigate bleeding and thrombotic risks. In study part #2, we demonstrated that HCC in cirrhosis is associated with a more pronounced hypercoagulable profile due to increased platelet aggregation, activation of coagulation and plasmatic hypercoagulability, and reduced activation of fibrinolysis. These hypercoagulable changes provide explanation for the increased risk of portal vein thrombosis in patients with cirrhosis and HCC, and reinforce the need for studies on prophylactic anticoagulation for the prevention of thrombotic complications in these patients.File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.14242/218140
URN:NBN:IT:UNIPD-218140