Thrombin generation in patients with cirrhosis: The role of platelets

Abstract

Coagulation factor defects, thrombocytopenia, and thrombocytopathy are associated with cirrhosis. However, bleeding in patients who have cirrhosis does not entirely correlate with abnormal coagulation tests. Recently, it was shown that because of the concomitant abnormalities of the procoagulant and anticoagulant drives, thrombin generation in plasma patients with cirrhosis is normal when assessed with assays that include thrombomodulin (the main protein C activator). However, thrombin is also generated in vivo as a function of platelets, suggesting that thrombocytopenia and thrombocytopathy might affect thrombin generation in patients with cirrhosis. We addressed this issue using an assay that accounts for the contribution of plasma and platelets. The study showed that platelet-rich plasma with platelets adjusted by dilution of autologous platelet-rich into autologous platelet-poor plasma to a standard count (100 ؋ 10 9 /L) generates as much thrombin in patients with cirrhosis as in controls (1,063 nmol/L vs. 1,167 nmol/L; P value not significant). When platelets were adjusted to correspond to whole-blood counts, patients with cirrhosis generated significantly less thrombin than controls (949 nmol/L vs. 1,239 nmol/L; P < .001). Furthermore, thrombin generation correlated with platelet numbers ( ‫؍‬ 0.50; P < .001). In addition, the amount of thrombin generated as a function of the whole-blood patients' platelet counts increased significantly when the numbers were adjusted to 100 ؋ 10 9 /L (953 nmol/L vs.1,063 nmol/L; P < .001). In conclusion, severe thrombocytopenia may limit thrombin generation in patients with cirrhosis. These findings might justify platelet transfusion in patients with low platelet counts when they bleed spontaneously or before undergoing surgery or liver biopsy. Controlled clinical trials supporting this indication are warranted. (HEPATOLOGY 2006;44:440-445.)

Hemostatic balance in patients with liver cirrhosis: Report of a consensus conference

“…When the platelet count was adjusted to a standard value of 100 × 10 9 /L, platelet-rich plasma from patients with cirrhosis generated in vitro as much thrombin as that of healthy subjects [12]. Although the benefit of platelet infusion to avoid bleeding in cirrhotics has never been assessed in clinical trials, counts of 60 × 10 9 /L are considered sufficient to secure in vitro thrombin generation at the lower reference limit [12]. In hepatitis C-related cirrhosis, platelet numbers of ≤60 × 10 9 /L were associated with an increased risk of procedurerelated bleeding [13].…”

“…In patients with cirrhosis an adequate amount of thrombin is generated in vitro when platelet counts approximate 50-60 × 10 9 /L, optimal levels being seen with counts >100 × 10 9 /L [12]. However, the clinical value of these thresholds remains obscure, as at lower counts interaction of platelets with coagulation pathways is still seen in vivo.…”

Portal Vein Thrombosis in Cirrhosis

“…22 Patients with cirrhosis also suffer from defects of platelet function and number that can contribute to a bleeding tendency. 23 However, the platelet defects get balanced by increased levels of factor VIIIa/vWF, which increases platelet adhesion. 24 Three recent independent studies have been published specifically evaluating the prevalence of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with cirrhosis.…”

Anticoagulation in chronic liver disease

“…The interaction between liver injury and the coagulation cascade is multi-faceted and complex (Borensztajn et al, 2010). On the one hand, coagulopathy is a well-documented sequel of chronic liver failure; conversely, evidence is increasingly emerging which supports pro-fibrotic states as being prothrombotic, and that activation of the coagulation cascade has a role in the generation of chronic liver injury.Advanced fibrosis is associated with impaired synthesis of all clotting factors, except Factor VIII and von Willebrand factor (Tripodi et al, 2005;Tripodi et al, 2006). This defect is demonstrated by prolongation of the prothrombin time (PT) and the activated partial thromboplastin time (APTT), tests which both represent the status of procoagulant proteins synthesised by the liver.…”

“…Advanced fibrosis is associated with impaired synthesis of all clotting factors, except Factor VIII and von Willebrand factor (Tripodi et al, 2005;Tripodi et al, 2006). This defect is demonstrated by prolongation of the prothrombin time (PT) and the activated partial thromboplastin time (APTT), tests which both represent the status of procoagulant proteins synthesised by the liver.…”