title: Detection of the imbalance of procoagulant versus anticoagulant factors in cirrhosis by a simple laboratory method.
abstract: Patients with cirrhosis possess an imbalance in procoagulant versus anticoagulant activity due to increased factor VIII and decreased protein C. This imbalance can be detected by thrombin-generation assays performed in the presence/absence of thrombomodulin (predicate assay) that are not readily available in clinical laboratories. We sought to assess this hypercoagulability with a simpler thrombin-generation assay performed in the presence/absence of Protac, a snake venom that activates protein C in a manner similar to thrombomodulin (new assay). We analyzed blood from 105 patients with cirrhosis and 105 healthy subjects (controls). Results for the predicate-assay or the new-assay were expressed as ratio (with:without thrombomodulin) or as Protac-induced coagulation inhibition (PICI%). By definition, high ratios or low PICI% translate into hypercoagulability. The median(range) PICI% was lower in patients (74% [31%-97%]) than controls (93% [72%-99%]; P < 0.001), indicating that patients with cirrhosis are resistant to the action of Protac. This resistance resulted in greater plasma hypercoagulability in patients who were Child class C than those who were A or B. The hypercoagulability of Child C cirrhosis (63% [31%-92%]) was similar to that observed for patients with factor V Leiden (69% [15%-80%]; P = 0.59). The PICI% values were correlated with the levels of protein C (rho = 0.728, P < 0.001) or factor VIII (rho = -0.517, P < 0.001). Finally, the PICI% values were correlated with the predicate assay (rho = -0.580, P < 0.001).
  
  
  CONCLUSIONS
  The hypercoagulability of plasma from patients with cirrhosis can be detected with the new assay, which compares favorably with the other markers of hypercoagulability (i.e., high factor VIII and low protein C) and with the predicate-assay based on thrombin-generation with/without thrombomodulin. Advantages of the new assay over the predicate assay are easy performance and standardized results. Prospective trials are needed to ascertain whether it is useful to predict thrombosis in patients with cirrhosis.
authors.affiliation: Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Department of Internal Medicine and Medical Specialties, Università degli Studi di Milano, Milan, Italy. armando.tripodi@unimi.it
authors.forename: Armando
authors.initials: A
authors.lastname: Tripodi
authors.forename: Massimo
authors.initials: M
authors.lastname: Primignani
authors.forename: Laura
authors.initials: L
authors.lastname: Lemma
authors.forename: Veena
authors.initials: V
authors.lastname: Chantarangkul
authors.forename: Alessandra
authors.initials: A
authors.lastname: Dell'Era
authors.forename: Francesca
authors.initials: F
authors.lastname: Iannuzzi
authors.forename: Alessio
authors.initials: A
authors.lastname: Aghemo
authors.forename: Pier Mannuccio
authors.initials: PM
authors.lastname: Mannucci
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001777:Blood Coagulation; D001780:Blood Coagulation Tests; D005169:Factor VIII / Q000032:analysis*; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008103:Liver Cirrhosis / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000737:chemistry*; D011486:Protein C / Q000032:analysis*; D013917:Thrombin / Q000032:analysis*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D011486:Protein C; C049647:snake venom protein C activator; D005169:Factor VIII; D013917:Thrombin