Modulation of endothelial cell inflammatory integrins and stress markers with rh-factor VIIa in patients with advanced chronic hepatitis C.
Individuals with chronic hepatitis C (CHC) progress to cirrhosis and hepatic cancer. Individuals with advanced CHC are coagulopathic and can manifest fibrinolysis. The coagulopathy is a consequence of hepatocytic dysfunction. The fibrinolysis represents a response to local endothelial cell injury, and is of a low-grade. Based upon this hypothesis, the effect of the infusion of recombinant human factor VIIa (rh-FVIIa) on endothelial cell inflammatory integrins and measures of endothelial stress were determined in 17 individuals with advanced CHC. Immediately prior to the infusion of rh-FVIIa, the plasma levels of tissue factor (TF), Thrombomodulin (TM), human soluble ICAM-1 (hs-ICAM-1), human soluble VCAM-1 (hs-VCAM-1), human soluble L-Selectin (hs-L-Selectin), the prothrombin time and the activated partial thromboplastin time were determined. The same parameters were assayed at 5, 10, 30, 120, 240 and 360 min after infusion. TF and TM levels were very high at baseline consistent with a vascular endothelial stress response. Similarly hs-ICAM-1, hs-VCAM-1 as well as L-Selectin levels were increased. Thirty minutes after the infusion, a marked reduction in ICAM-1 and VCAM-1 and to a lesser degree L-Selectin levels was observed. This reduction persisted for 360 min. No change in measures of fibrinolysis [plasminogen activator inhibitor-1 (PAI-1), total tissue factor pathway inhibitor (t-TFPI), activated tissue factor pathway inhibitor (TFPIa), d-dimers (DD), FSP and fibrinogen levels] occurred. In addition, no change in plasma Annexin-V was observed. Based upon these data it can be concluded that: (1) rh-FVIIa corrects the coagulopathy seen in advanced CHC; (2) reduces endothelial cell injury and/or stress as evidenced by the TF, TM, hs-ICAM-1 and hs-VCAM-1 levels in plasma; (3) these changes in coagulation occurred without inducing a propagated vascular thrombosis.
Van Thiel
D H
DH
Loyola University (Chicago), Stritch School of Medicine, Maywood, IL 60153, USA. dvanthi@lumc.edu
Anantharaju
A
A
Mindikoglu
A L
AL
Shah
N
N
Leone
N
N
Bejna
J
J
Tarasuk
G
G
Todo
A
A
Mobarhan
S
S
George
M
M
D000328:Adult; D000368:Aged; D017304:Annexin A5 / Q000097:blood; D015415:Biomarkers / Q000097:blood*; D016022:Case-Control Studies; D019040:E-Selectin / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D015942:Factor VIIa / Q000627:therapeutic use*; D005260:Female; D019698:Hepatitis C, Chronic / Q000097:blood* / Q000188:drug therapy*; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood*; D016023:Integrins / Q000097:blood*; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D008297:Male; D008875:Middle Aged; D011336:Probability; D012016:Reference Values; D012307:Risk Factors; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D013312:Stress, Physiological; D018180:Thrombomodulin / Q000097:blood; D013925:Thromboplastin
D017304:Annexin A5; D015415:Biomarkers; D019040:E-Selectin; D018836:Inflammation Mediators; D016023:Integrins; D018180:Thrombomodulin; D018799:Intercellular Adhesion Molecule-1; D013925:Thromboplastin; D015942:Factor VIIa