Synthesis of clotting factors by the isolated perfused rat liver.

Abstract

The liver has been proposed as a site of synthesis of blood-clotting factors, in part because of the demonstrated dominant role of the liver in synthesis of all plasma protein fractions except the y-globulins (1, 2). In addition, observations after hepatectomy (3, 4) and hepatic injury (5, 6) and in hepatic disease (7,8) have provided a body of evidence consistent with hepatic synthesis of fibrinogen, prothrombin, and Factors V, VII, IX, and X. This evidence, however, has not been considered definitive, mainly because it is based on indirect observations in vivo in humans and in animals suffering from variable, often profound, metabolic abnormalities induced by hepatic dysfunction or extirpation.This report describes the use of the isolated perfused rat liver in a more direct experimental evaluation of the role of the liver in the production of blood-clotting factors. The use of the isolated perfused liver was encouraged by Lupton's observations of shortened prothrombin time during perfusions of 3 to 4 hours (9), and by Pool and Robinson's studies of changes in clotting factor activity during in vitro incubation of rat liver slices (10). Presented here is not only more detailed direct evidence of hepatic synthesis of prothrombin and Factor VII, but also the first direct evidence for hepatic synthesis of Factors V and X.

Tissue Factor Activity in Lymphocyte Cultures from Normal Individuals and Patients with Hemophilia A

“…Although it appeared that procoagulant activity persisted longer than tissue factor activity, the procoagulant activity was completely inhibited by incubation with the antibody to tissue factor. In all experiments where tissue factor was generated by the lymphocytes, the material was completely inhibited by the rabbit antihuman tissue factor antibody (Table II) (47,48), the site of production of factor VIII is unknown. Perfusion studies of livers and spleens (23)(24)(25) have revealed variable amounts of factor VIII activity in the perfusates.…”

Mechanism of Action of Vitamin K: Evidence for the Conversion of a Precursor Protein to Prothrombin in the Rat

“…Table 2, the administration of cycloheximide again prevented the incorporation of amino acids into the prothrombin produced after the administration of the antibiotic. There was a substantial incorporation of ['Hiaminoacids before cycloheximide and vitamin K treatment, and an insignificant (5,13,25,26). It is significant that the rapid initial burst of prothrombin seen in deficient animals after vitamin K administration (3,6,12) is not seen in the liver-perfusion studies, and that cycloheximide does block prothrombin production in vitamin K-deficient rats during the second hour after vitamin administration (12).…”

Generation of Coagulation Factors V, XI, and XII by the Isolated Rat Liver

“…Generation of factor V by the isolated liver also has been reported [2,6,9], but peak activities often were followed by disappearance of the coagu lant activity. Because, unlike human factor V, rat factor V is stable, its purported degradation during perfusion is curious.…”

“…The isolated rat liver generates the well-established vitamin K.-dependent factors: prothrombin and factors VII, IX, and X [3,5,6]. Other techniques, such as rat liver slices and liver homogenates, are confirmatory.…”