Generation of Factor VIII Coagulant Activity by Isolated, Perfused Neonatal Pig Livers and Adult Rat Livers

Abstract

Isolated, normal, neonatal pig livers released VIII:C into perfusates of porcine von Willebrand blood lacking VIIIR:AG and VIII:RWF. Neonatal von Willebrand livers released VIII:C only when partially purified VIIIR:AG was added to the von Willbrand blood. Adult rat livers, perfused with frozen-thawed erythrocytes suspended in Tyrode's solution containing 6% bovine serum albumin and hence no VIIIR:AG released VIII:C only when serum, adsorbed serum or cryoprecipitate from rat plasma was added to the perfusate. Cycloheximide blocked the release of VIII:C from rat liver.

The therapeutic effect of bone marrow–derived liver cells in the phenotypic correction of murine hemophilia A

“…Again within the liver, hepatocytes were found to be the major source of FVIII. 10,14,15 It was shown that transplanting human hepatocytes under the mouse kidney capsule elicits therapeutic effect through the secretion of FVIII. 16 Recently, a therapeutic effect of hepatocytes in hemophilia B mice has been documented.…”

“…8 However, liver perfusion 9,10 and orthotopic liver transplantation studies in both animals and humans [11][12][13] suggest that the primary site of FVIII synthesis is the liver. Various lines of evidence indicate that, within the liver, hepatocytes are the major FVIII-producing cells.…”

“…Various lines of evidence indicate that, within the liver, hepatocytes are the major FVIII-producing cells. 10,14,15 Thus, cell-based therapy using isolated hepatocytes has been proposed as an attractive approach to treat clotting disorders. The therapeutic effectiveness of human hepatocytes transplanted under the kidney capsules of mice has been demonstrated.…”

Changes in plasma factor VIII complex and serum lipid profile during atherogenesis in cynomolgus monkeys.

“…It is of interest in this regard that hepatic perfusion studies in animals have suggested that VIIIR:Ag may be needed for VIIMC release. 35 The examples of dissociated VIIIR :Ag and VIII :C levels cited above suggest there may be mechanisms of VIII :C stabilization in plasma in addition to the linkage with VWF. We speculate that one of the lipid fractions that has a similar time course to VIII: C might affect the VIII: C levels, for example, phospholipid, free fatty acids, or triglycerides.…”

Factor VIII-East Hartford (arginine 1689 to cysteine) has procoagulant activity when separated from von Willebrand factor.

“…This association is very important, as it is believed that vWf is required for Factor VIII production (3,4) and stabilization (5,6). Studies have localized the binding site ofvWfto the NH2-terminal portion of the Factor VIII light chain.…”