Summary
Parameters of the fibrinolytic system were studied in a primate model where the generation
of thrombin was promoted in vivo. The procoagulant stimulus used was a combination
of human factor Xa in combination with phosphatidylcholine/phos-phatidylserine lipid
vesicles (PCPS) as the source of coagulant active phospholipid. The dosage of each
component was formulated to provide a gradation of thrombin generating potential assessed
prior to in vivo study in an in vitro clotting assay. These ranged from 25.25 - 36.60
pMole/kg (factor Xa) and 18.85 - 56.30 nMole/kg (PCPS). In each case, the ratio of
the dose of factor Xa/PCPS was maintained at 0.65 (pMole factor Xa/ nMole PCPS). Individual
dosage combinations producing recalcification clotting times in vitro of 15, 20, 25
and 30 s were used in detailed in vivo studies. Previous studies in dogs had confirmed
the thrombin generating potential of factor Xa/PCPS infusions and demonstrated an
associated activation ot protein C and increased fibrinolytic activity. This has now
been extensively characterized in the chimpanzee as follows: 10 min after the infusion
of the highest dose (36.6 pMole factor Xa/56.3 nMole PCPS kg bodyweight), the level
of circulating t-PA had risen to 900 ng/ml (antigen), 885 IU/ml (functional). Dosage
was observed with the lowest dose of 12.25 pMole factor Xa and 18.85 nMole PCPS being
associated with relatively minor increases in circulating t-PA activity. There were
no changes in u-PA at any dosage during the full time course of the experimental period
(90 min). Plasminogen activation was also apparent with alpha-2 antiplasmin levels
falling to 30 - 40% of pre-infusion levels at the highest dosages. There was also
a significant consumption of fibrinogen and evidence of active fibrinolysis manifested
by major increases in the levels of FDP, D-dimer and B-beta 1-42. The data strongly
suggested that this was predominantly fibrinolysis rather than fibrinogenolysis and
that the fibrinolytic response observed resulted from a major release of t-PA from
available stores consequent to thrombin generation and presumably subsequent fibrin
generation. These data illustrate the enormous fibrinolytic potential of the intact
normal primate and may provide a model for study of the mechanism(s) by which the
regulation of t-PA availability can be up- or down-regulated in health and disease.
