The generation of thrombin in vivo induces the selective loss of high molecular weight multimers of von Willebrand factor and the reversible sequestration of platelets.
Various levels of thrombin generation were induced by the infusion of a combination of factor Xa (F.Xa) and phosphatidylcholine/phosphatidylserine (PCPS) vesicles into normal dogs and non-human primates. In the dog, an immediate loss of von Willebrand factor antigen (vWF:Ag) with a progressive recovery to normal levels by 45 min was observed. Multimeric assay demonstrated a selective loss of high molecular weight multimers (HMWM) with subsequent replacement. At low doses, in non-human primates (chimpanzees), identical changes to those seen in the dog were observed and this was associated with an equivalent loss of ristocetin co-factor activity (vWF:RCoF). At high dose a reversal of the wWF response occurred with levels increasing to twice that of baseline values by 2 min and multimeric analysis demonstrated the presence of abnormally large multimers and increased vWF:RCoF specific activity, suggesting that the response at each dosage reflected a net balance of consumption over release. This was supported by in vitro simulation where increasing thrombin generation was associated with a selective loss of HMWM without replacement. In both species, an immediate fall in platelet count occurred and this was directly correlated with the amount of thrombin generated. Full recovery occurred within 45 min and isotopic labelling studies demonstrated that platelet sequestration rather than consumption was occurring. These studies demonstrate that thrombin generation in vivo is associated with a selective loss of the multimeric forms of vWF known to interact with platelets and this may provide an in vivo model to characterize the physiology/pathophysiology of this primary event in haemostasis.
Toh
C H
CH
Department of Pathology, Queen's University, Kingston, Ontario, Canada.
Hoogendoorn
H
H
Giles
A R
AR
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D002679:Pan troglodytes; D010976:Platelet Count; D011817:Rabbits; D013917:Thrombin / Q000378:metabolism*; D014841:von Willebrand Factor / Q000378:metabolism*
D014841:von Willebrand Factor; D013917:Thrombin