Thrombotic thrombocytopenia induced in dogs and pigs: The role of plasma and platelet vWF in animal models of thrombotic thrombocytopenic purpura

William E. Sanders, Robert L. Reddick, Timothy C. Nichols, Kenneth M. Brinkhous, Marjorie S. Read

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Thrombotic thrombocytopenia with severe depletion of plasma yon Willebrand factor (vWF) was induced in normal large animals (5 dogs and 2 pigs) by botrocetin, a Bothrops factor requiring vWF for platelet agglutination. Botrocetin (90 to 100 U/kg, 2.14 to 2.38 mg/kg, in a single IV injection) reduced plasma vWF activity to <0.1 U/mL for 24 hours. During this period, multimeric analysis of plasma vWF antigen (Ag) revealed the loss of intermediate- and high-molecular-weight forms with a concomitant increase in lower molecular weight forms. A moderate reduction in factor VIII (FVIII) activity was observed. The vWF reduction was accompanied by transient thrombocytopenia and prolonged bleeding times during the deficiency state. Occlusive platelet thrombi were detected by transmission electron microscopy in the microcirculation of lung and spleen but not kidney or brain 30 minutes after the botrocetin injection. Recovery of plasma vWF and platelet count occurred within 48 hours and was associated with the appearance in the plasma of unusually large forms of vWF:Ag multimers. The vWF:Ag multimer distribution was normal at 72 hours. The ultrastructural distribution of vWF in unstimulated normal porcine and canine platelets was examined by using immunogold staining. VWF was detected in the α-granules of normal pig platelets but was not observed in platelets from normal dogs. However, both animals developed thrombotic thrombocytopenia when injected with botrocetin. A second group of animals (2 dogs and 3 pigs) with von Willebrand disease (vWD) was given a single botrocetin injection (91) to 100 U/kg). No thrombocytopenia occurred. Electron photomicrographs showed no platelet thrombi in any tissues examined. Porcine and canine platelets from vWD animals exhibited no specific labeling of vWF in any α-granule. The vWD animals were entirely protected from the thrombocytopenia and thrombogenic action of botrocetin. These data suggest that plasma vWF but not platelet vWF is required for the intravascular platelet and microthrombotic response and that the thrombotic thrombocytopenic syndrome cannot be induced in the absence of plasma vWF.

Original languageEnglish (US)
Pages (from-to)793-800
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume15
Issue number6
DOIs
StatePublished - Jun 1995
Externally publishedYes

Keywords

  • thrombotic thrombocytopenia
  • thrombotic thrombocytopenic purpura
  • von Willebrand disease
  • von Willebrand factor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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