Fibrinogen-coated albumin microcapsules reduce bleeding in severely thrombocytopenic
rabbits
Marcel Levi1, Philip W. Friederich1, Sarah Middleton2, Philip G. de Groot3, Ya Ping Wu3, Roy Harris2, Bart J. Biemond1, Harry F.G. Heijnen3, Jack Levin4
& Jan Wouter ten Cate1
1
Center for Hemostasis, Thrombosis, Atherosclerosis
and Inflammation Research, Academic Medical Center, University of Amsterdam
, Meibergdreef 9, 1105 AZ
Amsterdam, the Netherlands
2
Andaris, 1 Mere Way, Ruddington
, Nottingham NG11 6JS
United Kingdom
3
Department of Hematology, University of Utrecht,
P.O. Box 85500, 3508 GA Utrecht,
the Netherlands
4
Department of Laboratory Medicine, University of California
School of Medicine, and VA Medical Center, 4150 Clement Street
, San Francisco, California 94121,
USA
Severe thrombocytopenia frequently occurs in patients receiving chemotherapy
and in patients with autoimmune disorders. Thrombocytopenia is associated
with bleeding, which may be serious and life threatening1,
2,
3.
Current treatment strategies for thrombocytopenia may require transfusion
of allogeneic platelets, which is associated with serious drawbacks4.
These include the occurrence of anti-platelet antibodies, which may result
in refractoriness to further platelet transfusions, and the potential risk
of transfer of blood-borne diseases5,
6. Therefore, we have
recently developed a platelet substitute product (Synthocytes), which is composed
of human albumin microcapsules with fibrinogen immobilized on their surface.
Here we show that the intravenous administration of these microcapsules not
only corrects the prolonged bleeding time in rabbits rendered thrombocytopenic
either by anti-platelet antibodies or by chemotherapy, but also reduces bleeding
from surgical wounds inflicted in the abdominal skin and musculature. No potential
systemic prothrombotic effect of the microcapsules was observed in a model
of rabbit venous thrombosis. As for the mechanism of action, experiments with
normal and thrombocytopenic human blood in an endothelial cell matrix-coated
perfusion chamber demonstrated an interaction between the fibrinogen-coated
albumin microcapsules and native platelets. It was shown that the fibrinogen-coated
albumin microcapsules could facilitate platelet adhesion to endothelial cell
matrix and correct the impaired formation of platelet aggregates in relatively
platelet-poor blood. This study indicates that fibrinogen-coated albumin microcapsules
can act to improve primary hemostasis under thrombocytopenic conditions and
may eventually be a promising agent for prophylaxis and treatment of bleeding
in patients with severe thrombocytopenia.
