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Prolonged Bleeding Time With Defective Platelet Filopodia
Formation in the Wistar Furth Rat
Paula E. Stenberg,
Rosemary J. Barrie,
Tamara I. Pestina,
Shirley
A. Steward,
Julie T. Arnold,
Aparna K. Murti,
Nancy K. Hutson, and
Carl W. Jackson
From the Department of Pathology, Oregon Health Sciences University,
Portland, OR; and the Division of Experimental Hematology, St Jude
Children's Research Hospital, Memphis, TN.
Hereditary macrothrombocytopenia is a hallmark of Wistar Furth (WF)
rats. In addition, a platelet/megakaryocyte alpha granule defect,
similar to that of patients with gray platelet syndrome, is present.
Several observations indicate cytoskeletal abnormalities in WF
platelets and megakaryocytes, suggesting the potential for functional
defects in hemostatic processes requiring cytoskeletal reorganization,
such as platelet adhesion and spreading. However, no bleeding
abnormality has been noted. Here, we report a prolonged bleeding time
(>30 minutes in 10 of 11 rats tested) with defective clot formation
in the WF strain. Prolonged bleeding time can result from defects in
platelet adhesion, aggregation, or the release reaction. Because
aggregation to collagen and adenosine diphosphate were reported to be
normal, we determined whether WF rat platelets are defective in their
ability to adhere to substrates. Platelet adherence and spreading was
evaluated from 30 seconds to 30 minutes on Formvar-coated,
carbon-stabilized grids or poly-L-lysine-coated glass coverslips by
transmission electron microscopy or immunofluorescence, respectively,
and scanning electron microscopy. We classified the adhered platelets
according to their pattern of spreading, ie, rounded, rounded or
spreading with short filopodia, spindle-shaped, spreading with long
filopodia, spreading with lamellipodia, and fully spread. Adherent
normal rat platelets displayed all stages of spreading within 30 seconds to 2 minutes, including many spindle-shaped forms, and forms
with multiple, long filopodia. In contrast, adhered WF platelets at
these early time points rarely developed long filopodia or were spindle
shaped. The majority of adherent WF platelets at these early time
points were either round, spread with a few short filopodia, or
extensively spread with wide lamellipodial skirts. By 15 to 30 minutes,
most platelets in both Wistar and WF samples were fully spread. These
data show abnormal WF platelet spreading. The paucity of spindle-shaped
forms and forms with long filopodia may reflect an inability of WF
platelets to undergo the early stages of spreading, or, alternatively,
their more rapid than normal progression through these stages. We
hypothesize that this failure to spread normally may relate to
prolonged bleeding times in vivo and defective clot formation in WF
rats.
Blood, Vol. 91 No. 5 (March 1), 1998:
pp. 1599-1608
© 1998 by The American Society of Hematology.
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