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Blood, Vol. 92 No. 9 (November 1), 1998:
pp. 3035-3041
RAPID COMMUNICATION
Secretable Human Platelet-Derived Factor V Originates From the Plasma
Pool
Rodney M. Camire,
Eleanor S. Pollak,
Kenneth Kaushansky, and
Paula
B. Tracy
From the Department of Biochemistry, University of Vermont, College
of Medicine, Burlington; the Division of Hematology, The Children's
Hospital of Philadelphia, Philadelphia, PA; and the Division of
Hematology, University of Washington School of Medicine, Seattle.
Factor Va (FVa), derived from plasma or released from stimulated
platelets, is the essential protein cofactor of the prothrombinase complex. Plasma-derived factor V (FV) is synthesized by the liver, whereas the source of the platelet-derived cofactor has not been unambiguously identified. Megakaryocytes, platelet precursors, are
known to synthesize platelet proteins and to endocytose proteins from
plasma (ie, fibrinogen) and then package these proteins into  -granules. To determine which mechanism accounts for FV presence in
platelets, two patients heterozygous for FVLeiden who
underwent allogeneic transplantation from homozygous FV wild-type donors (bone marrow [BM] or liver) were studied. Patient JMW, whose
skin biopsy specimen showed heterozygous FVLeiden, received
a BM transplant from a wild-type homozygous FV donor as analyzed from
posttransplant peripheral blood cells. Patient FW, whose native liver
is heterozygous for FVLeiden, received a homozygous
wild-type FV liver. Because each individual has two distinct genetic
pools of factor V in liver and megakaryocytes, it was possible to
determine whether secretable platelet-derived FV was normal or
contained the FVLeiden mutation. Platelet-derived FVa
released from thrombin-activated platelets from a normal individual, an
individual heterozygous for the FVLeiden mutation, and the
two patients was incubated with phospholipid vesicles and activated
protein C (APC). Western blotting analyses using a monoclonal antibody
that allows distinction between platelet-derived FVa and
FVaLeiden subsequent to APC-catalyzed cleavage were then
performed. Based on the accumulation of proteolytic fragments derived
from APC-induced cleavage, analyses of platelet-derived FVa from JMW
demonstrated both normal FVa and FVaLeiden consistent with
a plasma-derived origin of the secretable platelet-derived FVa. Western
blotting analyses of the APC-cleaved platelet-derived FVa from FW
showed a wild-type phenotype, despite the presence of a
FVLeiden allele in her megakaryocyte genome, also
consistent with a plasma origin of her secretable platelet-derived FVa.
Platelets do not appear to endocytose the plasma cofactor, because a
35-hour incubation of platelet-rich plasma with 125I-factor
V showed no specific association/uptake of the radiolabeled ligand with
the platelet pellet. Collectively, these results show for the first
time that the majority of secretable platelet-derived factor V is
endocytosed by megakaryocytes from plasma and is not exclusively
synthesized by these cells, as previously believed.
© 1998 by The American Society of Hematology.
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