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In suspension the first response of platelets to stimulation is shape change which involves
a change from the normal discoid shape to spiny spheres containing many long
pseudopodia about 0.1 \xm in diameter and more than one platelet diameter long. This
process is mediated by the contractile microtubular system and is characterized
morphologically by the extension of short and long dendritic pseudopodia (White, 1987b,
1987c). The response is very fast, with a half life of 6 seconds (Derenleau et al, 1986),
and is independent of extracellular Ca2+ (Holmsen et al, 1974). The circumferential band
of microtubules disappears and actin filaments and single microtubules appear in the
newly formed pseudopods (Castle and Crawford, 1979). The mechanisms underlying
shape change seem to involve changes in cytoskeletal proteins (Pribluda and Rotman,
1982; Kometani et al, 1986; Yoshida et al, 1986), phosphorylation of myosin light chain
(Daniel et al, 1984) and the response is inhibited by microtubule-active drugs like
colchicine and vinca alkaloids (Menche et al, 1980). Shape change is an energy-requiring
process (Mills, 1973; Holmsen et al., 1974) due to formation of pseudopods and
recruitment of the membrane that would be required (the platelet volume remain constant,
but the platelet surface area increases by at least 50 %). During shape change, cryptic
receptors for fibrinogen are exposed on the platelet surface.

Adhesion could be defined as an platelet activation process where insoluble high
molecular weight proteins with repetitive structures (collagen and immune complexes) or
surfaces normally not in contact with platelets, e.g. nonphysiological agonists like artificial
surfaces, act as “agonists” and trigger platelet spreading on the surfaces themselves.
Resting platelets tend to adhere to almost any foreign surface they are exposed to, and this
process depends on the shear rate of the flowing blood. At low shear rates such as those
found in large veins, the platelets make contact with and spread onto components of the
subendothelial matrix such as collagen and fibronectin. See Table 9.5.1. for possible
receptors involved. Under conditions of high shear, such as found in arterioles and in the
microcirculation, the contact with and spreading on the subendothelium of platelets require
vWF (Baumgartner et al, 1980; Turitto et a/., 1983,1985). Glycoprotein Ib appears to be
the major vWF-binding site on the platelet surface that mediates platelet adhesion (Wagner
andMarder, 1984; Ruggeri and Zimmerman, 1987; Weiss et a/., 1974; Ruan et al, 1981).
The adhesion of platelets to glass or other surfaces are probably also mediated by
glycoproteins on the platelet surface (discussed further below in 9.5).

Platelets are small fragments of cytoplasm derived from megakaryocytes (Wright, 1906,
1910). They are about 3 nm in diameter and 1 nm thick and are therefore the smallest of
the blood cells (White, 1987c). The plasma membrane consists of phospholipids where the
negatively charged phosphatidylinositols and phosphatidylserines are located at the inner
leaflet of the membrane and involved in active signaling. Glycoproteins (parts of various
receptors) are extruding through the plasma membrane, with their cytoplasmic tails linked
to the cytoskeleton via proteins like actin (Painter et a/., 1985) and actin-binding protein
(Fox, 1985). The cytoskeleton in platelets consists primarily of actin filaments. It has been
estimated that 20-30 % of total platelet protein is actin (Harris and Weeds, 1978;
Rosenberg et a/., 1981; Fox et a/., 1984). For review of the organization of the platelet
cytoskeleton, see Fox (1993b). Platelets have most of the subcellular organelles that are
found in other cells except for nucleus. They are therefore deficient in DNA, except for
mitochondrial DNA. There are numerous organelles in the cytoplasm of the platelet: some
few and small, but active, mitochondria, storage granules, where a-granules and dense
granules are platelet-specific and empty their contents to the extracellular milieu upon
activation, peroxisomes, lysosomes and glycogen granules. The platelets contain two
different intracellular membrane systems. Firstly, there is an internal system called “dense
tubular system11 (DTS) which is a closed system like the endoplasmatic reticulum in other
cells. DTS is presumably the location for prostaglandin production (Gerrard et al.91978)
and storage of calcium ions (Isenberg et a/., 1995). Secondly, there is a penetrating
channel system, “open canalicular system” (OCS), which are imaginations of the plasma
membrane and serves as an export system for secretory products from the storage granules.
This channel system greatly increases the available surface area of the platelets. When the
platelets are activated in vitro, they loose their discoid shape and become more spherical
with long pseudopds. The organelles move to the center and become surrounded by a ring
of newly made microtubules and microfilaments (Stenberg et al, 1984; White, 1974,
1987c). Finally, the contents of the secretory organelles are extruded. At this stage in the
activation process the platelets are not able to return to their discoid shape. They are
sequestered and degraded by the liver and spleen and will be substituted with newly made
platelets from the megakaryocytes.

The present period is a very exciting one for those interested in GPIb-V-DC because in the
near future it is expected that a number of important advances will be made. Although we
have some ideas about the general structure of the complex we must admit that at the
moment the detailed structure, and in particular the molecular details of the interactions
between GPIb and vWf and how these two molecules adapt to and affect one another are
totally unknown. The structure of the Al domain of vWf was recently determined by Xray
crystallography and it must just be a question of time now until the structure of the
outer domain of GPIba containing the vWf binding site, is determined, first on its own, and
then complexed with the vWf domain, so that this riddle will be solved. Clearly this is not
a trivial undertaking but structural techniques continue to improve rapidly. Another area
where rapid developments are expected which should cast more light on GPIb-V-DC
function, is the mechanism of signal transduction. The main driving force here is the
identification and characterisation of the range of kinases, phosphatases and adaptor
molecules involved. Still, it is a kind of four dimensional jigsaw puzzle and new
techniques will need to be developed to simplify the analysis of all the pathways involved.
The development of lines of mice with each of the subunits of the complex, as well as
those with some of the essential signalling molecules “knocked out” will also provide
modified platelets for a clearer study of the function of this complex. Last but not least,
the development of practical inhibitors of GPIb-vWf interactions will allow the role of
these molecules in the development of thrombosis and its control to be clarified.

The genes for the subunits of the GPIb-V-IX complex have simple structures compared
to genes for other megakaryocytic specific proteins (Figure 4). There are only single
copies of each gene and unlike PF4 and PBP no pseudogenes have been found. Three of
the genes have a single exon containing all protein-encoding DNA separated by a small
intron from a small 5′ untranslated exon (105-107). In the case of the gene for GPDC there
are two small 5* untranslated exons. These small exons are probably involved in the tissue
specificity and efficiency of transcription (108). This structure is conserved in other
species where the sequence of these genes is known. In normal tissue GPIb-V-DC may
only be found in megakaryocytes and platelets and thus has a relatively restricted
expression pattern. The jury is still out on normal expression in other cells although, as
mentioned above, expression in endothelial cells has been reported by two groups.
Analysis of promoter regions of the genes for these subunits as well as other known
megakaryocyte specific genes such as PF4 and GPIIb, showed the presence of GATA and
Ets binding sequences which have a positive effect on expression whereas all these genes
appear to contain negative elements which prevent their expression in other types of tissue.
The promoter region of the gene for GPV has not yet been analysed in much detail as the
other but also contains conserved GATA and Ets binding sequences.

GPIb-V-DC subunits belong to the class of proteins that are thought to be normally specific
for the megakaryocytic cell lineage. There are a few other platelet proteins that also fall
in this category including GPIIb, probably also GPVI and, of course, the a-granule proteins
PF4 and platelet basic protein. Despite this lineage specificity there have been several
reports of expression of GPIb complex components on non-megakaryocytic cells. These
include endothelial cells, tonsillar cells and tumour cells. All of the components of the
GPIb-V-K complex have been reported to be expressed on cultivated HUVECs as well
as on adult endothelial cells and on tonsillar cells (97,98). The expression on endothelial
cells may be related to inflammatory conditions (99, 100). It was also suggested that the
GPIbb subunit expressed in endothelial cells may be larger than that expressed in platelets
(101). However, an alternative explanation has been proposed for the expression of a
larger form of GPIbb mRNA in a number of tissues which is based upon the observation
that there is a gene (hCDOeM) upstream of that for GPIbb which has an inefficient
polyadenylation signal so that the RNA polymerase tends to read through until it reaches
the GPIbb gene stop signal and thus produce an abnormally long message (102). The
protein coded by this abnormal message has not been identified but would not be expected
to be physiologically relevant. This longer message has been found in several cell types
not just in endothelial cells. The lack of expression of the normal length mRNA in
endothelial cells would then argue against functional relevance. If expression of GPIb-VK
on endothelial cells is confirmed it might be related to strengthening the attachment of
these cells to subendothelium, via vWf under high shear stress conditions.
There have also been several reports of GPIb complex proteins produced by neoplastic
tissue implying that normal tissue specificity controls have failed to operate. A protein
immunorelated to GPIba was detected on human breast carcinoma tissue but not on normal
breast tissue (103). Aberrant expression of GPIb and vWf by splenic marginal zone
lymphoma cells lead to acquired von Willebrand’s disease (104). The mechanisms of this
abnormal expression are of considerable interest because other megakaryocyte lineage
specific markers are apparently not expressed at the same time.

As well as loss of function mutations there are also gain of function mutations which are
classified as platelet-type von Willebrand’s disease (vWd) because originally the
symptoms showed some similarity to , in particular Type IEB. The reasons for this are
clear. Because of the enhanced avidity between GPIb and vWf platelets aggregate and are
removed from the circulation along with the larger vWf multimers. The patient therefore
has bleeding complications because of both the thrombocytopenia and the loss of these
higher, haemostatically more effective, multimers. Analysis of the vWf multimer
composition of plasma shows a typical reduction in higher multimers as found also with
Type HB von Willebrand disease. In the latter case the disorder is caused by mutations in
vWf leading to higher avidity for platelet GPIb. Two mutations have been detected in
GPIb leading to platelet-type vWd (35, 36). Both of these lie in the larger of the loops
making up the double loop structure (Figure 2) and in a domain which is implicated in
binding to both vWf as well as thrombin.