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2048 Part XII: Hemostasis and Thrombosis Chapter 120: Hereditary Qualitative Platelet Disorders 2049

platelet syndromes (Chap. 117), the large size of Bernard-Soulier plate- in fibrin-dependent, but not fibrin-independent, augmentation of
lets would tend to diminish the adverse hemostatic effects of the throm- platelet coagulant activity and thus fibrin-dependent coagulant activ-
bocytopenia because the platelet mass is better preserved. With only rare ity is likely to be abnormal in BSS. This finding may partially explain
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exceptions, however, the bleeding diathesis with BSS is more severe the variability in findings between the serum PT and some of the other
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than expected from the thrombocytopenia, reinforcing the conclusion assays as fibrin only forms in the serum PT. Abnormal membrane lipids
that a qualitative platelet defect is the predominant problem. 157,184 have also been reported. 204
The platelet GPIb–IX complex functions as a receptor for VWF The mechanism(s) producing the giant platelets in BSS has not
(Chaps. 112 and 126). 152,185,186 This interaction is crucial in the adhe- been identified, but since giant platelets are found in BSS variants in
sion of platelets to subendothelial surfaces, especially under high shear which GPIb/IX is present, but unable to bind ligand, it has been postu-
conditions, where VWF acts as a bridge between the subendothelial lated that the abnormality is a result of the inability of GPIb/IX to bind
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matrix and the platelet. 133,134 The relative roles of subendothelial VWF, an unknown marrow ligand. It cannot be because of an inability to
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plasma VWF, and platelet VWF have not been completely defined, but bind VWF as, with only rare exceptions, patients lacking VWF do
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they probably all contribute to platelet adhesion. The interaction of not have large platelets. Moreover, in a mouse model of BSS, restoring a
VWF with GPIb/IX initiates activation of integrin α β , 188,189 which can receptor with the GPIb transmembrane and cytoplasmic domains, but
IIb 3
also bind to VWF, but at a different site on the molecule. The interac- not the ligand-binding domain, partially corrected both the thrombo-
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tion of GPIb/IX with VWF also directly contributes to platelet–platelet cytopenia and large platelet size. A defect in GPIb/IX–mediated sig-
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interactions. 191–193 naling has also been proposed to cause the large platelets as a deficiency
GPIb/IX–VWF interactions can also occur in platelet suspensions of PLC has also been described in BSS. 152,207 A mechanical alteration in
at high shear rates; this can lead to platelet activation, with subsequent the plasma membrane of BSS platelets has been identified by micropi-
aggregation mediated by integrin α β . 187,194–196 Whether sustained pette experiments, showing the plasma membrane to be more deform-
IIb 3
shear rates in vivo ever reach the levels required to initiate VWF bind- able than normal. Megakaryocytes in BSS have increased ploidy and
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ing, however, is not established. volume, as well as alterations in the membrane demarcation system,
Abnormalities of the GPIb–IX complex can be a result of genetic granules, and microtubules. 181,182 Both the increased size and deform-
defects in GPIbα, GPIbβ, or GPIX, all of which are required for surface ability may reflect the loss of the normal interaction of GPIb/IX with the
expression. BSS is the most severe form of the disease and is caused by cytoskeleton via actin-binding protein (filamin-1; Chap. 112).
defects in both alleles of one of the proteins as a result of a homozygous Platelets from patients with BSS are deficient not only in GPIbα,
mutation, compound heterozygosity, or a combination of hemizygos- GPIbβ, and GPIX, which are known to be associated as a complex,
ity of GPIbβ because of a microdeletion and a mutation affecting the but also in GPV (Chap. 112). 152,166 All of these proteins share highly
other GPIbβ allele. These abnormalities have been termed the biallelic conserved leucine-rich regions. 152,187 One possible explanation for
forms. A macrothrombocytopenic syndrome associated with a mild the loss of surface expression of all the proteins is that they need to
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bleeding syndrome has been reported with heterozygous defects in form a complex during biosynthesis in order to be transported to the
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GPIbα and GPIbβ. Because obligate heterozygotes for the biallelic BSS surface ; evidence supports the need for GPIbα, GPIbβ, and GPIX to
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mutations do not commonly demonstrate macrothrombocytopenia, all be present for optimal surface expression, but data from mice defi-
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the heterozygous defects associated with macrothrombocytopenia may cient in GPV indicate that this glycoprotein is not required for surface
exert a dominant negative effect. 154 expression of the GPIb–IX complex. GPV may, however, improve the
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The platelets of patients with BSS have a decreased response to efficiency of expression of the other members of the complex. More-
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platelet activation by thrombin, especially at limiting concentrations of over, data from the BSS mouse expressing a chimeric GPIbα molecule
thrombin. 197–199 BSS platelets are deficient in two different proteins that in which the leucine-rich repeat domain was replaced with the external
interact with thrombin, namely GPIbα, which binds thrombin, and domain of another receptor indicate that complex formation does not
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GPV, which is a thrombin substrate (Chap. 112). The precise nature of require the GPIbα leucine-rich domain. 206
the interactions of thrombin with GPIbα and its biologic consequences At the molecular level, the platelets from different patients with
are still unclear, but binding of thrombin to GPIbα can initiate signal- BSS are heterogeneous, with many having no detectable GPIb and
ing within the platelet, perhaps directly through GPIbα crosslinking others having variable amounts, up to 50 percent of normal. 152,207,211–214
or indirectly by augmenting activation of other thrombin receptors There also is variability in the degree of concordance in the reduction of
(protease-activated receptors [PARs] 1 and 4) or other thrombin- GPIb and the other deficient proteins. 215,216
dependent events at the platelet surface. Paradoxically, mice deficient Molecular Defects The molecular biologic basis of BSS has been
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in GPV actually have increased sensitivity to thrombin activation and determined in 161 patients from 132 unrelated families and an online
variably increased thrombus formation, perhaps because GPV limits registry of defects is available at http://www.bernardsoulier.org/. An
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access of thrombin to GPIb. 200,201 Because thrombin is one of the major international consortium reported on 211 families with the recessive
physiologic activators of platelets, the loss of thrombin binding to form of BSS, which they termed “biallelic.” In total, 45 different muta-
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GPIbα may contribute to the hemorrhagic diathesis. tions have been reported in GPIbα, 52 in GPIbβ, and 28 in GPIX. No
Platelets from patients with BSS are defective in supporting defects in GPV have been identified in patients with BSS. The associa-
thrombin generation as judged by the serum PT, a test performed tion with consanguineous matings was reinforced as 85 percent of the
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with whole blood, but in other tests of platelet coagulant activity, BSS families had homozygous mutations and 13 percent were compound
platelets support coagulation as well as, or better than, normal plate- heterozygotes for defects in one of the genes. None of the variants were
lets. 124,203 Defects in collagen-induced coagulant activity and the associ- identified in several gene variant databases, suggesting that they are
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ation of factors V, VIII, and XI with BSS platelets have been described, all rare and likely entered the population relatively recently. A number
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but their significance is unclear. Similarly, GPIb/IX has been iden- of likely founder mutations have been identified in each of the three
tified as a binding site for other proteins involved in coagulation, genes in different populations. 154,218 The ancestry of seven apparently
including high-molecular-weight kininogen and factor XII, but the unrelated families with a GPIbβ W89D mutation was traced to a com-
contributions of these interactions to the coagulant abnormality are mon ancestor in 1671 in India. Five mutations in GPIX account for
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also uncertain. 170,172,173 Binding of VWF to GPIb/IX has been implicated 137 of the 184 affected GPIX alleles and GPIX N61S is found in 64

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