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2050 Part XII: Hemostasis and Thrombosis Chapter 120: Hereditary Qualitative Platelet Disorders 2051

Although, the large size of the platelets in BSS and the thrombo- has been termed both pseudo-VWD and platelet-type VWD. At present,
cytopenia make it technically difficult to perform platelet aggregation 55 patients are listed in the database of patients with this disorder (www
studies, in general, aggregation induced by ADP, epinephrine, or col- .pt-vwd.org). 282,283
lagen is either normal or enhanced. 160,257,258 The aggregation response
to thrombin is usually dose-dependent, being essentially normal in
response to high doses of thrombin but characterized by a prolonged Etiology and Pathogenesis
lag phase and diminished aggregation in response to low doses of A qualitative abnormality in GPIb is responsible for this disorder, with
thrombin. 197,259 ongoing in vivo binding of high-molecular-weight VWF multimers to
platelets causing depletion of the plasma high-molecular-weight mul-
Platelet Coagulant Activity The coagulant activity of platelets timers. In addition, the binding of the VWF to platelets may lead to
from patients with BSS has been variably reported as reduced, nor- shortened platelet survival, perhaps accounting for the variable throm-
mal, or increased. 124,202,203 The variable presence of fibrin in the different bocytopenia. Inheritance is autosomal dominant.
277
assays used to assess platelet coagulant activity may account for these Abnormalities in the Mr of GPIb were identified in two families,
inconsistent results as GPIb–VWF interactions enhance platelet coagu- but these may have resulted from a now-recognized polymorphism in
lant activity when fibrin is present, but not when it is absent. 126 GPIb (Chap. 112) rather than being related to the functional disorder.
Heterozygous point mutations in the GPIbα gene causing a variety of
Platelet-Thrombin Interactions Both GPIb and the seven- missense alterations (G233V, G233S, M239V, D235Y, W230L) have
transmembrane domains PAR-1 and PAR-4 receptors are required for been found in several different families. 271,278,284–289 The G238V muta-
maximal response to thrombin. 167,259 Two different crystal structures tion is the most common among the patients in the database, affect-
of the interactions between thrombin and GPIbα have been reported; ing 31 of 35 patients. All of these mutations are in the R-loop (also
in one, two molecules of thrombin bind to each GPIbα molecule, rais- termed β-switch) in the carboxyterminal flanking sequence of the
ing the possibility that free thrombin or thrombin adherent to fibrino- leucine-rich repeats, a region implicated in ligand binding (see
gen can cluster GPIb–IX–V complexes. 167,260,261 GPV, which is missing Fig. 120–4). 152,187,290–293 Molecular modeling suggests that the M239V
from the platelet surface in BSS, is cleaved by thrombin, but the cleav- substitution produces a significant conformational change in the mol-
age is neither necessary nor sufficient for thrombin-induced platelet ecule, and this was confirmed by crystallographic analysis. It has
295
294
activation. 262,263 In fact, platelets of mice lacking GPV have increased been proposed that the platelet-type VWD mutations either destabilize
responsiveness to thrombin, perhaps because GPV ordinarily limits the compact triangular structure of the R-loop by interfering with the
access of thrombin to GPIbα or inhibits GPIbα crosslinking. 200,201 D235-K237 salt bridge or stabilizing the extended β-hairpin form of the
282
R-loop, which is better able to engage the VWF A1 domain. A mouse
Ex Vivo Interaction with Subendothelial Surfaces Platelets from model of the GPIbα G233V mutation recapitulated many of the human
patients with BSS demonstrate defective adhesion to subendothelial manifestations and had an unexpected increase in bone mass. Recom-
296
surfaces, especially at shear rates greater than 650 s . The binant GPIbα fragments containing the G233V and M239V mutations
–1 133,134,158,264
results are similar to those in patients with VWD. demonstrated enhanced interactions with VWF in several different
Shear-Induced Platelet Aggregation Unlike normal plate- systems, including ones under shear stress. 297,298 An increase in platelet
lets, platelets from patients with BSS are not aggregated by high shear GPIb/IX expression has also been reported. 278,281 An in-frame 27-base-
rates. 194,195 The initial interaction in this process appears to be bind- pair (bp) deletion in the macroglycopeptide region of GPIbα has also
279
187
ing of VWF to GPIb, with subsequent activation of integrin α β . been reported to cause platelet-type VWD. Because the deletion may
IIb 3
perhaps through signaling via the protein 14-3-3ζ associated with the lead to the loss of up to four glycosylation sites, it has been proposed
cytoplasmic domain of GPIbα, 196,265 Fcγ receptor IIA, GPVI, and/or that the glycans play a negative regulatory role in ligand binding. 282
the Fc receptor γ chain (Chap. 112). 266–268 Pathologic shear stress has
been reported to increase binding of α-actin to GPIb/IX as part of the Clinical Features
signaling process. 268–270 Patients have variable thrombocytopenia and mild to moderate
mucocutaneous hemorrhage. A study of 13 patients with six different
mutations using a standardized bleeding assessment tool found a wide
Therapy range of clinical severity, with approximately 40 percent having a nor-
The therapy of BSS is described in the section “Management of Inherited mal bleeding score and the remainder having a wide range of abnor-
Platelet Function Disorders” below. Splenectomy has been performed mal scores. Bleeding scores did not correlate with age or sex, but did
271
when the diagnosis of immune thrombocytopenia was mistakenly correlate with reductions in both platelet count and ristocetin cofactor
made, but this usually does not normalize the platelet count or improve activity. All patients had macrothrombocytopenia. Of note, pregnancy
the bleeding diathesis. 249 may exacerbate the thrombocytopenia and bleeding symptoms. 278

GPIbα (CD42b,c): PLATELET-TYPE (PSEUDO-) Laboratory Features and Differential Diagnosis
VON WILLEBRAND DISEASE Mild thrombocytopenia and somewhat enlarged platelets are present
in some, but not all, patients. Plasma VWF levels are variably reduced,
Definition and History with a disproportionate reduction in plasma high-molecular-weight
A heterogeneous group of patients has been described with mild to multimers. Platelet VWF multimers are normal.
moderate bleeding symptoms, variably enlarged platelets, variable The most characteristic laboratory finding in platelet-type VWD
thrombocytopenia, and diminished plasma high-molecular-weight is enhanced platelet aggregation in response to low concentrations of
271
299
VWF multimers. The fundamental defect in these patients is thought ristocetin 272–276,278,288 or botrocetin. This same abnormality is present
to be an enhanced interaction between an abnormal platelet GPIb/IX in patients with type 2b VWD, as is selective depletion of plasma high-
receptor and normal plasma VWF. 272–281 Because these patients have molecular-weight VWF multimers (Chap. 126). In platelet-type VWD,
some of the hallmarks of VWD, but the defect is in platelet GPIb/IX, it however, the defect is in platelet GPIbα, whereas in type 2b VWD, the

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