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2046 Part XII: Hemostasis and Thrombosis Chapter 120: Hereditary Qualitative Platelet Disorders 2047

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with GT fail to adhere to glass, 18,20,121 and this forms the basis of their patients in 1976 and 192 in 1991. The mortality rate decreased sub-
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abnormality in the glass bead retention assay. Platelet coagulant activ- stantially during this time interval.
ity has been variably reported as normal or abnormal. 18–21,124–126 A defect α β : Select Macrothrombocytopenias Five heterozygous
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in platelet microparticle formation and support of thrombin generation missense mutations in four different amino acids in integrin α β (α
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has been identified in some patients, 125–128 but not in all patients. Inte- G991C, R995Q, and R995W, and β L718P and D723H), as well as sev-
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grins α β and α β bind prothrombin, probably accounting for some eral different deletions, lead to variably mild reductions in both inte-
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of the abnormalities identified. 130,131 grin α β expression and platelet aggregation, as well as constitutively
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In flow-chamber studies, thrombasthenic platelets adhere nor- active receptors, in patients with inherited aniso- and macrothrombo-
mally to deendothelialized blood vessels at low and intermediate cytopenia. 144–150 The defects cluster on both sides of the transmembrane
shear rates, but do not spread normally or form platelet thrombi. 132–134 domains, and include both members of the α R995-β D723 salt bridge
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A defect in adhesion occurs at higher shear rates. A paradoxical proposed to maintain the receptor in a low affinity state. Proplatelet
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increase in fibrin formation on these surfaces has been observed with formation has been reported to be abnormal in several reported cases.
thrombasthenic platelets, but the explanation for this phenomenon
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remains unknown. In contrast to normal blood, blood from nearly
all patients with GT fails to occlude a 150-μm PFA-100 aperture in GLYCOPROTEIN Ib (CD42b,c)–IX (CD42a)–V:
collagen-coated membranes under high sheer, either in the presence BERNARD-SOULIER SYNDROME
of ADP or epinephrine. 136,137 Definition and History
Platelet integrins α β and α β can be quantitated by several tech- BSS is an inherited disorder of the platelet GPIb–IX–V complex charac-
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niques, including, monoclonal antibody binding (using flow cytome- terized by thrombocytopenia, giant platelets, and a failure of the plate-
try or radiolabeled binding), immunoblotting, and surface-labeling lets to bind GPIb ligands, most importantly, VWF and thrombin. 152–155
followed by sodium dodecylsulfate polyacrylamide gel electrophoresis In 1948 Bernard and Soulier described two children from a con-
(SDS-PAGE). Based on such studies, GT patients are subcategorized by sanguineous family who had a severe bleeding disorder characterized
integrin α β content into those with less than 5 percent of normal (type I), by mucocutaneous hemorrhage, variable thrombocytopenia, and giant
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5 to 20 percent (type II), or 50 percent or more (variants). 22,138 In one platelets. 156,157 Beginning in the early 1970s, BSS platelets were shown
review of 64 patients, 78 percent were type I, 14 percent were type II, to have a functional defect in VWF-dependent platelet adhesion and
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and 8 percent were variants. This subtyping predated the identification agglutination. 158–160 In 1975, Nurden and Caen identified an abnormal-
of integrin α β abnormalities as the cause of GT and was based on ity in platelet GPIb as the cause of the functional defect. Later studies
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functional data; this categorization provides only limited information. confirmed the defect in VWF–GPIb interactions 162–164 and identified
Measuring integrin α β content is technically more demanding additional defects in platelet GPV and GPIX. 165,166 Subsequent studies
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than measuring that of integrin α β because there are only approxi- have identified additional ligands for the GPIb–IX complex, including
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mately 50 to 100 integrin α β receptors per platelet. The integrin α β thrombin, P-selectin, leukocyte integrin α β , high-molecular-
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169
167
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level is very useful, however, in making a preliminary assessment of weight kininogen, thrombospondin-1, and coagulation factors XI
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whether the patient has a defect in the α or β subunits, because, in and XII (Chap. 112), but the precise contributions of these interac-
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general, patients who lack integrin α β receptors have a defect in the tions to the disorder are not well defined. Molecular defects in the genes
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β rather than α subunit. A β subunit missense mutation (H280P) for GPIbα, GPIbβ, and GPIX, but not GPV have been identified in BSS.
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that differentially affected integrin α β more than α β has, however, Mouse models of BSS have been produced by gene targeting of GPIbα
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been described. 69 and GPIbβ, and like humans, mice deficient in GPV do not demon-
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Fibrinogen-binding studies assess the function of the integrin strate the typical features of human BSS. 176,177
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α β complex. Early studies used radiolabeled fibrinogen to the bind-
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ing of fibrinogen when the platelets are stimulated with ADP or a sim- Etiology and Pathogenesis
ilar agonist. Fibrinogen can also be labeled with a fluorescent molecule This rare disease, with a prevalence estimated as less than one in
and then flow cytometry can be used to measure fibrinogen binding. 1,000,000, has been reported from countries around the world. 152,154,157,165
These techniques are most useful in detecting qualitative abnormalities Both autosomal recessive (“biallelic”) and autosomal dominant
of integrin α β in patients with variant GT. The binding of a monoclo- (“monoallelic”) forms of the disorder have been described, with the
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nal antibody (PAC1) to platelets gives similar information because the biallelic producing the most severe symptoms and the monoallelic
antibody only binds to the activated form of the integrin. 140 causing macrothrombocytopenia and a mild or no bleeding syndrome.
Carriers of GT have essentially normal platelet function. Their Consanguinity is common in the biallelic form, with 85 percent of the
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platelets, however, only contain approximately 60 percent of the normal reported cases being homozygous for the causative mutation. 154
number of integrin α β receptors; the overlap in values between nor- Six different features of BSS may contribute to the hemorrhagic
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mal individuals and carriers, however, doesn’t permit for unequivocal diathesis: thrombocytopenia, abnormal platelet adhesive interactions
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diagnosis of carriers by this technique. Carrier detection is most accu- with VWF, abnormal platelet interactions with thrombin, abnormal
rately performed by DNA analysis. platelet coagulant activity, abnormal platelet interactions with P-selectin,
Platelet fibrinogen is reduced to approximately 10 percent of normal and abnormal platelet interactions with leukocyte integrin α β .
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in patients with marked reductions in integrin α β 18,21,43,44 but is variably The pathophysiology of the thrombocytopenia is uncertain. Early
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reduced in patients with significant amounts of integrin α β . 138,141,142 studies suggested a marked shortening of platelet survival, presumably
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from the decrease in platelet surface charge resulting from the GPIb
Therapy and Prognosis defect. 178,179 Later studies using 111 In-oxine to label platelets reported
Therapy of GT patients is discussed in the section entitled “Manage- more modest or no shortening of platelet survival, indicating that inef-
ment of Inherited Platelet Function Disorders.” Although GT is a severe fective thrombopoiesis and/or decreased thrombopoiesis may contrib-
disease, the prognosis for survival is generally good. In one series, two of ute to the thrombocytopenia. 180,181 Morphologic abnormalities have
64 patients died of hemorrhage and in another series, three of 43 patients been identified in BSS megakaryocytes and these may contribute to
died of hemorrhage. 22,33 A nationwide survey in Japan identified 98 GT abnormal platelet production. Based on observations in other giant
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