Autoimmune Thrombocytopenia by Yoji Ishida & Yoshiaki Tomiyama

Author:Yoji Ishida & Yoshiaki Tomiyama
Language: eng
Format: epub
Publisher: Springer Singapore, Singapore

5 Bernard-Soulier Syndrome

Bernard-Soulier syndrome (BSS) is an autosomal recessive bleeding disorder characterized by giant platelets, thrombocytopenia, prolonged bleeding time, and absent ristocetin-induced platelet agglutination [31, 32]. This syndrome is caused by the deficiency of platelet glycoprotein (GP)Ib-IX-V complex, the platelet receptor for von Willebrand factor (VWF), due to compound heterozygous or homozygous mutations in the genes for GPIbα(GP1BA), GPIbβ(GP1BB), or GPIX(GP9). As a result of the absence of GPIb-IX-V complexes on the platelet membrane, platelets are unable to adhere to the vascular subendothelium. Thus, patients manifest a severe bleeding tendency from early childhood, primarily from mucocutaneous tissues; purpura, epistaxis, menorrhagia, and gingival bleeding are common, but hemarthroses and deep visceral hematomas are rare. The cytoplasmic domain of GPIbα, on the other hand, associates with actin via filamin A, and the defective linkage between GPIb-IX-V and cytoskeleton is the primary proposed mechanisms for the large platelet size in BSS [33, 34]. In addition, recent studies indicate that proplatelet formation is defective in megakaryocytes, suggesting defective interactions between GPIb-IX-V and filamin A-actin adversely affect both platelet morphogenesis and megakaryocytopoiesis [35].

Although BSS is a very rare disorder with an estimated prevalence of less than 1 in one million, the calculated frequency of BSS heterozygotes is 1 in 500, indicating that a sizable number of heterozygous carriers are present in the normal population [36, 37]. It is worth to note that although heterozygous BSS carriers are generally asymptomatic with mild or moderate thrombocytopenia, they have large platelets. Individuals with a heterozygous mutation have been often identified as having undifferentiated thrombocytopenia. In Italy, the Bolzano variant (GP1BA p. A172V) was found to be responsible for the autosomal dominant macrothrombocytopenia previously known as a Mediterranean macrothrombocytopenia [38, 39]. Likewise, GP1BB p. Y113C is prevalent in autosomal dominant macrothrombocytopenia in Japan [40, 41]. In addition, patients with DiGeorge/velocardiofacial syndrome due to a heterozygous chromosome 22q11.2 microdeletion, which includes the GP1BB gene, have macrothrombocytopenia [42, 43].

The classical diagnostic features are a prolonged bleeding time, moderate to severe thrombocytopenia, and giant platelets. Especially, giant platelets and the absence of ristocetin-induced platelet agglutination are the laboratory hallmarks of BSS. Flow cytometric determination of platelet GPIb/IX expression is a convenient method for a definite diagnosis. This also allows an evaluation of platelet size, and double labeling of GPIb/IX and GPIIb/IIIa permits determination of comparative expression levels. In a typical case of BSS, the fluorescence intensities of normal mouse IgG and anti-GPIIb/IIIa antibody are increased, which is reflected by giant platelets with a large surface area. In contrast, GPIbα, GPIbβ, and GPIX are all decreased. However, the abnormalities of the GPIb-IX-V complex are heterogeneous; residual amounts of the complex and/or some of the subunits are often present. Evaluating GPIbα, GPIbβ, and GPIX expression highlights selective deficiencies and candidate genes for investigation. Accordingly, the most deficient subunit in the platelets is often found to indicate the genetic basis: patients with residual GPIbβ and GPIX are often associated with a GP1BA mutation, and those with residual GPIbα and GPIbβ are often associated with a GP9 mutation [16, 36].

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