An 8-Year-Old Girl With Thrombocytopenia

An 8-year-old girl was found to be thrombocytopenic through a preoperative complete blood count in anticipation of a tonsillectomy. She had no history of bleeding, bruising, or petechiae. Complete blood count was significant for thrombocytopenia (platelet count = 59 000/ μL) with many large platelets seen on peripheral blood examination (mean platelet volume = 19.2 fL). Figure 1 demonstrates features of the patient's peripheral blood smear including macrothrombocytopenia and mature neutrophils devoid of significant morphologic abnormalities (Wright-Giemsa stain, original magnifications ;ts40 and ;ts100 [inset]). A presumptive clinical diagnosis of immune thrombocytopenic purpura was made. The patient's platelet count, however, remained unchanged despite administration of intravenous immunoglobulin and a course of steroid treatment. Platelet aggregation studies (Figure 2) showed markedly decreased aggregation with all ristocetin concentrations. Mildly decreased platelet aggregation was seen with adenosine diphosphate, collagen, epinephrine, and arachidonic acid, which was attributed to the patient's thrombocytopenia. Figure 2 depicts the following agonists used for the aggregation study: Tracing 1, ristocetin, 1.5 mg/mL; Tracing 2, ristocetin, 1.2 mg/mL; Tracing 3, ristocetin, 0.4 mg/mL; and Tracing 4, arachidonic acid, 5.0 mg/mL. Platelet marker study by flow cytometry showed decreased platelet CD42b (GPIb) with normal CD41 and CD61. Complete blood count performed on the parents showed no thrombocytopenia and normal mean platelet volume (the mother had a platelet count of 259 000/μL with a mean platelet volume of 6.7 fL; the father had a platelet count of 194 000/μL with a mean platelet volume of 8.4 fL). Marker study by flow cytometry of the parents' platelets showed no decrease in GPIb, supporting an autosomal recessive mode of inheritance. Figure 3 represents platelet GPIb by flow cytometry and reveals a decreased level in the patient (21.2% [Figure 3, A]) and normal levels in the mother and father (95.5% [Figure 3, B] and 92.4% [Figure 3, C], respectively). Ultrastructure study of platelets from the patient showed no abnormalities, and no inclusions were seen in the neutrophils (findings not shown).What is your diagnosis?Most thrombocytopenias in children are acquired and attributed to an immunologic mechanism resulting in increased peripheral consumption of platelets (immune thrombocytopenic purpura). Despite high prevalence and a wide spectrum of clinical pathologic findings, immune thrombocytopenic purpura must not be used as a default diagnosis for inadequately investigated cases of thrombocytopenia. An atypical clinical course should serve as a red flag and be followed by proper studies to determine other possibilities including inherited platelet abnormalities. We present a case that was initially misconstrued clinically as immune thrombocytopenic purpura. A lack of response (to intravenous immunoglobulin and steroids) prompted further investigation. Additional studies, including platelet markers by flow cytometry, revealed the diagnosis of a mild variant of Bernard-Soulier thrombocytopenia.The differential diagnosis of thrombocytopenia with large platelets includes such rare disorders as May-Hegglin anomaly, Sebastian platelet syndrome, Montreal platelet syndrome, and gray platelet syndrome, in addition to Bernard-Soulier syndrome.May-Hegglin anomaly is the most prevalent among these rare disorders and follows an autosomal dominant mode of inheritance. It is characterized by mild to moderate thrombocytopenia, giant platelets, and spindle-shaped inclusions (resembling Dohle bodies) in the cytoplasm of neutrophils. Ultrastructure studies show that these inclusions contain parallel filaments studded with ribosomes.1Sebastian platelet syndrome is also inherited in an autosomal dominant fashion. It is characterized by thrombocytopenia, large platelets, and spherical inclusions in neutrophils. On ultrastructure examination, the neutrophil inclusions consist of unorganized filaments.2 Clinically, the syndrome usually manifests with mild bleeding tendency.Montreal platelet syndrome is another rare disorder inherited as an autosomal dominant trait, which manifests clinically with bleeding tendency. Laboratory findings include thrombocytopenia, large platelets, prolonged bleeding time, and spontaneous platelet aggregation.Gray platelet syndrome, another rare platelet dysfunction disorder, is inherited in an autosomal dominant mode. It is characterized by thrombocytopenia and giant platelets that appear pale on a stained peripheral blood smear (hence the name gray platelet) due to decreased or absent platelet alpha granules.Bernard-Soulier syndrome is the only disorder in this group that is inherited in an autosomal recessive mode. Bernard-Soulier syndrome is a bleeding diathesis caused by a deficiency or dysfunction of platelet glycoprotein Ib-IX-V complex. This results in the platelet's inability to bind to von Willebrand factor. Clinically most patients present in infancy or childhood with ecchymoses, epistaxis, and gingival bleeding. Other manifestations may include posttraumatic hemorrhage, menorrhagia, and gastrointestinal bleeds. Laboratory findings include thrombocytopenia, giant platelets, prolonged bleeding time, and abnormal platelet aggregation with ristocetin.The diagnosis is suspected based on the previously described clinical manifestation and typical laboratory findings and may be confirmed with flow study of platelets showing decreased or absent CD42b (GPIb). Molecular studies have identified at least 18 different mutations in the genes of the glycoprotein Ib-IX-V complex that result in Bernard-Soulier syndrome. In symptomatic patients, platelet transfusion is the only effective treatment.In our patient, the absence of Dohle bodies helps to exclude May-Hegglin anomaly, and the lack of spherical neutrophil inclusions on ultrastructure examination excludes Sebastian platelet syndrome. The presence of platelet alpha granules excludes gray platelet syndrome. The morphologic and platelet marker findings, along with the mode of inheritance, support the diagnosis of Bernard-Soulier syndrome in our patient. The lack of significant clinical bleeding may be explained by the partial deficiency of platelet's GPIb and suggests a mild variant form of Bernard-Soulier syndrome.34

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