An approach to isolated thrombocytopenia in an outpatient setting

A 22-month-old boy was evaluated because of thrombocytopenia. He was of Mediterranean descent and born to consanguineous parents. His first documented platelet count was performed at 10 months of age when he presented to the emergency room with a 2-day history of bleeding from his frenulum after trauma to his mouth. Complete blood count (CBC) showed marked isolated thrombocytopenia with a platelet count of 34 × 109/L; this was thought to be due to viral suppression. Many large platelets were reported on the peripheral blood smear (PBS) (Figure 1) and there was an elevated Immature Platelet Fraction (IPF). The thrombocytopenia persisted on subsequent follow-up investigations. He continued to have mild bruising but no other bleeding. Upon further questioning, the parents recalled that the patient had also presented to the emergency room at 20 days of age, with bleeding 4 hours postcircumcision. A CBC had been requested but the platelet count was not reportable due to a clot in the specimen, and no follow-up was arranged at that time, as the bleeding subsided. Physical examination, growth and development were normal, except for mild bruising noted on his lower extremities. (Wright-Giemsa, 60×): Composite image of the peripheral blood smear findings. (A) Many giant platelets are present (block arrow), and are larger than the size of the normal red cells. (B) Giant platelet with normal neutrophil and red cells. The patient was referred to a paediatric Hematology service. A diagnosis of Bernard-Soulier syndrome (BSS) was confirmed with specialized testing. The defect in BSS is the missing platelet membrane glycoprotein GP1b complex, which is the receptor for von Willebrand factor. On platelet aggregometry testing this results in a failure of platelets to aggregate with ristocetin. On flow cytometry, platelets have absent CD42. BSS is a rare (1:1000 000) autosomal recessive inherited platelet disorder characterized by giant platelets, thrombocytopenia and mild to moderate bleeding diathesis. Due to its rare nature, the initial presentation of these patients may be to their paediatrician, and not to a hematologist who would be more familiar with BSS. As a result, initial investigations will consist of routine laboratory tests, including a CBC and morphology review of the peripheral blood. We will use this case to illustrate an approach to isolated thrombocytopenia in an outpatient setting. Isolated moderate to marked thrombocytopenia is uncommon in an outpatient setting. Pre-analytical issues with samples would be the first thing to consider when one encounters a laboratory report with thrombocytopenia. Difficult blood collections or suboptimal sample volumes are more common in the paediatric setting, and can lead to spurious platelet counts due to fibrin clots or platelet clumping. Both of these can be noted on a PBS and many laboratories comment on these findings in their report. In an asymptomatic patient, always consider repeating the sample prior to launching into an extensive investigation. Immune thrombocytopenia (ITP) is the most commonly encountered thrombocytopenic state in a relatively well child. Acute ITP typically presents with moderate to marked thrombocytopenia (1–50 × 109/L). On PBS, large platelets are often noted, and are typical of active bone marrow thrombopoiesis. However, these giant forms are occasional and should not be the predominant finding. Other morphologic findings that could be reported include the presence of reactive lymphocytes. Significant quantitative decreases in the red cell and white cell lineages should not be present, and may warrant further investigation. Other than BSS, there are other heritable thrombocytopenic states. One classification scheme for these disorders involves assessment of platelet size on PBS. Wiskott-Aldrich syndrome is an X-linked disorder with marked thrombocytopenia, small platelets and the clinical presentation of severe immunodeficiency. Moderate thrombocytopenia and large platelets is a feature of the MYH9-related diseases (e.g., May-Hegglin). This family of disorders is associated with other findings on the PBS, including Döhle bodies in the white blood cells. This feature may be missed if the laboratory is not alerted to look for it. The inherited bone marrow failure syndromes are another category of rare disorders that could present with isolated thromobocytopenia (1). As a group, these syndromes are often associated with physical and neurocognitive abnormalities and individuals are at increased risk to develop aplastic anemia and/or malignant transformation. Modern CBC analyzers provide additional information in the assessment of a thrombocytopenic patient. The availability of the parameters will be dependent on the analyzer and the reporting practice of the lab. Mean Platelet Volume measures the overall size of a platelet population, similar to the Mean Corpuscular Volume for the red cell population. The IPF is similar to a ‘reticulocyte count’ for platelets. The IPF has been used to separate thrombocytopenic states into underproduction states (low IPF; e.g., chemotherapy, aplastic anemia) versus peripheral destruction with an appropriate bone marrow response (high IPF, e.g., ITP). A PBS review by an experienced morphologist provides additional information. Slide review still remains the gold standard for assessment of platelet size. Additionally, morphologic abnormalities in the red cell and white cell lineages can be evaluated. Preanalytical issues with samples are encountered more frequently in the paediatric setting and should always be considered if the laboratory results do not appear to match the clinical circumstances. A careful review of the PBS provides useful information in the evaluation of a patient with thrombocytopenia. Communication of relevant clinical information to laboratory professionals will further improve the yield of this test. Familiarity with the clinical and laboratory features of BSS (moderate thrombocytopenia with predominance of large platelets and early age of presentation) may help to separate out this disorder from other causes of isolated thrombocytopenia presenting in childhood.

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