Introduction

In clinical practice, when elderly patients present with thrombocytosis, myeloproliferative diseases such as chronic myeloid leukemia and essential thrombocythemia are suspected first [1]. Other causes such as chronic inflammation, chronic iron deficiency and post-splenectomy status are also suspected. In addition, collagen disease-related hyposplenia should be included in the differential diagnosis of thrombocytosis in this age group [2]. However, even when dealing with elderly patients, caution must be exercised because very rare causes that can be responsible for persistent thrombocytosis also exist. In such rare hyposplenic cases, the absence of clinical symptoms relevant to thrombocytosis may mask the clues leading to the correct diagnosis.

Case reports

Case 1

A 72-year-old man of healthy appearance who was 161-cm tall and weighed 67 kg was referred to us for persistent thrombocytosis. He did not have a history of splenectomy, congenital cardiac anomalies, or severe infections in his early childhood/young adulthood. His family history was not significant. He had a gastric ulcer a year previously that had been treated conventionally. Thrombocyte counts that exceeded 500,000/μl had been recorded repeatedly for over 15 years. Over the past few years, the patient had been treated for hypertension and hyperlipidemia. His laboratory data were as follows: WBC 11,400/μl, Hb 12.1 g/dl, platelet counts 566,000/μl, serum ferritin 24.2 ng/ml,AST 22 U/ml, ALT 27 U/ml, LDH 147 U/ml, total protein 7.6 g/dl, albumin 4.5 g/dl, BUN 17.0 mg/dl, creatinine 0.62 mg/dl, and CRP 0.27 mg/dl. The serum IgG (1,356 mg/dl), IgA (293 mg/dl) and IgM (64 mg/dl) levels and the NAP score (195, normal range 170–367) were all within normal ranges. Platelet counts over the past 1 year were median 515,000 (range 464,000–566,000)/μl. Bone marrow aspiration showed normocellular smear with an M/E ratio 3.3 in association with an increase of megakaryocytes/active platelet production. Chromosome analysis revealed 45, X, −Y [9/20] and 46, XY [11/20]; however, no morphological features suggestive of myelodysplasia were noted. To rule out essential thrombocythemia, the patient was screened for the JAK2 V617F mutation but it was not found. Chronic myeloid leukemia was excluded on the basis of the absence of BCR-ABL mRNA transcripts. Surprisingly, an ultrasound of his abdomen revealed that the spleen was absent, although the patient had never undergone splenectomy or received abdominal radiation therapy. The absence of the spleen was confirmed by a computed tomography (CT) scan, which revealed the presence of a very small vestigial tissue (Fig. 1a). It was not possible to perform 99mTc-labeled red cell scintigraphy to evaluate the function of this residual spleen but its hypofunction was evident from the presence of Howell–Jolly bodies on a blood smear (Fig. 1b). To rule out the possible involvement of autoimmune disease, the patient was also screened for anti-nuclear, anti-DNA, and anti-phospholipid antibodies but such antibodies were not detected. Eventually, the patient was diagnosed with persistent thrombocytosis due to non-familial type isolated congenital asplenia (ICA; OMIM#271400) that had not been diagnosed earlier because the patient had managed to escape severe infectious or thrombotic events until the age of 72 years. As a result of this diagnosis, the patient was given 23-valent pneumococcal vaccine.

Fig. 1
figure 1

Case 1: a CT scan of the abdomen. The arrowhead shows a small vestigial spleen. b The peripheral blood smear shows the presence of Howell–Jolly bodies (arrows)

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Case 2

A 74-year-old man of healthy appearance who was 161-cm tall and weighed 60.3 kg was referred to our hospital because of thrombocytosis (>500,000/μl). Assessment of his past history revealed that he had been treated for hypertension, hyperlipidemia and hyperuricemia for the last few years and that he underwent subtotal gastrectomy for a perforated stomach 20 years previously. It was not possible to retrieve the medical chart that detailed the surgical procedure of the gastrectomy, but according to the patient, he was treated for severe panperitonitis at the time of the surgical procedure. After recovering, he did well for nearly 20 years without experiencing any septic or thrombotic events until a few years ago, when his home physician noted that he had thrombocytosis. A physical examination revealed a 15-cm long scar resulting from a longitudinal median incision on the abdomen, and his liver and spleen were not palpable. His laboratory data were as follows: WBC 6,900/μl, Hb 11.8 g/dl, platelet counts 525,000/μl, serum ferritin 10.0 ng/ml,AST 16 U/ml, ALT 14 U/ml, LDH 166 U/ml, total protein 7.3 g/dl, albumin 4.4 g/dl, BUN 17.9 mg/dl, creatinine 1.00 mg/dl, and CRP 0.04 mg/dl. His levels of serum IgG (1,485 mg/dl), IgA (130 mg/dl) and IgM (78 mg/dl) were all within normal ranges. Platelet counts over the past 1.5 years were median 461,000 (range 435,000–606,000)/μl. Bone marrow aspiration showed hypercellular smear with an M/E ratio 2.3 in association with an increase of megakaryocytes/active platelet production. No morphological features suggestive of myelodysplasia were noted and the karyotype was 46, XY [20/20]. To rule out essential thrombocythemia, the patient was screened for the JAK2 V617F mutation but it was not detected. The patient was also screened for anti-nuclear, anti-DNA, and anti-rheumatoid factors but none of the tests returned a positive result. Surprisingly, a CT scan of his abdomen showed an atrophied spleen with a spotty calcification (Fig. 2a). Careful observation of his blood smear revealed the presence of Howell–Jolly bodies (Fig. 2b). After the diagnosis of atrophied spleen, the patient was given the 23-valent pneumococcal vaccine.

Fig. 2
figure 2

Case 2: a CT scan of the abdomen. The arrowhead shows an atrophied spleen with spotty calcification. b The peripheral blood smear shows the presence of Howell–Jolly body (arrow)

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Discussion

Both patients described here had persistent thrombocytosis due to hyposplenia, which is a very rare cause of thrombocytosis in elderly patients. The first case had ICA while the second had an atrophied spleen that was probably the result of past panperitonitis, although the precise mechanism involved remains unknown. Neither patient had a history of splenectomy nor abdominal irradiation. Autoimmune diseases were also excluded. Case 2 was in a slightly iron-deficient status on admission; however, platelet counts did not significantly reduced following the administration of sodium ferrous citrate. As is well known, there are two types of congenital asplenia, namely the Ivemark syndrome, which is usually associated with major cardiac malformations, and ICA. ICA is a very rare condition that occurs sporadically or has a familial association [3, 4]. In the recent review by Mahlaoui et al. [4], they found 50 reported cases of ICA in the literature that included 24 sporadic and 26 familial cases: of these cases, 33 were children and 13 were adults (the age was not available for four cases).Thus, the diagnosis of ICA in our Case 1 had some precedent in the medical literature. In contrast, it was difficult to find cases of intra-abdominal infection-related hyposplenia that resembled our Case 2 in the literature. With regard to gastrointestinal disease-related thrombocytosis, while reports on celiac disease-related thrombocytosis are available [5, 6], these cases were unrelated to hyposplenia.

It is well known that patients with asplenia or hyposplenia are susceptible to life-threatening or fatal septicemia caused by encapsulated pathogens [7]. Thus, it was surprising that neither of our patients ever experienced such life-threatening infectious events previously. The French study by Mahlaoui et al. [4] revealed that 15 of their own series of 20 patients sustained 18 episodes of invasive bacterial infection, with nine patients (45 %) dying from fulminant infection [4]. Moreover, their own series included three adult patients with ICA who had invasive bacterial infections at the ages of 20, 26 and 43 years, respectively. Moreover, the three case reports of adult ICA with life-threatening infection that could be found in the literature revealed that the patients were 28, 60 and 67 years of age, respectively [3, 8, 9]. In addition, three adult cases of ICA with thrombocytosis but no infectious events were found: these patients were 37, 56, and 56 years of age, respectively [10, 11]. Thus, our patients, who were both over 70, are the oldest cases of hyposplenia-induced thrombocytosis diagnosed in the absence of infectious events. Notably, reflecting another risk associated with thrombocytosis in adults, the literature also describes the case of a 44-year-old female with ICA who had chronic thromboembolic pulmonary hypertension [12].

The diagnosis of asplenia or hyposplenia can be achieved by detecting Howell–Jolly bodies on blood smears and by showing the absence or atrophy of the spleen by ultrasound or CT scanning of the abdomen with or without scintigraphy. In our patients, CT scans revealed that both had vestigial spleen tissue. The current guidelines for preventing infections in hyposplenic patients, which include patient education, provision of antibiotic prophylaxis, and vaccination, are well defined [4]. In terms of management in our patient, the indication of low-dose aspirin is uncertain because both had asymptomatic reactive thrombocytosis at low risk for thrombotic events.

In summary, if persistent thrombocytosis is observed, even in elderly patients, it should be kept in mind that very rare causes such as hyposplenia are possible. If hyposplenia is confirmed, appropriate measures that prevent life-threatening infection and thrombotic events must be taken immediately.