Acquired Amegakaryocytic Thrombocytopenia Misdiagnosed as Immune Thrombocytopenia: A Case Report



 

Arya Mariam Roy MD12; Manojna Konda MD12; George K Sidarous12; Dinesh Atwal MD12; Steven A Schichman MD, PhD12; Anuradha Kunthur MD12

Perm J 2020;24:19.203 [Full Citation]

https://doi.org/10.7812/TPP/19.203
E-pub: 12/02/2020

ABSTRACT

Introduction: Acquired amegakaryocytic thrombocytopenia (AATP) is a rare bleeding disorder that causes severe thrombocytopenia with preserved hematopoiesis of other cell lineages. Many cases are misdiagnosed and treated as immune thrombocytopenia.

Case Presentation: We report a case of AATP, in a 50-year-old man, that was treated as immune thrombocytopenia for years with no clinical response. The disorder later was diagnosed as AATP after bone marrow biopsy and was successfully treated with cyclosporine.

Discussion: The exact mechanism of AATP remains unclear; it is suspected to be an immune-mediated process. Patients with AATP present with severe bleeding and thrombocytopenia, which is usually unresponsive to high-dose corticosteroids. There are no standard treatment guidelines for AATP. Cyclosporine and antithymocyte globulin are found to be effective in some cases. The prompt diagnosis of AATP is vital because it carries high mortality because of excessive bleeding, and it can progress into aplastic anemia or myelodysplastic syndrome.

INTRODUCTION

Acquired amegakaryocytic thrombocytopenia (AATP) is a rare hematologic disorder characterized by thrombocytopenia resulting from marked reduction or absence of bone marrow megakaryocytes with preserved hematopoiesis of other cell lineages.1 Although the exact prevalence of AATP is not known,2 it is very likely that the incidence rates could be higher than reported because many of the cases are either underdiagnosed or misdiagnosed as immune thrombocytopenia (ITP), formerly called idiopathic thrombocytopenic purpura. It is crucial to differentiate AATP from other acquired causes of thrombocytopenia, the most common being ITP, because corticosteroids and intravenous immunoglobulins (IVIG), which are the mainstay for management of ITP, have been found to be mostly ineffective in AATP.3,4

Although the exact pathogenesis of AATP has not been fully elucidated, a dysregulated immune system is suspected to be the primary culprit.2 Standard treatment guidelines for AATP are yet to be established because the available literature contains only case reports and a few small case series. We describe a patient who was treated for ITP for several years but had gradually worsening platelet counts and later received a diagnosis of AATP and was successfully treated with cyclosporine.

CASE PRESENTATION

Presenting Concerns

A 50-year-old man with a previous diagnosis of ITP (chronic idiopathic thrombocytopenic purpura) reestablished care in our clinic because of a recent drop in his platelet count. He reported that ITP was diagnosed 6 years earlier, in 2012, and his platelet count was 50 × 103/μL at the time of initial diagnosis. He received a 15-day course of prednisone, 1 mg/kg daily, at that time, with some improvement in his platelet count. His platelet count remained stable at around 100 × 103/μL to 150 × 103/μL for 5 years after the diagnosis of ITP and then gradually started to trend down. His platelet count on presentation to our clinic in August 2018 was 19 × 103/μL. He denied a history of major bleeding or hematoma but reported having easy bruisability and prolonged bleeding after trivial trauma for years. He had no personal or family history of bleeding disorders, autoimmune disorders such as rheumatoid arthritis or lupus, or malignancy.

Results of his laboratory workup on presentation to our clinic showed anemia with a hemoglobin level of 11.5 g/dL, thrombocytopenia with a platelet count of 19 × 103/μL, and normal white blood cell count. Results of the physical examination were unremarkable. Workup including HIV, hepatitis C virus, Helicobacter pylori, and liver function tests as well as a coagulation panel, antinuclear antibody panel, and rheumatoid factor yielded negative or normal results. Vitamin B12 and folate levels were normal. A peripheral blood film (“peripheral smear”) had unremarkable findings except for a decreased number of platelets. Abdominal images showed no splenomegaly or malignancy.

Therapeutic Intervention and Treatment

The patient received a 4-day course of oral dexamethasone, 40 mg daily, without experiencing any improvement in platelet count. A bone marrow biopsy specimen showed varying cellularity with an average cellularity of approximately 20%. The biopsy specimen also showed normal erythropoiesis and myelopoiesis, but a markedly decreased number of megakaryocytes with no morphologic evidence of myelodysplastic syndrome (MDS). There was less than 1 megakaryocyte per high-power field (Figures 1 and 2). Fluorescence in situ hybridization and cytogenetic test results were negative for MDS. Flow cytometry results of bone marrow demonstrated no monoclonality or malignancy. This picture was consistent with amegakaryocytic thrombocytopenia rather than ITP because there is usually a compensatory increase in megakaryocytes in the bone marrow in ITP. Antibodies against thrombopoietin (TPO) were not detectable. Additionally, an antiplatelet antibody panel was performed by an external laboratory, and results were negative as well. We could not find a cause of the AATP in this case.

Figure 1

Figure 1. Varying cellularity in the bone marrow of a man with a misdiagnosis of immune thrombocytopenia. (Compare these photomicrographs with Figure 2.) A. Bone marrow shows a region of 40% cellularity (×10). B. Higher magnification view (×20) of the same area showing a rare megakaryocyte in the bone marrow (arrow).

Figure 2

Figure 2. Photomicrograph of a different part of the same patient’s bone marrow showing 0% cellularity (with no hematopoietic cells) but intact adipocyte framework (×10).

Follow-up and Outcomes

The patient was started on a regimen of cyclosporine with a goal serum level between 150 ng/mL and 400 ng/mL. He experienced improvement in platelet counts to greater than 50 × 103/μL over 8 weeks (Figure 3). He has continued treatment with cyclosporine, 200 mg twice daily, for more than a year, and platelet counts continue to stay above 50 × 103/μL. A detailed timeline of the case appears in Table 1.

Figure 3

Figure 3. Graph of timeline of platelet count (×103/μL) response to cyclosporine therapy. BID = twice daily; CyA = cyclosporine; D = day.

Table 1. Timeline of the case

Relevant medical history and interventions:A 50-year-old man with a diagnosis of chronic idiopathic thrombocytopenic purpura since 2012 presented with no family history of bleeding disorders.
Date Summaries from initial and follow-up visits Diagnostic testing Interventions
8/7/2018 On initial presentation to our clinic, patient reported easy bruising and prolonged bleeding on trivial trauma Laboratory tests on presentation included:Hemoglobin: 11.5 g/dLWBC: 3.8 × 103/μLPlatelet count: 19 × 103/μLHIV, HCV, Helicobacter pylori, liver function test, coagulation panel, antinuclear antibody, rheumatoid factor, vitamin B12, folate: Normal resultsCT scan of abdomen and pelvis: Normal resultsPeripheral smear: Decreased number of platelets Dexamethasone, 40 mg daily, for 4 d without improvement in platelet count
9/4/2018 On follow-up visit, no new symptoms Platelet count: 17 × 103/μL Bone marrow biopsy: Varying cellularity from 40% to 0% with normal erythropoiesis and myelopoiesis but absent megakaryocytes; no morphologic evidence of MDS. Fluorescence in situ hybridization and cytogenetics were negative for MDS. Flow cytometry of bone marrow was negative for monoclonality or malignancy.
9/18/2018 Diagnosis of AATP made from bone marrow biopsy. Reported new spontaneous bruises on inner left thigh Platelet count: 18 × 103/μLAntibodies against thrombopoietin: NegativeAntiplatelet antibody panel: Negative Started on regimen of cyclosporine, 2.5 mg/kg/d (150 mg twice daily)
9/25/2018 Patient tolerated cyclosporine, denied adverse effects Platelet count: 22 × 103/μLCyclosporine level: 116.1 ng/mL Cyclosporine dose increased to 175 mg twice daily
10/9/2018 Patient tolerated cyclosporine, denied adverse effects Platelet count: 33 × 103/μLCyclosporine level: 142.3 ng/mL Cyclosporine dose increased to 200 mg twice daily
12/11/2018 Patient tolerated cyclosporine Platelet count: 56 × 103/μLCyclosporine level: 213.9 ng/mL Continued cyclosporine, 200 mg twice daily
4/16/2019 No new bleeding; patient tolerated cyclosporine Platelet count: 62 × 103/μLCyclosporine level: 202.4 ng/mL Cyclosporine dose reduced to 175 mg twice daily
11/12/2019 No new symptoms; patient denied bleeding Platelet count: 67 × 103/μLCyclosporine level: 183.0 ng/mL Received cyclosporine, 175 mg twice daily
02/04/2020 On most recent clinic visit, no rash or bleeding Platelet count: 68 × 103/μLCyclosporine level: 146.8 ng/mL Continued Cyclosporine 175 mg twice daily

AATP = acquired amegakaryocytic thrombocytopenia; CT = computed tomography; HCV = hepatitis C virus; MDS = myelodysplastic syndrome; WBC = white blood cells.

DISCUSSION

The causes of acquired thrombocytopenia are quite extensive and include acquired marrow hypocellularity, qualitative defect in platelet production with adequate marrow cellularity, defective thrombopoietic control with normal marrow, and peripheral destruction of the platelets.2

Our patient was previously given a diagnosis of ITP and received systemic corticosteroids with some initial improvement in his platelet counts. However, the gradual worsening of his platelet counts over the years and a poor response to high-dose corticosteroids the second time raised the possibility of other causes of his thrombocytopenia. Furthermore, the absence of megakaryocytes on bone marrow biopsy in our patient is inconsistent with ITP and more consistent with AATP because there is usually a compensatory increase in megakaryocytes in the bone marrow in ITP. This emphasizes the importance of performing a bone marrow biopsy in patients with unexplained, isolated thrombocytopenia or in patients with an ITP diagnosis if they are not adequately responding to corticosteroids or IVIG.

AATP can be idiopathic and occur as a primary disorder or be seen in association with lymphoproliferative disorders1; autoimmune disorders such as systemic lupus erythematosus,5 rheumatoid arthritis,1 or Still disease6; viral infections such as cytomegalovirus,2 Epstein-Barr virus,7 parvovirus B19,8 or hepatitis C9; exposure to environmental toxins such as benzene1; and vitamin B12 deficiency.10 It could also be a precursor for aplastic anemia,11 MDS,12 or acute leukemia.4 In our patient, we could not find any cause for AATP, and hence it is likely idiopathic.

Although the exact mechanism of AATP remains unclear, it is strongly suspected to be an immune-mediated process. The primary regulator of platelet production is TPO, which is mainly produced by the hepatocytes.7 It binds to the TPO cellular-myeloproliferative leukemia receptor on megakaryocytes and hematopoietic stem cells, affecting nearly all stages of platelet production including proliferation, differentiation, and maturation of megakaryocyte into platelets. Dysregulated humoral immunity as one of the mechanisms for AATP has been proposed because of the presence of anti-TPO immunoglobulin G antibodies13 and autoantibodies against the cellular-myeloproliferative leukemia receptor,5,8 blocking the function of TPO. Cell-mediated immunity appears to play a more important role because T lymphocytes obtained from a patient with AATP were found to selectively inhibit megakaryocyte lineage in vitro.14 The response of AATP to immunosuppressants further supports the immune-mediated pathogenesis of AATP.

There are no standard treatment guidelines for AATP. Unlike in ITP, prednisone and IVIG have been found to be largely inefficacious or transiently effective in patients with AATP.2-4 Although there is no expert consensus, cyclosporine monotherapy has been found to be quite effective in several reported cases,4,6-9 including our patient. Cyclosporine with a target serum level between 150 and 350 ng/mL has been found to be most effective.2 Cyclosporine needs to be continued for several weeks to months for complete remission. The dose can be tapered after the normalization of platelet counts.2 In patients with severe bleeding from thrombocytopenia or who are refractory to treatment with cyclosporine alone, administration of antithymocyte globulin along with cyclosporine has been found to be effective.4

Other therapies such as rituximab,3 mycophenolate mofetil,15 danazol,16 and azathioprine17 have also been used to treat AATP with varying success. In patients refractory to cyclosporine or antithymocyte globulin and in patients with relapsed disease or disease progression into aplastic anemia or MDS, allogeneic bone marrow transplant should be strongly considered, especially in relatively young patients with matched siblings.18 Some case reports showed that alemtuzumab, a T cell-depleting agent19, and TPO receptor agonists such as eltrombopag and romiplostim have also been found to evoke a satisfactory response in patients with refractory AATP.20

The prognosis and clinical course of AATP is variable, with some patients achieving remission and having a durable response, whereas others have a long relapsing-remitting disease course. Furthermore, there are a few patients who progress rapidly to aplastic anemia,11 MDS,12 or even leukemia4 despite aggressive immunosuppressive treatment, which makes regular long-term follow-up necessary.

CONCLUSION

AATP is a rare disease that can easily be confused with other causes of thrombocytopenia, especially ITP. This case report highlights the importance of performing a bone marrow biopsy in cases of unexplained thrombocytopenia and in patients who have a diagnosis of ITP but do not adequately respond to corticosteroids or IVIG, to rule out amegakaryocytic thrombocytopenia. This form of thrombocytopenia requires prompt treatment and close follow-up. Additionally, our observations also confirm successful treatment of this rare entity with cyclosporine.

Disclosure Statement

The author(s) have no conflicts of interest to disclose.

Acknowledgments

Kathleen Louden, ELS, of Louden Health Communications performed a primary copy edit.

Author Affiliations

1John L McClellan Memorial Veterans Hospital, Little Rock, AR

2University of Arkansas for Medical Sciences, Little Rock, AR

Corresponding Author

Dinesh Atwal, MD ()

How to Cite this Article

Roy AM, Konda M, Sidarous GK, Atwal D, Schichman SA, Kunthur A. Acquired amegakaryocytic thrombocytopenia misdiagnosed as immune thrombocytopenia: A case report. Perm J 2020;24:19.203. DOI: 10.7812/TPP/19.203

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Keywords: acquired amegakaryocytic thrombocytopenia (AATP), chronic idiopathic thrombocytopenic, hematologic process, immune thrombocytopenia (ITP), immune-mediated process

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