Acquired Amegakaryocytic Thrombocytopenia with Glycoprotein IIb/IIIa Antibody in a Patient with Mantle Cell Lymphoma.

Background Acquired amegakaryocytic thrombocytopenia (AAMT) is a rare disorder characterized by thrombocytopenia, marked megakaryocytic hypoplasia, and preserved other-lineage hematopoiesis in the bone marrow. The etiology of AAMT remains poorly understood owing to its rarity. Case description We encountered a diagnostically challenging case involving a 66-year-old man who showed severe thrombocytopenic bleeding with isolated megakaryocytic hypoplasia, elevated serum thrombopoietin levels, glycoprotein IIb/IIIa antibody positivity, and prolonged platelet transfusion refractoriness following mantle cell lymphoma (MCL). Treatment with corticosteroids and intravenous immunoglobulin was ineffective, while a combination of multiagent chemotherapy, including rituximab, was beneficial for both thrombocytopenia and MCL. Ultimately, the patient was diagnosed with AMMT and immune thrombocytopenia (ITP)-like platelet destruction. Discussion This case suggests that AAMT and ITP are non-exclusive and sometimes overlap as components of a broad spectrum of platelet-related autoimmune diseases.

Successful avatrombopag combined with cyclosporine treatment for carboplatin/pegylated liposomal doxorubicin/bevacizumab-induced acquired amegakaryocytic thrombocytopenia in a patient with recurrent ovarian cancer: case report.

Carboplatin/pegylated liposomal doxorubicin/bevacizumab is an accepted standard anti-cancer treatment option for recurrent ovarian cancer. However, the occurrence of adverse events associated with this therapeutic regimen limits its continued clinical use. Among these adverse events, acquired amegakaryocytic thrombocytopenia is a rare but often potentially life-threatening adverse effect, and is intolerant to multiple treatment approaches. We report, for the first time, the successful treatment using avatrombopag combined with cyclosporine in one case of carboplatin/pegylated liposomal doxorubicin/bevacizumab-induced acquired amegakaryocytic thrombocytopenia, which was refractory or intolerant to glucocorticoids, intravenous immunoglobulin, recombinant human thrombopoietin, androgen, and even thrombopoietin receptor receptor agonist eltrombopag and herombopag. To date, this case manifests as normal platelet counts that are independent of transfusion. Our findings suggest that this combination is a potential and valuable alternative in acquired amegakaryocytic thrombocytopenia.

A novel missense mutation in the MECOM gene in a Chinese boy with radioulnar synostosis with amegakaryocytic thrombocytopenia.

Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT) type 2, caused by MDS1 and EVI1 complex locus (MECOM) gene mutations, is a rare inherited bone marrow failure syndrome (IBMFS) with skeletal anomalies, characterized by varying presentation of congenital thrombocytopenia (progressing to pancytopenia), bilateral proximal radioulnar synostosis, and other skeletal abnormalities. Due to limited knowledge and heterogenous manifestations, clinical diagnosis of the disease is challenging. Here we reported a novel MECOM mutation in a Chinese boy with typical clinical features for RUSAT-2. Trio-based whole exome sequencing of buccal swab revealed a novel heterozygous missense mutation in exon 11 of the MECOM gene (chr3:168818673; NM_001105078.3:c.2285G > A). The results strongly suggest that the variant was a germline mutation and disease-causing mutation. The patient received matched unrelated donor hematopoetic stem cell transplantation (HSCT). This finding was not only expanded the pathogenic mutation spectrum of MECOM gene, but also provided key information for clinical diagnosis and treatment of RUSAT-2.

Genomic and computational analysis of four novel variants of MPL gene in Congenital Amegakaryocytic Thrombocytopenia.

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, genetic, autosomal recessive disorder characterized by severe thrombocytopenia, due to inefficient bone marrow megakaryopoiesis eventually leading to aplasia. Majority of the cases are due to homozygous or compound heterozygous mutations in MPL gene encoding for thrombopoietin (THPO) receptor protein. CAMT can be diagnosed at early phase of life, with major complication of transfusion dependency and hematopoietic transplantation as only curative treatment. We have investigated the sequence variations in MPL gene of 7 bone marrow failure (BMF) subjects, who presented with clinically diverse phenotypes, through next generation sequencing (NGS). Plasma THPO levels were estimated using ELISA. Insilico sequence and structure-based analyses were performed to understand the structural and functional implications of mutations, identified through NGS. We studied 7 CAMT subjects suspected of BMF, who presented with severe thrombocytopenia followed by pancytopenia, bleeding manifestation and physical anomalies. The plasma THPO levels were significantly elevated (p<0.05) in all the cases. Molecular analysis by NGS identified 9 genomic mutations in MPL gene. These included 7 non-synonymous substitution, 1 nonsense substitution and 1 in-del mutations, of which 4 are novel mutations. Insilico analysis predicted damaging effects on THPO-R and its reduced affinity for THPO for all the identified mutations. CAMT is a rare disorder with diverse clinical phenotypes and diagnosis is challenging. The elevated plasma THPO levels should be considered for the primary diagnosis and prognosis of the disease. However, molecular analysis of MPL gene is important for the diagnosis and management of the disease through genetic counselling. Though the cytokines, THPO-R agonist are used for the treatment of CAMT, HSCT is the only curative therapy.

Perinatal-lethal nonimmune fetal hydrops attributed to MECOM-associated bone marrow failure.

Pathogenic variants in MECOM, a gene critical to the self-renewal and proliferation of hematopoietic stem cells, are known to cause a rare bone marrow failure syndrome associated with amegakaryocytic thrombocytopenia and bilateral radioulnar synostosis known as RUSAT2. However, the spectrum of disease seen with causal variants in MECOM is broad, ranging from mildly affected adults to fetal loss. We report two cases of infants born preterm who presented at birth with symptoms of bone marrow failure including severe anemia, hydrops, and petechial hemorrhages; radioulnar synostosis was not observed in either patient, and, unfortunately, neither infant survived. In both cases, genomic sequencing revealed de novo variants in MECOM considered to be responsible for their severe presentations. These cases add to the growing body of literature that describe MECOM-associated disease, particularly MECOM as a cause of fetal hydrops due to bone marrow failure in utero. Furthermore, they support the use of a broad sequencing approach for perinatal diagnosis, as MECOM is absent from available targeted gene panels for hydrops, and highlight the importance of postmortem genomic investigation.

Radiation­induced pure red cell aplasia combined with acquired amegakaryocytic thrombocytopenia in a thymoma after rapid response to radiotherapy: A case report and literature review.

Thymoma combined with pure red cell aplasia (PRCA) and acquired amegakaryocytic thrombocytopenia (AAMT) has been rarely reported, often occurring in the initial stage of treatment and after chemotherapy or thymectomy, while PRCA and AAMT occurring after radiotherapy for thymoma has not been reported. The present study describes the case of a 42-year-old female patient with thymoma complicated by radiation-induced PRCA and AAMT after a rapid response to radiotherapy, who was in complete remission without recurrence after adjustment of initial symptomatic therapy to cyclosporine combined with prednisone. After 1 month, the patient underwent complete resection of mediastinal tumor. Next-generation sequencing revealed that the DNA damage repair pathway-related gene MSH3 was mutated, with p.A57P in abundance of 9.21%. To the best of our knowledge, the present study is the first to report that PRCA and AAMT secondary to thymoma after radiotherapy may be associated with increased sensitivity to radiotherapy caused by a mutation in the MSH3 gene.

Reduced-intensity conditioning is effective for allogeneic hematopoietic stem cell transplantation in infants with MECOM-associated syndrome.

Mutations in the MECOM encoding EVI1 are observed in infants who have radioulnar synostosis with amegakaryocytic thrombocytopenia. MECOM-associated syndrome was proposed based on clinical heterogeneity. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for progressive bone marrow failure. However, data regarding allogeneic HSCT for this rare disease are limited. We retrospectively assessed overall survival, conditioning regimen, regimen-related toxicities and long-term sequelae in six patients treated with allogeneic HSCT. All patients received a reduced-intensity conditioning (RIC) regimen consisting of fludarabine, cyclophosphamide or melphalan, and rabbit anti-thymocyte globulin and/or low-dose total body/thoracic-abdominal/total lymphoid irradiation, followed by allogeneic bone marrow or cord blood transplantation from unrelated donors between 4 and 18 months of age. All patients survived and achieved stable engraftment and complete chimerization with the donor type. Moreover, no patient experienced severe regimen-related toxicities, and only lower grades of acute graft-versus-host disease were observed. Three patients treated with low-dose irradiation had relatively short stature compared to three patients not treated with irradiation. Therefore, allogeneic HSCT with RIC is an effective and feasible treatment for infants with MECOM-associated syndrome. Future studies are needed to evaluate the use of low-dose irradiation to avoid risks of other long-term sequelae.

Refractory Acquired Amegakaryocytic Thrombocytopenia with Rapid Progression to Aplastic Anaemia in SLE.

Acquired amegakaryocytic thrombocytopenia (AAMT) is a rare cause of thrombocytopenia seen in systemic lupus erythematosus (SLE) that is frequently misdiagnosed as immune thrombocytopenic purpura (ITP). Often patients do not respond to standard ITP treatment. Prompt bone marrow biopsy and further workup should ensue as it is a diagnosis of exclusion. While no standard guidelines exist, the mainstay of treatment is immunosuppressive therapy. Some cases are refractory and should have a follow-up biopsy, typically showing worsening disease. The exact pathogenesis is unclear; multiple mechanisms may be involved, suggesting AAMT may be a syndrome of various aetiologies rather than a distinct pathology. A common complication is aplastic anaemia, and the patient may need a haematopoietic stem cell transplant (HSCT). We present a young man with severe refractory AAMT in the setting of SLE that progressed to aplastic anaemia and required an HSCT. We then discuss and interpret the literature on AAMT.

Acquired Amegakaryocytic Thrombocytopenia Progressing to Aplastic Anaemia.

Acquired amegakaryocytic thrombocytopenia (AAMT) is a rare disorder of the bone marrow characterized by a lack of megakaryocytes and preservation of other cell lines. It can occur due to an intrinsic stem cell defect or secondary to viral infections, autoimmune disorders, lymphoproliferative disorders or environmental toxins. With time, it can progress to aplastic anaemia (AA) and can have a poor prognosis. No standard guidelines exist for the treatment of AAMT progressing to AA. Herein, we report a rare case of AAMT leading to AA and review the handful of cases previously published in the literature. LEARNING POINTS: Acquired amegakaryocytic thrombocytopenia can present as isolated severe thrombocytopenia which can initially be misdiagnosed as immune thrombocytopenia.Lack of response to steroids and intravenous immunoglobulin should raise suspicion for acquired amegakaryocytic thrombocytopenia.Over time, acquired amegakaryocytic thrombocytopenia can progress to aplastic anaemia, which confers a worse prognosis.

A novel Mecom gene mutation associated with amegakaryocytic thrombocytopenia in a premature infant.

BACKGROUND: Hereditary bone marrow failure syndromes are a category of biologically different syndromes that can cause cytopenia in at least one hematopoietic cell lineage. CASE: We present a 29-week-old male infant who had a low Apgar Score, advanced delivery room resuscitation, widespread petechial rash, and ecchymoses at birth, without any dysmorphic features. Initial laboratory tests revealed bicytopenia (platelet count 7x10 3 /uL, hemoglobin of 3.9 g/dL, neutrophil 2.0x103 /uL) with findings of disseminated intravasculer coagulation (DIC). Imaging studies demonstrated accompanying left-sided congenital pulmonary airway malformation. On the second postnatal week pancytopenia occurred and the bone marrow findings were consistent with congenital amegakaryocytic thrombocytopenia. Further evaluations for differential diagnosis of pancitopenia were performed and the results of congenital viral infections, metabolic and immunologic tests were negative. While supportive treatments were in progress, haploidentical bone marrow transplantation (BMT) was performed from the father at 84th day due to unavailability of HLA-matched relative or nonrelative donor. Whole exome sequencing revealed a novel heterozygous frameshift variation (c.1242dupT [p. Thr538fs]) in exon 8 of the MECOM gene and validated by Sanger sequencing. No variation was detected in the parents genetic analysis. CONCLUSIONS: In this report, we present a patient with congenital bone marrow failure successfully treated with haploidentic BMT and describe a novel, de novo pathogenic variant in MECOM gene.

Acquired Amegakaryocytic Thrombocytopenia Associated With Autoimmune Hemolytic Anemia.

Acquired amegakaryocytic thrombocytopenia (AATP) is a thrombocytopenic disorder characterized by a decrease in megakaryocytes in the bone marrow. AATP is effectively treated with immunosuppressive therapy. We report a case of a 68-years-old male referred to us due to purpuric lesions on the extremities and was noted to be thrombocytopenic. Bone marrow biopsy showed AATP with autoimmune hemolytic anemia (AIHA). Only two cases of AATP associated with AIHA have been reported. AATP should be differentiated carefully from other causes of peripheral destruction of platelets, such as immune thrombocytopenia (ITP).

Non-myeloablative conditioning is sufficient to achieve complete donor myeloid chimerism following matched sibling donor bone marrow transplant for myeloproliferative leukemia virus oncogene (MPL) mutation-driven congenital amegakaryocytic thrombocytopenia: Case report.

Background: Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare platelet production disorder caused mainly by loss of function biallelic mutations in myeloproliferative leukemia virus oncogene (MPL), the gene encoding the thrombopoietin receptor (TPOR). Patients with MPL-mutant CAMT are not only at risk for life-threatening bleeding events, but many affected individuals will also ultimately develop bone marrow aplasia owing to the absence of thrombopoietin/TPOR signaling required for maintenance of hematopoietic stem cells. Curative allogeneic stem cell transplant for patients with CAMT has historically used myeloablative conditioning; however, given the inherent stem cell defect in MPL-mutant CAMT, a less intensive regimen may prove equally effective with reduced morbidity, particularly in patients with evolving aplasia. Methods: We report the case of a 2-year-old boy with MPL-mutant CAMT and bone marrow hypocellularity who underwent matched sibling donor bone marrow transplant (MSD-BMT) using a non-myeloablative regimen consisting of fludarabine, cyclophosphamide, and antithymocyte globulin (ATG). Results: The patient achieved rapid trilinear engraftment and resolution of thrombocytopenia. While initial myeloid donor chimerism was mixed (88% donor), due to the competitive advantage of donor hematopoietic cells, myeloid chimerism increased to 100% by 4 months post-transplant. Donor chimerism and blood counts remained stable through 1-year post-transplant. Conclusion: This experience suggests that non-myeloablative conditioning is a suitable approach for patients with MPL-mutant CAMT undergoing MSD-BMT and is associated with reduced risks of conditioning-related toxicity compared to traditional myeloablative regimens.

Successful treatment of acquired amegakaryocytic thrombocytopenia with eltrombopag and immunosuppressant.

Acquired amegakaryocytic thrombocypenia (AAMT) is an extremely rare hematologic disorder and standard treatment strategy has not been established. We described herein two cases of AAMT who were fully responded to eltrombopag and immunosuppressant. Patient 1 was refractory to steroid, IVIG and recombinant human thrombopoietin (rhTPO). Patient 2 did not respond to high dosage of steroid, IVIG, rhTPO and rituximab. Moreover, his AAMT progressed to aplastic anemia in 5 months. Both patients took eltrombopag and immunosuppressant, then they achieved long-term remission without obvious side effects. Our findings suggest that this combination can be a valuable alternative in AAMT.

Outcomes in Hematopoietic Stem Cell Transplantation for Congenital Amegakaryocytic Thrombocytopenia.

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, inherited bone marrow failure syndrome. Hematopoietic stem cell transplantation (HSCT) is considered a curative treatment option, but existing descriptions of patient and transplant characteristics and outcomes after related and unrelated donor HSCT are sparse. We describe outcomes after HSCT for congenital amegakaryocytic thrombocytopenia (CAMT; n = 86) from 2000 to 2018. We conducted an analysis of data collected by the Center for International Blood and Marrow Transplant Research on patients with CAMT receiving therapeutic allogeneic HSCT. The predominant donor type was HLA-matched or mismatched unrelated donors (n = 58, 67%). The remaining included HLA-matched sibling (n = 23, 27%) and HLA-mismatched relative (n = 5, 6%). The predominant graft types were bone marrow (n = 53, 62%) and cord blood (n = 25, 29%). The median age at transplantation was 3 years, with 82 of 86 patients being transplanted aged ≤10 years. The 5-year graft failure-free and overall survival were 83% (95% confidence interval [CI], 74-90) and 86% (95% CI, 78-93), respectively. An examination for risk factors confirmed mortality was higher after HLA-mismatched relative and mismatched unrelated donor HSCT compared to HLA-matched sibling and matched unrelated donor HSCT (hazard ratio 3.52, P = .04; 75% versus 93%). The 1-year incidence of graft failure was 19% after HLA-mismatched HSCT (n = 32) compared to 7% after HLA-matched HSCT (n = 54, P = .15). Day-100 grade II-IV acute graft-versus-host disease was 13%, 26%, and 30% after HLA-matched sibling, HLA-matched and mismatched unrelated donor HSCT. The 5-year incidence of chronic graft-versus-host disease was 33% with 24 of 28 patients having received grafts from HLA-matched (n = 13) and mismatched unrelated (n = 11) donors. Although HLA-matched donors are preferred, HLA-mismatched donors also extend survival for CAMT.

Anti Thymocyte Globulin-Based Treatment for Acquired Bone Marrow Failure in Adults.

Idiopathic acquired aplastic anemia can be successfully treated with Anti Thymocyte Globulin (ATG)-based immune suppressive therapy and is therefore considered a T cell-mediated auto immune disease. Based on this finding, several other forms of idiopathic acquired bone marrow failure are treated with ATG as well. For this review, we extensively searched the present literature for evidence that ATG can lead to enduring remissions in different forms of acquired multi- or single-lineage bone marrow failure. We conclude that ATG-based therapy can lead to an enduring hematopoietic response and increased overall survival (OS) in patients with acquired aplastic aplasia. In patients with hypocellular myelodysplastic syndrome, ATG can lead to a hematological improvement without changing the OS. ATG seems less effective in acquired single-lineage failure diseases like Pure Red Cell Aplasia, Amegakaryocytic Thrombocytopenia and Pure White Cell Aplasia, suggesting a different pathogenesis in these bone marrow failure states compared to aplastic anemia. T cell depletion is hypothesized to play an important role in the beneficial effect of ATG but, as ATG is a mixture of polyclonal antibodies binding to different antigens, other anti-inflammatory or immunomodulatory effects could play a role as well.

Congenital amegakaryocytic thrombocytopenia - Not a single disease.

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare inherited bone marrow failure syndrome (IBMFS) that is characterized by severe thrombocytopenia at birth due to ineffective megakaryopoiesis and development towards aplastic anemia during the first years of life. CAMT is not a single monogenetic disorder; rather, many descriptions of CAMT include different entities with different etiologies. CAMT in a narrow sense, which is primarily restricted to the hematopoietic system, is caused mainly by mutations in the gene for the thrombopoietin receptor (MPL), sometimes in the gene for its ligand (THPO). CAMT in association with radio-ulnar synostosis, which is not always clinically apparent, is mostly caused by mutations in MECOM, rarely in HOXA11. Patients affected by other IBMFS - especially Fanconi anemia or dyskeratosis congenita - may be misdiagnosed as having CAMT when they lack typical disease features of these syndromes or have only mild symptoms. This article reviews scientific and clinical aspects of the various disorders associated with the term "CAMT" with a main focus on the disease caused by mutations in the MPL gene.

Immune-mediated thrombocytopenia induced with durvalumab after chemoradiotherapy in a non-small cell lung cancer patient: A case report.

We describe a case of a 60-year-old man with a prolonged thrombocytopenia during a durvalumab maintenance therapy after chemoradiotherapy for locally advanced non-small cell lung carcinoma. Bone marrow specimen was normoplastic with the marked megakaryocyte depletion, which was assumed to be an acquired amegakaryocytic thrombocytopenic purpura. Although hematological disorders as immune-related adverse events (irAE) are rare, we should pay more attention to hematological disorders with durvalumab especially after concurrent chemoradiotherapy.

Acquired amegakaryocytic thrombocytopenia after durvalumab administration.

Immune checkpoint inhibitors (ICIs), despite their ability to potentiate antitumor T-cell responses, may cause various immune-related adverse events. Most cases of thrombocytopenia induced by ICIs have revealed a pathophysiologic mechanism of immune thrombocytopenia with increased platelet destruction and preserved megakaryocytes. Acquired amegakaryocytic thrombocytopenic purpura (AATP) is an unusual disorder characterized by thrombocytopenia with markedly diminished bone marrow megakaryocytes in the presence of otherwise normal hematopoiesis. AATP caused by ICIs has not been reported on. Herein, we present the case of a 79-year-old man diagnosed with squamous cell carcinoma of the lung who developed AATP after two courses of durvalumab, a drug targeting programmed death-ligand 1. Two weeks after the second cycle, his platelet count decreased to 2.1 × 104/µL. After the patient underwent platelet transfusion, his platelet count increased to 8.1 × 104/µL the next day but subsequently decreased repeatedly even after the ICI was discontinued. Six weeks after the second cycle, he developed interstitial pneumonia and was administered prednisolone (50 mg/day). However, thrombocytopenia did not improve. Bone marrow biopsy showed scarce megakaryocytes (< 1 megakaryocyte/10 high-power fields) with preservation of myeloid and erythroid series. Myelodysplasia, myelofibrosis, or metastatic lesions were not observed. Cytogenetic analysis showed a normal male karyotype of 46XY. Hence, the patient received eltrombopag, a thrombopoietin receptor agonist, and his platelet count subsequently improved. After recovery, bone marrow aspiration revealed a normal number of megakaryocytes. AATP is rarely the type of thrombocytopenia induced by ICIs and may be successfully treated with thrombopoietin receptor agonists.