{"doi":"10.1111/bjh.19935","title":"Fatal thrombotic microangiopathy during induction for acute myeloid leukemia: A case report and review of vascular complications in germline GATA2 haploinsufficiency","abstract":"The GATA family of transcription factors, including GATA2, is key haematopoietic transcription factor that regulates haematopoiesis by promoting haematopoietic stem cell (HSC) survival, proliferation and differentiation while preventing HSC apoptosis.1 While cytopenias, haematological malignancies and immune deficiency are the hallmark manifestations of GATA2 deficiency, GATA2 also plays a key role in maintaining healthy endothelial function through its mediation of key inflammatory, stress-regulated and adhesion factors (Figure 1).2, 3 Here, we review vascular complications seen in GATA2 deficiency and highlight a case of fatal thrombotic microangiopathy (TMA) during acute myeloid leukemia (AML) induction therapy. An 18-year-old female presented with pancytopenia and was subsequently diagnosed with AML. Cytogenetics revealed KMT2A gene locus copy number gain with KMT2A partial tandem duplication (MLL-MLL fusion) and a GATA2 mutation. Germline testing confirmed GATA2 haploinsufficiency (missense mutation in R396Q). She enrolled on the Children's Oncology Group (COG) study AAML1831 Arm B and was induced with CPX-351 and Gemtuzumab. She had numerous bacterial, fungal and viral infections as well as a non-occlusive line-associated venous thromboembolism (VTE) requiring anticoagulation. Induction II was complicated by streptococcus bacteraemia and significant mucocutaneous bleeding without significant thrombocytopenia requiring frequent product transfusions. Given the unclear aetiology of ongoing bleeding, manual review of a blood film was performed on day 18 which revealed significant thrombocytopenia, discordant with lab-reported values. On day 25, with improving pancytopenia, she had an unwitnessed fall. She returned to her neurological baseline, but 3 h later, was found unresponsive with frank oropharyngeal bleeding and hypoxia requiring emergent intubation. Work-up revealed a respiratory acidosis and an acute haemoglobin decline from 9.1 to 5.8 g/dL. An emergent head computed tomography (CT) revealed new obstructive hydrocephalus with clinical onset of anisocoria, prompting extra ventricular drain (EVD) placement at bedside. Over the next 12 h, she continued to clinically deteriorate with fixed, dilated pupils and lack of a gag reflex in the setting of new bloody cerebral spinal fluid drainage. Repeat head CT confirmed extensive multifocal posterior fossa haemorrhages with herniation. Given her grim prognosis, the family elected to withdraw care (Figure 2A). The aetiology of her central nervous system haemorrhage, rapid decline and ultimate demise was unclear at the time of death. The family consented to a full autopsy which surprisingly revealed TMA of the lungs, kidney, intestines, and brain (Figure 2B), with no evidence of infection. Mature macrophages within the cerebral and cerebellar haemorrhages indicated that microinfarcts due to TMA were antecedent to her fall. Thus, we hypothesize that her intracranial bleeding and subsequent complications including herniation and death could have resulted from severe TMA. While cytopenias, haematological malignancies, and immune deficiency are the hallmark manifestations of GATA2 deficiency, GATA2 also plays a key role in maintaining healthy endothelial function through its mediation of key inflammatory, stress regulated and adhesion factors.2, 3 Despite these known roles of GATA2 in both endothelial cell function and integrity, vascular manifestations of GATA2 haploinsufficiency are relatively uncommon. The most common manifestation is thrombosis, which can be either venous or arterial in nature and has a reported incidence of approximately 25% in GATA2 cohort studies.1, 4, 9, 10 TMA as a vascular manifestation of GATA2 deficiency has only been previously reported after allogeneic HCT.11 TMAs are a group of disorders characterized by microangiopathic anaemia, thrombocytopenia and organ dysfunction that span a variety of syndromes.12 Organ manifestations vary by TMA syndrome, thoug","journal":"British Journal of Haematology","year":2024,"id":507200,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9677,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":402916,"name":"Satheesh Chonat","orcid":"0000-0002-5909-0800","position":1,"is_corresponding":false},{"id":453342,"name":"Kirsten M. Williams","orcid":"0000-0001-9372-5286","position":2,"is_corresponding":false},{"id":1358489,"name":"Waitman K. Aumann","orcid":"0000-0002-6984-3255","position":3,"is_corresponding":false},{"id":1358490,"name":"Jason Stevenson","orcid":"0000-0002-2548-158X","position":4,"is_corresponding":false},{"id":1358833,"name":"Julie Yin","orcid":null,"position":5,"is_corresponding":false},{"id":1358834,"name":"Michael Schniederjan","orcid":null,"position":6,"is_corresponding":false},{"id":783974,"name":"Staci D. Arnold","orcid":"0000-0001-6053-8521","position":7,"is_corresponding":false},{"id":856459,"name":"Michelle Long Schoettler","orcid":"0000-0003-4565-6399","position":8,"is_corresponding":false},{"id":340749,"name":"Erin Frost","orcid":null,"position":0,"is_corresponding":true}],"reference_count":17,"raw_metadata":null,"created_at":"2026-07-19T02:10:58.484528Z","pmid":"39648368","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}