Nonbacterial Thrombotic Endocarditis Associated with Acute Promyelocytic Leukemia: An Autopsy Case Report

Valve vegetation is one of the most fearful findings for physicians. The first diagnosis that comes to their mind is infective endocarditis (IE), but it can also be noninfective; nonbacterial thrombotic endocarditis (NBTE). NBTE can be even more challenging than IE for physicians because of the wide range of differential diagnoses such as malignancies, autoimmune disorders and human immunodeficiency virus. A 45-year-old woman presented at the emergency room with a sudden onset of dysarthria and right-sided hemiplegia. Laboratory data showed her blood counts and coagulation test were mostly normal and the magnetic resonance imaging detected a high-signal-intensity change in her left brain. An echocardiogram found a vegetation-like structure on her atrial valve. We highly suspected IE leading to cerebral embolism. The clot was successfully removed by our neurosurgeons and anticoagulation therapy was started concurrently. Her state of consciousness improved, but then she suffered a brain hemorrhage and died. The autopsy revealed that the cause of her vegetation was acute promyelocytic leukemia (APL). Based on these findings, it is important to remember that APL can be the cause of NBTE even if the blood count and coagulation tests are almost normal.

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Arsenic Trioxide Potentiates Extracellular Traps-Formation Cell Death in Acute Promyelocytic Leukemia through mTOR-Regulated Autophagy

Blood ◽

10.1182/blood.v128.22.1575.1575 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1575-1575

Author(s):

Tao Li ◽

Muhua Cao ◽

Ruishuang Ma ◽

Xiaoming Wu ◽

Lu Zhao ◽

...

Keyword(s):

Cell Death ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Promyelocytic Leukemia ◽

Extracellular Dna ◽

Apoptosis Resistance ◽

Dna Complexes ◽

Nb4 Cells ◽

Wide Range

Abstract Background:Emerging clinical data shows that arsenic trioxide (ATO) exerts selective cytotoxicity against acute promyelocytic leukemia (APL) without severe side effects that mainly ascribed to nonspecific induction of apoptosis. It is attractive to speculate whether other uncovered APL cell death exists which can be specifically sparked by ATO administration. We have recently demonstrated that APL cells can undergo a previously unrecognized pathway for death by releasing extracellular DNA traps (ETs), termed ETosis (Ma R et al, Cell Death Dis 2016). However, besides apoptosis, whether ATO induces this APL-specific ETotic cell death remains to be explored. We wereto investigated the effects of a wide range of concentrations of ATO on ETotic death in APL cells and elucidate the underlying molecular mechanisms. Methods: Bone marrow samples were obtained from sixteen APL patients before and after the continuous administration of ATO for two weeks. APL cells were isolated and cultured in the presence and absence of ATRA for 3 days. We used confocal microscopy to image ET formation by APL cells and the percentage of ETotic cells was simultaneously quantified. ELISA was used to measure the concentration of myeloperoxidase (MPO)-DNA complexes in the supernant. We also assessed the effects of a wide range of concentrations (0.1, 0.25, 0.5, 0.75, 1.0, 2.0 μM) of ATO treatment for 24, 48 and 72 hours on ETosis in APL-cell line NB4 cells in vitro. Autophagy activation and leukemia-initiating cell (LIC) activity were evaluated by immunoblotting and imaged by immunostaining. LICs were analyzed using colony-forming unit (CFU) assays, and identified and quantified by flow cytometry. Results: APL cells isolated from ATO-treated APL patients underwent significantly increased spontaneous (P = 0.005) and ATRA-stimulated (P = 0.002) ETosis compared to those from newly diagnosed patients (n = 16). In vitro ATO treatment showed that the percentage of ETotic NB4 cells dramatically increased at 0.5 μM (8 ± 1.6%), peaked at 0.75 μM (15 ± 2.4%) and was gradually suppressed at higher concentrations. The concentration of MPO-DNA complexes, an indirect marker of ETosis, parallelled the dose-dependent change in the percentage of ETotic cells. Interestingly, inhibition experiments indicated that ATO caused concentration-dependent APL cell death: ATO primarily triggered ETosis at moderate concentrations (0.5 to 0.75 μM) and switched to apoptosis at relatively high doses (1.0 to 2.0 μM). Furthermore, We found that ATO induced ETosis through mammalian target of rapamycin (mTOR)-regulated autophagy. Surprisingly, inhibition of ETosis spared LIC activity from ATO reduction, while combined treatment with ATO and rapamycin further increased ETosis-mediated LIC loss (~3.5-fold). Conclusion s : This is the first study to show that ATO potentiates ETotic death in APL cells through mTOR-regulated autophagy. Importantly, further investigation suggests that ATO specifically targets the APL LICs to ETosis. This implies that, in combination with ATO, therapy-triggered ETosis by targeting the corresponding signaling pathways could be a novel and effective strategy to improve a long relapse-free survival through LIC clearance, avoid lethal apoptosis-related complications and overcome apoptosis resistance. Conflict of interest statement: None. Disclosures No relevant conflicts of interest to declare.

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Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid

Blood ◽

10.1182/blood-2011-04-346437 ◽

2011 ◽

Vol 118 (5) ◽

pp. 1248-1254 ◽

Cited By ~ 204

Author(s):

Jae H. Park ◽

Baozhen Qiao ◽

Katherine S. Panageas ◽

Maria J. Schymura ◽

Joseph G. Jurcic ◽

...

Keyword(s):

Clinical Trials ◽

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Death Rate ◽

Early Death ◽

Promyelocytic Leukemia ◽

Care Providers ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Wide Range

Abstract The incidence of early death in a large population of unselected patients with acute promyelocytic leukemia (APL) remains unknown because of the paucity of outcome data available for patients treated outside of clinical trials. We undertook an epidemiologic study to estimate the true rate of early death with data from the Surveillance, Epidemiology, and End Results (SEER) program. A total of 1400 patients with a diagnosis of APL between 1992 and 2007 were identified. The overall early death rate was 17.3%, and only a modest change in early death rate was observed over time. The early death rate was significantly higher in patients aged ≥ 55 years (24.2%; P < .0001). The 3-year survival improved from 54.6% to 70.1% over the study period but was significantly lower in patients aged ≥ 55 years (46.4%; P < .0001). This study shows that the early death rate remains high despite the wide availability of all-trans retinoic acid and appears significantly higher than commonly reported in multicenter clinical trials. These data highlight a need to educate health care providers across a wide range of medical fields, who may be the first to evaluate patients with APL, to have a major effect on early death and the cure rate of APL.

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Risk factors of thrombosis in chinese subjects with acute promyelocytic leukemia

10.21203/rs.3.rs-158017/v1 ◽

2021 ◽

Author(s):

Xueya Zhang ◽

Xizhe Guo

Keyword(s):

Risk Factors ◽

Acute Promyelocytic Leukemia ◽

Detection Rate ◽

Disease Risk ◽

Laboratory Data ◽

Female Gender ◽

Promyelocytic Leukemia ◽

Rare Manifestation ◽

Chinese Subjects ◽

Pai 1

Abstract Acute promyelocytic leukemia (APL) is a kind of malignant hematologic disease. Thrombosis is a rare manifestation of APL. However, the risk factors of thrombosis related to chinese APL patients are not fully understood. Clinical and laboratory data of 44 consecutively chinese APL patients were collected and analyzed. 1 arterial and 6 venous thrombosis occurred in 44 patients, including 22 males and 22 females, with a median age of 44 years (range 18–74 years). The ratio of male and female gender (P = 0.68), age (P = 0.823), white blood cell count (P = 0.077), hemoglobin (P = 0.409), platelets (P = 0.334), disease risk stratification (P = 0.475), CD2 (P = 0.737), khorana score (P = 0.52), differentiation syndrome (DS) (P = 0.562) and gene mutation related to prognosis of APL, including DNMT3A (P = 0.44), TET2 (P = 0.43), IDH1 (P = 0.6), IDH2 (P = 0.66), NRAS (P = 0.66), ASXL1(P = 0.9) in the two groups with and without thrombosis were not statistically significant. The detection rate of PAI-1 genotype 4G4G was 71.4% (5/7) in 7 patients with thrombosis, while the detection rate of PAI-1 genotype 4G4G in 37 patients without thrombosis was 8.1% (3/37). The differences between the two groups in WT-1 (P = 0.01), PAI-1 4G4G (P = 0.0009), bcr3 (P = 0.027), CD15 (P = 0.005), and FLT3-ITD mutation (P = 0.0008) were statistically significant. The results suggested the PAI-1 gene 4G4G type, PML/RARa (bcr3), CD15, WT-1 and FLT3-ITD mutations excluding DNMT3A, TET2, IDH1/2, NRAS and ASXL1 are risk factors of thrombotic events in chinese APL patients.

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Risk factors of thrombosis in Chinese subjects with acute promyelocytic leukemia

Thrombosis Journal ◽

10.1186/s12959-021-00294-7 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Xueya Zhang ◽

Xizhe Guo

Keyword(s):

Risk Factors ◽

Venous Thrombosis ◽

Acute Promyelocytic Leukemia ◽

Detection Rate ◽

Disease Risk ◽

Laboratory Data ◽

Female Gender ◽

Promyelocytic Leukemia ◽

Increased Risk ◽

Pai 1

Abstract Background Acute promyelocytic leukemia (APL) is a special type of acute myeloid leukemia Thrombosis is at increased risk complication in patients with this disease. However, the risk factors of thrombosis related to Chinese APL patients are not fully understood. Methods In this study, clinical and laboratory data of 44 consecutively Chinese APL patients were collected and analyzed. Results One arterial and 6 venous thrombosis occurred in 44 patients, including 22 males and 22 females, with a median age of 44 years (range from 18 to 74 years). The ratio of male and female gender, age, white blood cell count, hemoglobin, platelets, disease risk stratification, CD2, Khorana score, differentiation syndrome (DS) and gene mutation related to prognosis of APL, including DNMT3A, TET2, IDH1, IDH2, NRAS and ASXL1 in the two groups with and without thrombosis were not statistically significant. The detection rate of PAI-1 genotype 4G4G was 71.4% (5/7) in 7 patients with thrombosis, while the detection rate of PAI-1 genotype 4G4G in 37 patients without thrombosis was 8.1% (3/37). The differences between the two groups in WT-1 (P = 0.01), PAI-1 4G4G (P = 0.0009), bcr3 (P = 0.027), CD15 (P = 0.005), and FLT3-ITD mutation (P = 0.0008) were statistically significant. Using multivariate analysis, the risk factors of venous thrombosis in APL were CD15 (P = 0.043), PAI-1 4G4G (P = 0.009), WT-1 (P = 0.043) and FLT3/ITD (P = 0.013), respectively. Conclusion Our results suggested the PAI-1 gene 4G4G type, CD15, WT-1 and FLT3-ITD mutations excluding DNMT3A, TET2, IDH1/2, NRAS and ASXL1 are risk factors of thrombotic events in Chinese APL patients.

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