Coagulopathy in APL: a step forward?

Avvisati, Giuseppe

doi:10.1182/blood-2012-05-427427

Cited by 11 publications

(4 citation statements)

References 8 publications

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“…An increased frequency of serious bleeding problems is a characteristic of APL [69]. The molecular mechanism behind the hemostatic abnormalities in APL, which include elevated circulating levels of uPA and tPA and lower levels of PAI-1, α 2 -plasmin inhibitor, and TAFI, have been clarified in the last ten years [70][71][72][73][74][75][76]. In turn, the S100 protein, a calcium-binding protein belonging to the S100 family, forms a heterotetrameric complex with annexin A2, a protein receptor with a great affinity for plasminogen and tPA and a powerful cofactor for the conversion of plasminogen to plasmin.…”

Section: Acute Promyelocytic Leukemia (Apl)mentioning

confidence: 99%

Fibrinolysis-Related Bleeding Troubles

2023

jblooddisordl

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An intricate enzymatic process called fibrinolysis is used to eliminate blood clots and stop vascular clogging. Numerous cofactors that make up the fibrinolytic system regulate fibrin breakdown and uphold the hemostatic balance. Different disease events that promote prothrombotic or hemorrhagic states based on the form of aberration are linked to the dysregulation of fibrinolysis. This review is centered on fibrinolysis ailments that can be either heritable or acquired and affect both adults and children. A shortage of one of the fibrinolysis inhibitors deficiencies, such as Plasminogen Activator Inhibitor Type 1 (PAI-1) or 2-plasmin inhibitor, or an overabundance of one of the activators, such as tissue-type plasminogen activator or urokinase-type plasminogen activator, can lead in hyperfibrinolytic bleeding. Delayed bleeding following trauma, surgery and dental interventions is a hallmark of fibrinolytic illnesses with a bleeding phenotype. Bleeding in states like menorrhagia and epistaxis, which has significant fibrinolytic activity, is also frequent. The most extreme bleeding episodes are experienced by patients with 2-plasmin inhibitor deficiency. Interestingly, it was found that, particularly in patients with PAI-1 deficiency, hyperfibrinolytic diseases are linked to a high prevalence of obstetric problems such as miscarriage and preterm delivery. Due to ignorance and a lack of reliable diagnostic tools, hyperfibrinolytic diseases are likely to be underdiagnosed. The vast majority of individuals whose bleeding was deemed to be “of unknown origin” may have a hyperfibrinolytic disease. Because these conditions may typically be successfully treated with antifibrinolytic drugs, early detection is crucial.

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Section: Acute Promyelocytic Leukemia (Apl)mentioning

confidence: 99%

Fibrinolysis-Related Bleeding Troubles

2023

jblooddisordl

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“…APL is characterized by an increased incidence of severe bleeding complications [47]. The hemostatic abnormalities in APL have the laboratory features of primary hyperfibrinolysis (i.e., elevated circulating levels of u-PA and t-PA and reduced levels of PAI-1, α2-antiplasmin and TAFI), and the responsible molecular mechanism has been elucidated in the last decade [49][50][51][52][53][54][55]. The fusion protein PML-RAR-enhances the expression of the S100 protein (a member of the S100 family of calcium-binding proteins), which in turn forms a heterotetrameric complex with annexin A2, a protein receptor with a strong affinity for plasminogen and t-PA as well as a potent cofactor for the conversion of plasminogen to plasmin.…”

Section: Acute Promyelocytic Leukemiamentioning

confidence: 99%

Bleeding Disorders in Primary Fibrinolysis

Franchini

Zaffanello

Mannucci

2021

IJMS

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Fibrinolysis is a complex enzymatic process aimed at dissolving blood clots to prevent vascular occlusions. The fibrinolytic system is composed of a number of cofactors that, by regulating fibrin degradation, maintain the hemostatic balance. A dysregulation of fibrinolysis is associated with various pathological processes that result, depending on the type of abnormality, in prothrombotic or hemorrhagic states. This narrative review is focused on the congenital and acquired disorders of primary fibrinolysis in both adults and children characterized by a hyperfibrinolytic state with a bleeding phenotype.

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“…and early haemorrhagic death if not promptly diagnosed 3,4 . With the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), APL treatment has achieved good outcomes.…”

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confidence: 99%

Metabolomics Reveals that Cysteine Metabolism Plays a Role in Celastrol-Induced Mitochondrial Apoptosis in HL-60 and NB-4 Cells

Chen

Yang

et al. 2020

Sci Rep

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Recently, celastrol has shown great potential for inducing apoptosis in acute myeloid leukemia cells, especially acute promyelocytic leukaemia cells. However, the mechanism is poorly understood. Metabolomics provides an overall understanding of metabolic mechanisms to illustrate celastrol's mechanism of action. We treated both nude mice bearing HL-60 cell xenografts in vivo and HL-60 cells as well as NB-4 cells in vitro with celastrol. Ultra-performance liquid chromatography coupled with mass spectrometry was used for metabolomics analysis of HL-60 cells in vivo and for targeted L-cysteine analysis in HL-60 and NB-4 cells in vitro. Flow cytometric analysis was performed to assess mitochondrial membrane potential, reactive oxygen species and apoptosis. Western blotting was conducted to detect the p53, Bax, cleaved caspase 9 and cleaved caspase 3 proteins. Celastrol inhibited tumour growth, induced apoptosis, and upregulated pro-apoptotic proteins in the xenograft tumour mouse model. Metabolomics showed that cysteine metabolism was the key metabolic alteration after celastrol treatment in HL-60 cells in vivo. Celastrol decreased L-cysteine in HL-60 cells. Acetylcysteine supplementation reversed reactive oxygen species accumulation and apoptosis induced by celastrol and reversed the dramatic decrease in the mitochondrial membrane potential and upregulation of pro-apoptotic proteins in HL-60 cells. In NB-4 cells, celastrol decreased L-cysteine, and acetylcysteine reversed celastrol-induced reactive oxygen species accumulation and apoptosis. We are the first to identify the involvement of a cysteine metabolism/reactive oxygen species/p53/Bax/caspase 9/ caspase 3 pathway in celastrol-triggered mitochondrial apoptosis in HL-60 and NB-4 cells, providing a novel underlying mechanism through which celastrol could be used to treat acute myeloid leukaemia, especially acute promyelocytic leukaemia.Acute leukemia is the most common malignant hematological malignancy, of which acute myeloid leukemia (AML) accounts for over 80% of all acute leukemias in individuals aged >18 years 1 . Chemotherapy is the main treatment of AML. There are still problems such as drug resistance and relapse of leukemia after drug withdrawal, which seriously affect the quality of life and long-term survival of patients. Therefore, it is of great significance to find effective new antineoplastic drugs and explore new therapeutic schemes.Acute promyelocytic leukaemia (APL), a unique subtype of acute myeloid leukaemia (AML), is a devastating disease characterized by neoplastic proliferation of cells in the bone marrow that have a promyelocytic phenotype and fail to terminally differentiate 2 . Unlike other forms of AML, APL can cause diffuse intravascular coagulopathy

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Coagulopathy in APL: a step forward?

Cited by 11 publications

References 8 publications

Fibrinolysis-Related Bleeding Troubles

Fibrinolysis-Related Bleeding Troubles

Bleeding Disorders in Primary Fibrinolysis

Metabolomics Reveals that Cysteine Metabolism Plays a Role in Celastrol-Induced Mitochondrial Apoptosis in HL-60 and NB-4 Cells

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