Lusutrombopag: A Review in Thrombocytopenia in Patients with Chronic Liver Disease Prior to a Scheduled Procedure

Shirley, Matt; McCafferty, Emma H.; Blair, Hannah A.

doi:10.1007/s40265-019-01197-8

Cited by 9 publications

(4 citation statements)

References 20 publications

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“…Traditionally, thrombocytopenia in cirrhotic patients was believed to stem from decreased endogenous thrombopoietin synthesis due to hepatocyte damage or excessive platelet destruction from hypersplenism. 2 , 16 , 17 However, the intracellular homeostasis of platelets is of great significance for maintaining their lifespan and function. 18 , 19 In recent years, it has been discovered that platelets can degrade damaged organelles through autophagy mechanisms to maintain intracellular homeostasis, which is similar to nucleated cells.…”

Section: Discussionmentioning

confidence: 99%

Hydrogen Sulfide Promotes Platelet Autophagy via PDGFR-α/PI3K/Akt Signaling in Cirrhotic Thrombocytopenia

Yang,

Li,

et al. 2024

J Clin Transl Hepatol

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Background and Aims The role of platelet autophagy in cirrhotic thrombocytopenia (CTP) remains unclear. This study aimed to investigate the impact of platelet autophagy in CTP and elucidate the regulatory mechanism of hydrogen sulfide (H 2 S) on platelet autophagy. Methods Platelets from 56 cirrhotic patients and 56 healthy individuals were isolated for in vitro analyses. Autophagy markers (ATG7, BECN1, LC3, and SQSTM1) were quantified using enzyme-linked immunosorbent assay, while autophagosomes were visualized through electron microscopy. Western blotting was used to assess the autophagy-related proteins and the PDGFR/PI3K/Akt/mTOR pathway following treatment with NaHS (an H 2 S donor), hydroxocobalamin (an H 2 S scavenger), or AG 1295 (a selective PDGFR-α inhibitor). A carbon tetrachloride-induced cirrhotic BALB/c mouse model was established. Cirrhotic mice with thrombocytopenia were randomly treated with normal saline, NaHS, or hydroxocobalamin for 15 days. Changes in platelet count and aggregation rate were observed every three days. Results Cirrhotic patients with thrombocytopenia exhibited significantly decreased platelet autophagy markers and endogenous H 2 S levels, alongside increased platelet aggregation, compared to healthy controls. In vitro, NaHS treatment of platelets from severe CTP patients elevated LC3-II levels, reduced SQSTM1 levels, and decreased platelet aggregation in a dose-dependent manner. H 2 S treatment inhibited PDGFR, PI3K, Akt, and mTOR phosphorylation. In vivo , NaHS significantly increased LC3-II and decreased SQSTM1 expressions in platelets of cirrhotic mice, reducing platelet aggregation without affecting the platelet count. Conclusions Diminished platelet autophagy potentially contributes to thrombocytopenia in cirrhotic patients. H 2 S modulates platelet autophagy and functions possibly via the PDGFR-α/PI3K/Akt/mTOR signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Hydrogen Sulfide Promotes Platelet Autophagy via PDGFR-α/PI3K/Akt Signaling in Cirrhotic Thrombocytopenia

Yang,

Li,

et al. 2024

J Clin Transl Hepatol

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“…Both agents have been shown to increase platelet production in patients who are thrombocytopenic due to chronic liver disease. Both drugs have now been approved by the FDA and the EMA for patients with liver disease and thrombocytopenia requiring a medical procedure that carries a significant risk of bleeding [76,77]. Avatrombopag was also effective for patients with ITP who needed to discontinue romiplostim or eltrombopag [78].…”

Section: The Clinical Uses Of Thrombopoietin and Thrombopoietin Recep...mentioning

confidence: 99%

Thrombopoietin, the Primary Regulator of Platelet Production: From Mythos to Logos, a Thirty-Year Journey

Kaushansky

2024

Biomolecules

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Thrombopoietin, the primary regulator of blood platelet production, was postulated to exist in 1958, but was only proven to exist when the cDNA for the hormone was cloned in 1994. Since its initial cloning and characterization, the hormone has revealed many surprises. For example, instead of acting as the postulated differentiation factor for platelet precursors, megakaryocytes, it is the most potent stimulator of megakaryocyte progenitor expansion known. Moreover, it also stimulates the survival, and in combination with stem cell factor leads to the expansion of hematopoietic stem cells. All of these growth-promoting activities have resulted in its clinical use in patients with thrombocytopenia and aplastic anemia, although the clinical development of the native molecule illustrated that “it’s not wise to mess with mother nature”, as a highly engineered version of the native hormone led to autoantibody formation and severe thrombocytopenia. Finally, another unexpected finding was the role of the thrombopoietin receptor in stem cell biology, including the development of myeloproliferative neoplasms, an important disorder of hematopoietic stem cells. Overall, the past 30 years of clinical and basic research has yielded many important insights, which are reviewed in this paper.

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“…Small orally bioavailable TPO receptor agonists, namely, avatrombopag and lusutrombopag, act selectively on the human TPO receptor and activate signal transduction pathways, thereby promoting the proliferation and differentiation of bone marrow cells into megakaryocytes and increasing the platelet levels. These drugs represent a promising emerging therapeutic option for the treatment of thrombocytopenia to prevent hemorrhagic events and raise the platelet count before scheduled procedures[ 22 - 24 ].…”

Section: Introductionmentioning

confidence: 99%

Minimum platelet count threshold before invasive procedures in cirrhosis: Evolution of the guidelines

Biolato¹,

Vitale²,

Galasso³

et al. 2023

World J Gastrointest Surg

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Cirrhotic patients with severe thrombocytopenia are at increased risk of bleeding during invasive procedures. The need for preprocedural prophylaxis aimed at reducing the risk of bleeding in cirrhotic patients with thrombocytopenia who undergo scheduled procedures is assessed via the platelet count; however, establishing a minimum threshold considered safe is challenging. A platelet count ≥ 50000/μL is a frequent target, but levels vary by provider, procedure, and specific patient. Over the years, this value has changed several times according to the different guidelines proposed in the literature. According to the latest guidelines, many procedures can be performed at any level of platelet count, which should not necessarily be checked before the procedure. In this review, we aim to investigate and describe how the guidelines have evolved in recent years in the evaluation of the minimum platelet count threshold required to perform different invasive procedures, according to their bleeding risk.

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Lusutrombopag: A Review in Thrombocytopenia in Patients with Chronic Liver Disease Prior to a Scheduled Procedure

Cited by 9 publications

References 20 publications

Hydrogen Sulfide Promotes Platelet Autophagy via PDGFR-α/PI3K/Akt Signaling in Cirrhotic Thrombocytopenia

Hydrogen Sulfide Promotes Platelet Autophagy via PDGFR-α/PI3K/Akt Signaling in Cirrhotic Thrombocytopenia

Thrombopoietin, the Primary Regulator of Platelet Production: From Mythos to Logos, a Thirty-Year Journey

Minimum platelet count threshold before invasive procedures in cirrhosis: Evolution of the guidelines

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