• Hematopoietic stem cells
• Megakaryocytes differentiation
• PVA
• Serum-free culture
• r-HSA

• Megakaryocytes/cytology
• Megakaryocytes/metabolism
• Megakaryocytes/drug effects
• Animals
• Cell Differentiation/drug effects
• Hematopoietic Stem Cells/cytology
• Hematopoietic Stem Cells/drug effects
• Hematopoietic Stem Cells/metabolism
• Mice
• Cell Culture Techniques/methods
• Humans
• Polyvinyl Alcohol/pharmacology
• Polyvinyl Alcohol/chemistry
• Cells, Cultured
• Recombinant Proteins/pharmacology
• Recombinant Proteins/metabolism
• Mice, Inbred C57BL
• Serum Albumin, Human/metabolism

• critical limits
• critical values
• point-of-care testing
• visualization

• UC2023-24 Edward A. Dickson Emeritus Professorship

• Neurosurgery
• Subdural hematoma
• Thrombocytopenia
• Traumatic brain injury

• Humans
• Hematoma, Subdural, Acute/diagnostic imaging
• Hematoma, Subdural, Acute/surgery
• Retrospective Studies
• Hematoma, Subdural/diagnostic imaging
• Hematoma, Subdural/surgery
• Hematoma, Subdural, Intracranial/surgery
• Glasgow Coma Scale

Thrombocytopenia is one of the most common complications of cancer therapy. Until now, there are still no satisfactory medications to treat chemotherapy and radiation-induced thrombocytopenia (CIT and RIT, respectively). Caulis Polygoni Multiflori (CPM), one of the most commonly used Chinese herbs, has been well documented to nourish blood for tranquilizing the mind and treating anemia, suggesting its beneficial effect on hematopoiesis. However, it is unknown whether CPM can accelerate megakaryopoiesis and thrombopoiesis. Here, we employ a UHPLC Q–Exactive HF-X mass spectrometer (UHPLC QE HF-X MS) to identify 11 ingredients in CPM. Then, in vitro experiments showed that CPM significantly increased megakaryocyte (MK) differentiation and maturation but did not affect apoptosis and lactate dehydrogenase (LDH) release of K562 and Meg-01 cells. More importantly, animal experiments verified that CPM treatment markedly accelerated platelet recovery, megakaryopoiesis and thrombopoiesis in RIT mice without hepatic and renal toxicities in vivo. Finally, RNA-sequencing (RNA-seq) and western blot were used to determine that CPM increased the expression of proteins related to PI3K/Akt and MEK/ERK (MAPK) signaling pathways. On the contrary, blocking PI3K/Akt and MEK/ERK signaling pathways with their specific inhibitors suppressed MK differentiation induced by CPM. In conclusion, for the first time, our study demonstrates that CPM may be a promised thrombopoietic agent and provide an experimental basis for expanding clinical use.

• avatrombopag
• chronic liver disease
• ethnicity
• thrombocytopenia
• thrombopoietin receptor

Considering a high prevalence of congenital and especially acquired bleeding disorders, their heterogeneity and the multitude of possible treatments strategies, a review of the scientific data on this topic is needed to implement a treatment guide for healthcare professionals.

A selective literature review was performed via PubMed for articles describing oral surgery / dental implant procedures in patients with congenital and acquired bleeding disorders. Out of the existing literature, potential treatment algorithms were extrapolated.

In order to assess the susceptibility to bleeding, risk stratification can be used for both congenital and acquired coagulation disorders. This risk stratification, together with an appropriate therapeutic pathway, allows for an adequate and individualized therapy for each patient. A central point is the close interdisciplinary cooperation with specialists. In addition to the discontinuation or replacement of existing treatment modalities, local hemostyptic measures are of primary importance. If local measures are not sufficient, systemically administered substances such as desmopressin and blood products have to be used.

Despite the limited evidence, a treatment guide could be developed by means of this narrative review to improve safety for patients and practitioners. Prospective randomized controlled trials are needed to allow the implementation of official evidence-based guidelines.

• Japan
• avatrombopag
• clinical trial
• liver disease
• phase 2
• thrombocytopenia

• Carica papaya
• Immunomodulation
• Interleukin-11
• Thrombocytopenia
• Thrombopoietin

Aplastic anemia is an intractable disease characterized by pancytopenia, susceptibility to infection, and difficulty in achieving hemostasis. In patients with severe periodontal disease and aplastic anemia, spontaneous bleeding from the gingival tissue due to thrombocytopenia and during brushing is common, which may further exacerbate dental issues. Comprehensive periodontal treatment for patients with aplastic anemia is highly challenging and requires collaboration with a hematologist. Here, we discuss the case of a patient with aplastic anemia and severe periodontitis who was successfully treated in collaboration with our hematology department.

A 36-year-old Japanese woman with chief complaints of spontaneous gingival bleeding, pain, and increasing tooth mobility consulted our department. She had developed pancytopenia at age 11 years and was later diagnosed with aplastic anemia, making her susceptible to infection due to leukopenia. The results of the initial periodontal examination led to a diagnosis of severe generalized periodontitis (generalized stage IV grade C periodontitis) caused by leukopenia and poor oral hygiene. We adopted a comprehensive treatment plan, including invasive dental procedures. The patient exhibited no postoperative bleeding due to aplastic anemia-induced thrombocytopenia and experienced a good outcome.

Both physicians and dentists should be aware that immunocompromised patients with aplastic anemia are at risk of developing severe periodontitis with severe alveolar bone resorption if the condition is combined with poor oral hygiene. Even in the presence of aplastic anemia, patients with severe periodontitis can undergo comprehensive dental treatment, including dental extraction and periodontal surgery, if bleeding and susceptibility to infection are controlled. This requires the cooperation of the patient and hematologists and can ultimately contribute to improving the patient’s quality of life.

• Aplastic anemia
• Dentistry
• Hematology
• Oral medicine
• Severe periodontitis

• Japan
• algorithm
• blood transfusion
• chronic liver disease
• thrombocytopenia
• thrombopoietin receptor agonist

Avatrombopag (Doptelet^®) is an orally administered second generation thrombopoietin receptor agonist (TPO-RA) approved for the treatment of primary chronic immune thrombocytopenia (ITP) in adult patients who are refractory or have an unsatisfactory response to other treatments, as well as for the treatment of thrombocytopenia in adult patients with chronic liver disease (CLD) scheduled to undergo an invasive procedure. In phase III studies, avatrombopag was associated with a significantly greater platelet response than placebo in patients with chronic ITP, and was superior to placebo in reducing the requirement for platelet transfusion or rescue procedures for bleeding caused by surgery in patients with CLD with a platelet count < 50 × 10⁹/L at baseline. Longer term data indicate that avatrombopag is associated with high durable response rates in ITP and may have corticosteroid-sparing effects. The drug was generally well tolerated in both indications. Avatrombopag thus represents a convenient and effective second-line treatment for patients with chronic ITP and can prevent bleeding events in patients with CLD scheduled to undergo a procedure, offering a useful alternative to other available treatments in both indications.

Avatrombopag (Doptelet^®) is an orally administered drug that mimics the natural compound (thrombopoietin) responsible for stimulating the production of platelets, an essential component of the clotting process that prevents excessive bleeding. Several conditions can cause reduced platelet levels (thrombocytopenia) to the point that intervention is needed to prevent excessive blood loss. Avatrombopag is approved for the treatment of primary chronic immune thrombocytopenia (ITP) and to prevent bleeding caused by surgery in patients with low platelet levels caused by chronic liver disease (CLD). Clinical trials in patients with ITP show that avatrombopag quickly increases platelet levels and that this increase is maintained in the longer term in many patients. Similarly, clinical trials in patients with low platelet levels because of CLD showed that giving avatrombopag prior to surgery reduced the need for platelet transfusions or rescue procedures for bleeding. Avatrombopag is thus a convenient and effective treatment for patients with chronic ITP and can prevent bleeding events in patients with CLD scheduled to undergo a procedure. In both indications avatrombopag offers a useful alternative to other available treatments.

• Bleeding risk
• Pediatrics
• Platelet transfusion
• Thrombocytopenia

• Cell differentiation
• Haematopoietic stem and progenitor cells
• Human pluripotent stem cells
• Single cell RNA sequencing

• chemotherapy
• myelopreservation
• myeloprotection
• myelosuppression
• small cell lung cancer
• trilaciclib

• chemotherapy
• myelopreservation
• myelosuppression
• small cell lung cancer (SCLC)
• trilaciclib

• G1 Therapeutics, Inc.

• Freistaat Thüringen
• Deutsche Forschungsgemeinschaft

Thrombocytopenia, defined as a platelet count <150,000/μL, is the most common complication of advanced liver disease or cirrhosis with an incidence of up to 75%. A decrease in platelet count can be the first presenting sign and tends to be proportionally related to the severity of hepatic failure. The pathophysiology of thrombocytopenia in liver disease is multifactorial, including (i) splenomegaly and subsequently increased splenic sequestration of circulating platelets, (ii) reduced hepatic synthesis of thrombopoietin with missing stimulation both of megakaryocytopoiesis and thrombocytopoiesis, resulting in diminished platelet production and release from the bone marrow, and (iii) increased platelet destruction or consumption. Among these pathologies, the decrease in thrombopoietin synthesis has been identified as a central mechanism. Two newly licensed oral thrombopoietin mimetics/receptor agonists, avatrombopag and lusutrombopag, are now available for targeted treatment of thrombocytopenia in patients with advanced liver disease, who are undergoing invasive procedures. This review summarizes recent advances in the understanding of defective but at low level rebalanced hemostasis in stable cirrhosis, discusses clinical consequences and persistent controversial issues related to the inherent bleeding risk, and is focused on a risk-adapted management of thrombocytopenia in patients with chronic liver disease, including a restrictive transfusion regimen.

• advanced liver disease
• bleeding risk
• cirrhosis
• hemostasis
• thrombocytopenia
• thrombopoietin receptor agonists/mimetics

Since the dawn of medicine, scientists have carefully observed, modeled and interpreted the human body to improve healthcare. At the beginning there were drawings and paintings, now there is three-dimensional modeling. Moving from two-dimensional cultures and towards complex and relevant biomaterials, tissue-engineering approaches have been developed in order to create three-dimensional functional mimics of native organs. The bone marrow represents a challenging organ to reproduce because of its structure and composition that confer it unique biochemical and mechanical features to control hematopoiesis. Reproducing the human bone marrow niche is instrumental to answer the growing demand for human erythrocytes and platelets for fundamental studies and clinical applications in transfusion medicine. In this review, we discuss the latest culture techniques and technological approaches to obtain functional platelets and erythrocytes ex vivo. This is a rapidly evolving field that will define the future of targeted therapies for thrombocytopenia and anemia, but also a long-term promise for new approaches to the understanding and cure of hematologic diseases.

• AE, adverse event
• CLD, chronic liver disease
• CT, computerised tomography
• GCP, Good Clinical Practice
• HR, hazard ratio
• ICF, informed consent form
• ICH, International Conference on Harmonisation
• ITT, intention-to-treat
• LUSU, lusutrombopag
• Lusutrombopag
• MRI, magnetic resonance imaging
• Magnitude
• PBO, placebo
• PP, per protocol
• PT, platelet transfusion
• Platelet
• Procedural
• TCP, thrombocytopaenia
• TEAE, treatment-emergent adverse event
• Thrombocytopaenia
• US, ultrasonography
• WHO, World Health Organization

• platelet transfusion
• transfusion medicine
• transfusion strategy
• transfusion therapy

• cancer
• case study methods
• clinical decisions
• haemato-oncology
• platelets
• qualitative
• transfusion

Trilaciclib is a first-in-class CDK4/6 inhibitor that transiently arrests hematopoietic stem and progenitor cells (HSPCs) in the G1 phase of the cell cycle to preserve them from chemotherapy-induced damage (myelopreservation). We report integrated analyses of preclinical and clinical data that informed selection of the recommended Phase II dose (RP2D) used in trilaciclib trials in extensive-stage small cell lung cancer (ES-SCLC).

A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model developed from preclinical data guided selection of an optimal dose for G1 bone marrow arrest in a first-in-human Phase I study (G1T28-1-01). PK, PD, safety, and efficacy data from G1T28-1-01 and two Phase Ib/IIa studies (G1T28-02/-03) in ES-SCLC were analyzed to support RP2D selection.

Model simulation of bone marrow arrest based on preclinical data predicted that a ≥ 192 mg/m² dose would induce a 40–50% decrease in total bone marrow proliferation in humans and almost 100% cell cycle arrest of cycling HSPCs. Consistent with this model, analysis of bone marrow aspirates in healthy volunteers after trilaciclib 192 mg/m² administration demonstrated almost 100% G1 arrest in HSPCs and 40% decrease in total bone marrow proliferation, with minimal toxicity. G1T28-02/-03 reported similar PK parameters with trilaciclib 200 mg/m² but slightly lower exposures than expected compared with healthy volunteers; consequently, 240 and 280 mg/m² doses were also tested to match healthy volunteer exposures. Based on PK and relevant safety data, 240 mg/m² was selected as the RP2D, which was also favored by myelopreservation endpoints in G1T28-02/-03.

Integrated PK/PD, safety, and efficacy data support 240 mg/m² as the RP2D for trilaciclib.

NCT02243150; NCT02499770; NCT02514447.

The online version contains supplementary material available at 10.1007/s00280-021-04239-9.

• CDK4/6 inhibitor
• Chemotherapy-induced myelosuppression
• Myelopreservation
• Pharmacodynamics
• Pharmacokinetics
• Trilaciclib

• cancer
• chemotherapy
• myelosuppression
• patient burden
• quality of life
• real world

• G1 Therapeutics, Inc. (Research Triangle Park, NC, USA)

• Anemia
• Chemotherapy
• Myelopreservation
• Myelosuppression
• Neutropenia
• Patient-reported outcomes
• Small cell lung cancer
• Topotecan
• Trilaciclib

• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Double-Blind Method
• Humans
• Lung Neoplasms/drug therapy
• Pyrimidines
• Pyrroles
• Quality of Life
• Small Cell Lung Carcinoma
• Topotecan/therapeutic use

• G1 Therapeutics, Inc.

• INR
• Liver cirrhosis
• bleeding
• oral bleeding
• platelets
• systematic review
• tooth extraction

• Chronic Liver Disease
• Hepatocellular Carcinoma
• Invasive Procedure
• Thrombopoietin Receptor Agonist

• force spectroscopy
• hemocompatibility
• modification
• nano/microstructured surface
• physicochemical surface modifications
• platelet-surface activation

• Anemia
• Cirrhosis
• Hepatocellular carcinoma
• Microwave ablation
• Minimally invasive
• Thrombocytopenia

• human platelet antigens
• genotyping
• platelet-donor registry
• platelet transfusion

• Alleles
• Antigens, Human Platelet/genetics
• Argentina
• Blood Donors
• Blood Platelets
• Genotyping Techniques
• Humans
• Platelet Transfusion
• Registries

• Eltrombopag
• Mechanism of action
• Megakaryopoiesis
• Romiplostim
• Thrombocytopenia

• Chronic liver disease
• Cirrhosis
• Platelets transfusion
• Thrombocytopenia
• Thrombopoietin receptor agonists
• Treatment algorithm

• Cirrhosis
• Hemostatic Balance
• Radiofrequency Ablation
• Thrombopoietin Receptor Agonist

• Aged
• Catheter Ablation/methods
• Cinnamates/therapeutic use
• Double-Blind Method
• Female
• Follow-Up Studies
• Humans
• Incidence
• Japan/epidemiology
• Liver Cirrhosis/complications
• Liver Cirrhosis/surgery
• Male
• Platelet Transfusion/trends
• Postoperative Hemorrhage/epidemiology
• Postoperative Hemorrhage/etiology
• Postoperative Hemorrhage/prevention & control
• Retrospective Studies
• Thiazoles/therapeutic use
• Thrombocytopenia/complications
• Thrombocytopenia/therapy
• Treatment Outcome

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare disease caused by mutations in TYMP, the gene encoding for the enzyme thymidine phosphorylase. The resulting enzyme deficiency leads to a systemic accumulation of thymidine and 2’-deoxyuridine and ultimately mitochondrial failure due to a progressive acquisition of secondary mitochondrial DNA (mtDNA) mutations and mtDNA depletion. MNGIE is characterised by gastrointestinal dysmotility, cachexia, peripheral neuropathy, ophthalmoplegia, ptosis and leukoencephalopathy. The disease is progressively degenerative and leads to death at an average age of 37.6 years. Patients invariably encounter misdiagnoses, diagnostic delays, and non-specific clinical management. Despite its rarity, MNGIE has invoked much interest in the development of therapeutic strategies, mainly because it is one of the few mitochondrial disorders where the molecular abnormality is metabolically and physically accessible to manipulation. This review provides a resume of the current diagnosis and treatment approaches and aims to increase the clinical awareness of MNGIE and thereby facilitate early diagnosis and timely access to treatments, before the development of untreatable and irreversible organ damage.

• MNGIE
• Mitochondrial neurogastrointestinal encephalomyopathy
• TYMP
• mitochondrial DNA
• mitochondrial disease
• thymidine phosphorylase

• Adult
• Benzoates/therapeutic use
• Deamino Arginine Vasopressin/therapeutic use
• Hemostatics/therapeutic use
• Humans
• Hydrazines/therapeutic use
• Plasma
• Platelet Transfusion/methods
• Postoperative Care/methods
• Postoperative Hemorrhage/prevention & control
• Pyrazoles/therapeutic use
• Randomized Controlled Trials as Topic
• Receptors, Fc/therapeutic use
• Recombinant Fusion Proteins/therapeutic use
• Thrombocytopenia/complications
• Thrombocytopenia/therapy
• Thrombopoietin/therapeutic use

• 13/89/09 Department of Health

• Adult
• Humans
• Myelodysplastic Syndromes/congenital
• Myelodysplastic Syndromes/therapy
• Platelet Transfusion/methods

• 13/89/09 Department of Health

• Adult
• Anesthesia, Epidural/adverse effects
• Child
• Humans
• Platelet Transfusion
• Retrospective Studies
• Spinal Puncture/adverse effects
• Thrombocytopenia/complications
• Thrombocytopenia/therapy

• 13/89/09 Department of Health
• SRP/13/89/09 Department of Health

• 13/89/09 Department of Health
• 16895 Cancer Research UK
• SRP/13/89/09 Department of Health

• chronic liver disease
• cirrhosis
• thrombocytopenia
• thrombopoietin