scholarly journals Regulating billions of blood platelets: glycans and beyond

Blood ◽  
2015 ◽  
Vol 126 (16) ◽  
pp. 1877-1884 ◽  
Author(s):  
Renata Grozovsky ◽  
Silvia Giannini ◽  
Hervé Falet ◽  
Karin M. Hoffmeister
Keyword(s):  
Platelet Count ◽  
Posttranslational Modifications ◽  
Platelet Transfusion ◽  
Blood Platelets ◽  
Arterial Occlusion ◽  
Organ Damage ◽  
Spontaneous Bleeding ◽  
Platelet Production ◽  
Pathological Conditions

Abstract The human body produces and removes 1011 platelets daily to maintain a normal steady state platelet count. Platelet production must be regulated to avoid spontaneous bleeding or arterial occlusion and organ damage. Multifaceted and complex mechanisms control platelet production and removal in physiological and pathological conditions. This review will focus on different mechanisms of platelet senescence and clearance with specific emphasis on the role of posttranslational modifications. It will also briefly address platelet transfusion and the role of glycans in the clearance of stored platelets.

scholarly journals Role of Carica papaya leaf extract tablets/capsules on platelet counts in cases of dengue thrombocytopenia

2018 ◽  
Vol 5 (4) ◽  
pp. 845
Author(s):  
Venugopal K. ◽  
Suresh R. M. ◽  
Halesha B. R.
Keyword(s):  
Platelet Count ◽  
Dengue Fever ◽  
Platelet Transfusion ◽  
Leaf Extract ◽  
Carica Papaya ◽  
Average Duration ◽  
Control Group ◽  
Study Group ◽  
Supportive Treatment

Background: Thrombocytopenia is the hallmark laboratory finding in dengue fever and leads to bleeding manifestations when reduced markedly. So, this causes panic amongst the patient and relatives about the possibility of severity and leading to various complications including bleeding tendencies. Platelet transfusion is the only definitive treatment and it is indicated only in severe cases with bleeding manifestations. Prophylactic platelet transfusion is not much useful unless it’s reduced below 10,000cells/cumm. Carica papaya leaf extract (CPLE) are believed to have some role in improving platelets and its role is unclear. Hence, this study is taken up to evaluate the role of CPLE in improving dengue thrombocytopenia.Methods: Total 500 patients were included in the study; out of which 380 were males and 120 were females. Patients of dengue fever with thrombocytopenia (Platelet count <1, 50,000 cells/cumm) matching inclusion criteria were included in the study. After the inclusion, patients were randomized into two groups. Study group and control group by simple randomization (even/odd method). The study group treated with CPLE 1100mg three times daily for five days along with symptomatic and supportive treatment. The control group was given only symptomatic and supportive treatment. The average platelet count, average duration of stay and transfusion requirement of platelets were compared using student ‘t’ test.Results: Increased platelet counts were noted early in the treated group than the controlled group. The average duration of hospital stay was 5.42±0.98 days in study group and 7.2±0.97 days in controlled group. The requirement of platelets is more in control group than study group and it was statistically significant.Conclusions: Carica papaya leaf extract tablets can be used in patients with dengue thrombocytopenia with clear advantages over control group.

scholarly journals Regulation of Platelet Production and Life Span: Role of Bcl-xL and Potential Implications for Human Platelet Diseases

2020 ◽  
Vol 21 (20) ◽  
pp. 7591
Author(s):  
Emma C. Josefsson ◽  
William Vainchenker ◽  
Chloe James
Keyword(s):  
Life Span ◽  
Human Platelet ◽  
Inflammatory Diseases ◽  
Blood Platelets ◽  
Intrinsic Apoptosis ◽  
Tumour Angiogenesis ◽  
Platelet Production ◽  
Family Protein ◽  
Platelet Number

Blood platelets have important roles in haemostasis, where they quickly stop bleeding in response to vascular damage. They have also recognised functions in thrombosis, immunity, antimicrobal defense, cancer growth and metastasis, tumour angiogenesis, lymphangiogenesis, inflammatory diseases, wound healing, liver regeneration and neurodegeneration. Their brief life span in circulation is strictly controlled by intrinsic apoptosis, where the prosurvival Bcl-2 family protein, Bcl-xL, has a major role. Blood platelets are produced by large polyploid precursor cells, megakaryocytes, residing mainly in the bone marrow. Together with Mcl-1, Bcl-xL regulates megakaryocyte survival. This review describes megakaryocyte maturation and survival, platelet production, platelet life span and diseases of abnormal platelet number with a focus on the role of Bcl-xL during these processes.

Thrombocytopenia and disorders of platelet function

2020 ◽  
pp. 5520-5532
Author(s):  
Nicola Curry ◽  
Susie Shapiro
Keyword(s):  
Platelet Count ◽  
Platelet Function ◽  
Vital Role ◽  
Nutritional Deficiencies ◽  
Platelet Destruction ◽  
Spontaneous Bleeding ◽  
Platelet Production ◽  
Normal Platelet ◽  
First Line Therapy ◽  
Adults And Children

The platelet is the smallest circulating blood cell. In health, it plays a vital role in haemostasis, and in disease contributes to problems of bleeding and/or thrombosis. The number of platelets produced is under tight homeostatic control, regulated by the cytokine thrombopoietin. A normal platelet count lies within the range 150 to 450 × 109/litre. Thrombocytopenia is defined as a reduction in the number of circulating platelets to fewer than the normal reference range (typically <150 × 109/litre). Spontaneous bleeding is uncommon unless the platelet count falls below 10 to 20 × 109/litre or unless there is abnormal platelet function. Thrombocytopenia can be classified according to three main pathologies: (1) increased platelet destruction, (2) reduced platelet production, and (3) increased platelet sequestration. Disorders of increased platelet destruction may be immune mediated or nonimmune. Primary immune thrombocytopenia (ITP) is an acquired disorder affecting both adults and children, characterized by an isolated thrombocytopenia (platelet count <100 × 109 /litre) for which no precipitant can be found. Primary ITP is a diagnosis of exclusion. Corticosteroids are the main first-line therapy for adult ITP, commonly prednisolone. Nonimmune causes of platelet destruction include microangiopathic haemolytic disorders such as thrombotic thrombocytopenic purpura, haemolytic uraemic syndrome, and disseminated intravascular coagulation. Decreased platelet production—most cases are acquired, with common or important causes being toxins (drugs, alcohol), nutritional deficiencies (folate or vitamin B12), bone marrow infiltration, and myelodysplastic syndrome. Disorders of platelet distribution and platelet sequestration include splenomegaly and hypersplenism, haemodilution, and extracorporeal circulation. Disorders of platelet function are usually acquired. The most common causes are medications and toxins, systemic disorders, and haematological diseases. Congenital disorders are a rare cause of symptomatic bleeding.

scholarly journals Bone Marrow Macrophage Galectin-3 Regulates Platelet Production through Recognition of O-Glycans on Megakaryocytes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 409-409
Author(s):  
Melissa M Lee-Sundlov ◽  
Renata Grozovsky ◽  
Silvia Giannini ◽  
Martina McGrath ◽  
Haley E Ramsey ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Antigen Expression ◽  
Blood Platelet ◽  
Activated Macrophages ◽  
Bone Marrow Macrophage ◽  
Platelet Production ◽  
Platelet Counts ◽  
Pathological Conditions ◽  
Galectin 3

Abstract Bone marrow (BM) macrophages maintain both survival and retention of hematopoietic stem cells and regulate erythropoiesis. The role of macrophage lectins and glycans in thrombopoiesis remains unclear. We report a novel role for bone marrow macrophage galectin-3 in maintaining platelet counts, by phagocytosing megakaryocytes (MKs) expressing the Thomsen-Friedenreich (TF) antigen, which is often exposed under pathological conditions, such as cancer and malignancies. The TF antigen is a disaccharide presented in cryptic form on O-glycans and covered by a sialic acid moiety. The sialyltransferase ST3Gal1 transfers sialic acid onto the TF antigen. To investigate the role of O-glycans in thrombopoiesis, we generated mice with increased TF antigen in MKs by generating St3gal1loxP/PF4+ mice specifically lacking ST3Gal1 in the MK lineage. As expected, St3gal1loxP/PF4+ circulating platelets and BM MKs had increased TF antigen expression, compared to controls, as evidenced by peanut agglutinin (PNA) binding. Other blood cell lineages had no increase in TF antigen expression. St3gal1loxP/PF4+ mice developed mild thrombocytopenia, but surprisingly had virtually normal platelet clearance. BM MK colony forming units and in vitro proplatelet production were normal in St3gal1loxP/PF4+ mice, suggesting that extrinsic factors in the St3gal1loxP/PF4+BM environment affected platelet production. St3gal1loxP/PF4+ BM smears revealed increased hemophagocytosis, indicative of an increase in phagocytic macrophages. In vivo macrophage ablation by injection of clodronate-encapsulated liposomes significantly reduced the numbers of activated macrophages, thereby normalizing blood platelet counts and size. Flow cytometric phenotypic analysis of BM-derived macrophages showed an increased population of activated macrophages in St3gal1loxP/PF4+ mice, compared to controls, specifically macrophages with increased galectin-3 expression, a ligand for the TF antigen. Immunofluorescence staining of BM sections using a specific antibody towards the TF antigen showed that MK progenitors and pro-platelet-like structures expressed TF antigen in control BMs, which is significantly increased in St3gal1loxP/PF4+ mice and co-localized with galectin-3 expressing macrophages, supporting the notion that MK O-glycans and macrophage galectin-3 play a role in thrombopoiesis under steady state and pathological conditions. Consistent with this notion, galectin-3 deficient mice have slightly, but significantly increased blood platelet counts. We conclude that galactin-3 plays a minor role in normal thrombopoiesis. Activation of galectin-3 expressing macrophages by the MK TF antigen leads to MK phagocytosis, inhibition of platelet formation and thrombocytopenia. Disclosures No relevant conflicts of interest to declare.

Transfusion Therapy with Platelet Concentrates

1998 ◽  
Vol 21 (6_suppl) ◽  
pp. 98-102
Author(s):  
G. Isacchi
Keyword(s):  
Platelet Count ◽  
Cancer Patients ◽  
Death Rate ◽  
Platelet Transfusion ◽  
Lymphoblastic Leukemia ◽  
Transfusion Trigger ◽  
Platelet Concentrates ◽  
Transfusion Therapy ◽  
Platelet Production ◽  
Life Threatening

At the end of 1960, the concept that platelet transfusion could reduce the death rate due to hemorrhage was confirmed by the reduction of life-threatening bleeding and prolonged survival in thrombocytopenic patients affected with acute leukemia and aplastic anemia. Thrombocytopenia is the result of an imbalance between platelet production and destruction: usually no bleeding problem will occur until circulating platelets fall below 20000/μl and even a platelet count of 5000/μl may be present in many patients without bleeding. Because of the high risk of alloimmunization in multiply transfused thrombocytopenic patients with random platelet concentrates, the main dilemma is the choice of strategy: “prophylactic”versus “therapeutic” treatment with platelet concentrates of cancer patients and the platelet count selected as the “transfusion trigger” for platelet support in patients without active bleeding. We describe our experience of 367 retrospective non-randomized leukemic patients transfused with platelet concentrates. A total of 225 patients (61.3%) received support therapy: the transfusions were administered prophylactically at a platelet count below 20000/μl in the group of patients with acute lymphoblastic leukemia (35% transfused) and acute myeloblastic leukemia (78% transfused). Only14 hemorrhagic episodes were observed in 148 patients receiving prophylactic platelets (9%), while 21 severe hemorrhages (27%) were documented in patients treated with therapeutic platelet concentrates. Several studies have concluded that maintaining the platelet count above 20000/μl was not justified in the majority of cancer patients. In the absence of more definitive data, a “transfusion trigger” of 10000/μl is selected for platelet transfusion support in leukemic non-bleeding patients receiving chemotherapy.

scholarly journals Interplay between the tyrosine kinases Chk and Csk and phosphatase PTPRJ is critical for regulating platelets in mice

Blood ◽  
2020 ◽  
Vol 135 (18) ◽  
pp. 1574-1587 ◽  
Author(s):  
Zoltan Nagy ◽  
Jun Mori ◽  
Vanesa-Sindi Ivanova ◽  
Alexandra Mazharian ◽  
Yotis A. Senis
Keyword(s):  
Platelet Count ◽  
Tyrosine Kinases ◽  
Tyrosine Phosphatase ◽  
Src Family Kinases ◽  
Feedback Mechanisms ◽  
Platelet Production ◽  
Tyrosine Residues ◽  
Therapeutic Benefits ◽  
Auxiliary Role

Abstract The Src family kinases (SFKs) Src, Lyn, and Fyn are essential for platelet activation and also involved in megakaryocyte (MK) development and platelet production. Platelet SFKs are inhibited by C-terminal Src kinase (Csk), which phosphorylates a conserved tyrosine in their C-terminal tail, and are activated by the receptor-type tyrosine phosphatase PTPRJ (CD148, DEP-1), which dephosphorylates the same residue. Deletion of Csk and PTPRJ in the MK lineage in mice results in increased SFK activity, but paradoxically hypoactive platelets resulting from negative feedback mechanisms, including upregulation of Csk homologous kinase (Chk) expression. Here, we investigate the role of Chk in platelets, functional redundancy with Csk, and the physiological consequences of ablating Chk, Csk, and PTPRJ in mice. Platelet count was normal in Chk knockout (KO) mice, reduced by 92% in Chk;Csk double KO (DKO) mice, and partially rescued in Chk;Csk;Ptprj triple KO (TKO) mice. Megakaryocyte numbers were significantly increased in both DKO and TKO mice. Phosphorylation of the inhibitory tyrosine of SFKs was almost completely abolished in DKO platelets, which was partially rescued in Src and Fyn in TKO platelets. This residual phosphorylation was abolished by Src inhibitors, revealing an unexpected mechanism in which SFKs autoinhibit their activity by phosphorylating their C-terminal tyrosine residues. We demonstrate that reduced inhibitory phosphorylation of SFKs leads to thrombocytopenia, with Csk being the dominant inhibitor in platelets and Chk having an auxiliary role. PTPRJ deletion in addition to Chk and Csk ameliorates the extent of thrombocytopenia, suggesting targeting it may have therapeutic benefits in such conditions.

scholarly journals Regulation of Nuclear Factor-kappaB Function by O-GlcNAcylation in Inflammation and Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Angela Rose Liu ◽  
Parameswaran Ramakrishnan
Keyword(s):  
Cell Proliferation ◽  
Posttranslational Modifications ◽  
Nuclear Factor Kappab ◽  
Nuclear Factor ◽  
Cancer Cell Proliferation ◽  
The Past ◽  
Pathological Conditions ◽  
Evolutionarily Conserved ◽  
Made In

Nuclear factor-kappaB (NF-κB) is a pleiotropic, evolutionarily conserved transcription factor family that plays a central role in regulating immune responses, inflammation, cell survival, and apoptosis. Great strides have been made in the past three decades to understand the role of NF-κB in physiological and pathological conditions. Carcinogenesis is associated with constitutive activation of NF-κB that promotes tumor cell proliferation, angiogenesis, and apoptosis evasion. NF-κB is ubiquitously expressed, however, its activity is under tight regulation by inhibitors of the pathway and through multiple posttranslational modifications. O-GlcNAcylation is a dynamic posttranslational modification that controls NF-κB-dependent transactivation. O-GlcNAcylation acts as a nutrient-dependent rheostat of cellular signaling. Increased uptake of glucose and glutamine by cancer cells enhances NF-κB O-GlcNAcylation. Growing evidence indicates that O-GlcNAcylation of NF-κB is a key molecular mechanism that regulates cancer cell proliferation, survival and metastasis and acts as link between inflammation and cancer. In this review, we are attempting to summarize the current understanding of the cohesive role of NF-κB O-GlcNAcylation in inflammation and cancer.

scholarly journals Antithrombotic therapy as a risk factor for nasal bleeding

2021 ◽  
Vol 20 (1) ◽  
pp. 35-40
Author(s):  
A. I. Izvin ◽  
◽  
I. M. Veshkurtseva ◽  
M. A. Rebyatnikova ◽  
A. V. Rudzevich ◽  
...  
Keyword(s):  
Risk Factor ◽  
Interdisciplinary Approach ◽  
Underlying Disease ◽  
Antithrombotic Drugs ◽  
Spontaneous Bleeding ◽  
Pathological Conditions ◽  
Hemorrhagic Complications ◽  
Leading Position ◽  
Nasal Bleeding

Among the spontaneous bleeding of various localizations, nasal hemorrhages (epistaxis) take a leading position. According to various authors, the proportion of patients with nosebleeds admitted to both the therapeutic and specialized otorhinolaryngological departments is increasing from year to year. Recurrent and profuse nosebleeds can often pose a real threat to the patient’s life, which requires urgent measures. Nosebleeds are often a symptom of a number of pathological conditions, developing, among other things, against the background of drug therapy of the underlying disease. In recent years, antithrombotic drugs have been widely used, prescribed both for therapeutic and prophylactic purposes. The use of this group of drugs is associated with certain risks of developing hemorrhagic complications, including nosebleeds, which significantly complicates the tactics of managing such patients, transferring epistaxis from a highly specialized problem to a general clinical one, requiring an interdisciplinary approach in each specific case. The article presents an analysis of the etiological factors in the development of nasal hemorrhages, the role of antithrombotic drugs in the development of these complications is studied (according to the data of the otorhinolaryngological department of the Tyumen Regional Clinical Hospital No. 2).

scholarly journals Lipid chaperones and associated diseases: a group of chaperonopathies defining a new nosological entity with implications for medical research and practice

2020 ◽  
Vol 25 (6) ◽  
pp. 805-820
Author(s):  
Antonella D’Anneo ◽  
Celeste Caruso Bavisotto ◽  
Antonella Marino Gammazza ◽  
Letizia Paladino ◽  
Daniela Carlisi ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Neurological Diseases ◽  
Genetic Alterations ◽  
Fatty Acid Binding Proteins ◽  
Fatty Acid Binding ◽  
Cell Compartments ◽  
Pathological Conditions ◽  
Pathogenic Factors ◽  
Nosological Entity

Abstract Fatty acid–binding proteins (FABPs) are lipid chaperones assisting in the trafficking of long-chain fatty acids with functions in various cell compartments, including oxidation, signaling, gene-transcription regulation, and storage. The various known FABP isoforms display distinctive tissue distribution, but some are active in more than one tissue. Quantitative and/or qualitative changes of FABPs are associated with pathological conditions. Increased circulating levels of FABPs are biomarkers of disorders such as obesity, insulin resistance, cardiovascular disease, and cancer. Deregulated expression and malfunction of FABPs can result from genetic alterations or posttranslational modifications and can be pathogenic. We have assembled the disorders with abnormal FABPs as chaperonopathies in a distinct nosological entity. This entity is similar but separate from that encompassing the chaperonopathies pertaining to protein chaperones. In this review, we discuss the role of FABPs in the pathogenesis of metabolic syndrome, cancer, and neurological diseases. We highlight the opportunities for improving diagnosis and treatment that open by encompassing all these pathological conditions within of a coherent nosological group, focusing on abnormal lipid chaperones as biomarkers of disease and etiological-pathogenic factors.

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