What is the name of the disorder in which granules are unstable?
This syndrome is associated with the loss of α -granule proteins. The abnormal serglycin may account for the low content of α-granule proteins in these cells. This rat platelet disorder is similar to a human disorder known as gray platelet syndrome. α -Granules appear to be unstable in the human gray platelet syndrome.
What causes gray platelet syndrome?
Platelet α-granule deficiency, gray platelet syndrome or α-storage pool disease, is caused by the reduction or absence of platelet α-granules ( Figure 62.9 ). The affected patients have a history of a bleeding diathesis and demonstrate a mild thrombocytopenia. Platelets appear grayish in blood smears stained with Wright’s stain. Ultrastructural studies reveal absence or markedly reduced numbers of α-granules in the affected platelets. The basic defect seems to be the inability of megakaryocytes to transfer endogenously synthesized proteins into α-granule precursors. The affected patients show a prolonged bleeding time and variable responses in platelet aggregation studies. The most consistent finding is impairment of thrombin-induced aggregation.
What is the role of fibrinogen in hemostasis?
Fibrinogen plays a critical role in both primary and secondary hemostasis. Fibrinogen released from platelet alpha granules serves as a bridge for the platelet glycoprotein IIb/IIIa receptor on the platelet surface during platelet aggregation. After the formation of a platelet plug, the coagulation cascade is activated and thrombin is generated. Thrombin subsequently cleaves fibrinogen to fibrin inducing release of FPA and FPB from the central E domain to form a fibrin clot. The fibrin units are assembled into an organized polymeric structure and cross-linked by factor XIIIa to further stabilize the fibrin clot. Antithrombin is an important regulator of coagulation; it inhibits thrombin formation and sequesters circulating thrombin within fibrin. Fibrinogen also interacts with plasminogen, tissue plasminogen activator, and α2-antiplasmin to help regulate fibrin deposition and fibrinolysis.
What is PF4 79?
The basic platelet α -granule protein PF4 79 has been found in human atherosclerotic plaques, 80 and could serve as a growth factor for arterial smooth muscle cells.
Why are platelet granules so dense?
Platelet dense granules are so called because of their relative opacity under electron microscopy. This opacity is due to the high amount of nonprotein content packed in dense granules. Nonetheless, Hernandez-Ruiz et al.127 have recently characterized the dense granular proteome.
What are the granules in platelet releasate?
Granule contents contribute to the propagation of platelet activation as well as other processes such as coagulation, inflammation, angiogenesis, arteriosclerosis, and wound healing. α-granules are major contributors to the protein component of the platelet releasate.
What is TG in exocytosis?
An unexpected involvement of cytoplasmic TG in exocytosis of platelet α-granules was discovered when Walther and coauthors (2003) reported that TG-mediated serotonylation of the small regulatory GTPases RhoA and Rab4A, which renders them constitutively activated, induced vesicle release and subsequent platelet aggregation. Later, a modulation of insulin secretion by pancreatic β cells was found to be regulated by TG-driven serotonylation of Rab3A and Rab27A GTPases, as inhibition of this process was shown to block hormone release (Paulmann et al., 2009 ). These important findings open a new avenue of research indicating that TG2-driven monoaminylation of multiple regulatory GTPases is involved in several aspects of intracellular vesicular trafficking and vesicle-based secretion processes in various cell types ( Walther et al., 2011 ).
What is PF4 produced by?
PF4 is a chemokine produced by megakaryocytes and released from platelet α-granules upon platelet activation. Released PF4 binds cell-surface glycosaminoglycans and heparin. Formation of the PF4-heparin complex causes a conformational change in the protein leading to exposure of cryptic epitopes to which the antibodies in HIT are usually generated. The anti-PF4/heparin antibodies, which are of IgG isotype, bind to PF4 through their F (ab) domains. Serial PF4 molecules align on the platelet surface and several IgG molecules bind, leading to the formation of large immune complexes that cross-link the platelet FcγIIa receptors, and resulting in platelet aggregation and an associated platelet procoagulant response. 116 HIT antibodies also bind to endothelial cells and monocytes resulting in additional procoagulant effects through increased expression of tissue factor and formation of platelet-monocyte aggregates leading to thrombin generation. Therefore in HIT the clinical manifestations are the result of both FcγIIa-dependent platelet activation and activation of the coagulation system through tissue factor expression and platelet activation.
What are the granules of platelets?
Platelet α -granules contain serglycin and many proteins that are involved in platelet activation during thrombus formation, inflammation, and atherosclerosis. Only one natural model of a defect in serglycin structure has been described 21: we have described abnormal platelet chondroitin sulfate proteoglycans that involve shortening of GAG chain length and a decrease in total GAG mass per cell by about 60% in Wistar Furth macrothrombocytopenic (platelets are abnormally large and are severely reduced in number) rats. This syndrome is associated with the loss of α -granule proteins. The abnormal serglycin may account for the low content of α -granule proteins in these cells. This rat platelet disorder is similar to a human disorder known as gray platelet syndrome. α -Granules appear to be unstable in the human gray platelet syndrome. Premature release of α -granule growth factors or chemokines from megakaryocytes into the marrow in this disorder, as well as in myeloproliferative disorders and myelofibrosis is thought to cause the lethal marrow fibrosis which is commonly found in these disorders. We have shown that proteoglycan synthesis in normal megakaryocytes appears to be directed towards storage of these molecules in α -granules during production of normal platelets, and that 85% of the platelet proteoglycans are released by thrombin treatment. 31 In contrast, we, and others, have found that the human hematopoietic tumor cell lines constitutively secrete the bulk of their proteoglycans. 11,12 Similarly, Wickenhauser et al. 78 have shown that lysozyme is constitutively released by megakaryocytes from patients with polycythemia vera but not from normal megakaryocytes. This is of interest because lysozyme interacts with chondroitin sulfate serglycin, 39,40 suggesting that lysozyme is released as a complex with serglycin. The basis for the differences in secretion patterns between normal and malignant cells is not understood. It is possible that the serglycin/protein complexes are not formed properly, are directed to constitutive secretory vesicles instead of storage granules, or that the storage granules have defective storage and/or release mechanisms.
What causes gray platelet syndrome?
Platelet α-granule deficiency, gray platelet syndrome or α-storage pool disease, is caused by the reduction or absence of platelet α-granules ( Figure 62.9 ). The affected patients have a history of a bleeding diathesis and demonstrate a mild thrombocytopenia. Platelets appear grayish in blood smears stained with Wright’s stain. Ultrastructural studies reveal absence or markedly reduced numbers of α-granules in the affected platelets. The basic defect seems to be the inability of megakaryocytes to transfer endogenously synthesized proteins into α-granule precursors. The affected patients show a prolonged bleeding time and variable responses in platelet aggregation studies. The most consistent finding is impairment of thrombin-induced aggregation.
Why are platelet granules so dense?
Platelet dense granules are so called because of their relative opacity under electron microscopy. This opacity is due to the high amount of nonprotein content packed in dense granules. Nonetheless, Hernandez-Ruiz et al. 127 have recently characterized the dense granular proteome. This group identified 40 proteins, including actin-associated proteins, glycolytic enzymes, and regulatory proteins that have not previously been attributed to dense granules. The authors also identified 14-3-3ζ in dense granules, a protein that regulates GPIb function and is found in atherosclerotic plaques. 127
What is a TG PF4?
Beta-thromboglobulin and platelet factor 4 (βTG-PF4) are specific platelet alpha-granule proteins that are released upon platelet activation. Release of either protein can be measured by ELISA using commercially available kits. For (βTG and PF4 measurements, venous blood is collected into a precooled polypropylene syringe and then immediately transferred into plastic tubes containing an anticoagulant mixture (EDTA, theophylline plus 1 × 10- 4 M PGE1). The blood is maintained, chilled, and centrifuged within 15 min of blood collection to obtain the PPP for analysis. The PPP is carefully removed and stored at -20 °C.
What is TG in exocytosis?
An unexpected involvement of cytoplasmic TG in exocytosis of platelet α-granules was discovered when Walther and coauthors (2003) reported that TG-mediated serotonylation of the small regulatory GTPases RhoA and Rab4A, which renders them constitutively activated, induced vesicle release and subsequent platelet aggregation. Later, a modulation of insulin secretion by pancreatic β cells was found to be regulated by TG-driven serotonylation of Rab3A and Rab27A GTPases, as inhibition of this process was shown to block hormone release ( Paulmann et al., 2009 ). These important findings open a new avenue of research indicating that TG2-driven monoaminylation of multiple regulatory GTPases is involved in several aspects of intracellular vesicular trafficking and vesicle-based secretion processes in various cell types ( Walther et al., 2011 ).
What are the two main classes of granules?
Two main classes of granules are present in platelets: α-granules and dense granules. Granule contents contribute to the propagation of platelet activation as well as other processes such as coagulation, inflammation, angiogenesis, arteriosclerosis, and wound healing.
What is the nuage?
In 1957, André and Rouiller first coined the term " nuage ". (French for "cloud"). Its amorphous and fibrous structure occurred in drawings as early as in 1933 (Risley). Today, the nuage is accepted to represent a characteristic, electrondense germ plasm organelle encapsulating the cytoplasmic face of the nuclear envelope of the cells destined to the germline fate. The same granular material is also known under various synonyms: dense bodies, mitochondrial clouds, yolk nuclei, Balbiani bodies, perinuclear P granules in Caenorhabditis elegans, germinal granules in Xenopus laevis, chromatoid bodies in mice, and polar granules in Drosophila. Molecularly, the nuage is a tightly interwoven network of differentially localized RNA-binding proteins, which in turn localize specific mRNA species for differential storage, asymmetric segregation (as needed for asymmetric cell division ), differential splicing and/or translational control. The germline granules appear to be ancestral and universally conserved in the germlines of all metazoan phyla .
What are the granules of platelets?
Dense granules (also known as δ-granules) are the second most abundant platelet granules, with 3–8 per platelet. They measure about 150 nm in diameter 2. These granules, unique to the platelets, are a subtype of lysosome-related organelles (LROs), a group that also includes melanosomes, lamellar bodies of the type II alveolar cells, and lytic granules of cytotoxic T cells. Dense granules mainly contain bioactive amines (for example, serotonin and histamine), adenine nucleotides, polyphosphates, and pyrophosphates as well as high concentrations of cations, particularly calcium. These granules derive their name from their electron-dense appearance on whole mount electron microscopy, which results from their high cation concentrations . Dense granule exocytosis is typically evaluated by ADP/ATP release by using luciferase-based luminescence techniques, release of preloaded [ 3H] serotonin, or membrane expression of lysosome-associated membrane protein 2 (LAMP2) or CD63 by flow cytometry.
How does insulin mature?
Insulin granules mature in three steps: (1) the lumen of the granule undergoes acidification, due to the acidic properties of a secretory granule; (2) proinsulin becomes insulin through the process of proteolysis. The endoproteases PC1/3 and PC2 aid in this transformation from proinsulin to insulin; and (3) the clathrin protein coat is removed.
What is the function of immature insulin granules?
Immature insulin granules function as a sorting chamber during the maturation process listed below. Insulin and other insoluble granule components are kept within the granules. Other soluble proteins and granule parts then bud off from the immature granule in a clathrin-coated transport vesicle.
What are the granules of leukocytes?
The granules of leukocytes are classified as azurophilic granules or specific granules . Leukocyte granules are released in response to immunological stimuli during a process known as degranulation .
What is a granule in biology?
small particle, often in plants. For other uses, see Granule (disambiguation). In cell biology, a granule is a small particle. It can be any structure barely visible by light microscopy. The term is most often used to describe a secretory vesicle .
What is the T granule?
An electron-dense granule defined by the presence of Toll-like receptor 9 (TLR9) and protein disulfide isomerase (PDI), terme d the T granule, has also been described, although its existence remains controversial.
