Thrombopoietin
Encyclopedia
Thrombopoietin also known as megakaryocyte growth and development factor (MGDF) is a protein
that in humans is encoded by the THPO gene
.
Thrombopoietin is a glycoprotein
hormone
produced mainly by the liver
and the kidney
that regulates the production of platelet
s by the bone marrow
. It stimulates the production and differentiation of megakaryocyte
s, the bone marrow cells that fragment into large numbers of platelets.
Megakaryocytopoiesis is the cellular development process that leads to platelet production. The protein encoded by this gene is a humoral growth factor that is necessary for megakaryocyte
proliferation and maturation, as well as for thrombopoiesis. This protein is the ligand for MLP/C_MPL, the product of myeloproliferative leukemia virus oncogene.
is located on the long arm of chromosome 3 (q26.3-27). Abnormalities in this gene occur in some hereditary forms of thrombocytosis
(high platelet count) and in some cases of leukemia
. The first 155 amino acid
s of the protein share homology
with erythropoietin
.
and stromal cells in the bone marrow
. In the liver, its production is augmented by interleukin 6
(IL-6).. However, physiologically, the liver and the bone marrow stromal cells are the primary sites of thrombopoietin production.
Thrombopoietin regulates the differentiation of megakaryocyte
s and platelets, but studies on the removal of the thrombopoietin receptor show that its effects on hematopoiesis are more versatile.
Its negative feedback
is different from most hormones in endocrinology
: the effector regulates the hormone directly. Thrombopoietin is bound to the surface of platelets by the mpl receptor (CD 110) and destroyed, thereby reducing megakaryocyte exposure to the hormone.
Therefore, the rising and dropping platelet concentrations regulate the thrombopoietin levels. Low platelets lead a higher degree of thrombopoietin exposure to the undifferentiated bone marrow cells; leading to differentiation into megakaryocyte
s and further maturation of these cells. On the contrary, high platelet concentrations lead to the reversal of these physiologic mechanisms.
.
Trials of a modified recombinant form, megakaryocyte growth and differentiation factor (MGDF), were stopped when healthy volunteers developed autoantibodies to endogenous thrombopoietin and then developed thrombocytopenia themselves. Romiplostim
and Eltrombopag
, structurally different compounds which stimulate the same pathway, are used instead.
A quadrivalent peptide analogue is undergoing development, as well as several small molecule
agents, including several non-peptide ligands of c-Mpl, which act as thrombopoietin analogues.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the THPO gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Thrombopoietin is a glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
hormone
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
produced mainly by the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
and the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
that regulates the production of platelet
Platelet
Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...
s by the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
. It stimulates the production and differentiation of megakaryocyte
Megakaryocyte
The megakaryocyte is a bone marrow cell responsible for the production of blood thrombocytes , which are necessary for normal blood clotting...
s, the bone marrow cells that fragment into large numbers of platelets.
Megakaryocytopoiesis is the cellular development process that leads to platelet production. The protein encoded by this gene is a humoral growth factor that is necessary for megakaryocyte
Megakaryocyte
The megakaryocyte is a bone marrow cell responsible for the production of blood thrombocytes , which are necessary for normal blood clotting...
proliferation and maturation, as well as for thrombopoiesis. This protein is the ligand for MLP/C_MPL, the product of myeloproliferative leukemia virus oncogene.
Genetics
The thrombopoietin geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
is located on the long arm of chromosome 3 (q26.3-27). Abnormalities in this gene occur in some hereditary forms of thrombocytosis
Thrombocytosis
Thrombocytosis is the presence of high platelet counts in the blood, and can be either primary or reactive...
(high platelet count) and in some cases of leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
. The first 155 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s of the protein share homology
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
with erythropoietin
Erythropoietin
Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production...
.
Function and regulation
In the liver it is produced by parenchymal cells and sinusoidal endothelial cells. In the kidney it is made by proximal convoluted tubule cells. Along with these it is made by striated muscleStriated muscle
Striated muscle tissue is a form of fibers that are combined into parallel fibers. More specifically, it can refer to:* Cardiac muscle .* Skeletal muscle* Branchiomeric muscles...
and stromal cells in the bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
. In the liver, its production is augmented by interleukin 6
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
(IL-6).. However, physiologically, the liver and the bone marrow stromal cells are the primary sites of thrombopoietin production.
Thrombopoietin regulates the differentiation of megakaryocyte
Megakaryocyte
The megakaryocyte is a bone marrow cell responsible for the production of blood thrombocytes , which are necessary for normal blood clotting...
s and platelets, but studies on the removal of the thrombopoietin receptor show that its effects on hematopoiesis are more versatile.
Its negative feedback
Feedback
Feedback describes the situation when output from an event or phenomenon in the past will influence an occurrence or occurrences of the same Feedback describes the situation when output from (or information about the result of) an event or phenomenon in the past will influence an occurrence or...
is different from most hormones in endocrinology
Endocrinology
Endocrinology is a branch of biology and medicine dealing with the endocrine system, its diseases, and its specific secretions called hormones, the integration of developmental events such as proliferation, growth, and differentiation and the coordination of...
: the effector regulates the hormone directly. Thrombopoietin is bound to the surface of platelets by the mpl receptor (CD 110) and destroyed, thereby reducing megakaryocyte exposure to the hormone.
Therefore, the rising and dropping platelet concentrations regulate the thrombopoietin levels. Low platelets lead a higher degree of thrombopoietin exposure to the undifferentiated bone marrow cells; leading to differentiation into megakaryocyte
Megakaryocyte
The megakaryocyte is a bone marrow cell responsible for the production of blood thrombocytes , which are necessary for normal blood clotting...
s and further maturation of these cells. On the contrary, high platelet concentrations lead to the reversal of these physiologic mechanisms.
Therapeutic use
Despite numerous trials, thrombopoietin is not used therapeutically. Theoretical uses include the procurement of platelets for donation, recovery of platelet counts after myelosuppressive chemotherapyChemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
.
Trials of a modified recombinant form, megakaryocyte growth and differentiation factor (MGDF), were stopped when healthy volunteers developed autoantibodies to endogenous thrombopoietin and then developed thrombocytopenia themselves. Romiplostim
Romiplostim
Romiplostim is a fusion protein analog of thrombopoietin, a hormone that regulates platelet production. The drug was developed by Amgen and is marketed under the trade name Nplate through a restricted usage program called NEXUS...
and Eltrombopag
Eltrombopag
Eltrombopag is a medication that has been developed for conditions that lead to thrombocytopenia . It is a small molecule agonist of the c-mpl receptor, which is the physiological target of the hormone thrombopoietin...
, structurally different compounds which stimulate the same pathway, are used instead.
A quadrivalent peptide analogue is undergoing development, as well as several small molecule
Small molecule
In the fields of pharmacology and biochemistry, a small molecule is a low molecular weight organic compound which is by definition not a polymer...
agents, including several non-peptide ligands of c-Mpl, which act as thrombopoietin analogues.