Thrombopoietin (THPO) also known as megakaryocyte growth and development factor (MGDF) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''THPO''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. Thrombopoietin is a

glycoprotein Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...

hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...

produced by the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

and

kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...

which regulates the production of

platelet Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...

s. It stimulates the production and differentiation of

megakaryocyte A megakaryocyte () is a large bone marrow cell with a lobation, lobated nucleus that produces blood platelets (thrombocytes), which are necessary for normal blood coagulation, clotting. In humans, megakaryocytes usually account for 1 out of 10,00 ...

s, the bone marrow cells that bud off large numbers of

platelets Platelets or thrombocytes () are a part of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a blood clot. Platelets have no cell nucleus; they are fragments of cyto ...

. Megakaryocytopoiesis is the cellular development process that leads to platelet production. The protein encoded by this gene is a humoral growth factor necessary for

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

is located on the long arm of

chromosome 3 Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans more than 201 million base pairs (the building material of DNA) and represents about 6.5 percent of the total DNA ...

(q26.3-27). Abnormalities in this gene occur in some

hereditary Heredity, also called inheritance or biological inheritance, is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic inform ...

forms of

thrombocytosis In hematology, thrombocythemia is a condition of high platelet (thrombocyte) count in the blood. Normal count is in the range of 150 to 450 platelets per liter of blood, but investigation is typically only considered if the upper limit exceeds 7 ...

(high platelet count) and in some cases of

leukemia Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...

. The first 155

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

s of the protein share homology with

erythropoietin Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production ( erythropoiesis) in th ...

Function and regulation

Thrombopoietin is produced in the liver by both parenchymal cells and

sinusoidal A sine wave, sinusoidal wave, or sinusoid (symbol: ∿) is a periodic wave whose waveform (shape) is the trigonometric sine function. In mechanics, as a linear motion over time, this is '' simple harmonic motion''; as rotation, it correspond ...

endothelial cells, as well as in the kidney by proximal convoluted tubule cells. Small amounts are also made by

striated muscle Striated muscle tissue is a muscle tissue that features repeating functional units called sarcomeres. Under the microscope, sarcomeres are visible along muscle fibers, giving a striated appearance to the tissue. The two types of striated muscle a ...

and bone marrow stromal cells. In the liver, its production is augmented by

interleukin 6 Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smoo ...

(IL-6). However, the liver and the kidney are the primary sites of thrombopoietin production. Thrombopoietin regulates the differentiation of

s and

, but studies on the removal of the thrombopoietin receptor show that its effects on

hematopoiesis Haematopoiesis (; ; also hematopoiesis in American English, sometimes h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten ...

are more versatile. Its negative feedback is different from that of most hormones in

endocrinology Endocrinology (from ''endocrine system, endocrine'' + ''wikt:-logy#Suffix, -ology'') is a branch of biology and medicine dealing with the endocrine system, its diseases, and its specific secretions known as hormones. It is also concerned with the ...

: The effector regulates the hormone directly. Thrombopoietin is bound to the surface of platelets and megakaryocytes by the mpl receptor (

CD 110 The thrombopoietin receptor also known as the myeloproliferative leukemia protein or CD110 (Cluster of Differentiation 110) is a protein that in humans is encoded by the ''MPL'' (myeloproliferative leukemia virus) oncogene. Discovery In 1990 ...

). Inside the platelets it gets destroyed, while inside the megakaryocytes it gives the signal of their maturation and consecutively more platelet production. The bounding of the hormone at these cells thereby reduces further megakaryocyte exposure to the hormone. Therefore, the rising and dropping platelet and megakaryocyte concentrations regulate the thrombopoietin levels. Low platelets and megakaryocytes lead a higher degree of thrombopoietin exposure to the undifferentiated bone marrow cells, leading to differentiation into

s and further maturation of these cells. On the other hand, high platelet and megakaryocyte concentrations lead to more thrombopoetin destruction and thus less availability of thrombopoietin to bone marrow. TPO, like EPO, plays a role in brain development. It promotes

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

of newly generated neurons, an effect counteracted by EPO and

neurotrophin Neurotrophins are a family of proteins that induce the survival, development, and function of neurons. They belong to a class of growth factors, secreted proteins that can signal particular cells to survive, differentiate, or grow. Growth facto ...

Therapeutic use

Despite numerous trials, thrombopoietin has not been found to be useful therapeutically. Theoretical uses include the procurement of platelets for donation, and recovery of platelet counts after myelosuppressive

chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...

. 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.

Romiplostim Romiplostim, sold under the brand name Nplate among others, is a fusion protein analog of thrombopoietin, a hormone that regulates platelet production. The most common side effects in adults include headache, infections of the nose and throat, ...

and

Eltrombopag Eltrombopag, sold under the brand name Promacta among others, is a medication used to treat thrombocytopenia (abnormally low platelet counts) and severe aplastic anemia. Eltrombopag is sold under the brand name Revolade outside the US and is ma ...

, compounds that are structurally different to thrombopoietin but stimulate the same pathway by binding to and activating the thrombopoietin receptor, are used instead. A quadrivalent peptide analogue is being investigated, as well as several

small-molecule In molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs are small molecules; t ...

agents, and several non-peptide ligands of ''c-Mpl'', which act as thrombopoietin analogues.

Discovery

Thrombopoietin was cloned by five independent teams in 1994. Before its identification, its function has been hypothesized for as much as 30 years as being linked to the

cell surface receptor Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integra ...

''c-Mpl'', and in older publications ''thrombopoietin'' is described as ''c-Mpl ligand'' (the agent that binds to the c-Mpl molecule). Thrombopoietin is one of the Class I hematopoietic cytokines.

References

External links

Longer summary on thrombopoietin
{{Cytokine receptor modulators Growth factors Thrombopoietin receptor agonists