Von Willebrand factor
Encyclopedia
von Willebrand factor is a blood
glycoprotein
involved in hemostasis
. It is deficient or defective in von Willebrand disease
and is involved in a large number of other diseases, including thrombotic thrombocytopenic purpura
, Heyde's syndrome
, and possibly hemolytic-uremic syndrome
. Increased plasma levels in a large numbers of cardiovascular, neoplastic and connective tissue diseases are presumed to arise from adverse changes to the endothelium
, and may contribute to an increased risk of thrombosis.
present in blood plasma
and produced constitutively in endothelium
(in the Weibel-Palade bodies
), megakaryocyte
s (α-granules of platelet
s), and subendothelial connective tissue
.
protein. Every monomer contains a number of specific domains with a specific function; elements of note are:
Monomers are subsequently N-glycosylated
, arranged into dimers in the endoplasmic reticulum
and into multimers in the Golgi apparatus
by crosslinking of cysteine
residues via disulfide bond
s. With respect to the glycosylation, vWF is one of only a few proteins that carry ABO blood group system
antigens.
Multimers of vWF can be extremely large, >20,000 kDa
, and consist of over 80 subunits of 250 kDa each. Only the large multimers are functional. Some cleavage products that result from vWF production are also secreted but probably serve no function.
and, thus, has no catalytic activity. Its primary function is binding to other proteins, in particular factor VIII
and it is important in platelet adhesion to wound sites.
vWF binds to a number of cells and molecules. The most important ones are:
vWF plays a major role in blood coagulation. Therefore, vWF deficiency or dysfunction (von Willebrand disease) leads to a bleeding tendency, which is most apparent in tissues having high blood flow shear in narrow vessels. From studies it appears that vWF uncoils under these circumstances, decelerating passing platelets.
) of vWF is largely mediated by the protein ADAMTS13
(acronym of "a disintegrin-like and metalloprotease with thrombospondin type 1 motif no. 13"). It is a metalloproteinase
that cleaves
vWF between tyrosine
at position 842 and methionine
at position 843 (or 1605–1606 of the gene) in the A2 domain. This breaks down the multimers into smaller units, which are degraded by other peptidases.
or acquired defects of vWF lead to von Willebrand disease (vWD), a bleeding diathesis
of the skin and mucous membranes, causing nosebleed
s, menorrhagia
, and gastrointestinal bleeding. The point at which the mutation
occurs determines the severity of the bleeding diathesis. There are three types (I, II and III), and type II is further divided in several subtypes. Treatment depends on the nature of the abnormality and the severity of the symptoms. Most cases of vWD are hereditary, but abnormalities of vWF may be acquired; aortic valve stenosis
, for instance, has been linked to vWD type IIA, causing gastrointestinal bleeding
- an association known as Heyde's syndrome
.
In thrombotic thrombocytopenic purpura
(TTP) and hemolytic uremic syndrome (HUS), ADAMTS13 either is deficient or has been inhibited by antibodies
directed at the enzyme. This leads to decreased breakdown of the ultra-large multimers of vWF and microangiopathic hemolytic anemia
with deposition of fibrin and platelets in small vessels, and capillary necrosis. In TTP, the organ most obviously affected is the brain; in HUS, the kidney.
Higher levels of vWF are more common among people that have had ischemic stroke (from blood-clotting) for the first time. Occurrence is not affected by ADAMTS13, and the only significant genetic factor is the person's blood group
.
doctor who in 1924 first described a hereditary bleeding disorder in families from the Åland islands, who had a tendency for cutaneous and mucosal bleeding, including menorrhagia
. Although von Willebrand could not identify the definite cause, he distinguished von Willebrand disease (vWD) from hemophilia and other forms of bleeding diathesis
.
In the 1950s, vWD was shown to be caused by a plasma factor deficiency (instead of being caused by platelet disorders), and, in the 1970s, the vWF protein was purified.
with Collagen, type I, alpha 1.
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
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...
involved in hemostasis
Hemostasis
Hemostasis or haemostasis is a process which causes bleeding to stop, meaning to keep blood within a damaged blood vessel . Most of the time this includes blood changing from a liquid to a solid state. Intact blood vessels are central to moderating blood's tendency to clot...
. It is deficient or defective in von Willebrand disease
Von Willebrand disease
von Willebrand disease is the most common hereditary coagulation abnormality described in humans, although it can also be acquired as a result of other medical conditions. It arises from a qualitative or quantitative deficiency of von Willebrand factor , a multimeric protein that is required for...
and is involved in a large number of other diseases, including thrombotic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura is a rare disorder of the blood-coagulation system, causing extensive microscopic thromboses to form in small blood vessels throughout the body...
, Heyde's syndrome
Heyde's syndrome
Heyde's syndrome is a syndrome of aortic valve stenosis associated with gastrointestinal bleeding from colonic angiodysplasia. It is named after Dr. Edward C. Heyde, who first described the association in 1958...
, and possibly hemolytic-uremic syndrome
Hemolytic-uremic syndrome
Hemolytic-uremic syndrome , abbreviated HUS, is a disease characterized by hemolytic anemia, acute renal failure and a low platelet count . It predominantly, but not exclusively, affects children. Most cases are preceded by an episode of diarrhea caused by E. coli O157:H7, which is acquired as a...
. Increased plasma levels in a large numbers of cardiovascular, neoplastic and connective tissue diseases are presumed to arise from adverse changes to the endothelium
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
, and may contribute to an increased risk of thrombosis.
Synthesis
vWF is a large multimeric glycoproteinGlycoprotein
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...
present in blood plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
and produced constitutively in endothelium
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
(in the Weibel-Palade bodies
Weibel-Palade body
Weibel-Palade bodies are the storage granules of endothelial cells, the cells that form the inner lining of the blood vessels and heart. They store and release two principal molecules, von Willebrand factor and P-selectin, and thus play a dual role in hemostasis and inflammation...
), megakaryocyte
Megakaryocyte
The megakaryocyte is a bone marrow cell responsible for the production of blood thrombocytes , which are necessary for normal blood clotting...
s (α-granules 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), and subendothelial connective tissue
Connective tissue
"Connective tissue" is a fibrous tissue. It is one of the four traditional classes of tissues . Connective Tissue is found throughout the body.In fact the whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the toes determine the form of...
.
Structure
The basic vWF monomer is a 2050-amino acidAmino 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...
protein. Every monomer contains a number of specific domains with a specific function; elements of note are:
- the D'/D3 domain, which binds to factor VIIIFactor VIIIFactor VIII is an essential blood clotting factor also known as anti-hemophilic factor . In humans, Factor VIII is encoded by the F8 gene...
- the A1 domain, which binds to:
- plateletPlateletPlatelets, 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...
GPIb-receptor - heparinHeparinHeparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
- possibly collagenCollagenCollagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
- platelet
- the A3 domain, which binds to collagen
- the C1 domain, in which the RArginineArginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
GGlycineGlycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
DAspartic acidAspartic acid is an α-amino acid with the chemical formula HOOCCHCH2COOH. The carboxylate anion, salt, or ester of aspartic acid is known as aspartate. The L-isomer of aspartate is one of the 20 proteinogenic amino acids, i.e., the building blocks of proteins...
domain binds to platelet integrinIntegrinIntegrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
αIIbβ3 when this is activated - the "cysteine knot" domain (at the C-terminal end of the protein), which vWF shares with platelet-derived growth factorPlatelet-derived growth factorIn molecular biology, platelet-derived growth factor is one of the numerous growth factors, or proteins that regulate cell growth and division. In particular, it plays a significant role in blood vessel formation , the growth of blood vessels from already-existing blood vessel tissue. Uncontrolled...
(PDGF), transforming growth factorTransforming growth factorTransforming growth factor is used to describe two classes of polypeptide growth factors, TGFα and TGFβ....
-β (TGFβ) and β-human chorionic gonadotropinHuman chorionic gonadotropinHuman chorionic gonadotropin or human chorionic gonadotrophin is a glycoprotein hormone produced during pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast .. Some tumors make this hormone; measured elevated levels when the patient is not...
(βHCG, of pregnancy testPregnancy testA pregnancy test attempts to determine whether or not a woman is pregnant.These markers are found in urine and blood, and pregnancy tests require sampling one of these substances. The first of these markers to be discovered, human chorionic gonadotropin , was discovered in 1930 to be produced by...
fame).
Monomers are subsequently N-glycosylated
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
, arranged into dimers in the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
and into multimers in the Golgi apparatus
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
by crosslinking of cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
residues via disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
s. With respect to the glycosylation, vWF is one of only a few proteins that carry ABO blood group system
ABO blood group system
The ABO blood group system is the most important blood type system in human blood transfusion. The associated anti-A antibodies and anti-B antibodies are usually IgM antibodies, which are usually produced in the first years of life by sensitization to environmental substances such as food,...
antigens.
Multimers of vWF can be extremely large, >20,000 kDa
KDA
KDA may refer to:* Karachi Development Authority* Kongsberg Defence & Aerospace* Kotelawala Defence Academy* Kramer Design Associates* Lithium diisopropylamide, KDA is the potassium analogue of lithium diisopropylamideOr kDa may refer to:...
, and consist of over 80 subunits of 250 kDa each. Only the large multimers are functional. Some cleavage products that result from vWF production are also secreted but probably serve no function.
Function
von Willebrand factor is not an enzymeEnzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
and, thus, has no catalytic activity. Its primary function is binding to other proteins, in particular factor VIII
Factor VIII
Factor VIII is an essential blood clotting factor also known as anti-hemophilic factor . In humans, Factor VIII is encoded by the F8 gene...
and it is important in platelet adhesion to wound sites.
vWF binds to a number of cells and molecules. The most important ones are:
- Factor VIII is bound to vWF while inactive in circulation; factor VIII degrades rapidly when not bound to vWF. Factor VIII is released from vWF by the action of thrombinThrombinThrombin is a "trypsin-like" serine protease protein that in humans is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the first step of the coagulation cascade, which ultimately results in the stemming of blood loss...
. - vWF binds to collagen, e.g., when it is exposed in endothelial cellsEndotheliumThe endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
due to damage occurring to the blood vessel. - vWF binds to platelet gpIb when it forms a complex with gpIX and gpV; this binding occurs under all circumstances, but is most efficient under high shear stressShear stressA shear stress, denoted \tau\, , is defined as the component of stress coplanar with a material cross section. Shear stress arises from the force vector component parallel to the cross section...
(i.e., rapid blood flow in narrow blood vessels, see below). - vWF binds to other platelet receptors when they are activated, e.g., by thrombinThrombinThrombin is a "trypsin-like" serine protease protein that in humans is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the first step of the coagulation cascade, which ultimately results in the stemming of blood loss...
(i.e., when coagulation has been stimulated).
vWF plays a major role in blood coagulation. Therefore, vWF deficiency or dysfunction (von Willebrand disease) leads to a bleeding tendency, which is most apparent in tissues having high blood flow shear in narrow vessels. From studies it appears that vWF uncoils under these circumstances, decelerating passing platelets.
Catabolism
The biological breakdown (catabolismCatabolism
Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy. In catabolism, large molecules such as polysaccharides, lipids, nucleic acids and proteins are broken down into smaller units such as monosaccharides, fatty acids, nucleotides, and amino...
) of vWF is largely mediated by the protein ADAMTS13
ADAMTS13
ADAMTS13 —also known as von Willebrand factor-cleaving protease —is a zinc-containing metalloprotease enzyme that cleaves von Willebrand factor , a large protein involved in blood clotting...
(acronym of "a disintegrin-like and metalloprotease with thrombospondin type 1 motif no. 13"). It is a metalloproteinase
Metalloproteinase
Metalloproteinases constitute a family of enzymes from the group of proteases, classified by the nature of the most prominent functional group in their active site. These are proteolytic enzymes whose catalytic mechanism involves a metal. Most metalloproteases are zinc-dependent, but some use...
that cleaves
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
vWF between tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
at position 842 and methionine
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
at position 843 (or 1605–1606 of the gene) in the A2 domain. This breaks down the multimers into smaller units, which are degraded by other peptidases.
Role in disease
HereditaryGenetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
or acquired defects of vWF lead to von Willebrand disease (vWD), a bleeding diathesis
Bleeding diathesis
In medicine , bleeding diathesis is an unusual susceptibility to bleeding mostly due to hypocoagulability, in turn caused by a coagulopathy . Several types are distinguished, ranging from mild to lethal...
of the skin and mucous membranes, causing nosebleed
Nosebleed
Epistaxis or a nosebleed is the relatively common occurrence of hemorrhage from the nose, usually noticed when the blood drains out through the nostrils...
s, menorrhagia
Menorrhagia
Menorrhagia is an abnormally heavy and prolonged menstrual period at regular intervals. Causes may be due to abnormal blood clotting, disruption of normal hormonal regulation of periods or disorders of the endometrial lining of the uterus...
, and gastrointestinal bleeding. The point at which the mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
occurs determines the severity of the bleeding diathesis. There are three types (I, II and III), and type II is further divided in several subtypes. Treatment depends on the nature of the abnormality and the severity of the symptoms. Most cases of vWD are hereditary, but abnormalities of vWF may be acquired; aortic valve stenosis
Aortic valve stenosis
Aortic valve stenosis is a disease of the heart valves in which the opening of the aortic valve is narrowed. The aortic valve is the valve between the left ventricle of the heart and the aorta, which is the largest artery in the body and carries the entire output of blood.-Pathophysiology:The...
, for instance, has been linked to vWD type IIA, causing gastrointestinal bleeding
Gastrointestinal bleeding
Gastrointestinal bleeding or gastrointestinal hemorrhage describes every form of hemorrhage in the gastrointestinal tract, from the pharynx to the rectum. It has diverse causes, and a medical history, as well as physical examination, generally distinguishes between the main forms...
- an association known as Heyde's syndrome
Heyde's syndrome
Heyde's syndrome is a syndrome of aortic valve stenosis associated with gastrointestinal bleeding from colonic angiodysplasia. It is named after Dr. Edward C. Heyde, who first described the association in 1958...
.
In thrombotic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura
Thrombotic thrombocytopenic purpura is a rare disorder of the blood-coagulation system, causing extensive microscopic thromboses to form in small blood vessels throughout the body...
(TTP) and hemolytic uremic syndrome (HUS), ADAMTS13 either is deficient or has been inhibited by antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
directed at the enzyme. This leads to decreased breakdown of the ultra-large multimers of vWF and microangiopathic hemolytic anemia
Microangiopathic hemolytic anemia
In medicine microangiopathic hemolytic anemia is a microangiopathic subgroup of hemolytic anemia caused by factors in the small blood vessels. It is identified by the finding of anemia and schistocytes on microscopy of the blood film.-Presentation:It is referred as Runner's anemia...
with deposition of fibrin and platelets in small vessels, and capillary necrosis. In TTP, the organ most obviously affected is the brain; in HUS, the kidney.
Higher levels of vWF are more common among people that have had ischemic stroke (from blood-clotting) for the first time. Occurrence is not affected by ADAMTS13, and the only significant genetic factor is the person's blood group
Blood type
A blood type is a classification of blood based on the presence or absence of inherited antigenic substances on the surface of red blood cells . These antigens may be proteins, carbohydrates, glycoproteins, or glycolipids, depending on the blood group system...
.
History
vWF is named after Dr. Erik von Willebrand (1870–1949), a FinnishFinland
Finland , officially the Republic of Finland, is a Nordic country situated in the Fennoscandian region of Northern Europe. It is bordered by Sweden in the west, Norway in the north and Russia in the east, while Estonia lies to its south across the Gulf of Finland.Around 5.4 million people reside...
doctor who in 1924 first described a hereditary bleeding disorder in families from the Åland islands, who had a tendency for cutaneous and mucosal bleeding, including menorrhagia
Menorrhagia
Menorrhagia is an abnormally heavy and prolonged menstrual period at regular intervals. Causes may be due to abnormal blood clotting, disruption of normal hormonal regulation of periods or disorders of the endometrial lining of the uterus...
. Although von Willebrand could not identify the definite cause, he distinguished von Willebrand disease (vWD) from hemophilia and other forms of bleeding diathesis
Bleeding diathesis
In medicine , bleeding diathesis is an unusual susceptibility to bleeding mostly due to hypocoagulability, in turn caused by a coagulopathy . Several types are distinguished, ranging from mild to lethal...
.
In the 1950s, vWD was shown to be caused by a plasma factor deficiency (instead of being caused by platelet disorders), and, in the 1970s, the vWF protein was purified.
Interactions
von Willebrand factor has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with Collagen, type I, alpha 1.
External links
See also
- von Willebrand diseaseVon Willebrand diseasevon Willebrand disease is the most common hereditary coagulation abnormality described in humans, although it can also be acquired as a result of other medical conditions. It arises from a qualitative or quantitative deficiency of von Willebrand factor , a multimeric protein that is required for...
- Bernard-Soulier syndromeBernard-Soulier syndromeBernard–Soulier syndrome , also called hemorrhagiparous thrombocytic dystrophy, is a rare autosomal recessive coagulopathy that causes a deficiency of glycoprotein Ib , the receptor for von Willebrand factor, which is important in clot formation.The incidence is estimated to be less than 1 in 1...