ADAMTS13 (
a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13)—also known as
von Willebrand factor-cleaving protease (VWFCP)—is a
zincZinc , also known as spelter, is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
-containing metalloprotease
enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at...
that cleaves
von Willebrand factorVon 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.- Synthesis :vWF...
(vWf), a large protein involved in
blood clottingCoagulation is a complex process by which blood forms clots. It is an important part of hemostasis , wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
. It is secreted in
bloodBlood is a specialized bodily fluid that delivers necessary substances to the body's cells — such as nutrients and oxygen — and transports waste products away from those same cells....
and degrades large vWf multimers, decreasing their activity.
Since 1982 it had been known that
thrombotic thrombocytopenic purpuraThrombotic 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), one of the
microangiopathic hemolytic anemiaIn medicine microangiopathic hemolytic anemia is a microangiopathic subgroup of hemolytic anemia caused by factors in the small blood vessels...
s (see below), was characterised in its familial form by the presence in plasma of unusually large von Willebrand factor multimers (ULVWF).
In 1994, VWF was shown to be cleaved between a
tyrosineTyrosine or 4-hydroxyphenylalanine, is one of the 20 amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group...
at position 1605 and a
methionineMethionine is an α-amino acid with the chemical formula HO
2CCHCH
2CH
2SCH
3. This essential amino acid is classified as nonpolar.-Function:...
at 1606 by a plasma metalloprotease when it was exposed to high levels of shear stress.
ADAMTS13 (
a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13)—also known as
von Willebrand factor-cleaving protease (VWFCP)—is a
zincZinc , also known as spelter, is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
-containing metalloprotease
enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process are called substrates, and the enzyme converts them into different molecules, called the products. Almost all processes in a biological cell need enzymes to occur at...
that cleaves
von Willebrand factorVon 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.- Synthesis :vWF...
(vWf), a large protein involved in
blood clottingCoagulation is a complex process by which blood forms clots. It is an important part of hemostasis , wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
. It is secreted in
bloodBlood is a specialized bodily fluid that delivers necessary substances to the body's cells — such as nutrients and oxygen — and transports waste products away from those same cells....
and degrades large vWf multimers, decreasing their activity.
Discovery and function
Since 1982 it had been known that
thrombotic thrombocytopenic purpuraThrombotic 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), one of the
microangiopathic hemolytic anemiaIn medicine microangiopathic hemolytic anemia is a microangiopathic subgroup of hemolytic anemia caused by factors in the small blood vessels...
s (see below), was characterised in its familial form by the presence in plasma of unusually large von Willebrand factor multimers (ULVWF).
In 1994, VWF was shown to be cleaved between a
tyrosineTyrosine or 4-hydroxyphenylalanine, is one of the 20 amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group...
at position 1605 and a
methionineMethionine is an α-amino acid with the chemical formula HO
2CCHCH
2CH
2SCH
3. This essential amino acid is classified as nonpolar.-Function:...
at 1606 by a plasma metalloprotease when it was exposed to high levels of shear stress. In 1996, two research groups independently further characterized the enzyme that cleaved VWF. In the next two years, the same two groups showed that the congenital deficiency of vWf-cleaving
proteaseA protease breaks down proteins. A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein...
was associated with formation of
plateletPlatelets, or thrombocytes , are small, irregularly-shaped anuclear cells , 2-3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is between 8 and 12 days...
microthrombi in the small blood vessels. In addition, they reported that in majority of patients IgG
antibodiesAntibodies are gamma globulin proteins that are found in blood or other bodily fluids of vertebrates, and are used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses...
, directed against this enzyme, caused TTP in non-familial cases.
Proteomics
Genomically, ADAMTS13 shares many properties with the 19 member
ADAMTS familyADAM protein is a family of peptidase proteins. ADAMs are also known as the Adamalysin family. ADAMs are classified as Sheddases because they cut off or shed extracellular portions of transmembrane proteins. For example, ADAM 10 can cut off part of the HER2 receptor, activating it...
, all of which are characterised by a protease domain (the part that performs the protein hydrolysis), an adjacent
disintegrinDisintegrins are peptides isolated from the venom of various snakes of the viper family. They interact with the beta 1 and beta 3 families of integrin proteins...
domain and one or more
thrombospondinThrombospondins are secreted proteins with antiangiogenic abilities.-Types:The thrombospondins are a family of multifunctional proteins. The family consists of thrombospondins 1-5 and can be divided into 2 subgroups: A, which contains TSP-1 and -2, and B, which contains TSP-3, -4 and -5...
domains. ADAMTS13 in fact has eight thrombospondin domains. It has no hydrophobic transmembrane domain, and hence it not anchored in the cell membrane.
Role in disease
Deficiency of ADAMTS13 was originally discovered in Upshaw-Schülman syndrome, the recurring familial form of TTP. By that time it was already suspected that TTP occurred in the autoimmune form as well, owing to its response to
plasmapheresisPlasmapheresis is the removal, treatment, and return of blood plasma from blood circulation. It is thus an extracorporeal therapy...
and characterisation of IgG inhibitors. Since the discovery of ADAMTS13, specific
epitopeAn epitope, also known as antigenic determinant, is the part of a macromolecule that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope...
s on its surface have been shown to be the target of inhibitory antibodies.
Especially since the link between
aortic valve stenosisAortic valve stenosis is a valvular heart disease caused by the incomplete opening of the aortic valve.The aortic valve controls the direction of blood flow from the left ventricle to the aorta. When in good working order, the aortic valve does not impede the flow of blood between these two spaces...
and
angiodysplasiaIn medicine , angiodysplasia is a small vascular malformation of the gut. It is a common cause of otherwise unexplained gastrointestinal bleeding and anemia. Lesions are often multiple, and frequently involve the cecum or ascending colon, although they can occur at other places...
was proven to be due to high
shear stressA shear stress, denoted , is defined as a stress which is applied parallel or tangential to a face of a material, as opposed to a normal stress which is applied perpendicularly.-General shear stress:...
(
Heyde's syndromeHeyde'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...
), it has been accepted that increased exposure of vWf to ADAMTS13 due to various reasons would predispose to bleeding by causing increased degradation of vWf. This phenomenon is characterised by a form of
von 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...
(type 2a).
Further reading
- Furlan M, Lammle B. Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease. Best Pract Res Clin Haematol 2001;14:437-54. PMID 11686108.
- Tsai HM. Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J Am Soc Nephrol 2003;14:1072-81. PMID 12660343.
External links