ADAMTS13
Encyclopedia
ADAMTS13—also known as von Willebrand factor-cleaving protease (VWFCP)—is a zinc
-containing metalloprotease enzyme
that cleaves von Willebrand factor
(vWf), a large protein involved in blood clotting
. It is secreted in blood
and degrades large vWf multimers, decreasing their activity.
(TTP), one of the microangiopathic hemolytic anemia
s (see below), was characterized 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 tyrosine
at position 1605 and a methionine
at 1606 by a plasma metalloprotease enzyme when it was exposed to high levels of shear stress. In 1996, two research groups independently further characterized this enzyme. In the next two years, the same two groups showed that the congenital deficiency of a vWF-cleaving protease
was associated with formation of platelet
microthrombi
in the small blood vessels. In addition, they reported that IgG antibodies
directed against this same enzyme caused TTP in a majority of non-familial cases.
, all of which are characterised by a protease domain (the part that performs the protein hydrolysis), an adjacent disintegrin
domain and one or more thrombospondin
domains. ADAMTS13 in fact has eight thrombospondin domains. It has no hydrophobic transmembrane domain, and hence it not anchored in the cell membrane.
and characterisation of IgG inhibitors. Since the discovery of ADAMTS13, specific epitope
s on its surface have been shown to be the target of inhibitory antibodies.
Especially since the link between aortic valve stenosis
and angiodysplasia
was proven to be due to high shear stress
(Heyde's syndrome
), 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 disease
(type 2a).
Zinc
Zinc , or 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 enzyme
Enzyme
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...
that cleaves von Willebrand factor
Von Willebrand factor
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...
(vWf), a large protein involved in blood clotting
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, 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 blood
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....
and degrades large vWf multimers, decreasing their activity.
Discovery and function
Since 1982 it had been known that thrombotic thrombocytopenic purpuraThrombotic 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), one of the 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...
s (see below), was characterized 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 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 1605 and a 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 1606 by a plasma metalloprotease enzyme when it was exposed to high levels of shear stress. In 1996, two research groups independently further characterized this enzyme. In the next two years, the same two groups showed that the congenital deficiency of a vWF-cleaving protease
Protease
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 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...
microthrombi
Thrombus
A thrombus , or blood clot, is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system...
in the small blood vessels. In addition, they reported that IgG 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 against this same enzyme caused TTP in a majority of non-familial cases.
Proteomics
Genomically, ADAMTS13 shares many properties with the 19 member ADAMTS familyADAMTS
ADAMTS is a family of peptidases. 19 members of this family have been identified in humans. Known functions of the ADAMTS proteases include processing of procollagens and von Willebrand factor as well as cleavage of aggrecan, versican, brevican and neurocan...
, all of which are characterised by a protease domain (the part that performs the protein hydrolysis), an adjacent disintegrin
Disintegrin
Disintegrins are a family of small proteins from viper venoms that function as potent inhibitors of both platelet aggregation and integrin-dependent cell adhesion....
domain and one or more thrombospondin
Thrombospondin
Thrombospondins are secreted proteins with antiangiogenic abilities. TSP was discovered by Nancy L. Baenziger.-Types:The thrombospondins are a family of multifunctional proteins...
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
Plasmapheresis 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 epitope
Epitope
An epitope, also known as antigenic determinant, is the part of an antigen 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 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...
and angiodysplasia
Angiodysplasia
In 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 stress
Shear stress
A 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...
(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...
), 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 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...
(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
- The MEROPSMeropsMerops may refer to:* Merops , a genus of bee-eaters.* MEROPS, an on-line database for peptidases.It may also refer to several figures from Greek mythology:* King of Ethiopia, husband of Clymene, who lay with Helios and bore Phaethon...
online database for peptidases and their inhibitors: M12.241