Von Willebrand factor

The von Willebrand factor is encoded by the VWF gene located on the short arm of the 12th chromosome at locus 13.3 (from 5 948 874 to 6 124 670 base pairs ). More than 300 mutations of the VWF gene are known, leading to von Willebrand disease ^[1] .

Synthesis

VWF is a large multimeric plasma plasma glycoprotein that is constantly produced as ultra-large multimers by endothelial cells (in Weibel-Palade bodies ), megakaryocytes (platelet α-granules) and subendothelial connective tissue ^[2] .

Structure

The VWF monomer is a protein consisting of 2050 amino acid residues . Each monomer contains a number of domains that perform specific functions; Among them it is worth highlighting:

• domain D '/ D3 ( ), which binds to coagulation factor VIII ;
• domain A1, which binds to platelet glycoprotein Ib , heparin, and possibly collagen ;
• A3 domain ( ), which binds to collagen;
• domain C1, in which the arginine - glycine - aspartate (RGD) motif binds to platelet integrin α _{IIb β 3} upon platelet activation;
• the cysteine ​​node domain is located at the C-terminus of the protein ( ). Platelet growth factor (PDGF), transforming growth factor β (TGFβ) and human chorionic gonadotropin β (βHCG) also have such a domain ^[2] .

After synthesis, the monomers undergo , are assembled into dimers in the endoplasmic reticulum and into multimers in the Golgi apparatus by forming disulfide bridges between cysteine residues . Dimerization is carried out by protein disulfide isomerase ^[3] . VWF is one of the few proteins that carry the antigens ^[2] .

VWF multimers can be very large: consist of more than 80 subunits weighing 250 kDa each and have a mass of more than 20,000 kDa . Only large multimers are functional ^[2] .

Catabolism

The biological destruction ( catabolism ) of von Willebrand factor is mainly carried out by the enzyme - , which cuts VWF between the residues of tyrosine 842 and methionine 843 in domain A2. This leads to the decomposition of multimers into small components, which are destroyed by other peptidases ^[4] .

The von Willebrand factor plays an important role in the attachment of platelets to the sites of vascular damage, binding to other proteins, primarily blood clotting factor VIII. Coagulation factor VIII is associated with VWF when it is circulating in an inactive state through the bloodstream and is rapidly destroyed when it is not associated with VWF. The association of factor VIII with VWF is destroyed by thrombin . In addition, VWF binds to collagen ( ^5] ), including when it comes into contact with endothelial cells as a result of damage to the vessel. It has been shown that in the binding of VWF to collagen there is a cooperative effect ^[6] . VWF binds to glycoprotein Ib when it forms a complex with glycoproteins IX and V. This binding can occur under any conditions, but it is most severe under conditions of strong shear stress , that is, with rapid movement of blood in narrow vessels. Finally, VWF binds to other platelet receptors when they are activated, such as thrombin (that is, when coagulation stimulation has already occurred) ^[2] .

Thus, VWF plays an important role in blood coagulation (coagulation), therefore, its deficiency or dysfunction increases the tendency to bleeding, especially in tissues in which there is a high speed of blood flow in narrow vessels. Under these conditions, VWF unfolds, decreasing the platelet velocity ^[2] . The refolding rate of the A2 domain of VWF increases in the presence of calcium ions, so that VWF can function as a shear stress sensor ^[7] .

Hereditary or acquired defects of von Willebrand factor lead to von Willebrand disease - hemorrhagic diathesis of the skin and mucous membranes , which is expressed in nosebleeds , , and . The point of occurrence of a mutation determines the severity of symptoms of hemorrhagic diathesis ^[8] . There are three types of von Willebrand disease (I, II and III), and type II, in turn, is divided into several subtypes. Most cases of von Willebrand disease are hereditary, but the disease can also be acquired. So, aortic valve stenosis is associated with von Willebrand disease type IIA and therefore leads to gastrointestinal bleeding; such a related disease is called Heyde's syndrome ^[9] .

With thrombotic purpura and uremic-hemolytic syndrome, a deficiency of the ADAMTS13 enzyme or its suppression by antibodies is observed. This leads to a decrease in the destruction of ultra-large multimers of VWF and , in which fibrin and platelets accumulate in narrow vessels, which leads to capillary necrosis. With thrombotic purpura, the brain is mainly affected, and with uremic hemolytic syndrome, the kidneys are affected ^[10] .

High levels of VWF in the blood are characteristic of people who survived their first ischemic stroke as a result of blood clotting. ADAMTS13 is not associated with this, and the patient’s blood group may be the only significant genetic factor in the event of such a stroke ^[11] .

The factor is named after the Finnish doctor Eric Adolf von Willebrand (1870-1949), who in 1924 described a hereditary blood disease (later known as Willebrand disease) in several families from the Aland Islands . Members of these families were prone to bleeding from the skin and mucous membranes (including menorrhagia). Although von Willebrand was unable to establish the cause of the disease, he was able to distinguish it from hemophilia and other forms of hemorrhagic diathesis ^[12] . In the 1950s, it was shown that von Willebrand’s disease was caused by a lack of blood plasma factor rather than impaired platelet function, and in the 1970s, von Willebrand factor ^[2] was .

• Blackshear JL , Kusumoto H. , Safford RE , Wysokinska E. , Thomas CS , Waldo OA , Stark ME , Shapiro BP , Ung S. , Moussa I. , Agnew RC , Landolfo K. , Chen D. Usefulness of Von Willebrand Factor Activity Indexes to Predict Therapeutic Response in Hypertrophic Cardiomyopathy. (Eng.) // The American journal of cardiology. - 2015. - DOI : 10.1016 / j.amjcard.2015.11.01.016 . - PMID 26705879 .
• Hudzik B. , Kaczmarski J. , Pacholewicz J. , Zakliczynski M. , Gasior M. , Zembala M. Von Willebrand factor in patients on mechanical circulatory support - a double-edged sword between bleeding and thrombosis. (English) // Kardiochirurgia i torakochirurgia polska = Polish journal of cardio-thoracic surgery. - 2015. - Vol. 12, no. 3 . - P. 233-237. - DOI : 10.5114 / kitp.2015.54459 . - PMID 26702279 .
• Li Y. , Li L. , Dong F. , Guo L. , Hou Y. , Hu H. , Yan S. , Zhou X. , Liao L. , Allen TD , Liu JU Plasma von Willebrand factor level is transiently elevated in a rat model of acute myocardial infarction. (English) // Experimental and therapeutic medicine. - 2015. - Vol. 10, no. 5 . - P. 1743-1749. - DOI : 10.3892 / etm.2015.2721 . - PMID 26640545 .