Von Willebrand factor

Biochemistry

Synthesis

VWF is a large multimeric glycoprotein present in blood plasma and produced constitutively as ultra-large VWF in endothelium (in the Weibel–Palade bodies) and megakaryocytes (α-granules of platelets).

Structure

VWF is synthesized as a prepropeptide comprising 2813 amino acids in endothelial cells and megakaryocytes. The prepropeptide includes a 22-amino acid signal peptide (SP), a 741-amino acid propeptide (VWFpp), and a 2050-amino acid mature VWF monomer. The signal peptide directs the prepropeptide to the endoplasmic reticulum, where it is cleaved, resulting in the formation of pro-VWF. Pro-VWF undergoes glycosylation, forms disulfide bonds, and dimerizes under neutral pH and the influence of Protein Disulfide Isomerase A1 (PDIA1).

Dimerized pro-VWF is then transported to the Golgi apparatus, where it forms "dimeric bouquets" and undergoes further glycosylation. The propeptide is cleaved by furin, but remains associated with the mature VWF in a non-covalent manner. This association persists until the propeptide dissociates, yielding mature VWF monomers, which subsequently dimerize and multimerize. Although the fundamental structure of mature VWF is monomeric, the smallest form detectable in blood plasma is a VWF dimer.

The basic monomer of VWF, a 2050-amino acid protein, contains several key domains with specific functions:

• The D'/D3 domain: Binds to factor VIII, heparin, and P-selectin.
• The A1 domain: Binds to the platelet GPIb-receptor, collagen types IV and VI, heparin, and osteoprotegerin.
• The A2 domain: Unfolds to expose the cleavage site for ADAMTS13 protease, which cleaves VWF into smaller multimers. Unfolding is influenced by blood shear flow, calcium binding, and a "vicinal disulfide" at the A2-domain's C-terminus.
• The A3 domain: Acts as the primary collagen binding site for VWF, binding to collagen types I and III.
• The C4 domain: Contains an RGD motif that binds to platelet integrin αIIbβ3.
• The CK (cystine knot) domain at the protein's C-terminal end: Involved in VWF dimerization.

VWF is one of the few proteins carrying ABO blood group antigens. After glycosylation in the Golgi apparatus, VWF is packaged into storage granules, Weibel–Palade bodies (WPBs) in endothelial cells, and α-granules in platelets.

Function

Von Willebrand Factor's primary function is binding to other proteins, in particular factor VIII, and it is important in platelet adhesion to wound sites. It is not an enzyme and, thus, has no catalytic activity.

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 thrombin. In the absence of VWF, factor VIII has a half-life of 1–2 hours; when carried by intact VWF, factor VIII has a half-life of 8–12 hours.
• VWF binds to collagen, e.g., when collagen is exposed beneath endothelial cells due to damage occurring to the blood vessel. Endothelium also releases VWF which forms additional links between the platelets' glycoprotein Ib/IX/V and the collagen fibrils
• 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 stress (i.e., rapid blood flow in narrow blood vessels, see below).
• VWF binds to other platelet receptors when they are activated, e.g., by thrombin (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. Recent research also suggests that von Willebrand Factor is involved in the formation of blood vessels themselves, which would explain why some people with von Willebrand disease develop vascular malformations (predominantly in the digestive tract) that can bleed excessively.

Catabolism

The biological breakdown (catabolism) of VWF is largely mediated by the enzyme 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.

The half-life of vWF in human plasma is around 16 hours; glycosylation variation on vWF molecules from different individuals result in a larger range of 4.2 to 26 hours. Liver cells as well as macrophages take up vWF for clearance via ASGPRs and LRP1. SIGLEC5 and CLEC4M also recognize vWF.

Role in disease

Main article: von Willebrand disease

Hereditary or acquired defects of VWF lead to von Willebrand disease (vWD), a bleeding diathesis of the skin and mucous membranes, causing nosebleeds, 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. High plasma VWF levels were found to be an independent predictor of major bleeding in anticoagulated atrial fibrillation patients. VWF is a marker of endothelial dysfunction, and is consistently elevated in atrial fibrillation, associated with adverse outcomes.

History

VWF is named after Erik Adolf von Willebrand, a Finnish physician who in 1926 first described a hereditary bleeding disorder in families from Åland. Although von Willebrand did 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. Harvey J. Weiss and coworkers developed a quantitative assay for VWF function that remains a mainstay of laboratory evaluation for VWD to this day.

Interactions

Von Willebrand Factor has been shown to interact with Collagen, type I, alpha 1.

Recently, It has been reported that the cooperation and interactions within the von Willebrand Factors enhances the adsorption probability in the primary haemostasis. Such cooperation is proven by calculating the adsorption probability of flowing VWF once it crosses another adsorbed one. Such cooperation is held within a wide range of shear rates.

References

References

1. (1998). "Biochemistry and genetics of von Willebrand factor". Annual Review of Biochemistry.
2. (2017). "Thrombosis and Embolism: From Research to Clinical Practice".
3. (2018). "Robbins basic pathology". Elsevier.
4. (January 2017). "Von Willebrand factor and angiogenesis: basic and applied issues". Journal of Thrombosis and Haemostasis.
5. (July 2005). "ADAMTS13 turns 3". Blood.
6. (March 2015). "von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends". Blood.
7. (October 2006). "Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor". Journal of Thrombosis and Haemostasis.
8. (July 2003). "Acquired von Willebrand syndrome in aortic stenosis". The New England Journal of Medicine.
9. (January 2004). "von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura". Seminars in Hematology.
10. (September 2016). "The VWF-GPIb axis in ischaemic stroke: lessons from animal models". Thrombosis and Haemostasis.
11. (June 2011). "Plasma von Willebrand factor levels are an independent risk factor for adverse events including mortality and major bleeding in anticoagulated atrial fibrillation patients". Journal of the American College of Cardiology.
12. (2020). "Endothelial function in patients with atrial fibrillation". Annals of Medicine.
13. (May 1999). "Hereditär pseudohemofili". Fin Läkaresällsk Handl.
14. (December 1973). "Von Willebrand factor: dissociation from antihemophilic factor procoagulant activity". Science.
15. (November 1973). "Defective ristocetin-induced platelet aggregation in von Willebrand's disease and its correction by factor VIII". The Journal of Clinical Investigation.
16. (November 1986). "Isolation and characterization of a collagen binding domain in human von Willebrand factor". The Journal of Biological Chemistry.
17. (August 2015). "Cooperation within von Willebrand factors enhances adsorption mechanism". Journal of the Royal Society, Interface.