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von Willebrand Factor is a large multimeric clotting protein which plays a significant role in the process of blood coagulation. It is mainly secreted by the vascular endothelial cells and also by megakaryocytes in the bone marrow. The vWF performs two important functions in the process of blood coagulation, and that’s why it is very important. First, it is responsible in bringing together the elements to form the primary hemostatic plug. It serves as an anchor for platelets at the site of injury in the blood vessel. Second, it acts as a protective chaperone for Factor VIII, to avoid lysis by proteolytic agents in the blood. The Factor VIII also released by vWF at the site of injury, whereby it brings about the completion of the Intrinsic Pathway of blood coagulation, and seals the site of injury with Fibrin.
von Willebrand Disease (vWD) is the most common inherited bleeding disorder in human beings the world over. Although, mutations in the vWF gene are responsible for the type of vWD in a patient, the transmission of vWD to the next generation is not solely linked to the vWF gene, but involves linkages with other genes such as the ABO blood type genes. The gene that encodes von Willebrand Factor is present on the short chromatid of chromosome 12, and is 178kb long with 52 exons or coding sites. Most of the exons are small, some as small as 41 base pairs (Schneppenheim, 2011). Exon 28, which has 1379 base pairs, is the largest. Mutations in the genes encoding vWF are primarily responsible for most vWD cases. Mutations can cause qualitative or quantitative deficiencies of vWF. Mutations in the vWF gene and the vWD that is attributed to the mutations are shown in Figure 1.
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Figure : Upper panel: vWF Exons coding for the domains;
Lower panel: Locations of mutations and their corrseponding vWD types
The multimeric von Willebrand Factor contains identical subunits of 250kDa each. These subunits dimerize (into 500 kilo Daltons subunits) and then multimerize into clusters greater than 10 mega Daltons in weight (Sadler JE, 2006). The vWF performs two functions – serve as an anchor for binding platelets to the site of injury and bind to and stabilize Factor VIII from degradation by proteases in the blood and presenting it only at the site of injury. A vWF monomer has a repeated domain structure – S – D1 – D2 – D’ – D3 – A1 – A2 – A3 – D4 – B1 – B2 – B3 – C1 – C2 – CK (Figure 1). The monomer is 2813 amino acids long. At the N-terminal is the 22 amino acid long signal peptide. Domains D’ and D3 are specific to Factor VIII binding. Platelets bind to vWF at its A1domain with their Glycoprotein (GP)-1b surface receptors. The A3 domain is specific to collagen, predominantly type III (J. Siekmann, 1998). Thus, domains A1 and A3 are necessary and must be fully functional to form the primary hemostatic plug in the process of coagulation.
Figure 2: Domains of vWF protein, (U.S. Department of Health and Human Services, 2007)
Overview of the clotting cascade
A brief overview of the blood clotting cascade is necessary to understand the function of vWF in the process of clotting. The process of blood coagulation involves platelets and clotting proteins. At the site of injury in a blood vessel, the subendothelial collagen (types I and III) in the extracellular matrix of the blood vessel is exposed to blood. vWF that is present in the blood binds to the exposed collagen with its A3 domain. The flow of blood causes the multimers of the anchored vWF to unfold and expose the sites of platelet binding on the A1 domain (Figure 2). The platelets bind to this domain with their Gp-Ib receptor proteins present on the platelet cell surface. The binding of platelets to vWF activates them and a chemical messenger – Thromboxane A2 is released by the platelets. Thromboxane A2 at the site of injury attracts more platelets in the blood, and aids in platelet aggregation. Platelets flowing in the blood stream bind to the activated platelets with a surface protein – Gp IIb/IIIa. Fibrinogen (Factor I) is present in between the GP-IIb/IIIa receptors of two platelets. Thus, a primary hemostatic plug, though weak in strength, is formed.
Figure 3: Sequence of events of blood coagulation due to vWF
(U.S. Department of Health and Human Services, 2007)
The unfolding of the multimers of vWF also releases Factor VIII at the site of injury. In the Intrinsic pathway of coagulation, Factor VIII is essential in catalyzing the conversion of Factor IX to Factor X, and eventually, prothrombin is catalyzed to from thrombin. Thrombin catalyzes the conversion of Fibrinogen (Factor I) into Fibrin. The fibrin forms a thick proteinaceous mesh, which seals the loss of blood from the blood vessel, this completing the process of hemostasis. Tissue repair and wound healing ensues.
von Willebrand Disease
von Willebrand Disease (vWD) is a deficiency of von Willebrand Factor. Based on the quantitative and qualitative deficiency, it is classified into subtypes. Combinations of assays are done to detect vWF levels in human plasma. Results of these tests report vWF levels in International Units per deciliter (IU/dL). The plasma concentration of vWF in healthy individuals is reported to be at around 10µg/mL (Mannucci, 1998), and the corresponding IU measurement is 100 IU/dL.
The classification of the vWD types is based on the criteria developed by the vWF Subcommittee of the International Society of Thrombosis and Haemostasis at Carrboro, North Carolina, USA in 1994. Annual meetings are held by ISTH to review diagnosis and management guidelines for vWD by experts all over the world. The standard guidelines for the diagnosis and treatment of vWD in the USA is based on the vWF Report by the National Heart, Lung and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services, which was released in 2007 by the expert panel on vWF, chaired by Dr. William L. Nichols, Jr., M.D. The ISTH holds annual meetings all over the world to discuss updates on vWD. The first vWD classification by the ISTH in 1994 was based on information about mutations on the vWF gene. However, because it was appropriate to only a small population of the human race, it was overruled in 2006 and was replaced by the new method based on response to treatment with DDAVP or other blood based therapeutics. vWD is classified based on qualitative and quantitative deficiencies. Partial quantitative deficiency is type 1 vWD and total quantitative deficiency is type 3. Qualitative deficiency is type 2, and is subdivided into types 2A, 2B, 2M and 2N based on the functions of the vWF which are affected. Quantitative deficiencies of vWF are discussed first – types 1 and 3 vWD. The main laboratory tests to analyze vWF in patient samples are – vWF:Antigen activity (vWF:Ag), Factor VIII: Coagulation activity (FVIII:C) and vWF: Ristocetin Cofactor activity (vWF:RCo).
Type 1 vWD
A patient with partial quantitative deficiency of vWD is diagnosed as type 1 vWD. The level of vWF in the plasma, though low, can still carry out the formation of the primary hemostatic plug, and also protect Factor VIII. In most type 1 vWD cases, Factor VIII levels are very mildly affected. It is hard to accurately diagnose type 1 vWD because, the vWF levels also depend on the ABO blood grouping. The average vWF level in healthy individuals with blood type O is about 75 IU/dL. It is reasonable to classify the condition of a patient with less than 20 IU/dL vWF level as type 1 vWD because this indicates a probable hereditary mutation. The vWF:Ag and vWF:RCo tests show similar reductions in vWF activity for type 1 vWD patients compared to the reference plasma by ISTH (U.S. Department of Health and Human Services, 2007).
Type 3 vWD
When the vWF activity of a plasma sample is less than 10 IU/dL, it is classified as type 3 vWD.84-86 Major mutations such as frameshifts, large deletions, splice-site mutations, and missense mutations can be causes for type 3 vWD (U.S. Department of Health and Human Services, 2007). Sometimes, clearance of vWF from the blood stream due to autoimmune disorders can decrease vWF quantity in the blood to type 3 levels of vWD. This is also one of the causes of of Acquired von Willebrand Syndrome – AVWS.
Type 2 vWD
Type 2 vWD is a qualitative deficiency of vWF, where, although the vWF may be produced in normal quantities, fails to perform its tasks effectively. Based on the defect in the von Willebrand Factor, it is mainly classified into types 2A, 2B, 2M and 2N. In type 2A vWD, the vWF – platelet binding activity is decreased due to the absence or deficiency of high molecular weight multimers of vWF. There is a sharp fall in the vWF:RCo activity, but not much decrease in vWF:Ag and FVIII:C activity. This is because the vWF is still able to bind to Factor VIII. (Ruggeri ZM, 1980) The high molecular weight multimers are either degraded by proteolytic enzymes in the blood or have not been produced due to mutations in the exons of the vWF gene that code for the A2 and/or the D3 domain. (Schneppenheim R, 2001), (Sutherland JJ, 2004) . Type 2B VWD is characterized by an abnormal increase in the vWF-platelet binding affinity, which leads to depletion of large, functional VWF multimers, and also a fall in platelet numbers (Zimmerman TS, 1986) The platelets circulating in the blood stream are blocked with the mutant vWF, due to which, there is a great difficulty in the formation of the primary hemostatic plug. Thus, thrombocytopenia ensues, along with increased Ristocetin Induced Platelet Aggregation (RIPA) even at low concentrations of Ristocetin. Mutations in the A1 domain are responsible for type 2B vWD (Huizinga EG, 2002). In type 2M vWD the vWF – platelet binding activity is reduced. But unlike the type 2A vWD, there is no decrease in the quantities of high molecular weight multimers. This phenomenon is only due to a decreased affinity to the Gp-1b receptors on the platelets (Ginsburg D, 1993), (Schneppenheim R, 2001), (Meyer D, 2001), (Rabinowitz I, 1992) (Mazurier C, 2001). The vWF:Ag, vWF:RCo and FVIII:C activities in types 2A and 2M vWD are similar. They can only be diagnosed based on high resolution gel electrophoresis images. (Meyer D, 2001). Another phenotype of type 2M vWD is the failure of vWF to bind to collagen in the extracellular matrix of the vascular sub-endothelium. vWD type 2N is due to the absence of vWF-Factor VIII binding. This is due to mutations in the D’ and D3 domains of the vWF protein (Ginsburg D, 1993), (Mazurier C, 2001). The laboratory tests for this type of vWD indicate normal levels for vWF:Ag and vWF:RCo tests, but the FVIII:C activity is only about 10% of normal levels.
Acquired von Willebrand Syndrome
Acquired von Willebrand Syndrome (AVWS) is type of vWD which is not genetically linked. There are three mechanisms by which it is manifested: Autoimmune reactions against vWF, Increased proteolysis of vWF by a protease – ADAMTS13 (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13), or abnormal increase in the binding affinity of vWF to platelets or other cell surface receptors (U.S. Department of Health and Human Services, 2007).
Diagnosis of vWD
The diagnosis of von Willebrand Disease and its sub-type is made based on an initial review of previous health conditions and familial history of bleeding disorders, which is done in the clinic, and then obtaining plasma samples of the patient for laboratory tests.
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