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.
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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 guideliles 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.
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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. Laboratory tests like vWF:Ag and vWF:RCo show similar reductions in vWF activity for a type-1 vWD patient compared to the reference plasma by ISTH.