Life Cycle of Factor VIII
HRF, Inc.
Introduction
The factor VIII serves the body in the way that it reduces the severe bleeding. More importantly, it is the part that initiates the blood clotting process in order to reduce the bleeding. The factor VIII’s life cycle begins from the early to an advanced stage that will persist until the cell dies. However, the life cycle of the factor VIII consists of many stages that cannot be covered in this paper alone. This paper will evaluate the biosynthesis and secretion of the factor VIII that are the first stages of the life cycle. Later, it will show how the stages in the life cycle leads to the Hemophilia A. then, it will address the assembly of the Von Willebrand Factor and its importance to the life cycle as well.
Biosynthesis and the Secretion of the Factor VIII
The first stage is the biosynthesis and the secretion of the factor VIII, which entails various essential processes that ensures easy growth of the cells. In the body, tissues such as the kidney, liver, spleen and the lymph nodes all possess the ability to express the factor VIII gene. In fact, transplantation studies reveal that the liver tends to be the primary source of the gene. A study on the hemophilic patients also reveals the same scenario. In the liver, the hepatocytes are the cells that are known to produce the factor VIII mainly. Within the hepatocytes, the rough endoplasmatic reticulum and the Golgi apparatus are the ones known to house the factor VIII protein[1]. The study of the factor VIII secretion process is focused on the gene expression only. More importantly, the study reveals that the factor is expressed poorly with the low expression being associated with its mRNA. The inefficient secretion also asserts on the way that it has a low expression. The secretion process begins with the mature 2332 amino acid polypeptide moving to the endoplasmatic reticulum, a place that sees the N-linked glycosylation[2]. In the ER, it still interacts with other chaperone proteins that include calnexin and calreticulin. The interaction leaves multiple molecules of the factor making it hard to move to the Golgi apparatus. The factor VIII later goes to the Golgi apparatus where it undergoes the N-linked oligosaccharides, O-linked glycosylation as well as the sulfation of Tyr-residues[3]. Besides that, it also goes through the intracellular proteolysis. All these steps help in the creation of the complex structures.
Factor VIII and Hemophilia A
During the biosynthesis and the secretion process some defects might arise that will go ahead to affect the factor VIII structures in the long run. Some slight rearrangements or even deletions of the cells might result in impaired RNA processing or even the translation. Defective secretion might even result from the single missense mutations that are a result of the less factor VIII in codon 2307[4]. From such defective secretions and biosynthesis, the patient might end up experiencing the hemophilia A. The defective secretions are not the only reason for the mutations but also the lower levels of factor VIII protein in the body as well[5]. The reduced levels often results some defects that also causes a number of mutations that leads to the hemophilia A.
Assembly of the Von Willebrand Factor (vWF)
Another important part in the life cycle of the factor VIII is the assembly of the Von Willebrand Factor (vWF). Its presence in the factor VIII plays a crucial role in the blood clotting process and its absence will also result in severe blood loss as well. The vWF has various parts that serve as binding sites that also helps in the assembly of its different parts. In fact, the interaction between factor VIII heterodimer and vWF results in a noncovalent complex that is also stable[6]. The binding sites include the aminoterminal end of the light chain while another rests at the carboxyterminal end. Both of these ends react synergistically in the process of binding the vWF[7].
Benefits of the vWF
The presence of the vWF in the factor VIII-vWF complex helps in preventing the scenario that the binding might occur prematurely to reach the factor X-activating complex[8]. The presence of the vWF makes sure the factor VIII light chain cannot bind with the factor IXa as well. More importantly, the factor VIII has high affinity for the vWF and not the factor IXa thereby preventing the binding of the two components instead[9]. In this case, the inhibition of the proteins from binding serves an important part since it helps in maintaining the form that factor VIII is needed to be.
Von Willebrand Factor and Hemophilia A
Evidently, the vWF is an essential part of the factor VIII physiology since it helps in stabilizing its heterodimeric structure. In rare occasions some people might have undetectable vWF proteins in their blood stream meaning that they have the von Willebrand disease (vWD)[10]. Often, these patients will have a secondary deficiency of the factor VIII as well as it will exist and have a half life too. At times, they might have the vWF flowing in their bloodstream yet their factor VIII levels have decreased instead[11]. In the process, they have the mutation where the factor VIII and vWF domain will interfere with the structure and leads to the defective binding of the vWF and factor VIII. Certain pair mutations of vWF and factor VIII are known to result in the impaired complex assembly. The mutations often interfere with the amino acid Tyr thereby being one of the factors that also lead to hemophilia A[12]. In this case, one might have the von Willebrand disease and still have the hemophilia A as well.
Conclusion
The short description of the factor VIII life cycle illustrates the way the secretion and biosynthesis of the proteins might even lead to hemophilia A. More specifically, the defective additions and gross deletions of the cells in the secretion and biosynthesis often lead to mutations that might result in the hemophilia A. Besides that, the presence of the vWF also serves an important in the structure of the factor VIII. Unfortunately, some defective pairing of factor VIII and vWF results in certain mutations that might also lead to hemophilia A.
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Bibliography
Dumont, Jennifer A., Tongyao Liu, Susan C. Low, Xin Zhang, George Kamphaus, Paul Sakorafas, Cara Fraley et al. “Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs.” Blood 119, no. 13 (2012): 3024-3030.
Lenting, P. J., C. Casari, O. D. Christophe, and C. V. Denis. “von Willebrand factor: the old, the new and the unknown.” Journal of Thrombosis and Haemostasis 10, no. 12 (2012): 2428-2437.
Lenting, Peter J., Jan A. van Mourik, and Koen Mertens. “The life cycle of coagulation factor VIII in view of its structure and function.” Blood 92, no. 11 (1998): 3983-3996.
Pegon, Julie N., Mohamad Kurdi, Caterina Casari, Soline Odouard, Cécile V. Denis, Olivier D. Christophe, and Peter J. Lenting. “Factor VIII and von Willebrand factor are ligands for the carbohydrate-receptor Siglec-5.” Haematologica 97, no. 12 (2012): 1855-1863.
Shen, Betty W., Paul Clint Spiegel, Chong-Hwan Chang, Jae-Wook Huh, Jung-Sik Lee, Jeanman Kim, Young-Ho Kim, and Barry L. Stoddard. “The tertiary structure and domain organization of coagulation factor VIII.” Blood 111, no. 3 (2008): 1240-1247.
Ward, Natalie J., Suzanne MK Buckley, Simon N. Waddington, Thierry VandenDriessche, Marinee KL Chuah, Amit C. Nathwani, Jenny McIntosh et al. “Codon optimization of human factor VIII cDNAs leads to high-level expression.” Blood 117, no. 3 (2011): 798-807.
[1] Lenting, Peter J., Jan A. van Mourik, and Koen Mertens. “The life cycle of coagulation factor VIII in view of its structure and function.” Blood 92, no. 11 (1998): 3983-3996.
[2] Shen, Betty W., Paul Clint Spiegel, Chong-Hwan Chang, Jae-Wook Huh, Jung-Sik Lee, Jeanman Kim, Young-Ho Kim, and Barry L. Stoddard. “The tertiary structure and domain organization of coagulation factor VIII.” Blood 111, no. 3 (2008): 1240-1247.
[3] Ibid, 1.
[4] Ibid, 1.
[5] Ibid, 2.
[6] Ward, Natalie J., Suzanne MK Buckley, Simon N. Waddington, Thierry VandenDriessche, Marinee KL Chuah, Amit C. Nathwani, Jenny McIntosh et al. “Codon optimization of human factor VIII cDNAs leads to high-level expression.” Blood 117, no. 3 (2011): 798-807.
[7] Pegon, Julie N., Mohamad Kurdi, Caterina Casari, Soline Odouard, Cécile V. Denis, Olivier D. Christophe, and Peter J. Lenting. “Factor VIII and von Willebrand factor are ligands for the carbohydrate-receptor Siglec-5.” Haematologica 97, no. 12 (2012): 1855-1863.
[8] Ibid, 7.
[9] Ibid, 7.
[10] Dumont, Jennifer A., Tongyao Liu, Susan C. Low, Xin Zhang, George Kamphaus, Paul Sakorafas, Cara Fraley et al. “Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs.” Blood 119, no. 13 (2012): 3024-3030.
[11] Lenting, P. J., C. Casari, O. D. Christophe, and C. V. Denis. “von Willebrand factor: the old, the new and the unknown.” Journal of Thrombosis and Haemostasis 10, no. 12 (2012): 2428-2437.
[12] Ibid, 11.