Rob Markowitz NSA
The Conservation of Coagulation Factor V Protein, and its Role in Factor V Leiden Thrombophilia
Introduction: The cascade which must occur for blood to successfully clot is complex, multivariable, and fraught with opportunities to go awry. The coagulation process requires the organization of platelets, enzymes, cofactors, and fibrin to develop a protective covering when blood vessels become injured to prevent loss of blood and prohibit infection.1 While some pathologies related to clotting are a result of age, environment, or lifestyle, the most common cause of thrombophilia, an increased propensity to form blood clots in the vessels, is an inherited genetic mutation known as Factor V Leiden
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It is interesting to note that even with such an elevated risk, only roughly a tenth of those carrying the mutation will have a thrombotic event which leaves room to investigate the influence of other factors both endogenous and external.4 To this end, it is necessary to better understand the coagulation factor V protein, including it’s conservation among organisms to determine a suitable model in which to study, and in the future develop therapeutic interventions. Additionally, coagulation factor V protein presents an excellent opportunity to build upon a solid base of knowledge in regards to how organisms have evolved blood clotting functions. Given how fundamental the protein’s function is and blood clotting as a whole is, it serves as a valuable tool to probe the development of similar systems in other organisms, and assess which divergent proteins may have shared a common ancestral path.
Methods:
To fully understand the role of coagulation factor V protein, a review of the medical and scientific literature was conducted utilizing PubMed5. This was necessary to understand the implications of the mutated protein in the development of factor V Leiden thrombophilia, as well as its function as part of the cascade when the wild type gene is present. Search terms used were “Factor V
Ragni, Margaret V. "New and Emerging Agents for the Treatment of Hemophilia: Focus on Extended Half-Life Recombinant Clotting Proteins." Springer Link. Springer International Publishing, 27 Aug. 2015. Web. 29 Aug. 2015. .
According to the National Hemophilia Foundation (n.d.), von Willebrand disease (VWD) is a genetic disorder caused by missing or defective von Willebrand factor (VWF), a clotting protein. VWF binds factor VIII, a key clotting protein, and platelets in blood vessel walls, which help form a platelet plug during the clotting process. The condition is named after Finnish physician Erik von Willebrand, who first described it in the 1920s (National Hemophilia Foundation, n.d.). The seriousness of the bleeding varied between family
Venous thrombi, composed predominately of red blood cells but also platelets and leukocytes bound together by fibrin, form in sites of vessel damage and areas of stagnant blood flow such as the valve pockets of the deep veins of
It inhibits thrombosis by inactivating co-factors Va, and VIIIa (Neyrinck, 2009). When deficient, Factor V can cause excessive blood clotting and Factor VIII, being an essential clotting factor, can cause blood to profusely move out of tissues once cut or damaged (Faust, 2001 and Yan, 2001). Thrombin may become limited, one reason being the decrease of plasma D-dimer, which again stimulates fibrinolysis (Bernard, 2001).
Venous thrombosis and arterial thrombosis are considered to be distinct pathophysiological processes due to their evident anatomical variances. With one having to deal with platelet activation while the other involving the clotting system activation, arterial thrombosis and venous thrombosis are similar yet vastly different when it comes to the processes that are performed for the body. These same processes that help the body have to be performed accordingly or the signs and symptoms begin to show. For instance, venous thrombosis can lead to Chronic Venous Insuffiency and other issues when a body part is congested. This is most commonly causes by valvular incompetence in the low-pressure superficial venous system; however, it can also be causes
Collagen and von Willebrand factor can initiate coagulation by causing platelet activation which triggers coagulation.
Hemostasis is the process whereby blood coagulates at the site of an injury to a blood vessel. Cellular components involved in hemostasis include platelets, endothelial cells of blood vessels, tissue factor-bearing cells, and coagulation factors (Davoren & Wang, 2014). Coagulation factors are specialized plasma proteins that circulate in the bloodstream in inactive forms. Most coagulation factors are activated by enzymes that catalyze their conversion to active forms. The active forms then contribute to hemostasis. Factors VIII (FVIII) and IX (FIX) are the factors involved in the most common forms of hemophilia. The coagulation cascade has many steps and reciprocal interactions; however, FVIII and FIX are most involved with the following steps:
Factor V Leiden as named after the Dutch city Leiden in which it was discovered. Factor V Leiden is a genetic blood clotting disorder that results from a mutation of the Factor V gene. Most of the time you will inherit Factor V Leiden from your family. If kept under control blood clots are mostly harmless, but if left uncared you can have a piece of the blood clot break and enter your lung there it will cause serious damage like a heart attack or stroke.
There are two types of Hemophilia, type A and type B, Hemophilia A is associated with blood clots after injury or a type of surgery, Hemophilia A is a disease in which a type of protein that is used to stop clotting is changed or mutated. This all starts after the bleeding has begun, little molecules send out a signal for a protein called factor 12 to be activated, then this protein goes on to activate other proteins till the protein Fibrinogen is activated which stops the bleed and forms a stable clot, but, when Hemophilia is brought in, this can cause major problems. It occurs in the factor 8 gene. Hemophilia causes this gene to be mutated, which is located on the X chromosome. The instructions for making the gene are altered which makes the protein changed as well. In a minor case only a small part of
The production of ClotX is built upon recombinant protein technology, which involves the isolation of human protein genes that are then cloned into expression vectors. These expression vectors are used to transform human protein genes into a target cell, which has conventionally been bacterial and mammalian cells. Currently, competing technology that exists involves the production of recombinant fibrinogen, which is a coagulation factor, utilizing a mammalian cell culture system that has the production capacity of 5 μg protein product/ml culture every month. Current production of recombinant fibrinogen utilizes mammalian cells, specifically CHO DG44, however, high-level expression of
You mentioned hemophilia so I just wanted to explain what it was. Hemophilia is an inherited disease that affects the clotting process of your blood. Therefore, if you have hemophilia you do stand a chance of sever bleeding if you incur an injury or cut. There is a protein that is called clotting factor that a person might have little or none at all. It is a protein used for blood clotting that helps blood platelets stick together. (NIH
Each treatment should be treated case-by-case to ensure that the patient is receiving the best possible care. Suggested treatments consist of regular infusions of DDAVP and/or clotting factor, first aid for minor cuts, physical therapy, fibrin sealants and clot-preserving medications. For Hemophilia C, clotting factor XI is available only in Europe and in the United States bleeding episodes are treated through plasma infusions. Clotting factor XI is not available in the United States because Factor XI concentrates are blood products with a concentrated form of Factor XI. Meanwhile, available only in certain areas of Europe, these blood concentrates are made through a series combining thousands of different blood donors. Therefore, the United States only keeps frozen plasma instead. Fibrin sealants work by applying the medication directly to the site of the wound, from there the Fibrin promotes clotting and healing. Clot-preserving medications can also be applied directly to the wound. However, this time the medication preserves the clot from breaking down and assists in ending the
Alprolix is a recombinant fusion protein that is consisted of the human Coagulation Factor IX sequence linked to the Fc domain of human immunoglobin G Subclass 1 (IgG1); which temporarily replaces the missing Coagulation Factor XI needed to promote blood clotting. What differentiates Alprolix from the other Factor IX products on the market is their clotting factor IX linkage to the Fc region of human IgG1, which binds to the Fc receptor (FcRn). It is believed that FcRn enables Alprolix to use a naturally occurring pathway to extend the plasma half-life. Alprolix is ultimately the first long acting Coagulation Factor IX treatment, decreasing frequent product infusions and improving patient care management.
Hemophilia A is a disorder in which the blood doesn’t clot normally due to the lack of blood clothing factor VIII. Hemophilia A is also known as the ‘Classic Hemophilia.’ According to the CDC, hemophilia will occur in approximately 1 in 5,000 live births. It is called classic hemophilia due to the fact that this hemophilia is four times more common as hemophilia B. This disorder is mainly a hereditary bleeding disorder which is caused by an inherited X linked recessive trait. Some acquired forms do exist as well, largely in older patients, due to autoantibodies directed against factor VIII. The defected gene is located on the X chromosome. And it results from a heterogeneous mutation in factor VIII gene that maps for Xq28.
Factor X is activated by other coagulation factors (XII becomes XIIa, XI – XIa, IX- IXa, VIII and lastly, X). Factor IXa normally activates factor X to factor Xa. Then Factor Xa activates other blood proteins, including factor V, and factor II (prothrombin) which is converted to thrombin. This chain reaction allows the coagulation process to continue. If one of the coagulation factors is absent or deficient, the chain reaction is broken, and the bleeding is not