The Blood Clotting Cascade Biology Essay

The Blood Clotting Cascade Biology Essay 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 thats 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. C:UsersTj WorkDropboxTjBlood SensorThesisvWF Domains rot.jpg 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 prot ein 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 10Â µg/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.

Macbeth Character Analysis Essay

In this essay I will write about the character of Macbeth and what my first impressions are of him, such as his bravery, strength, determination and courage. I will also write about how he is introduced, his reaction to the encounter with the weird sisters, his attitude towards Banquo, Duncan and Malcolm. Also, his relationship with his wife, Lady Macbeth. My very first impression of Macbeth was that he was was brave as the captain said, â€Å"For brave Macbeth – well he deserves that name†¦Ã¢â‚¬ . Also, the captain implied that he is very strong and a great fighter, â€Å"†¦ With his brandished steel, which smoked with bloody execution, like valour’s minion carved out his passage, till he faced the slave†¦Ã¢â‚¬ . This means that he stands with his sword covered in blood which shows he has killed a lot of people and valour’s minion means bravery’s favourite. The captain also says how merciless Macbeth is as he kills the traitor Macdonwald, â€Å"†¦which never shook hands, nor bade farewell to him, till he unseamed him from the nave to the chops, and fixed his head upon our battlements†. This quote shows how merciless Macbeth is as it states that he ‘carved’ his way through the army, and how he killed Macdonwald even after bring tired and bruised without even speaking to him. He even paraded his head on the battlefield to show everybody what he had done. Our first impressions of Macbeth are that he is brave, merciless and a great fighter. The three witches soon appeared and told their predictions; â€Å"All hail Macbeth, hail to thee, Thane of Glamis!† â€Å"All hail Macbeth, hail to thee, Thane of Cawdor!† â€Å"All hail Macbeth, hail to thee, that shalt be King hereafter!†. After Macbeth heard the wierd sisters he was too shocked to speak as Banquo said, â€Å"Good sir, why do you start, and seem to fear things that do sound so fair†¦Ã¢â‚¬  He finally answered back by asking them to tell more and in more detail. He started to question the three witches and himself as he was confused; â€Å"†¦I know I am Thane of Glamis, but how of Cawdor? The thane of Cawdor lives†¦Ã¢â‚¬  . He was trying to figure out what this all meant and how these creatures got this information. He again tried to question them but the suddenly vanished into thin air, â€Å"The earth hath bubbles, as the water has, and these are of them.†. He asked Banquo if this was real or if they had eaten some kind of hallucinogens or drugs, â€Å"Were such things here as we do speak about? Or have we eaten on the insane root†¦Ã¢â‚¬  He then started thinking about being Thane of Cawdor and whether or not this could be true. The two messengers came, nearly straight after the predictions by the three witches, and told Macbeth that he was given the title Thane of Cawdor. Macbeth was in shock and Banquo said that evil was at work, Macbeth asked the messengers why he was the new Thane even though the old Thane still lived. He thanked the messengers and said to himself that more was to come as this is shown in the quote, â€Å"Glamis, and Thane of Cawdor. The greatest is behind.†. This means that the greatest prize is still to come and this is referring to him being King. His first thoughts of the three witches after they appeared and told their predictions were that they were some kind of supernatural beings and so Macbeth tried to find out what they meant, where they received this information and why they were telling him this. He was first thinking this was some kind of hoax but after the messengers came and said that the King had named him the Thane of Cawdor, he began to consider what it will mean if the third prediction is to come true. Banquo is Macbeth’s best friend and he trusts him with his life and vice versa. He respects Banquo and he uses his advice most of the time. They are partners in war and in friendship and do almost everything together. He likes Banquo but he sometimes has different thoughts than him as this quote states, â€Å"†¦But ’tis strange: And oftentimes, to win us to our harm, the instruments of darkness tell us truths†¦in deepest consequences.† This quote means that the recent occurrences are unnatural and the forces of evil encourage them to do things, which are misleading, and there could be some consequences later. Duncan is the King of Scotland and Macbeth had given him the most respect he has ever given anyone. Macbeth was loyal to the King and fought for him and the country of Scotland. Macbeth thinks that Duncan is a good King and uses his power to good strength and also the fact that he has a good judgement, this quote shows this, â€Å"Strong both against the deed; then†¦besides Duncan hath borne his faculties so meek, hath been so clear in his great office†¦Ã¢â‚¬  This means that Macbeth thinks King Duncan is a good king who is not corrupt. Macbeth does not like Malcolm even though he is related to him, Malcolm is the heir to the throne and that is a bit of a pain in the neck. Macbeth wants to be king but cannot as Malcolm is the heir so, as you would imagine he is an obstacle in Macbeth’s ambition and target, this quote shows this. â€Å"The Prince of Cumberland-that is a step†¦Ã¢â‚¬  Lady Macbeth is Macbeth’s wife and Macbeth loves her very much and so he sends her a letter telling her that he has become the Thane of Cawdor, â€Å"They met me in a day of success†¦they have more in them than mortal knowledge†¦came missives from the King, who hailed me ‘Thane of Cawdor’†¦ â€Å" Lady Macbeth is the kind of person that gets what she wants and I don’t think that Macbeth likes this that much. She persuades him to murder Duncan nearly straight after she recieves his letter. Macbeth likes Lady Macbeth but he doesn’t like the way she gets her way but he still goes with the flow, â€Å"Was the hope drunk wherein you dressed yourself†¦and live a coward in thine own esteem†¦each corporal agent to this terrible feat. Away, and mock the time with fairest show†¦ â€Å" Here, Lady Macbeth uses reverse psychology by accusing him of cowardice and a lack of love or her. Overall the first impressions we get of Macbeth are that he is brave and a good fighter and that he is loyal to his country and the King. His first impressions of the three witches were the same as anybody else, surprise and that the witches are some strange people or that they are seeing things. He likes Banquo and respects him and he is very loyal to Duncan who is like a father figure to him. He doesn’t like Malcolm that much as he is an obstacle but he is still related to him. His relationship with Lady Macbeth is very good but you get the impression that she is very much in control of their relationship.

Effective is Priestly in conveying them Essay

Priestly chose to write this play when he did, in 1945 because he had seen both world wars. He set it in 1912 because he knew what was to come, this way he had an insight to what was going to happen, so he could show the ignorance of the upper sector. Mr. Birling should understand the common people better than he does, especially as he came from a working class background. It would seem that he does not appreciate the working class anymore, as he would not even increase the wages of his workers. â€Å"They were averaging about twenty-two and six which was neither more nor less then is paid generally in our industry. They wanted the rates raised so that they could average about twenty-five shillings a week. † It is also evident that he runs his life by looking after himself first, as he tells Gerald and Eric at the beginning of the play â€Å"And as you were saying, dad, a man has to look after himself. † Mrs. Birling should have some understanding of Eva Smith because she is a governor of a charitable organisation to help women in desperate situations. But her ignorance gets in the way of her work, she doesn’t even think there is a possibility of there being more than one Birling family, so she dismisses Eva Smith straight away. â€Å"Yes I think it was simply a piece of gross impertenance – quite deliberate – and natrally that was one of the things that pedjudiced me against her. † Mrs. Birling’s ignorance is also apparent when she is saying what should happen to the young man who impregnated Eva Smith. Sheila had to learn, not to use status as an extended tool for jealousy. After Sheila has been told about her involvement in Eva Smith’s death she seems genuinly sorry for what she has done â€Å"And I know I’m to blame – and I’m desperately sorry† As well as what Sheila says, the stage directions like â€Å"distressed† are used to show how she is feeling. Her youth also opens her to the exposure of Inspector Goole â€Å"We are most impressionable on the young† this also makes us realise how Inspector Goole â€Å"breaks down the barriers†. When you are â€Å"far gone†, or as you would more commonly say it now, drunk, you are quite likely to get yourself into some sort of trouble as Eric learns. Unlike his parents and Sheila, Eric realises that what he did was wrong at the time and tried to make amends for it by giving Eva Smith money. â€Å"I insisted on giving her enough money to keep her going† At first when Eva Smith left him he didn’t change his ways, you can see this when he â€Å"helps himself to the decanter†. After the Inspector has gone through the events it looks like Eric has finally come to grips with what he has done and will make some sort of effort to change now, because of the imppression left on him by the Inspector. The message Inspector Goole is trying to present is that, whatever you do, you will eventually be judged for it. â€Å"We are members of one body. And I tell you that the time will soon come when, if men will not learn that lesson, then they will be taught it in fire, blood and anguish. † Inspector Goole also delivers the message that everyone must look after everyone else, and almost exactly contradicts Mr. Birling’s teaching of â€Å"every man has to look out for himself† or else the world will turn into a cold, miserable place, full of hatred and selfishness.

Roles Of Law Enforcement And Intelligence - 1503 Words

Roles of Law Enforcement and Intelligence in Counter-Terrorism After 9/11 September 11, 2001 marks one of the darkest, if not the darkest, days in United States history. It is a day in the history of our country in which everyone remembers where they were and what they were doing when they heard the news that two planes had flown into the World Trade Center in New York City, taking out both of the Twin Towers. All in all there were close to 3,000 people who lost their lives on that fateful day between New York City, Washington DC, and Pennsylvania. This was the worst terrorist attack that the United States had ever seen. The events of September 11 have been a catalyst for many different changes within the United States. The attacks on the†¦show more content†¦There has been a substantial change since September 11, 2001 in how law enforcement agencies attempt to prevent terrorism as well as how they respond to terrorism, and the role of intelligence agencies in preventing terrorism. Intelligence agencies are â€Å"permitted to college a large amount of foreign intelligence that is of interest to law enforcement† (Permanent Select Committee on Intelligence). That which qualifies as interest to law enforcement, and is in the realm of what intelligence is to be looking for is defined as â€Å"Information concerning†¦activities directed against the United States, international terrorist and international narcotics activities, and hostile activities directed against the United States by foreign powers, organizations, persons or their agents† (Permanent Select Committee on Intelligence). Intelligence agencies are also collecting information for â€Å"political and military intelligence for policy makers† (Permanent Select Committee on Intelligence. Intelligence focuses on many types of information, and â€Å"there are few rules governing intelligence gathering†, (Permanent Select Committee on Intelligence). Within the United States we have many different intelligence agencies, most of which existed during September 11. One of the most well known intelligence agencies is The Central Intelligence Agency, their