The Nature of the Disease - Coursework Example

Anticoagulants Name Institution Date Anticoagulants Description of the nature of the disease/condition (Deep venous thrombosis) Deep venous thrombosis (DVT) is the blood clot (thrombus) formation in the leg’s deep vein (Beek et al, 2009, pg 45). DVT tends to take place within leg veins, like the femoral or popliteal veins, also within the pelvis’ deep veins. A number of people might develop DVT and not discover because there is no symptoms (Welch & Bonner, 2010, pg 10). Generally, though, individuals experience swelling, tenderness, pain, warmth and redness within the affected region; superficial veins might swell up as well. DVT ought to be managed as a medical emergency (Welch & Bonner, 2010, pg 39). Of the DVTs cases, 3 percent that occur within the leg ultimately kill the person, chiefly because of complications related to pulmonary embolism (Beek et al, 2009, pg 46). In case the clot is dislodged and penetrates the lung, some of the symptoms and signs that may show pulmonary embolism include and not limited to: chest pain, wheezing, breathlessness, lightheadedness, coughing which might produce bloodstained sputum, accelerated heartbeat, and unexplained anxiety (Shorr, 2007, pg 129). There are various causes of DVT. Occasionally, an individual may develop DVT without apparent reason. On the other hand, in various cases, occurrence of DVT is connected to the following conditions or circumstances. a) inactivity- once the body of a human is not active for long, there is tendency of blood accumulating within the pelvic region and lower limbs (Beek et al, 2009, pg 56). This may not be an issue in most situations, because immediately an individual resumes physical activity, the flow of blood accelerates and redistribution of blood occurs within the body. However, once there is prolonged inactivity, blood accumulation within the legs may slow down the flow of blood, which eventually increases the possibility of formation of clots (Shorr, 2007, pg 86). Inactivity might be as a result of disability, sitting during long journeys, or being hospitalized. b) Surgery or injury- surgery or injury which causes damage to the veins can decrease blood flow, hence increase the risks of blood clots’ formation (Shorr, 2007, pg 90). General anesthetics may cause veins’ dilation, which increases the possibility of formation of blood clots and pools. c) genetics- a disorder or condition that increases the possibility of blood clot may be inherited (Shorr, 2007, pg 96). In various cases the possibility exists only once there is a combination of at least other risk factors. With regards to diagnosis, there are various ways in which DVT can be diagnosed. One of DVT’s diagnoses is the D-dimer test (Beek et al, 2009, pg 38). This is a fragment of protein which is found in the blood following degradation of blood clot through fibrinolysis. Once more than specific quantity is seen in blood test, then there is possible the individual has a clot of blood within the vein. Ultrasound is another method through which DVT can be diagnosed (Shorr, 2007, pg 58). This kind of scan is able to detect blood clots within the veins, and also establish the speed of blood flow in the vein. A Doppler sonography is able to establish the speed of blood flow (Shorr, 2007, pg 60). Anticoagulants such as heparin are used in the treatment of DVT (Shorr, 2007, pg 62). Anticoagulants are medications that prevent clots from becoming bigger, and also preventing them from breaking off thereby bringing about pulmonary embolism (Apostolakis et al, 2009, pg 74). Description of heparin history Heparin is among the oldest medications presently still in extensive clinical use (Lever, 2012, pg 21). Heparin occurs naturally as glycosaminoglycan whose prime function is inhibition of blood coagulation (Lever, 2012, pg 32). Heparin’s invention in 1916 predates the Food and Drug Administration’s establishment of the United States, even though it did not go into clinical experiments until 1935 (Lever, 2012, pg 32). Heparin was initially isolated from liver cells of the canine, thus its name (‘’hepar’’ translates to “liver” in Greek). The discovery of heparin can be associated with the activities of research by two men William Henry Howell and Jay McLean (Lever, 2012, pg 35). In 1916, a second-year student McLean, at the medical school in Johns Hopkins University worked under Howell’s guidance investigating preparations of pro-coagulant, when he made isolation of a phosphatide anti-coagulant that is fat-soluble in the liver tissue of a canine (Lever, 2012, pg 40). In 1918 it was Howell who invented the term “heparin” for this kind of an anticoagulant that is fat-soluble. During the start of 1920s, Howell made an isolation of a polysaccharide anticoagulant that is water-soluble, which was termed “heparin” as well, even though it was different from the previously isolated phosphatide preparations (Lever, 2012, pg 46). It is likely that McLean’s work transformed the Howell group’s focus to seek anticoagulants, which finally resulted in the discovery of polysaccharide. McLean was a surgeon. At 67 years of age, he died of ischaemic heart disease. During the 1930s, various researchers did heparin investigation (Lever, 2012, pg 46). At Karolinska Institutet, Erik Jorpes made a publish of his research on heparin’s structure in 1935, which facilitated the Vitrum AB a Swedish company to launch the primary heparin product used intravenously in 1936 (Lever, 2012, pg 50). Between the years 1933 and 1936, then a constituent of the University of Toronto, Connaught Medical Research Laboratories, perfected a mechanism for making safe, non-harmful heparin that may possibly be given to patients in a solution of salt (Lever, 2012, pg 60). The primary human heparin trial started in May 1935, and, in 1937, it was evident that Connaught’s heparin was actually safe, readily-available, and helpful blood anticoagulant. Before 1933, heparin was obtainable, although in small quantities, and was exceedingly expensive, toxic, hence, of no clinical value (Lever, 2012, pg 65). In 1928, the physiologist and physician Charles Best, most renowned for his insulin work at the Connaught Laboratories, Toronto, started to gather a team of physiologists, clinicians, and biochemists at the town’s university (Piyathilake & Liang, 2012, pg 120). Some of his few years were spent in the National Institute of Medical Research and he chose to make development of heparin into something helpful for clinical and research purposes. In 1929 he turned out to be the Head of Physiology and a professor at the university. During this period, Best together with his graduate student named Arthur Charles, started to work in deep (Piyathilake & Liang, 2012, pg 127). Their goals were twofold; further purification of heparin to eliminate or decrease its side effects as well as demonstrating its effects in thrombus formation prevention. In 1929, a Swedish physiologist Erik Jorpes visited Best in order to observe insulin production at Toronto. Jorpes was oriented around the Laboratories and later introduced on heparin work. He subsequently went back to Stockholm and started his own trial to isolate and distinguish the substance (Piyathilake & Liang, 2012, pg 130). In 1933, four years following Best’s team being serious on their project, Charles together with his skilled colleague David Scott, who served at the Connaught Laboratories as an assistant director, published a chain of papers about their work (Piyathilake & Liang, 2012, pg 132). The initial paper outlined a procedure for isolation preparation of crude heparin from the bovine liver. To raise the quantity of the yielded heparin, the tissue was to be autolysed although the decaying tissue’s smell was so pathetic that there had to be a shift of production from the city’s laboratories to the neighborhood Connaught Farm (Piyathilake & Liang, 2012, pg 144). The next paper summarized an extra-hepatic tissues’ survey where heparin may possibly be identified, to some extent due to the high expense of liver (Piyathilake & Liang, 2012, pg 156). Their conclusion was that lung tissues, muscle, and liver were heparin’s most abundant areas. Nearly a decade before, Howell had argued that heparin had a role in blood fluidity, he thought that even though heparin’s amount within circulation was perhaps small, its general effectiveness was higher there (Piyathilake & Liang, 2012, pg 146). Mechanism of action with regards to DVT Conventionally, heparin has been indicated for patients admitted with DVT. The major objective for DVT’s treatment is the prevention of pulmonary embolism (PE), reduction of morbidity, and prevention or reduction of the possibility of getting postphlebitic syndrome (Freedman & Loscalzo, 2009, pg 122). Anticoagulation is still the foundation of the primary DVT’s treatment (Malone & Agutter, 2007, pg 137). Regular Unfractionated Heparin (UFH) was the typical care until Low-Molecular-Weight Heparin (LMWH) was introduced. The fragments of LMWH exert their effect of anticoagulation through inhibition of the activity of factor X that is activated (Garg et al, 2011, pg 32). The complications of hemorrhagic linked to heparin are believed to come from the bigger fragments of the higher-molecular-weight. Heparin is actually a polysaccharide that is sulfated with a range of molecular weight of 3000-3000 Da. It causes its major effect of anticoagulation through inactivation of thrombin and activation of factor X (factor Xa) via an antithrombin (AT)-dependent method (Piyathilake & Liang, 2012, pg 167). Heparin attaches to AT via a pentasaccharide of high affinity, which exists on nearly 1/3 of molecules of heparin. For thrombin inhibition, heparin ought to attach to both the AT and coagulation enzyme, but attaching to the enzyme is not generally needed for factor Xa inhibition (Garg et al, 2011, pg 121). Heparin molecules with not more than 18 saccharides do not have the chain length that bridges between AT and thrombin and hence are not able to inhibit thrombin. On the contrary, very small fragments of heparin that contain the sequence of pentasaccharide cause inhibition of factor Xa through AT (Garg et al, 2011, pg 103). Through inactivation of thrombin, heparin does not just prevent formation of fibrin but also causes inhibition of thrombin-induced activation of platelets as well as of factors V and VII (Piyathilake & Liang, 2012, pg 108). The principal heparin limitation comes from its tendency to attach to surfaces and proteins that are positively charged. Pharmacokinetic restrictions are brought about through AT-independent attachment of heparin to proteins discharged from endothelial cells, platelets, and plasma proteins, leading to a variable anticoagulant reaction as well as the phenomenon of resistance of heparin. AT-independent attaching to endothelial cells and macrophages also leads to clearance that is dose-dependent. Other limitations are: 1) heparin’s inability to inactivate factor Xa within the thrombin or prothrombinase complex bound to subendothelial surfaces or to fibrin and 2) heparin-induced thrombocytopenia as well as osteopenia complications (Piyathilake & Liang, 2012, pg 109). Since the anticoagulant reaction to heparin differs among patients who have thromboembolic conditions, it is typical practice to regulate heparin dosage and monitor its consequences through activated thromboplastin time (APTT) measurement or, once very high dosage is used, through the activated clotting time (ACT) (Piyathilake & Liang, 2012, pg 111). The APTT’s value is limited since commercial reagents of APTT differ significantly in heparin responsiveness. The APTT ought to be measured every 6 hours following heparin’s bolus dose, and the ongoing intravenous (IV) dose ought to be adjusted with regards to the result (Garg et al, 2011, pg 101). Several nomograms of heparin-dose-adjustment have been created, but none of them is applicable to every reagent of APTT, and the range of therapeutic ought to be customized accordingly. Standardization may be achieved through calibration against concentration of plasma heparin by application of a therapeutic parameter of 03-0.7 U/mL, with respect to the chromogenic assay of anti-factor Xa, or a level of heparin of 0.2-0.4 U/mL, by titration of protamine sulfate (Garg et al, 2011, pg 163). The heparin dose should be decreased when used concomitantly with IV platelet glycoprotein (GP) IIb/IIIa receptor antagonists or fibrinolytic agents (Piyathilake & Liang, 2012, 76). Besides anticoagulant effects, heparin is thought to raise the permeability of the vessel wall, suppresses the vascular smooth muscle cells’ proliferation, and suppresses formation of osteoblast and activates osteoclats, consequences that enhance bone loss (Piyathilake & Liang, 2012, pg 100). Of the 3 consequences, osteopenic effect is the only one that is relevant clinically, and all the 3 are not dependent of the heparin’s anticoagulant activity (Piyathilake & Liang, 2012, pg 106). Quantitative structure-activity relationships relevant to heparin Quantitative structure activity relationship (QSAR) analysis assists in the rational exploration of molecules that are active biologically (Garg et al, 2011, pg 102). With the assistance of QSAR studies, it is easy to estimate new chemical compounds’ characteristics without testing and synthesizing them. Heparin, the choice drug for thromboembolic disorders’ prevention and treatment, has been indicated to interact with various proteins. Regardless of its widespread use in medicine, not much is known concerning the specific sequences that work together with particular proteins (Garg et al, 2011, pg 104). The polysaccharide heparin catalyzes antithrombin (AT) and various serine proteases, and between thrombin and heparin cofactor II (HC II). The way activity is affected by structure is not by and large well established, and just in the AT binding case has a physical composition been established as being in charge of a given function Garg et al (2011, pg 133). A short series of defined structure is essential for binding of AT-binding, thus, activity with AT. Since additional properties like molecular weight, charge density, and thrombin affinity can also noticeably influence heparin’s activity, the molecule ought to have numerous functional domains (Garg et al, 2011, pg 140). Heparin is not just a multifaceted mixture of various glycosaminoglycan chains, however individual chains appear to have numerous functional domains as well, a number of which have been acknowledged with domains of structure for inhibitor as well as protease binding (Garg et al, 2011, pg 143). In a study by Garg et al, (2011 pg 145) scientifically fractionated heparins were utilized to functionally separate the effects of AT-affinity and charge density domains. The 2 phase separation method is not sensitive to molecular weight for the molecular weights that are more than 10,000 and segregates heparins with regards to charge density. The divisions were then fractionated through AT affinity into VLA and HA subfractions of similar charge density (Garg et al, 2011, pg 146). In this method, three series were produced (the HA, VLA, and low affinity (LA) heparins) of very homogeneous heparins with characteristics that were methodically related and that may possibly be used to functionally separate the charge-density and AT affinity effects (Garg et al, 2011, pg 147). Apart from VLA heparins that are not active with AT, the heparins’ activities with both inhibitors display similar association with the density of the charge (Garg et al, 2011). The domain of charge-density acts equally with the different inhibitors, implying that the charge-density effect mechanism might not entail the inhibitor. A justification is that charge density reveals its effect via the domain of protease-binding (Eldridge, 2009, pg 50). Interactions involving proteins and heparin/HS have been illustrated quantitatively using various techniques like trapping and quantifying complexes of HS/protein on surfaces, affinity coelectrophoresis (ACE), ITC, and optical biosensors. Immunoprecipitation and filter trapping have been used in separation of heparin/HS-protein compounds from molecules that are free (Eldridge, 2009, pg 60). The amount of complex created at equilibrium is established by the use of heparin/HS that are labeled. Labeled species of heparin/HS are used in ACE as well, where they are put on electrophoresis via agarose gel lanes that have a protein at different concentrations and the changes in labeled materials’ migration determined (Garg et al, 2011, pg 118). Optical biosensors distinguish an alteration in refractive index on compound creation at the area where there is immobilization of one partner. Using this method, the attachment of soluble heparin/HS to proteins that are immobilized has been seen. On the other hand, this is frequently hard since GAGs like HS and heparin, as most carbohydrates that occur naturally, have refractive indices that are low, leading to a small indication on mass basis (Eldridge, 2009, pg 75). References Apostolakis, S, Shantsila, E, & Lip GY, 2009, New anticoagulants for the prevention of deep venous thrombosis: time to consider cost effectiveness?, Pharmacoeconomics, 27, 10, 793-5. Beek, EJ, Büller, HR, & Oudkerk M, 2009, Deep vein thrombosis and pulmonary embolism, Chichester, UK: J. Wiley-Blackwell. Eldridge, SL, 2009, Development of analytical methods for trace impurity analysis and structure determination of heparin/heparan sulfate-derived oligosaccharides, Riverside, Calif.: University of California, Riverside. Freedman, JE & Loscalzo J, 2009, New therapeutic agents in thrombosis and thrombolysis, New York: Informa Healthcare. Garg, HG, Linhardt, RJ & Hales CA, 2011, Chemistry and Biology of Heparin and Heparan Sulfate, New York: Elsevier. Lever, R, 2012, Heparin: A century of progress, Heidelberg [u.a.: Springer. Malone, PC & Agutter PS, 2007, The Aetiology of Deep Venous Thrombosis: A Critical, Historical and Epistemological Survey, New York: Springer. Piyathilake, DE & Liang R, 2012, Heparin: Properties, uses, and side effects, Hauppauge] N.Y: Nova Biomedical. Shorr, AF, 2007, Management of venous thromboembolism, New York, N.Y: Excerpta Medica. Welch, E & Bonner L, 2010, Venous thromboembolism: A nurse's guide to prevention and management, Chichester, West Sussex, U.K: Wiley-Blackwell. Read More