The Process of Blood Clotting - Essay Example

? Coagulation: Overview, Pathways, Clot Formation, and Effects on Coagulants Coagulation: Overview The process of blood clotting is referred to as coagulation, which is essential during hemostasis. Hemostasis takes place in order to terminate the flow of blood from an injured vessel (Hoffbrand, Moss & Pettit 2006). Coagulation begins when platelets and fibrin forms clot on the wall of the injured blood vessel as a means to terminate the bleeding and to instigate the restoration of the injured vessels. However, disarray during the process of coagulation could result to either thrombosis or hemorrhage (Hoffman, Benz, Shattil, Furie & Silberstein 2008). The process of coagulation requires a platelet and a coagulation factor in order to function, which usually involves a cell and a protein. It automatically starts once the endothelium lining of a blood vessel has been affected due to damage (Hoffbrand, et. al 2006). When the blood is exposed to protein components, the site's blood platelets and plasma fibrinogens would react towards the damage and begin the clotting process (Mann, Brummel-Ziedins, Orfeo & Butenas, 2006). Primary hemostasis commences, wherein platelets would form a plug where the vessel has been damaged. After which, the secondary hemostasis proceeds concurrently, wherein coagulation factors located in the blood plasma would react towards the cascade to produce fibrin strands, in order to reinforce the platelet plug (Hoffman & Monroe 2007). The Coagulation Cascade The coagulation pathway is also referred to as the blood clotting system, which functions as a proteolytic cascade. The enzymes present in the blood clotting system are represented in the plasma in its inactive form, or as zymogens. These zymogens would then go through the process of activation by means of the proteolytic cleavage, which would trigger the active factor from the antecedent particle (Hoffman, et al. 2008). The mechanism in which the coagulation system functions is through a cycle of positive and negative feedback series that regulate the activation process. In essence, the objective of the coagulation pathway's process is to create thrombin. Thrombin would then produce the substance responsible for forming a clot, which is fibrin, which is a result of converting fibrinogen (Hoffbrand, et. al 2006). The process of creating thrombin is distributed into three stages: the extrinsic and instrinsic pathways serve as substitute conduits in producing factor X, whereas the final common pathway forms thrombin (Mosnier 2004). The formation of fibrin is achieved through two pathways of the coagulation cascade of secondary hemostasis. These two pathways are referred to as the: 1) contact activation pathway; and the 2) tissue factor pathway (Hoffbrand, et. al 2006). The two aforementioned pathways are also known as the intrinsic and extrinsic pathway. It is important to note that both pathways are equal in nature and would lead to one pathway (Hoffman & Monroe, 2001). The extrinsic or the tissue factor pathway is the main conduit in the instigation of the blood coagulation process. Both pathways serve as a string of reactions, wherein active components would be formed through the inactive enzyme precursor of a serine protease and its corresponding glycoprotein co-factor. These active components would then trigger the preceding reaction in cascade. These processes would then produce cross-linked fibrin (Mann, et. al 2006). Coagulation factors disseminate to the damaged blood vessels as inactive zymogens, and are usually composed of enzymes or serine proteases, which serve the purpose of slicing other proteins based on a definite serine deposit. Concessions to coagulation factors apart from serine proteases are glycoproteins (FVIII and FV) and transglutaminase (FXIII) (Hoffman & Monroe, 2001). The coagulation cascade is typically follows the division of three conduits. The aforementioned extrinsic and intrinsic pathways activate the common conduit of factor X, which is thrombin and fibrin (Hoffman, et al. 2008). Tissue factor pathway The function of the extrinsic pathway is to initiate the process wherein the thrombin would be released simultaneously, referred to as the "thrombin burst". Thrombin is considered as the most essential component of the coagulation cascade due its function of feedback activation. The FVIIa is distributed on a larger volume as compared to other activated coagulation factors (Mosnier 2004). When a blood vessel gets injured, the FVII component would abscond from the circulation and would proceed to interact with the tissue factor expressed on cells that bears tissue factors, which are stromal fibroblasts and leukocytes, in order to generate an activated complex (Furie & Furie, 2008). The activated complex would then activate FIX and FX, whereas FVII would be activated by thrombin, FXIa, FXII and FXa. Prothrombin would be activated to thrombin through the formulation of the prothrombinase complex (Mann, et. al 2006). Upon the activation of the thrombin, it would then activate the other constituents of the coagulation cascade. Contact activation pathway The FXII, prekallikrein, and high-molecular-weight kininogen produces primary complex on collagen, which initiates the intrinsic pathway. The prekallikrein would then be modified to kallikrein, and FXII would be converted to FXIIa (Galiani & Renne 2007). FXIa would be generated from the conversion of FXIIa to FXI. The tenase complex would be formulated through the activation of FIX along with its co-factor FVIIIa (Hoffbrand, et. al 2006). The tenase complex would then activate FX to FXa. The function that the contact activation pathway serves in the process of instigating clot formation is important for patients with chronic deficiencies of FXII, HMWK, and prekallikrein, in order to ensure the absence of a bleeding disorder. In addition, its main role is directed towards the inflammation of the damaged blood vessel (Galiani & Renne 2007). Final common pathway The thrombin serves a wide degree of roles; essentially, it is responsible in producing the foundation of a hemostatic plug through the converting fibrinogen to fibrin. Thrombin is also responsible in the activation of Factors V and VIII, including the inhibitor protein C, considering the manifestation of thrombomodulin (Hoffbrand, et. al 2006). In addition, thrombin is also responsible in activating Factor XIII, which helps in generating covalent bonds. These covalent bonds would then form activated monomers, which would produce fibrin polymers (Hoffman & Monroe 2001). The maintenance of the coagulation cascade in a prothrombotic state is achieved through the generation of the tenase complex, by means of the continuous activation of FVIII and FIX. The coagulation cascade would be continuously maintained in this state until it is becomes regulated by the anticoagulant conduits (Hoffman & Monroe 2007). Clot Formation The ultimate outcome of the clotting pathway is the generation of thrombin in order to convert fibrinogen into fibrin. When exposed to thrombin, fibrinogen would proceed to a quick proteolysis and would release fibriopeptide A. The release of the fibrinopeptide A is not enough to make the fibrin particle insoluble, which is necessary in the process of clot formation. However, the release of the small peptide A would help in the formation of complexes that are adjoining fibrin and fibrinogen particles (Hoffbrand, et. al 2006). Fibrinopeptide B, the second peptide, would be cleaved by thrombin (Mann, et. al 2006). The proteolytic cleave of the second peptide B would form fibrin monomers, which would then polymerize instantaneously to create an insoluble gel. The function of thrombin on FXIII would produce the transamidating enzyme FXIIIa, which would stabilize the polymerzied fibrin binded by noncovalent and electrostatic forces. The formed clots, or the insoluble fibrin aggregates, along with the thrombi, or the aggregated platelets, would obstruct the injured blood vessel as a means to avert continuous bleeding (Hoffman, et al. 2008). It's important to note that the plasma enzyme systems and the coagulation pathway is interconnected. The process of clot removal or fibrinolysis, includes plasminogen activator activity, which is the outcome of the contact activation of coagulation pathway. The conversion of plasma prekallikrein to kallikrein is instigated by an activated Hageman factor and its peptides. Kallikrein would then catalyze kininogens to release bradykinin in the plasma (Hoffman & Monroe 2007). The functions of kinins are to dilate small blood vessels, trigger smooth muscle contraction, increase the permeablity of vessel walls, and to induce a decrease in the patient's blood pressure. The production of a vascular permeability factor and chemotactic peptides for professional phagocytes are processed through activating the coagulation pathway (Hoffman & Monroe, 2001). Cofactors In order for the coagualation cascade to function properly, there are other factors necessary apart from the proteins and platelets. Other substances needed in the process of coagulation are: 1) calcium and phospolipid; and 2) Vitamin K. Phospolipidserves as a platelet membrane component, which is required along with Calcium in the process tenase and prothrombinase complexes to operate (Mann, et. al 2006). The substance calcium helps in mediating the combination of the complexes by means of the terminal gamma-carboxy deposits on FXa and FIXa to the phospolipid surfaces generated by platelets, including the procoagulantmicrovesicles sloughed from these platelets. On the other hand, vitamin K is needed in the process of hepatic gamma-glutamyl carboxylase which augments a carboxyl group to glutamic acid deposits on Proteins S, C and Z (Ansell, Hirsh & Poller, et al. 2004). In addition, it also adds a carboxyl group on FII, FVI, FIX, and FX. Vitamin K's process of oxidation is through augmenting the gamma-carboxyl group to glutamate deposits on the immature clotting factors. In addition, the Vitamin K epoxide reducatase enzyme is essential as it would serve as the recipient of warfarin and other anticoagulant drugs. Dicumarol, phenprocoumon and acenocoumarol blocks VKORC, thus producing the deficit of decreased Vitamin K. This process would then lead to the inhibition of the development of clotting factors. The consequence of Vitamin K deficiency is correlated to the coagulation factors' capability to connect to phospolipid (Hirsh, O'Donnell & Eikelboon 2007). Regulators The coagulation cascade's regulatory function serves two roles: 1) to restrict the degree of the formation of the fibrin clot in order to prevent ischemia of tissues; and 2) to impede the probability of pervasive thrombosis through containing the formation of clot only within the parameters of the blood vessel damage. Coagulation cascade and the activation of platelets are regulated through five mechanisms. Without regulation, abnormalities would occur, which would lead to an escalated probability towards thrombosis (Mann, et. al 2006). 1. TFPI (Tissue Factor Pathway Inhibitor) The TFPI serves to restrict the operation of the tissue factor (TF). In addition, its role is to impede the disproportionate activation of factors VII and X through the mediation of tissue factors. The Tissue Factor Pathway Inhibitor is a type of protein that serves as a mediator of the response inhibition of the TF-FVIIa complex, in order to reduce the activation of FIX and FX. The TFPI would be able to attain its inhibition of FVIIa-TF complex with the presence of FXa, even in small volumes (Hoffman & Monroe 2007). Once the factor VIIa-Tissue Factor complex begins to cascade, complexes are generated together with small volumes of thrombin and FXa. The restricted volume of FXa would proceed to feedback inhibition of its fusion through the Tissue Factor Pathway Inhibitor. The presence of heparin would boost the productivity of the TFPI, as it would bind TFPI and TF-FVIIa complex, which would enhance both complexes' interaction (Hoffman & Monroe, 2001). 2. Antithrombin Antithrombin is a protein prodcued by liver and endothelial cells, whose function is to fuse and inactivate thrombin and other serine proteases. However, the process of inactivating serine proteases by the antithrombin is comparatively protracted, as the serine proteases would still be able to produce fibrin and thrombin before it becomes full inactivated. The presence of sulfated flycosaminoglycans such as heparin would help in the instant obstruction of the serine proteases' capacity to form fibrin. Heparin is relased by normal endothelial cells (Perzborn, Strassburger & Wilmen et al. 2005).The role of antithrombin is to bind with heparan sulfates in order to inactive serine proteases, as a means to ensure that fibrin clot would not occur in sites that do not have a damaged blood vessel. Once AT binds with heparin, its main target is to inactivate thrombin, prior to fibrin (Furie & Furie, 2008). Antithrombin is considered a serpin, or a serine protease inhibitor whose function serves to reduce the following serine proteases: thrombin; factors IXa, Xa, and XIIa. Antithrombins are persistently active; however, its bond to the aforementioned factors is proliferated by the manifestation of a heparan sulfate or the intake of heparins. A patient would present with thrombophilia if there is either a qualitative or quantitative scarcity of antithrombin (Perzborn, Strassburger & Wilmen et al. 2005) 3. Thrombomodulin Thrombomodulin is a cell receptor whose function is to bind thrombin. Upon the formation of a complex of both particles, a modification in the thrombin molecule would transpire. The modified thrombin particle would simultaneously activate protein C, but would eventually exhaust its functions of activating platelets and protease (Furie & Furie, 2008). In essence, the fusion of thrombomodulin to thrombin helps in the process of converting thrombin from an effective procoagulant to an anticoagulant. If a patient manifests a normal physiological state, the presence of thrombomodulin is essential as it would impede the clot formation system in blood vessels that are not damaged (Hoffbrand, et. al 2006). 4. Protein C and Protein S The role of proteins C and S is to inactivate FVa and FVIIIa. Protein C would be activated to a serine protease through the fusion of thrombin to thrombomodulin. The role of protein S is to increase the productivity of protein C. Inactivating FVa and FVIIa would dramatically reduce the pace of producing thrombin, which helps in regulating the cascade (Hoffman, et al. 2008). Protein C is an essential regulator as it is considered a key physiological anticoagulant. Activated protein C (APC) is formed through the activation of a thrombin by a vitamin K dependent serine protease enzyme. Its activation follows the order beginning with the coalescence of protein C and thrombin with a cell surface protein thrombomodulin. Factors Va and VIIIa would then be reduced through the presence of proteins C, S and a phospholipid (Hoffman & Monroe 2007). 5. Prosyacyclin (PGI2) Prosyacyclin is the substance that is responsible in the activation of platelet Gs protein-linked receptors. Through this process, the adenylyl cyclase would then be activated, which would then trigger cAMP. The reduction of platelet activation through cAMP is done through the reduction of cytosolic degrees of calcium. This process would then impede the emission of granules which serves to activate additional platelets and further the process of the coagulation cascade (Hoffman & Monroe, 2001). Fibrinolysis The process of fibrinolysis entails the process of reorganizing and resorbing the clot formation of the blood vessels, as catalyzed by an enzyme called plasmin. During the process, the plasmin is being regulated by several inhibitors and activators (Hoffman & Monroe 2007). The process of coagulation overlaps the role of an individual's immune system, as coagulation has the capacity to trap microbes during the clot formation. In addition, substances produced during the coagulation process complements one's natural immune system through its capability to enhance vascular permeability. These by-products of the coagulation system could also serve the role of chemotactic agents for phagocytic cells, and some also serve antimicrobial purposes (Furie & Furie, 2008). Testing There are various tests available to analyze the role of the coagulation system. Common tests are as follows: 1) fibrinogen testing; 2) platelet count; 3) platelet function testing; 4) aPTT; and 5) PT. Other tests include the following: 1) thromboelastography; 2) miscellaneous platelet function tests; 3) euglobin lysis time; 4) genetic tests; 5) dilute Russell's viper venom time; 6) antiphosholipid antibodies; 7) coagulation factor assays; 8) mixing test; 9) bleeding test; and 10) TCT (Hoffman & Monroe 2007). The activation process of the plasma's contact factors would lead to instigation of the intrinsic pathway, which could then be evaluated through the aPTT test. On the other hand, the extrinsic pathway is instigated through the discharge of a cellular lipoprotein, which could then be assessed through the PT test. The results of prothrombin time exams are presented as as ratio as a means to track the dosage of oral anticoagulants. On the other hand, the monitoring of fibrinogen in terms of quantitative and qualitative measures is assessed through the thrombin clotting time (Hoffman & Monroe, 2001). Evaluating the specific volume of the presence of fibrinogen in the blood can be processed through the use of the Clauss method in line with fibrinogen testing (Hoffbrand, et. al 2006). If either the tissue factor or the contact activation pathway has a coagulation factor present, then the defect of that specific factor would only be shown in one of the tests done. However there are factors that are exempted from this rule and can only be detected by either an aPTT or a PT test, which are as follows: 1) fibrinogen; 2) prothrombin; and 3) other variants of FX.For these factors, if there is an abnormal result present in either the PT or aPTT test, there is a necessity to employ other testing as a means to identify if any of the factors contain atypical concentrations. On the other hand, defects present concerning fibrinogen, regardless if it’s quantitative or qualtitative, will present results in all the screening exams processed (Furie & Furie, 2008). Effects of Different Variables on Coagulants Procoagulants Procoagulants are taken in order to help the coagulation process in sealing damaged blood vessels on a quicker pace. Hemostatic agents, such as adsorbent chemicals, are commonly applied in severe injuries that involve traumatic bleeding. On the other hand, fibrin glue and thrombin is intended for the treatment of bleeding and to thrombose aneurysms, while the usage of desmopressin is for enhancing the function of the platelets, through the activation of the arginine vasopressin receptor 1A (Furie & Furie, 2008). Hemophilia is treated through the use of coagulation factor concentrates, by means of reversing the outcomes produced by anticoagulants and for the treatment of bleeding patients presenting with a damaged coagulation factor synthesis or a heightened utilization (Mann, et. al 2006). The most commonly utilized coagulation factor products are as follows: 1) cryoprecipiate; 2) prothrombin complex concentrate; and 3) fresh frozen plasma. In the event of a severe bleeding, the commonly used procoagulant is recombinant activated human factor VII. In order to impede fibrinolysis, the utilization of tranexamic and aminocaproic acids is advised, as the usage of both would also help in decreasing the rate of the patient's bleeding (Furie & Furie, 2008). Anticoagulants The most common medications used in order to apply anti-platelet agents are as follows: 1) dipyridamole; 2) aspirin; 3) clopidogrel; 4) ticlopidine; 5) prasugrel; and 6) parenteral glycoprotein IIb/IIIa inhibitors. As for anticoagulants, the most commonly used medications are warfarin and heparin. Warfarin is used to have an effect on the clotting factors that rely on vitamin K, which are FII, FVII, FIX and FX. On the other hand, heparin and its associated compounds enhance the function of antithrombin on FXa and thrombin (Harenberg & Wehling 2008). References Ansell, J., Hirsh, J., Poller, L., et al. 2004. The pharmacology and management of the vitamin K antagonists, The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy, 126, 204-33. Furie, B. & Furie, B.C. 2008. Mechanisms of thrombus formation. New England Journal of Medicine, 359, 938-49. Galiani D., & Renne T. 2007. The intrinsic pathway of coagulation: A target for treating thromboembolic disease?, Journal of Thrombosis and Haemostology, 5,1106-12. Harenberg, J. & Wehling, M. 2008. Current and future prospects for anticoagulant therapy: Inhibitors of factor Xa and factor IIa, Seminars on Thrombosis and Hemostology, 34, 39-57. Hirsh, J., O'Donnell, M. & Eikelboon, J.W. 2007. Beyond unfractionated heparin and warfarin: current and future advances. Journal of Circulation, 116, 552-60. Hoffbrand, V., Moss, P.A. & Pettit, J.E. 2006. Essential Haematology. Blackwell Publication. Hoffman, M. & Monroe, D.M. 2001. A cell-based model of hemostasis. Thrombosis and Haemostology, 85, 958-65. Hoffman, M. & Monroe, D.M. 2007. Coagulation 2006: A modern view of hemostasis. Hematol Hematology/Oncology Clinics of North America, 21, 1-11. Hoffman, R., Benz, E.J., Shattil, S.J., Furie, B. & Silberstein, L.E. 2008. Hematology: Basic Principles and Practice, 5th ed. Philadelphia, PA: Elsevier. Mann, K.G., Brummel-Ziedins, K., Orfeo, T. & Butenas, S. 2006. Models of blood coagulation. Blood Cells, Molecules, and Diseases, 36, 108-17. Mosnier, L.O. 2004. Thrombin activatable fibrinolysis inhibitor (TAFI) at the interface between coagulation and fibrinolysis, Pathophysiology of Haemostasis and Thrombosis, 33, 375-81. Perzborn, E., Strassburger, J., Wilmen, A., et al. 2005. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939 – an oral, direct Factor Xa inhibitor, Journal of Thrombosis and Haemostology, 3, 514-21. Read More