Fibrin (also called Factor Ia ) is a fibrous , non-globular protein involved in the clotting of blood . It is formed by the action of the protease thrombin on fibrinogen , which causes it to polymerize . The polymerized fibrin, together with platelets , forms a hemostatic plug or clot over a wound site.
34-479: When the lining of a blood vessel is broken, platelets are attracted, forming a platelet plug . These platelets have thrombin receptors on their surfaces that bind serum thrombin molecules, which in turn convert soluble fibrinogen in the serum into fibrin at the wound site. Fibrin forms long strands of tough insoluble protein that are bound to the platelets. Factor XIII completes the cross-linking of fibrin so that it hardens and contracts. The cross-linked fibrin forms
68-512: A hemorrhage . Dysfunction or disease of the liver can lead to a decrease in the production of fibrin's inactive precursor, fibrinogen , or to the production of abnormal fibrinogen molecules with reduced activity ( dysfibrinogenaemia ). Hereditary abnormalities of fibrinogen (the gene is carried on chromosome 4) are both quantitative and qualitative in nature and include afibrinogenaemia , hypofibrinogenaemia , dysfibrinogenaemia, and hypodysfibrinogenemia . Reduced, absent, or dysfunctional fibrin
102-470: A blocked coronary artery. As such, the same factors that cause platelets to coagulate during hemostasis can also contribute to unwanted thrombosis. While the general mechanisms of hemostasis and platelet plug formation have already been discovered, there is still much to learn in terms of the chemicals contributing to the process. Only the key factors have been identified; there are still many molecules present during hemostasis that scientists do not understand
136-429: A clot network. Fibrin assembly facilitates intermolecular antiparallel C-terminal alignment of gamma-chain pairs, which are then covalently 'cross-linked' by factor XIII ('plasma protransglutaminase') or XIIIa to form 'gamma-dimers'. The image at the left is a crystal structure of the double-d fragment from human fibrin with two bound ligands. The experimental method used to obtain the image was X-ray diffraction, and it has
170-413: A mesh atop the platelet plug that completes the clot. Fibrin was discovered by Marcello Malpighi in 1666. Excessive generation of fibrin due to activation of the coagulation cascade leads to thrombosis , the blockage of a vessel by an agglutination of red blood cells, platelets, polymerized fibrin and other components. Ineffective generation or premature lysis of fibrin increases the likelihood of
204-419: A resolution of 2.30 Å. The structure is mainly made up of single alpha helices shown in red and beta sheets shown in yellow. The two blue structures are the bound ligands . The chemical structures of the ligands are Ca ion, alpha-D-mannose (C 6 H 12 O 6 ), and D-glucosamine (C 6 H 13 NO 5 ). Platelet plug The platelet plug, also known as the hemostatic plug or platelet thrombus ,
238-468: A result of its motion. The significance of ATP is in its ability to store potential energy within the phosphate bonds. The energy stored between these bonds can then be transferred to do work. For example, the transfer of energy from ATP to the protein myosin causes a conformational change when connecting to actin during muscle contraction . It takes multiple reactions between myosin and actin to effectively produce one muscle contraction, and, therefore,
272-526: A temporary blockage of the break in the vasculature. As such, platelet plug formation occurs after vasoconstriction of the blood vessels but before the creation of the fibrin mesh clot, which is the more permanent solution to the injury. The result of the platelet plug formation is the coagulation of blood. It can also be referred to as primary hemostasis. For many years, the critical role that platelets (also known as thrombocytes) played in hemostasis and blood coagulation went unnoticed by scientists. Even though
306-446: Is a result of dephosphorylation of ATP by enzymes known as ATPases . The cleavage of a phosphate group from ATP results in the coupling of energy to metabolic reactions and a by-product of ADP. ATP is continually reformed from lower-energy species ADP and AMP. The biosynthesis of ATP is achieved throughout processes such as substrate-level phosphorylation , oxidative phosphorylation , and photophosphorylation , all of which facilitate
340-419: Is an aggregation of platelets formed during early stages of hemostasis in response to one or more injuries to blood vessel walls . After platelets are recruited and begin to accumulate around the breakage, their “sticky” nature allows them to adhere to each other. This forms a platelet plug, which prevents more blood from leaving the body as well as any outside contaminants from getting in. The plug provides
374-634: Is an important organic compound in metabolism and is essential to the flow of energy in living cells . ADP consists of three important structural components: a sugar backbone attached to adenine and two phosphate groups bonded to the 5 carbon atom of ribose . The diphosphate group of ADP is attached to the 5’ carbon of the sugar backbone, while the adenine attaches to the 1’ carbon. ADP can be interconverted to adenosine triphosphate (ATP) and adenosine monophosphate (AMP). ATP contains one more phosphate group than ADP, while AMP contains one fewer phosphate group. Energy transfer used by all living things
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#1733094037406408-426: Is formed after the temporary blockage is created. This process involves the conversion of fibrinogen, a soluble glycoprotein, into fibrin , an insoluble glycoprotein, using the enzyme thrombin . The fibrinogen forms fibrin to encase the platelet thrombus, thus creating a secondary hemostatic plug that is much more stable and securely attached to the vessel wall. Due to the shear force, a platelet thrombus attached to
442-575: Is likely to render patients as hemophiliacs . Fibrin from various different animal sources is generally glycosylated with complex type biantennary asparagine-linked glycans . Variety is found in the degree of core fucosylation and in the type of sialic acid and galactose linkage. Fibrin is formed after thrombin cleavage of fibrinopeptide A (FPA) from fibrinogen Aalpha-chains, thus initiating fibrin polymerization. Double-stranded fibrils form through end-to-middle domain (D:E) associations, and concomitant lateral fibril associations and branching create
476-450: Is the initial phase of free-energy release in the breakdown of glucose and can be split into two phases, the preparatory phase and payoff phase. ADP and phosphate are needed as precursors to synthesize ATP in the payoff reactions of the TCA cycle and oxidative phosphorylation mechanism. During the payoff phase of glycolysis, the enzymes phosphoglycerate kinase and pyruvate kinase facilitate
510-464: Is used (GTP + ADP → GDP + ATP). Oxidative phosphorylation produces 26 of the 30 equivalents of ATP generated in cellular respiration by transferring electrons from NADH or FADH2 to O 2 through electron carriers. The energy released when electrons are passed from higher-energy NADH or FADH2 to the lower-energy O 2 is required to phosphorylate ADP and once again generate ATP. It is this energy coupling and phosphorylation of ADP to ATP that gives
544-545: The cytoplasm , the viscous fluid that fills living cells, where the glycolytic reactions take place. The citric acid cycle , also known as the Krebs cycle or the TCA (tricarboxylic acid) cycle is an 8-step process that takes the pyruvate generated by glycolysis and generates 4 NADH, FADH2, and GTP, which is further converted to ATP. It is only in step 5, where GTP is generated, by succinyl-CoA synthetase, and then converted to ATP, that ADP
578-474: The addition of a phosphate group to ADP by way of substrate-level phosphorylation . Glycolysis is performed by all living organisms and consists of 10 steps. The net reaction for the overall process of glycolysis is: Steps 1 and 3 require the input of energy derived from the hydrolysis of ATP to ADP and P i (inorganic phosphate), whereas steps 7 and 10 require the input of ADP, each yielding ATP. The enzymes necessary to break down glucose are found in
612-415: The addition of a phosphate group to ADP. ADP cycling supplies the energy needed to do work in a biological system, the thermodynamic process of transferring energy from one source to another. There are two types of energy: potential energy and kinetic energy . Potential energy can be thought of as stored energy, or usable energy that is available to do work. Kinetic energy is the energy of an object as
646-415: The availability of large amounts of ATP is required to produce each muscle contraction. For this reason, biological processes have evolved to produce efficient ways to replenish the potential energy of ATP from ADP. Breaking one of ATP's phosphorus bonds generates approximately 30.5 kilojoules per mole of ATP (7.3 kcal ). ADP can be converted, or powered back to ATP through the process of releasing
680-406: The binding of the adhesive platelets with vWF and fibrinogen. ADP can then catalyze the aggregation of platelets, allowing for fibrinogen to link two platelets together. As more platelets accumulate, they release more chemicals, which in turn attract even more platelets. This is a positive feedback loop that eventually results in the formation of the platelet thrombus. A secondary hemostatic plug
714-409: The blood vessel's walls can easily be swept away or disintegrated. As such, after the platelets have been anchored to the vessel wall, have been linked together, and have been enmeshed in fibrin, they must also be consolidated to ensure they can withstand such force. This is accomplished by factor XIII , also known as fibrin stabilizing factor, an enzyme that crosslinks fibrin. Factor XIII is critical in
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#1733094037406748-423: The body without any noticeable aggregation of platelets. This is because platelets are not initially programmed to accumulate by themselves because this could cause an undesirable thrombosis. However, during hemostasis, coagulation is desired. As such, the platelets in the plasma must be alerted to the need for a plug formation. Any discontinuity detected in the vascular endothelium triggers an automatic response in
782-464: The chemical energy available in food; in humans, this is constantly performed via aerobic respiration in the mitochondria . Plants use photosynthetic pathways to convert and store energy from sunlight, also conversion of ADP to ATP. Animals use the energy released in the breakdown of glucose and other molecules to convert ADP to ATP, which can then be used to fuel necessary growth and cell maintenance. The ten-step catabolic pathway of glycolysis
816-450: The clotting system, which in turns stimulates thrombin production. Thrombin also causes platelet aggregation. As such, more often than not, platelet adhesion and activation occur in overlapping steps, where one directly influences and contributes to the other. Once platelets are activated, when they come across injured endothelium cells, the von Willebrand factor (vWF) and fibrinogen will act as anchors to allow platelets to adhere onto
850-497: The consolidation of a hemostatic plug. Those who are found to be deficient in the enzyme exhibit delayed bleeding after surgical procedures. While platelet activation and plug formation are necessary for the cessation of bleeding and vascular injuries, if platelet adhesion and aggregation occur in an unwarranted location, the result will instead be vascular obstruction and thrombosis. This is commonly observed in myocardial infarctions, in which platelet aggregation and adhesion result in
884-430: The damaged cells as well as more space for adhesion to occur. After platelets make contact with the focal point of the vascular injury, they begin to interact with each other to form a platelet aggregate. Platelet aggregation is mainly mediated by β3 (αIIbβ3) integrin and its ligands, such as vWF and fibrinogen. While platelet membranes have binding sites for fibrinogen, they must be induced by thrombin. Thrombin triggers
918-412: The electron transport chain the name oxidative phosphorylation. During the initial phases of glycolysis and the TCA cycle , cofactors such as NAD+ donate and accept electrons that aid in the electron transport chain 's ability to produce a proton gradient across the inner mitochondrial membrane. The ATP synthase complex exists within the mitochondrial membrane (F O portion) and protrudes into
952-407: The existence of platelets as a cell fragment was initially discovered in 1882, it took scientists until the 1960s before they moved their interest from the interaction of platelets with blood coagulation to the interaction of platelets with themselves. The discovery of adenosine diphosphate (ADP) as the primary inducer of platelet aggregation was a major breakthrough in the field of hematology. It
986-458: The matrix (F 1 portion). The energy derived as a result of the chemical gradient is then used to synthesize ATP by coupling the reaction of inorganic phosphate to ADP in the active site of the ATP synthase enzyme; the equation for this can be written as ADP + P i → ATP. Under normal conditions, small disk-shape platelets circulate in the blood freely and without interaction with one another. ADP
1020-638: The platelet interact with other surfaces, like the inside of a damaged vessel wall. At high shear stress levels, the GP1b-von Willebrand Factor will initiate the platelet adhesion. This process will then be mediated by integrins, such as β1 (α2β1, α5β1) and β3 (αIIbβ3) integrins. In addition, platelets are activated, they will also change shape in their cortical actin cytoskeleton. The platelets will transform from smooth, biconcave discs to fully spread cells. This dramatically increases their surface area and therefore allows for both increased blockage of
1054-483: The role they play. Fibrinogen and vWF are known critical factors in hemostasis. However, it has been discovered that even in mice who lack both of these components, hemostasis and thrombosis still occur. This seems to suggest that there are other contributing molecules still undiscovered that may also play an important role in platelet aggregation and adhesion. Adenosine diphosphate Adenosine diphosphate ( ADP ), also known as adenosine pyrophosphate ( APP ),
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1088-406: The vessel wall. These molecules are released from the platelet themselves as a result of degranulation, a physiological change in the platelet's shape due to the secretion of the contents of the dense granules and alpha granules. From the dense granules, serotonin and adenosine diphosphate are released. From the alpha granules come molecules such as the platelet-derived growth factor, fibrinogen, and
1122-409: The von Willebrand factor (vWF), a glycoprotein critical in platelet activation and adhesion. The ADP secreted from the dense granules then binds to receptors on the membrane of platelets. However, to allow for platelet adhesion to occur requires an additional molecule. Glycoprotein lb is a protein on the surface of the platelet membrane that binds to vWF. When vWF is bound to glycoprotein lb, it helps
1156-439: Was followed by the discovery of the platelet release reaction, as well as the aggregating properties of thrombin and collagen . The platelet plug formation is the second step of hemostasis. It occurs after vasoconstriction. During the process, platelets begin to accumulate, or aggregate, on the damaged vessel wall. Platelet plug formation occurs in three major steps: Under normal physiological conditions, blood flows through
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