Thrombin: Key Roles in Blood Coagulation and Beyond

Introduction to Thrombin

Thrombin refers to a naturally occurring enzyme responsible for converting fibrinogen to fibrin, which is a key phase during blood coagulation cascade. Further, thrombin is a special molecule which acts both as a pro-coagulant and anti-coagulant. Pro-coagulant and anticoagulant functions therefore are the major roles carried out by thrombin enzyme. Pro-coagulant functions involve the activation of blood platelets through thrombin’s receptors located in the platelets. Thrombin regulates its self-generation by activating coagulation factors V, V11 and X1 leading to the induction of thrombin. Thrombin excites factor X1, consequently inhibiting fibrin clots from fibrinolysis. As an anti-coagulant, thrombin’s function is transacted through binding to thrombomodulin which is a receptor protein located at the blood vessels’ endothelial membrane, thereby initiating a sequence of reactions which induce fibrinolysis. Thrombin constitutes of chemotactic traits enabling it induce its effects during vascular injury. Besides, it comprises of mitogenic properties which stimulates the growth of mammalian cells and fibroblasts (Taslimi, and Golshani, 2011). Despite the fact that thrombin is essential to blood coagulation excessive of it is neurotoxic. For those pursuing further study, seeking biomedical science dissertation help can provide valuable insights into this complex subject.

Role and Formation of Thrombin

Thrombin is a major enzymes associated with haemostasis. It is a component of the serine protease group of enzymes, and is formed from its active precursor prothrombin under the influence of factor Xa, as a component of the prothrombinase complex along the walls of activated cells. According to Taslimi, and Golshani (2011), thrombin is formed from a series of complex proteolytic events which are triggered when creptic tissue factor react with plasma factor Vila to trigger the complex sequence of events which see through the formation of the blood coagulation enzyme complexes which result into effective generation of the enzyme. During these events, thrombin takes part in the generation of the precursors (catalysts) linked in the production and precursors leading to attenuation of its secretion. In the body, thrombin serves as a pro-anticoagulant not only by converting fibrinogen to fibrin, but equally through associating with protease-activated receptor cells to excite different procoagulant cells. Besides, thrombin equally associates with glycoprotein complex along the platelets surface to induce platelet aggregation after joining thrombomodulin to inspire the activation of protein C.

The Production of Thrombin in the Context of Haemostasis

Upon vascular injuries, relentless oozing of blood is managed through the process of haemostasis. During haemostasis, serine protease, thrombin is formed spontaneously at the damaged site to aid in the process of blood clot formation and other processes which influence inflammation and fibrinolysis. Clemetson (2012) noted that these processes encompass various cleavage reactions that ought to be firmly monitored to curb thrombosis or bleeding. During tissue damage, vessel damage introduces the cell surface receptor, and tissue factor that is found in extravascular surface of the blood cells. Thrombin starts as an inactive prothrombin, which is converted into thrombin under the presence of factor Xa as a catalyst. The conversion involves two fundamental proteolytic cleavages which yield three intermediates namely; prothrombin 2 meizothrombin and fragment 1.2.

Coagulation Cascade and the Function of Thrombin in Blood Clotting

Platelets in isolation would not secure the injury on the vascular tissue. A clot should be formed on the injured surface under the presence of clotting factors. These factors are identified by roman numerals ranging from I to XII. The clotting factors activate one another through the process of clotting cascade leading to the conversion of soluble fibrinogen into insoluble fibrin, which stick together to form a clot. The clotting cascade transpires through 2 distinct pathways which are interactive namely intrinsic and extrinsic pathways. Intrinsic pathway is excited by trauma within the vascular system. The activation of intrinsic pathway is facilitated by platelets, collagen, chemicals or exposed endothelium, and it involves factors XI, IX, VII, and XII. On the other hand, extrinsic pathway is activated by interior trauma which makes blood ooze from the vascular tissue. This pathway is faster relative to intrinsic pathway and involves factor VII. Berliner (2012) suggests that the two pathways conjoin at the common pathway to complete the blood clotting process, under the involvement of factors 1, V, II and X.

When the blood vessels are injured, nearby platelets are triggered to secret prothrombin which consequently activates the translation of prothrombin to thrombin under the influence of calcium ions. The produced thrombin’s role is to initiate the transformation of soluble plasma protein, fibrinogen into insoluble threads or fibers known as fibrin. The fibrin threads engulf the platelet plug on an injured surface of the blood vessel to induce an interwoven network of threads and the framework of the clot (Ruiz‐Loredo, López, and López‐Colomé, 2011). The thread fibers assist in holding the blood cells, platelets and other molecules tight at the surface of injury, serving the role of temporal blood clot. This temporary fibrin clot potentially forms in a few seconds which consequently lower the rate at which blood oozes before the platelets attach. Consequently, the platelets in the clot start to shrink, becoming firm thus tightening the clot and integrating the vessel walls to induce the process of wound recovery. The entire process of blood clotting and tightening takes less than one hour. Notably, the role of thrombin therefore is to act the role of serine protease, initiating the conversion of soluble fibrinogen to insoluble fibrin, as well as catalysing other various coagulation-associated reactions (Danckwardt, Hentze, and Kulozik, 2013).

The Role of Thrombin in Protein C Activation

Thrombin serves a key role in activating protein C when the two bind together. This activation activation is fostered by the availability of thrombomodulin and endothelial protein C receptors. Berliner (2012) suggests that the excitation of this protein C is effectively catalysed on the endothelia cell surface by thrombin enzyme bound to thrombomodulin which acts as a cofactor to thrombin. The ability of thrombin to highly bond with thrombomodulin results into highly amplified rate of protein activation.

The Action of Thrombin on Platelets

Thrombin influences the excitation of platelets and aggregation through activating protease-activated receptors on the platelets’ cell membrane. Upon exposes to platelets, thrombin secret their granules and emit the contents of these granules into the immediate plasma. Thrombin therefore influences platelets aggregation which is the ability to cling with one another to form a platelet thread (plug).

Diseases Associated with Afibrinogenemia and Von Willebrand disease; and how how Measuring Thrombin is Useful in a Lab Setting

Von Willebrand disease refers to inheritable disease induced by mutations or variations in the VWF gene which offers commands for the synthesis of von Willebrand factor, an important element in the formation of blood clot and prevention of too much blood loss during injury. People with Von Willebrand disease normally are characterized by nosebleeds, proneness to bruises, heavy menstrual breeding, bleeding into the spaces between joints, bleeding gums and prolonged oozing of blood during injuries. Without effective attention, women with this condition might have difficulties in carrying pregnancy to maturity, thus leading to miscarriages (Kalz, Ten Cate, and Spronk, 2014).

Traditionally, the generation of thrombin has been investigated through carrying out coagulation tests, prothrombin time, and activated partial thrompoplastin time (Golebiewska, and Poole, 2015). Contemporary studies however, have showcased that these tests are not vibrant in representing the state of balance occurring in vivo. Thrombin tests are important because they form a basis of investigating excessive breeding or anomalous blood clot formation. The test therefore helps in evaluating the level and role of fibrinogen, and also helps in the detection of heparin contamination.

Anti-coagulants are medicines which assist in the prevention of blood clots. Such medication is granted to individuals with Afibrinogenemia condition to lower their chances of incurring severe conditions such as heart attacks and strokes. Anticoagulants function by tampering with the process of blood clotting. The common prescribed anticoagulant is warfarin which makes the blood flow in the veins easy and therefore lessening the danger of blood clot. Warfarin is prescribed to people who have had previous blood clot such as pulmonary embolism, and deep vein thrombosis. This includes individuals with a mechanical heart valve, thrombophilia, and atrial fibrillation (Heemskerk, Mattheij, and Cosemans, 2013).

Modern (newer) alternatives are prescribed as capsules or tablets. There is equally heparin which is prescribed as an injection. New anticoagulant drugs such as factor Xa inhibitor, thrombin inhibitor, factor IX inhibitor, novel vitamin K antagonists and tissue factor inhibitor are deemed more effective relative to traditional drugs such as heparin sodium, sulodexide and warfarin. Such traditional drugs are characterized by various limitations such as they are unpredictable and therefore uncertain in guaranteeing full protection from blood clots. Laboratory test is therefore vital in making necessary adjustments to these drugs. Osteoporosis and thrombocytopenia which are induced by heparin have tangible risk of complications. Moreover, parenteral administration such as heparin is not suitable especially for parents discharged from hospital.

Modern anticoagulant medications are taken orally and are not influenced by drugs or food interactions. These drugs are equally safe and convenient as opposed to traditional medicines (Teresa et al., 2015).

Conclusion

In conclusion, blood coagulation is an important process which ensure vascular injuries do not lead to excessive oozing of blood which otherwise might cause anaemia and other severe injuries. As discussed above, thrombin serves an instrumental role in the process of blood coagulation, especially in the converting of fibrinogen to fibrin. Whereas the process of blood clotting has connection with genetic composition, the need for measuring thrombin in the lab becomes instrumental in understanding how thrombin functions, and therefore laying key foundation to medication as well to blood coagulation-related challenges such as thrombosis.

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References

Berliner, L.J. ed., 2012. Thrombin: structure and function. Springer Science & Business Media.

Clemetson, K.J., 2012. Platelets and primary haemostasis. Thrombosis research, 129(3), pp.220-224.

Danckwardt, S., Hentze, M.W. and Kulozik, A.E., 2013. Pathologies at the nexus of blood coagulation and inflammation: thrombin in hemostasis, cancer, and beyond. Journal of Molecular Medicine, 91(11), pp.1257-1271.

Golebiewska, E.M. and Poole, A.W., 2015. Platelet secretion: From haemostasis to wound healing and beyond. Blood reviews, 29(3), pp.153-162.

Heemskerk, J.W.M., Mattheij, N.J.A. and Cosemans, J.M.E.M., 2013. Platelet‐based coagulation: different populations, different functions. Journal of Thrombosis and Haemostasis, 11(1), pp.2-16.

Kalz, J., Ten Cate, H. and Spronk, H.M., 2014. Thrombin generation and atherosclerosis. Journal of thrombosis and thrombolysis, 37(1), pp.45-55.

Maragoudakis, M.E. and Tsopanoglou, N.E. eds., 2010. Thrombin: physiology and disease (Vol. 19). Springer Science & Business Media.

Ruiz‐Loredo, A.Y., López, E. and López‐Colomé, A.M., 2011. Thrombin promotes actin stress fiber formation in RPE through Rho/ROCK‐mediated MLC phosphorylation. Journal of cellular physiology, 226(2), pp.414-423.

Taslimi, R. and Golshani, K., 2011. Thrombotic and hemorrhagic presentation of congenital hypo/afibrinogenemia. The American journal of emergency medicine, 29(5), pp.573-e3.

Teresa, S.M., Marta, M., Emiliano, D.B., Mariangela, F., Raffaele, P. and Ezio, Z., 2015. Thrombosis of abdominal aorta in congenital afibrinogenemia: case report and review of literature. Haemophilia, 21(1), pp.88-94.