Blood acting coagulation lecture (original) (raw)
The hemostatic system comprises platelet aggregation, coagulation and fibrinolysis also termed primary, secondary and tertiary hemostasis. From the platelet transcriptome 6000 mRNA species and represent receptors, ion channels, signalling molecules, kinases, phosphatases, and structural, metabolic and regulatory proteins. This abundance of regulatory proteins points towards the importance of signal transduction in platelet function. First platelets adhere to collagen, this induces activation signals such as TXA 2 that induces further Ca 2+ increase. Consecutively, fibrinogen binds to the integrin α IIb β 3 resulting in aggregation.This self-amplifying process is controlled by signals, from endothelial cells, to restrict the platelet plug to the site of vessel injury.
Blood Coagulation and Fibrinolysis
Angewandte Chemie International Edition in English, 1971
As a result of advances in protein chemistry it is now widely accepted that blood coagulation proceeds via a series of reaction steps of the nature o f enzyme-substrate reactions catalyzed by phospholipids. This also applies to the compensatory process of fibrinolysis. The factors taking part in both mechanisms as well as the inhibitors regulating the equilibrium have been shown to be proteins, some of them with a high carbohydrate content. Modern diagnostic methods and therapy are based on this knowledge.
Management of bleeding disorders by prohemostatic therapy
International Journal of Hematology, 2002
Pro-hemostatic therapy aims at an improvement of hemostasis, which may be achieved by amelioration of primary hemostasis, stimulation of fibrin formation or inhibition of fibrinolysis. These treatment strategies may be applied to specifically correct a defect in one of the pathways of coagulation, but have in some situations also been shown to be effective in reducing bleeding in patients without a primary defect in coagulation. Besides the transfusion of platelets in case of thrombocytopenia or severe platelet disorders, a pharmacological improvement of primary hemostasis may be achieved by the administration of desmopressin. The administration of DDAVP results in a marked increase in the plasma concentration of Von Willebrand factor (and associated coagulation factor VIII) and (also by yet unexplained additional mechanisms) a remarkable potentiation of primary hemostasis as a consequence. DDAVP is used for the prevention and treatment of bleeding in patients with von Willebrand disease or mild hemophilia A, and further in patients with an impaired function of primary hemostasis, such as in patients with uremia, liver cirrhosis or in patients with aspirin-associated bleeding. Based on the current insight that activation of coagulation in vivo predominantly proceeds by the tissue factor/factor VII(a) pathway, recombinant factor VIIa has been developed as a prohemostatic agent and has recently become available for clinical use. Indeed, in uncontrolled clinical studies this compound has been shown to exert a potent procoagulant activity and appeared to be highly effective in the prevention and treatment of bleeding, although most experience so far has been obtained in patients with severe and complicated coagulation defects. At present, a more general use of this agent for bleeding patients without an apparent coagulation defect is the subject of a number of ongoing clinical trials. Agents that exert anti-fibrinolytic activity are aprotinin and the group of lysine analogues. The pro-hemostatic effect of these agents proceeds not only by the inhibition of fibrinolysis (thereby shifting the procoagulant/anticoagulant balance towards a more procoagulant state), but also due to a protective effect on platelets, as has been demonstrated at least for aprotinin. The mechanism of this platelet-protective effect has, besides a potential prevention of plasmin-mediated loss of platelet receptors not been elucidated. Whether the pro-hemostatic effect of the anti-fibrinolytic agents will eventually result in a higher incidence of thromboembolic complications is still a matter of debate (see further), however, this has so far not been shown in straightforward clinical trials.
Introduction to haemostasis from a pharmacodynamic perspective
British Journal of Clinical Pharmacology, 2011
Biochemical characterization of the haemostatic system has advanced significantly in the past decades. Sub-systems, such as coagulation, fibrinolysis, blood cells and platelets and the vessel wall have been studied by specialists, mostly separately and independently. The time has come to integrate the approaches, and, in particular, to develop tests to document the state of the whole system and to have available adequate pharmacodynamic tests to evaluate treatments. Many examples are available to show that traditional general methods of clotting and lysis do not provide the information that is desired. The present tendency is to use specific methods for specific factors or effects which are very limited in pharmacological information. There is also increasing awareness of the occurrence of rather broad interindividual variability in the haemostatic system. This suggests that individually tailored treatments are required. This is the more relevant since haemostasis is a balance and treatment should be positioned between efficacy and safety. The conclusion is reached that there is a need for integrated or global methods or sets of methods that reflect the complexity and individual status appropriately and allow the practitioner to judge the effects of interventions and their individual aspects.
The hemostatic system. 1st Part
2019
The hemostatic system is a complex ancestral pathway physiologically dedicated to protect the individual from bleeding. It starts immediately after an endothelial injury. Platelets and blood coagulation act synergically to provide a strength clot able to stop bleeding. In healthy subjects, the hemostatic system is able to work to avoid an excess of fibrin formation and deposition within the blood vessels on the one hand but is ready to stop bleeding on the other. To reach this crucial objective, a fine regulation of its activity is required. In other words, all actions of the hemostatic system are under control to assure a perfect balance to maintain people distant from both Scylla (bleeding) and Charybdis (thrombosis). Fibrinolysis is a complementary defensive system essential to regulate fibrin deposition via its dissolution. It is, in turn, well controlled to avoid bleeding and thrombosis by a fine control of its inducers and inhibitors. The aim of this review is to provide a pic...
Current Concepts of Hemostasis
Anesthesiology, 2004
The revised model of coagulation has implications for therapy of both hemorrhagic and thrombotic disorders. Of particular interest to anesthesiologists is the management of clotting abnormalities before, during, and after surgery. Most hereditary and acquired coagulation factor deficiencies can be managed by specific replacement therapy using clotting factor concentrates. Specific guidelines have also been developed for perioperative management of patients using anticoagulant agents that inhibit platelet or coagulation factor functions. Finally, recombinant factor VIIa has been used off-label as a hemostatic agent in some surgical situations associated with excessive bleeding that is not responsive to conventional therapy.
Inhibitors of propagation of coagulation: factors V and X
British Journal of Clinical Pharmacology, 2011
Cardiovascular diseases are still the most important cause of morbidity and mortality in western countries and antithrombotic treatment is nowadays widely used. Drugs able to reduce coagulation activation are the treatment of choice for a number of arterial and/or venous thromboembolic conditions. Some of the drugs currently used for this purpose, such as heparins (UFH or LMWH) and VKA, have limitations consisting of a narrow therapeutic window and an unpredictable response with the need of laboratory monitoring in order to assess their efficacy and safety. These drawbacks have stimulated an active research aimed to develop new drugs able to act on single factors involved in the coagulation network, with predictable response. Intense experimental and clinical work on new drugs has focused on synthetic agents, which could preferably be administered orally and at fixed doses. The most advanced clinical development with new anticoagulants has been achieved for those inhibiting FXa and some of them, like fondaparinux, are already currently used in clinical practice. Other agents, such as rivaroxaban, apixaban, otamixaban and edoxaban are under development and have already been studied or are currently under investigation in large scale phase III clinical trials for prevention and treatment of venous thromboembolism, atrial fibrillation and acute coronary syndromes. Some of them have proved to be more effective than conventional therapy. Data on some agents inhibiting FVa are still preliminary and some of these drugs have so far been considered only in patients with disseminated intravascular coagulation secondary to sepsis. Investigators. Antithrombotic therapy with fondaparinux in relation to interventional management strategy in patients with ST-and non-ST-segment elevation acute coronary syndromes: an individual patient-level combined analysis of the Fifth and Sixth Organization to Assess Strategies in Ischemic Syndromes (OASIS 5 and 6) randomized trials. Circulation 2008; 118: 2038-46. 23 Warkentin TE, Cook RJ, Marder VJ, Sheppard JA, Moore JC, Eriksson BI, Greinacher A, Kelton JG. Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin. Blood 2005; 106: 3791-6. 24 Warkentin TE. Fondaparinux: does it cause HIT? Can it treat HIT? Expert Rev Hematol 2010; 3: 567-81. V. Toschi & M. Lettino 576 / 72:4 / Br J Clin Pharmacol 25 Harenberg J, Wehling M. Current and future prospects for anticoagulant therapy: inhibitors of factor Xa and factor IIa. Semin Thromb Haemost 2008; 34: 39-57. 26 Harenberg J, Vukoievic Y, Milkus G, Joerg I, Weiss C. Long elimination half-life of idraparinux may explain major bleeding and recurrent events of patients from the van Gogh trials. J Thromb Haemost 2008; 6: 890-2. 27 Savi P, Herault JP, Duchaussoy P, Millet L, Schaeffer P, Petitou M, Bono F, Herbert JM. Reversible biotinylated oligosaccharides: a new approach for a better management of anticoagulant therapy.
Haemostasis is a complex and sophisticated process that requires the interplay of multiple physiological pathways. Cellular and molecular mechanisms interact to seal damaged blood vessels with localized clot formation preventing significant bleeding. Once vascular integrity is restored, clot breakdown occurs and normal haemostasis is reinstated. Thrombohaemorrhagic imbalance may occur in the periopera-tive period or during critical illness, leading to an increased risk of thrombosis, bleeding or in some instances both. Therefore an understanding of the normal physiological processes is important for the anaesthetist as: (i) it allows us to identify targets for the therapeutic modulation of bleeding and thrombosis; (ii) many commonly encountered medications alter the normal haemostatic pathways and it is important to recognize their effects; and (iii) it enables enhanced understanding of the dynamic tests of haemostasis and clotting.
Prevention and treatment of bleeding by pro-hemostatic treatment strategies
Wiener medizinische Wochenschrift (1946), 2003
Pro-hemostatic therapy may achieve an improvement of hemostasis, by amelioration of primary hemostasis, stimulation of fibrin formation or inhibition of fibrinolysis. Pro-hemostatic interventions appear to be effective in reducing peri-operative blood loss and reducing transfusion requirements in specific situations and may be helpful adjuncts in the management of severe spontaneous and post-operative bleeding. The risk of a higher incidence of thrombotic complications associated with the use of pro-hemostatic therapy is unknown but seems not to be very high in clinical practice. There is a need for more systematic and adequately controlled clinical observations to better establish the efficacy and safety of pro-hemostatic interventions.
Baillière's Clinical Haematology, 1994
The fibrinolytic system, in common with the coagulation, kinin and complement pathways, operates by a cascade of reactions, each catalysed by a serine protease. The generation of protease activity requires the activation of a single-chain form (zymogen) to produce an active two-chain form. The central reaction of the fibrinolytic cascade is the activation of plasminogen to form plasmin, a reaction carried out by the plasminogen activators, tissue plasminogen activator (tPA) and urokinase (uPA). A second common feature of the serine protease cascades is their regulation by inhibitors of the serpin (serine protease inhibitor) superfamily. These inhibitors act as pseudosubstrates, containing a reactive centre that mimics the protease's natural substrate and is important in defining its target proteases. The inhibitors of fibrinolysis all have an arginine residue in their reactive centre, consistent with their target proteases' specificity for Arg-X bonds. The principal plasminogen activator inhibitors are PAI-1 and PAI-2, while plasmin is inhibited mainly by a2-antiplasmin (reviewed by . A third regulatory feature, specific to fibrinolysis, is the effect of fibrin, which is not only the substrate for the system but also participates actively in its regulation.
Diathesis Hemorrhagic, Coagulation and Fibrinolytic System
Biomolecular and Health Science Journal
Bleeding is one of the most common complaints when coming to the hospital which can be mild to life-threatening. The balance of the impaired hemostasis system allows for abnormal bleeding such as hemorrhagic diathesis. Balance between blood clotting and bleeding is always maintained in the body under normal physiology. The coagulation system stops existing bleeding with vasoconstricts of blood vessels and the formation of early platelet plugs, this blockage is strengthened by the presence of a cascade of coagulations to form stable and sturdy blockages. Once bleeding has stopped, the fibrinolytic pathway is initiated to dissolve the blood clot to restore normal blood flow. balance the coagulants, fibrinolytic and inhibitor systems, creating a perfect physiological balance. Hemostatic imbalance is a global problem that can lead to thrombosis or hemorrhage.