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W2078337807 abstract "Br J Anaesth 2002; 88: 848–63 Br J Anaesth 2002; 88: 848–63 This review concentrates on discussing the various therapeutic agents available to prevent or inhibit clot formation. Particular emphasis is placed on therapies associated with modification to coagulation factors, and the inhibitors of thrombin formation and action. The genesis of ischaemic cardiovascular disease is related to inappropriate platelet function and/or thrombin generation in excess amounts or at inappropriate sites. The most commonly used agents currently available to inhibit or slow thrombin production include vitamin K antagonists and heparin, acting through circulating or endothelial‐derived intermediaries. More recently, a number of agents, which can act to directly inhibit thrombin, have been licensed for use in humans. It is expected that the range of these compounds will eventually grow to replace the use of unfractionated heparin (UFH) and vitamin K antagonists within the next few years. To better understand the mechanism of action of all of these compounds, a brief description of the mechanism of clot formation and the pivotal role of thrombin in this process is required together with the mechanisms for localizing and controlling this activity. The aim of the coagulation phase of haemostasis is the generation of fibrin strands that will bind and stabilize the weak platelet haemostatic plug. There are no covalent bonds holding the platelets together during the formation of the primary haemostatic plug. If left in this state the platelet plug, formed by platelet aggregation, would come apart in a few hours, resulting in late bleeding. The process of blood coagulation, with soluble factors in the blood entering into a chain of reactions that lead to the formation of fibrin, is intended to be localized to the area where the original platelet plug was formed. This localization is achieved by two methods. First, the chain of reactions which led to the conversion of fibrinogen to fibrin are programmed to occur, and are most efficient and explosive, when restricted to a surface, such as platelet phospholipid. Second, there are a series of inhibitors that are intended to constrain the reaction to the site of injury and platelet deposition. These inhibition processes include the following. 1. Circulating factors such as antithrombin III (ATIII) and heparin cofactor II (HCII). 2. Those derived from endothelium such as tissue factor pathway inhibitor (TFPI). 3. The thrombomodulin system, which converts prothrombotic thrombin to an anticoagulant through the activation of circulating protein C. Historically, the blood coagulation system is divided into two initiating pathways: the tissue factor (extrinsic) pathway and the contact factor (intrinsic) pathway which meet at a final, common pathway, whereby factor Xa converts prothrombin to thrombin which then acts on fibrinogen. These pathways were identified and categorized during experiments to examine the effects of sufficiency and deficiency of the various circulating factors on assays of plasma coagulation. At present the immediate clinical investigation of haemostatic disorders still requires this compartmentalized, cascade‐type model as the laboratory‐based tests of coagulation focus on each of these separate aspects. The prothrombin time (PT) is a plasma and test‐tube variant of the extrinsic pathway, and the activated clotting time (ACT) or activated partial thromboplastin time (aPTT) of the intrinsic system for blood and plasma, respectively. This model based on the concept of a waterfall or cascade is an over simplification of the system, as proteins from each pathway can influence one another. It is probably more correct to think of the coagulation system as an interactive network with carefully placed amplifiers and restraints. Fibrin formation is a process of initiation and amplification. The specific properties of platelets and the coagulation system cooperate to ensure that fibrin formation occurs only at the localized site where it is required to initiate wound repair. This is achieved by a number of physico‐chemical means. The surface of resting platelets contains acidic phospholipids such as phosphatidylserine that have their negatively charged pole directed inward. Spontaneous reversal of this charge is countered by a specific enzyme system in the platelet (a flipase), implying that this charge reversal is of pivotal importance. When the platelet becomes activated, the negatively charged phospholipid remains on the outside surface of the platelet membrane and is not flipped internally. The coagulation system relies primarily on a group of soluble factors that circulate in the plasma. These factors are synthesized in the liver and expressed into the circulation (Table 1). Most coagulation factors are identified by Roman numerals, the active form denoted by the lower case ‘a’. They circulate in an inactive, zymogen form and become active after proteolytic cleavage. The exception to this is factor VII that can circulate as an active protease. Apart from factor XIII, which is a transglutaminase, all the active factors are serine protease related to the digestive enzyme, trypsin. Other factors in the coagulation process, such as tissue factor, factor V, factor VIII, and high molecular weight kininogen (HK) act as co‐factors.Table 1Coagulation factorsStandard nomenclatureTraditional nameMolecular weightPlasma concentrationHalf‐life(Da)(µg ml–1)(h)Factor IFibrinogen340 0002000–400090Factor IIProthrombin72 00012065Factor IIITissue factor45 0000–Factor IVCalcium40100–Factor VProaccelerin330 0001015Factor VIIProconvertin48 00015Factor VIIIAntihaemophilic factor360 0000.0510Factor IXChristmas factor57 500425Factor XStuart‐Prower factor55 0001240Factor XIPlasma thromboplastin antecedent160 000645Factor XIIHageman factor85 0004050Factor XIIIFibrin stabilizing factor320 00020200 Open table in a new tab Factors VII, IX, X, and prothrombin depend on the presence of vitamin K for their conversion to a protein which can optimally participate in the generation of thrombin. These vitamin K‐dependent coagulation factors possess groups of negatively charged glutamic acids at their N‐terminal regions. Vitamin K acts as a co‐factor for an enzyme that adds carboxylic acid to the glutamic acid, forming gamma‐carboxy glutamic acid, with a resultant higher density of negative charges localized to the N‐terminus. Most of the vitamin K‐dependent factors have between nine and 12 of these gamma‐carboxy glutamic acid groups available for reaction. This charged area of the polypeptide is the part of the molecule that binds or attaches to the organizing surface of the platelet (Fig. 1). It is obvious that the highly negatively charged surface of the activated platelet, produced by the expression of acid phospholipids, and a protein that is also negatively charged, will not come together. The role of calcium ions, with their positive charge, is to act as a buffer or sandwich between these areas of charge. In addition, calcium can induce a conformational change in the coagulation protein to enhance or enable binding to the surface of the activated platelet. This process has been likened to landing on the deck of an aircraft carrier. The conformational change produced by calcium will cause the vitamin K‐dependent protein to drop its ‘tailhook’, which can then catch the ‘wire’ on the activated platelet surface. By this process, the coagulation proteins arrest and stop at the site of the injury. A recurrent theme in the coagulation system is the formation of activation complexes involving a serine protease, a zymogen or substrate, a co‐factor, and an organizing surface, usually provided by the platelet membrane. These factors must be presented to each other in a tightly controlled way to ensure the process of coagulation is amplified and progressed with sufficient rapidity. This elegant organization can be appreciated by considering the formation of thrombin from prothrombin, which is the best characterized of such reactions. It is axiomatic that production of thrombin needs to be explosive at the site of the injury in order to prevent it being washed away to cause havoc elsewhere in the vascular tree. The major problem to overcome in this process is to enable factor Xa to remove the restraint or protective bubble over the active site on prothrombin at a sufficient rate. Acceleration of the process is achieved by maximizing the encounter of active site and substrate by appropriate orientation of each molecule (Fig. 2a). Factor V overcomes this problem by engaging itself into the organizing surface and then holding the two factors by a ‘handle’ to align the proteins in the required configuration (Fig. 2a). This surface‐bound enzymatically active system is called the ‘prothrombinase complex’. An identical series of reactions occurs to produce factor Xa. In this case, the non‐vitamin K‐dependent co‐factor VIII reaches up from its binding site on a platelet surface and grabs both factor IXa (the serine protease) and factor X (the zymogen), aligning them correctly for maximum interaction and generating factor Xa. The factor IXa, VIII, and X complex is referred to as the ‘tenase’ and factor Xa, V, and II as the ‘prothrombinase’ complex (Fig. 3). Factor V is synthesized in the liver and has a half‐life of about 5–6 h in stored blood and about 15 h in circulating plasma. In addition to the 10 µg ml–1 circulating in plasma, a significant reserve of factor V is contained in platelets. This platelet factor V adds a further 25% to the circulating pool and is released to the cell surface when the platelet is stimulated by a variety of agonists. Factor VIII is a large unstable molecule that circulates in complex with von Willebrand Factor (vWF). Plasma half‐life without the vWF is 2.5 h compared with about 10–12 h with this co‐factor. The pivotal importance of these co‐factors (V and VIII) becomes obvious when the kinetics of the reactions were considered. If we assume first that the rate constant for the conversion of prothrombin to thrombin by factor Xa in an aqueous solution is unity, then addition of calcium ions to this mixture will make the reaction rate 2.3 times faster. Activation of prothrombin by factor Xa is 22 times more likely to occur with both factor Xa and prothrombin combining on the negatively charged surface of platelet phospholipid than if the enzyme and substrate were just floating in solution. The addition of factor V to this mixture, by holding factor Xa and prothrombin in place and aligning them correctly, so they have no choice but to have a productive interaction, accelerates the reaction by 278 000‐fold. If similar kinetics are assumed for the activation of factor Xa, then simple mathematics show a colossal 7.7 million‐fold acceleration of thrombin generation in a fully active system. Put another way, a fluid phase two‐step coagulation process for the generation of thrombin, involving first the activation of factor X to Xa followed by the activation of prothrombin to thrombin would require about 3 months (89 days). This same reaction would take only 1 s in the unrestricted fully intact system. If the process works properly then explosive thrombin formation should occur only where it is directed and required. Factor Xa can also be generated by a different, surface‐dependent, pathway. The so‐called tissue factor or extrinsic pathway is considered to be the principal initiating pathway of coagulation in vivo. In this reaction, factor X is cleaved by the serine protease, factor VII. Factor VII is held in the appropriate configuration by endothelial surface‐bound tissue factor (Fig. 4). Tissue factor (TF) is a glycoprotein consisting of an extracellular, transmembrane, and cytoplasmic domain that is not observed free in the circulation. This factor is normally only expressed at sites physically separated from circulating blood such as the subendothelium of blood vessels, organ capsules, cells of epithelial surfaces, and the nervous system. Animal brain tissues are the usual source of tissue thromboplastin used for stimulation of coagulation in the PT test. The fact that TF requires phospholipid for full activity and that it has a large transmembrane domain help to retain the TF:factor VIIa:factor X activating complex at the cell surface, ensuring that coagulation is localized to the site of injury. The factor Xa formed remains bound in the surface phospholipid and forms the prothrombinase complex with factor V and prothrombin. Circulating factor VII is an unusual coagulation protein for two reasons: (1) the non‐activated (zymogen) form has some proteolytic activity and (2) about 1% of the circulating form exists as the active enzyme, factor VIIa. Either form can bind readily to TF and the complex thus formed will have enough activity to cleave factor X to factor Xa. Factor Xa will then rapidly convert the factor VII:TF complex to factor VIIa:TF and can thus potentiate the reaction. In addition to activating factor X, the factor VIIa:TF complex can also cleave factor IX to form factor IXa, which can then itself activate factor X as described above. This illustrates the lack of division of the contact and TF pathways in vivo. Peripheral blood cells do not normally express TF. However, circulating monocytes and endothelial cells can be induced to produce TF by a variety of stimuli including endotoxin, tumour necrosis factor, interleukin 1, immune complexes, hypoxia, and hypothermia. This stimulation and expression of TF by phlogistic agents is thought to play a part in the consumptive coagulopathy associated with sepsis. Thrombin is a serine protease that has become the focus of considerable research interest. This interest is driven by observations of the ubiquitous actions of thrombin and also by advances in our understanding of the molecular mechanisms involved in the structure and activity of this protease. In turn, this has lead to the development of agents that have either a direct effect on the cleavage site of the molecule or can in some other way inhibit the ability of thrombin to catalyse the conversion of fibrinogen to fibrin. The thrombin molecule can be simplistically viewed as a sphere with a Γ shaped groove along its equatorial axis (Fig. 5). The horizontal part of the groove extends around the molecule. The left‐hand part of the horizontal section is included with the vertical area to make up the active proteolytic site. The extended horizontal groove, distal to the active site, is one of a number of anion binding exosites on the surface of the thrombin molecule. This specific exosite of thrombin is important as it is involved with thrombin inhibition/binding by the heparin: ATIII complex and also the carboxyl tail of hirudin (see below). Thrombin cleaves fibrinogen by the removal of two small polypeptides (termed fibrinopeptide A and B, respectively) to expose a site in the centre of the molecule. This is able to tether to the bulbous ends of other fibrinogen, or fibrin, molecules made from the β and γ chains. The longer α chain of the fibrin molecule projects from the bulbous end and acts to wrap the polymer and protect the binding sites. The fibrinogen molecule has a number of fascinating aspects to its chemistry and evolution. In particular, with reference to this review, is that about 40% of thrombin is incorporated into fibrin during its formation from fibrinogen. This thrombin is thus protected from natural inhibitors.25Francis CW Markham Jr, RE Barlow GH et al.Thrombin activity of fibrin thrombi and soluble plasmic derivatives.J Lab Clin Med. 1983; 102: 220-230PubMed Google Scholar 49Liu CY Nossel HL Kaplan KL. The binding of thrombin by fibrin.J Biol Chem. 1979; 254: 10421-10425Abstract Full Text PDF PubMed Google Scholar The process of thrombin generation must be localized and contained to prevent global thrombosis after minor injury. It is a basic tenet in biochemistry that every activator will have a cognate inhibitor and this is true for the coagulation system. The natural inhibitors fall into two main groups, endothelial or hepatic, based on their synthetic site. An alternate classification could be to separate the inhibitors into those that aim to inhibit thrombin production and those that directly inhibit this enzyme. Endothelial‐derived factors include TFPI and activated protein C (aPC). This latter protease has been investigated as a means of preventing thrombus formation or extension. The fascination with aPC and its generation are 2‐fold. First, thrombin is responsible for the generation of aPC. Thrombin is held on the endothelial surface by a co‐factor/receptor called thrombomodulin. The active site of the thrombin cleaves the protein C moiety to release aPC (Fig. 6). This clever device allows thrombin to be converted from a procoagulant to an anticoagulant protein. aPC is a serine protease that cleaves a peptide from the arms of factor V and factor VIII, thereby preventing appropriate participation in the tenase and prothrombinase complex (Fig. 7). Resistance to this cleavage is observed in patients who have a single point mutation in their factor V (so‐called factor V Leiden). Similar to a genetic absence of protein C, this is not a lethal gene. However, patients with the Leiden mutation are at substantially increased risk of venous thrombosis,4Bertina RM Koeleman BP Koster T et al.Mutation in blood coagulation factor V associated with resistance to activated protein C.Nature. 1994; 369: 64-75Crossref PubMed Scopus (3811) Google Scholar and myocardial infarction in certain populations.66Rosendaal FR Siscovick DS Schwartz SM et al.Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women.Blood. 1997; 89: 2817-2821Crossref PubMed Google Scholar The second interest in the relationship between thrombin and protein C lies in the evolution of these proteins. Genomic mapping suggests that these proteins developed and evolved together. We also increasingly recognize a functional relationship between these proteins. One example is that cleavage by thrombin, to release the tethered ligand of the thrombin receptor, occurs at a site with structural and amino acid sequence homology with protein C.Fig 7Sites of inhibition of thrombin generation by antithrombin III, shown as an open cross‐shaped box. Weight of line represents inhibitor capacity, with inhibition of thrombin strongest and that of factor IXa relatively weak. Activated protein C is shown overlapping factor V and VIII as the hexagonal symbol, and tissue factor pathway inhibitor by a moiety with three domains filled by horizontal lines. This moiety prevents proper interaction between VIIa and X. It is easy to appreciate that a natural inhibitor controls each phase of the process of thrombin generation. It is also apparent why this balance can be disturbed by relative lack of any of the inhibitors. Examples include reduction of protein C concentration with warfarin therapy and of AT III by consumption following prolonged heparin administration.View Large Image Figure ViewerDownload (PPT) TFPI is a relatively new addition to the ranks of the inhibitors of coagulation.65Rapaport SI. Regulation of the tissue factor pathway.Ann N Y Acad Sci. 1991; 614: 51-62Crossref PubMed Scopus (17) Google Scholar Human TFPI is a protease inhibitor that consists of three Kunitz‐type serine protease inhibitor like domains (K1, K2, and K3) flanked by a negatively charged N‐terminus and a positively charged C‐terminal tail. TFPI is synthesized and released from the endothelium and appears to be the main inhibitor of the TF pathway in vivo. The majority of TFPI (85%) is bound to the endothelium and can be rapidly released on stimulation. The remaining 15% is associated with plasma lipoproteins accounting for its early title of lipoprotein‐associated coagulation inhibitor. Thrombin production is inhibited and slowed as follows. The second domain (K2) of TFPI binds (reversibly) to the active site of factor Xa inhibiting this protease (Fig. 7). The K1 domain then interacts with the TF:factor VIIa catalytic complex forming an inactive complex.28Hamamoto T Yamamoto M Nordfang O et al.Inhibitory properties of full‐length and truncated recombinant tissue factor pathway inhibitor (TFPI). Evidence that the third Kunitz‐type domain of TFPI is not essential for the inhibition of factor VIIa‐tissue factor complexes on cell surfaces.J Biol Chem. 1993; 268: 8704-8710Abstract Full Text PDF PubMed Google Scholar Individuals with congenital TFPI deficiency have not been identified. Mice homozygous for deletion of K1 in the TFPI gene die in utero implying that such a deficiency is not compatible with life. Of interest is that the inhibitor site of the K1 domain differs by only 1 amino acid residue from the inhibitor Kunitz domain of aprotinin. These circulating factors include a number of serine protease inhibitors or serpins. This superfamily of proteins plays a major role in the regulation of coagulation, fibrinolysis, and inflammation. The serpins function as suicidal inhibitors, presenting their reactive centre as a pseudo‐substrate for their target. Although hydrolysis is attempted by the protease it cannot be completed and a tight 1:1 complex is formed which is rapidly cleared from the circulation. For example, the half‐life of the thrombin– ATIII (TAT) complex is about 5 min. The two plasma inhibitors found most commonly are ATIII, which accounts for about 60% of plasma anticoagulant activity, and HCII which accounts for a further 30% of the total activity. ATIII is synthesized in the liver and is not vitamin K‐dependent. This inhibitor irreversibly neutralizes factors Xlla, Xla, IXa, Xa, and thrombin (Fig. 7). In vivo, glycosaminoglycans such as heparan sulphate on the endothelial cell surface are the initiators of the enhanced ATIII inhibitory function.53Marcum JA Rosenberg RD. Anticoagulantly active heparin‐like molecules from vascular tissue.Biochemistry. 1984; 23: 1730-1737Crossref PubMed Scopus (172) Google Scholar Heparan is a varying chain length mucopolysaccharide or glycosaminoglycan that is tethered to the surface of the endothelium by a protein skeleton. Contact with this surface will induce a conformational change in ATIII. This combination produces the physiological effect of a vascular surface with profound anticoagulant properties. ATIII has a biological half‐life of 3–5 days and is produced at a relatively constant rate.14Collen D Schetz J de Cock F Holmer E Verstraete M. Metabolism of antithrombin III (heparin cofactor) in man: effects of venous thrombosis and of heparin administration.Eur J Clin Invest. 1977; 7: 27-35Crossref PubMed Scopus (140) Google Scholar It is not an acute phase respondent and so production does not change rapidly in response to stress. Deficiency of ATIII can be congenital or acquired. The normal range for ATIII is based on a comparison with pooled plasma and is quoted as 85–120%. The congenital forms can be divided into those associated with an absence or reduction of ATIII in the plasma and those associated with an amino acid sequence that bestows inappropriate inhibitory activity to the molecule. Both these defects are associated with an increased risk of thromboembolic disease. Acquired ATIII deficiency is seen in a number of states including certain chemotherapeutic regimens (l‐asparaginase treatment), hepatic failure, nephrotic syndrome, severe pre‐eclampsia, shock, disseminated intravascular coagulation (DIC), and after certain surgeries such as those involving extracorporeal circulation. ATIII deficiency is also seen in chronic heparin administration, to produce ‘heparin resistance’. Pregnancy represents an interesting example and model of reduced ATIII activity that is relevant to other clinical arenas. Fibrinogen concentration and platelet count increase during pregnancy,57Nilsson IM Kullander S. Coagulation and fibrinolytic studies during pregnancy.Acta Obstet Gynecol Scand. 1967; 46: 273-285Crossref PubMed Scopus (78) Google Scholar and in pre‐eclampsia there are diminished levels of ATIII. This fall in ATIII levels reflects a consumptive process as the plasma TAT complexes increase as ATIII levels drop.44Kobayashi T Tokunaga N Sugimura M et al.Coagulation/fibrinolysis disorder in patients with severe preeclampsia.Semin Thromb Hemost. 1999; 25: 451-454Crossref PubMed Scopus (43) Google Scholar The level of ATIII that may be cause for concern has not been accurately defined. However, patients who have undergone shock and demonstrate levels of ATIII below 50–60% of normal activity have an increased morbidity and mortality.7Blauhut B Kramar H Vinazzer H Bergmann H. Substitution of antithrombin III in shock and DIC: a randomized study.Thromb Res. 1985; 39: 81-89Abstract Full Text PDF PubMed Scopus (166) Google Scholar 24Fourrier F Chopin C Huart JJ et al.Double‐blind, placebo‐controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation.Chest. 1993; 104: 882-888Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar 54Massignon D Lepape A Bienvenu J et al.Coagulation/fibrinolysis balance in septic shock related to cytokines and clinical state.Haemostasis. 1994; 24: 36-48PubMed Google Scholar 85Wilson RF Mammen EF Robson MC et al.Antithrombin, prekallikrein, and fibronectin levels in surgical patients.Arch Surg. 1986; 121: 635-640Crossref PubMed Scopus (43) Google Scholar Patients with levels below 20% have near 100% mortality. Replacement or enhancement of ATIII concentrations has been suggested in a number of these conditions. Concentrates from human sources have been available for some time and have shown some benefits in patients with sepsis syndrome. A recombinant form of ATIII has entered clinical trials as a method of reducing ‘heparin resistance’ in patients before heart surgery. HCII is the second plasma thrombin inhibitor. The endothelial glycosaminoglycan, dermatan sulphate has a specific binding site for HCII.52Maimone MM Tollefsen DM. Structure of a dermatan sulfate hexasaccharide that binds to heparin cofactor II with high affinity.J Biol Chem. 1990; 265: 18263-18271Abstract Full Text PDF PubMed Google Scholar This binding site is a hexasaccharide without structural similarity with the pentasaccharide of heparan or heparin. Included in this category are recombinant agents equivalent to some naturally occurring proteins and totally synthetic agents. A most important point to note is that at times these drug therapies will produce prothrombotic or hypercoagulable states. Warfarin therapy is associated with cutaneous thrombosis.71Schramm W Spannagl M Bauer KA et al.Treatment of coumarin‐induced skin necrosis with a monoclonal antibody purified protein C concentrate.Arch Dermatol. 1993; 129: 753-756Crossref PubMed Scopus (66) Google Scholar 73Soundararajan R Leehey DJ Yu AW Ing TS Miller JB. Skin necrosis and protein C deficiency associated with vitamin K depletion in a patient with renal failure.Am J Med. 1992; 93: 467-470Abstract Full Text PDF PubMed Scopus (21) Google Scholar This latter effect is a result of the action of warfarin to reduce effective protein C concentration (a vitamin K‐dependent factor) and induce a prothrombotic protein C deficiency.30Hirsh J. Oral anticoagulant drugs.N Engl J Med. 1991; 324: 1865-1875Crossref PubMed Scopus (524) Google Scholar Moreover, studies in patients given warfarin immediately after myocardial revascularization show a short period of a hypercoagulable state, due directly to the administration of warfarin.38Iguchi A Sato K. Protein C response to induction of warfarin treatment after coronary bypass operation.Thorac Cardiovasc Surg. 1994; 42: 222-224Crossref PubMed Scopus (6) Google Scholar Heparin will induce a thrombotic state by direct or immune‐mediated platelet activation as described later. The first group of antithrombin drugs discussed are not direct inhibitors of thrombin but aim to slow thrombin generation and presentation. Reduction in clotting factor activity is produced when patients are given vitamin K antagonists. The first oral anticoagulant used was dicoumarol that was isolated from spoilt clover. This agent had a poor absorption and non‐linear kinetics and is no longer used. The three widely used drugs are warfarin, phenprocouman, and acenocouman. Warfarin is the best known of this class of agent and is used prophylactically in atrial fibrillation, venous thrombosis, pulmonary embolism, and in patients with prosthetic heart valves. The effect of warfarin is monitored by the PT or the International Normalized Ratio (INR). The INR was developed by the World Health Organization in the early 1980s to eliminate problems in oral anticoagulant therapy caused by variability in the sensitivity of different commercial sources and different batches of thromboplastin. The INR is derived by raising the observed ratio of PT in control and patient plasma to the power of an International Sensitivity Index (ISI). The ISI is a measure of the response to a thromboplastin preparation and is typically between 2 and 2.6 for most commercial rabbit‐brain thromboplastins.30Hirsh J. Oral anticoagulant drugs.N Engl J Med. 1991; 324: 1865-1875Crossref PubMed Scopus (524) Google Scholar The INR has for no obvious reason been only slowly adopted within North America compared with the rest of the international community. The PT ratio, which has been adopted by centres in North America, is not directly interchangeable with INR. This adds some confusion when discussing results from studies of the effects of an anticoagulant regimen on outcome. An INR of 2.5 is adequate for treating venous thrombosis, pulmonary thromboembolism and for a" @default.
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W2078337807 title "Thrombin generation and its inhibition: a review of the scientific basis and mechanism of action of anticoagulant therapies" @default.
W2078337807 cites W1527719951 @default.
W2078337807 cites W1536230526 @default.
W2078337807 cites W1560970554 @default.
W2078337807 cites W1563465184 @default.
W2078337807 cites W1581586115 @default.
W2078337807 cites W1595121326 @default.
W2078337807 cites W1786317249 @default.
W2078337807 cites W188744978 @default.
W2078337807 cites W1964168896 @default.
W2078337807 cites W1964718193 @default.
W2078337807 cites W1965958910 @default.
W2078337807 cites W1969930542 @default.
W2078337807 cites W1971553369 @default.
W2078337807 cites W1972999624 @default.
W2078337807 cites W1973192017 @default.
W2078337807 cites W1980660976 @default.
W2078337807 cites W1982771854 @default.
W2078337807 cites W1988776154 @default.
W2078337807 cites W199040808 @default.
W2078337807 cites W2000339248 @default.
W2078337807 cites W2001888044 @default.
W2078337807 cites W2002611635 @default.
W2078337807 cites W2004964926 @default.
W2078337807 cites W2005718289 @default.
W2078337807 cites W2009199306 @default.
W2078337807 cites W2010671553 @default.
W2078337807 cites W2016822743 @default.
W2078337807 cites W2024482902 @default.
W2078337807 cites W2026266457 @default.
W2078337807 cites W2029970434 @default.
W2078337807 cites W2033704853 @default.
W2078337807 cites W2034931168 @default.
W2078337807 cites W2035002089 @default.
W2078337807 cites W2035916179 @default.
W2078337807 cites W2036385266 @default.
W2078337807 cites W2045865674 @default.
W2078337807 cites W2046958433 @default.
W2078337807 cites W2051551497 @default.
W2078337807 cites W2053557642 @default.
W2078337807 cites W2057899470 @default.
W2078337807 cites W2059905474 @default.
W2078337807 cites W2065724919 @default.
W2078337807 cites W2066490209 @default.
W2078337807 cites W2075196907 @default.
W2078337807 cites W2077771517 @default.
W2078337807 cites W2080902048 @default.
W2078337807 cites W2081380404 @default.
W2078337807 cites W2081689955 @default.
W2078337807 cites W2082188869 @default.
W2078337807 cites W2099599536 @default.
W2078337807 cites W2103442479 @default.
W2078337807 cites W2112799238 @default.
W2078337807 cites W2118531224 @default.
W2078337807 cites W2125047098 @default.
W2078337807 cites W2135525689 @default.
W2078337807 cites W2138444098 @default.
W2078337807 cites W2138849164 @default.
W2078337807 cites W2149096804 @default.
W2078337807 cites W2164729929 @default.
W2078337807 cites W2171004180 @default.
W2078337807 cites W2335822722 @default.
W2078337807 cites W2406868216 @default.
W2078337807 cites W2408432433 @default.
W2078337807 cites W2412034839 @default.
W2078337807 cites W2412399708 @default.
W2078337807 cites W2470401733 @default.
W2078337807 cites W268361966 @default.
W2078337807 cites W3125065962 @default.
W2078337807 cites W4205312708 @default.
W2078337807 cites W4210960533 @default.
W2078337807 cites W4233413596 @default.
W2078337807 cites W4236398792 @default.
W2078337807 cites W4248750125 @default.
W2078337807 cites W4290382983 @default.
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