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And Factor Xa-Inhibitors for Prevention and Treatment of Thromboses Faktor II- Und Faktor Xa-Inhibitoren in Der Pra¨ Vention Und Therapie Von Thrombosen

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And Factor Xa-Inhibitors for Prevention and Treatment of Thromboses Faktor II- Und Faktor Xa-Inhibitoren in Der Pra¨ Vention Und Therapie Von Thrombosen Article in press - uncorrected proof J Lab Med 2009;33(2):121–127 ᮊ 2009 by Walter de Gruyter • Berlin • New York. DOI 10.1515/JLM.2009.023 2009/23 Ha¨ mostaseologie Redaktion: C. Schambeck Factor II- and factor Xa-inhibitors for prevention and treatment of thromboses Faktor II- und Faktor Xa-Inhibitoren in der Pra¨ vention und Therapie von Thrombosen Matthias Orth* tiven Thromboseprophylaxe sowie die Mo¨ glichkeiten eines Dosismonitorings vorgestellt. Vinzenz von Paul Kliniken gGmbH, Institut fu¨r Laboratoriumsmedizin, Stuttgart, Germany Schlu¨ sselwo¨ rter: Anti Xa-Inhibitoren; aPTT; direkte Thrombininhibitoren; Ecarin chromogener Assay; Thera- Abstract piekontrolle; Prothrombinase-induced Clotting Time (PiCT). The desired properties of an ideal anticoagulant should be reliable action, a defined, selective mode of action, a wide therapeutic window, and predictable pharmaco- Introduction kinetics. Numerous new substances were developed as a substitute for oral anticoagulants and heparins. Owing Major surgery, such as total hip replacement and total to their superiority in clinical studies, some of these drugs knee replacement, is associated with a very high risk of have already been approved. The hemostaseological developing deep vein thrombosis (DVT) and pulmonary laboratory is now challenged to detect a sufficient anti- embolism. Certain medical conditions, such as chronic coagulation while avoiding bleeding by overdosing. The atrial fibrillation (AF), are associated with embolic stroke. purpose of this review is to describe novel anticoagulants Therefore, prophylactic anticoagulation is the standard of in current use and the possible tests for drug monitoring care in these patients and is supported by Grade 1A in heparin-induced thrombocytopenia and in the peri- evidence recommendations w1x. Thromboprophylaxis has operative prevention of thromboses. been obtained either by the injection of heparin or other pentasaccharides or by the oral administration of vitamin Keywords: anti-Xa inhibitors; aPTT; direct thrombin K antagonists, in particular phenprocoumon. Heparin, a inhibitors; ecarin chromogenic assay; monitoring; polydisperse mixture of glycosaminoglycan chains, is prothrombinase-induced clotting time. used without fractionation (‘‘unfractionated heparin’’, UFH) or after chemical degradation and fractionation Zusammenfassung (‘‘low molecular weight heparin’’, LMWH). In most cases, Ziel eines idealen Antikoagulanz ist eine zuverla¨ ssige sufficient anticoagulation can be achieved by once a day Wirkung, ein definierter selektiver Wirkungsmechanis- administration of oral anticoagulants or of LMWH. UFH, mus, eine große therapeutische Breite und eine vorher- an alternative to LMWH, is used less frequently owing to sagbare Pharmakokinetik. Als Ersatz fu¨ r die oralen the much higher risk of developing heparin-induced Antikoagulantien und Heparine wurden verschiedene thrombocytopenia, a potentially life threatening situation w x neue Substanzen entwickelt, und aufgrund ihrer U¨ berle- 2 , and because of multiple injections needed daily. The genheit in klinischen Studien teilweise bereits zugelas- advantage of UFH is the rapid onset of action. The readily sen. Das ha¨ mostaseologische Labor ist nun gefordert, available drug monitoring, and the availability of an eine ausreichende Antikoagulation festzustellen bzw. antidote, which makes it the treatment of choice in U¨ berdosierungen zu erkennen. In diesem Review werden situations, such as patients with renal insufficiency or in die neuen Antikoagulantien zur Therapie der Heparin- cardiac surgery. induzierten Thrombozytopenie (HIT2) und zur periopera- Coagulation monitoring has formed the cornerstone to the effective management of patients receiving oral anti- *Correspondence: PD Dr. Matthias Orth, Vinzenz von Paul coagulants (‘‘vitamin K antagonists’’, VKAs), but the mon- Kliniken gGmbH, Institut fu¨ r Laboratoriumsmedizin, Adlerstr. 9, itoring of VKAs can be challenging: VKAs suffer from a 70199 Stuttgart, Germany very narrow therapeutic range. In addition, the pharmaco- Tel.: q49 (0711) 64892760 Fax: q49 (0711) 64892688 kinetics is effected by two common polymorphisms of E-Mail: [email protected] the VKORC1 and the CYP2C9 genes w3x. However, only Article in press - uncorrected proof 122 Orth: Factor II- and factor Xa-inhibitors ;40% of the individual dose needed for stable antico- techniques (in particular for replacing molecules formerly agulation can be explained by these polymorphisms. obtained from animal sources) and combinatory chem- Other factors are very important, such as vitamin K istry. The latter embrace small molecules designed derived from the diet, the absorption of vitamin K from specifically either to block the catalytic activity of coagu- the chyme (which is affected by, e.g., pancreas insuffi- lation enzymes or to interact directly with anticoagulant ciency) and the production of vitamin K by intestinal proteins. bacteria (which can be easily diminished by antibiotic Different experimental models of blood coagulation, treatment). Owing to the slow onset of action, its unpre- such as the ‘‘waterfall-cascade’’, the ‘‘autoprothrombin dictable pharmacology and numerous food and drug model’’, the cell-based model of coagulation and the interactions, monitoring and dose adjusting of VKAs is cumulative 4-component model wtissue factor (TF)-medi- mandatory and is achieved by international normalized ated thrombin generation, TF activation of the blood ratio (INR) testing from citrated plasma in the hemo- coagulation proteome, TF-activated and contact path- staseological laboratory, or less frequent, from whole way-inhibited whole blood in vitro, and bloodshed form (capillary) blood in a point-of-care testing (POCT) setting. microvascular wounds in vivoxw6x, were the basis for the While the therapy with UFH is routinely adjusted either development of substances able to modulate the coagu- by the aPTT or the thrombin time, monitoring of LMWH lation pathway at almost every step. is only performed in a subset of patients. The test per- In short, replacing heparin or VKA in the perioperative formed, anti-FXa, measures the inhibition of the activated prophylaxis of venous thrombo-embolism (VTE) or the coagulation factor Xa. Monitoring of LMWH therapy is prevention of stroke in chronic atrial fibrillation (CAF) has advisable during pregnancy, obesity and renal insuffi- not been the primary focus in the development of sub- ciency (however, kidney failure is a contraindication for stances inhibiting tissue factor/FVII, FIX, or FVIII. The some LMWH). Given highly variable inter- and intra-indi- potential advantages of these ‘‘upstream targets’’ are vidual pharmacokinetics due to subcutaneous injection, additional features, such as the inhibition of metastatic due to absorption of the highly charged heparin to sev- disease (e.g., in rNAPc2), or the effects on sepsis (e.g., eral surfaces, and due to the heterogeneity of heparins, in rTFPI). The number of these drugs under current devel- the results of a single anti-FXa analysis in the monitoring opment is very small. of LMWH therapy can only give an estimate for adjusting Current clinical data support that factor IIa and factor the correct dosing. From an analytical standpoint, how- Xa are the ideal targets for anticoagulation in terms of ever, the testing per se is highly reproducible with a varia- efficacy and safety, and numerous drugs were developed tion coefficient between 1% and 7%. A disadvantage of or are under current development to modulate thrombin heparins is the dependence of raw material from and factor Xa. animal sources: most of the unprocessed heparin is First evaluation of novel anticoagulants was carried out obtained from porcine mucosa and the recent adultera- in short-term indications, such as the prevention VTE after tion of these raw materials led to a worldwide recall of total hip or knee replacement surgery. This approach many heparins w4x. is ideal for anticoagulant drug development, because The significant limitations of VKAs and of heparins and studies with well-defined efficacy (proof of principle) and the increasing need for safe anticoagulation owing to the safety endpoints can be carried out in a population in higher incidence both of hip and knee surgery and of AF which there is a relatively high rate of VTE events, and in older patients due to the current demographic devel- bleeding can be monitored and controlled in a hospital opment (the current number of patients with AF is 5.8 environment w7x. As a consequence of the short-term Mio and this will increase to ;11 Mio in 2040 w5x), foster observation periods so far, the new oral anticoagulants the development of new anticoagulants for both short- are only approved for the postoperative anticoagulation. term and long-term use. The ideal anticoagulant should However, long-term studies (phase III studies) are cur- be for oral administration, should have a qualified repro- rently performed and approval for the outpatient use ducible production process, should be free from non- (such as AF) is expected for some of these drugs in hemorrhagic side effects, should have predictable the near future w8x. This will be a new challenge for pharmacokinetics and pharmacodynamics, should not the hemostaseological laboratory: these drugs have suffer from interaction with drugs or food intake, should the potential to interfere with many coagulation tests in have a wide therapeutic window, should have an appro- current use and anticoagulation monitoring
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