The type-1 plasminogen activator inhibitor (PAI-1) is probably the most regulated component of the entire fibrinolytic system, and is present in increased concentrations in many different disease states. PAI-1 activity and antigen are the two parameters of the fibrinolytic system that vary most widely. Restriction fragment length polymorphism studies of the PAI-1 gene revealed two alleles at the 3' untranslated end of the gene. Elevated levels of PAI-1 have been found to be associated with deep vein thrombosis (DVT) and arterial thrombotic events in patients with atherosclerosis, particularly in coronary heart disease, myocardial infarction, and stroke. For patients with an established episode of DVT the evidence for an association between elevated PAI-1 levels and the risk to experience a further episode of a thromboembolic event is weak. In apparently healthy volunteers, two of the components of the fibrinolytic system, namely t-PA and PAI-1, fluctuate quite remarkably during a 24-h period.

Until recently, vitamin K antagonists (VKAs) were the only available oral anticoagulants evaluated for long-term treatment of patients with coronary heart disease (CHD), particularly after an acute coronary syndrome (ACS). Despite efficacy in this setting, VKAs are rarely used because they are cumbersome to administer. Instead, the more readily manageable antiplatelet agents are the mainstay of prevention in ACS patients. This situation has the potential to change with the introduction of non-VKA oral anticoagulants (NOACs), which are easier to administer than VKAs because they can be given in fixed doses without routine coagulation monitoring. The NOACs include dabigatran, which inhibits thrombin, and apixaban, rivaroxaban and edoxaban, which inhibit factor Xa. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischaemia in ACS patients, most of whom were also receiving dual antiplatelet therapy with aspirin and clopidogrel. Although at the doses tested rivaroxaban was effective and apixaban was not, both agents increased major bleeding. The role for the NOACs in ACS management, although promising, is therefore complicated, because it is uncertain how they compare with newer antiplatelet agents, such as prasugrel, ticagrelor or vorapaxar, and because their safety in combination with these other drugs is unknown. Ongoing studies are also now evaluating the use of NOACs in non-valvular atrial fibrillation patients, where their role is established, with coexistent ACS or coronary stenting. Focusing on CHD, we review the results of clinical trials with the NOACs and provide a perspective on their future incorporation into clinical practice.

Summary Anticoagulants are a mainstay of cardiovascular therapy, and parenteral anticoagulants have widespread use in cardiology, especially in acute situations. Parenteral anticoagulants include unfractionated heparin, low-molecular-weight heparins, the synthetic pentasaccharides fondaparinux, idraparinux and idrabiotaparinux, and parenteral direct thrombin inhibitors. The several shortcomings of unfractionated heparin and of low-molecular-weight heparins have prompted the development of the other newer agents. Here we review the mechanisms of action, pharmacological properties and side effects of parenteral anticoagulants used in the management of coronary heart disease treated with or without percutaneous coronary interventions, cardioversion for atrial fibrillation, and prosthetic heart valves and valve repair. Using an evidence-based approach, we describe the results of completed clinical trials, highlight ongoing research with currently available agents, and recommend therapeutic options for specific heart diseases.

Summary Oral anticoagulants are a mainstay of cardiovascular therapy, and for over 60 years vitamin K antagonists (VKAs) were the only available agents for long-term use. VKAs interfere with the cyclic inter-conversion of vitamin K and its 2,3 epoxide, thus inhibiting γ-carboxylation of glutamate residues at the amino-termini of vitamin K-dependent proteins, including the coagulation factors (F) II (prothrombin), VII, IX and X, as well as of the anticoagulant proteins C, S and Z. The overall effect of such interference is a dose-dependent anticoagulant effect, which has been therapeutically exploited in heart disease since the early 1950s. In this position paper, we review the mechanisms of action, pharmacological properties and side effects of VKAs, which are used in the management of cardiovascular diseases, including coronary heart disease (where their use is limited), stroke prevention in atrial fibrillation, heart valves and/or chronic heart failure. Using an evidence-based approach, we describe the results of completed clinical trials, highlight areas of uncertainty, and recommend therapeutic options for specific disorders. Although VKAs are being increasingly replaced in most patients with non-valvular atrial fibrillation by the new oral anticoagulants, which target either thrombin or FXa, the VKAs remain the agents of choice for patients with atrial fibrillation in the setting of rheumatic valvular disease and for those with mechanical heart valves.

SummaryContrary to previous models based on plasma, coagulation processes are currently believed to be mostly cell surface-based, including three overlapping phases: initiation, when tissue factor-expressing cells and microparticles are exposed to plasma; amplification, whereby small amounts of thrombin induce platelet activation and aggregation, and promote activation of factors (F)V, FVIII and FXI on platelet surfaces; and propagation, in which the Xase (tenase) and prothrombinase complexes are formed, producing a burst of thrombin and the cleavage of fibrinogen to fibrin. Thrombin exerts a number of additional biological actions, including platelet activation, amplification and self-inhibition of coagulation, clot stabilisation and anti-fibrinolysis, in processes occurring in the proximity of vessel injury, tightly regulated by a series of inhibitory mechanisms. ″Classical″ anticoagulants, including heparin and vitamin K antagonists, typically target multiple coagulation steps. A number of new anticoagulants, already developed or under development, target specific steps in the process, inhibiting a single coagulation factor or mimicking natural coagulation inhibitors.

Until recently, vitamin K antagonists were the only available oral anticoagulants, but with numerous limitations that prompted the introduction of new oral anticoagulants targeting the single coagulation enzymes thrombin (dabigatran) or factor Xa (apixaban, rivaroxaban, and edoxaban) and given in fixed doses without coagulation monitoring. Here we review the pharmacology and the results of clinical trials with these new agents in stroke prevention in atrial fibrillation and secondary prevention after acute coronary syndromes, providing perspectives on their future incorporation into clinical practice. In phase III trials in atrial fibrillation, compared with warfarin, dabigatran etexilate 150 mg B.I.D. reduced the rates of stroke/systemic embolism without any difference in major bleeding; dabigatran etexilate 110 mg B.I.D. had similar efficacy with decreased bleeding; apixaban 5 mg B.I.D. reduced stroke, systemic embolism, and mortality as well as major bleeding; and rivaroxaban 20 mg Q.D. was noninferior to warfarin for stroke and systemic embolism without a difference in major bleeding. All these agents reduced intracranial hemorrhage. Edoxaban is currently being evaluated in a further large phase III trial. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischemia in patients with acute coronary syndromes who were mostly receiving dual antiplatelet therapy, with conflicting results on efficacy but consistent results for increased major bleeding. Overall, the new oral anticoagulants are poised to replace vitamin K antagonists for many patients with atrial fibrillation and may have a role after acute coronary syndromes. Although convenient to administer and manage, they present challenges that need to be addressed.

Until recently, vitamin K antagonists were the only available oral anticoagulants, but with numerous limitations that prompted the introduction of new oral anticoagulants targeting the single coagulation enzymes thrombin (dabigatran) or factor Xa (apixaban, rivaroxaban, and edoxaban) and given in fixed doses without coagulation monitoring. Here we review the pharmacology and the results of clinical trials with these new agents in stroke prevention in atrial fibrillation and secondary prevention after acute coronary syndromes, providing perspectives on their future incorporation into clinical practice. In phase III trials in atrial fibrillation, compared with warfarin, dabigatran etexilate 150 mg B.I.D. reduced the rates of stroke/systemic embolism without any difference in major bleeding; dabigatran etexilate 110 mg B.I.D. had similar efficacy with decreased bleeding; apixaban 5 mg B.I.D. reduced stroke, systemic embolism, and mortality as well as major bleeding; and rivaroxaban 20 mg Q.D. was noninferior to warfarin for stroke and systemic embolism without a difference in major bleeding. All these agents reduced intracranial hemorrhage. Edoxaban is currently being evaluated in a further large phase III trial. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischemia in patients with acute coronary syndromes who were mostly receiving dual antiplatelet therapy, with conflicting results on efficacy but consistent results for increased major bleeding. Overall, the new oral anticoagulants are poised to replace vitamin K antagonists for many patients with atrial fibrillation and may have a role after acute coronary syndromes. Although convenient to administer and manage, they present challenges that need to be addressed. (J Am Coll Cardiol 2012; 59:1413-25) (C) 2012 by the American College of Cardiology Foundation

When Ichose to become aphysicianatage 15, Ihad in mind to practiceinternal medicine in amedium-sized city not too farf rom Zurich, Switzerland.H owever, fate decided otherwise.A fter my graduation from medical school Iwas searching hard to find aplace as an intern and resident butrealized thatthis washardly possible in the city of Zurich.At that timeabout threequartersofall internsand residents were unpaid, and even these volunteer positions were extremely hardtoget.Iwent to asmallerhospital in the vicinity of Zurich where Dr.Fritz Koller(Fig. 1) washead of the internal medicine department.Asking him for an internship, Iw as told thatthere wasalong waiting list to obtain an unpaidinternship, but-"Do youhavethe scientific fire for research" he asked me unexpectedly.Iwas baffled at this question butDr.Kollerexplained to me that therew as ap osition availablea th is haemostasis research laboratoryatthe Department of Medicine of the University Hos-pitalinZurich.The Emil BarrelFoundation sponsoredthis position with $125/month.Istarted afew days later and wastold to find out more about the presumptivef actor Xt hat had been postulatedb yF rançoisDuckert, Paul Flückiger, Martin Matter and Fritz Koller(1).The fiftieswere an exciting time in the fieldofblood coagulation.In the fortiesfactor V/labile factor/accelerinhad just been discovered.In1949 Alexanderetal.postulated, on the basis of quite inconclusive data,t he existenceo faf urther coagulation factor,t ermeds erum prothrombinc onversion accelerator (SPCA)(2).Afirst caseofacongenital deficiencyofthis factor wasdescribed in 1951(3).In the same year further publications confirmed the existenceo fas tablef actor,p resenti np lasma (Owen and Bollman),calledproconvertin by Owren and factor VII by Kolleretal.(4, 5).Thelatterarticle becameacitation classic and has nowbeen cited477 times (6).Paul Owren waspossibly aware of the forthcoming article by Kollere ta l., when in spring 1951, he publishedaone-page description of proconvertin in the ScandinavianJournal of Clinical and LaboratoryInvestigation (4), followedafew monthslater by morecomplete descriptions (7, 8).In 1952 plasma thromboplastin component (PTC)/ Christmasf actor (later on calledf actor IX) wasi ndependentlyd iscovered by Aggeler et al. in SanFrancisco and by Biggsetal.in

Guidelines and Expert Consensus Documents aim to present all the relevant evidence on a particular issue in order to help physicians to weigh the benefits and risks of a particular diagnostic or therapeutic procedure. They should be helpful in everyday clinical decision-making. A great number of Guidelines and Expert Consensus Documents have been issued in recent years by different organizations, the European Society of Cardiology (ESC) and by other related societies. By means of links to web sites of National Societies several hundred guidelines are available. This profusion can put at stake the authority and validity of guidelines, which can only be guaranteed if they have been developed by an unquestionable decision-making process. This is one of the reasons why the ESC and others have issued recommendations for formulating and issuing Guidelines and Expert Consensus Documents. In spite of the fact that standards for issuing good quality Guidelines and Expert Consensus Documents are well defined, recent surveys of Guidelines and Expert Consensus Documents published in peer-reviewed journals between 1985 and 1998 have shown that methodological standards were not complied within the vast majority of cases. It is therefore of great importance that guidelines and recommendations are presented in formats that are easily interpreted. Subsequently, their implementation programmes must also be well conducted. Attempts have been made to determine whether guidelines improve the quality of clinical practice and the utilization of health resources. The ESC Committee for Practice Guidelines ( CPG ) supervises and coordinates the preparation of new Guidelines and Expert Consensus Documents produced by Task Forces, expert groups or consensus panels. The Committee is also responsible for the endorsement of these Guidelines and Expert Consensus Documents or statements. The role of aspirin and other platelet-active drugs in the treatment and prevention of atherothrombosis has been reviewed recently by the Sixth American …

Carlo Patrono (Chairperson)* (Italy), Fedor Bachmann (Switzerland), Colin Baigent (UK), Christopher Bode (Germany), Raffaele De Caterina (Italy), Bernard Charbonnier (France), Desmond Fitzgerald (Ireland), Jack Hirsh (Canada), Steen Husted (Denmark), Jan Kvasnicka (Czech Republic), Gilles Montalescot (France), Luis Alberto Garcia Rodriguez (Spain), Freek Verheugt (The Netherlands), Jozef Vermylen (Belgium), Lars Wallentin (Sweden)

The formation of a haemostatic thrombus is a useful defence mechanism for the closure of vascular lesions. However, undesirable thrombi are also formed in closed vessels, e.g. over atherosclerotic plaques or after rupture of such plaques. It has long been assumed that the primary function of the fibrinolytic system consists of dissolving such thrombi, a task to which it often does not measure up. Indeed, repeat venography in patients with deep venous thrombosis treated with heparin and oral anticoagulation alone often shows only minimal resorption of the venous thrombus (Duroux et al. 1991). The situation is somewhat more favourable for arterial thrombi. The classical work of Dewood et al. (1980) has demonstrated that coronary thrombi undergo thrombolysis in the absence of thrombolytic therapy. While thrombotic lesions were present in 87% of patients undergoing coronary angiography 1–4 h after the onset of symptoms, this figure was only 68% in patients examined 6–12 h after start of symptoms (p < 0.01). In the UPET study the spontaneous recanalisation of pulmonary emboli was quite remarkable. Seven days after the embolic event, pulmonary angiography no longer showed a difference between control patients and those who had been treated with urokinase (Urokinase Pulmonary Embolism Trial 1970).

At the turn of this century, the Belgian physiologist Nolf (1908) observed that under certain experimental conditions the lysis of a blood clot could be obtained and introduced the concept of the “fourth state of blood coagulation,” namely the dissolution of thrombi. During the same period Loeb in Germany was studying the process of wound healing. He observed that epithelial cells were able to liquefy the fibrinous wound scab and thus assured their progression into the scab. He concluded that epithelial cells were able to produce “peptonizing enzymes” (Loeb 1904; Fleisher and Loeb 1915). In 1936, the Russian investigator Yudin (1936,1937) observed that cadaver blood was fluid and caused, after transfusion into man, a fibrinolytic state. In the 1930s and 1940s, Macfarlane and Biggs in Oxford were able to demonstrate, using a dilute plasma clot lysis assay, that several pathophysiological conditions triggered a release of fibrinolytic activity in man, such as surgery, trauma, physical exercise, mental stress, or the intravenous injection of adrenaline (MacFarlane 1937; MacFarlane and Biggs 1946; Biggs et al. 1947). During the same time period, Christensen and MacLeod (1945) discovered the zymogen plasminogen in human serum that could be activated by streptokinase (SK) to form active plasmin, and Astrup and collaborators started their seminal work on the fibrinolytic system at the Carlsberg Foundation Research Institute in Copenhagen. Astrup and Permin (1947) were the first investigators who clearly demonstrated that there exist two different plasminogen activators in mammalians, tPA and urokinase. Astrup and Müllertz (1952) also developed a sensitive test to measure the activity of tPA, the plasminogenenriched fibrin plate test.

the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and free for general use.

Clopidogrel, a potent novel platelet ADP-receptor antagonist, induces a significant inhibition of ADP-induced platelet aggregation. Maximum inhibition of 40 to 50% is observed 2 to 5 hours after a single 400 mg dose. The same level of inhibition is achieved with 75 mg once daily at steady state, i.e., after 3 to 7 days of repeated dosing. Based on these data, two studies were undertaken to investigate whether a treatment regimen comprising a large initial dose (loading dose) of clopidogrel, followed by daily doses of 75 mg, might provide a sustained steady-state level of inhibition of platelet aggregation induced by 5 microM of ADP within hours after first dosing. In one study, 10 healthy male subjects received a 375 mg loading dose of clopidogrel on day 1, then daily doses of 75 mg from day 2 to day 10. Mean inhibition of platelet aggregation, already significant at 30 minutes, reached 55+/-8.2% (+/-SEM) at 60 minutes, and a maximum of 80+/-3.6% at 5 hours. No further significant change was observed between 5 hours and 24 hours, and from day 2 through day 10 with subsequent daily doses of 75 mg. In the second study, conducted according to a randomized, single-blind design, four parallel treatment groups of nine healthy male subjects received a loading dose of 75 mg, 150 mg, 225 mg, or 300 mg of clopidogrel on day 1, respectively, and 75 mg once daily from day 2 to day 5. Mean (+/-SD) inhibition of platelet aggregation over the 2 to 24 hours post-loading dose period was 22+/-14.5%, 21+/-13.4%, 35+/-20.6% and 31+/-13.3%, respectively. On day 5, it was 48+/-14.7%, 33 +/-14.1%, 51+/-15.7% and 40+/-10.9% for the 75, 150, 225 and 300 mg loading dose groups, respectively. The smallest day 1 to day 5 difference was observed for the 300 mg group and the largest for the 75 mg group, indicating that the development of the full inhibitory effect of clopidogrel was faster with the loading doses higher than with 75 mg, and fastest with the 300 mg loading dose. These data and those of previous studies indicate that a dose of 300 to 400 mg produces a rapid onset of the pharmacodynamic action of clopidogrel, with levels of inhibition close to steady-state reached within 2 hours.

We investigated various pharmacokinetic and pharmacodynamic parameters in a 63-year-old man, resistant to warfarin, fluindione, acenocoumarol and phenprocoumon. Daily doses of up to 30 mg of the long-acting phenprocoumon yielded a drug concentration of 85 mg/l (usual range 1-5 mg/l) but the international normalized ratio remained around 1. The plasma half-life of phenprocoumon was approximately 350 h (normal 120-150 h). Thus, the resistance was not due to malabsorption or to an accelerated metabolism of the drug. The level of vitamin K1 (1,202 ng/l) was insufficient to induce resistance. Decarboxyprothrombin concentrations were low, demonstrating that the gamma-carboxylation of the precursors of the vitamin K-dependent coagulation factors was not effectively reduced. The concentration of vitamin K epoxide, normally increased under oral anticoagulation, correlated to the vitamin K concentration (r2 = 0.77) but the quotient epoxide/vitamin K remained 4-fold lower than that of 22 warfarin-sensitive patients, suggesting an absence of blockade of the vitamin K reductase by phenprocoumon. This resistance to all the molecular forms of the vitamin K antagonists is most likely due to a reduced affinity of the drugs to a mutant vitamin K reductase.

Dose intensity may be an important determinant of the outcome in cancer chemotherapy, but is often limited by cumulative haematological toxicity. The availability of haematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) and of peripheral blood progenitor cell (PBPC) transplantation has allowed the development of a new treatment strategy in which several courses of high-dose combination chemotherapy are administered for the treatment of solid tumours. PBPCs were mobilised before chemotherapy using 12 or 30 micrograms kg-1 day-1 G-CSF (Filgrastim) for 10 days, and were collected by 2-5 leucaphereses. The yields of mononuclear cells, colony-forming units and CD34-positive cells were similar at the two dose levels of Filgrastim, and the numbers of PBPCs were sufficient for rescue following multiple cycles of chemotherapy. High-dose chemotherapy (cyclophosphamide 2.5 g m-2 for 2 days, etoposide 300 mg m-2 for 3 days and cisplatin 50 mg m-2 for 3 days) was administered sequentially for a median of three cycles (range 1-4) to ten patients. Following the 30 evaluable cycles, the median duration of leucopenia < or = 0.5 x 10(9) l-1 and < or = 1.0 x 10(9) l-1 was 7 and 8 days respectively. The median time of thrombopenia < or = 20 x 10(9) l-1 was 6 days. There was no cumulative haematological toxicity. The duration of leucopenia, but not of thrombopenia, was inversely related to the number of reinfused CFU-GM (granulocyte-macrophage colony-forming units). In the majority of patients, neurotoxicity and ototoxicity became dose limiting after three cycles of therapy. However, the average dose intensity delivered was about three times higher than in a standard regimen. The complete response rate in patients with small-cell lung cancers was 66% (95% CI 30-92%) and the median progression-free survival and overall survival were 13 months and 17 months respectively. These results are encouraging and should be compared, in a randomised fashion, with standard dose chemotherapy.

The type-2 plasminogen activator inhibitor (PAI-2) belongs to the ovalbumin subfamily of serpins. It exhibits close to 50% homology with several recently cloned protease inhibitors such as the leukocyte elastase inhibitor, the placental thrombin inhibitor and the squamous cell carcinoma antigen. PAI-2 exists in an intracellular, nonglycosylated form of 47 kDa and a secreted, glycosylated form of about 60 kDa. The PAI-2 gene does not have a signal peptide which might explain why the major portion of PAI-2 remains intracellularly. Several response elements have been identified in the promoter region which are necessary for constitutive and phorbol ester and retinoic acid induced expression of the gene. These include two AP-1 sites, and response elements for cAMP, glucocorticoids and retinoic acid. The physiological function of PAI-2 has not been clearly elucidated. It may have cytoprotective functions and appears to play a role in programmed cell death.