Current Pharmaceutical Design - Volume 12, Issue 10, 2006

Hereditary Hemorragic Teleangiectasia or Osler-Weber-Rendu disease represents a rare genetic disorder which is under intensive investigation in view of its multidisciplinary aspects. In the present hot topic issue entitled: "Molecular and Clinical Aspects of Hereditary Hemorragic Telangiectasia: A Rare Disease" the full spectrum of this disease has been emphasized starting from basic concepts to diagnostic criteria and innovative therapeutic procedures. In the first paper of this special issue Daina and associates [1] have pointed out the salient features of Hereditarry Hemorragic Telangiectasia (HHT), stating that this disease is more frequent than previously estimated and, therefore, diagnostic and therapeutic technologies have improved the recognition of the disease. Lenato and Guanti [2] have provided information about genetic and molecular aspects of HHT, claiming that the variability observed among members of the same family has not yet been explained , despite the sharing of the same disease-causing mutation. In three consecutive papers the immulological aspects of HHT have been investigated. The role of Transforming Growth Factor-beta in the regulation of the immune response and of cellular proliferation has been discussed [3]. In addition, novel findings demonstrate that in HHT patients the T-helper (h)-1 response is ablated, while the Th2 response seems to dominate the immune scenario [4]. This defect of the adaptive immunoresponse could downregulate the phagocytic activity, as observed in another group of patients [5]. Sabba and associates [6] have outlined the broad spectrum of clinical manifestation observed in all organs in HHT patients. Giordano and associates [7] have placed emphasis on the pediatric aspects of HHT with the aim to establish reliable screening protocols for the prevention and cure of the disease. Memeo and associates [8] have illustrated some diagnostic imaging procedures for visceral involvement and, in particular, ultrasonography seems to be the best screening modality for hepatic and pulmonary localizations. Geisthoff and associates [9] have reviewed all the therapeutical treatments for recurrent hepistaxis in HHT. Endovascular treatment of pulmonary and cerebral arteriovenous malformations in HHT patients has been presented by De Cillis and associates [10]. Finally, Pasculli and associates [11] have concluded that appropriate screening programs are mandatory and multispecialistic cooperation is needed. Special Centers developed in the world are currently working to formulate better therapeutical approaches for HHT based on gene therapy in order to cure this condition. References [1] Daina E, D'Ovidio F, Sabbà C. Introduction: Hereditary Hemorragic Telangiectasia as a rare disease. Curr Pharm Design 2006; 12(10): 1171-1172. [2] Lenato GM, Guanti G. Hereditary Haemorrhagic Telangiectasia (HHT): genetic and molecular aspects. Curr Pharm Design 2006; 12(10): 1173-1193. [3] Jirillo E, Amati L, Suppressa P, Cirimele D, Guastamacchia E, Covelli V, Tafaro E, Sabbà C. Involvement of the transforming growth factor b in the pathogenesis of hereditary hemorrhagic teleangiectasia. Curr Pharm Design 2006; 12(10): 1195-1200. [4] Amati L, Passeri ME, Resta F, Triggiani V, Jirillo E, Sabbà C. Ablation of T-Helper 1 cell derived cytokines and of monocyte-derived tumor necrosis factor b in hereditary hemorrhagic teleangiectasia: immunological consequences and clinical considerations. Curr Pharm Design 2006; 12(10): 1201-1208. [5] Cirulli A, Loria MP, Dambra P, Di Serio F, Ventura MT, Amati L, Jirillo E, Sabbà C. Patients with hereditary hemorrhagic telangectasia (HHT) exhibit a deficit of polymorphonuclear cell and monocyte oxidative burst and phagocytosis: a possible correlation with altered adaptive immune responsiveness in HHT. Curr Pharm Design 2006; 12(10): 1209-1215. [6] Sabbà C, Gallitelli M, Pasculli G, Suppressa P, Resta F, Guastamacchia E, Tafaro E. HHT: a rare disease with a broad spectrum of clinical aspects. Curr Pharm Design 2006; 12(10): 1217-1220. [7] Giordano P, Nigro A, Del Vecchio GC, Sabba C, De Mattia D. HHT in childhood: screening for special patients. Curr Pharm Design 2006; 12(10): 1221-1225. [8] Memeo M, Scardapane A, Stabile Ianora AA, Sabbà C, Angelelli G. Hereditary hemorrhagic teleangiectasia: diagnostic imaging of visceral involvement. Curr Pharm Design 2006; 12(10): 1227-1235. [9] Geisthoff UW, Fiorella ML, Fiorella R. Treatment of recurrent epistaxis in HHT. Curr Pharm Design 2006; 12(10): 1237-1242. [10] De Cillis E, Burdi N, Bortone AS, D'Agostino D, Fiore T, Ettorre GC, Resta M. Endovascular treatment of pulmonary and cerebral arteriovenous malformations in patients affected by hereditary hemorrhagic teleangiectasia. Curr Pharm Design 2006; 12(10): 1243-1248. [11] Pasculli G, Sallustio G, Sabbà C. The need for an interdisciplinary network of investigations on HHT. Curr Pharm Design 2006; 12(10): 1249-1251.

A disease is considered rare in the United States when it affects one individual per 1, 250 and one individual per 2, 000 in Europe. Most rare diseases (RD) are of genetic origin; their rarity involves a difficult and/or late diagnosis. The greatest barrier to prevention, diagnosis and treatment of RD is inadequate knowledge. Hereditary haemorrhagic telangiectasia (HHT) is a "rare" genetic disorder that is becoming more commonly recognised. Recent evidence indicates that it is more frequent (1-2/10, 000) than previously estimated. We suppose that the frequent misdiagnosis and the different genetic penetrance have led to an underestimation of real prevalence. In fact, progress in scientific knowledge and improvement in diagnostic and therapeutic technologies has unmasked conditions which were not fully known previously, determining a fictitious decrease in disease frequency.

Hereditary Haemorrhagic Telangiectasia, or Rendu-Osler-Weber syndrome, is a rare autosomal dominant disorder involving the vascular system and is characterised by a highly variable expressivity and age-dependent penetrance. Diagnosis is based on the presence of at least three of four of the following symptoms: spontaneous epistaxis, cutaneous telangiectases, arteriovenous malformations in internal organs and familiarity. Recurrent complications are severe anaemia, stroke, portal and pulmonary hypertension. The peculiar characteristic of this disease is the diffusion of arteriovenous malformations, that is, localised abnormal arteriovenous connections affecting both microvasculature and large vessels. HHT is actually a heterogenous genetic disorder, divided into two clinically indistinguishable forms: HHT1 caused by mutations in endoglin gene mapping on chromosome 9q, and HHT2 caused by mutations in ALK1 located on chromosome 12q. Haploinsufficiency is the underlying mechanism for endoglin and most ALK1 mutations. Such mutations lead to a deficiency in angiogenesis, i.e. the sprouting of new vessels from pre-existing ones. To date, little is still known about the mechanism(s) responsible for lesion formation, development and slow growth. Current models focus on the role that TGF- β superfamily members, a vast group of multifunctional cytokines, play in endothelial responses to angiogenic stimuli. As both genes seem to act in TGF-β signal transduction pathways, SMAD proteins are also thought to be involved. There is no clear explanation accounting for the strong variability shown even among members of the same family despite the sharing of the same disease-causing mutation, and why lesions are spatially discrete.

Hereditary hemorrhagic telangiectasia (HHT) is characterized by vessel alterations such as dilatation of postcapillary venules and arterio-venous communications, which account for the major clinical manifestations of the disease. Two types of HHT have been characterized HHT-1 and HHT-2, respectively, depending the former on endoglin mutations and the latter on activin receptor-like kinase 1 (ALK-1) mutations. Both endoglin and ALK-1 bind to the transforming growth factor (TGF) superfamily which, physiologically, regulates the activities of endothelial cells and also those related to the extracellular matrix. In this review, the salient features of TGF-β will be outlined with special reference to its activity on the immune system and on tumorigenesis. Furthermore, the involvement of TGF-β in the pathogenesis of some gastrointestinal diseases will be discussed and, in particular, in the course of liver disease, Helicobacter pylori infection and inflammatory bowel disease. In the light of these data and of animal model of HHT, the potential risk of developing other diseases in HHT patients will be discussed.

Experimental evidences on the adaptive immune response in patients with hereditary hemorragic telagiectasia (HHT) are lacking. Here, we report in 9 patients with HHT a multiple deficit involving the intracellular expression of T helper (h)1-derived cytokines [Interferon (IFN)-γ, Interleukin (IL)-2 and Tumor Necrosis Factor (TNF)-α] and of monocyte- derived TNF-α. On the other hand, percentages of Th2-derived cytokines (IL-4, IL-5 and IL-10) were normal or, in some cases, above normality. Quite interestingly, monocyte-derived IL-10 was detectable in 5 out of 9 patients in a percentage of cells comparable to controls or exceeding normal levels. Taken together, these data point out, in HHT, an ablation of Th1-responses, while Th2-type cytokines are preserved, thus exerting either a suppressive effect on Th1-cells (via IL-4 and IL-10) or an antiinflammatory response on monocyte-derived TNF-α (via IL-10). Furthermore, monocytederived IL-10 may also contribute to the antiinflammatory activity seen in HHT. According to current literature even if patients with HHT do not exhibit certain diseases, such as autoimmune diseases, cancer and abnormal responses to pathogens, the observed immune deficits need to be diagnosed and therapeutically corrected.

Hereditary Hemorrhagic Telangiectasia (HHT) is a rare genetic disease characterized by mutations occurring in the endoglin and ALK-1, two receptors of transforming growth factor-β1. From a pathogenic point of view, a possible involvement of the immune system in HHT has been suggested since a mononuclear cell infiltrate was found around the area of telangiectases. Up until now, no information has been available about the role played by leukocytes in HHT and the mechanisms elicited by secretion of their mediators. However, the fact that a deficit of adaptive immunity in HHT has been reported in a companion paper in this issue will represent a great contribution to the understanding of HHT pathogenesis. The purpose of this study was to evaluate whether patients with HHT manifest also alterations in the innate immune response. Therefore, the phenotype of T, B and natural killer lymphocytes, serum immunoglobulin levels, phagocytosis and oxidative burst activity exerted by polymorphonuclear cells (PMN) and monocytes (MO) were analyzed in 22 patients. Twenty individuals demonstrated single or multiple deficits of PMN and MO functions, while the immunophenotype of lymphocytes and serum concentrations of immunoglobulins were normal. To the best of our knowledge, this is the first demonstration of a reduction in PMN and MO functions in HHT, thus suggesting a higher susceptibility to infectious complications in these patients. The relationship between innate immune deficits and T helper 1 and monocyte-derived cytokine dysfunction in HHT, as previously reported, is discussed.

HHT is an autosomal dominant disease characterised by diffuse muco-cutaneous and visceral telangiectases in potentially all organs. Mutations in two different genes identify HHT type 1 and HHT type 2: endoglin located on chromosome 9q33-q34 and ALK-1 or ACVRL1 on chromosome 12q13, respectively. The existence of a third locus has also been hypothesised. HHT-1 is considered a more severe form of the disease with an earlier onset of epistaxis and telangiectases and a higher prevalence of pulmonary arteriovenous malformations than that found in HHT-2 subjects. Usually, a typical HHT patient has epistaxis, muco-cutaneous telangiectases and GI bleeding in later life, even though this clinical scenario represents only one of the possible HHT patterns. In fact, vascular malformations often remain silent until the onset of a severe complication, which frequently is the first clinical manifestation of HHT. The lung and brain are of particular concern because each may contain clinically silent lesions that can result in sudden morbidity and mortality. At present, awaiting the availability of genetic testing, only an expert in the clinical patterns and diagnostic imaging of HHT can permit a definite diagnosis in individuals at high risk for the disease.

Hereditary hemorrhagic telangiectasia (HHT) or the Rendu-Osler-Weber disease is a systemic fibrovascular autosomal dominant dysplasia, recognised when three of the following four clinical manifestations are present, according to the proposal of Shovlin .: recurrent nosebleeds, lelangiectasias of the skin, visceral lesions, and positive family history. HHT is often difficult to diagnose on the basis of history and physical examination alone, especially in infants and children. The signs and symptoms of HHT are nonspecific and are extremely variable within families. Given the frequent occurrence of clinically silent lesions in lung and brain arteriovenous malformations which can result in morbidity or death, much consideration should be given to screening patients with HHT for asymptomatic fistulae and to their treating once they are discovered. Presymptomatic interventions in such cases may substantially affect the outcome. It may be possible to state that lesions of HHT arise early in life, but do not reach sufficient size to cause symptoms until the second decade. Furthermore, as clinical manifestations often occur later in life, the development and the implementation of a molecular diagnosis will allow the identification of subjects with no evident signs of the disease but carrying the familial mutation. This is fundamental in order to establish reliable screening protocols for the prevention and cure of the disease and, to determine the presence of family members with no disease-associated mutation, who do not require further clinical screening.

Hereditary Haemorrhagic Telangiectasia (HHT), also known as Rendu-Osler-Weber disease, is an autosomaldominant vascular disease characterised by mucocutaneous or visceral angiodysplastic lesions (telangiectases and arteriovenous malformations), which may be widely distributed throughout the cardiovascular system. Its diagnosis is based on clinical criteria. Liver, lungs and brain, in order of prevalence, are the most frequently involved visceral districts of the body other than skin and nasal mucosa. Liver involvement is frequent and characterised by the presence of intrahepatic shunts, disseminated intraparenchymal telangiectases and other vascular lesions. Although it is usually asymptomatic, congestive cardiac failure, portal hypertension, portosystemic encephalopathy, cholangitis or atypical cirrhosis are possible complications. Pulmonary arteriovenous malformations involve more than one third of HHT patients and can consist of diffuse telangiectases or high-flow low-pressure shunts between pulmonary arteries and veins. Pulmonary involvement can cause serious complications: hypoxaemia, pulmonary or pleural hemorrhage, paradoxical embolism into cerebral circulation. Various types of cerebrovascular malformations can affect HHT patients and the most common are arteriovenous malformations, consisting of one or more feeding arteries connected to one or more draining veins. Diagnostic imaging has a fundamental role in detecting the alterations involving these various districts in the body. The possibility to perform fast and complete studies and to provide high quality multiplanar and angiographic reconstructions, gives multi-detector row helical computed tomography and magnetic resonance the ability to detect and characterise the complex anatomopathological alterations typical of HHT. Ultrasonography seems to be the best screening modality for hepatic and pulmonary involvement.

No optimal treatment modality is currently available for the treatment of recurrent epistaxis in HHT. In this review, different therapeutic concepts are discussed together with their pathophysiologic background. Patients often profess a preventive effect for nasal ointments and use packings which can be self-administed in the case of bleeding. An effective first-line treatment for physicians is the endonasal laser coagulation or argon plasma coagulation. A second line surgical procedure is septodermoplasty according to Saunders which can provide long-lasting relief if performed correctly. There have been reports on antifibrinolytic agents and hormones, but their efficacy has yet to be determined.

Hereditary Haemorrhagic Teleangiectasia (HHT) is a vascular disorder of angiogenesis transmitted in an autosomal dominant pattern, characterised by heterogeneity in clinical manifestations. One of the most important organ involved is lung, including pulmonary arteriovenous malformations (PAVM). PAVM occur in 20 to 30% of the HHT population and recently are considered a marker of disease. PAVM are direct artery-to-vein connections with low pressure and without an interveining capillary bed. PAVM are classified as simple (supplied by one feeding artery) or complex (receiving blood supply from two or more feeding artery). According to the international reports, treatment it's recommendable for all PAVM with feeding vessels 3mm or larger, in order to reduce the risk of cerebral ischaemia and neurologic manifestations frequently attributed to paradoxical embolisation. Transcatheter embolotherapy of PAVM is a form of treatment based on occlusion of the feeding artery to a PAVM by using platinum coils or detachable balloons. The technique of coil embolisation involves the exact localisation of PAVM by pulmonary angiography followed by superselective percutaneous caheterisation of feeding artery obtained by using a dedicated 7F guiding catheter, which coaxially allocates a 5F hydrophilic catheter advanced in order to perform both superselective angiography of feeding artery and embolisation itself. Inside the 5F catheter the platinum coils are advanced using a .035" guide-wire and released until an optimal occlusion of feeding artery is achieved. At the end of the procedure angiographic control is performed in order to verify the occlusion of feeding artery. The use of platinum coils is preferable over detachable balloons when feeding artery are greater than 7mm in diameter and have irregular anatomical configuration. On the other hand, the principal advantage of using detachable balloons is that the balloon itself can be deflated and repositioned if necessary. Transcatheter embolotherapy is technically safe and clinically effective and may represent the primary choice of treatment in HHT patients. On the other hand the most common complications of this treatment (pleurisy and air embolism) can be prevented by using some tips during the embolisation procedure like "anchor technique," "scaffold technique" and "balloon assisted technique." Cerebral arteriovenous malformations (CAVM) are present in 10-20% of patients with HHT and multiple in 50% of cases. Cortical surface is the most frequent localisation. Angiography is needed to diagnose all CAVM and to clarify the angioarchitecture of the lesion. In HHT CAVM are usually either micro-AVM, with a nidus not bigger than 1 cm, or small AVM, with a nidus between 1 and 3 cm. Quite frequently there are lesions characterised by arteriovenous fistulas. In the three patterns of CAVM usually found in HHT, small AVM are the most risky for bleeding although the risk is lower than that associated with sporadic ones. It is estimated from 0.38 to 0.69% per year in spite of the general incidence of bleeding in sporadic CAVM that ranges from 2 to 4% per year. In HHT patients, at present, the precise indications and timing of treatment are not established. Trend is to treat small AVM and AVF and to follow-up micro-AVM with MRI and angiography. As for sporadic CAVM, treatment of small AVM is usually referred to stereotactic radiosurgery. Endovascular embolisation is proposable if the lesion is easily reachable by microcatheterism and the position of the microcatheter is safe. Glue is used for embolisation and the technique is briefly discussed.

In the last years, the understanding of HHT has greatly progressed. The two genes for most on cromosomes 9 and 12 have been discovered and the existence of a third involved gene has been predicted. Recent progress in the field of genetics has allowed the identification of many gene mutation thus facilitating the characterisation of the at risk members of the same family. Complications from bleeding or shunting (pulmonary AVMs) may be sudden and life-threatening (hemothorax, haemoptysis, stroke and brain abscess). Catastrophic events are preventable by early diagnosis and treatment. Appropriate screening programmes are mandatory and multi-specialistic cooperation is needed. Special centers have been developed in the world, where physicians, who are specialised and trained in all aspects of HHT, are working to develop better therapeutic approaches for the disease and to locate new genes in view of the future potential of gene therapy for this condition.

Atherothrombotic diseases and especially coronary and cerebrovascular diseases are the most important causes of death in industrialized countries. The use of platelet aggregation inhibitors in this context improves morbidity and mortality. The effect of acetylsalicylic acid (ASA) as an inhibitor of the cylooxygenase is well established as shown in numerous major trial. In recent years, the dual role of P2Y1 and P2Y12 receptors in platelet aggregation by ADP has been firmly established. Thienopyridines act as inhibitors of the P2Y12 receptor with beneficial effects in atherothrombotic diseases, either as a stand alone therapy or in combination with aspirin. In this edition of "Drugs in interventional cardiology", the variety of indications for thienopyridines will be discussed. In the first article, Robert F. Storey will provide an overview on the biology and pharmacology of the platelet P2Y12 receptor [1]. Thereafter, potential problems associated with thieonopyridine treatment will be mentioned. Gurbel and co-workers discuss the phenomenon and clinical implications of clopidogrel resistance [2] before potential drug-drug interaction between thienopyridines and statins will be summarized by Neubauer and Mügge [3]. Our group from Lubeck and Aachen will discuss indications for thienopyridines in percutaneous coronary interventions [4] before Franke and Kühl will evaluate the role of antiplatelet agents in the management of patients receiving intracardiac closure devices [5]. Finally, Prof. Diener will provide an up-to-date review on primary and secondary stroke prevention using antiplatelet drugs [6]. I would like to thank all authors for their contribution. References [1] Storey RF. Biology and pharmacology of the platelet P2Y12 receptor. Curr Pharm Design 2006; 12(10): 1255- 1259. [2] Gurbel PA, Lau WC, Bliden KP, Tantry U. Clopidogrel Resistance: Implications for Coronary Stenting. Curr Pharm Design 2006; 12(10): 1261-1269. [3] Neubauer H, Mügge A.Thienopyridines and Statins: Assessing a Potential Drug-Drug Interaction. Curr Pharm Design 2006; 12(10): 1271-1280. [4] Radke PW, Hoffmann R, Zernecke A, Kaiser A, Schunkert H, Weber C. Thienopyridines in percutaneous coronary interventions: Standard procedures and high risk subsets. Curr Pharm Design 2006; 12(10): 1281- 1286. [5] Franke A, Kühl HP. The role of antiplatelet agents in the management of patients receiving intracardiac closure devices. Curr Pharm Design 2006; 12(10): 1287-1291. [6] Diener HC. Primary and Secondary Stroke Prevention with Antiplatelet Drugs. Curr Pharm Design 2006; 12(10): 1293-1297.

Platelets possess two receptors for ADP, P2Y1 and P2Y12. ADP is released from platelet dense granules upon platelet activation by numerous agonists and thereby amplifies platelet responses regardless of the initial stimulus. The P2Y1 receptor is one of many platelet receptors coupled to Gq and initiates ADP-induced activation. The P2Y12 receptor on the other hand is linked to Gi and plays a special role in the amplification of platelet activation initiated by numerous other pathways. Platelet activation leads to a range of responses that play a critical role in arterial thrombosis and the inflammatory responses associated with this, including platelet aggregation, dense and α granule secretion and procoagulant activity. P2Y12 receptor activation yields powerful amplification of these processes such that P2Y12 receptor antagonists may have dramatic inhibitory effects on platelet function regardless of the activating stimuli. This phenomenon, coupled with the restricted distribution of the P2Y12 receptor in humans, makes the receptor an ideal target for pharmaceutical therapy. This has already been established by the therapeutic success of clopidogrel, which acts, via an active metabolite, on this receptor. However, current therapeutic regimens of clopidogrel yield variable and incomplete P2Y12 receptor blockade and more effective strategies to block P2Y12 receptor activation offer the potential of greater clinical efficacy.

Clopidogrel, in combination wih aspirin, is currently the drug of choice to prevent thrombosis after coronary stent implantation. Currently, clopidogrel is administered to the vast majority of patients without any assessment of platelet inhibition. Response variability and resistance, however, definitely occur to clopidogrel treatment. Preliminary data support the hypothesis that patients with reactive or clopidogrel nonresponsive platelets are at risk for thrombotic events. However, the magnitude of the clinical effect remains unknown and relationship between nonresponsiveness and risk of clinical events is under-investigated. Several important questions that must be answered are: A) What is the relation of clopidogrel resistance and high platelet reactivity to the occurrence of stent thrombosis, recurrent myocardial infarction, stroke and death?; B) Is there a threshold of platelet reactivity that correlates with the onset of thrombotic risk?; and C) What is the cost of administering clopidogrel to non-responsive patients? Finally, our understanding of the clinical relevance of drug resistance and high platelet reactivity should be facilitated by the use of validated point-of-service devices. The mechanisms of the response variability to clopidogrel remain incompletely defined. The contribution of intra- and extracellular pathways are under investigation.

Clopidogrel and statins are frequently administered in patients with ischemic heart disease or other atherothrombotic manifestations and are effective in the prevention of cardiovascular disease. The thienopyridine clopidogrel is a pro-drug metabolised in the liver via the cytochrome P450 (CYP) 3A4 system to the active compound which inhibits the P2Y12 ADP platelet receptor. The assumption exists that the effect of clopidogrel in inhibiting platelet aggregation is attenuated by co-administration of lipophilic statins such as atorvastatin or simvastatin which are metabolised by the CYP3A4 system to inactive substrates. Assessing a possible drug-drug interaction ex-vivo, inconclusive studies have been published: In an aggregometer study, a strong and dose-dependent interference between atorvastatin and the inhibitory effect of clopidogrel on platelet function was observed. Another study, measuring the effect of clopidogrel by flow cytometry, found a significant attenuation of the clopidogrel effect by lipophilic statins, predominantly in the loading phase. In contrast a recent study, which used 600mg clopidogrel for loading, found no significant interference between various statins and clopidogrel on ADP-induced platelet aggregation and in addition another study revealed no attenuation of the clopidogrel effect despite statin co-medication after 5 weeks. Additionally, retrospective analysis of clinical studies (CREDO-study) or registries (MITRA-PLUS) revealed no significant influence of different statins on the clinical outcome in patients treated with clopidogrel. However, these clinical studies showed a trend towards a diminishing effect of clopidogrel on those treated with cytochrome CYP3A4 metabolised statins. Even more important seems to be the considerable variability in the response of the antiplatelet effect of clopidogrel. A certain percentage of patients apparently do not respond adequately to clopidogrel treatment. This effect of clopidogrel resistance seems to be more important as the potential interference between CYP3A4 metabolized statins and clopidogrel. Finally, up until now sufficient evidence has not been gained to prefer hydrophil statins on patients receiving clopidogrel co-medication or when to discontinue the use of statins in clopidogrel treatment. Prospective studies are necessary in order to evaluate the magnitude of clopidogrel resistance and the impact of clopidogrel co-medication as well as to redefine antithrombotic therapy for this subgroup.

Due to the significant clinical and economic consequences of subacute stent thrombosis and the use of more complex devices (brachytherapy, drug eluting stents) in a variety of clinical situations (i.e. acute coronary syndromes), initiation and duration of a combined antiplatelet therapy using aspirin and a thienopyridine drug has become an issue of ongoing discussion in interventional cardiology. This review will provide a short introduction into the pathophysiology of stent thrombosis before standard procedures and critical issues on the use of thienopyridines in the setting of coronary interventions are discussed. Furthermore, clinically relevant issues that are not clearly covered by recommendations or guidelines like thienopyridines after coronary interventions in patients on chronic oral anticoagulation are also addressed.

Transcatheter closure of septal defects has become a widely used alternative to surgery or life-long anticoagulant therapy especially in patients with atrial septal defects (ASD) and patent foramen ovale (PFO). Post-procedural complications include thrombus formation on the occluder in about 0-10% of all cases. Therefore antithrombotic prophylaxis after device implantation is believed to be necessary, but still is variable and remains controversial. To date no randomized studies have been published to assess the optimal anticoagulation strategy. Thus, therapy is based on empirical data, local experience and case reports from the literature. The present review tries to give an overview on most of these mainly retrospective single center studies and summarizes their results. Factors influencing the rate of thrombus formation may be device type, existence of thrombophilic disorders and prophylactic medication. Thrombus formation has been described for each of the existing occluder types without a significant difference between the devices. For antithrombotic prophylaxis, most centers at present use either acetyl salicylic acid alone (ASA; 81 to 325 mg) for 6 months or a combination of ASA and clopidogrel (75 mg) for 6 to 8 weeks followed by ASA for additional 4 to 8 months. Inherited thrombophilic disorders should be excluded before device implantation in order to adapt antithrombotic prophylaxis. Follow-up examinations after device implantation should be performed using TEE within the first 4 weeks after implantation. Thus, thrombi may be recognized early enough to extend the antithrombotic regimen in order to avoid surgical device explantation.

Aspirin is not effective in the primary prevention of stroke. Patients with TIA or ischemic stroke carry a risk of recurrent stroke between 5 and 20% per year. In patients with TIA or ischemic stroke of noncardiac origin antiplatelet drugs are able to decrease the risk of stroke by 11-15% and the risk of stroke, MI and vascular death by 15-22%. Aspirin is the most widely used drug. It is affordable and effective. Low doses of 50-325 mg aspirin are as effective as high doses and cause less gastrointestinal side effects. Severe bleeding complications are dose-dependent. The combination of aspirin with slow release dipyridamole is superior to aspirin alone for stroke prevention. Clopidgrel is superior to aspirin in patients at high risk of recurrence. The combination of aspirin plus clopidogrel is not more effective than clopidogrel alone but carries a higher bleeding risk. None of the antiplatelet agents is able to reduce mortality.