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En la profilaxis de la enfermedad tromboembolica venosa en los pacientes hospitalizados por una afeccion aguda grave se ha utilizado, con exito pero sin modificacion de la mortalidad, esencialmente, una heparina de bajo peso molecular (HBPM) o el pentasacarido fondaparinux. La estrategia sugerida actualmente por las sociedades cientificas se basa en el uso de un sistema de clasificacion por puntos del riesgo tromboembolico asociado a un sistema de clasificacion por puntos de prediccion del riesgo hemorragico. Un pequeno numero de situaciones clinicas (cancer, trombofilia, accidente cerebrovascular, viajes largos, hospitalizacion en unidades de cuidados intensivos, etc.) son objeto de una propuesta de enfoque preventivo en funcion del nivel de riesgo. Finalmente, a pesar de progresos importantes, no se ha llegado a un consenso sobre la tromboprofilaxis en los pacientes hospitalizados en un entorno medico no quirurgico. Existe una tendencia a reducir la duracion del tratamiento en comparacion con las estrategias mas antiguas. No debe utilizarse sistematicamente, sino que debe decidirse en funcion de los sistemas de clasificacion por puntos validados prospectivamente.

La profilassi della malattia tromboembolica venosa nei pazienti ricoverati per una patologia acuta grave ha utilizzato, con successo ma senza modificazione della mortalita, essenzialmente un’eparina di basso peso molecolare (EBPM) o il pentasaccaride (fondaparinux). La strategia attualmente consigliata dalle societa scientifiche si basa sull’utilizzo di un punteggio di rischio tromboembolico associato a un punteggio di predizione del rischio emorragico. Un piccolo numero di situazioni cliniche (cancro, trombofilia, accidente vascolare cerebrale, lunghi viaggi, ricovero in un’unita di terapia intensiva, ecc.) e oggetto di una proposta di atteggiamento preventivo in funzione del livello di rischio. Complessivamente, malgrado importanti progressi, la tromboprofilassi nei pazienti ricoverati in ambiente medico non giunge a un consenso. Vi e la tendenza a ridurre la durata del trattamento rispetto alle strategie piu antiche. La tromboprofilassi non deve essere utilizzata sistematicamente, ma deve essere decisa in funzione dei punteggi validati prospetticamente.

Heparins and vitamin K antagonists (VKA) used commonly are the standard treatment of venous and arterial thromboses. They are very efficient and safe, but have some limitations: iatrogenicity, laboratory monitoring, parenteral use for heparins and fondaparinux. Nowadays, four new inhibitors of factor Xa are used orally (rivaroxaban, apixaban, edoxaban, betrixaban), and they are at least as efficient as heparins and vitamin K antagonists. The objective is to substitute these indirect inhibitors of factor Xa (heparins, low molecular weight heparins and fondaparinux) in the prevention of venous and arterial thromboembolic episodes. The new direct inhibitors do not require routine laboratory monitoring of blood coagulation. They inhibit the extrinsic and the intrinsic pathways of blood coagulation. Rivaroxaban and apixaban are efficacious and safe in the prevention of cerebral infarcts in patients with non-valvular fibrillation. Apixaban is another direct inhibitor of factor Xa used orally which is developed in the same indications as rivaroxaban. Edoxaban and betrixaban are also in development. The objective of this work is to study the pharmacodynamic, pharmacokinetic, the efficacy and safety of these four oral direct factor Xa inhibitors.

The vascular endothelium has been characterized in every organ system, and is described as a selective permeable barrier and as a dynamic and disseminated organ with endocrine function. These activities have been shown to result from the interactions of ligands with membrane-bound receptors as well as through specific junctional proteins and receptors that govern cell-cell interactions. The endothelial cells' movement (e.g., angiogenesis) has been hypothesized to occur following the release of stimuli that could promote the formation of new blood vessels. Angiogenesis has also been reported to be the continued expansion of the vascular tree in avascular regions, as a result of the sprouting of endothelial cells from existing vessels. Most commonly, angiogenesis has been characterized during wound healing and tumour growth. Herein we summarize and discuss the latest results from fundamental laboratory research aimed at proving a link between the proliferation of cancer and angiogenesis, as well as the new rationale around novel pro- and anti-angiogenic molecules.

Resume Introduction Les necroses cutanees sont des complications rares des traitements anticoagulants oraux par anti-vitamine K (AVK). Elles se manifestent par des necroses hemorragiques et surviennent habituellement a l’instauration du traitement. Nous decrivons un cas atypique de necroses cutanees apparues apres deux ans de traitement par fluindione, revelant un deficit genetique en proteine C. Observation Une femme de 70 ans, aux antecedents de maladie veineuse thromboembolique et d’obesite, consultait en urgence pour une vaste zone de necrose cutanee hemorragique de la paroi abdominale. Elle etait traitee depuis deux ans par fluindione. Le diagnostic de necrose cutanee induite par le traitement AVK etait retenu, permettant de mettre en evidence un deficit genetique en proteine C. Une recidive a la reprise d’un traitement du meme type, malgre une administration concomitante d’heparine de bas poids moleculaire, ne permettait pas la poursuite de l’anticoagulation orale par AVK. Discussion L’originalite de cette observation reside dans la survenue tardive de la necrose cutanee. Cet evenement indesirable a ete decrit a l’instauration des AVK, notamment entre le troisieme et le sixieme jours, en raison d’un etat d’hypercoagulabilite transitoire chez les patients deficitaires en proteine C ou, plus rarement, en proteine S. La survenue tardive d’une necrose cutanee, plusieurs annees apres le debut du traitement par AVK, peut s’expliquer par une aggravation brutale du deficit preexistant en proteine C sous l’influence de facteurs infectieux et iatrogenes.

Les antagonistes de la vitamine K (AVK) et les heparines sont les therapeutiques de reference de la prevention des accidents thromboemboliques veineux et arteriels. Ils ont de nombreux avantages et un petit nombre d’inconvenients: iatrogenicite et necessite d’une surveillance biologique pour les AVK, activite limitee a la voie parenterale pour les heparines.

Assisted reproductive techniques (ART) concern procedures designed to increase fertility of couples: artificial insemination, in vitro fertilization (IVF), either classical or after intracytoplasmic sperm injection (ICSI), transfer of frozen embryos, or gamete intrafallopian transfer. Their use has greatly increased these last years. They may be associated with severe ovarian hyperstimulation syndrome and one possible major complication is venous or arterial thrombosis. Thromboses are rare but potentially serious with important sequellae. They are mostly observed in unusual sites such as head and neck vessels and the mechanism is still unknown although hypotheses have been proposed. This review is an update of our knowledge and an attempt to consider guidelines for the prevention and treatment of ART-associated thromboses, which frequently occur when the woman is pregnant. Prevention of severe ovarian hyperstimulation by appropriate stimulation procedures, detection of women at risk of hyperstimulation and of women at high risk of thrombosis should allow reduction of the risk of thrombosis, possibly by administration of a thromboprophylaxis at a timing and dose which can be only determined by extrapolation.

There are strong demands for innovative anti-thrombogenic materials, such as carbon, because of their necessity in fabricating artificial organs and progressive surgical vascular prostheses. Serial platelet deposition, surface topography, and patency were evaluated in control standard (N 45) and carbon-lined (N 45), small diameter (4 mm inner diameter) polytetrafluoroethylene grafts implanted in the abdominal aortic replacement in rabbits. A pilot study of 80 animals—40 carbon-lined (CL) and 40 standard (ST) grafts were used to develop microsurgical techniques. The 2-hour graft patency (Doppler and angiographic studies) showed better patency rate in the CL group (93% vs 80%). In 10 animals (5 ST and 5 CL grafts) the platelet deposition on each prostheses was quantitated by means of Indium 111 labeled platelets in a dual, isotope-platelet imaging technique. Platelet deposition on ST grafts 2 hours after insertion was significantly higher than on the CL grafts (6.60±1.98×103 platelets/mm2 vs 0.82±0.25×103 platelets/mm2;p

Resume Les traitements par les deux principaux inhibiteurs de l’agregation plaquettaire, l’aspirine et le clopidogrel, sont utilises regulierement au long cours par plus d’un million de francais, et le plus souvent, dans la prevention secondaire des accidents thrombotiques arteriels tels que l’infarctus du myocarde, les accidents vasculaires cerebraux ou les complications ischemiques de l’arteriopathie des membres inferieurs. Le terme de « resistance » souvent utilise est source de confusion. Il doit etre explicite et il semble plus judicieux de parler de « variabilite de reponse », terme plus generalement accepte par les specialistes et les chercheurs. Il est preferable d’utiliser le terme de variabilite de reponse plaquettaire car les veritables resistances pharmacologiques sont rares et ce distinguo peut avoir une importance clinique en terme pronostic. De nombreux travaux tant biologiques que cliniques et une abondante litterature ont ameliore la comprehension de ce sujet. Divers examens d’exploration des fonctions plaquettaires peuvent etre utilises pour evaluer l’impact biologique du traitement. Ils devraient dans un proche avenir contribuer a la mise en place de recommandations ou de suggestions pour l’optimisation des modalites therapeutiques. Les resultats attendus de larges etudes prospectives en cours devront au prealable confirmer l’interet potentiel et la pertinence clinique de ces tests avant leur utilisation en routine.

Resume A l’inverse des anciens medicaments, heparines et antagonistes de la vitamine K (AVKs), les nouveaux anticoagulants ont ete prepares pour agir sur une seule cibleles principales caracteristiques de ces nombreuses molecules sont : — leur lieu d’action dans la cascade de la coagulation, et leur mecanisme d’action indirecte en general dependant de l’antithrombine (Fondaparinux et Idraparinux) ou directe (Dabigatran, Rivaroxaban…) ; — la specificite des nouvelles molecules qui ne doivent pas inhiber d’autres enzymes : trypsine, kallikreine, activateur tissulaire du plasmingoene ou t-PA, etc. ; — leur activite par voie parenterale et/ou par voie orale ; — leurs caracteres pharmacocinetiques et leur elimination, le plus souvent renale (Hirudine, Fondaparinux) ou par metabolisme hepatique (Argatroban) doivent etre etablis ; — la tolerance : risque hemorragique (toutes les molecules), intolerance hepatique inattendue pour le Ximelagatran ; — l’existence ou non d’un antidote specifique et le cout du medicament sont aussi des caracteristiques importantes ; — une nouvelle molecule est enregistree en France : l’Arixtra ® ou Fondaparinux, en chirurgie orthopedique majeure, dans le traitement de la thrombose veineuse et de l’embolie pulmonaire et dans leur prevention en milieu medical. Toutefois l’objectif des laboratoires pharmaceutiques est de remplacer les AVKs dans la fibrillation auriculaire. Il existe un besoin reel dans cette indication et le nombre des patients est important et augmente avec le vieillissement de la population.

SummaryLow-molecular-weight heparins (LMWHs) have become the corner stone of antithrombotic treatment but their administration protocol needs to be optimized for certain groups of patients. In this paper, we studied the influence of nadroparin treatment on clot formation process assessed by thromboelastography in patients with carotid artery disease undergoing angioplasty and stenting. Standard thromboelastography assays (in-TEM® and ex-TEM® ) and minimal TF-triggered thromboelastography assay in citrated whole blood were performed in normal volunteers (n=20), in patients with carotid artery disease receiving only antiplatelet treatment (n=30), and in patients undergoing angioplasty receiving nadroparin 5750 anti-Xa IU s.c. twice daily (n=60). Blood samples were collected four hours after a second injection of nadroparin. In a subgroup of LMWH-patients (n=18) blood samples were also obtained prior to first injection of LMWH. Antiplatelet treatment had no effect on any parameter of the thromboelastographic pattern. Nadroparin treatment resulted in significant prolongation of clotting time (CT) and clot formation time (CFT) and significantly reduced α-angle in minimal TF-triggered thromboelastography and 30–38% of nadroparin treated patients had thromboelastographic parameters beyond the normal maximum limit. In-TEM test revealed a significant prolongation of clotting time while ex-TEM was not modified, and 20 to 30% of the patients had thromboelastographic parameters beyond the normal maximum limit. Anti factor-Xa activity in platelet-poor plasma (PPP) was also measured, and statistical analysis showed that prolongation of CFT of minimal TF-triggered TEM was significantly correlated to the levels of anti-Xa activity in patients’ plasma (p=0.04; r2 =0.7). There was no statistical correlation for any other parameter in all tests. In conclusion, the present study shows that nadroparin treatment in patients with carotid artery disease undergoing endovascular procedures induces significant modification of the thrombus kinetics assessed by minimal TF-triggered whole blood thromboelastography. The clinical relevance of these findings has to be evaluated in future studies.

Increased affinity of Von Willebrand factor (VWF) for its platelet receptor GPIb-GPIX complex is responsible of an hemorrhagic disease, which is the Von Willebrand disease (VWD) type 2B when the molecular abnormality is located on the VWF, and the platelet-type 2B VWD when the mutation concern the platelet receptor. Haemostatic abnormalities in these bleeding disorders are similar; prolonged bleeding time, fluctuating thrombocytopenia, decreased factor VIII-VWF complex, and an increased response to low dose of ristocetin in platelets rich plasma. High molecular weight VWF multimers are decreased. We report here 2 cases of type 2B VWD and 1 case of platelet type 2B VWD. The distinction between these 2 diseases was established by studying platelet aggregation with weak doses of ristocetin in mixtures of washed platelets (of normal control or patient)+poor platelets plasma (normal or patient). In one case, VWD 2B was discovered late in a 49 years old man, and the factor VIIIC-VWF complex was not diminished. The distinction between these two congenital diseases is important for the treatment of bleeding manifestations which need VWF concentrates infusions in type 2B VWD and administration of platelets concentrates in pseudo type 2B VWD.

Resume Le traitement anti-thrombotique par l’aspirine, un antiinflammatoire non steroidien (AINS) de reference, est une pratique courante. Cependant, sa toxicite gastro-intestinale, largement admise aujourd’hui, limite cette pratique et justifie son utilisation a faible posologie. La toxicite de l’aspirine est particulierement liee a sa capacite de supprimer la synthese des prostaglandines (PGs) cytoprotectrices, generees par la cyclooxygenase-1 (COX-1), enzyme d’expression constitutive. Les inhibiteurs selectifs de la COX-2, isoforme inductible des COXs de decouverte plus recente, exercent des effets potentiellement antiinflammatoires. Ces inhibiteurs, compares a ceux de la COX-1, sont associes a des risques moindres d’ulcere du tractus digestif et attenuent l’expression des composants inflammatoires leucocytaires, aux proprietes proatherothrombotiques. Neanmoins, des donnees recentes attribuent a certains de ces inhibiteurs un facteur de risque cardiovasculaire non negligeable. La 5-lipoxygenase (5-LOX), une enzyme essentiellement exprimee par les leucocytes, est responsable de la synthese des leucotrienes, principaux mediateurs lipidiques de l’inflammation. La mise au point des inhibiteurs mixtes des deux isoformes de COX et de la 5-LOX pourrait inaugurer une nouvelle voie therapeutique prometteuse. En effet, ces inhibiteurs empecheraient non seulement l’activation des plaquettes, des cellules endotheliales et des leucocytes mais s’opposeraient egalement a leurs interactions aussi bien au plan metabolique que fonctionnel. Outre leur large spectre d’inhibition, ces inhibiteurs seraient depourvus ou legerement pourvus d’effet gastrotoxique indesirable. La polyvalence de tels inhibiteurs pourrait etre particulierement benefique dans le traitement et la prise en charge de l’atherosclerose ou l’interaction leucoplaquettaire domine le processus inflammatoire sous-jacent. (J Mal Vasc 2006 ; 31 : 4-9).

Clot-associated prothrombinase and thrombin activities may contribute to thrombus extension after thrombolytic and anticoagulant treatment. We studied prothrombin activation after adding human purified prothrombin to human clot. By using two different drugs with an exclusive direct anti-activated factor X activity (DX9065a) or anti-activated factor II activity (r-hirudin), we tried to determine whether clot-bound thrombin and prothrombinase could be inhibited in our experimental system when human purified prothrombin was added. Standard clots were prepared from platelet-poor human plasma after addition of calcium. We measured clot-bound thrombin or free thrombin using a direct simple chromogenic assay. In parallel, prothrombin fragment 1 + 2 measurement was used to monitor prothrombin activation. For this, two protocols were used. We introduced the direct inhibitors before starting the activation process (protocol A) or at the time of the activation process (protocol B). We found a direct correlation between thrombin generation and prothrombin fragment 1 + 2 with an increase of thrombin activity on clots and in the incubation mixtures when clots were incubated in human purified pothrombin alone. Two protocols were used: in the first, clots were pre-incubated in presence of drugs before adding prothrombin; and in the second, clots were incubated in the presence of prothrombin and drugs. Prothrombin activation was not inhibited when clots were incubated with r-hirudin and consequently thrombin generation still occurred. However, added r-hirudin blocks thrombin activity on the clots and in the incubation mixture, but does not prevent prothrombin activation, as shown by the increase of prothrombin fragment 1 + 2. In contrast, DX9065a did not suppress clot-bound thrombin. However, DX9065a blocks prothrombin activation whichever protocol was used. The results show that hirudin is a poor inhibitor of thrombin generation in contrast to DX9065a. On the other hand, DX9065a cannot inhibit thrombin bound to clot in contrast to hirudin.

Thrombolysis and percutaneous transluminal angioplasty represent the cornerstone of the pharmacologic treatment of and the interventional approach to patients with myocardial infarction (MI). They are very effective. However, they are hampered by some critical limitations. Therefore, alternatives to standard thrombolytic therapy have been developed. Platelet glycoprotein (GP) IIb/IIIa blockade is under investigation and seems very attractive. This review will focus on the use of GP IIb/IIIa antagonists and thrombin inhibitors as adjunctive therapies to the thrombolytic treatment of patients with acute MI.

Whole blood coagulation analysers are widely used during percutaneous coronary interventions. The precise degree of anticoagulation in patients is important in this setting. The aim of this investigation was to compare the results obtained with ACT (Hemochron) and HMT, the Heparin Management Test (TAS) in patients undergoing percutaneous coronary interventions. Patients ( n =100) were enrolled prospectively. Each patient received 10,000 units of heparin. At the end of the procedure, the mean ACT was 284±31 seconds and the mean HMT was 292±33 seconds. The correlation between the two methods was highly significant ( r =0.64, p

La thromboelastographie mise au point par Hartert en 1948 apres une periode d’etudes enthousiastes avait perdu de son interet durant de nombreuses annees. Recemment, grâce aux progres de l’instrumentation et a l’informatisation, cet examen a ete ressuscite. Ce regain d’attention par la communaute meedicale est lie aux possibilites d’une etude globale de la coagulation en sang total et d’une biologie delocalisee.

Staphylokinase (SAK), a protein with known profibrinolytic properties, has recently given encouraging results in acute myocardial infarction and in peripheral arterial occlusion. The aims of this study were to compare SAK with alteplase (recombinant tissue plasminogen activator rt-PA) in a rabbit arterial thrombosis model, in terms of femoral blood flow kinetics during and after thrombolysis, and to examine the biological effects of systemic fibrinolysis in vivo. We compared two modes of intravenous rt-PA administration, two modes of intravenous SAK administration and three different SAK dose regimens in a rabbit model of femoral artery thrombosis. The main finding was that the infusion of SAK following a single bolus administration gave statistically higher blood flow values than the infusion of the same dose of rt-PA following a single bolus administration (P < 0.05). In this experimental model, we also confirmed that SAK is a fibrin-specific and plasminogen-saving fibrinolytic agent at doses below 0.5 mg/kg. However, at higher doses (1.0 and 1.5 mg/kg), which are above usual therapeutic doses, SAK significantly reduced fibrinogen levels in a dose- and time-dependent manner (P < 0.05). These results indicate that SAK compares favorably with rt-PA in an rabbit arterial thrombosis model, yielding higher blood flow values. Moderate-dose SAK seems to be a fibrin-specific plasminogen activator, but in our model very high doses were associated with a decrease of fibrinogen.

Heparins and vitamin K antagonists (VKA) used commonly are the standard treatment of venous and arterial thromboses. They are very efficient and safe, but have some limitations: iatrogenicity, laboratory monitoring, parenteral use for heparins and fondaparinux. Nowadays, four new inhibitors of factor Xa are used orally (rivaroxaban, apixaban, edoxaban, betrixaban), and they are at least as efficient as heparins and vitamin K antagonists. The objective is to substitute these indirect inhibitors of factor Xa (heparins, low molecular weight heparins and fondaparinux) in the prevention of venous and arterial thromboembolic episodes. The new direct inhibitors do not require routine laboratory monitoring of blood coagulation. They inhibit the extrinsic and the intrinsic pathways of blood coagulation. Rivaroxaban and apixaban are efficacious and safe in the prevention of cerebral infarcts in patients with non-valvular fibrillation. Apixaban is another direct inhibitor of factor Xa used orally which is developed in the same indications as rivaroxaban. Edoxaban and betrixaban are also in development. The objective of this work is to study the pharmacodynamic, pharmacokinetic, the efficacy and safety of these four oral direct factor Xa inhibitors.

New oral anticoagulants which specifically inhibit factor Xa (FXa) or thrombin (FIIa) do not require routine laboratory monitoring. However, they induce a state of hypocoagulation and increase the risk of bleeding. In some clinical situations, such as emergency surgery, hemorrhagic episodes, or recurrent stroke, coagulation monitoring may be useful. A significant number of publications have reported uncontrollable hemorrhagic complications and deaths in patients treated with these new anticoagulants. The selection of the most appropriate clotting assay is based on the drug used and the availability of the test. The new anticoagulants influence all global clot-based tests. Prothrombin time and partial thromboplastin time measured before and after treatment are considered as qualitative tests since they are not specific. Specific anti-Xa and anti-IIa assays are available and results can be expressed in nanogram per milliliter of plasma using calibrated plasmas containing well-established amounts of drug. The fact that there is no specific antidote to reverse the anticoagulant action of the new anticoagulants can impair management of hemorrhagic complications; clinical experience is still limited. Pro-hemostatic treatment with non-activated or activated prothrombin complexes (FEIBA(®)), or as a last recourse with FVIIa concentrates (NovoSeven(®)), has been used with variable results. Some suggestions for the management of patients with bleeding have been published but there is still little clinical evidence for these interventions.

New direct oral anticoagulants (NOAC), inhibitors of factor IIa or Xa, are expected to be widely used for the treatment of venous thromboembolic disease, or in case of atrial fibrillation. Such anticoagulant treatments are known to be associated with haemorrhagic complications. Moreover, it is likely that such patients on long-term treatment with NOAC will be exposed to emergency surgery or invasive procedures. Due to the present lack of experience in such conditions, we cannot make recommendations, but only propose management for optimal safety as regards the risk of bleeding in such emergency conditions. In this article, only dabigatran and rivaroxaban were discussed. For emergency surgery at risk of bleeding, we propose to dose the plasmatic concentration of drug. Levels inferior or equal to 30ng/mL for both dabigatran and rivaroxaban, should enable the realization of a high bleeding risk surgery. For higher concentration, it was proposed to postpone surgery by monitoring the evolution of the drug concentration. Action is then defined by the kind of NOAC and its concentration. If the dosage of the drug is not immediately available, proposals only based on the usual tests, PT and aPTT, also are presented. However, these tests do not really assess drug concentration or bleeding risk. In case of severe haemorrhage in a critical organ, it is proposed to reduce the effect of anticoagulant therapy using a nonspecific procoagulant drug (activated prothrombin concentrate, FEIBA, 30-50U/kg, or non-activated 4-factors prothrombin concentrates 50U/kg). For any other type of severe haemorrhage, the administration of such a procoagulant drug, potentially thrombogenic in these patients, will be discussed regarding concentration of NACO and possibilities for mechanical haemostasis.

Studies on the pharmacological and pharmacodynamic properties of heparins are complicated by the heterogeneity of heparin preparations. It is important to consider the molecular weight distribution, which may differ from one preparation to another. Molecules with a molecular weight ranging from about 2000 to 5000D are abundant in low molecular weight heparins (LMWHs), while they are present at a very low concentration in standard heparin. The clinical relevance of this difference is not fully understood. Recent work from our laboratory demonstrates that factor VII activation to factor VIIa in vitro is significantly inhibited by heparins. This is another aspect of some importance in understanding the mechanism of action of heparins. The bioavailability and plasma clearance of anti-Xa activity are well documented. In contrast, clear results regarding the bioavailability of anti-IIa activity are still missing. Recent data indicate that the anti-Xa activity of different molecules of heparin does not increase in parallel with the molecular weight of the heparin chain. In contrast, the anti-IIa activity of different molecules of heparin increases in parallel with the molecular weight. This could explain why activated partial-thromboplastin time is less prolonged with LMWHs than with standard heparin. There is growing evidence that anti-Xa activity contributes to the antithrombotic effect of heparins, although it is generally accepted that anti-IIa activity plays a major role. There have been 3 important findings from recent work on the pharmacology of heparins: i) heparin at a very low dose has thrombopoietic activity; ii) in hip surgery, the incidence of heparin-induced thrombocytopenia is significantly lower in patients receiving subcutaneous LMWHs for 2 weeks compared with patients receiving unfractionated heparin; and iii) the risk of osteoporosis with long term treatment with LMWHs seems lower than with standard heparin.

A considerable amount of work has been devoted to thrombolytic therapy (about 3000 references from 1991 to 1995 in a Medline search). The most important and well established indication of thrombolytic treatment is acute myocardial infarction (MI). Megatrials have evidenced a significant 30 to 40% reduction in hospital mortality in the treated patients. However, lack of sufficient thrombolysis in approximately 25% of patients, reocclusion in 6 to 16% of patients and intracranial hemorrhage in about 0.5% of patients are the main concerns regarding thrombolysis. Three approaches should improve the results of thrombolytic therapy in acute MI: earlier medical treatment, use of more efficacious thrombolytic agents in combination with more active antithrombotic agents and reduction of severe bleeding with safer combination of drugs. An improved of laboratory monitoring may also reduce the incidence of severe hemorrhagic events. In acute pulmonary embolism (PE), a change of indication for treatment based on echocardiography and high probability ventilation-perfusion lung scan results (without requiring pulmonary angiography) could broaden the use of thrombolysis. However, thus far, there has not been a demonstration of a reduction in mortality in large controlled studies. Thrombolysis in acute ischemic stroke is an attractive treatment but thrombolytic treatment is still at an experimental stage. However, the successful use of rt-PA in acute MI has renewed the interest in thrombolysis for focal cerebro-vascular ischaemia. Large controlled studies with SK, rt-PA or UK locally or intravenously administered have been recently undertaken to evaluate the benefit/risk ratio of treatment which seems surprisingly variable in different subgroups of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

SummaryExposure to streptokinase (SK) elicits anti-SK antibodies (Abs), which inhibit fibrinolysis and induce platelet aggregation. The mechanism of the latter is not fully understood, although it seems to involve platelet binding by a plasminogen streptokinase and anti-SK ternary complex. Anti-SK Abs were purified by affinity chromatography from serum of patients having received SK for acute myocardial infarction (AMI), and were shown to be of the IgG type. Their effects were studied with (i) human platelets in citrated plasma in the presence of SK or acetylated plasminogen-SK activator complex (APSAC), and (ii) in washed platelets, resuspended in Tyrode buffer after lowering the ionic strength, in the presence of APSAC (which provides both SK and plasminogen). An antibody concentration-response curve was obtained, showing a plateau in the presence of 0.1 mg/ml IgG. By increasing the concentration of APSAC, we obtained a unimodal response curve, the optimal concentration of APSAC being 0.05 U/ml. Aggregation was suppressed by chelating calcium with EDTA, blocking fibrinogen binding by the synthetic peptide Arg-Gly-Asp-Ser (RGDS), and raising intraplatelet cAMP with Iloprost (a prostacyclin analogue). Aggregation required the interaction of the anti-SK Ab Fc domain with the platelet Fc-gamma receptor type II, also known as CD32, since: (i) it was blocked by the monoclonal antibody IV-3 directed against CD32, (ii) it did not occur with F(ab)’2 fragments, which block the response to the intact IgG. The clinical relevance of these platelet-activating anti-SK antibodies remains to be determined. Two factors might influence clinical outcome: (i) the amount and type of pre-existing anti-SK Abs; (ii) the known interindividual variability of the platelet response to binding and activation by IgG involving the CD32 molecule.

SummaryTo assess the role of genetic and environmental factors in the predisposition to atherosclerosis, 682 students whose father had suffered a myocardial infarction before the age of 55 (“cases”) and 1312 controls matched for age and sex, were recruited from 14 Universities in Europe. Fibrinogen, factor Vile and PAI-1 were compared between cases and controls across European regions. Fibrinogen and factor Vile were positively correlated with BMI, smoking and contraception. PAI-1 was positively and independently correlated with BMI and waist-to-hip ratio, and negatively with contraception. Factor Vile and PAI-1 were correlated with cholesterol and triglycerides, and fibrinogen was weakly correlated with LDL-cholesterol. After adjustment for covariates and lipids, fibrinogen level was significantly higher in male cases than in controls (2.38 vs 2.29, p

Cutaneous necrosis is a rare complication of vitamin K antagonist therapy. It presents as cutaneous hemorrhagic necrosis and usually occurs at the start of treatment. We describe an atypical case of recurrent skin necrosis after two years of treatment with fluindione.A 70-year old woman with a history of venous thromboembolism and obesity presented with a large haemorrhagic necrosis of the abdominal wall. She had been treated with fluindione for two years. Genetic protein C deficiency was discovered. Resumption of vitamin K antagonist therapy was followed by recurrence of skin necrosis despite concomitant administration of heparin. Treatment with vitamin K antagonists could not be continued.This observation is unusual due to the late onset of skin necrosis. The condition usually begins shortly after initiation of vitamin K antagonist therapy, generally between the third and the sixth day of treatment. It is due to a transient hypercoagulable state in patients with protein C deficiency or, in rare cases, protein S deficiency. This late-onset skin necrosis, occurring many years after initiation of anticoagulant therapy, may be explained by a sudden worsening of pre-existing protein C deficiency due to infectious and iatrogenic factors.

Homozygous or double heterozygous protein-C deficiency can present at birth with purpura fulminans or later in life with venous thrombosis. Two homozygous patients who had previously sustained thrombotic episodes were investigated at a time when they were asymptomatic and not receiving antithrombotic therapy. The plasma levels of protein-C antigen and activity in both individuals were approximately 20% of normal. We administered a highly purified plasma-derived protein C concentrate to these individuals and monitored levels of several markers of in vivo coagulation activation. Assays for protein-C activation (activated protein C and protein C activation peptide) showed a sustained increase from reduced baseline levels, whereas thrombin generation (as measured by prothrombin fragment F1 + 2) gradually decreased over about 24 hours into the normal range. These investigations provide direct evidence that protein C is converted to activated protein C in vivo, and that the protein-C anticoagulant pathway is a tonically active mechanism in the regulation of hemostatic system activation in humans.

Increased plasma fibrinogen concentration is a major cardiovascular risk factor. Conflicting results on genetic variations in plasma fibrinogen levels have been reported. Furthermore, whether fibrinogen genotype is associated with the risk of ischemic heart disease has not been studied so far. An HaeIII restriction fragment length polymorphism of the beta-fibrinogen gene was used in a case-control study to investigate the genetic variation at this locus in relation to plasma fibrinogen concentrations and the risk of myocardial infarction (MI). Five hundred thirty-three male patients aged 27-66 years and 648 control subjects were recruited from four World Health Organization MONICA centers in Northern Ireland and in France. The absence of the HaeIII cutting site (H2 allele) was associated with a significant rise in fibrinogen concentrations in both patients and control subjects. The effect of the HaeIII polymorphism on plasma fibrinogen levels did not significantly differ between centers. Fibrinogen levels were higher in smokers than in nonsmokers. The difference between the two groups was larger in subjects with the genotype H2H2 than in those with either genotype H1H1 or H1H2, regardless of the case-control status. However, there was no significant interaction between smoking status and genotype in their effects on variance in fibrinogen levels, whereas fibrinogen levels. HaeIII genotype accounted for approximately 1% of the total variance in fibrinogen levels, whereas smoking and age together explained 7% and 5% in control subjects and patients, respectively. The frequency of the H2 allele was 0.21 in control subjects and 0.19 in patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Assisted reproductive techniques (ART) concern procedures designed to increase fertility of couples: artificial insemination, in vitro fertilization (IVF), either classical or after intracytoplasmic sperm injection (ICSI), transfer of frozen embryos, or gamete intrafallopian transfer. Their use has greatly increased these last years. They may be associated with severe ovarian hyperstimulation syndrome and one possible major complication is venous or arterial thrombosis. Thromboses are rare but potentially serious with important sequellae. They are mostly observed in unusual sites such as head and neck vessels and the mechanism is still unknown although hypotheses have been proposed. This review is an update of our knowledge and an attempt to consider guidelines for the prevention and treatment of ART-associated thromboses, which frequently occur when the woman is pregnant. Prevention of severe ovarian hyperstimulation by appropriate stimulation procedures, detection of women at risk of hyperstimulation and of women at high risk of thrombosis should allow reduction of the risk of thrombosis, possibly by administration of a thromboprophylaxis at a timing and dose which can be only determined by extrapolation.

Thrombin inhibition is an important objective in the prevention and treatment of thrombosis. A new molecule, dabigatran etexilate or Pradaxa(®), has been recently licensed for thromboprophylaxis in major orthopedic surgery in several countries but not in the USA. In contrast, the FDA has approved it for prevention in patients with non-valvular atrial fibrillation. This new orally active anticoagulant is being developed for the treatment of venous thromboembolism and acute coronary syndromes in patients with non-valvular atrial fibrillation. Dabigatran is a reversible inhibitor of free thrombin and clot-bound thrombin. An oral thrombin inhibitor melagatran is no longer available due to hepatic toxicity. Several other thrombin inhibitors are used via parenteral administration: lepirudine and desirudine, bivalirudine and argatroban. They are mostly given to patients with heparin-induced thrombocytopenia (HIT). Bivalirudine is used for acute coronary syndrome in patients undergoing percutaneous interventions. The main pharmacologic characteristics of thrombin inhibitor agents are presented focusing on dabigatran etexilate and including the main results of clinical trials.

The purpose of this work was to analyse management practices for patients given anticoagulants or antiplatelet agents such as aspirin, clopidogrel and who are to undergo an invasive procedure or surgery. The modalities for the transition from oral agents to low-molecular-weight-heparin (LMWH) or unfractionated heparin (UFH) are studied. The recommendations or suggestions using the ACCP score: grade 1 recommendations are strongly motivated and indicate whether the benefit overbalances or not the risk, the burden, and the cost of the treatment. Grade 2 recommendations are considered to be suggestions. They imply that the individual physician chooses between different therapeutic strategies. For the purpose of this work, the most important recommendations are the following

Guidelines concerning the prevention and treatment of pregnancy-associated venous thromboembolism (VTE) have been elaborated by the American College of Chest Physicians and published in Chest in 2008. In this review, they have been compared with European guidelines and discussed taking into account the papers published since 2008.Most recommendations are of low grade of evidence because randomized studies are lacking during pregnancy and many reflect guidelines proposed by experts. The decisions on the most appropriate prophylaxis, dose to be administered and moment of pregnancy for starting prophylaxis are often decided case by case after careful assessment of the risk of pregnancy-associated VTE, on one hand, and the risk for the mother, on the other.Risk factors (ageor= 35, obesity, history of VTE with or without sequellae, in vitro fertilization)or thrombophilia have to be taken into account. Scores have been proposed to improve standardisation and evaluation of the risk of VTE and they should be validated.

OBJECTIVE--To determine whether prophylactic treatment with low molecular weight heparin reduces the incidence of thrombosis in patients who have had general or orthopaedic surgery. DESIGN--Meta-analysis of results from 52 randomised, controlled clinical studies (29 in general surgery and 23 in orthopaedic surgery) in which low molecular weight heparin was compared with placebo, dextran, or unfractionated heparin. SUBJECTS--Patients who had had general or orthopaedic surgery. INTERVENTION--Once daily injection of a low molecular weight heparin compared with placebo, dextran, or unfractionated heparin. MAIN OUTCOME MEASURES--Incidence of deep venous thrombosis, pulmonary embolism, major haemorrhages, and death. RESULTS--The results confirm that low molecular weight heparins are more efficacious for the prophylactic treatment of deep venous thrombosis than placebo (common odds ratio 0.31, 95% confidence interval 0.22 to 0.43; p < 0.001) and dextran (0.44, 0.30 to 0.65; p < 0.001). The results suggest that low molecular weight heparins are also more efficacious than unfractionated heparin (0.85, 0.74 to 0.97; p = 0.02), with no significant difference in the incidence of major haemorrhages (1.06, 0.93 to 1.20; p = 0.62). CONCLUSIONS--Low molecular weight heparins seem to have a higher benefit to risk ratio than unfractionated heparin in preventing perioperative thrombosis. However, it remains to be shown in a suitably powered clinical trial whether low molecular weight heparin reduces the risk of fatal pulmonary embolism compared with heparin.

BACKGROUND Plasmin has been reported both to activate platelets and to inhibit platelet functions. The latter effect was thought to be caused by proteolysis of the main membrane glycoproteins. METHODS AND RESULTS We found that incubation of citrated human platelet-rich plasma with streptokinase (SK) (300 IU/ml) does not produce any detectable activation but leads to a time-dependent inhibition of ADP-induced aggregation accompanied by substantial fibrinogenolysis. These effects were abrogated by previous addition of a plasmin inhibitor, aprotinin. Crossover experiments (SK-treated or control platelets mixed with SK-treated or control plasma) demonstrated that the platelets remained functional and that the aggregation defect was caused by fibrinogenolysis. Further experiments (addition of purified fibrinogen to fibrinogen-depleted plasma with either SK or thrombin) suggested that in addition to the low residual level of fibrinogen, fibrinogen degradation products had an inhibitory effect. Under the same conditions, tissue-type plasminogen activator (t-PA) (3,000 ng/ml) had no effect on platelet aggregation, and plasma fibrinogen was not significantly lowered. The effects on glycoproteins IIb-IIIa of incubation with SK, t-PA, or plasmin were assessed with immunoblots with murine monoclonal antibodies directed against either part of the complex, which is the receptor for fibrinogen. Proteolysis was detected only in the presence of EDTA, a potent chelator of divalent cations. CONCLUSIONS The incubation of human platelets in citrated plasma with SK concentrations obtained during therapy leads to an aggregation defect that is related to the decrease in fibrinogen, the adhesive protein involved in this function, and to the impeding effect of fibrinogen degradation products on its binding onto platelets but not to an alteration of the corresponding platelet receptor, the heterodimer glycoproteins IIb-IIIa.