Haemostasis最新文献

Theoretically, thrombolytic therapy would appear to offer benefits over standard heparin therapy in the treatment of venous thromboembolism based on the more rapid resolution of thrombus. In this paper, the results of clinical trials performed with thrombolytic agents in the initial treatment of both deep vein thrombosis (DVT) and pulmonary embolism (PE) are reviewed. Although there have been positive findings with surrogate markers, studies to date have failed to demonstrate that thrombolytic therapy is associated with an improved long-term clinical outcome in patients with DVT or PE. Recent reports have suggested that thrombolytic agents could be clinically useful in a subgroup who have right ventricular dysfunction on echocardiography. Randomized clinical trials, with clinically relevant endpoints, are required to determine the efficacy and safety of thrombolytic therapy in these patients.

This review article begins by discussing the molecular basis of the blood anticoagulant effect of heparin and some species of heparan sulphate (HS). A highly specific pentasaccharide sequence, containing a glucosamine 3-O-sulphate group, is a key structural element for this action. The biosynthesis of heparin and HS is outlined. Different types of HS proteoglycans exist. Analysis of HS preparations from different mammalian organs has indicated that the structural variability of the polysaccharide is due to regulated polymer modification. In addition to antithrombin, HS chains bind a very large number of other proteins in vivo. Such binding often appears to depend on the presence of specific sequences of different monosaccharide building-blocks and has diverse implications. Many physiological and pathological processes in the mammalian body appear to be influenced or regulated by HS proteoglycans. For example, the proper assembly of HS chains is believed to play an important role in normal embryonic and mammalian development. Diseases such as diabetes, amyloidosis and Alzheimer's may be associated with changes in HS structure. Finally, the possibilities and strategies for developing drugs based on HS chemistry are discussed.

The antiphospholipid syndrome (APS) is now emerging as an important cause of recurrent pregnancy loss. A variety of treatments, including steroids, aspirin, heparin and immunoglobulin, alone or in combination, have been assessed in experimental studies and in clinical trials. Steroids are no longer recommended as first-line therapy for patients with APS without overt lupus, because they are associated with significant foetal and maternal morbidity. Based on data from recent trials, heparin plus low-dose aspirin appears to be the regimen of choice for patients with APS who have a history of thrombosis or pregnancy losses with aspirin alone. Aspirin is safe in pregnancy. Subcutaneous heparin does not cross the placenta and therefore has no adverse effects on the foetus. For the mother, however, potential side effects of heparin treatment include bleeding, thrombocytopenia and osteoporosis. Warfarin must be avoided during the first trimester but may have a role to play subsequently in certain subsets of patients. Some studies have demonstrated that combined therapy with prednisone and aspirin, or with heparin and aspirin, may improve the outcome in women with autoimmune disorders who are undergoing in-vitro fertilization.

Women with mechanical heart valves require anticoagulation during pregnancy. Continued anticoagulation with coumadin throughout the first trimester can result in foetopathic effects in 6.4% (95% CI, 4. 6-8.9%) of cases. Replacement of warfarin with heparin between 6 and 12 weeks' gestation eliminates this risk. Although warfarin does cross the placenta, adverse central nervous system effects associated with its use are very few. Warfarin is effective in preventing maternal thromboembolic complications, while the effectiveness of heparin in preventing valve thrombosis is unproven. The optimal management (grade C2 recommendation) of women with mechanical heart valves may involve the use of warfarin throughout pregnancy except for two time periods - between 6 and 12 weeks' gestation and after 36 weeks of gestation. During these times, adjusted-dose unfractionated heparin should be used to rigorously maintain a therapeutic mid-interval activated partial thromboplastin time of 2.0 to 2.5 times the control. The additional use of low-dose aspirin should be considered, particularly in women with high-risk valves, women with previous transient ischaemic attacks and/or strokes, and women with atrial fibrillation.

Data from several large-scale studies have suggested that low-molecular-weight heparin (LMWH) may be superior to standard heparin therapy in the setting of unstable coronary syndromes. Studies looking at the optimal duration of treatment have produced conflicting results; however, data from a recent large trial suggest that prolongation of treatment is associated with a significant benefit. The recommended initial treatment for patients with unstable coronary syndromes is a combination of LMWH and aspirin. Stablilized patients at moderate or high risk - such as those with ST-segment depression or increased troponin levels - should continue with this treatment until they have undergone coronary angiography and, if appropriate, an invasive procedure. In a recent small study among patients with acute myocardial infarction, the use of LMWH as an adjunct to streptokinase produced significant therapeutic benefits. Other potential uses for LMWH include a role in angioplasty.

Direct thrombin inhibitors may offer advantages over indirect thrombin inhibitors in the management of patients with acute coronary syndromes (ACS). Two direct thrombin inhibitors, hirudin and bivalirudin, have been investigated in Phase II and Phase III clinical trials. Based on the results of a meta-analysis of study data from 25,000 patients, hirudin appears to be more effective than unfractionated heparin (UFH) in the treatment of patients with ACS, but it is associated with an increased rate of major bleeding. A meta-analysis of a smaller patient population has suggested that bivalirudin, too, may be more efficacious than UFH and may also be safer.

Venous thromboembolism (VTE) is an important cause of obstetric morbidity and mortality. Its management during pregnancy is problematic because anticoagulants, the cornerstone of initial therapy for VTE, may have significant foetal as well as maternal side effects. Unfractionated heparin has been the anticoagulant of choice in pregnancy; however, there is growing clinical experience with low-molecular-weight heparin (LMWH) in this patient population. A recently published systematic review of the literature suggests that the use of LMWH during pregnancy is not associated with adverse foetal/infant outcomes. Moreover, its long-term use appears to be safe for the mother, as symptomatic osteoporosis, bleeding and heparin- induced thrombocytopenia occurred only infrequently. There are limited data regarding the efficacy of anticoagulant therapy in the treatment of VTE during pregnancy, and treatment recommendations have largely been extrapolated from data in non-pregnant patients and case series of pregnant patients. This paper will briefly review the challenges and areas of controversy associated with the use of anticoagulants in the treatment of pregnancy-associated VTE.

Hereditary thrombophilia increases the risk of thrombosis during pregnancy and postpartum. The recommendations resulting from the Fifth American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy were published in Chest in late 1998. However, levels of evidence on this subject were low (C2). Furthermore, since publication of this ACCP consensus, new studies have demonstrated the safety of low-molecular-weight heparins (LMWHs) in pregnant women. In addition, it is now clear that all thrombophilias are not associated with the same level of thrombotic risk: factor V Leiden mutation and factor II 20210A variant are associated with a lower risk than antithrombin deficiency. Consequently, the ACCP recommendations have been reconsidered in the light of a more widespread use of LMWH and taking into account the differences in the level of risk of the different thrombophilias. A prophylaxis of thrombosis in pregnant women with thrombophilia is proposed based on published data and our personal experience. Although laboratory monitoring is usually not required during treatments with LMWH, it seems to be needed in pregnant women who receive long-term treatments.