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Purpose: This review describes recent views on blood coagulation and abnormalities of its physiological control that predispose to thrombosis, suggests that venous thrombosis and pulmonary embolism are more prevalent in Asia than was previously thought, and examines recent trials of novel anticoagulants for thrombosis prevention., Sources: 'Medline' was used to search for publications in English or with English language abstracts., Content and Conclusions: The study of blood coagulation is basic to understanding clotting and bleeding disorders, their prevention and treatment. Tissue factor, factor Xa, and thrombin are pivotal; together with physiological controls (positive and negative feedback loops, and natural anticoagulants) that first enhance thrombin generation but then preserve vessel patency by limiting haemostatic plug formation to areas of injury. Abnormalities in these mechanisms can increase thrombosis risk (thrombophilia). The traditional impression that venous thromboembolism is rare in Asia has been reinforced by the rarity of thrombophilic genetic polymorphisms outside of European populations. Nevertheless, there is increasing evidence for an increasing prevalence of symptomatic vein thrombosis and pulmonary embolism in Asia, and that thrombosis rates in 'high risk' clinical settings among elderly patients (as after major joint surgery or a stroke) now approach levels reported from the West. This indicates the need for greater clinical awareness of these conditions. Drugs now used routinely for thrombosis prevention in the West (especially low molecular weight heparins) are effective and relatively safe. New anticoagulants were even more effective in recent trials. There is urgent need for studies in Asia that define the locally relevant benefits and hazards of the increasing range of agents now available.

Fondaparinux (a synthetic heparin analogue) (Sanofi-Synthelabo; Paris, France and Organon Research; Oss, The Netherlands) is the subject of intense recent clinical evaluation for the prevention and treatment of venous and arterial thromboembolism. The drug replicates the sulphated antithrombin-binding pentasaccharide sequence in heparin and induces potent and specific antithrombin-mediated anti-Xa activity with excellent bioavailability and a long circulating half-life of 18 hours that makes it ideal for once-daily subcutaneous dosing. Its very short chain length ensures this heparin pentasaccharide (PS) is devoid of anti-factor IIa activity. No need for laboratory monitoring is anticipated. Fondaparinux does not cross-react ex vivo with the anti-platelet antibodies responsible for heparin-induced thrombocytopenia. Fondaparinux was evaluated in four large, randomized, placebo-controlled, double-blind phase III trials of deep vein thrombosis prevention after major joint surgery where the PS given after surgery was compared with a low molecular weight heparin (LMWH). LMWH was started before surgery in two comparisons and soon after surgery in the others. The trials shared the same blindly adjudicated efficacy and safety endpoints: efficacy was measured by recording subclinical deep vein thrombosis detected by screening with bilateral venography, plus clinically suspected and confirmed symptomatic thrombosis and embolism; safety was indicated by the rate of major bleeding. Bleeding was considered major if it caused death or reoperation, affected an internal organ, or was overt and associated with a bleeding index of 2 or more. By comparison with LMWH, 2.5 mg/d of the PS beginning 4 to 8 hours after wound closure reduced venous thromboembolism rates by 56% and 26% after elective hip replacement, 63% after knee replacement, and 62% after hip fracture surgery. In three studies and overall, the effect was statistically very significant and included similarly reduced rates of proximal deep vein thrombosis. In absolute terms, the DVT rates with PS are the lowest yet seen after major joint surgery. Trends toward more major bleeding with PS in three studies were statistically significant in one trial. PS did not increase risks from reoperation, internal bleeding, or death because of bleeding, because between-group differences were caused entirely by an excess of patients with a raised bleeding index. Post hoc analysis suggests this excess can be explained by too-early postoperative drug administration and may be avoided without loss of efficacy by giving the first PS injection 6 to 8 hours after surgery. Results of phase III treatment trials for DVT/PE will soon be available, but studies in coronary artery disease are less advanced., (Copyright 2002 Lippincott Williams & Wilkens, Inc.)

To determine the incidence and prognostic significance of mutation in the N-ras gene in de novo acute myeloid leukemia (AML) we performed an analysis of bone marrow smears from 219 patients with de novo AML treated between 1984 and 1986 and followed for at least six years. DNA extracted from bone marrow smears taken at diagnosis was screened for the presence of mutations in codons 12 and 13 of exon 1 by using the polymerase chain reaction to insert an Hph1 restriction enzyme site into DNA. Presumptive mutations were confirmed by direct sequencing. Mutations were detected in a total of 26 patients (12%); in nine patients (4%) in codon 12 only, in ten patients (5%) in codon 13 only, and in seven patients (3%) in both codons. Mutations in codon 12 or codon 13 were not associated with any clinical features. Mutations in codon 12 had no prognostic significance but mutations in codon 13 were associated with an increased remission rate, a more durable remission, and a significantly prolonged survival which appeared to be independent of other prognostic factors.