We have identified a genetic polymorphism of factor VII that is strongly associated with plasma factor VII coagulant activity (factor VIIc) in healthy individuals from the United Kingdom. This polymorphism was detected after Msp I digestion of polymerase chain reaction-amplified genomic DN A. In a sample of 284 men, the frequency of the M2 allele (loss of cutting site) is 0.1, and individuals with the M1M2 genotype have factor VIIc levels 22% below the sample mean (p<0.0001). F actor VII is a serine protease found in plasma and is one of the vitamin K-dependent coagulation factors, along with prothrombin (factor II), factors IX and X, and proteins C and S (for review, see Reference 1). Factor VII is synthesized principally in the liver and is secreted as a single-chain glycoprotein of apparent M, 48,000.
2Cleavage of human factor VII to factor Vila, a two-chain form held together by disulfide bonds, results in a 20-to 25-fold increase in enzyme activity.2 This cleavage can be effected by a number of activated coagulation factors, including factors Xlla, Xa, and IXa and thrombin.2 In the presence of tissue factor and calcium ions, factor Vila converts factor X to factor Xa in the initiating reaction of the extrinsic coagulation pathway.
The proven benefit of aspirin in the secondary prevention of cardiovascular disease and its possible value in primary prevention must be weighted against its potential hazards. This paper is an overview of the gastrointestinal toxicity of aspirin, its most serious complication after intracerebral haemorrhage. Information on toxicity has been drawn only from randomised trials, thus avoiding the potential biases of observational studies. All randomised placebo controlled trials listed in the Anti‐platelet Trialists Collaboration where a direct aspirin‐placebo comparison was possible were included. Twenty‐ one trials were included, all but one of secondary prevention. There were over 75,000 person years of aspirin exposure. The pooled odds ratios for categories of gastrointestinal bleeding (e.g. haematemesis, melaena) were between 1.5‐2.0; fatal bleeds were very rare. The risk of peptic ulcers was 1.3 and of upper gastrointestinal symptoms 1.7. These risks were lower than those found in observational studies. Attributable disease rates are also presented. For haematemesis for example they varied from 0.2‐1.0 per 1000 person years. Toxicity was dose related. Aspirin does have significant gastrointestinal toxicity, although this is rarely fatal. More recent work has demonstrated the efficacy of low doses of aspirin (75 mg daily) but there is limited information yet available on its toxicity.
SummaryWe investigated the association between fibrinogen levels and a HaeIII restriction fragment length polymorphism located at −453 bp from the start of transcription of the β fibrinogen gene. 292 healthy men aged 45 to 69 years, recruited from general practices throughout Britain, were studied. None had a history of ischaemic heart disease. 41.1% (120) were smokers and fibrinogen levels were higher in this group. The frequency of the noncutting allele (designated H2) was 0.19 and was the same in smokers and non-smokers. The H2 allele was associated with elevated levels of fibrinogen in both smokers and non-smokers and the effect of genotype was similar in both groups. After smoking, HaeIII genotype was the strongest predictor of fibrinogen levels and explained 3.1% of the variance in fibrinogen levels. These results confirm earlier studies that variation at the fibrinogen locus contributes to the between-individual differences in plasma fibrinogen level.
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