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Most people with haemophilia who were treated with blood products before the introduction of virus-inactivation procedures were infected with the hepatitis-C virus (HCV). However, there is little quantitative information about the long-term effects on mortality of such infection. We carried out a cohort study of mortality from liver cancer and liver disease in 4865 haemophilic men and boys in the UK. They were treated between 1969 and 1985 with blood products carrying a high risk of HCV infection, and were followed up from first recorded exposure to Jan 1, 1993. Based on death-certificate information, mortality was 16·7 times higher than in the general population for liver disease (95% CI 12·5–22·0; 51 deaths), and 5·6 times higher (1·8–13·0; five deaths) for liver cancer. For men and boys with severe haemophilia who were not infected with HIV-1, the cumulative risks of death from chronic or unspecified liver disease or from liver cancer in the 25 years since first recorded exposure to high HCV-risk products were 1·4% (0·7–3·0) at all ages, and 0·10% (0·01–0·7), 2·2% (0·8–6·1), and 14·3% (4·5–40·9) for those with first recorded exposure at ages under 25, 25–44, and 45 or older. For those with haemophilia and HIV-1 infection, the corresponding risks were 6·5% (4·5–9·5) at all ages, and 3·8% (2·1–6·8), 17·1% (10·0–28·5), and 18·7% (6·4–47·6) in the three age-groups. In those with severe haemophilia, age-standardised all-cause mortality was stable during 1969–84 but increased during 1985–92 in both HIV-1-infected and HIV-1-uninfected groups. Among those not infected with HIV-1, the increase in all-cause mortality resulted largely from deaths attributed to chronic or unspecified liver disease or liver cancer in men aged over 45. There is an emerging risk of mortality from liver disease and liver cancer in the UK haemophilia population in individuals both infected and uninfected with HIV-1, which probably results from infection with hepatitis C.

The hemostasis laboratory has a vital role in the diagnosis and management of patients with familial and acquired hemorrhagic and thrombotic disorders.Rapid changes in the number and complexity of tests in this discipline have presented challenges for laboratories, as they develop quality programs for the oversight of this testing.

\"Over the last decades, major progress has been made in quality assurance of hemostatic laboratory assays. This book will be an indispensable part of every hemostasis laboratory, where, given its hands-on nature, it will rarely sit to get dusty on the shelves.\" -Frits R. Rosendaal, Leiden University Medical Center The hemostasis laboratory has a vital role in the diagnosis and management of patients with familial and acquired hemorrhagic and thrombotic disorders. Its role in the monitoring traditional anticoagulant therapy as well as therapy using new anticoagulants presents new challenges to the laboratory. Quality in Laboratory Hemostasis and Thrombosis not only addresses these important issues, but also covers international guidelines for testing, the development of international standard materials, management of hemostasis testing from the laboratory to the point of care as well as molecular genetic testing. Designed as a guide for all those working in hemostasis laboratories, this book details a quality program that, when put into place, will help to improve standards in testing. All of the authors are internationally recognised for their work in hemostasis and thrombosis. Using their experience, they provide information on standards, equipment and methods that will guide the development of a quality program to support all activities in the hemostasis laboratory.

To compare the inhibitory effects of aspirin on prostaglandin synthesized by vessel walls and platelets, we obtained vein segments from five subjects before they were given 150 or 300 mg of aspirin and at various intervals afterward. We then measured prostacyclin (PGI 2 ) synthesis with a radioimmunoassay for its stable metabolite, 6-keto-prostaglandin F 1α . Platelet production of thromboxane A 2 was measured with a radioimmunoassay for its stable metabolite, thromboxane B 2 . Two hours after aspirin had been given, 81 to 100 per cent inhibition of PGI 2 synthesis was demonstrated; 86 per cent inhibition was still evident in one subject tested eight hours after administration. Simultaneously, platelet production of thromboxane B 2 was completely inhibited for more than 24 hours. We conclude that there is little difference between the initial inhibitory response of platelet cyclooxygenase and that of vessel-wall cyclooxygenase to these doses of aspirin. Our results also indicate that in male subjects the prolonged template bleeding time after aspirin is not the consequence of selective inhibition of platelet production of thromboxane. (N Engl J Med. 1981; 304:76–9.) IT has been recognized for several years that aspirin inhibits platelet aggregation by acetylating the enzyme cyclooxygenase. 1 , 2 However, the potentially beneficial effect of aspirin on prostaglandin biosynthesis in platelets may be offset by a similar inhibitory effect on prostacyclin (PGI 2 ) generated by normal vascular endothelial cells. In this study, we measured PGI 2 synthesized by segments of veins obtained before a single low dose of aspirin was given to normal volunteers and at various times afterward. The results were compared with the inhibitory effect of aspirin on platelet production of thromboxane A 2 (TXA 2 ), determined in . . .

Sequences within intron 22 of the factor VIII (FVIII) gene have been implicated in the cause of haemophilia in almost 50% of severely affected patients. The changes result from intrachromosomal rearrangements of the tip of the long arm of the X chromosome, one break-point being within intron 22 of the FVIII gene. The rearrangements can be identified by Southern blot and we report use of this procedure to detect rearrangements in 11 of 23 unrelated families with severe haemophilia A. Of 22 patients studied, none of the 10 with the gene rearrangement had at any time developed inhibitors to FVIII, compared with 7 of 12 lacking the rearrangement.

This chapter deals with issues relating to the assay of clotting factors in plasma with particular emphasis on FVIII:C. This includes pre analytical variables, the influence of different assay components, appropriate assay design and calibration, assays in the presence of lupus anticoagulant and assays in the presence of severe deficiency or elevated levels. The importance of using more than one type of Factor VIII assay in the initial investigation of patients with suspected hemophilia is discussed. This chapter includes discussion of assays in plasma from patients treated with concentrates but will not address the assignment of potencies to concentrates (addressed elsewhere in this book).

An External Quality Assessment (EQA) program is able to determine the accuracy of the results obtained by individual laboratories by comparing the results obtained on the same sample with those obtained by other participating laboratories. Larger programs are also able to provide important information in respect of the reliability and efficiency of different reagents and different instrument‐reagent combinations. An inherent problem for EQA providers is the establishment of target values. The large number of variables that operate within virtually all laboratory hemostasis procedures precludes the use of reference methods for the generation of target values. It also limits the value of assessment against the overall median value. For this reason, individual laboratory results are ideally assessed against the peer group median result. The statistical assessment of individual laboratory performance is also problematic and different programs have adopted different criteria for the determination of satisfactory performance. This issue is currently being addressed by an international group of EQA providers. The growing introduction of EQA programs in the developing world represents an important advance in respect of the diagnosis and management of patients with hemostatic and thrombotic disorders.

Many tests performed in coagulation laboratories are vital for the accurate diagnosis and safe management of patients with familial and acquired bleeding and thrombotic disorders. It is particularly important that results are accurate and reliable when investigations are undertaken to determine possible familial disorders of hemostasis. A laboratory error may lead to misdiagnosis, and whether an error leads to a subject being misdiagnosed as having, or not having, a familial defect, there could be serious clinical consequences. Adequate internal quality control procedures are a critical part of the quality management system that seeks to ensure that test results are safe to release for patient management decisions. This chapter addresses the nature of internal quality control materials and their properties in relation to hemostasis testing, including a discussion of preparation and storage of such materials. The frequency of testing is described with reference to published guidelines as well as sections on out of limits IQC results. Readers are reminded that IQC testing and regular scrutiny of results obtained should be merely one component of the quality assurance and quality management program, and that quality control is a continuous process and is the responsibility of all staff at all levels in the hemostasis laboratory.

Mean-field coupled lattice maps are used to approximate the physics of driven threshold systems with long range interactions. However, they are incapable of modeling specific features of the dynamic instability responsible for generating avalanches. Here we present a method of simulating specific frictional weakening effects in a mean field slider block model. This provides a means of exploring dynamical effects previously inaccessible to discrete time simulations. This formulation also results in Abelian avalanches, where rupture propagation is independent of the failure sequence. The resulting event size distribution is shown to be generated by the boundary crossings of a stochastic process. This is applied to typical models to explain some commonly observed features.