Viral safety of coagulation factor concentrates: memoirs from an insider.

The purpose of this essay is to recall the actions taken globally to improve the viral safety of coagulation factor concentrates, mainly in the years 1985-1990, at a time of confusing and often contradictory information on bloodborne viral infections in multitransfused patients with hemophilia (PWHs). I shall first recall the problem of the transmission and control of the hepatitis viruses, and then that of HIV: not only for temporal reasons, but also because understanding the progress of knowledge on hepatitis and the poor success of the early measures taken to tackle this problem in PWHs is essential to understand how the problem of HIV transmission was ultimately dealt with successfully.

Haemophilia, human immunodeficiency virus and human immunodeficiency virus pathogenesis.

In July 1982, the occurrence of three cases of acquired immunodeficiency syndrome (AIDS) in men with haemophilia was an immediate signal to Oscar Ratnoff that AIDS was transmissible through blood products. Work that he led provided important and clear indication that the AIDS agent was transmissible through pooled plasma products and had rapidly infected many men who had haemophilia. Before the blood supply was protected, the risk for infection in haemophilia was related directly to the intensity of therapy with pooled anti-haemophilic factor concentrates. Studies performed among the small proportion of haemophiliacs who remained uninfected despite heavy exposure to these plasma products revealed that the rare protective genotype - homozygosity for the 32 base pair deletion in the CCR5 gene was heavily concentrated in this population. Among those who did not have this protective genotype, a state of diminished immune activation distinguished these high risk uninfected haemophiliacs from haemophiliacs who later acquired human immunodeficiency virus (HIV) infection and from healthy uninfected controls. Immune activation state may not only predict risk for HIV acquisition but also appears to be an important predictor and likely determinant of HIV disease progression. The potential drivers of immune activation in chronic HIV infection include HIV itself, other co-infecting pathogens, homeostatic responses to cytopenia as well as the recently recognised phenomenon of translocation of microbial products across a damaged gut mucosal surface. This latter process is particularly compelling as clinical studies have shown a good relationship between indices of microbial translocation and markers of both immune activation and T cell homeostasis in chronic HIV infection. More recently, we have also found evidence that these microbial products also may drive a heightened tendency to thrombus formation in HIV infection via induction of monocyte tissue factor expression. Thus systemic exposure to microbial elements that are translocated through a gut mucosa damaged in the first few weeks of HIV infection may contribute to the pathogenesis of both immune deficiency and the heightened risk for vascular events that have been noted in persons with HIV infection.

Quantifying the source of infection for HIV-infected hemophiliacs in the U.K. from 1979 to 1984.

There is considerable literature on the risk of HIV infection for individuals suffering from hemophilia A in the United Kingdom (U.K.) during the period 1979-1984 when the sources of Factor VIII clotting factor were contaminated with HIV. Toward the end of this period, several investigators reported HIV prevalence among hemophiliacs, often classified by the severity of disease and, to some extent, the source of the clotting factor with which individuals were infused. In the U.K., hemophilia A patients typically received clotting factor from the local National Health Service (NHS) supplies or from commercial product usually imported from the United States. Litigation on behalf of U.K. hemophiliacs, their survivors, and estates remains unresolved, cases in which it becomes important to quantify the fraction of U.K. hemophiliac HIV infections attributable to imported blood product. For HIV-infected individuals who received Factor VIII from one source exclusively, the source of infection is clear, assuming no other risk factors. For patients who used both types of clotting factor, the source of infection is uncertain. For the U.K. as a whole, we produce quantitative estimates of the conditional probability of infection due to a specific source, based on HIV prevalence in groups exclusively exposed to a specific source and the percentage of clotting factor that was imported. With plausible estimates of these input parameters, an estimate of the conditional probability of infection due to imported product is 0.93 (95 per cent CI: 0.90-0.96). This estimate is relatively insensitive to changes in input parameters, but may vary over subgroups of hemophiliacs.

Haemate P von Willebrand factor/factor VIII concentrate: 25 years of clinical experience.

Although von Willebrand disease (VWD) has a very long history, our understanding and treatment of the bleeding disorder has only evolved during the past 50 years or so. It was not until the 1920s that VWD was first recognized as a disease separate from that of classical haemophilia. It then took another 30 years before the first effective treatment was developed. Since then, the medical management of VWD has evolved considerably, but not without its ups and downs. One of the key milestones in the evolution of the treatment of VWD was the development of Haemate P/Humate-P (CSL Behring) - the first virus-inactivated factor VIII plasma product. For 25 years, this concentrate has demonstrated excellent clinical efficacy and safety for patients with VWD and for those with haemophilia. This article provides an historical overview of the early landmark efforts to ensure a safe plasma-derived replacement product and outlines the clinical evolution in the use of Haemate P.

Control of coagulation: a gift of Canadian agriculture.

Vitamin K, heparin and their antagonists remain the basis of coagulation therapies today, more than half a century after their discovery. Failure of blood clotting in chicks that were fed a fat-depleted diet was observed by William McFarlane, William Graham Jr. and Frederick Richardson of the Ontario Agricultural College; it led to the search that yielded vitamin K. Investigation of hemorrhagic disease in cattle by Francis Schofield of the Ontario Veterinary College found an anti-thrombin substance in spoiled clover which was later characterized as dicoumarol, a vitamin K antagonist, and led to the development of warfarin. In Toronto, a systematic approach lead by Charles Best resulted in the world's first plentiful supply of purified heparin. Clinical usefulness of heparin in thrombosis, embolism, cardiovascular surgery, dialysis and transplantation was demonstrated first by Gordon Murray and Louis Jaques. The roles and the careers of Canadian coagulation research pioneers are briefly presented in this review, which shows how clinical medicine benefited by the systematic development of agricultural science in Guelph, Ontario.