Automated assays for von Willebrand factor activity.

von Willebrand factor (VWF) ristocetin cofactor activity (VWF:RCo) by platelet aggregometry has been considered the gold standard for evaluating the ability of VWF to bind platelets for over 40 years. Many automated systems no longer require platelets and rather rely on agglutination of latex particles. Automated methods of measuring VWF activity have improved performance characteristics and are performed on the same coagulation instruments used for routine testing via immunoturbidimetric methodology. Alternatively, a newer chemiluminescence assay system for measuring VWF activity demonstrates excellent performance characteristics. As these methods are becoming widely used, it is important to assess their performance in diagnosing and monitoring different types of von Willebrand disease. We review the automated methodologies and the published performance of these VWF assays. Advantages and limitations of these automated methods are discussed.

Diagnosing von Willebrand disease: a short history of laboratory milestones and innovations, plus current status, challenges, and solutions.

von Willebrand disease (VWD) is a disorder characterized by deficiency of, or defects in, von Willebrand factor (VWF). VWD was originally identified by Erik Adolf von Willebrand, who in early 1924 investigated a large family suffering from a bleeding disorder that seemed to differ from hemophilia. Erik von Willebrand undertook some initial laboratory investigations to conclude the involvement of a plasma factor, the lack of which prolonged the bleeding time, but failed to impair coagulation times and clot retraction. By the end of the 1960s, VWD was accepted as a combined deficiency of factor VIII (FVIII) and another plasma factor responsible for normal platelet adhesion. Just how these two functions were related to each other was less clear and the diagnostic tests available at the time were poorly reproducible, cumbersome, and unreliable; thus, VWD was poorly delineated from other coagulation and platelet disorders. The early 1970s saw a revolution in diagnostics when ristocetin was identified to induce platelet aggregation, and this formed the basis of the first consistent and reliable VWF "activity" test, permitting quantification of the platelet adhesive function missing in VWD. Concurrently, immunoprecipitating techniques specific for VWF were defined, and the application of such technologies permitted a clearer understanding of both VWF and VWD heterogeneity. Continued exploration of the structure and function of VWF contributed greatly to the understanding of platelet physiology, ligand receptor interaction and pathways of cellular interaction and activation. Recently, additional assays evaluating other functions of VWF, including collagen binding, platelet glycoprotein Ib binding, and FVIII binding, have improved the diagnosis of VWD. The purpose of this narrative review is to explore the history of phenotypic VWD diagnostics, with a focus on laboratory milestones from the past as well highlighting recent and ongoing innovations, and ongoing challenges and possible solutions.

Treatment of haemophilia patients in East Germany prior to and after reunification in 1990.

The reunification of Germany in 1990 brought with it major challenges in terms of unifying the care offered to haemophilia patients. At that time, most of the treatment centres belonged to the largest regional hospitals. The centre for paediatric haemophilia patients in Leipzig was at the University Hospital. In this centre, early prophylaxis was offered to all patients with severe haemophilia A or B. For over 20 years, the treatments of choice in the German Democratic Republic were cryoprecipitate for haemophilia A and prothrombin complex concentrate for haemophilia B. Cryoprecipitate was relatively effective during minor surgery, in cases of mild to moderate bleeding, and for prophylaxis; however, unpleasant, relevant side-effects and hepatitis virus transmission were frequently encountered in clinical practice. Reunification coincided with the availability of virus-safe, high-purity plasma-derived factor VIII concentrates (e.g. Beriate(®) P), which changed the outlook for patients in terms of convenience, tolerability, and virus safety; and these new products quickly became the treatments of choice for haemophilia A patients at the Leipzig Children's Hospital. Today, 20 years later, nearly all of the patients initiated on Beriate(®) P at the time of reunification continue with that treatment, and are still benefitting from its excellent efficacy, tolerability, and virus-safety profile.

Cryoprecipitate: an outmoded treatment?

Cryoprecipitate is an allogeneic blood product prepared from human plasma. It contains factors VIII, von Willebrand factor (vWF), fibrinogen, fibronectin and factor XIII. Its use was first described in the 1960s for treatment of patients with factor VIII deficiency. It has also been used to treat patients with congenital hypofibrinogenaemia. Now, the most common use of cryoprecipitate is fibrinogen replacement in patients with acquired hypofibrinogenaemia and bleeding. Despite almost 50 years of use, evidence of efficacy is limited. This review provides an overview of the history of cryoprecipitate use, the current debates on the use of this product and future developments.

[Von Willebrand and his factor]. / Von Willebrand en zijn factor.

Erik Adolf von Willebrand (1870-1949) studied medicine in Helsinki, where he subsequently joined the staff at the Deaconess Hospital. Haematological disorders were his main interest. In 1924 he was consulted about 5-year-old Hjördis S. She suffered from a severe bleeding disorder, as did six of her ten siblings; three of her sisters had died. In a Finnish article in a Journal in 1926 (in the Swedish language) he plotted the family pedigree (bleeding disorder in three preceding generations, on the part of both parents). Von Willebrand also distinguished the disorder from haemophilia and thrombopathies with purpura. His conjecture that the disorder was a special form of thrombocyte dysfunction would eventually be borne out, though the key factor is severe deficiency of a specific plasma protein. In milder, autosomal dominant forms of the disease, the protein is partly deficient or abnormal.

2B or not to be--the 45-year saga of the Montreal Platelet Syndrome.

Over 45 years ago, Montreal Platelet Syndrome was first described as a rare inherited platelet disorder characterised by macrothrombocytopenia with spontaneous platelet clumping, abnormal platelet shape change upon stimulation and a defect in platelet calpain. This syndrome has now been reclassified as type 2B von Willebrand disease with the V1316M VWF mutation in the only kindred ever reported. We herein revisit the historical platelet characteristics originally described in Montreal Platelet Syndrome in light of the new diagnosis. This paper will review the 45-year saga of Montreal Platelet Syndrome, a story that highlights the value of revisiting a rare diagnosis to look for a more common explanation.

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.