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Notes: Summary. The application of coagulation factor therapy by continuous infusion (CI) was first suggested by Brinkhous in the early 1950s [1]. The recent introduction of this mode of therapy to everyday practice was made possible after the demonstration of a good stability of most factor concentrates which were also found safe regarding potential bacterial contamination. Other developments included a better understanding of the pharmacokinetics of factors concentrates as well as the availability of a new delivery system. Continuous infusion was shown to be superior to bolus injection (BI) in achieving a stabile haemostatic effect, in the prevention of post-operative bleeding and was found to save between 20–50% in the required factor. This mode of therapy was found effective in haemophilia A and B as well as among patients with inhibitors to FVIII and with von Willebrand disease (vWD).

Notes: Summary. Diagnosis and therapy for the vast majority of haemophiliacs in the world remain beyond their reach. Health care costs for hemophilia replacement products keep rising. Global inequities for financing health care result in most hemophiliacs being undertreated. The transfusion-transmitted disease, factor VIII inhibitors, is common. Its predictability escapes detection. Management has progressed substantially and offers many therapeutic modalities. Programs for prophylaxis or immune tolerance induction are impossible for most patients. Thus, the challenge for haemophiliacs is to attain these goals.

Notes: Summary. Radiological and orthopaedic outcome in severe and moderate haemophilia A and B patients undergoing long-term prophylactic treatment were prospectively investigated focusing on the age of onset of prophylaxis and the number of joint bleedings prior to treatment. We report on 21 patients with severe and moderate haemophilia A and B receiving prophylactic treatment of between 3.1 and 16.1 year's duration. Three patient groups were evaluated according to the age at onset of prophylaxis. In group I prophylactic treatment was initiated in the first 2 years of life. Patients in group II received prophylaxis at the age of 3–6 years. Late-onset or secondary prophylactic treatment was started at the age of 6 years and above in seven patients (group III). All patients received virus-inactivated F VIII or F IX concentrates at dosages of 30–50 IU/kg body weight i.v. three times per week for those with haemophilia A and twice per week for those with haemophilia B. Elbow, knee and ankle joints were investigated at 3–4-yearly intervals according to the radiological and orthopaedic scores recommended by the World Federation of Haemophilia. The total number of joint bleedings before and after start of prophylaxis were recorded in all patients. In group I 7/8 patients had unaffected joints with constant radiological and orthopaedic scores of zero or 1, after a median of 11.25 years of prophylactic treatment. One patient in this group demonstrated mild radiological alterations (score 4). Patients in group II showed neither radiological nor orthopaedic alterations at study entry. Surprisingly, worsening joint scores could be detected despite ongoing prophylaxis after the 3-year interval (median orthopaedic score 4, median radiological score 8). Treatment group III already showed considerable joint damage at study entry with a median radiological score of 11 (0–33) and a median orthopaedic score of 4 (0–11). Despite prophylactic treatment, both radiological (median 19.5, range 2–47) and orthopaedic scores (median 8, range 2–12) deteriorated after 3 years. Prior to onset of prophylaxis, no or only one joint bleeding occurred in treatment group I. In group II, a median of six joint bleeds (range 1–8) was reported before prophylaxis was started. Patients in group III usually experienced a median of more than 10 joint haemorrhages (range 6–10 or more). Under prophylactic treatment the number of joint bleedings decreased significantly in group II and III. However, radiological and orthopaedic scores increased as a sign of progressing osteoarthropathic alterations in patients reporting more than five joint haemorrhages before onset of prophylaxis whereas no joint alterations could be assessed in patients with no or only one joint bleeding episode prior to prophylaxis. Even a small number of joint bleedings seems to cause irreversible osteoarthropathic alterations leading to haemophilic arthropathy. Once apparent, further progression of joint damage could not be arrested despite of prophylactic treatment (groups II and III). In order to prevent haemophilic arthropathy, effective prophylaxis should be started before or at least after the first joint bleeding in severe haemophilia A and B.

Notes: Summary. The development of inhibitor antibodies is a serious complicaiton of haemophilia in young children. Occurrence of anaphylaxis at the time of inhibitor development is a recently described complication unique to haemophilia B. Management of these inhibitor patients with allergy is complicated due to the absence of any readily available products for treatment of acute bleeding episodes. Clinical experience suggests that recombinant activated factor VII is the most appropriate and logical treatment for acute bleeding episodes in these patients. From the limited information available regarding immune tolerance induction (ITI) in these patients, it appears that ITI regimens have been only minimally successful and are associated with a high rate of complication (nephrotic syndrome).

Notes: Summary. Combined deficiency of coagulation factor V and factor VIII is an autosomal recessive disorder which has been observed in a number of populations around the world. However, this disease appears to be most common in the Mediterranean basin, particularly in Jews of Sephardic and Middle Eastern origin living in Israel. We have taken a positional cloning approach toward identifying the gene responsible for this disorder. We initially studied 14 affected individuals from nine unrelated Jewish families using a panel of polymorphic genetic markers spaced throughout the human genome. The combined factors V and VIII deficiency gene was mapped to a locus on the long arm of chromosome 18 with a maximal LOD score of 13.22. A detailed genetic analysis identified two distinct haplotypes among these families, suggesting two independent founders or, alternatively, a single ancient founder with a more recent split of these subpopulations. Further work to identify and characterize the gene responsible for combined factors V and VIII deficiency should provide important insights into the biosynthesis of these homologous proteins.

Notes: A 13-year-old boy with severe haemophilia presented at the National Centre with gross swelling of his foot and infrapatella area, and reported that several months previously he had kicked a football and had instantly developed a bleed in his foot. Despite replacement factor the swelling failed to subside. He had ambulated for a while using crutches and when he eventually presented himself the X-rays revealed two separate pseudotumours. The patient underwent a transfemoral amputation.

Notes: Summary. In this report we describe an in vitro model of blood coagulation reactions that mimics as closely as possible the in vivo condition. Our model indicates that the tissue factor—factor VIIa complex initiates coagulation by activating small amounts of both factor IX and factor X in the environment of the tissue factor bearing cell. Factor Xa and factor IXa formed in the initial reaction then play very distinct roles in the subsequent interactions of the clotting mechanism leading to a burst of thrombin generation on the platelet surface. Our results also indicate that factor XI can be activated by thrombin in the absence of factor XII and that the function of factor XI is simply to enhance conversion of factor IX to factor IXa resulting in enhanced thrombin generation on the platelet surface.

Notes: Summary. Over the past 15 years, our knowledge of the molecular basis of haemophilia B has increased dramatically. Following the cloning and characterization of the factor IX gene in 1982, major advances have been made in documenting the molecular pathology that underlies this condition. This review will summarize the current state of information in this area, and the reader is referred to the Haemophilia B Mutation Database World Wide Web site at for a complete current listing of the mutations that cause this phenotype. In addition, other recent reviews have discussed complementary issues relating to this topic [1–3].