Notes: Summary. Quality assurance is a vital prerequisite of good laboratory practice. The application and continuous scrutiny of adequate internal quality control measures are essential to ensure that laboratory performance is consistent from day to day. External quality assessment is particularly important to verify the accuracy and reliability of laboratory results Consequently, without appropriate IQC and EQA, laboratory results can have no true validity.

Notes: Summary. In view of reported discrepancies between different factor VIII assays, the influence of phospholipids on the performance of one-stage clotting (OS) and chromogenic substrate (CS) assays was evaluated. The B domain deleted recombinant factor VIII, rVIII SQ, two full-length recombinant products and a plasma derived factor VIII concentrate were each diluted into severe haemophilia A plasma and assayed against a plasma standard. The one-stage activity was 50, 80, 75 and 106%, respectively, of the chromogenic result. Variations in the phospholipid concentration did not affect the chromogenic assay, except at very low levels where the apparent activity increased. In contrast, dilution of the phospholipid reagent had a substantial influence on the activity measured by OS assays, especially in the case of rVIII SQ. At low levels of phospholipid, the one-stage activity of rVIII SQ exceeded the chromogenic result. When mixtures of phosphatidylserine (PS) and phosphatidyl-choline (PC) were used as a source of phospholipid, the OS results for rVIII SQ agreed well with the CS activity as long as the content of PS was below 10%, i.e., closer to the physiological level. At higher levels of PS, as in most commercial APTT reagents, the OS activity decreased. When the APTT reagent was replaced by platelets in the OS assay, the results compared well with those obtained by the CS assay for both t-VIII SQ and full-length factor VIII products.

Notes: Summary. von Willebrand disease is the most frequent of inherited bleeding disorders (1:100 affected individuals in the general population). The aim of treatment is to correct the dual defects of haemostasis, i.e., abnormal coagulation expressed by low levels of factor VIII and abnormal platelet adhesion expressed by a prolonged bleeding time. There are two main options available for the management of von Willebrand disease: desmopressin and transfusion therapy with blood products. Desmopressin is the treatment of choice in patients with type 1 von Willebrand disease, who account for approximately 80% of cases. This pharmacological compound raises endogenous factor VIII and von Willebrand factors and thereby corrects the intrinsic coagulation defect and the prolonged bleeding time in most type 1 patients. In type 3 and in the majority of type 2 patients desmopressin is not effective, and it is necessary to resort to plasma concentrates containing factor VIII and von Willebrand factor. Treated with virucidal methods, these concentrates are effective and currently safe, but the bleeding time defect is not always corrected by them. Platelet concentrates or desmopressin can be used as adjunctive treatments when poor correction of the bleeding time after concentrates is associated with continued bleeding.

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: Summary.  Recombinant activated factor VII (rFVIIa), licensed in 1999 for treatment of haemophilia patients with inhibitors (HI), represents an important advance in the therapeutic armamentarium. Standard bolus dosing ranges from 90 to 120 mcg kg−1 every 2–3 h until arrest of bleeding. As licensure, clinical use of rFVIIa has increased and broadened. Clinicians now use a wide dose range, 90–300 mcg kg−1. High-dose regimens may optimize thrombin generation or burst, and may allow for prolonged dose interval. The Hemophilia and Thrombosis Research Society (HTRS) maintains a registry database to study haemophilia treatment and related disorders, particularly treatment of acute bleeding in HI, acquired haemophilia, FVII deficiency and von Willebrand's disease (VWD). To assess the effect of rFVIIa dose on efficacy and safety in the treatment of acute bleeding in HI, data from the HTRS database from January 2000 through June 2002 were analysed. Bleeding episodes were grouped by bolus rFVIIa dose range: 〈100, 100–150, 150–200 and 〉200 mcg kg−1. Investigator-reported efficacy for the first 72 h of treatment was evaluated. Thirty-eight congenital HI patients were treated for 555 bleeding episodes. Patient age range was 1–55 years (median: 14). Bleeding episodes were spontaneous (45%), caused by trauma (38%), or because of surgery, dental, diagnostic, or medical procedures (17%); bleeding occurred in joint, muscle, and intra/extracranial sites. Treatment location included: 80% at home, 12% at other facilities (treatment centres, ER, inpatient and OR), and 8% at both home/other facilities. Median total dose given over 72 h was 360 mcg kg−1 (range: 40–4281, mean: 537). Bleeding stopped in 87% of the episodes. Bleeding cessation rate was 84% for the three lower dose groups, and 97% for the highest dose group (P 〈 0.001). Five patients experienced nine adverse events (AEs). AE rates were 〈1% for 〈100, 5% for 100–150, 0% for 150–200, 〈1% for 〉200 mcg kg−1 dose group. Decreased therapeutic response accounted for eight of the nine AEs. These data, which represent the most comprehensive report of rFVIIa use since the USA licensure, demonstrate that bleeding episodes in HI patients can be treated safely and effectively at home and that doses up to 346 mcg kg−1 appear to be well-tolerated. Additionally, rFVIIa doses 〉200 mcg kg−1 appear to significantly increase efficacy (97% in the high-dose group, compared with 84% in the lower dose groups). Optimal dosing remains to be determined; specifically, what the lowest effective dose is and whether a single high-dose bolus eliminates the need for repeated dosing. Recombinant FVIIa appears to have a wide safety margin that may allow dose escalation to address these questions.

Notes: Summary. Rifampicin synoviorthesis has been empirically used for the treatment of haemophilic synovitis for some time. This paper reports on the experience of three Latin American centers with this treatment and compares it with radioactive synoviorthesis results. Chemical synoviorthesis with rifampicin is best indicated in younger patients (〈15 years) and small joint (ankles and elbows).

Notes: Summary. This paper reviews personal experience in the treatment of recurrent haemarthrosis and chronic synovitis by non-surgical means. Experience with synoviorthesis with rifampicine and radioactive colloids is analyzed, and a multiple chromosomal study to demonstrate safety of radioactive injections is described. The results obtained are so very satisfactory as to recommend non-aggressive synoviorthesis as the treatment of choice to prevent recurrence of bleeding. Long experience in the treatment of chronic arthropathy with intrarticular corticosteroids and hyaluronic acid has shown very promising results.

Notes: Summary. Joint and muscle injury associated with direct damage to the tissues and muscle atrophy may ensue following immobility. Rehabilitation of the injury is linked with the return to normal functional values such as range of motion, muscle strength, and muscle tone. It is, however, likely that subtle changes or differences still exist in the site of injury or haemarthrosis. In particular proprioception may be distorted due to the direct injury of sensory receptors and to feedback systems. The implications of such damage are important, where proprioception plays an important part in the control, timing and organisation of coordinated bodily actions.

Notes: Summary. In haemophilic arthropathy there is a progressive limitation of the range of motion (ROM) which may lead to disabilities in the activities of daily living (ADL). In the literature the pathology of haemophilic arthropathy is described extensively, but only one paper describing functional limitations caused by limited range of motion (LOM) in haemophilia was found. The aim of the pilot study was to estimate on theoretical grounds, how many patients with haemophilia might suffer from functional disabilities. Material: ROM of elbows, knees and ankles of 155 Haemophilia A and B patients. Methods: flexion and extension were measured with an ordinary goniometer. The ROM of joints of patients with haemophilia was compared with normal values. Results: 39 of 155 patients had a normal ROM in both elbows; 22 in one elbow; 34 patients had disabilities in ADL with both arms; 14 with one arm; 18 were able to compensate; 89 had no problems; 79 of 155 patients had a near normal ROM of both knees; 38 patients could not ride an ordinary bicycle. Conclusion: only limited data are available concerning the normal ROM needed for individual ADL. Until additional data are available, it is not possible to predict which patients will be disabled in their activities of daily living and individual counselling should be done during the yearly outpatient comprehensive care clinics. Conservative and surgical measures should be taken to ensure elbow flexion of at least 120° and knee flexion of 100° for Western societies. In Asian countries patients with haemophilia need maximum knee flexion and ankle dorsi flexion.

Notes: Summary. Musculoskeletal dysfunction is a common manifestation of haemophilia. This dysfunction may be associated with imbalances between muscle groups. Evidence emerging from the literature suggests that the rehabilitation of this dysfunction is very relevant for the patient with musculoskeletal problems. Treatment of muscle imbalance may be linked with a reduction in recurrence of symptoms. Further research is needed to establish the relevance of this area in patients with haemophilia but the clinical evidence supports the developing work in this field.