[Revision consensus hemophilia: treatment and responsibility. Nederlandse Vereniging van Hemophilia Patients]. / Herziening consensus hemofilie: behandeling en verantwoordelijkheid. Nederlandse Vereniging van Hemophilia Patienten.

Haemophilia is an X-linked clotting disease occurring in 1400 men in the Netherlands. As the result of factor VIII or IX deficiency, haemophilia patients suffer from severe bleedings, spontaneous or caused by trauma. Bleedings mostly occur in major joints and muscles. Repeated bleedings can cause disability. Treatment of haemophilia consists of replacement therapy with factor VIII or IX. The first aim of treatment is to prevent bleedings (prophylaxis). The second aim is to limit joint damage in case of bleeding by timely and adequate substitution therapy. In addition, physical therapy and sports are used to keep patients in shape. Until the introduction of recombinant factor VIII in 1992 only plasma derived factor VIII and IX products were available. Substitution therapy has caused various side effects, such as allergic reactions. Since the introduction of ultra-pure concentrates, allergic reactions have grown rare. Viral infections like HIV and hepatitis C, which were transmitted through blood products, have not occurred in Dutch haemophilia patients since the introduction of adequate viral inactivation steps. In case of development of antibodies against factor VIII or IX, therapy with factor VIII or IX products is insufficient. Antibody formation is more often seen in haemophilia A (25%) than in haemophilia B (2%). In most cases antibodies disappear during so-called immune tolerance induction. This therapy consists of regular infusion with factor VIII or IX. Once an inhibitor has disappeared, patients can be treated normally once more. As haemophilia is a rare and complex disease patients should be treated in specialized centres, preferably by a comprehensive care team. This is even more justified because treatment of haemophilia is costly. Over the last 20 years haemophilia treatment has improved much. This has resulted in a decrease of the number and of the duration of hospitalization, and a decrease in days lost at school or work. This has led to great improvement of the social life of haemophilia patients.

Assessment of a bleeding risk index in two cohorts of patients treated with oral anticoagulants.

In two cohorts of patients on oral anticoagulant therapy, routinely treated by the Leiden Thrombosis Service, the frequency of major bleeding complications was assessed during two years (1988 and 1991). With Poisson regression analysis the influence of the risk factors age, sex, target zone, achieved INR and type of coumarin derivative used were determined. Subsequently, a bleeding risk index was calculated, combining the results of the two cohorts. For various types of patients the relative risk of major bleeding complications was assessed. Age and achieved INR were the most important and consistent risk factors: rate ratio (RR) for age in 1988 1.46 per 10 years increase (95% confidence interval [CI] 1.20-1.78) and in 1991 1.57 per 10 years increase (95% CI 1.23-2.00); RR per unit increase in achieved INR in 1988 1.42 (95% CI 1.21-1.68) and in 1991 1.44 per unit increase in achieved INR (95% CI 1.18-1.74). Two methods were used to combine the results of 1988 and 1991. In the first method the mean bleeding risk index was calculated: In (incidence) [natural logarithm of the incidence rate of major bleeding] = -5.64+ 0.42 * age +0.26 * sex -0.29 * target range +0.36 * achieved INR -0.36 * coumarin type. In the second method only the consistent risk factors age and achieved INR were used: In (incidence) = -5.64 -0.42 * age +0.36 * achieved INR. These bleeding risk indexes can be used to assess the risk of major bleeding complications of individual patients and allow more individualized care by individual tailoring the desired anticoagulation.

Assessment of therapeutic quality control in a long-term anticoagulant trial in post-myocardial infarction patients.

Various methods have been described to evaluate efficacy of anticoagulant therapy using the international normalized ratio (INR). We compared the following approaches: (1) total INR's or the most recent measurement; (2) percent time within therapeutic range, with INR changing directly or halfway between visits; and (3) total observation time assuming INR changing linearly. The study population comprised 1700 post myocardial infarction patients. Treatment comprised 3725 patient-years. There were 61,471 INR assessments with target therapeutic level of 2.8-4.8. Acenocoumarol as well as phenprocoumon were employed. Therapeutic achievement in the first months of treatment was low: less than 60% of INR's were in range. Treatment stabilized after 6 months. Patients on acenocoumarol were within range 70% of the time compared to 80% for phenprocoumon. Method 3 is preferred because it incorporates time and is capable of calculating incidence rates at different INR levels. Our findings call for an urgent improvement of standard of anticoagulant control in the first months following commencement of treatment.

[Consensus diagnosis pulmonary embolism]. / Consensus diagnostiek longembolie.

Pulmonary embolism is a frequent occurrence and requires adequate diagnosis and treatment to avoid unnecessary mortality and complications. However, until recently, the optimal diagnostic management was not determined. This prompted the organisation of a consensus meeting. The advised diagnostic strategy was derived from available data in the literature, a cost-effectiveness analysis, and the discussions which took place at the meeting. The preferred diagnostic strategy consists of a combination of perfusion-ventilation lung scintigraphy, ultrasonography of the legs, and finally pulmonary angiography. Perfusion scintigraphy is performed first. If a normal perfusion is seen further anticoagulant therapy may be withheld. Ventilation scintigraphy is performed if a segmental or larger perfusion defect is found. If a normal ventilation scan is obtained (mismatch) the diagnosis of pulmonary embolism is sufficiently certain to warrant institution of long-term anticoagulant therapy. In all other lung scan findings (non-conclusive or non-diagnostic) the meeting advised to perform ultrasonography of the legs. If deep venous thrombosis is detected the patient requires long-term anticoagulant therapy. If a normal ultrasound result is found, pulmonary angiography is required as the final test in the diagnostic strategy.

A randomized and blinded comparison of three bleeding time techniques: the Ivy method, and the Simplate II method in two directions.

We compared the Ivy bleeding time method and two alternatives of the Simplate II method (incisions in horizontal and vertical direction) with each other, with regard to the sensitivity, the specificity, the costs and the burden for the patient. In the aspirin study an aspirin-induced bleeding defect was used. Seventy-two healthy volunteers were randomized to receive either 500 mg acetylsalicylic acid (ASA) or a placebo. Double blinding was maintained throughout the study. In the anticoagulation study 62 patients participated, who received oral anticoagulants (OAC) for various reasons. All participants received two bleeding time methods. The burden for the participants of each method was screened by a small standard questionnaire. The differences in sensitivity and specificity between the three methods proved minimal. The Ivy method was more often preferred by the participants than the Simplate methods. Since a choice on the basis of sensitivity and specificity appears not possible, we prefer the Ivy method because of lower costs and less burden.

Physical condition, longevity, and social performance of Dutch haemophiliacs, 1972-85.

A study was carried out among haemophiliacs in The Netherlands to evaluate the effect of modern substitution treatment (replacing the missing clotting factors) on medical and social performance. Three questionnaires were sent between 1972 and 1985. The use of prophylactic treatment in the group of patients with severe and moderately severe haemophilia increased from 21% (n = 242) in 1972 to 36% (n = 559) in 1985. Home treatment programmes increased from 4% to 53%. Overall mortality was 2.1 times higher than in the general male population, which leads to a calculated life expectancy of 66 years compared with 74 years in the general male population. Severe joint impairment was prominent in the older age groups, reflecting insufficient treatment in the past. A sharp decrease in the use of inpatient and outpatient hospital facilities was observed as well as much less absence from school and work. It is concluded that the high costs of modern substitution treatment are fully justified.