Treatment of haemophilia A and B and von Willebrand's disease: summary and conclusions of a systematic review as part of a Swedish health-technology assessment.

In an ongoing health-technology assessment of haemophilia treatment in Sweden, performed by the governmental agency Dental and Pharmaceutical Benefits Agency (TLV; tandvårds-och lakemedelsförmånsverket), the Swedish Council on Health Technology Assessment (SBU; statens beredning för medicinsk utvardering) was called upon to evaluate treatment of haemophilia A and B and von Willebrand's disease (VWD) with clotting factor concentrates. To evaluate the following questions: What are the short-term and long-term effects of different treatment strategies? What methods are available to treat haemophilia patients that have developed inhibitors against factor concentrates? Based on the questions addressed by the project, a systematic database search was conducted in PubMed, NHSEED, Cochrane Library, EMBASE and other relevant databases. The literature search covered all studies in the field published from 1985 up to the spring of 2010. In most instances, the scientific evidence is insufficient for the questions raised in the review. Concentrates of coagulation factors have good haemostatic effects on acute bleeding and surgical intervention in haemophilia A and B and VWD, but conclusions cannot be drawn about possible differences in the effects of different dosing strategies for acute bleeding and surgery. Prophylaxis initiated at a young age can prevent future joint damage in persons with haemophilia. The available treatment options for inhibitors have been insufficiently assessed. The economic consequences of various treatment regimens have been insufficiently analysed. Introduction of national and international registries is important.

Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study.

BACKGROUND AND PURPOSE: Patients treated with oral anticoagulants (ACs) have an increased risk of intracerebral hemorrhage (ICH), which is more often fatal than spontaneous ICH. Options to reverse the AC effect include intravenous administration of vitamin K, plasma, and coagulation factor concentrate. However, the optimal management of AC-related ICH has not been determined in any randomized trial. In this study, the present management of AC-related ICH was surveyed, and determinants of survival were assessed. METHODS: We retrospectively reviewed the medical records of all AC-related ICHs at 10 Swedish hospitals during a 4-year period, 1993 to 1996. Survival status after the ICH was determined from the Swedish National population register. RESULTS: We identified 151 patients with AC-related ICH. Death rates were 53.6% at 30 days, 63.6% at 6 months, and 77.5% at follow-up (mean 3.5 years). The case fatality ratio at 30 days was 96% among patients unconscious on admission (n=27), 80% among patients who became unconscious before active treatment was started (n=15), 55% among patients in whom no special action was taken except withdrawal of AC treatment (n=42), and 28% among patients given active anti-coumarin treatment while they were still conscious (n=64). The case fatality ratio at 30 days was 11% in the group treated with plasma (n=18), 30% in the group treated with vitamin K (n=23), and 39% in the group treated with coagulation factor concentrate (n=23). Within the first 24 to 48 hours after admission, 47% of the patients deteriorated. Choice of therapy to reverse the AC effect differed substantially between the hospitals (P<0.0001), as did the time interval from symptom onset to start of treatment. Multiple logistic regression analysis showed only 2 factors (intraventricular extension of bleeding and ICH volume) that were independently related to case fatality at both 30 days and 6 months. The results were similar when the analysis was restricted to patients who were conscious on admission. CONCLUSIONS: In AC-related ICH, a progressive neurological deterioration during the first 24 to 48 hours after admission is frequent, and the mortality is high. Choice of therapy to reverse the AC effect differed considerably between the hospitals. There was no evidence that any treatment strategy was superior to the others. A randomized controlled trial is needed to determine the best choice of treatment.

Heparin and fibrinolysis--comparison of subcutaneous administration of unfractionated and low molecular weight heparin.

The effects on the fibrinolytic system after a single s.c. bolus injection (at 9 a.m.) of either 5000 IU conventional heparin or 5000 anti-Xa U of a fractionated low molecular weight heparin (Fragmin, KabiVitrum, Sweden) were investigated in 9 healthy volunteers. The effects were compared to those of an injection of normal saline in 6 volunteers. Samples for biochemical analyses were taken regularily during 6 hours after drug or placebo administration. In the coagulation system the following parameters were measured: Activated partial thromboplastin time (APTT), anti-Xa activity, thrombin time and fibrinogen. The fibrinolytic system was monitored by analysing: plasminogen, alpha 2-antiplasmin, fibrin(ogen) degradation products (FDP), euglobulin clot lysis time (ECLT), tissue plasminogen activator (t-PA) activity, t-PA antigen and plasminogen activator inhibitor (PAI) activity. Injection of the 2 drugs was followed by elevations in APTT and anti-Xa activity, and were more pronounced for Fragmin than heparin. The fibrinolytic system exhibited a diurnal variation with decreasing PAI activity and increasing t-PA activity during the day. Volunteers receiving normal saline (placebo) showed a similar pattern. The results were unrelated to heparin. It is concluded from this study that neither heparin nor Fragmin had any significant effect on the fibrinolytic parameters when measured after a single s.c. bolus injection since the observed variations were within the diurnal range.

A comparison between effects of estradiol valerate and low dose ethinyl estradiol on haemostasis parameters.

Ethinyl estradiol (EE) is still used to some extent as hormonal replacement therapy (HRT) in the climacteric period. As regards oral contraception, it is well known that the induced increase in cardiovascular disease is related to the estrogen component (invariably EE) in a dose-related fashion. Considerably lower doses of EE are needed in HRT compared to oral contraception. To delineate and compare effects of EE and estradiol valerate (E2V) in doses needed in HRT on haemostasis parameters, 24 postmenopausal women were engaged in a study with an open cross-over design. The doses compared (10 micrograms EE and 2 mg E2V daily) are the lowest which eliminate climacteric symptoms in a majority of women. Unlike E2V, EE caused increased levels of factor VII:Ag, factor VIII:C and beta-thromboglobulin, which may be changes towards hypercoagulability. Both estrogens decreased the AT III activity. Long-term administration (6 + 12 w) of the estrogens induced further changes in haemostatic parameters. 10 micrograms EE increased factor VII:Ag in contrast to 2 mg E2V. Furthermore both estrogens increased factor VIII:C and factor II-VII-X. A decrease in platelet count was induced by both EE and E2V. Oral contraception and adjuvant estrogen therapy in men with prostatic carcinoma are known to imply an increased cardiovascular risk. It is noteworthy that the pattern of changes in haemostatic parameters induced by as little as 10 micrograms of EE is the same as seen after the administration of combined oral contraceptives or the substantially higher doses of EE given as adjuvant therapy to men with prostatic carcinoma.

Blood group lewis phenotype on erythrocytes and in saliva in alcoholic pancreatitis and chronic liver disease.

The distributions of ABO, rhesus, and Lewis blood group antigens were studied in patients with alcoholic cirrhosis, alcoholic pancreatitis, chronic active hepatitis, and primary biliary cirrhosis. There were no differences in frequencies of ABO and rhesus blood group antigens between the groups or in comparison with a control group of blood donors. Lewis phenotype Le (a- b-), however, was more common on erythrocytes than in saliva in patients with alcoholic cirrhosis, alcoholic pancreatitis, and severe renal disease but equally common in saliva and on red blood cells in patients with non-alcoholic liver disease. It is suggested that Lewis typing should be performed on saliva because blood typing may give misleading results in some patients.

Abdominal obesity is associated with an impaired fibrinolytic activity and elevated plasminogen activator inhibitor-1.

Recent epidemiologic studies have shown that abdominal obesity, characterized by a high waist to hip circumference ratio (WHR), is associated with increased cardiovascular morbidity and mortality. The present study examines components of the fibrinolytic system in obese and lean middle-aged women with a high and low WHR. Ten women in each group were carefully matched with respect to age, body weight, lean body mass, and body fat. Fibrinogen and endothelial type of plasminogen activator inhibitor -1 (PAI-1) were significantly elevated in the obese women with a high WHR compared with the obese women with a low WHR or with both groups of lean women. In addition, obese women with a high WHR exhibited a greater metabolic risk profile (elevated glucose, insulin, and triglyceride levels). When all subjects were pooled for the analyses, both fibrinogen and PAI-1 levels correlated positively with glucose and insulin levels. PAI-1 was also negatively related to degree of insulin sensitivity measured with the euglycemic clamp technique. In the obese groups, WHR but not body mass index (BMI), correlated with PAI-1 levels. No such correlations were seen in the lean groups. In conclusion, the data show that a high WHR in obese, but not lean middle-aged women, is associated with an impaired fibrinolytic activity. This perturbation becomes enhanced when it is associated with hyperinsulinemia and insulin resistance, which is a typical feature of abdominal obesity.

NovoSeven in warfarin-treated patients.

Haemorrhages represent a major complication of treatment with vitamin K antagonists. In cases of severe bleeding, a prompt effect on the increased International Normalized Ratio value is vital to achieve haemostasis. As conventional treatment, that is plasma or plasma-derived concentrates, carries the risk of blood-borne virus transmission, new treatments are needed. An open, multicentre pilot trial is currently under way to determine the effect of recombinant activated factor VII (rFVIIa; NovoSeven) administered to patients experiencing a bleeding episode after receiving vitamin K antagonists. When rFVIIa was given to a patient with a warfarin-induced nosebleed, it had an immediate haemostatic effect and the International Normalized Ratio value virtually normalized.

Comparison of various D-dimer tests for the diagnosis of deep venous thrombosis.

Analyses of D-dimers in plasma are frequently used as diagnostic tools for deep venous thrombosis (DVT). Enzyme-linked immunosorbent assays (ELISAs) are considered to be the method of choice for quantitative assays, but are time consuming. Therefore, we have assessed plasma levels of D-dimers in patients with clinically suspected DVT using quantitative (Asserachrom D-Di ELISA and TintElize), semiquantitative (Minutex latex, D-Di latex, NycoCard D-Dimer) and qualitative (INSTANT.I.A) assays. Phlebography was used as the gold standard to verify or exclude the suspected diagnosis. We conclude that the fast assays, INSTANT.I.A and Minutex, have essentially the same negative predictive value [91% and 89%, respectively, using a cut-off value < 0.5 mg/l fibrinogen equivalent units (FEU)] for excluding DVT as the Asserachrom D-Di ELISA and TintElize tests (92%). The D-Di Latex assay had a negative predictive value of 82% (cut-off < 0.5 mg/l FEU) and turned out to be less useful in our material. The NycoCard D-dimer assay had a negative predictive value of 100% when using the cut-off value < 0.5 mg/l FEU, but this was substantially lower when the cut-off was changed to < or = 0.5 mg/l. Thus, we conclude that several fast tests offer a simpler and more rapid way of determining plasma levels of D-dimer than conventional ELISA methods without loss of clinical usefulness in excluding DVT.

Workshop: Patient Self-Management: Update of Ongoing Studies in Sweden.

Anti-vitamin K (AVK) therapy (e.g., warfarin) requires regular blood tests for adequate dosing of the drug. The therapeutic window for these drugs is narrow, with a risk of bleeding if the dose is too high and of thrombotic complications if the dose is too low. Moreover, the required dose to achieve an optimal level of anticoagulation is individual and depends on such factors as the general health of the patient, food intake, and concomitant medication. Although control requires regular monitoring, most patients are reluctant to visit an anticoagulation clinic (ACC) more than 6-12 times yearly because each visit costs the patient both money and time. The development of prothrombin time (PT) monitors that are simple to operate and highly portable has made self-management possible for large groups of patients on long-term AVK therapy. Self-management increases the safety of AVK therapy through frequent testing (3-4 times per month) and timely dose adjustments when they are indicated. The concept of self-management of AVK therapy was introduced in Germany a decade ago with great success. Swedish patient education in self-management was started in September 1996. As of May 1997, 38 patients have completed the training program, 37 of whom have continued with self-management. Experience with the first seven groups of patients has convinced us that self-management is possible and has great potential. Randomized controlled studies are needed to determine the cost effectiveness of self-management with regard to a reduction in bleeding and thrombotic complications.

Haemostatic disorders in habitual nose-bleeders.

Ninety-one habitual nose-bleeders were screened for haemostatic disorders. 46 screening results in 38 nose-bleeders were outside the normal range. After extended investigation, it was found that 25 (27 per cent) habitual nose-bleeders had haemostatic disorders, all except one in the primary haemostasis. The disorders found could be classified as mild bleeding disorders (MBD) and compared to the estimated frequency of MBD in the population there was an increased incidence of haemostatic disorders in the habitual nose-bleeders. Abnormal vessels in the nasal mucosa were present in 85 per cent of the investigated nose-bleeders, equally distributed between nose-bleeders with and without haemostatic disorders. This indicates that abnormal vessels and haemostatic disorders in habitual nose-bleeders, it is possible to detect previously unknown but clinically important disorders.

Incidence of symptoms and AIDS in 146 Swedish haemophiliacs and blood transfusion recipients infected with human immunodeficiency virus.

The times from infection with the human immuno-deficiency virus (HIV) to the onset of the first clinical symptom and the development of AIDS were studied prospectively in 98 haemophiliacs and 48 blood transfusion recipients infected with the virus. Patients were followed up for a median of 61 months after infection, the dates of infection being either known exactly or estimated from the interval between the last negative and first positive HIV antibody test result. The rate of progression to AIDS was significantly higher for the transfusion recipients than for the haemophiliacs. The difference in time to the occurrence of the first clinical symptom was less pronounced between the two groups, though pointing in the same direction. The results suggest that on average roughly half of all patients positive for HIV will develop some clinical sign or symptom within five to six years after infection.

[Better AVK treatment with self monitoring. Dosage can be regulated in time]. / Bättre AVK-terapi med egenkontroll. Dosen kan justeras i tid.

As long-term anticoagulant treatment, with warfarin for instance, is associated with a risk of both thrombotic and thrombolytic complications, blood testing for dose regulation is necessary at 3-8-week intervals, which is expensive and inconvenient for patients who must take time off work and travel to and fro. A new technique, using small portable monitors designed for home use by patients, makes self-management of anticoagulant treatment possible. In Germany, over 25,000 patients had their own monitor by the end of 1998. After appropriate instruction, the German patients are able to monitor their prothrombin time and adjust their anticoagulant treatment accordingly. In case of problems they contact their GP. In a two-year pilot study conducted at the Anticoagulation Clinic of Sahlgrenska University Hospital, Gothenburg, in 1996-98, where 51 patients on long-term anticoagulant treatment were trained in self-management, the results of over 1,000 patient-hours of treatment showed self-management to be at least as safe as management by the clinic. The level of patient satisfaction is high, in terms of safety and freedom from regular hospital attendance during working hours, and the convenience of self-monitoring on holiday or business trips. As the patients do their testing once a week, the risk of complications is also reduced.

[Hemophiliacs with HIV. Slower progression of the infection among younger patients and at higher dosages of factor concentrates]. / Blödarsjuka med HIV. Långsammare infektionsförlopp hos yngre och vid större förbrukning av faktorkoncentrat.

HIV disease progression and the effect of replacement therapy with clotting factor concentrates (CFCs) were studied in 100 Swedish haemophiliacs, mean age at seroconversion 29 years (range, 4-72). On average 16 years after seroconversion, 67 per cent of the patients had CD4+ cell counts of < 200 x 10(6)/l, 50 per cent had developed AIDS, and 58 per cent had died. HIV disease progression was significantly slower in those aged less than 28 (median age) at seroconversion (P = 0.004). Moreover, mortality was inversely correlated to total annual CFC consumption after adjustment for age and HIV-related therapy, i.e., Pneumocystis carinii prophylaxis and antiretroviral drugs (P = 0.014), but unrelated to the purity of the CFCs used. After adjustment for age, annual CFC consumption and HIV-therapy, prophylactic replacement therapy was not associated with significantly better survival than on-demand treatment. It is concluded that in HIV-positive haemophiliacs replacement therapy may have a beneficial effect on the immune system, and that CFC purity and the regimen (prophylaxis vs on-demand) would seem to be factors of minor importance.

Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays.

INTRODUCTION: Rivaroxaban is an oral direct factor Xa inhibitor developed for prophylaxis and treatment of thromboembolic disorders. Laboratory monitoring is not necessary but the dose-dependent effects on common reagents and assay procedures are largely unknown. OBJECTIVES: To investigate the effect of rivaroxaban on commonly used coagulation assays. MATERIALS AND METHODS: Rivaroxaban was added to plasma from healthy subjects in the concentration range 0-1000 µg L(-1) and analyzed using different reagents for activated partial thromboplastin time (APTT), prothrombin time (PT), antithrombin, fibrinogen and activated protein C (APC) resistance assays. RESULTS: At an expected peak concentration of rivaroxaban in clinical use, the APTTs were almost invariably prolonged but at lower concentrations the effect was weak. The concentration needed to double the APTT varied between 389 ± 106 and 617 ± 149 µg L(-1) for different reagents. The PT assays showed a marked degree of difference. In general, the Quick PT type assays were more sensitive compared with the Owren type PT assays. The results from antithrombin assays were dependent on the type of reagent, with the Xa-based assay being sensitive for rivaroxaban with an estimated increase of 0.09 IU mL(-1) per 100 µg L(-1) rivaroxaban. There were only minor effects on fibrinogen assays based on thrombin reagents. The APTT-based assay for APC resistance is affected in a dose-dependent manner whereas an assay based on the activation of coagulation at the prothrombinase level was unaffected. CONCLUSIONS: Different assays, and even different reagents within an assay group, display variable effects by therapeutic concentrations of rivaroxaban.