Confusion around the official classification of arthropathy.
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Hemarthrosis↗
Biomedical subjects
S Schulman
Publications and source records attributed to S Schulman.
Low PAI-1 activity in relation to the risk for perioperative bleeding complications in transurethral resection of the prostate.
INTRODUCTION: Low levels of plasminogen activator inhibitor type 1 (PAI-1) have been associated with increased risk for perioperative bleeding in some case reports. The aim of this study was to investigate prospectively whether low PAI-1 activity increases the risk for perioperative bleeding in patients undergoing transurethral resection of prostate, an organ with high fibrinolytic activity. PATIENTS AND METHODS: 62 patients with benign prostatic hyperplasia planned for transurethral resection were included. Blood samples for PAI-1 were taken together with other routine preoperative blood samples 1week before surgery but analyzed after the hospitalization. The intraoperative blood loss was determined by measuring the amount of hemoglobin in the irrigating fluid. The postoperative blood loss was estimated from calculations of hemoglobin mass (Hb mass), which is a product of hemoglobin concentration and blood volume. Hb mass was calculated before surgery and on the day of discharge, and was adjusted for intraoperative blood loss and transfused Hb mass. Bleeding complications were defined as re-operation due to bleeding, more than 40ml intraoperative bleeding/g resected prostatic tissue or postoperative blood loss corresponding to more than 100g of hemoglobin. RESULTS: Bleeding complications were observed in 3 of 4 (75%) patients with low PAI-1 levels, defined as <1U/ml, and in 16 of 58 (28%) patients with PAI-1 levels >1U/ml (P=0.082). After adjustment for resection time, resected prostatic mass and systolic blood pressure this became borderline significant (odds ratio 11.8; 95% confidence interval 1.00-139; P=0.05). CONCLUSION: Low PAI-1 activity may contribute to the risk of bleeding after transurethral resection of the prostate.
Aged↗
An illustrative case and a review on the dosing of recombinant factor VIIa in congenital factor XI deficiency.
Recombinant activated factor VII (rFVIIa) has been used in a very limited number of patients with severe factor XI (FXI) deficiency. The dose and duration of treatment has varied greatly between these case reports. In a few of these cases there was also evidence of thrombotic complications. We present here a report on one additional patient with congenital FXI deficiency. For two major orthopaedic procedures in this patient we used rFVIIa as a single bolus dose followed by continuous infusion at a low rate. The data from these treatment episodes, together with those from a review of the published cases, lend support to the concept of using much lower doses than in haemophilia with inhibitors. A bolus dose of 20 microg kg(-1) and thereafter maintenance of the FVII activity at approximately 3 IU mL(-1) appears effective and safe.
Factor VII↗
Evaluation of low PAI-1 activity as a risk factor for hemorrhagic diathesis.
BACKGROUND: Prospective studies of the epidemiology and clinical significance of low plasminogen activator inhibitor type 1 (PAI-1) activity are lacking. OBJECTIVE: To evaluate the prevalence of low PAI-1 activity in patients with a bleeding tendency in comparison with a normal population. METHODS: In 586 consecutive patients, referred because of bleeding symptoms, we added analyses of PAI-1 activity and tissue plasminogen activator complex with PAI-1 (t-PA-PAI-1) to the routine investigation, consisting of platelet count, bleeding time, prothrombin time, activated partial thromboplastin time, fibrinogen, factor VIII, von Willebrand factor activity, and antigen. Controls were 100 blood donors and 100 age- and sex-matched healthy individuals. The latter were also evaluated regarding the previous bleeding episodes. The bleeding history was classified as clinically significant or not, and the criteria were fulfilled in 75% of the patients and 18% of the healthy controls. RESULTS: The routine laboratory investigation of the patients was negative in 57%. Low PAI-1 activity, defined as <1.0 U mL(-1), was found in 23% of the patients and in 13% and 10% of the blood donors and healthy controls, respectively (odds ratio and 95% CI, 2.04; 1.11-3.77 and 2.75; 1.39-5.42, respectively). The difference remained statistically significant after the adjustment for body mass index, use of estrogens, sex and age (odds ratio for patients vs. healthy controls 3.23; 95% CI, 1.22-8.56, P = 0.019). The distribution of the 4G/5G genotypes in the patients was not different from that of two control populations. No specific symptom predicted for low PAI-1, which did not aggravate the clinical picture in association with the other hemostatic defects. Low tPA-PAI-1 was not associated with the increased bleeding tendency. CONCLUSION: Low PAI-1 activity is common in patients with a bleeding diathesis, but it is a risk factor of minor clinical importance and not associated with specific bleeding manifestations.
Adolescent↗
Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months.
BACKGROUND: The influence of the duration of anticoagulant therapy after venous thromboembolism (VTE) on the long-term morbidity and mortality is unclear. AIM: To investigate the long-term sequelae of VTE in patients randomized to different duration of secondary prophylaxis. METHODS: In a multicenter trial comparing secondary prophylaxis with vitamin K antagonists for 6 weeks or 6 months, we extended the originally planned 2 years follow-up to 10 years. The patients had annual visits and at the last visit clinical assessment of the post-thrombotic syndrome (PTS) was performed. Recurrent thromboembolism was adjudicated by a radiologist, blinded to treatment allocation. Causes of death were obtained from the Swedish Death Registry. RESULTS: Of the 897 patients randomized, 545 could be evaluated at the 10 years follow-up. The probability of developing severe PTS was 6% and any sign of PTS was seen in 56.3% of the evaluated patients. In multivariate analysis, old age and signs of impaired circulation at discharge from the hospital were independent risk factors at baseline for development of PTS after 10 years. Recurrent thromboembolism occurred in 29.1% of the patients with a higher rate among males, older patients, those with permanent triggering risk factor - especially with venous insufficiency at baseline - signs of impaired venous circulation at discharge, proximal deep vein thrombosis, or pulmonary embolism. Death occurred in 28.5%, which was a higher mortality than expected with a standardized incidence ratio (SIR) of 1.43 (95% CI 1.28-1.58), mainly because of a higher mortality than expected from cancer (SIR 1.83; 95% CI 1.44-2.23) or from myocardial infarction or stroke (SIR 1.28; 95% CI 1.00-1.56). The duration of anticoagulation did not have a statistically significant effect on any of the long-term outcomes. CONCLUSION: The morbidity and mortality during 10 years after the first episode of VTE is high and not reduced by extension of secondary prophylaxis from 6 weeks to 6 months. A strategy to reduce recurrence of VTE as well as mortality from arterial disease is needed.
Aged↗
Hypercoagulability preceding cancer. Are anticoagulants also antineoplastic?
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Anticoagulants↗
Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients.
Summary. A variety of definitions of major bleeding have been used in published clinical studies, and this diversity adds to the difficulty in comparing data between trials and in performing meta-analyses. In the first step towards unified definitions of bleeding complications, the definition of major bleeding in non-surgical patients was discussed at the Control of Anticoagulation Subcommittee of the International Society on Thrombosis and Haemostasis. Arising from that discussion, a definition was developed that should be applicable to studies with all agents that interfere with hemostasis, including anticoagulants, platelet function inhibitors and fibrinolytic drugs. The definition and the text that follows have been reviewed and approved by the cochairs of the subcommittee and the revised version is published here. The intention is to also seek approval of this definition from the regulatory authorities.
Anticoagulants↗
Does an enzyme other than thrombin contribute to unexpected changes in the levels of the different forms of thrombin activatable fibrinolysis inhibitor in patients with hemophilia A, hemophilia B and von Willebrand disease?
Pro-thrombin activatable fibrinolysis inhibitor (pro-TAFI), also called plasma procarboxypeptidase B or U, is one of the modulators of fibrinolysis in blood. Pro-TAFI is activated by thrombin/thrombomodulin complex or by plasmin to a carboxypeptidase B-like enzyme (TAFI) of 35.8 kD molecular weight. TAFI spontaneously becomes inactive as a result of a temperature-dependent conformational change in the protein (TAFIi). In this study, pro-TAFI, total TAFI antigen and TAFI-TAFIi antigen levels were measured in 32 patients with hemophilia A, 4 patients with hemophilia B, 21 patients with von Willebrand disease (VWD) and 13 healthy controls. A statistically significant decrease in pro-TAFI was found in all groups (10.72+/-4.57 mg/L (p<0.001); 8.00+/-2.35 mg/L (p<0.01) and 8.98+/-2.33 mg/L (p <0.001) for hemophilia A, hemophilia B and VWD, respectively) compared to controls (17.85+4.61 mg/L). A statistically significant increase in TAFI-TAFIi antigen was found in hemophilia A (1.05+/-1.01 mg/L) (p<0.05) and in VWD patients (0.96+/-1.01 mg/L) (p<0.05) compared to controls (0.55+/-0.36 mg/L). There was no difference in total TAFI antigen levels between any group of patients and the controls. Neither did pro-TAFI nor TAFI-TAFIi levels differ within the group of hemophilia A patients in relation to severity (mild, moderate and severe) or among the VWD patients in relation to subtype (type 1, type 2A and type 3). These findings indicate an increased conversion of pro-TAFI to TAFI and/or TAFIi in patients with bleeding disorders. As thrombin generation is seriously impaired in these patients and almost absent in hemophilia A and B and in type 3 VWD, it is possible that plasmin mediates pro-TAFI activation in these patients. Enhanced fibrinolysis via generation of plasmin has previously been reported in hemophilia and VWD. Activation of pro-TAFI by plasmin may be a feedback mechanism that counterbalances increased fibrinolysis in patients with bleeding disorders. The relationship between the TAFI activation pathway and bleeding complications associated with hemophilia A, hemophilia B and VWD requires further investigation.
Adult↗
Costs of on-demand and prophylactic treatment for severe haemophilia in Norway and Sweden.
The expected annual cost (in the year 2000 prices) for a 30-year-old patient with average individual and treatment characteristics for on-demand EUR 51,832 (95% CI: 44,324-59,341) and for prophylaxis EUR 146,118 (95% CI: 129,965-162,271), was obtained from panel-data analysis of an 11-year retrospective panel of 156 patients with severe haemophilia in Norway and Sweden. Costs included haemophilia-related treatment costs within the health-care sector (factor concentrate, doctors' visits, diagnostic procedures, hospitalisation, invasive procedures, etc.) and cost for haemophilia-related resource use in other sectors (lost production, use of special equipment, adaptation of workplace and domicile, etc). Although costs of lost production, reconstructive surgery and hospitalisation were higher for on-demand, they did not balance out the higher costs of factor-concentrate consumption in prophylaxis. The cut-off risk of premature death, where on-demand and prophylaxis would have been equally costly, was 3.7 percentage units higher for on-demand than for prophylaxis. Such a great risk difference has not been reported elsewhere to our knowledge. Estimated cost-elasticities indicated that annual costs of prophylaxis would increase by approximately the same proportion as a potential increase in the price of factor concentrate and decrease less than proportionately with a reduction in prescribed dose kg(-1). For on-demand, the annual costs would increase by approximately the same proportion as an increase in the prescribed dose kg(-1).
Adult↗
Continuous infusion of B-domain deleted recombinant factor VIII (ReFacto) in patients with haemophilia A undergoing surgery: clinical experience.
This retrospective, open-label, non-comparative study evaluated continuous infusion of recombinant factor VIII (ReFacto), B-domain deleted recombinant FVIII (BDDrFVIII), in patients with haemophilia A undergoing surgery and requiring >5 consecutive days of treatment. Sixteen patients from eight centres underwent a total of 20 procedures. Haemostatic outcome was assessed as 'excellent' or 'good' in 75% of procedures, and target FVIII:C levels were maintained throughout the continuous infusion period. The reported volume of blood loss during surgery was also within the normal range for non-haemophilic patients for the type of surgery performed. Red blood cell transfusions were required to balance excessive blood loss during BDDrFVIII continuous infusion in eight (40%) procedures (seven patients), five with bleeding or requiring volume replacement and three to treat anaemia secondary to blood loss. Non-serious adverse events considered by investigators as possibly or probably related to BDDrFVIII continuous infusion were infrequent (n = 5) considering the duration of treatment (n =239 cumulative days of continuous infusion), and all of these were mild-to-moderate in severity. No thromboembolic complications were reported except for one case of thrombophlebitis occurring at the infusion site. Only two patients (four events) experienced serious adverse bleeding; BDDrFVIII was otherwise well-tolerated. These data show that continuous infusion of BDDrFVIII provides reliable haemostasis and is an effective and well-tolerated regimen for patients with haemophilia A undergoing surgery.
Adolescent↗
Minimizing factor requirements for surgery without increased risk.
The most common type of surgical procedure in patients with haemophilia is orthopaedic surgery on the lower limb. These procedures are of great importance for the improvement of the function and quality of life of patients with haemophilia, but in many countries resources are lacking to provide the factor concentrates needed for these operations. We have attempted to reduce the level of replacement during and after total hip or total knee replacement without jeopardizing the outcome of the procedures. The results from 30 operations in 27 patients are presented. Steady-state levels down to 0.5 IU mL(-1) did not appear to increase the amount of blood loss or cause an increased incidence of complications, compared with higher levels. In addition, we review the possibilities to reduce the amount of factor concentrate by performing a combination of orthopaedic procedures and using local haemostatic agents or antifibrinolytic agents.
Aged↗
Vitamin K antagonists and cancer: rebuttal.
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Humans↗
Continuous intravenous infusion of a plasma-derived factor IX concentrate (Mononine) in haemophilia B.
This prospective, multicentre, open-label study evaluated the efficacy and safety of a plasma-derived factor IX concentrate [Mononine, Coagulation Factor IX (Human) Monoclonal Antibody Purified] administered by continuous intravenous (CIV) infusion to patients with haemophilia B. Admission criteria included documented diagnosis of haemophilia B (mild, moderate, or severe). Twenty-eight patients (25 surgery, two trauma, one severe spontaneous haemorrhage) were enrolled to receive a therapeutic bolus dose followed by CIV infusion of factor IX (FIX) to maintain FIX:C plasma levels of 0.4-1.0 IU mL(-1) (i.e. 40-100%). A median intravenous bolus dose of 54.2 IU kg(-1) FIX was administered to a subset of 13 non-emergency patients 7-21 days prior to CIV infusion to determine pharmacokinetic parameters in order to guide the dosing for CIV. For treatment, a bolus injection (median FIX dose; 89.6 IU kg(-1)) (range, 12.4-108.3), followed by a median total CIV infusion dose of 396.4 IU kg(-1) (range, 44.9-785.5) was administered at a median rate of 3.84 IU kg(-1) h(-1) (range, 1.74-7.33) for 107.17 h (range, 31.75-144). Twenty-four patients completed 72-120 h of FIX CIV infusion. Overall, 'excellent' (i.e. achievement of normal haemostasis) efficacy was reported in 23 of 24 (96%) evaluable patients, and 'good' (i.e. slight oozing) efficacy was reported in one (4%) patient. Median FIX:C was 72-86% for all patients receiving FIX by CIV on all days. Nine patients reported 13 adverse events that were possibly related to study medication but were not deemed serious by the investigator and were mainly because of local irritation at the infusion site. FIX CIV infusion therapy is safe and effective in the treatment of haemophilia B patients undergoing surgery, exposed to trauma, or experiencing severe spontaneous haemorrhage.
Adolescent↗
Continuous infusion.
There is evidence, albeit scientifically weak, for improved cost/benefit with administration of factor concentrates by continuous infusion when high-dose replacement is necessary, as several studies have shown a reduced requirement for the concentrate. There is evidence from only one study for fewer bleeding complications with continuous infusion. There is evidence from two studies that additional therapy with tranexamic acid reduces the risk of bleeding complications in patients receiving continuous infusion. Future studies should address the question of minimum steady-state levels required for haemostasis, comparisons with bolus injection using a randomized design and investigate the risk of inhibitor formation.
Blood Coagulation Disorders↗
On-demand vs. prophylactic treatment for severe haemophilia in Norway and Sweden: differences in treatment characteristics and outcome.
Using an 11-year panel of 156 Norwegian and Swedish patients with severe haemophilia, and including retrospective case-book data from birth, we compared the differences in the haemophilia-related resource use between on-demand and prophylactic treatment. Patients treated on-demand had more surgery (arthrodeses, prostheses implantations and synovectomies) and more days lost from work. Median annual factor-concentrate consumption among adults (18+) was 211,000 IU [interquartile range (IQR) 154,000-268,000] or 3,024 IU kg-1 year(-1) for patients on prophylactic treatment and 55,000 IU (IQR 28,000-91,000) for on-demand patients (780 IU kg(-1) year(-1)). This was partly explained by the fact that the median dose per kg body weight was twice as great 28, (IQR 24-32) for prophylaxis compared with 14 (IQR 12-16) for on-demand. Prescribed dose per kg body weight was found to be an important factor explaining the variation in total annual factor-concentrate consumption per patient for both types of treatment. Other variables included in the panel-data regression analysis were the number of weeks on secondary prophylaxis for on-demand patients and age, body weight and type of haemophilia for children (0-17 years) on prophylaxis. Differences were consistently substantial and will affect both costs and benefits of the two treatment strategies.
Absenteeism↗
Novel anticoagulant agents: introduction.
In this Minisymposium three principles for anticoagulant therapy are discussed and examples of novel, selective coagulation inhibitors at the stage of advanced clinical trials are given. This introduction attempts to explain the different mechanisms of action on a broad scale, and also includes a brief look at effects on inflammation and cancer.
Anti-Inflammatory Agents↗
A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I.
This randomized, controlled, multicentre study evaluated the efficacy and tolerability of the oral direct thrombin inhibitor ximelagatran, compared with a low-molecular-weight heparin (dalteparin) followed by warfarin, in the treatment of deep vein thrombosis (DVT) of the lower extremity. Patients with acute DVT received oral ximelagatran (24, 36, 48 or 60 mg twice daily) or dalteparin and warfarin for 2 weeks. Evaluation of paired venograms from 295 of 350 patients showed regression of the thrombus in 69% of patients treated with ximelagatran and 69% of patients treated with dalteparin and warfarin. Progression was observed in 8% and 3% of patients, respectively. Changes in thrombus size according to the Marder score were similar in all groups. Treatment discontinuation due to bleeding occurred in two patients receiving ximelagatran (24- and 36-mg groups) and in two patients receiving dalteparin and warfarin. Reduction in pain, edema and circumference of the affected leg was similar in all groups. Oral ximelagatran appears to be a promising alternative to current anticoagulant therapy to limit the progression of acute DVT, and it seems to possess a wide therapeutic window.
Acute Disease↗
Unresolved issues in anticoagulant therapy.
Large randomized clinical trials have clarified some issues of anticoagulation and have led to progress, such as outpatient treatment of acute deep vein thrombosis with low-molecular-weight heparin. However, many uncertainties remain and are reviewed here. When should thrombolytic therapy be used, apart from patients in shock due to pulmonary embolism? How should low-molecular-weight heparin be used in patients with extreme obesity or renal failure? The optimal duration of anticoagulation after venous thromboembolism has been the subject of many debates. With the recognition of an increasing number of risk factors for recurrence, the picture becomes increasingly complex. Lower intensity of anticoagulation with vitamin K antagonists and novel anticoagulant drugs are possible alternatives in extended secondary prophylaxis. For stroke prophylaxis in non-valvular atrial fibrillation, there is a gray zone between the groups where there is a clear indication for aspirin or for vitamin K antagonists. Anticoagulation in connection with cardioversion raises questions regarding optimal postprocedure therapy. Fine tuning of prophylaxis against thromboembolism in patients with prosthetic heart valves requires more studies of subgroups, homogenous for position and type of valve as well as presence of atrial fibrillation. The management of these patients in case of surgical procedures has not been studied properly. Secondary prophylaxis after myocardial infarction may achieve the best effect with vitamin K antagonists at an INR of 2.0-2.5 in combination with low-dose aspirin, but is it really cost-effective? Finally, many controversies exist regarding anticoagulation during pregnancy.
Anticoagulants↗