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.     

Prothrombotic gene variation and new vascular events after cerebral ischemia of arterial origin

Summary. Background: Several genetic variants involved in hemostasis have been associated with ischemic stroke or myocardial infarction (MI). Stroke patients who carry a prothrombotic genotype may also be at increased risk for subsequent vascular events. Patients and methods: We included 887 patients with non‐disabling cerebral ischemia of arterial origin, who were referred to the University Medical Center Utrecht in the Netherlands between 1995 and 2005 and followed them for the occurrence of ischemic stroke, MI or death. The primary outcome was a composite of death from all vascular causes, non‐fatal ischemic stroke, non‐fatal MI, whichever happened first. We selected 22 prothrombotic variants in 14 genes that were previously associated with ischemic stroke or MI or had evidence of functionality. Results: During a 4.6‐year mean follow‐up period new vascular events occurred in 135 patients (annual event rate 3.3%). None of the 22 variants was associated with the occurrence of new vascular events. Eight additional analyses with secondary outcomes or among subgroups revealed four associations that were likely to be false positive after accounting for multiple testing. Conclusions: In this cohort, prothrombotic genetic variants do not affect the risk of new vascular events after cerebral ischemia of arterial origin. This study does not support the use of prothrombotic genetic variants to identify stroke patients at increased risk for new vascular events or to guide antithrombotic treatment.     

Scientific and standardization committee communications: classification and nomenclature of disintegrins isolated from snake venoms

Summary.  Viper venoms from the Elapidae, Hydrophiidae, Atractaspididae, Viperidae and Colubridae families contain at least 25 separate classes of biologically active compounds, including enzymes and non-enzymatic molecules. Nomenclature standardization of these by structure and function has been reported for prothrombin activators. No such agreement has been made for the nomenclature and classification of disintegrins. At the 51st Annual SSC Meeting in Sydney Australia (August 2005), we reported the variety of names given to the 78 disintegrins then known, and proposed a nomenclature standardization method for the naming of future members in this protein family. The summary of these recommendations will provide guidance as disintegrin discoveries move beyond high pressure liquid chromatography (HPLC) separation methods to mass spectrometry, proteomics and cloned cDNA.
View the complete paper on the International Society on Thrombosis and Haemostasis website, http://www.isth.org . ( http://www.med.unc.edu/isth/ssc/communications/exogenous/disintegrins/disintegrins.htm ). This abstract is co-published in Toxicon .     

Rituximab for congenital haemophiliacs with inhibitors: a Canadian experience

When a high titre inhibitor develops in a patient with haemophilia, attempts are made to eradicate it through immune tolerance induction therapy (ITI) involving the frequent and regular administration of factor, usually for months to years. ITI is successful in only two thirds of patients prompting investigators to explore alternate regimens to use in haemophiliacs failing conventional ITI. Rituximab is an anti-CD20 monoclonal antibody, which has shown promise in the treatment of B-cell-mediated disorders. We developed a protocol for the use of rituximab in haemophilia A (HA) patients failing conventional ITI or in those haemophiliacs where the likelihood of success of conventional ITI is poor. Patients receive 375 mg m(-2) of intravenous rituximab weekly for 4 weeks followed by monthly (up to 5 months) until inhibitor disappearance and establishment of normal FVIII pharmacokinetics (recovery and half-life). Patients are concurrently placed on recombinant FVIII (100 U kg(-1) day(-1)). We have placed five haemophiliacs (four children with severe HA, and one adult with mild HA) on this protocol. In three patients (two with severe HA and one with mild HA) inhibitors disappeared although in neither severe haemophiliac did FVIII pharmacokinetics completely normalize. The fourth patient had a significant drop in inhibitor titres although not a complete disappearance of the inhibitor. All four of these patients ceased bleeding following rituximab. The fifth patient had no response to rituximab. This non-responding patient was not placed on concurrent FVIII. Our five cases suggest that rituximab may hold promise in the eradication of inhibitors. Prospective randomized studies are required to determine the value of this agent in inhibitor management.     

Obliterative portal venopathy: A comparative study of 184 cases of extrahepatic portal obstruction and 469 cases of idiopathic portal hypertension

Abstract A total of 184 cases of extrahepatic portal obstruction (EHPO), mostly demonstrated by intraoperative portography and studied at 17 institutes during the period 1957–1983, were compared with 469 cases of idiopathic portal hypertension (IPH) similarly studied. Of the cases of EHPO, there were 101 males and 83 females; 93 were under 20 years of age and the average age was 25.9 years (i.e. much younger than that of IPH cases). There were two age peaks, one before age 19 years and the other at age 40–49 years. One out of three adult cases had a history of abdominal surgery, but otherwise the aetiologic factor was difficult to elicit. Bleeding was the initial symptom in the majority, and splenectomy and haematological findings of hypersplenism were less pronounced compared with IPH. Liver function tests were almost always normal. The liver appeared normal macroscopically in 69% and histologically in 35%. The changes seen in the remainder were similar to those in IPH; they were less frequent in young patients than in cases above age 20 years. Compared with IPH, the wedged hepatic venous pressure in patients with EHPO was lower and the gradient from the portal venous pressure was greater. It is concluded that extrahepatic portal obstruction is less common compared with IPH in Japan, and that there are cases particularly among adults that present clinicopathological features very similar to those of IPH. It is unclear at present whether these two disorders represent two different disease entities, or whether they represent one disorder with differences in the site of involvement along the portal vein system.     

Effects of amlodipine on transient myocardial ischaemia in patients with a severe coronary condition treated with a beta-blocker

The purpose of this trial was to study the additional anti-ischaemiceffects of amlodipine in coronary patients with ambulant ischaemiadespite beta-blocker therapy. Beta-blockers are the most effectivedrug therapy for reducing the frequency and duration of ambulatoryischaemic episodes. However, the therapeutic advantage of combinedcalcium antagonist-beta-blocker treatment remains questionable. Three hundred and thirteen patients with documented coronaryartery disease, a positive exercise test within 6 months beforeentry and background beta-blocker therapy, were screened. Inclusioncriteria (4 episodes of transient ST segment depression of 1.0 mm and/or 20 min of ischaemia) were demonstrated in a 48h ECG during the placebo run-in period in 84 (25%) of the patients.Eighty-nine percent of the ischaemic episodes were silent. Theeligible patients were then randomized in a 2-week, double-blind,parallel group study comparing placebo to amlodipune 10 mg dailyadded to the beta-blocker. The anti-ischaemic efficacy of thecombination therapy was assessed by 48 h ECG monitoring andexercise tests. Compared to placebo, amlodipine did not significantly reduceeither the frequency (3.7±4.3 vs 4±4.8 episodesin the amlodipune group) or the duration of ambulatory ischaemia(mean duration: 43.9±57.1 vs 39.6±65.7 min, totalduration 3.1±6.7 vs 2.8±6.1 h). Exercise-inducedST segment depression tended to decrease with amlodipine (58%vs 73% in the placebo group) and the ischaemia-free workloadcapacity was increased (+1.7 stage vs 0.7 stage in the placebogroup, P=0.08). These results suggest that 2 weeks treatment with amlodipinemay not provide any additional anti-ischaemic benefit in patientswith ambulant ischaemia resistant to a beta-blocker therapy.