Per Morten Sandset

Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study

Summary Background Patients with acute ischaemic stroke and atrial fibrillation have an increased risk of early stroke recurrence, and anticoagulant treatment with heparins has ben widely advocated, despite missing data on the balance of risk and benefit. Methods Heparin in Acute Embolic Stroke Trial (HAEST) was a multicentre, randomised, double-blind, and double-dummy trial on the effect of low-molecular-weight heparin (LMWH, dalteparin 100 IU/kg subcutaneously twice a day) or aspirin (160 mg every day) for the treatment of 449 patients with acute ischaemic stroke and atrial fibrillation. The primary aim was to test whether treatment with LMWH, started within 30 h of stroke onset, is superior to aspirin for the prevention of recurrent stroke during the first 14 days. Findings The frequency of recurrent ischaemic stroke during the first 14 days was 19/244 (8·5%) in dalteparin-allocated patients versus 17/225 (7·5%) in aspirin-allocated patients (odds ratio=1·13, 95% CI 0·57–2·24). The secondary events during the first 14 days also revealed no benefit of dalteparin compared with aspirin: symptomatic cerebral haemorrhage 6/224 versus 4/225; symptomatic and asymptomatic cerebral haemorrhage 26/224 versus 32/225; progression of symptoms within the first 48 hours 24/224 versus 17/225; and death 21/224 versus 16/225. There were no significant differences in functional outcome or death at 14 days or 3 months. Interpretation The present data do not provide any evidence that LMWH is superior to aspirin for the treatment of acute ischaemic stroke in patients with atrial fibrillation. However, the study could not exclude the possibility of smaller, but still worthwhile, effects of either of the trial drugs.

Heparin induces release of extrinsic: Coagulation pathway inhibitor (EPI)

Extrinsic pathway inhibitor (EPI) is a potent inhibitor of the factor VIIa-tissue thromboplastin complex. The effect of heparin on EPI activity was studied using a chromogenic substrate assay. Addition of heparin to test plasma or whole blood in vitro increased EPI activity. This increase in EPI activity was reduced by the addition of polybrene and/or antibodies to antithrombin (anti-AT). Polybrene was therefore added to the assay system. However, part of this effect (up to 20% of baseline value) was not abolished. After intravenous injection, EPI activity increased dose-dependently. The increase was about 200% of baseline value after 7500 U heparin, and was not reduced by the addition of polybrene and/or anti-AT. A slower and prolonged increase in EPI activity occurred after subcutaneous injections of unfractionated heparin and low molecular weight heparin (LMWH). Venous occlusion failed to increase EPI activity levels. Normal EPI values were observed in patients with severe liver cirrhosis and during warfarin treatment. Gel filtration of human endothelial cell culture supernatant revealed one inhibitory fraction with molecular weight about 43.000. We conclude that EPI probably is produced in endothelial cells and may be released by heparin.

Ante- and postnatal risk factors of venous thrombosis: a hospital-based case–control study

Summary.  Objective: To study ante‐ and postnatal risk factors of venous thrombosis (VT) in pregnancy. Methods: A hospital‐based case–control study. Cases were women with objectively verified VT during pregnancy or postpartum. Two controls were selected for each case. Validated risk factors were analyzed using chi‐square test and logistic regression. Results: In total 559 cases with no prior VT, 268 ante‐ and 291 postnatal cases were identified together with 1229 controls. Risk factors for antenatal VT were assisted reproduction technique (ART), antepartum immobilization, cigarette smoking, and slight weight gain (<7 kg). Conception after ART and multiple pregnancy had an additive effect, whereas antepartum immobilization and high body mass index (BMI) had a multiplicative effect on the risk for antepartum VT. No other interaction was found between risk factors for antepartum VT. Risk factors for postnatal VT were antepartum immobilization, cigarette smoking, intrauterine fetal growth restriction (IUGR), preeclampsia, emergency cesarean section, postpartum hemorrhage, infection, surgery, and age and parity. Antepartum immobilization, high BMI and reoperation on the indication of bleeding showed multiplicative effects on the risk of postnatal VT. Conclusions: Ante‐ and postpartum risk factors differed markedly. More attention should be paid to pregnant women of high BMI who are immobilized.

Association between acute hypobaric hypoxia and activation of coagulation in human beings

The risk of venous thrombosis is thought to be increased by flying. In a study of 20 healthy male volunteers who were suddenly exposed to a hypobaric environment similar to that encountered within aeroplane cabins, markers of activated coagulation transiently Increased by two-fold to eight-fold. We suggest that hypobaric hypoxia, with sedentariness and dehydration, may cause this increased risk of venous thrombosis.

Catheter‐directed thrombolysis vs. anticoagulant therapy alone in deep vein thrombosis: results of an open randomized, controlled trial reporting on short‐term patency

Summary.  Background: Approximately one in four patients with acute proximal deep vein thrombosis (DVT) given anticoagulation and compression therapy develop post‐thrombotic syndrome (PTS). Accelerated removal of thrombus by thrombolytic agents may increase patency and prevent PTS. Objectives: To assess short‐term efficacy of additional catheter‐directed thrombolysis (CDT) compared with standard treatment alone. Patients and methods: Open, multicenter, randomized, controlled trial. Patients (18–75 years) with iliofemoral DVT and symptoms < 21 days were randomized to receive additional CDT or standard treatment alone. After 6 months, iliofemoral patency was investigated using duplex ultrasound and air‐plethysmography assessed by an investigator blinded to previous treatment. Results: One hundred and three patients (64 men, mean age 52 years) were allocated additional CDT (n = 50) or standard treatment alone (n = 53). After CDT, grade III (complete) lysis was achieved in 24 and grade II (50%–90%) lysis in 20 patients. One patient suffered major bleeding and two had clinically relevant bleeding related to the CDT procedure. After 6 months, iliofemoral patency was found in 32 (64.0%) in the CDT group vs. 19 (35.8%) controls, corresponding to an absolute risk reduction (RR) of 28.2% (95% CI: 9.7%–46.7%; P = 0.004). Venous obstruction was found in 10 (20.0%) in the CDT group vs. 26 (49.1%) controls; absolute RR 29.1% (95% CI: 20.0%–38.0%; P = 0.004). Femoral venous insufficiency did not differ between the two groups. Conclusions: After 6 months, additional CDT increased iliofemoral patency from 36% to 64%. The ongoing long‐term follow‐up of this study will document whether patency is related to improved functional outcome.

The quantitative association of plasma endotoxin, antithrombin, protein C, extrinsic pathway inhibitor and fibrinopeptide a in systemic meningococcal disease

We have evaluated the quantitative relationship between lipopolysaccharide (LPS, endotoxin), fibrinopeptide A (FPA), antithrombin (AT), protein C (PC) and extrinsic pathway inhibitor (EPI) in plasma from 39 consecutively admitted patients with systemic meningococcal disease (SMD). The most severely ill patients with fulminant meningococcal septicemia (n = 13, 6 dead) had significantly (p less than 0.01) higher plasma levels of LPS and FPA and lower levels of PC and AT on admission as compared with the less severe clinical presentations (n = 26, 1 dead). The levels of EPI on admission were significantly (p less than 0.05) higher in nonsurvivors vs survivors with fulminant septicemia. As the disease progressed, the levels of LPS, FPA, AT and PC declined, while the levels of EPI increased. Three of six nonsurviving septicemic patients had levels of EPI greater than 200% within 16 hours of admission vs two of 30 survivors (p = 0.02). The results suggest that increasing levels of LPS in SMD elicit increasing consumption coagulopathy, contributing to the organ pathophysiology. The kinetics of EPI, inhibiting the thromboplastin-FVIIa-FXa complex, differs markedly from the kinetics of AT and PC i.e. increases as opposed to decreases.

European Stroke Initiative Recommendations for Stroke Management

This article summarises recommendations for acute management of stroke by the European Stroke Initiative (EUSI), on behalf of the European Stroke Council (ESC), the European Neurological Society (ENS), and the European Federation of Neurological Societies (EFNS).

A sensitive assay of extrinsic coagulation pathway inhibitor (EPI) in plasma and plasma fractions

We have previously shown that addition of adsorbed plasma to a mixture of TP and FVII reduces the amount of subsequently added FX that can be activated. We now report that this inhibitory effect of plasma is increased dramatically by first incubating TP and FVII with a minor amount of FX. This results in a progressive loss in the ability of TP-FVIIa to convert subsequently added FX to FXa. An assay system quantitating the inhibitory effect of 1 microliter of heated, citrated plasma is described. Optimal inhibition is obtained when the initial amount of FX added is about 0.00125 U, which is 1/16 of the amount used as reagent to measure remaining TP-FVIIa. FVII and FX must be removed from test plasma prior to assay. The inhibitory activity is reduced more by BaSO4 adsorption than by heating plasma to 56 degrees C for 15 minutes. Gel filtration of plasma separates three distinct fractions with inhibitory activity.

THE PRESENT STATUS OF TISSUE FACTOR PATHWAY INHIBITOR

Tissue factor pathway inhibitor (TFPI) is the factor Xa-dependent inhibitor of the factor VIIa/tissue factor complex. The plasma concentration of this 276 amino acid, 40 kDa glycoprotein is normally about 100 ng/ml. There are three intravascular pools of TFPI: 50-90% is on the endothelium, 10-50% is in plasma and less than 2.5% is in platelets. The TFPI in plasma is mainly associated with lipoproteins-only about 5% is free TFPI. The lipoprotein-associated TFPI seems to be of less anticoagulant effect than the free TFPI. Both unfractionated heparin, low-molecular-weight heparins and pentosan polysulphate induce release of TFPI after intravenous injection, whereas dermatan sulphate does not. The interactions with TFPI account for a considerable amount of the anticoagulant effect of heparin. Studies have shown increased TFPI levels in plasma from patients with advanced malignancy and in subjects with fatal DIC or septicaemia. The reason for this is unknown. For measuring the anticoagulant activity of TFPI in plasma, end-point or antigen assays may be less useful than the clotting assay with dilute tissue factor. Animal studies indicate that the main physiological role of TFPI is the inhibition of small amounts of tissue factor. TFPI is probably essential for a normal haemostatic balance.

Chromogenic substrate assay of extrinsic pathway inhibitor (EPI): levels in the normal population and relation to cholesterol.

A two-stage chromogenic substrate assay was standardized to measure extrinsic pathway inhibitor (EPI) activity in plasma and serum samples. In the first stage, diluted plasma or serum (0–0.8%) was incubated with factor VHa (25 pM), tissue thromboplastin (tissue factor, TF, 1% v/v) with excess binding sites for factor VIIa, and factor Xa (0.8 nM). In the second stage, excess factor X and chromogenic substrate were added as substrate for residual TF/factar VIIa catalytic activity. Heating the samples at 56±C for 15 min before assay removed ≥95% of the factor VII amidolytic activity of the samples, defibrinated the plasma, and produced only slight reduction of EPI activity. The coefficient of variation for the same sample assayed on different days was 8.7–10.6% and the intra-assay coefficient of variation was 5.0%. Addition of anti-EPI immunoglobulin to normal plasma completely abolished the EPI activity of the sample. EPI activity was stable in plasma samples stored at – 20± C, but in serum, some samples lost > 50% activity after 3 months at – 70± C. Median EPI activity of umbilical cord blood was 45% (range 33 – 93%). In a cohort of healthy blood donors (n = 176) EPI activity was significantly correlated with age; the regression line was y = 68% + 0.60x (r = 0.39). The approximated standard deviation for the regression line was 17.9% and the age-adjusted reference limits were determined. Equal levels were seen in maies and females. EPI activity was significantly correlated with total cholesterol (r = 0.58), and multiple regression showed that cholesterol was a stronger predictor of EPI activity than age.