Effect of Ramipril on Urinary Protein Excretion in Maintenance Renal Transplant Patients Converted to Sirolimus.

This prospective, randomized, double-blind, placebo-controlled study evaluated the effects of ramipril on urinary protein excretion in renal transplant patients treated with sirolimus following conversion from a calcineurin inhibitor. Patients received ramipril or placebo for up to 6 weeks before conversion and 52 weeks thereafter. Doses were increased if patients developed proteinuria (urinary protein/creatinine ratio ≥0.5); losartan was given as rescue therapy for persistent proteinuria. The primary end point was time to losartan initiation. Of 295 patients randomized, 264 met the criteria for sirolimus conversion (ramipril, 138; placebo, 126). At 52 weeks, the cumulative rate of losartan initiation was significantly lower with ramipril (6.2%) versus placebo (23.2%) (p < 0.001). No significant differences were observed between ramipril and placebo for change in glomerular filtration rate from baseline (p = 0.148) or in the number of patients with biopsy-confirmed acute rejection (13 vs. 5, respectively; p = 0.073). One patient in the placebo group died due to cerebrovascular accident. Treatment-emergent adverse events were consistent with the known safety profile of sirolimus and were not potentiated by ramipril co-administration. Ramipril was effective in reducing the incidence of proteinuria for up to 1 year following conversion to sirolimus in maintenance renal transplant patients.

Advantages and limitations of the new anticoagulants.

During recent years, three new anticoagulants (dabigatran, rivaroxaban and apixaban) have been introduced to the market, probably with one more anticoagulant (edoxaban) in the next 2 years. This review is not intended to compare the efficacy and risks of these new agents, but rather to detail the advantages and limitations. The pharmacokinetic characteristics of these drugs have few drug and food interactions, predictable dose responses, and rapid onset and offset, thus resulting in simplified management of the patient requiring anticoagulant therapy. No routine laboratory monitoring is required. A somewhat unexpected, but exciting observation involving the new anticoagulants, is the uniform reduction in intracranial bleeding by one-half compared with warfarin. The potential limitations of the new anticoagulants include uncertainty regarding assessment of drug levels, safe drug levels for major surgery, management of major bleeding, renal dependence, multiple dose regimens, adherence in the absence of frequent monitoring and unknown, rare side effects that were not captured in the trials. This review should clarify some of these concerns.

Fatty acids and TxA(2) generation, in the absence of platelet-COX-1 activity.

BACKGROUND AND AIMS: Omega-3 fatty acids suppress Thromboxane A(2) (TxA(2)) generation via mechanisms independent to that of aspirin therapy. We sought to evaluate whether baseline omega-3 fatty acid levels influence arachidonic acid proven platelet-cyclooxygenase-1 (COX-1) independent TxA(2) generation (TxA(2) generation despite adequate aspirin use). METHODS AND RESULTS: Subjects with acute myocardial infarction, stable CVD or at high risk for CVD, on adequate aspirin therapy were included in this study. Adequate aspirin action was defined as complete inhibition of platelet-COX-1 activity as assessed by <10% change in light transmission aggregometry to ≥1 mmol/L arachidonic acid. TxA(2) production was measured via liquid chromatography-tandem mass spectrometry for the stable TxA(2) metabolite 11-dehydro-thromboxane B2 (UTxB2) in urine. The relationship between baseline fatty acids, demographics and UTxB(2) were evaluated. Baseline omega-3 fatty acid levels were not associated with UTxB(2) concentration. However, smoking was associated with UTxB(2) in this study. CONCLUSION: Baseline omega-3 fatty acid levels do not influence TxA(2) generation in patients with or at high risk for CVD receiving adequate aspirin therapy. The association of smoking and TxA(2) generation, in the absence of platelet COX-1 activity, among aspirin treated patients warrants further study.

Associations of thrombocytopenia, transaminase elevations, and transfusion with laboratory coagulation tests in women with preeclampsia: a cross-sectional study.

BACKGROUND: Women with preeclampsia may develop coagulopathy, predisposing to bleeding complications. Although guidelines and prior studies conflict, we hypothesized that in preeclampsia, abnormal coagulation test results are more common in women with thrombocytopenia or transaminase elevations and increase the transfusion risk. Our objectives were to investigate: 1. patterns of coagulation testing; 2. relationships between platelet count, transaminase level, and the risk of abnormal coagulation tests; 3. risk of bleeding complications; and 4. characteristics of patients with markedly abnormal coagulation parameters. METHODS: We conducted a cross-sectional study of deliveries of women with preeclampsia who had undergone activated partial thromboplastin time (aPTT) or international normalized ratio (INR) testing at one of two hospitals between 1994 and 2018. RESULTS: Of 10 699 women with preeclampsia, 3359 (32.7%) had coagulation testing performed and aPTT or INR elevations were present in 124 (3.7 %). Coagulation abnormalities were more common in women with thrombocytopenia or transaminase elevations (n=82) compared with those without (n=42) (6.7%, 95% CI 5.5 to 8.2 vs 1.8%, 95% CI 1.3 to 2.5). Transfusion was more common among women with abnormal coagulation parameters (n=124) compared with those without (n=39) (33.1 vs 7.0%, P <0.001). Among 26 patients with an aPTT ≥40 s or an INR ≥1.4, six required transfusion (all had placental abruption and disseminated intravascular coagulopathy). CONCLUSIONS: Coagulation testing was inconsistently performed in this cohort. Platelet counts and transaminase levels inadequately detected abnormal coagulation test results. Abnormal coagulation test results were associated with a markedly higher risk for red blood cell transfusion.

Anticoagulation strategies and risk of bleeding events in critically ill COVID-19 patients.

OBJECTIVE: To evaluate the rate of thrombosis, bleeding and mortality comparing anticoagulant doses in critically ill COVID-19 patients. DESIGN: Retrospective observational and analytical cohort study. SETTING: COVID-19 patients admitted to the intensive care unit of a tertiary hospital between March and April 2020. PATIENTS: 201 critically ill COVID-19 patients were included. Patients were categorized into three groups according to the highest anticoagulant dose received during hospitalization: prophylactic, intermediate and therapeutic. INTERVENTIONS: The incidence of venous thromboembolism (VTE), bleeding and mortality was compared between groups. We performed two logistic multivariable regressions to test the association between VTE and bleeding and the anticoagulant regimen. MAIN VARIABLES OF INTEREST: VTE, bleeding and mortality. RESULTS: 78 patients received prophylactic, 94 intermediate and 29 therapeutic doses. No differences in VTE and mortality were found, while bleeding events were more frequent in the therapeutic (31%) and intermediate (15%) dose group than in the prophylactic group (5%) (p<0.001 and p<0.05 respectively). The anticoagulant dose was the strongest determinant for bleeding (odds ratio 2.4, 95% confidence interval 1.26-4.58, p=0.008) but had no impact on VTE. CONCLUSIONS: Intermediate and therapeutic doses appear to have a higher risk of bleeding without a decrease of VTE events and mortality in critically ill COVID-19 patients.

New aspects on treatment modalities for thromboembolic episodes.

Venous thromboembolism (VTE) has been treated with a glycosaminoglycan, followed by a vitamin K antagonist during the past 60 years. During the past two decades the glycosaminoglycans have undergone refinement, allowing for simplification of care for these patients, but parenteral administration is still required. Therefore, the current completion of phase III trials with selective, predictable and orally available anticoagulants with rapid onset brings promise for a change in paradigm in the treatment of VTE in the next few years. Whereas these efforts will lead to further simplification of the therapy there are also trials conducted to advance the treatment by rapid resolution of the thromboembolism in order to improve long-term outcome. Catheter-directed thrombolysis, perhaps also with thrombus fragmentation and stent insertion, if demonstrated to be successful for the reduction of the postthrombotic syndrome, will only be an alternative for a minority of patients due to the complexity, risks and cost of therapy. This treatment increases the complexity at the same time as new drug regimens offer simplicity. This review focuses on the novel therapies for VTE although the new anticoagulants will also play a major role in the management of arterial disease, which will be briefly presented.

Redistribution of membrane proteins in isolated mouse intestinal epithelial cells.

Single mouse intestinal epithelial cells (IEC) may be isolated by the use of a combination of methods used for the isolation of IEC from other species. Isolated cells remain viable for several hours. The membrane integral enzymes alkaline phosphatase and leucine aminopeptidase of isolated IEC are localized to the brush borders of IEC in tissue and in most newly isolated IEC. With time, both enzymes are found distributed over the entire cell surface. Redistribution appears to occur by diffusion in the plane of the membrane. It is slowed, but not blocked, if cells are maintained at 0 degrees C instead of at 37 degrees C, and it is not blocked by fixation in 0.5-3% paraformaldehyde. Drugs that alter cell membrane potential or that affect cell levels of ATP enhance the rate of redistribution of the enzymes.

6 versus 30 months anticoagulation for recurrent venous thrombosis in patients with high factor VIII.

Patients with first venous thromboembolism (VTE) and high factor VIII (FVIII) are at increased risk of recurrence. It is unknown whether these patients benefit from prolonged secondary thrombophrophylaxis. In a prospective trial patients with first spontaneous VTE and FVIII levels >230 IU/dl were randomized to discontinue vitamin K Antagonist (VKA) after 6 months or to continue VKA for additional 24 months. Patients were excluded if they had a natural inhibitor deficiency, lupus anticoagulant, cancer, were pregnant, required long-term antithrombotic therapy or had acute-phase reaction. Primary study endpoints were symptomatic recurrent VTE or major bleeding within 2 years. Follow-up was continued beyond 2 years. Of 3,219 screened patients 34 met the inclusion criteria. Mean observation time was 37 months. Two of 17 patients allocated to discontinue VKA and two of 17 patients randomized to prolonged anticoagulation had recurrent VTE within 2 years. In the prolonged treatment group, one patient had recurrence during VKA therapy and one patient 4 weeks after voluntary discontinuation of VKA. One major nonfatal bleeding (severe epistaxis) after 10 months of VKA occurred in the prolonged treatment group. Five patients allocated to prolonged anticoagulation had recurrent VTE after discontinuation of VKA. The probability of recurrence at 2 years after discontinuation of VKA was 30% (95% CI 13-46%). Patients with high FVIII are at increased risk of recurrence. Our findings in a small number of patients indicate that prolonged anticoagulation seems to be effective but that the benefit is not maintained after discontinuation of anticoagulation.

The plasma concentration of activated protein C appears normal in patients with haemophilia.

Increased concentration of activated protein C (APC) has been observed in patients with thromboembolic disorders, but whether the level of APC in patients with bleeding disorders is decreased remains unknown. Seventy patients with haemophilia A or B with mild, moderate or severe form were studied. Detailed information on bleeding, arthropathy and factor consumption was collected during a 10-year period. The clinical severity of the disease was expressed as the Hemophilia Severity Score (HSS). Plasma concentration of APC was measured as APC in complex with protein C inhibitor. The median concentration of APC-PCI complex in patients with haemophilia was 0.14 microg L(-1) and it did not differ between the types and forms. In 16 patients with severe haemophilia A and the inversion mutation in intron 22, there was no correlation between clinical severity and the concentration of APC-PCI complex. Patients with haemophilia appear to generate normal concentrations of APC during basal conditions. APC does not seem to be an important modulator of the phenotypic expression of haemophilia.

Factor VII deficiency: clinical manifestation of 717 subjects from Europe and Latin America with mutations in the factor 7 gene.

The congenital FVII deficiency (FVIID) is a rare haemorrhagic disorder with an autosomal recessive pattern of inheritance. Data on phenotype and the genotype from 717 subjects in Central Europe (six countries), Latin America (Costa Rica, Venezuela) and United States, enrolled in the Greifswald Registry of FVII Deficiency were analysed. We detected 131 different mutations in 73 homozygous, 145 compound heterozygous and 499 heterozygous subjects. Regional differences were observed in the mutation pattern and the clinical profile of the evaluated patients. Seventy-one per cent of homozygous and 50% of compound heterozygous subjects were symptomatic. The clinical manifestations of the homozygous subjects were characterized by intracranial haemorrhage (2%), gastrointestinal bleeding (17%), haemarthrosis (13%), epistaxis (58%), gum bleeding (38%), easy bruising (37%), haematoma (15%), haematuria (10%) and menorrhagia (19 of 26 females, 73%). The clinical variability and genotype-phenotype correlation was evaluated in the homozygous subjects. The pattern of bleeding symptoms among compound heterozygous patients was severe and similar to that of the homozygous patients. The large-scale analysis of 499 heterozygous subjects shows that 93 (19%) presented with spontaneous bleeding symptoms such as haemarthrosis (4%), epistaxis (54%), gum bleeding (14%), easy bruising (38%), haematoma (23%), haematuria (5%) and menorrhagia (19 of 45 females; 42%). The severe haemorrhages - intracranial and gastrointestinal - were not reported in heterozygous subjects. The clinical variability and the regional differences in the mutation pattern are discussed regarding care and treatment.

Low PAI-1 activity in relation to inflammatory parameters, insulin profile and body mass index.

BACKGROUND AND OBJECTIVE: High plasminogen activator inhibitor type 1 (PAI-1) activity is associated with inflammatory reactions and insulin resistance, but it is unclear what regulates PAI-1 activity at the low end. The purpose of this study was to investigate if patients with low PAI-1 activity have a lack of inflammatory response or a low insulin level. DESIGN: Retrospective cohort study with internal controls. SUBJECTS: Sixty-three patients referred for investigation of bleeding tendency and with low PAI-1 activity were compared with 118 patients with normal or high PAI-1 activity. OUTCOME: Levels of C-peptide, proinsulin, high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6). Adjustments were made for body mass index (BMI), oral oestrogens and age. Low PAI-1 activity was defined as less than 1 U mL(-1). RESULTS: Body mass index in the low normal range, oral oestrogens, young age and low C-peptide were significantly associated with low PAI-1 activity and there was a trend for association with IL-6 in univariable analysis. The effect of age disappeared after correction for oral oestrogens and the effect of C-peptide and IL-6 disappeared after further adjustments. Low BMI remained as the strongest predictor of low PAI-1 activity. CONCLUSION: Patients with bleeding tendency and low PAI-1 activity have inflammatory and insulin profiles similar to those with normal or high PAI-1, whereas BMI seems to be the most important determinant.

Clinical factors influencing the sensitivity to warfarin when restarted after surgery.

BACKGROUND AND OBJECTIVE: Resumption of oral anticoagulation after surgery may result in a different maintenance dose of warfarin than before the procedure. Knowledge of the clinical determinants of postoperative response could help avoid excessive anticoagulation in sensitive patients or avoid extended delays in achieving a therapeutic level in resistant patients. DESIGN: Retrospective review. SUBJECTS: Two hundred warfarin-treated patients who were managed by our clinic for surgery. OUTCOME: Two independent adjudicators classified the postoperative response to warfarin as Resistant, Normal or Sensitive, based on previous maintenance dose, international normalized ratio (INR) on the day of resumption, number of days until INR of >1.9 and doses of warfarin given. A third adjudicator resolved disagreements. Clinical data were extracted from the patient records and correlated with the response. RESULTS: Interobserver agreement for classification of postoperative response was moderate (weighted kappa 0.46) with 37 (18.5%) considered resistant, 135 (67.5%) normal, 27 (13.5%) sensitive and one patient was not classifiable. The main type of surgery was cardiac. In univariable analysis only addition of amiodarone after surgery was associated with a sensitive response (P = 0.04). After adjustment for all other factors with an ordered categorical response, amiodarone remained as the sole independent risk factor (P = 0.02) for a sensitive response, odds ratio 0.41 (95% confidence interval 0.19-0.89) for Normal instead of Sensitive or for Resistant instead of Normal. CONCLUSION: Altered sensitivity to warfarin occurs in about one-third of patients after surgery and can be predicted by the introduction of concomitant amiodarone therapy but not by patient factors or the nature of the procedure. Changes in concomitant medications after surgery should alert doctors of the potential for increased sensitivity to warfarin.

Ribose metabolism and nucleic acid synthesis in normal and glucose-6-phosphate dehydrogenase-deficient human erythrocytes infected with Plasmodium falciparum.

The metabolism of pentose-phosphate was investigated in Plasmodium falciparum-infected normal and glucose-6-phosphate dehydrogenase (G6PD)-deficient human red blood cells in vitro. 5'-Phosphoribosyl-1-pyrophosphate (PRPP) content of infected normal red blood cells was increased 50-60-fold at the parasite trophozoite growth stage over that of uninfected cells. The PRPP increment in infected G6PD-deficient cells at comparable stage and parasitemia was only 40% of the value in normal infected cells. Red blood cell PRPP synthetase activity did not change during the growth cycle of the parasite and was similar in both normal and G6PD-deficient cells. Reduced glutathione (GSH) content of G6PD-deficient cells under conditions of culture fell to low or undetectable levels. These low levels of GSH were shown to inhibit the function of red blood cell PRPP synthetase, which requires GSH for full activity. Measurements of the incorporation of 1-14C or 6-14C selectively labeled glucose into parasite nucleic acids revealed that in normal infected red cells, approximately 20% of the pentose was produced via the oxidation of glucose-6-phosphate, whereas in infected G6PD-deficient cells (Mediterranean type), none of the pentose was produced via the oxidative pathway. It is concluded that the low level of reduced GSH found in G6PD deficiency and the resultant partial inhibition of PRPP synthetase together with the missing oxidative pathway for ribose phosphate production can account fully for the reduced parasite growth rate in G6PD-deficient red blood cells described previously. Of these two mechanisms, the predominant one is the impaired PRPP synthetase activity due to low GSH levels in enzyme-deficient red blood cells. The contribution to the ribose-phosphate pool by the hexose monophosphate shunt is relatively minor. A co-existing oxidative stress (which is often hypothesized to mediate the destruction of parasitized red blood cells) is not required to explain growth inhibition in this scheme and does not represent the most straight-forward explanation of the data described in this report.

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.

Assessment of clinically relevant bleeding as a surrogate outcome for major bleeding: validation by meta-analysis of randomized controlled trials.

Essentials Surrogacy of clinically relevant bleeding (CRB) for major bleeding has never been validated. Our meta-analysis evaluated CRB surrogacy in trials of new versus traditional anticoagulants. Surrogacy was not validated in orthopedic surgery, venous thromboembolism or atrial fibrillation The difficulty in demonstrating the surrogacy may reflect a lack of homogeneity in its definition SUMMARY: Background Clinically relevant bleeding (CRB), comprising major bleeding and clinically relevant non-major bleeding, has been used as a surrogate for major bleeding in most anticoagulant trials. The validity of this surrogate to estimate trade-off between thrombotic and bleeding events in clinical trials was never assessed. Methods We systematically reviewed randomized phase III trials comparing new anticoagulants with the standard of care for venous thromboembolism prevention following major orthopedic surgery, venous thromboembolism (VTE) treatment, or stroke and systemic embolism prevention in atrial fibrillation (AF), and reporting both major bleeding and CRB rates. The validity of CRB as a surrogate for major bleeding was assessed according to the strength of the association between the relative risks of major bleeding and CRB, measured by the use of R2trial and its 95% confidence interval (CI). Results In the postoperative prophylactic setting (13 studies), major bleeding and CRB rates were 1.12% and 3.56%, respectively, and R2trial was 0.69 (95% CI 0.34-0.93). For acute VTE studies (n = 12), major bleeding and CRB rates were 1.87% and 9.07%; the corresponding R2trial values were 0.28 (95% CI 0.01-0.80) and 0.68 (95% CI 0.09-1.00) when only double-blind studies were considered (n = 7). For AF studies (n = 7; 22 strata), major bleeding and CRB rates were 4.82% and 15.3%, and R2trial was 0.59 (95% CI 0.15-0.82). Conclusion Despite an apparent correlation between CRB and major bleeding in major orthopedic surgery, AF, and double-blind acute VTE studies, the wide CIs suggest that CRB might not be an acceptable surrogate outcome in any of these settings.

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.

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.

Retrospective study of the correlation between the DNA repair protein alkyltransferase and survival of brain tumor patients treated with carmustine.

We tested the hypothesis that the level of the DNA repair protein O6-alkylguanine-DNA alkyltransferase in brain tumors was correlated with resistance to carmustine (BCNU) chemotherapy. Alkyltransferase levels in individual cells in sections from 167 primary brain tumors treated with BCNU were quantitated with an immunofluorescence assay using monoclonal antibodies against human alkyltransferase. Patients with high levels of alkyltransferase had shorter time to treatment failure (P = 0.05) and death (P = 0.004) and a death rate 1.7 times greater than patients with low alkyltransferase levels. Furthermore, the size of the subpopulation of cells with high levels of alkyltransferase was correlated directly with drug resistance. For all tumors the variables most closely correlated with survival, in order of importance, were age, tumor grade, and alkyltransferase levels. For glioblastoma multiforme, survival was more strongly correlated with alkyltransferase levels than with age. These results should encourage prospective studies to evaluate alkyltransferase levels as a method, for identifying brain tumor patients with the best likelihood of response to BCNU chemotherapy.

Effect of standardized perioperative dabigatran interruption on the residual anticoagulation effect at the time of surgery or procedure.

UNLABELLED: ESSENTIALS: Anticoagulants need to be stopped preprocedure so there is little or no remaining anticoagulant effect. We assessed the residual anticoagulant effect with standardized interruption for patients on dabigatran. With this protocol, 80-86% of patients had no residual anticoagulant effect at the time of a procedure. A standardized perioperative dabigatran protocol appears to be safe, but requires further study. BACKGROUND: In patients taking dabigatran who require treatment interruption for a surgery/procedure, a sufficient interruption interval is needed so that there is little or no residual anticoagulant effect at the time of the surgery/procedure. METHODS: A prospective cohort study of patients receiving dabigatran (110 mg or 150 mg twice daily) who required an elective surgery/procedure and received a standardized dabigatran interruption protocol based on surgery/procedure bleeding risk and renal function was performed. Before the surgery/procedure, a blood sample was taken for measurement of the prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and dilute thrombin time (dTT). We determined the proportion of all patients and those having a high bleeding risk surgery/procedure with normal coagulation test results at the time of the surgery/procedure. The APTT and dTT were considered to be most likely to reflect a dabigatran anticoagulant effect. Patients were followed up for 30 days postprocedure to assess for bleeding and thromboembolism. RESULTS: One hundred and eighty-one patients were studied: 118 with low bleeding risk, and 63 with high bleeding risk. For all patients, the proportions with normal PT, APTT, TT dTT levels were 92.8%, 79.6%, 33.1%, and 80.7%, respectively. In patients with high bleeding risk, the proportions with normal PT, APTT, TT dTT levels were 93.7%, 85.7%, 57.1%, and 87.3%, respectively. During follow-up, there was one (0.6%) major bleed, there were nine (5.0%) minor bleeds, and there was one (0.6%) transient ischemic attack. CONCLUSIONS: In patients receiving dabigatran who require an elective surgery/procedure, a standardized interruption protocol yielded 80-86% of patients with no residual anticoagulant effect at the time of surgery/procedure, and with a low incidence of bleeding.