Clinically relevant increases in the international normalized ratio and model of end-stage liver disease score by therapeutic doses of direct oral anticoagulants in patients with cirrhosis.

Background: Patients with cirrhosis are increasingly using direct oral anticoagulants (DOACs) in therapeutic doses for the treatment of portal vein thrombosis or for concomitant atrial fibrillation. DOACs may affect routine diagnostic tests of coagulation including the international normalized ratio (INR). The INR is a part of the model of end-stage liver disease (MELD) score, a validated score that predicts the mortality risk in patients with cirrhosis and is used to prioritize patients for liver transplantation. DOAC-induced increases in the INR may thus lead to artificial inflation of the MELD score. Objective: We studied the effect of DOACs on INR prolongation in patients with cirrhosis. Methods: We spiked plasma from 20 healthy individuals and 20 patients at the start of liver transplantation with DOACs in concentrations representing peak therapeutic levels. In addition, we studied INR increases in healthy controls and patients with mild cirrhosis who received the DOAC edoxaban for 1 week for study purposes. Results: In controls and patients, the INR increased by an ex vivo addition of a DOAC, and the INR increase in patients was proportional to the baseline INR values. The increase in INR translated to a median increase of between 3 and 10 MELD points, depending on the DOAC used. In controls and patients alike, the INR increased on the ingestion of edoxaban, which translated to an increase in 5 MELD points. Conclusions: Taken together, DOACs result in an INR increase that translates to clinically meaningful increases in MELD points in patients with cirrhosis, and precautions to avoid artificial inflation of the MELD score in these patients are warranted.

Growth differentiation factor-15 for prediction of bleeding in cancer patients.

BACKGROUND: Growth differentiation factor-15 (GDF-15) is a strong predictor for bleeding in patients with atrial fibrillation, but there are no data on cardiovascular outcomes for this biomarker in cancer patients. Bleeding risk assessment is important in cancer patients when considering primary thromboprophylaxis because it is associated with an increased bleeding risk. OBJECTIVES: To evaluate GDF-15 as predictor for bleeding events in cancer patients previously enrolled in the AVERT trial. PATIENTS/METHODS: In this trial, 574 participants were randomized to prophylactic apixaban or placebo and followed for 180 days for venous thromboembolism, major bleeding, clinically relevant nonmajor bleeding, and any bleeding. Plasma concentrations of GDF-15 were measured centrally with the Elecsys GDF-15 commercial assay kit (Roche Diagnostics GmbH). RESULTS: In apixaban recipients, the area under the receiver operator characteristic curve of GDF-15 for major bleeding was 0.73 (95% confidence interval [CI], 0.44-1.00). Compared with the lowest GDF-15 tertile (<1470 ng/L), major bleeding risk was significantly higher in the highest tertile (≥2607 ng/L; hazard ratio [HR] 3.19; 95% CI, 2.41-4.22), also when adjusting for sex, age, antiplatelet use, and gastrointestinal cancer (adjusted HR 2.80; 95% CI, 1.91-4.11). GDF-15 was also significantly associated with clinically relevant nonmajor bleeding (adjusted HR 1.67; 95% CI, 1.08-2.58) and any bleeding (adjusted HR 2.12; 95% CI, 1.38-3.25). CONCLUSIONS: Although hypothesis generating, this is the first study to show that GDF-15 predicts bleeding in cancer patients receiving thromboprophylaxis.

Risk factors for gastrointestinal bleeding in patients with gastrointestinal cancer using edoxaban.

BACKGROUND: In the Hokusai VTE Cancer study, the risk of major bleeding was 2.9% higher in the edoxaban group compared with the dalteparin group, mainly due to more gastrointestinal bleedings in patients with gastrointestinal cancer. The identification of risk factors for gastrointestinal bleeding may help to guide the use of DOACs in these patients. OBJECTIVES: To evaluate risk factors for gastrointestinal bleeding in patients with gastrointestinal cancer receiving edoxaban. PATIENTS/METHODS: In this nested case-control study in patients with gastrointestinal cancer randomized to edoxaban in the Hokusai VTE Cancer study, cases (patients with clinically relevant gastrointestinal bleeding during treatment) were randomly matched to three controls (patients who had no gastrointestinal bleeding). Data for the 4-week period prior to bleeding were retrospectively collected. Odds ratios (ORs) were calculated in a crude conditional logistic regression model and a multivariable model adjusted for age, sex, and cancer type. RESULTS: Twenty-four cases and 64 matched controls were included. In the multivariable analysis, advanced cancer, defined as regionally advanced or metastatic cancer (OR 3.6, 95% CI 1.01-12.6) and low hemoglobin levels (OR 4.8, 95% CI 1.5-16.0) were significantly associated with bleeding. There was no significant difference in patients with resected tumors (OR 0.4, 95% CI 0.1-1.4), or in patients on chemotherapy (OR 1.3, 95% CI 0.5-3.5). CONCLUSION: Advanced cancer and low hemoglobin levels were associated with an increased risk of gastrointestinal bleeding in patients with gastrointestinal cancer receiving edoxaban. We were unable to identify other risk factors, mainly due to limited statistical power.

Primary thromboprophylaxis in ambulatory cancer patients with a high Khorana score: a systematic review and meta-analysis.

Guidelines suggest thromboprophylaxis for ambulatory cancer patients starting chemotherapy with an intermediate to high risk of venous thromboembolism (VTE) according to Khorana score. Data on thromboprophylaxis efficacy in different Khorana score risk groups remain ambiguous. We sought to evaluate thromboprophylaxis in patients with an intermediate- to high-risk (≥2 points) Khorana score and an intermediate-risk score (2 points) or high-risk score (≥3 points) separately. MEDLINE, Embase, and CENTRAL were searched for randomized controlled trials (RCTs) comparing thromboprophylaxis with placebo or standard care in ambulatory cancer patients. Outcomes were VTE, major bleeding, and all-cause mortality. Relative risks (RRs) were calculated in a profile-likelihood random-effects model. Six RCTs were identified, involving 4626 cancer patients. Thromboprophylaxis with direct oral anticoagulants (DOACs) or low molecular weight heparin (LMWH) significantly reduced VTE risk in intermediate- to high-risk (RR, 0.51; 95% confidence interval [CI], 0.34-0.67), intermediate-risk (RR, 0.58; 95% CI, 0.36-0.83), and high-risk patients (RR, 0.45; 95% CI, 0.28-0.67); the numbers needed to treat (NNTs) were 25 (intermediate to high risk), 34 (intermediate risk), and 17 (high risk), respectively. There was no significant difference in major bleeding (RR, 1.06; 95% CI, 0.69-1.67) or all-cause mortality (RR, 0.90; 95% CI, 0.82-1.01). The numbers needed to harm (NNHs) for major bleeding in intermediate- to high-risk, intermediate-risk, and high-risk patients were 1000, -500, and 334, respectively. The overall NNH was lower in DOAC studies (100) versus LMWH studies (-500). These findings indicate thromboprophylaxis effectively reduces the risk of VTE in patients with an intermediate- to high-risk Khorana score, although the NNT is twice as high for intermediate-risk patients compared with high-risk patients.

Direct oral anticoagulants for cancer-associated venous thromboembolism: a systematic review and meta-analysis.

Direct oral anticoagulants (DOACs) are an emerging treatment option for patients with cancer and acute venous thromboembolism (VTE), but studies have reported inconsistent results. This systematic review and meta-analysis compared the efficacy and safety of DOACs and low-molecular-weight heparins (LMWHs) in these patients. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and conference proceedings were searched to identify relevant randomized controlled trials. Additional data were obtained from the original authors to homogenize definitions for all study outcomes. The primary efficacy and safety outcomes were recurrent VTE and major bleeding, respectively. Other outcomes included the composite of recurrent VTE and major bleeding, clinically relevant nonmajor bleeding (CRNMB), and all-cause mortality. Summary relative risks (RRs) were calculated in a random effects meta-analysis. In the primary analysis comprising 2607 patients, the risk of recurrent VTE was nonsignificantly lower with DOACs than with LMWHs (RR, 0.68; 95% CI, 0.39-1.17). Conversely, the risks of major bleeding (RR, 1.36; 95% CI, 0.55-3.35) and CRNMB (RR, 1.63; 95% CI, 0.73-3.64) were nonsignificantly higher. The risk of the composite of recurrent VTE or major bleeding was nonsignificantly lower with DOACs than with LMWHs (RR, 0.86; 95% CI, 0.60-1.23). Mortality was comparable in both groups (RR, 0.96; 95% CI, 0.68-1.36). Findings were consistent during the on-treatment period and in those with incidental VTE. In conclusion, DOACs are an effective treatment option for patients with cancer and acute VTE, although caution is needed in patients at high risk of bleeding.

Antithrombotic therapy for prophylaxis and treatment of venous thromboembolism in patients with cancer: review of the literature on current practice and emerging options.

The treatment of cancer-associated venous thromboembolism (VTE) is difficult because cancer patients with VTE on anticoagulation are at an increased risk of bleeding compared with patients without VTE. This review summarises the evidence supporting the current standard of care and emerging treatment options. In difficult-to-treat subpopulations, where clinical data are often lacking, this review also provides the best clinical practice strategies based on the available data. The use of therapeutic doses of parenteral anticoagulants in patients with cancer-associated VTE for at least 3 to 6 months is supported by the current clinical data. After major cancer surgery, extended thromboprophylaxis for approximately 1 month following hospital discharge is also supported. In select populations of ambulatory cancer patients with solid tumours, or in patients with myeloma receiving immunomodulatory agents in combination with chemotherapy and/or corticosteroids, pharmacological prophylaxis could be considered. Although parenteral anticoagulants may not be tolerated by some patients, the data pertaining to the use of direct oral anticoagulants (DOACs) in cancer patients with VTE at this point can only be considered hypothesis generating. Clarity of the use of DOACs is awaiting the results of head-to-head trials between DOACs and parenteral anticoagulants. In addition, because of the lack of clinical trials, there are still unanswered questions on the optimal treatment regimens in subpopulations at increased risk of bleeding, including cancer patients with thrombocytopenia and those with brain metastases. For clinicians to balance the risk of recurrent thrombosis with the chance of bleeding, they need to assess the relevant clinical data. Current data support the use of parenteral anticoagulants in cancer patients with VTE, but many unanswered questions pertaining to the optimal regimens in special subpopulations and regarding the efficacy and safety of DOACs remain. To address this need, there are currently several clinical trials under way.

Hypercoagulability causes atrial fibrosis and promotes atrial fibrillation.

AIMS: Atrial fibrillation (AF) produces a hypercoagulable state. Stimulation of protease-activated receptors by coagulation factors provokes pro-fibrotic, pro-hypertrophic, and pro-inflammatory responses in a variety of tissues. We studied the effects of thrombin on atrial fibroblasts and tested the hypothesis that hypercoagulability contributes to the development of a substrate for AF. METHODS AND RESULTS: In isolated rat atrial fibroblasts, thrombin enhanced the phosphorylation of the pro-fibrotic signalling molecules Akt and Erk and increased the expression of transforming growth factor ß1 (2.7-fold) and the pro-inflammatory factor monocyte chemoattractant protein-1 (6.1-fold). Thrombin also increased the incorporation of 3H-proline, suggesting enhanced collagen synthesis by fibroblasts (2.5-fold). All effects could be attenuated by the thrombin inhibitor dabigatran. In transgenic mice with a pro-coagulant phenotype (TMpro/pro), the inducibility of AF episodes lasting >1 s was higher (7 out of 12 vs. 1 out of 10 in wild type) and duration of AF episodes was longer compared with wild type mice (maximum episode duration 42.8 ± 68.4 vs. 0.23 ± 0.39 s). In six goats with persistent AF treated with nadroparin, targeting Factor Xa-mediated thrombin generation, the complexity of the AF substrate was less pronounced than in control animals (LA maximal activation time differences 23.3 ± 3.1 ms in control vs. 15.7 ± 2.1 ms in nadroparin, P < 0.05). In the treated animals, AF-induced α-smooth muscle actin expression was lower and endomysial fibrosis was less pronounced. CONCLUSION: The hypercoagulable state during AF causes pro-fibrotic and pro-inflammatory responses in adult atrial fibroblasts. Hypercoagulability promotes the development of a substrate for AF in transgenic mice and in goats with persistent AF. In AF goats, nadroparin attenuates atrial fibrosis and the complexity of the AF substrate. Inhibition of coagulation may not only prevent strokes but also inhibit the development of a substrate for AF.

The role of ADAMTS13 in acute myocardial infarction: cause or consequence?

AIMS: ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13, is a metalloprotease that cleaves von Willebrand factor (VWF). There is considerable evidence that VWF levels increase and ADAMTS13 levels decrease in ST-elevation myocardial infarction (STEMI) patients. It is unclear whether this contributes to no reflow, infarct size, and intramyocardial haemorrhage (IMH). We aimed to determine the role of ADAMTS13 in STEMI patients and to investigate the benefits of recombinant ADAMTS13 (rADAMTS13) in a porcine model of myocardial ischaemia-reperfusion. METHODS AND RESULTS: In 49 consecutive percutaneous coronary intervention (PCI)-treated STEMI patients, blood samples were collected directly after through 7 days following PCI. Cardiac magnetic resonance was performed 4-6 days after PCI to determine infarct size and IMH. In 23 Yorkshire swine, the circumflex coronary artery was occluded for 75 min. rADAMTS13 or vehicle was administered intracoronary following reperfusion. Myocardial injury and infarct characteristics were assessed using cardiac enzymes, ECG, and histopathology. In patients with IMH, VWF activity and VWF antigen were significantly elevated directly after PCI and for all subsequent measurements, and ADAMTS13 activity significantly decreased at 4 and 7 days following PCI, in comparison with patients without IMH. VWF activity and ADAMTS13 activity were not related to infarct size. In rADAMTS13-treated animals, no differences in infarct size, IMH, or formation of microthrombi were witnessed compared with controls. CONCLUSIONS: No correlation was found between VWF/ADAMTS13 and infarct size in patients. However, patients suffering from IMH had significantly higher VWF activity and lower ADAMTS13 activity. Intracoronary administration of rADAMTS13 did not decrease infarct size or IMH in a porcine model of myocardial ischaemia-reperfusion. These data dispute the imbalance in ADAMTS13 and VWF as the cause of no reflow.

The Effect of Age and Sex on Clinical Outcome after Intravenous Recombinant Tissue Plasminogen Activator Treatment in Patients with Acute Ischemic Stroke.

BACKGROUND: There are conflicting results regarding the effect of intravenous (IV) recombinant tissue plasminogen activator (rtPA) stroke treatment between men and women. Studies evaluating the impact of sex differences on functional outcome in relation to different age groups are nonexistent. AIM: The objective of the study is to examine the influence of sex differences in relation to age on the prognosis after IV rtPA treatment in acute stroke patients. METHODS: In this cohort study, 887 patients with acute ischemic stroke were treated with rtPA. Functional outcome after 3 months was determined with the modified Rankin Scale (mRS). Good outcome was defined as an mRS score of 2 or lower. Age was stratified in decades (41-50, 51-60, 61-70, 71-80, and >80 years). Multivariable analyses were performed with adjustment for age, sex, stroke severity (National Institutes of Health Stroke Scale [NIHSS]), and stroke subtype (Trial of Org 10172 in Acute Stroke Treatment). RESULTS: Fifty-five percent of the patients were men. The mean age was 67.4 (men) and 72.0 (women) years. Fifty-six percent of the men and 45% of the women had a favorable outcome (P = .001). After adjustment for NIHSS score and stroke subtype, the women had a better outcome in the age group 51-60 years compared with men (odds ratio [OR] .38, 95% confidence interval [CI] .15-.96). In the age group >80 years, men had a better outcome than women (OR 2.69, 95% CI 1.21-5.96). There were no significant differences in the other age groups. CONCLUSION: Men and women have different prognoses after IV rtPA treatment for acute ischemic stroke, which also depends on age. Women in middle age appear to have a better outcome than men, whereas at a more advanced age men appear to have a better outcome than women.

[Diagnostics and treatment of calf vein thrombosis]. / Diagnostiek en behandeling van kuitvenetrombose.

Calf vein thrombosis is a much-debated entity. The literature shows that progression to deep venous thrombosis or pulmonary embolism occurs infrequently and is usually detected using serial two-point ultrasonography. Additionally, undetected and untreated calf vein thrombosis is not associated with serious adverse events in large management trials studying diagnostic strategies for suspected deep venous thrombosis. Recurrent venous thromboembolism can occur after calf vein thrombosis, but anticoagulant treatment does not reduce the incidence. In this article, three case histories describe the anatomical considerations for proper diagnosis of calf vein thrombosis, some aspects of the natural course, and the treatment that these patients received. A case is made for restrictive use of prolonged anticoagulation therapy as a means to reduce thromboembolic complications. Because symptomatic treatment has not been studied, expert opinion suggests a short (3-week) course of therapeutically-dosed low-molecular-weight heparin.

Safety of anticoagulant treatment in cancer patients.

INTRODUCTION: Patients with cancer are at increased risk of (recurrent) venous thromboembolism. They are also at increased risk of bleeding. This makes treatment of venous thromboembolisms (VTE) in cancer patients challenging. AREAS COVERED: In this review, we will focus on the safety of anticoagulant treatment of VTE in cancer patients. We will discuss the absolute and relative bleeding risks associated with the various types of anticoagulants, specifically focusing on low-molecular-weight heparins (LMWH), vitamin K antagonist (VKA) and the new oral anticoagulants (NOACs). EXPERT OPINION: Monotherapy with LMWH is recommended for treatment of acute VTE in cancer patients. The bleeding risk associated with LMWH is comparable to VKAs, but LMWH are more effective in preventing recurrent VTE. More evidence on the efficacy and safety of NOACs in cancer patients is needed.

Thromboembolic resolution assessed by CT pulmonary angiography after treatment for acute pulmonary embolism.

The systematic assessment of residual thromboembolic obstruction after treatment for acute pulmonary embolism (PE) has been understudied. This assessment is of potential clinical importance, should clinically suspected recurrent PE occur, or as tool for risk stratification of cardiopulmonary complications or recurrent venous thromboembolism (VTE). This study aimed to assess the rate of PE resolution and its implications for clinical outcome. In this prospective, multi-center cohort study, 157 patients with acute PE diagnosed by CT pulmonary angiography (CTPA) underwent follow-up CTPA-imaging after six months of anticoagulant treatment. Two expert thoracic radiologists independently assessed the presence of residual thromboembolic obstruction. The degree of obstruction at baseline and follow-up was calculated using the Qanadli obstruction index. All patients were followed-up for 2.5 years. At baseline, the median obstruction index was 27.5 %. After six months of treatment, complete PE resolution had occurred in 84.1 % of the patients (95 % confidence interval (CI): 77.4-89.4 %). The median obstruction index of the 25 patients with residual thrombotic obstruction was 5.0 %. During follow-up, 16 (10.2 %) patients experienced recurrent VTE. The presence of residual thromboembolic obstruction was not associated with recurrent VTE (adjusted hazard ratio: 0.92; 95 % CI: 0.2-4.1).This study indicates that the incidence of residual thrombotic obstruction following treatment for PE is considerably lower than currently anticipated. These findings, combined with the absence of a correlation between residual thrombotic obstruction and recurrent VTE, do not support the routine use of follow-up CTPA-imaging in patients treated for acute PE.

Evaluation of coagulation activation after rhinovirus infection in patients with asthma and healthy control subjects: an observational study.

BACKGROUND: Asthma exacerbations are frequently triggered by rhinovirus infections. Both asthma and respiratory tract infection can activate haemostasis. Therefore we hypothesized that experimental rhinovirus-16 infection and asthmatic airway inflammation act in synergy on the haemostatic balance. METHODS: 28 patients (14 patients with mild allergic asthma and 14 healthy non-allergic controls) were infected with low-dose rhinovirus type 16. Venous plasma and bronchoalveolar lavage fluid (BAL fluid) were obtained before and 6 days after infection to evaluate markers of coagulation activation, thrombin-antithrombin complexes, von Willebrand factor, plasmin-antiplasmin complexes, plasminogen activator inhibitor type-1, endogenous thrombin potential and tissue factor-exposing microparticles by fibrin generation test, in plasma and/or BAL fluid. Data were analysed by nonparametric tests (Wilcoxon, Mann Whitney and Spearman correlation). RESULTS: 13 patients with mild asthma (6 females, 19-29 y) and 11 healthy controls (10 females, 19-31 y) had a documented Rhinovirus-16 infection. Rhinovirus-16 challenge resulted in a shortening of the fibrin generation test in BAL fluid of asthma patients (t = -1: 706 s vs. t = 6: 498 s; p = 0.02), but not of controls (t = -1: 693 s vs. t = 6: 636 s; p = 0.65). The fold change in tissue factor-exposing microparticles in BAL fluid inversely correlated with the fold changes in eosinophil cationic protein and myeloperoxidase in BAL fluid after virus infection (r = -0.517 and -0.528 resp., both p = 0.01).Rhinovirus-16 challenge led to increased plasminogen activator inhibitor type-1 levels in plasma in patients with asthma (26.0 ng/mL vs. 11.5 ng/mL in healthy controls, p = 0.04). Rhinovirus-16 load in BAL showed a linear correlation with the fold change in endogenous thrombin potential, plasmin-antiplasmin complexes and plasminogen activator inhibitor type-1. CONCLUSIONS: Experimental rhinovirus infection induces procoagulant changes in the airways of patients with asthma through increased activity of tissue factor-exposing microparticles. These microparticle-associated procoagulant changes are associated with both neutrophilic and eosinophilic inflammation. Systemic activation of haemostasis increases with Rhinoviral load. TRIAL REGISTRATION: This trial was registered at the Dutch trial registry (http://www.trialregister.nl): NTR1677.

Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A.

Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A.

Risk profile and clinical outcome of symptomatic subsegmental acute pulmonary embolism.

The clinical significance of subsegmental pulmonary embolism (SSPE) remains to be determined. This study aimed to investigate whether SSPE forms a distinct subset of thromboembolic disease compared with more proximally located pulmonary embolism (PE). We analyzed 3728 consecutive patients with clinically suspected PE. SSPE patients were contrasted to patients with more proximal PE and to patients in whom suspected PE was ruled out, in regards of the prevalence of thromboembolic risk factors and the 3-month risks of recurrent venous thromboembolism (VTE) and mortality. PE was confirmed in 748 patients, of whom 116 (16%) had SSPE; PE was ruled out in 2980 patients. No differences were seen in the prevalence of VTE risk factors, the 3-month risk of recurrent VTE (3.6% vs 2.5%; P = .42), and mortality (10.7% vs 6.5%; P = .17) between patients with SSPE and those with more proximal PE. When compared with patients without PE, aged >60 years, recent surgery, estrogen use, and male gender were found to be independent predictors for SSPE, and patients with SSPE were at an increased risk of VTE during follow-up (hazard ratio: 3.8; 95% CI: 1.3-11.1). This study indicates that patients with SSPE mimic those with more proximally located PE in regards to their risk profile and clinical outcome.

Stress-induced hyperglycaemia and venous thromboembolism following total hip or total knee arthroplasty: analysis from the RECORD trials.

Stress-induced hyperglycaemia is common during orthopaedic surgery. In addition, hyperglycaemia activates coagulation. The aim of the study was to assess whether stress-induced hyperglycaemia is associated with symptomatic or asymptomatic venous thromboembolism (VTE) following orthopaedic surgery. We performed post-hoc analyses in the four RECORD studies (REgulation of Coagulation in major Orthopaedic surgery reducing the Risk of Deep venous thrombosis and pulmonary embolism). Separate analyses were performed for patients undergoing elective total hip or knee replacement. Outcome measures were symptomatic VTE and "total VTE" (defined as the composite of symptomatic VTE, asymptomatic DVT assessed by per protocol venography and all cause mortality). Glucose levels were measured pre-op and 6 hours post-op, categorised into quartiles, based on the distribution in the respective cohorts. The influence of glucose, adjusted for body mass index, age, gender and diabetes mellitus on VTE was assessed by logistic regression analyses. A total of 12,383 patients were eligible for assessment of symptomatic VTE, and 8,512 patients were eligible for assessment of total VTE. Increased glucose levels after total hip replacement were associated with total VTE; adjusted odds ratio (OR) highest versus lowest quartile 1.9 (95% confidence interval [CI] 1.3 to 3.0). Furthermore, increase in glucose levels during total hip replacement was associated with total VTE (OR highest versus lowest quartile 1.8 (95%CI 1.2 to 2.8). This was not observed in patients undergoing total knee replacement, probably due to differences in the applied surgical procedures.