High rate of unprovoked recurrent venous thrombosis is associated with high thrombin‐generating potential in a prospective cohort study

Summary. Objective: To determine the predictive value of measurement of parameters of thrombin generation for unprovoked recurrent venous thrombosis. Methods: Measurements were made of thrombin generation in a prospective cohort study of 188 patients with a first episode of venous thrombosis that was unprovoked, or provoked by a non‐surgical trigger. Results: The endogenous thrombin potential (ETP) was the only parameter associated with unprovoked recurrent thrombosis in a multivariate model [hazard ratio (HR) 1.3 per 100 nmol L min^?1 increase, 95% confidence interval (CI) 1.0–1.6]. Patients with a high ETP had a significantly higher rate of unprovoked recurrence than those with a low ETP (HR 2.9, 95% CI  1.3–6.6, cumulative recurrence at 4 years 27% vs. 11%). Patients with an unprovoked first event had a significantly higher rate of unprovoked recurrence than those with a provoking factor (HR 2.7, 95% CI  1.2–6.1), and in these patients there was a significantly higher rate of unprovoked recurrence in association with a high ETP (HR 4.0, 95% CI  1.3–11.8). After adjustment for D‐dimer, thrombophilia, sex, and whether or not the first event was unprovoked, a high ETP remained a significant predictor of recurrence (HR 2.6, 95% CI  1.2–6.0). Conclusions: This study demonstrates a high rate of unprovoked recurrent venous thrombosis in patients presenting with a first episode of venous thrombosis and a high ETP.     

Coffee consumption is associated with a reduced risk of venous thrombosis that is mediated through hemostatic factor levels

Summary. Background: Coffee consumption is associated with a lower risk of venous thrombosis, but the role of confounding and the pathophysiology behind these findings are unclear. Objective: To assess the role of hemostatic factors in the relationship between coffee consumption and venous thrombosis. Methods: From a large case–control study, 1803 patients with a first venous thrombosis and 1803 partner controls were included. With conditional logistic regression, odds ratios (ORs) and 95% confidence intervals (CIs) for venous thrombosis were calculated for coffee consumption vs. no coffee consumption. In addition, mean differences in hemostatic factor levels between these groups were calculated in the controls. Results: Coffee consumption yielded a 30% lower risk of venous thrombosis than no coffee consumption (OR 0.7, 95% CI 0.5–0.9). Adjustment for several putative confounders (age, sex, body mass index, smoking, hormonal factors, statin, aspirin, alcohol, malignancy, and chronic disease) yielded an OR of 0.8 (95% CI 0.6–1.1). Results were similar for provoked and unprovoked events, and for deep vein thrombosis and pulmonary embolism. In controls, von Willebrand factor levels were 11 (3–19) IU dL^?1 lower and factor (F) VIII levels were 11 (1–21) IU dL^?1 lower in coffee consumers than in non‐consumers. After adjustment of the risk estimates for these hemostatic factors, the inverse association between coffee consumption and venous thrombosis diminished (OR 1.0, 95% CI 0.7–1.4). There was no association between coffee consumption and anticoagulant proteins, fibrinogen levels, or fibrinolytic markers. Conclusions: Coffee consumption is associated with a lower risk of venous thrombosis, which seems to be mediated through von Willebrand factor and FVIII.     

Increased levels of free thyroxine and risk of venous thrombosis in a large population‐based prospective study

Summary. Background: Recent studies have shown that high levels of free thyroxine (FT4), even without leading to hyperthyroidism, are associated with a procoagulant state. Objectives: The aim of our study was to determine whether high levels of thyroid hormones are associated with an increased risk of venous thrombosis. Patients/Methods: From a prospective nested case‐cohort design within the second Nord‐Trøndelag Health Study (HUNT2) cohort (1995–1997; 66 140 subjects), all patients with venous thrombosis during follow‐up (n = 515) and 1476 randomly selected age‐stratified and sex‐stratified controls were included. Relative and absolute risks for venous thrombosis were calculated for different cut‐off levels of thyroid hormones on the basis of percentiles in the controls and different times between blood sampling and thombosis. Results: In subjects with an FT4 level above the 98th percentile (17.3 pmol L^?1), the odds ratio (OR) was 2.5 (95% confidence interval [CI] 1.3–5.0) as compared with subjects with levels below this percentile. For venous thrombosis within 1 year from blood sampling, this relative risk was more pronounced, with an OR of 4.8 (95% CI 1.7–14.0). Within 0.5 years, the association was even stronger, with an OR of 9.9 (95% CI 2.9–34.0, adjusted for age, sex, and body mass index). For thyroid‐stimulating hormone, the relationship was inverse and less pronounced. The absolute risk within 6 months in the population for FT4 levels above the 98th percentile was 6.1 per 1000 person‐years (95% CI 1.7–15.7). Conclusions: Levels of FT4 at the upper end of the normal range are a strong risk factor for venous thrombosis. The risk increased with higher levels of thyroxine and shorter time between blood sampling and thrombosis. Further studies on the effect of clinical hyperthyroidism are warranted.     

Comparison between idiopathic deep vein thrombosis of the upper and lower extremity regarding risk factors and recurrence

Summary. Background: The pathogenesis and natural course of idiopathic upper extremity deep vein thrombosis (UEDVT) are unclear. Objective: To compare patients with UEDVT and with idiopathic lower extremity deep vein thrombosis (LEDVT) regarding risk factors and recurrence. Methods: We followed 50 patients with first idiopathic UEDVT and 841 patients with first idiopathic LEDVT for an average of 59 and 46 months, respectively. We excluded patients with natural inhibitor deficiency, lupus anticoagulant, cancer, pregnancy, isolated pulmonary embolism (PE), or long‐term antithrombotic treatment. The endpoint was recurrent venous thromboembolism (VTE). Results: In comparison to LEDVT patients, UEDVT patients were younger (38 ± 13 years vs. 49 ± 16 years, P < 0.001), slimmer (body mass index: 24 ± 4 vs. 27 ± 5, P < 0.001), less frequently had a family history of VTE (18% vs. 31%, P = 0.06) or concomitant PE (8% vs. 31%, P =0.001), were less frequently carriers of factor V Leiden (12% vs. 30%, P = 0.009), and had lower thrombin generation marker levels (D‐dimer, 283 ± 361 ng mL^?1 vs. 456 ± 446 ng mL^?1, P < 0.001; peak thrombin, 298 ± 101 nm vs. 363 ± 111 nm , P = 0.001). Recurrence occurred in two of 50 patients with UEDVT (4%) and in 129 of 841 patients with LEDVT (15%). After 5 years, the likelihood of recurrence was 2% [95% confidence interval (CI) 0–6] among UEDVT patients and 19% (95% CI  16–22; P = 0.02) among LEDVT patients. As compared to LEDVT patients, the adjusted risk of recurrence was 0.26 (95% CI  0.06–1.05; P = 0.059) in UEDVT patients. Conclusion: The pathogenesis and natural course of the disease differ between patients with idiopathic UEDVT and LEDVT.     

ABO genotype and risk of thrombotic events and hemorrhagic stroke

Summary. Background: The non‐O alleles of the ABO genotype have been associated with an increased risk of thrombosis. Risk associated with the specific A¹, A² or B alleles is not well defined. Objectives: To examine the association of the ABO genotype with myocardial infarction (MI), ischemic stroke, hemorrhagic stroke, and venous thrombosis (VT). Patients and methods: We used data from two ongoing population‐based case–control studies of MI, stroke, and VT. Cases included hypertensive adults and postmenopausal women with incident non‐fatal MI (n = 1063), ischemic stroke (n = 469), and hemorrhagic stroke (n = 91), and postmenopausal women with incident non‐fatal VT (n = 504). Controls were frequency matched to cases on age, sex, hypertension status, and year of identification. ABO genotypes were determined using single‐nucleotide polymorphisms, and subjects were grouped by diplotype according to the presence of O¹, O², A¹¹, A² and B alleles. Logistic regression was used to test the association of diplotypes with risk of each outcome. Results: As compared with the O¹O¹ group, the A¹¹ allele was associated with an increased risk of VT [odds ratio (OR) 1.79; 95% confidence interval (CI) 1.41–2.26] and MI (OR 1.23; 95% CI  1.05–1.44). The B allele was associated with an increased risk of VT (OR 1.82; 95% CI  1.29–2.57) and ischemic stroke (OR 1.59; 95% CI  1.17–2.17). The AB diplotype category was associated with a 2.7‐fold risk of VT (OR 2.70; 95% CI  1.73–4.21). No other associations reached significance. Conclusions: The VT and MI findings are confirmatory, and the ischemic stroke finding with the B allele is a novel finding and needs replication.     

HMG-CoA reductase inhibitors, other lipid-lowering medication, antiplatelet therapy, and the risk of venous thrombosis

Summary. Background: Statins [3‐hydroxymethyl‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitors] and antiplatelet therapy reduce the risk of atherosclerotic disease. Besides a reduction of lipid levels, statins might also have antithrombotic and anti‐inflammatory properties, and anti‐platelet therapy reduces clot formation. We have studied the risk of venous thrombosis with use of statins, other lipid‐lowering medication, and antiplatelet therapy. Materials and methods: Patients with a first episode of deep vein thrombosis in the leg or pulmonary embolism between March 1999 and September 2004 were included in a large population‐based case–control study (MEGA study). Control subjects were partners of patients (53%) or recruited via a random‐digit‐dialing method (47%). Participants reported different all‐medication use in a questionnaire. Results: Of 4538 patients, 154 used statins (3.3%), as did 354 of 5914 control subjects (5.7%). The use of statins [odds ratio (OR) 0.45; 95% confidence interval (CI) 0.36–0.56] but not other lipid‐lowering medications (OR 1.22; 95% CI  0.62–2.43), was associated with a reduced venous thrombosis risk as compared with individuals who did not use any lipid‐lowering medication, after adjustment for age, sex, body mass index, atherosclerotic disease, antiplatelet therapy and use of vitamin K antagonists. Different types and various durations of statin therapy were all associated with a decreased venous thrombosis risk. Antiplatelet therapy also reduced venous thrombosis risk (OR 0.56; 95% CI  0.42–0.74). However, sensitivity analyses suggested that this effect is most likely explained by a so‐called ‘healthy user effect’. Simultaneous use of medication most strongly reduced venous thrombosis risk. Conclusion: These results suggest that the use of various types of statins is associated with a reduced risk of venous thrombosis, whereas antiplatelet therapy and other lipid‐lowering medications are not.     

Factor V Leiden as a risk factor for preterm birth – a population‐based nested case–control study

Summary. Background: Preterm birth is a major cause of neonatal morbidity and mortality, occurring in 5–13% of deliveries in developed countries. Genetic thrombophilia can theoretically contribute to the induction of preterm delivery, but the role of thrombophilia as risk factor is unclear. Objectives: To assess factor V Leiden, FII G20210A and other selected inherited and acquired variables as risk factors for preterm birth. Patients/Methods: We performed a population‐based nested case–control study of 100 000 consecutive pregnancies in Finland. Cases and controls were identified by combining national registers. Clinical data were obtained from medical records and standardized questionnaires. We studied 324 cases with preterm delivery at or after 22 and before 37 completed weeks of gestation, and 752 controls. Results: FV Leiden was associated with a 2.4‐fold risk (95% confidence interval [CI] 1.3–4.6) of preterm birth in all pregnancies, and a 2.6‐fold risk (95% CI 1.4–5.1) in singleton pregnancies. FV Leiden was especially associated with late preterm birth at or after 32 weeks of pregnancy, with an odds ratio (OR) of 2.9 (95% CI 1.5–5.6) in all pregnancies and an OR of 3.1 (95% CI 1.6–6.2) in singleton pregnancies. FII G20210A was not associated with preterm birth. Twin pregnancy (OR 12.0, 95% CI 6.0–24.1) and a history of venous thrombosis (OR 3.8, 95% CI 1.4–9.8) were associated with increased risk. High educational level and modest overweight (body mass index 25–29.9 kg m^?2) had protective effects. Conclusions: Maternal carriage of FV Leiden was associated with increased risk of late but not early preterm birth. FII G20120A was not associated with preterm birth.     

Dynamic APTT parameters: applications in thrombophilia

Summary. Background: Patients with a history of venous thrombosis occasionally have shortened APTTs when compared with those of healthy references, but the clinical applicability of a shortened APTT is limited. Objectives: The present study aimed to characterize dynamic APTT profiles in patients with previously documented venous thrombosis and hypothesized that the APTT‐MaxVel was significantly elevated in patients with a history of venous thrombosis as compared with healthy controls. Methods: We performed a case control study, enrolling a total of 38 patients, 17 males and 21 females, with a verified recent venous thrombotic event, as well as 88 healthy controls. Fifty‐three per cent of patients were found to have a biochemical risk factor. A standard APTT was recorded in platelet‐poor plasma, and the digital clotting signal was processed using simple algorithms developed to derive dynamic coagulation parameters. Results: Patients had a significantly higher mean APTT‐MaxVel (195.5 s^?1; SD = 57; 95% CI, 176.8–214.1) as compared with healthy controls (137.3 s^?1; SD = 21; 95% CI, 130.7–143.8). Patients also had significantly shorter mean APTTs (26.9 s; SD = 3.2; 95% CI, 25.9–28.0) than healthy controls (28.5 s; SD = 2.8; 95% CI, 27.9–29.0). While only one out of 38 patients (2.6%) had a standard APTT below the lower reference interval, 15 of the 38 patients (38.5%) had an APTT‐MaxVel above the upper reference limit. Regression analysis revealed linear correlation between FVIII:C, the level of fibrinogen and APTT‐MaxVel (R² = 0.89, P < 0.05). Conclusions: Simple signal processing of the APTT and the use of dynamic parameters represents a stronger predictive marker for hypercoagulation in patients with verified venous thrombosis than the standard APTT measurement.     

The Wells rule and D‐dimer for the diagnosis of isolated distal deep vein thrombosis

Summary. Background: Pretest clinical probability with the Wells rule and D‐dimer have been widely investigated for the diagnosis of symptomatic proximal deep vein thrombosis (DVT) of the lower limbs, but they have not been formally tested for symptomatic isolated distal DVT diagnosis. Objective: To evaluate the diagnostic accuracy of the Wells rule and D‐dimer for isolated distal DVT. Design, Setting, and Patients: This was a single‐center, cross‐sectional study including 873 consecutive outpatients with suspected DVT, in whom pretest clinical probability determination, D‐dimer determination (STA Liatest; cut‐off of < 500 ng mL^?1) and complete compression ultrasonography of both lower limbs were performed. Results: The isolated distal DVT prevalence was 12.4% (90/725). The sensitivity of the Wells rule for isolated distal DVT was 47% (95% confidence interval [CI] 36–57%), the specificity was 74% (95% CI 70–77%), and the negative and positive predictive values were 91% (95% CI 88–93%) and 20% (95% CI 15–26%), respectively. Patients with isolated distal DVT had higher D‐dimer levels than patients without DVT (1759 ± 1576 vs. 862 ± 1079 ng mL^?1, P = 0.0001). D‐dimer was negative in 13 patients with isolated distal DVT. D‐dimer sensitivity and specificity for isolated distal DVT were 84% (95% CI 75–91%) and 50% (95% CI 46–54%), respectively, with a negative predictive value of 96% (95% CI 93–98%). In patients with low pretest clinical probability, the D‐dimer negative predictive value was 99% (95% CI 95–100%). Conclusion: In clinically suspected DVT with negative proximal compression ultrasonography, pretest clinical probability with the Wells rule has a low diagnostic accuracy for isolated distal DVT. D‐dimer has a better negative predictive value, but alone it does not exclude isolated distal DVT. In patients with low pretest clinical probability, D‐dimer had a negative predictive value of > 95% for isolated distal DVT.     

A randomized,double‐blind study of certoparin vs. unfractionated heparin to prevent venous thromboembolic events in acutely ill,non‐surgical patients: CERTIFY Study

Summary. Background: In medically ill patients, no contemporary double‐blind head‐to‐head evaluation of low molecular weight heparin vs. unfractionated heparin (UFH) for the prevention of venous thromboembolic events is available. Objectives: To compare the efficacy and safety of certoparin with those of UFH. Patients/Methods: In this double‐blind, randomized, controlled trial, acutely ill, non‐surgical patients aged ≥ 70 years were randomized to certoparin (3000 U of anti‐factor Xa once daily) or to UFH (5000 IU t.i.d.). The primary endpoint was the composite of proximal deep vein thrombosis as assessed by bilateral compression ultrasonography, symptomatic non‐fatal pulmonary embolism and venous thromboembolism‐related death, and was assessed by a blinded central adjudication committee. Non‐inferiority margins were set at 1.8 for the odds ratio (OR) and 3.45% for the absolute difference. Results: Three thousand two hundred and thirty‐nine patients aged 78.8 ± 6.3 years were treated for 9.1 ± 3.4 days. The incidence of the primary endpoint was 3.94% in the certoparin group and 4.52% in the UFH group, with a difference in proportions of ? 0.59% [95% confidence interval (CI) ?2.09 to 0.92; P < 0.0001 for non‐inferiority], and an OR of 0.87 (95% CI 0.60–1.26; P = 0.0001 for non‐inferiority). Major bleeding occurred in 0.43% of certoparin‐treated patients and 0.62% of UFH‐treated patients (OR 0.69; 95% CI 0.26–1.83). Any bleeding occurred at 3.20% in certoparin‐treated patients vs. 4.58% in UFH‐treated patients (OR 0.69; 95% CI 0.48–0.99; P < 0.05), and 5.73% of certoparin‐treated patients and 6.63% of UFH‐treated patients experienced serious adverse events. All‐cause mortality was 1.27% in certoparin‐treated patients and 1.36% in UFH‐treated patients. Conclusions: In acutely ill, non‐surgical elderly patients, thromboprophylaxis with certoparin (3000 U of anti‐FXa once daily) was non‐inferior to 5000 IU of UFH t.i.d., with a favorable safety profile.     

Sex hormone‐binding globulin levels are not causally related to venous thrombosis risk in women not using hormonal contraceptives

Summary. Background: Oral contraceptive use increases the risk of venous thrombosis as well as sex hormone‐binding globulin (SHBG) levels. Furthermore, increased SHBG levels are positively associated with activated protein C (APC) resistance and thrombotic risk in oral contraceptive users. Objectives: To determine whether increased SHBG levels are causally related to venous thrombosis in women not using hormonal contraceptives. Methods: Premenopausal women were selected from a case–control study on venous thrombosis, the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study (23 patients; 258 controls). Women using hormonal contraceptives were excluded. First, the risk of venous thrombosis with SHBG levels above the normal reference range (70 nm ) was determined. Second, because multiple regulatory factors affect SHBG levels and residual confounding may remain, we determined six single‐nucleotide polymorphisms (SNPs) in the SHBG gene and assessed the risk of venous thrombosis in a different case–control study, the Leiden Thrombophilia Study (LETS) (20 patients; 74 controls), and in the MEGA study. Finally, the association between SHBG levels and the normalized activated partial thromboplastin time‐based APC resistance (an intermediate endpoint for venous thrombosis) was determined. Results: Elevated SHBG levels (> 70.0 nm ) were associated with venous thrombosis (odds ratio 1.92; 95% confidence interval [CI] 0.74–5.00). However, this finding can be explained by residual confounding. Two SNPs in the SHBG gene affected SHBG levels, but not venous thrombosis risk. Furthermore, SHBG levels in controls were not associated with APC resistance (SHBG level, > 70.0 vs. ≤ 70.0 nm : mean difference in normalized APC sensitivity ratio, 0.03; 95% CI ?0.05 to 0.10). Exclusion of women with FV Leiden did not materially change these results. Conclusions: Increased SHBG levels are not causally related to the risk of venous thrombosis.     

Explanations for coagulation activation after air travel

Summary. Background: It is unknown whether venous thrombosis after long haul air travel is exclusively attributable to immobilization. Objectives: We determined whether the following mechanisms were involved: hypoxia, stress, inflammation or viral infection. Patients/Methods:  In a case crossover setting in 71 healthy volunteers who were exposed to an 8‐h flight, 8‐h movie marathon and 8 h of regular activities, we compared markers for several hypothetical pathways: plasminogen activator inhibitor‐1 (PAI‐1), stress, plasma factor (F)VIII coagulant activity (FVIIIc), soluble P‐selectine (sP‐selectine), interleukin‐8 (IL‐8) and neutrophil elastase. We reported earlier an activated clotting system, as evidenced by thrombin generation, in 17% of volunteers after the flight. Results: PAI‐1 increased by 4.2 ng mL^?1 (CI95:?49.5 to 6.5) in volunteers with an activated clotting system whereas it decreased in those without (?20.0 ng mL^?1, CI95:?33.2 to ?14.0). FVIIIc levels rose more in individuals with clotting activation (18.0%, CI95:?1.0 to 33.0) than in those without (2.0%, CI95:?2.0 to 5.0). The increases in FVIIIc were not associated with stress, which appeared unrelated to clotting activation. sP‐selectin increased in those with clotting activation (3.5 μg L^?1, CI95: ?3.0 to 10.0), but decreased in those without (?0.5 μg L^?1, CI95: ?2.0 to 2.0). Changes in levels of neutrophil elastase or IL‐8 were not different between the subjects with and without clotting activation. Conclusions: Our results do not support the hypotheses that stress, infection or air pollution are involved in the development of a prothrombotic state in air travellers. After long haul air travel, this state is more pronounced in patients with risk factors and may be caused by hypoxia, triggering systemic inflammation and platelet activation, leading to coagulation induction and degranulation of platelets.     

Markers of coagulation,fibrinolysis and inflammation in relation to post‐thrombotic syndrome

Summary. Background: Post‐thrombotic syndrome (PTS) occurs in 20–50% of patients after a deep venous thrombosis (DVT). It is difficult to accurately predict which patients will develop PTS. Biomarkers could be a valuable tool for PTS risk assessment. Objectives: To investigate whether increased levels of factor (F)VIII, C‐reactive protein (CRP) or D‐dimer, over time, are associated with the development of PTS in patients after an acute DVT. Methods: PTS status was assessed using the Villalta scale. Blood sampling was performed at three points during follow‐up. Results: A cohort of 228 consecutive patients was included after an acute DVT. At T1 (12 months after index DVT), both levels of D‐dimer (median 725 ng mL^?1 [interquartile range, IQR 400–1400[ vs. 378 ng mL^?1 [251–652] P = 0.004) and CRP (median 3.9 mg L^?1 [IQR 1.6–8.5] vs. 2.4 mg L^?1 [1.0–4.3] P = 0.018) were increased in patients with PTS, compared with patients without PTS. Factor (F)VIII was not associated with PTS. In the multivariate logistic regression analysis, varicosities (odds ratio [OR] 13.4 95% confidence interval [CI] 3.0–59.1 P = 0.001), a previous ipsilateral DVT (OR 6.3 95% CI 1.5–26.9 P = 0.012) and CRP > 5 mg L^?1 on T1 (OR 8.0 95% CI 2.4–26.4 P = 0.001) were significantly associated with PTS. Conclusions: Besides previous ipsilateral DVT and varicosities, CRP > 5 mg L^?1 at T1 was strongly and independently associated with PTS. Persistent inflammation rather than hypercoagulability might be the most important etiological factor in PTS, and may be a target for future therapy. The development of a risk score for PTS, including both clinical risk factors and biomarker levels, such as CRP, might be desirable.     

Clinical predictors of dual aspirin and clopidogrel poor responsiveness in stable cardiovascular patients from the ADRIE study

Summary. Background: Poor response to both aspirin and clopidogrel (dual poor responsiveness [DPR]) is a major risk factor for recurrent ischemic events. Objectives: The aim of this study was to identify factors associated with DPR, defined with specific tests, and derive a predictive clinical score. Methods: We studied 771 consecutive stable cardiovascular patients treated with aspirin (n = 223), clopidogrel (n = 111), or both drugs (n = 437). Aspirin responsiveness was evaluated by serum thromboxane (Tx)B₂ assay, and clopidogrel responsiveness by calculating the platelet reactivity index (PRI) on the basis of the phosphorylation status of the vasodilator phosphoprotein. The analysis was focused on patients treated with both drugs, and on independent predictors of DPR. Results: Among patients on dual therapy, there was no relevant correlation between TxB₂ levels and PRI values (r = 0.11). Sixty‐seven patients (15.4%) had DPR. Diabetes [odds ratio (OR) 1.89, 95% confidence interval (CI) 1.06–3.39], high body weight (> 86 kg vs. < 77 kg, OR 4.74, 95% CI 2.49–9.73), low aspirin dose (75–81 mg vs. ≥ 160 mg, OR 0.12, 95% CI 0.09–0.93) and high C‐reactive protein (CRP) level (> 1.6 mg L^?1 vs. < 0.6 mg L^?1, OR 3.66, 95% CI 1.74–8.72) were independently associated with DPR, via increased TxB₂ levels, increased PRI, or both. These associations with TxB₂ and PRI were reproduced across the whole population. With use of a factor‐weighed score (c‐index = 0.74), the predicted prevalence of DPR was 57% in the highest strata of the score as compared with < 4% for the lowest strata. Conclusions: Diabetes, body weight, the aspirin dose and CRP levels are readily available independent predictors of DPR, and some are potential targets for reducing its prevalence.     

N-terminal pro-brain natriuretic peptide used for the prediction of coronary artery stenosis

Background The level of the inactive N‐terminal fragment of pro‐brain (B‐type) natriuretic peptide (NT‐proBNP) is a prognostic marker in patients with acute and chronic coronary artery disease (CAD). It might also be valuable for non‐invasive diagnosis of coronary artery disease. Materials and methods The NT‐proBNP was measured in 781 consecutive patients with normal left ventricular function referred for coronary angiography owing to symptoms or signs of CAD. The diagnostic value of NT‐proBNP was assessed for predicting CAD at angiography. Results Elevated NT‐proBNP levels were associated with the extent of CAD and with the female sex (P < 0·001). The ability of NT‐proBNP to predict significant coronary disease at angiography was assessed separately for men using a cut‐off point of 85 pg mL⁻¹, positive likelihood ratio 2·2 (95% CI, 1·7–3·0), negative likelihood ratio 0·53 (95% CI 0·45–0·63) and area under the receiver‐operating‐characteristic (ROC) curve 0·72: for women, it was assessed using a cut‐off point of 165 pg mL⁻¹, positive likelihood ratio 2·4 (95% CI, 1·7–3·4), negative likelihood ratio 0·55 (95% CI, 0·44–0·70) and area under ROC curve 0·71. In multiple logistic‐regression analysis, NT‐proBNP added significant independent predictive power to other clinical variables in models predicting CAD (odds ratio 2·76, 95% CI, 1·76–4·32, P < 0·001). Conclusions The NT‐proBNP is a marker of non‐obstructive CAD and of significant coronary stenosis. In conjunction with other clinical information, measurement of NT‐proBNP with the use of sex‐specific reference ranges may improve the non‐invasive prediction of CAD.     

Determinants of impaired renal and vascular function are associated with elevated levels of procoagulant factors in the general population

Essentials

• Why venous thrombosis is more prevalent in chronic kidney disease is unclear.
• We investigated whether renal and vascular function are associated with hypercoagulability.
• Coagulation factors showed a procoagulant shift with impaired renal and vascular function.
• This suggests that renal and vascular function play a role in the etiology of thrombosis.

Summary

Background

Impaired renal and vascular function have been associated with venous thrombosis, but the mechanism is unclear.

Objectives

We investigated whether estimated glomerular filtration rate (eGFR), urinary albumin‐creatinine ratio (UACR), and pulse wave velocity (PWV) are associated with a procoagulant state.

Methods

In this cross‐sectional analysis of the NEO Study, eGFR, UACR, fibrinogen, and coagulation factors (F)VIII, FIX and FXI were determined in all participants (n = 6536), and PWV was assessed in a random subset (n = 2433). eGFR, UACR and PWV were analyzed continuously and per percentile: per six categories for eGFR (> 50^th [reference] to < 1st) and UACR (< 50^th [reference] to > 99th), and per four categories (< 50^th [reference] to > 95th percentile) for PWV. Linear regression was used and adjusted for age, sex, total body fat, smoking, education, ethnicity, total cholesterol, C‐reactive protein (CRP) and vitamin K antagonists use (FIX).

Results

Mean age was 55.6 years, mean eGFR 86.0 (12SD) mL 1.73 m^?² and median UACR 0.4 mg mmol^?1 (25th, 75th percentile; 0.3, 0.7). All coagulation factors showed a procoagulant shift with lower renal function and albuminuria. For example, FVIII was 22 IU dL^?1 (95% CI, 13–32) higher in the eGFR < 1st percentile compared with the > 50th percentile, and FVIII was 12 IU dL^?1 (95% CI, 3–22) higher in the UACR > 99th percentile compared with the < 50th percentile. PWV was positively associated with coagulation factors FIX and FXI in continuous analysis; per m/s difference in PWV, FIX was 2.0 IU dL^?1 (95% CI, 0.70–3.2) higher.

Conclusions

Impaired renal and vascular function was associated with higher levels of coagulation factors, underlining the role of renal function and vascular function in the development of venous thrombosis.

     

Effect of the selective serotonin reuptake inhibitor paroxetine on platelet function is modified by a SLC6A4 serotonin transporter polymorphism

Summary. Background: Selective serotonin reuptake inhibitors (SSRIs) have been associated with an increased bleeding tendency. Objectives: To prospectively quantify the dose‐response effects of paroxetine and the influence of the serotonin transporter gene (SLC6A4) promoter polymorphism (5‐HTTLPR) on platelet function. Methods: Nineteen drug‐free psychiatric outpatients (44.5 ± 10.8 years) were tested before and after 6 weeks of paroxetine treatment (20 mg day^?1). Based on clinical symptoms, paroxetine dosages were increased (40–50 mg day^?1) for 6 more weeks in 11 patients. Parameters related to platelet function were assessed by bleeding time, platelet function analyzer (PFA), platelet serotonin, platelet factor 4 (PF4), β‐thromboglobulin (β‐TG), and aggregation tests. Results: Paroxetine 20 mg day^?1 increased mean bleeding time by 1.2 min (95% confidence interval (95% CI) ?0.2–2.7) and reduced median platelet serotonin level (463 ng 10^?9 platelets; inter quartile range (IQR) 361–666), and platelet ß‐TG concentration (3.1 IU 10^?6 platelets; IQR 0.3–6.0). Other platelet parameters did not change significantly. Serial platelet aggregation tests did not become abnormal. Paroxetine dose‐escalation did not further influence platelet function. However, 5‐HTTLPR polymorphisms modified these effects: in L_A/L_A‐carriers, bleeding times did not change (?0.2 min; 95% CI ?0.6 to 0.9), while bleeding times significantly increased in <2L_A‐allele carriers (2.3 min; 95% CI 0.5 to 4.07; P = 0.032). Platelet serotonin decreases were larger in patients without L_A‐alleles (868 ng 10^?9 platelets; IQR 585 to 1213) than in ≥1 L_A‐allele carriers (457 ng 10^?9 platelets; IQR 392 to 598; P = 0.035). PFA closure time and PF4 increased significantly in patients without L_A‐alleles. Conclusions: Paroxetine 20 mg day^?1 does not increase overall bleeding time, but impairs platelet function by decreasing the levels of platelet serotonin and platelet ß‐TG. These paroxetine effects appear to be mediated by 5‐HTTLPR, with most pronounced effects in patients without L_A‐alleles.     

Hyperglycemia is a risk factor for high-grade envenomations after European viper bites (Vipera spp.) in children

Context: Hyperglycemia has been described in severe scorpion envenomation, we wanted to analyze if it was applicable to viper bites in children. Aim: To describe clinical, biological, and therapeutic characteristics of 83 children bitten by European viper (Vipera spp.) and to confirm that hyperglycemia is a risk factor for high-grade envenomation. Material and methods: A retrospective study was conducted between 2001 and 2014 in the pediatric emergency department of a tertiary level children’s hospital. Collected data were: age and sex of children; day and time of admission; day, time and circumstances of the accident; snake identification; bite location; envenomation severity; presence of fang marks; prehospital care; laboratory abnormalities, use of specific immunotherapy, associated treatments; length of stay; hospital course. Results: Eighty-three children were included (62 boys, 21 girls). The mean age was 7.4?±?3.9 years. Bites were most often located on the lower extremities (66%). The classification of envenomation was: 83% low grade (absent or minor envenomation) and 17% high grade (moderate to severe envenomation). All high-grade envenomations received specific immunotherapy (Viperfav^TM, (Aventis Pasteur, MSD, Lyon, France). Being bitten on an upper extremity (odds ratio [OR] 51.1 95% class interval [CI] [6.1–424], p?<?0.0001), during the afternoon (OR 13.4 95% CI [1.7–107.9], p?=?0.015), feeling violent pain (OR 4.2 95% CI [1.1–16.5], p?=?0.023), and high initial plasma glucose level (6.5?±?1.7?mmol/L versus 5.0?±?0.9?mmol/L, p?=?0.027) were associated with a significant risk of high-grade envenomation. Conclusion: We have confirmed a potential link between initial hyperglycemia and the risk of progression to high-grade envenomation as well as its association with other published predictive factors.     

Is the effect of acute hyperglycaemia on interdigestive antroduodenal motility and small-bowel transit mediated by insulin?

Acute hyperglycaemia inhibits antroduodenal motility. In non-diabetic subjects this inhibitory effect may result from reactive endogenous hyperinsulinaemia. Therefore, we investigated the effects of hyperinsulinaemia during both hyperglycaemia and euglycaemia on interdigestive antroduodenal motility (perfusion manometry) and duodenocaecal transit time (DCTT; lactulose breath-H₂ test). Six healthy volunteers (age 20–26 years) were studied for 240 min on three separate occasions in random order during: (a) i.v. saline (control); (b) acute hyperglycaemic hyperinsulinaemia (HG) with plasma glucose at 15 mmol L^?1; and (c) euglycaemic hyperinsulinaemia (HI) with plasma insulin at 80 mU L^?1 and glucose at 4–5 mmol L^?1. Results: DCTT was significantly (P < 0.05) prolonged during HG (158 ± 23 min) compared with control (95 ± 25 min), whereas HI had no effect (100 ± 17 min). Mean duration of complete migrating motor complex (MMC) cycles was significantly (P < 0.05) reduced during HG (63 ± 9 min) compared with control (103 ± 15 min) and HI (105 ± 16 min), which resulted from a significantly (P < 0.05) shorter duration of phase II. Antral motility was significantly (P < 0.05) reduced during both HI (20 ± 8 contractions 240 min^?1) and HG (9 ± 5) compared with control (43 ± 7). It is concluded that in healthy subjects hyperglycaemia prolongs DCTT, increases duodenal MMC cycle frequency and inhibits antral motility. Hyperinsulinaemia reduces antral motor activity but has no effect on interdigestive duodenal motility or DCTT. Thus, other factors, apart from insulin, mediate the inhibitory effect of hyperglycaemia on interdigestive intestinal motility and transit.     

Traffic exposure and incident venous thromboembolism in the Atherosclerosis Risk in Communities (ARIC) Study

Summary. Background: Two recent case–control studies in Italy reported that long‐term exposure to particulate air pollution or living near major traffic roads was associated with an increased risk of deep vein thrombosis (DVT). No prospective evidence exists on the possible association between long‐term traffic‐related air pollution and incident venous thromboembolism (VTE). Objectives: To examine the association between long‐term traffic exposure and incident VTE in a population‐based prospective cohort study. Methods: We studied 13 143 middle‐aged men and women in the Atherosclerosis Risk in Communities Study without a history of DVT or pulmonary embolism at baseline examination (1987–1989). The Geographical Information System‐mapped traffic density and distance to major roads in the four study communities served as measures of traffic exposure. We examined the association between traffic exposure and incident VTE with proportional hazards regression models. Results: A total of 405 subjects developed VTE in 2005. Traffic density was not significantly associated with VTE. Relative to those in the lowest quartile of traffic density, the adjusted hazard ratios across increasing quartiles were 1.18 (95% confidence interval [CI] 0.88–1.57), 0.99 (95% CI 0.74–1.34) and 1.14 (95% CI 0.86–1.51) (P‐value for trend across quartiles = 0.64). For residents living within 150 m of major roads, as compared with subjects living further away, the adjusted hazard ratio was 1.16 (95% CI 0.95–1.42, P = 0.14). Conclusions: This first prospective study in the general population does not support an association between air pollution exposure or traffic proximity and risk of DVT. More data may be needed to clarify whether traffic or air pollution influences the risk of VTE.