Torben Bjerregaard Larsen

Major genetic susceptibility for venous thromboembolism in men: A study of Danish twins

Background. Although several genetic determinants (mutations or polymorphisms) have been associated with increased risk of venous thromboembolism, the overall influence of genetic factors on this disease is unknown. Methods. We linked the Danish Twin Registry, which includes twins born 1870–1953, with the Danish National Registry of Patients, comprising all hospitalizations in Denmark since 1977. We then determined the risk of venous thromboembolism as determined from discharge diagnosis. Results. We identified 26,982 twins who were alive on 1 January 1977, and computed measures of familial and genetic association of venous thrombotic disorders. Individuals were classified according to zygosity and hospitalization with venous thromboembolism. Since 1977, 678 twins were hospitalized with an episode of venous thromboembolism. Of these, only 545 pairs (281 male pairs and 264 female pairs) were alive in 1977. For men, the concordance rates for mono- and dizygotic twin pairs, respectively, were 0.22 (95% confidence interval = 0.14 to 0.30) and 0.08 (0.04–0.12). The odds ratio (interpreted as the relative risk of venous thromboembolism for one twin, given venous thromboembolism in the partner twin) was 13.5 (7.3–24.8) among monozygotic twins and 3.8 (1.8–8.3) among dizygotic twins. The respective correlations for venous thromboembolism were 0.55 (0.38–0.70) and 0.26 (0.09–0.42). The proportion of the variance attributable to genetic effects on venous thromboembolism in males was 55% (39%–68%). The remaining variation could be attributed to men’s nonfamilial environments. In contrast, for women there was no intra–twin pair similarity for venous thromboembolism. Conclusions. We found differences in genetic susceptibility to venous thromboembolism between the sexes, with genetic factors playing a substantially stronger role in males than in females.

ABO blood groups and risk of venous thromboembolism during pregnancy and the puerperium. A population‐based, nested case–control study

Summary.u2002 Objectives:u2003To examine possible associations of ABO blood types with the risk of venous thromboembolism (VTE) in pregnancy and the puerperium. Patients and methods:u2003We conducted a nested case–control study within a cohort of 71u2003729 women who gave birth to 126u2003783 children in the North Jutland County, Denmark, from 1980 to 2001. We identified 129 cases with VTE in pregnancy (nu2003=u200361) or the puerperium (nu2003=u200368), and 258 controls with no VTE. We collected information on ABO blood groups and possible maternal confounding factors and estimated the relative risk [odds ratio (OR)]. Results:u2003Women with an A or AB blood group had elevated risk estimates of VTE in pregnancy or the puerperium compared with women with a O blood group [adjusted ORs 2.4, 95% confidence interval (CI) 1.3, 4.3, and 2.0, 95% CI 0.7, 5.8, respectively]. No increased risk estimate was found for group B (adjusted OR 1.2, 95% CI 0.5, 3.0). The increased risk estimates of VTE for blood groups A and AB appeared present in both pregnancy (adjusted ORs of 3.9, 95% CI 1.5, 9.7, and 2.2, 95% CI 0.4, 12.5) and in the puerperium (adjusted ORs of 2.4, 95% CI 1.0, 4.9 and 2.7, 95% CI 0.8, 9.3). Furthermore, blood groups A and AB appeared to be associated with increased risk estimates for both DVT and pulmonary embolism. Conclusion:u2003Keeping the modest statistical precision of our study in mind, blood groups A and AB may be associated with increased risk estimates for VTE in pregnancy and the puerperium.

High preoperative prevalence of deep venous thrombosis in patients with colorectal cancer.

Deep venous thrombosis (DVT) is a major complication of cancer and a predictor of reduced survival. The postoperative prevalence of DVT in colorectal cancer surgery is high, but the preoperative prevalence is unknown. The aim of this observational study was to estimate the preoperative prevalence of DVT in patients with colorectal cancer.

Changes in various metabolic parameters in blood and milk during experimental Escherichia coli mastitis for primiparous Holstein dairy cows during early lactation

BackgroundThe objective of this study was to characterize the changes in various metabolic parameters in blood and milk during IMI challenge with Escherichia coli (E. coli) for dairy cows during early lactation. Thirty, healthy primiparous Holstein cows were infused (h = 0) with ~20-40 cfu of live E. coli into one front mammary quarter at ~4-6 wk in lactation. Daily feed intake and milk yield were recorded. At –12, 0, 3, 6, 12, 18, 24, 36, 48, 60, 72, 96, 108, 120, 132, 144, 156, 168, 180 and 192 h relative to challenge rectal temperatures were recorded and quarter foremilk was collected for analysis of shedding of E. coli. Composite milk samples were collected at -180, -132, -84, -36, -12, 12, 24, 36, 48, 60, 72, 84, 96, 132 and 180 h relative to challenge (h = 0) and analyzed for lactate dehydrogenase (LDH), somatic cell count, fat, protein, lactose, citrate, beta-hydroxybutyrate (BHBA), free glucose (fglu), and glucose-6-phosphate (G6P). Blood was collected at -12, 0, 3, 6, 12, 18, 24, 36, 60, 72, 84, 132 and 180 h relative to challenge and analyzed for plasma non-esterified fatty acids (NEFA), BHBA and glucose concentration. A generalized linear mixed model was used to determine the effect of IMI challenge on metabolic responses of cows during early lactation.ResultsBy 12xa0h, E. coli was recovered from challenged quarters and shedding continued through 72xa0h. Rectal temperature peaked by 12xa0h post-challenge and returned to pre-challenge values by 36xa0h post-IMI challenge. Daily feed intake and milk yield decreased (P <0.05) by 1 and 2 d, respectively, after mastitis challenge. Plasma BHBA decreased (12xa0h; P <0.05) from 0.96u2009±u20091.1 at 0xa0h to 0.57u2009±u20090.64xa0mmol/L by 18xa0h whereas concentration of plasma NEFA (18xa0h) and glucose (24xa0h) were significantly greater, 11 and 27%, respectively, after challenge. In milk, fglu, lactose, citrate, fat and protein yield were lower whereas yield of BHBA and G6P were higher after challenge when compared to pre-challenge values.ConclusionsChanges in metabolites in blood and milk were most likely associated with drops in feed intake and milk yield. However, the early rise in plasma NEFA may also signify enhanced adipose tissue lipolysis. Lower concentrations of plasma BHBA may be attributed to an increase transfer into milk after IMI. Decreases in both milk lactose yield and % after challenge may be partly attributed to reduced conversion of fglu to lactose. Rises in G6P yield and concentration in milk after challenge (24 h) may signify increased conversion of fglu to G6P. Results identify changes in various metabolic parameters in blood and milk after IMI challenge with E. coli in dairy cows that may partly explain the partitioning of nutrients and changes in milk components after IMI for cows during early lactation.

Denaturing High-performance Liquid Chromatography mutation analysis in patients with reduced Protein S levels

BACKGROUNDnPatients with congenital Protein S deficiency have increased risk of venous thromboembolism. However, Protein S levels show large intra-individual variation and the biochemical assays have low accuracy and a high interlaboratory variability. Genetic analysis might aid in a more precise diagnosis and risk estimation. The aim was to design a high-throughput genetic analysis based on denaturing high-performance liquid chromatography to identify sequence variations in the gene coding for Protein S.nnnPATIENTSnIn total, 55 patients referred to the Section of Thrombosis and Haemostasis, Odense University Hospital, in the period 1998-2004 were included in the study.nnnRESULTSnMutations were found in ten of the 55 patients: Six different variants were identified, of which four were not previously reported: One were a nonsense mutation substituting a glutamine with a stopcodon (c.790C>T) and the rest were missense mutations (c.932T>G; c.1367A>G; c.1378T>C). Furthermore, four patients carried the same mutation (c.1045G>A), while two carried the Heerlen mutation (c.1378T>C).nnnCONCLUSIONSnThe reported method will be useful for rapidly detecting sequence variations in the gene coding for Protein S, giving a precise diagnosis and subsequently a better risk estimation.

The impact of selective and non-selective non-steroid anti-inflammatory drugs on secondary hemostasis in healthy volunteers

BACKGROUNDnClinical and epidemiological studies have associated selective COX-2 inhibitors with an increased risk of cardiovascular events. There are no clinical studies on the possible effects of these drugs on secondary hemostasis. The hypothesis for this study is that the use of selective COX-2 inhibitors could affect the secondary hemostasis and by that increase the risk of cardiovascular events in a population at high risk.nnnMETHODSnAn open-label randomized cross-over study was performed in 20 healthy male volunteers. The study consisted of two periods of each 21 days with medication, either celecoxib 100 mg b.i.d. or naproxen 250 mg b.i.d. Treatment periods were separated by a washout period of 28 days. Blood samples were obtained before the first medication period, and at the end of each medication period. Primary effect parameter was FXII level. Secondary effect parameters included a wide range of coagulation factors involved in secondary hemostasis.nnnRESULTSnThere was no statistically significant effect of celecoxib or naproxen on the primary effect parameter. Protein C activity was significantly decreased after treatment with naproxen (P<0.01), compared to baseline. Platelet function, demonstrated as closure time (CT), was at baseline 118+/-24 sec. (mean+/-SD). Naproxen prolonged CT to 171+/-50 sec. (P<0.001). Celecoxib did not change CT significantly (119+/-24 sec.).nnnCONCLUSIONSnNeither the selective COX-2 inhibitor celecoxib, nor the non-selective NSAID naproxen caused any change in the primary effect parameter from the secondary hemostasis.