Spontaneous coronary artery dissection in a young patient with antiphospholipid syndrome.

A 28-year-old man diagnosed with triple positive antiphospholipid syndrome (APS) and undergoing warfarin experienced three separate admissions to the cardiac ward within a one-month period due to escalating chest pain. While the initial two admissions revealed normal results in cardiological investigations, such as blood tests, electrocardiogram, and echocardiography, the third admission unveiled signs of ST-elevation myocardial infarction (STEMI), despite the patient maintaining an INR (International Normalized Ratio) of 4. Subsequent percutaneous coronary intervention (PCI) exposed spontaneous coronary artery dissection (SCAD) of type 3. Faced with hemodynamic instability and worsening symptoms, the patient underwent stenting and was prescribed dual antiplatelet therapy in addition to warfarin. A follow-up evaluation one month later indicated a normalization of his condition.

Rituximab-treated patients with lymphoma develop strong CD8 T-cell responses following COVID-19 vaccination.

B-cell depletion induced by anti-cluster of differentiation 20 (CD20) monoclonal antibody (mAb) therapy of patients with lymphoma is expected to impair humoral responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination, but effects on CD8 T-cell responses are unknown. Here, we investigated humoral and CD8 T-cell responses following two vaccinations in patients with lymphoma undergoing anti-CD20-mAb therapy as single agent or in combination with chemotherapy or other anti-neoplastic agents during the last 9 months prior to inclusion, and in healthy age-matched blood donors. Antibody measurements showed that seven of 110 patients had antibodies to the receptor-binding domain of the SARS-CoV-2 Spike protein 3-6 weeks after the second dose of vaccination. Peripheral blood CD8 T-cell responses against prevalent human leucocyte antigen (HLA) class I SARS-CoV-2 epitopes were determined by peptide-HLA multimer analysis. Strong CD8 T-cell responses were observed in samples from 20/29 patients (69%) and 12/16 (75%) controls, with similar median response magnitudes in the groups and some of the strongest responses observed in patients. We conclude that despite the absence of humoral immune responses in fully SARS-CoV-2-vaccinated, anti-CD20-treated patients with lymphoma, their CD8 T-cell responses reach similar frequencies and magnitudes as for controls. Patients with lymphoma on B-cell depleting therapies are thus likely to benefit from current coronavirus disease 2019 (COVID-19) vaccines, and development of vaccines aimed at eliciting T-cell responses to non-Spike epitopes might provide improved protection.

Myocardial infarction and future risk of cancer in the general population-the Tromsø Study.

The association between myocardial infarction (MI) and future risk of incident cancer is scarcely investigated. Therefore, we aimed to study the risk of cancer after a first time MI in a large cohort recruited from a general population. Participants in a large population-based study without a previous history of MI or cancer (n = 28,763) were included and followed from baseline to date of cancer, death, migration or study end. Crude incidence rates (IRs) and hazard ratios (HRs) for cancer after MI were calculated. During a median follow-up of 15.7 years, 1747 subjects developed incident MI, and of these, 146 suffered from a subsequent cancer. In the multivariable-adjusted model (adjusted for age, sex, BMI, systolic blood pressure, diabetes mellitus, HDL cholesterol, smoking, physical activity and education level), MI patients had 46% (HR 1.46; 95% CI: 1.21-1.77) higher hazard ratio of cancer compared to those without MI. The increased cancer incidence was highest during the first 6 months after the MI, with a 2.2-fold higher HR (2.15; 95% CI: 1.29-3.58) compared with subjects without MI. After a 2-year period without higher incidence rate, MI patients displayed 60% (HR 1.60; 95% CI: 1.27-2.03) higher HR of future cancer more than 3 years after the event. The increased IRs were higher in women than men. Patients with MI had a higher short- and long-term incidence rate of cancer compared to subjects without MI. Our findings suggest that occult cancer and shared risk factors of MI and cancer may partly explain the association.

COPD and risk of venous thromboembolism and mortality in a general population.

The relationship between chronic obstructive pulmonary disease (COPD) and risk of venous thromboembolism (VTE) has been scarcely studied in the general population. We aimed to investigate the association between COPD and risk of VTE and mortality in a population-based cohort.Spirometry was conducted in 8646 males and females, participating in the fifth (2001-02) and sixth (2007-08) surveys of the Tromsø Study. Incident VTE events during follow-up were registered from the date of inclusion to December 31, 2011. Cox-regression models with COPD stages and confounders as time varying covariates were used to calculate hazard ratios with 95% confidence intervals for VTE and all-cause mortality.During a median follow-up of 6.2 years, 215 subjects developed VTE. Subjects with COPD stage III/IV had a two-fold higher risk of secondary VTE compared to subjects with normal airflow (HR 2.05, 95% CI 1.02-4.10). COPD patients, particularly those with stage III/IV disease, with VTE had a higher mortality rate than COPD patients without VTE (50.2% versus 5.6% per year).Our findings suggest that patients with severe COPD may have increased risk of secondary VTE, and that COPD patients with VTE have a higher mortality rate than COPD patients without VTE.

Serum osteoprotegerin and future risk of cancer and cancer-related mortality in the general population: the Tromsø study.

The purpose was to investigate the association between serum osteoprotegerin (OPG) and risk of incident cancer and cancer mortality in a general population. OPG was measured in serum collected from 6,279 subjects without prior cancer recruited from a general population. Incident cancer and cancer-related mortality were registered from inclusion in 1994-95 until end of follow-up December 31, 2008. Cox regression models were used to estimate crude and adjusted (for age, sex and other confounders) hazard ratios and 95% confidence intervals (HR 95% CI). There were 948 incident cancers and 387 deaths in the cohort during 71,902 person-years of follow up (median 13.5 years). Subjects with serum OPG in the upper tertile had 79% higher risk of incident gastrointestinal cancer than those in the lowest tertile (HR 1.79, 95% CI 1.19-2.67). In women <60 years, serum OPG (per SD 0.81 ng/ml) was associated with reduced risk of incident cancer (all cancers merged; 0.73; 0.57-0.94) and breast cancer (0.51; 0.31-0.83) after adjustment. Subjects in the upper tertile of OPG had higher risk of cancer-related mortality (1.63; 1.16-2.28), particularly mortality from cancer in the gastrointestinal system (2.28; 1.21-4.28) compared to those in the lowest OPG tertile. No significant association was detected between OPG and risk of death from cancer in the respiratory system or death from prostatic cancer. Our findings from a large population based cohort study suggest that serum OPG was associated with increased risk of incident gastrointestinal cancer, inversely associated with breast cancer, and predicts cancer-related mortality.

Association of mild to moderate chronic kidney disease with venous thromboembolism: pooled analysis of five prospective general population cohorts.

BACKGROUND: Recent findings suggest that chronic kidney disease (CKD) may be associated with an increased risk of venous thromboembolism (VTE). Given the high prevalence of mild-to-moderate CKD in the general population, in depth analysis of this association is warranted. METHODS AND RESULTS: We pooled individual participant data from 5 community-based cohorts from Europe (second Nord-Trøndelag Health Study [HUNT2], Prevention of Renal and Vascular End-stage Disease [PREVEND], and the Tromsø study) and the United States (Atherosclerosis Risks in Communities [ARIC] and Cardiovascular Health Study [CHS]) to assess the association of estimated glomerular filtration rate (eGFR), albuminuria, and CKD with objectively verified VTE. To estimate adjusted hazard ratios for VTE, categorical and continuous spline models were fit by using Cox regression with shared-frailty or random-effect meta-analysis. A total of 1178 VTE events occurred over 599 453 person-years follow-up. Relative to eGFR 100 mL/min per 1.73 m(2), hazard ratios for VTE were 1.29 (95% confidence interval, 1.04-1.59) for eGFR 75, 1.31 (1.00-1.71) for eGFR 60, 1.82 (1.27-2.60) for eGFR 45, and 1.95 (1.26-3.01) for eGFR 30 mL/min per 1.73 m(2). In comparison with an albumin-to-creatinine ratio (ACR) of 5.0 mg/g, the hazard ratios for VTE were 1.34 (1.04-1.72) for ACR 30 mg/g, 1.60 (1.08-2.36) for ACR 300 mg/g, and 1.92 (1.19-3.09) for ACR 1000 mg/g. There was no interaction between clinical categories of eGFR and ACR (P=0.20). The adjusted hazard ratio for CKD, defined as eGFR <60 mL/min per 1.73 m(2) or albuminuria ≥30 mg/g, (versus no CKD) was 1.54 (95% confidence interval, 1.15-2.06). Associations were consistent in subgroups according to age, sex, and comorbidities, and for unprovoked versus provoked VTE, as well. CONCLUSIONS: Both eGFR and ACR are independently associated with increased risk of VTE in the general population, even across the normal eGFR and ACR ranges.

Diagnostic Blood Biomarkers for Acute Pulmonary Embolism: A Systematic Review.

(1) Background: The current diagnostic algorithm for acute pulmonary embolism (PE) is associated with the overuse of CT pulmonary angiography (CTPA). An additional highly specific blood test could potentially lower the proportion of patients with suspected PE that require CTPA. The aim was to summarize the literature on the diagnostic performance of biomarkers of patients admitted to an emergency department with suspected acute PE. (2) Methods: Medline and Embase databases were searched from 1995 to the present. The study selection process, data extraction, and risk of bias assessment were conducted by two reviewers. Eligibility criteria accepted all blood biomarkers except D-dimer, and CTPA was used as the reference standard. Qualitative data synthesis was performed. (3) Results: Of the 8448 identified records, only 6 were included. Eight blood biomarkers were identified, of which, three were investigated in two separate studies. Red distribution width and mean platelet volume were reported to have a specificity of ≥ 90% in one study, although these findings were not confirmed by other studies. The majority of the studies contained a high risk of selection bias. (4) Conclusions: The modest findings and the uncertain validity of the included studies suggest that none of the biomarkers identified in this systematic review have the potential to improve the current diagnostic algorithm for acute PE by reducing the overuse of CTPA.

Cystatin C is associated with risk of venous thromboembolism in subjects with normal kidney function--the Tromsø study.

BACKGROUND: Previous studies have shown an association between impaired kidney function, assessed by cystatin C-based estimated glomerular filtration rate, and venous thromboembolism. The aim of this study was to investigate whether serum cystatin C was associated with a risk of venous thromboembolism among subjects with normal kidney function in a prospective population-based study. DESIGN AND METHODS: Cystatin C was measured in serum from 3251 men and women with normal kidney function, aged 25-84 years, who participated in the Tromsø study in 1994-1995. Normal kidney function was defined as a creatinine-based estimated glomerular filtration rate greater than 90 mL/min/1.73 m(2) and absence of microalbuminuria. Incident venous thromboembolism was registered from the date of inclusion through to the end of follow-up, September 1, 2007. Cox-regression models were used to calculate hazard ratios with 95% confidence intervals for venous thromboembolism. RESULTS: There were 83 incident venous thromboembolic events, of which 53 (63.9 %) were provoked, during a median of 12.3 years of follow-up. A one standard deviation (0.11 mg/L) increase in serum cystatin C levels was associated with a 43% (hazard ratio 1.43; 95% confidence interval 1.17-1.72) increased risk of total venous thromboembolism. Subjects with cystatin C levels in the top quartile (≥ 0.87 mg/L) had a 2.5-fold (hazard ratio 2.51; 95% confidence interval 1.27-4.96) increased risk of venous thromboembolism compared to those with levels in the bottom quartile (≤ 0.72 mg/L) in adjusted analysis. The risk estimates were even higher for provoked venous thromboembolism (hazard ratio 3.11; 95% confidence interval 1.23-7.86). CONCLUSIONS: Serum cystatin C levels were associated with the risk of venous thromboembolism in subjects with normal kidney function. Our findings suggest that elevated serum cystatin C levels may promote venous thrombosis beyond reflecting impaired kidney function.

Testosterone, hemostasis, and cardiovascular diseases in men.

Men have a higher incidence of cardiovascular disease (CVD) than women, and adverse thrombotic events increase with age. Recent experimental cross-sectional, and case-control studies have shown that testosterone may affect the hemostatic/fibrinolytic system in men in several ways. It has been hypothesized that physiological doses of testosterone would have a beneficial effect on tissue factor-induced thrombin generation and the development of CVD. The search for eternal youth has created a market for testosterone treatment in aging men during the last few years. However, whether testosterone supplementation could be useful in the treatment of testosterone-deficient elderly men is still controversial. The present review focuses on the coagulation system and CVD from the perspective of testosterone.

Oral Anticoagulation Therapy for Venous Thromboembolism in Norway: Time Trends and Treatment Patterns.

PURPOSE: Data describing treatment patterns of patients with venous thromboembolism (VTE) patients in Scandinavia are scarce. This study sought to address this scarcity by describing demographic and clinical characteristics, trends in the use of oral anticoagulants (OACs), and treatment patterns in patients treated for VTE in Norway between 2013 and 2017. METHODS: Using data from Norway's nationwide registries, a cohort study included patients newly (after 2008) treated OACs who were diagnosed with VTE between January 2013 and December 2017 and were dispensed an OAC (warfarin, apixaban, rivaroxaban, dabigatran, or edoxaban) within 30 days. Patient characteristics and the percentage of patients with VTE who initiated treatment with each OAC for each calendar year were reported. Initial therapy persistence was assessed using Kaplan-Meier curves and compared between the OAC groups using the log-rank test. FINDINGS: The comorbidity burden was similar between patients taking warfarin and those taking apixaban but lower among patients taking rivaroxaban. Direct oral anticoagulant (DOAC) use increased from 33.2% to 93.6% during the study period, whereas warfarin use decreased. Persistence was higher in the apixaban cohort compared with the warfarin cohort, with the difference mostly apparent after 6 months, whereas persistence was similar between the patients taking rivaroxaban and those taking warfarin. IMPLICATIONS: Between 2013 and 2017, DOAC use among patients with VTEs increased markedly in Norway, whereas the use of warfarin decreased. Patients taking apixaban had higher persistence compared with those taking warfarin, whereas patients taking warfarin and those taking rivaroxaban had similar persistence. Further studies with longer follow-up are required to examine the use of extended OAC treatment for VTE.

Chronic Obstructive Pulmonary Disease and Risk of Mortality in Patients with Venous Thromboembolism-The Tromsø Study.

BACKGROUND: Previous studies have shown increased mortality in venous thromboembolism (VTE) patients with chronic obstructive pulmonary disease (COPD), but it is unknown to what extent the association is influenced by the severity of COPD and physical inactivity. OBJECTIVES: This article investigates whether COPD, and stages of COPD, influenced the risk of mortality after a first episode of VTE when physical inactivity was taken into account. METHODS: Patients with a first lifetime VTE (n = 256) were recruited among individuals who participated and performed spirometry in the fifth (2001-2002) and sixth (2007-2008) surveys of the Tromsø Study (n = 9577). All-cause mortality was registered up to December 31, 2015. RESULTS: There were 123 deaths during a median of 2.9 years of follow-up. The overall mortality rate was 11.9 (95% confidence interval [CI] 10.0-14.2) per 100 person-years. The risk of death was twofold higher in COPD patients compared with those with normal airflow (hazard ratio [HR] 2.00, 95% CI 1.30-3.08) after multivariable adjustment. The risk of death increased with the severity of COPD. VTE patients with COPD stage III/IV had a fivefold increased risk of death (HR 5.20, 95% CI 2.65-10.2) compared with those without COPD, and 50% of these patients died within 3.5 months after the incident VTE event. Adjustment for physical inactivity had minor effect on the risk estimates. CONCLUSION: VTE patients with COPD had increased risk of death, particularly patients with severe COPD. The detrimental effect of COPD on mortality in VTE patients was apparently explained by factors other than physical inactivity among patients with COPD.

Markers of endothelial cell activation and neutrophil extracellular traps are elevated in immune thrombocytopenia but are not enhanced by thrombopoietin receptor agonists.

INTRODUCTION: Patients with immune thrombocytopenia (ITP) are at increased risk of thrombosis, which seems to be further enhanced by treatment with thrombopoietin-receptor-agonists (TPO-RAs). The underlying mechanisms of thrombosis in ITP are not fully understood. Endothelial cell activation and neutrophil extracellular traps (NETs) play important roles in thrombosis, however, their roles in ITP itself, or in TPO-RA-treatment, have not yet been fully explored. We aimed to investigate whether endothelial cell activation and NETs are involved in the hypercoagulable state of ITP, and whether TPO-RA-treatment enhances endothelial cell activation and NET formation. MATERIAL AND METHODS: We measured markers of endothelial cell activation including intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1) and thrombomodulin in 21 ITP patients, and E-selectin in 18 ITP patients. Markers of NET formation, citrullinated histone H3-DNA (H3Cit-DNA) and cell-free DNA (cfDNA), were measured in 15 ITP patients. All markers were measured before, and 2 and 6 weeks after initiation of TPO-RA-treatment in ITP patients, and in matched controls. RESULTS: Higher levels of ICAM-1, thrombomodulin, and H3Cit-DNA were found in ITP patients, both before and after TPO-RA-treatment, compared with controls. No differences were found for VCAM-1, E-selectin or cfDNA. TPO-RA-treatment did not further increase markers of endothelial cell activation or NET formation. CONCLUSIONS: This study showed that ITP patients have increased endothelial cell activation and NET formation, both of which may contribute to the intrinsic hypercoagulable state of ITP. TPO-RA-treatment, however, did not further increase endothelial cell activation or NET formation indicating that other drug-associated prothrombotic mechanisms are involved.

Plasma free tissue factor pathway inhibitor (TFPI) levels and TF-induced thrombin generation ex vivo in men with low testosterone levels.

Low testosterone levels in men have been associated with cardiovascular risk factors, some prothrombotic factors, and lately also an increased risk of both cardiovascular disease and all-cause mortality. Experimental studies have shown increased synthesis and release of tissue factor pathway inhibitor (TFPI) by physiological levels of testosterone in endothelial cells. Our hypothesis was that elderly men with low testosterone levels would have lower plasma levels of plasma free TFPI with subsequent increased thrombin generation. Elderly men with low (n = 37) and normal (n = 41) testosterone levels were recruited from a general population, and tissue factor (TF)-induced thrombin generation ex vivo and plasma free TFPI Ag were measured. Elderly men with low testosterone levels had lower plasma free TFPI Ag (10.9 +/- 2.3 ng/ml vs. 12.3 +/- 3.0 ng/ml, p = 0.027) and shorter initiation phase of TF-induced coagulation assessed by lag-time (5.1 +/- 1.0 min vs. 5.7 +/- 1.3, p = 0.039). The differences between groups remained significant and were strengthened after adjustment for waist circumference and other cardiovascular risk factors. Lag-time increased linearly across quartiles of plasma free TFPI Ag (p<0.001). Multiple regression analysis revealed that total and free testosterone were independent predictors of plasma free TFPI Ag. Our findings suggest that low testosterone levels in elderly men is associated with low plasma free TFPI Ag and subsequent shortened initiation phase of TF-induced coagulation.

Elevated levels of platelet microparticles in carotid atherosclerosis and during the postprandial state.

BACKGROUND: Platelet microparticles (PMPs) possess proatherogenic and procoagulant properties which may play a role in atherogenesis and subsequent thromboembolic complications. The present study was conducted to investigate the possible relationship between carotid atherosclerosis and plasma concentrations of PMPs, and elucidate if plasma levels of PMPs were affected by postprandial hypertriglyceridemia. METHODS AND RESULTS: Subjects with ultrasound-assessed carotid atherosclerotic plaques (echogenic; n=20 and echolucent; n=20), assessed by ultrasonography, and subjects without carotid plaques (n=20) were recruited from a population-based study and underwent a standard fat tolerance test. Subjects with carotid plaques had significantly higher levels of large PMPs than subjects without carotid atherosclerotic plaques (96.7+/-50.4 microg/l versus 56.1+/-34.9 microg/l), after adjustments for traditional cardiovascular risk factors and use cardiovascular drugs (p=0.021). Plasma PMPs were not associated with plaque echogenicity. Postprandial hypertriglyceridemia induced a similar increase in plasma PMPs within all groups. Significant correlations were found between an increase in plasma triglycerides and percent elevation in total PMPs (r=0.29, p<0.05) and large PMPs (r=0.34, p<0.01) in the postprandial phase. CONCLUSIONS: Individuals with echogenic and echolucent carotid atherosclerotic plaques have statistically significant elevation of large plasma PMPs compared to age/sex-matched normal controls. Postprandial hypertriglyceridemia induces a significant, similar increase in plasma PMPs in individuals with and without carotid atherosclerotic plaques which could be of pathophysiological importance in atherogenesis.

Quality of Warfarin Therapy and Quality of Life are Improved by Self-Management for Two Years.

BACKGROUND: Studies from several countries show that self-management of vitamin K antagonist (e.g., warfarin) therapy reduce the risk of complications compared with conventional management. OBJECTIVES: The aim of this study was to investigate the quality of warfarin management when patients were transferred from conventional management to self-management in Norway. In addition, quality of life (QoL) before and after 2 years of warfarin self-management was investigated. MATERIALS AND METHODS: The study was longitudinal with a retrospective and prospective design where 126 patients on conventional management of long-term warfarin therapy underwent a 21-week training program of warfarin self-management followed by 2 years of self-management. The outcomes of the study were time in therapeutic range (TTR), the variance of international normalized ratio (INR) values, extreme INR values (INR ≤ 1.5 and ≥ 5), complications, and QoL, comparing the 2-year period of the conventional management with the 2-year period with the self-management. RESULTS: The median TTR was higher during self-management compared with conventional management (78.1% vs. 65.9%, respectively, p < 0.001). In addition, self-management resulted in lower INR variance (0.22 vs. 0.33, p < 0.001), reduced percentage of extreme INR values (1.8% vs. 5.3%, p < 0.001), less complications (0% vs. 5.6%), and improved QoL (p < 0.001) compared with conventional management. CONCLUSION: We used five different measures and found improved quality of warfarin self-management 2 years after patients were transferred from the conventional management.

D-Dimer Measured at Diagnosis of Venous Thromboembolism is Associated with Risk of Major Bleeding.

Identification of patients at risk of major bleeding is pivotal for optimal management of anticoagulant therapy in venous thromboembolism (VTE). Studies have suggested that D-dimer may predict major bleeding during anticoagulation; however, this is scarcely investigated in VTE patients. We aimed to investigate the role of D-dimer, measured at VTE diagnosis, as a predictive biomarker of major bleeding. The study population comprised 555 patients with a first community-acquired VTE (1994-2016), who were identified among participants from the Tromsø study. Major bleeding events were recorded during the first year after VTE and defined according to the criteria of the International Society on Thrombosis and Haemostasis. Cox-regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for age, sex, and duration of anticoagulant therapy. In total, 29 patients experienced major bleeding (incidence rate: 5.7/100 person-years, 95% CI: 4.0-8.2). The major bleeding risk was highest during the first 3 months, especially in patients with D-dimer ≥8.3 µg/mL (upper 20th percentile), with 28.8 major bleedings/100 person-years (95% CI: 13.7-60.4). Patients with D-dimer ≥8.3 µg/mL had a 2.6-fold (95% CI: 1.1-6.6) higher risk of major bleeding than patients with D-dimer ≤2.3 µg/mL (lower 40th percentile). Major bleeding risk according to D-dimer ≥8.3 versus ≤2.3 µg/mL was particularly pronounced among those with deep vein thrombosis (HR: 4.6, 95% CI: 1.3-16.2) and provoked events (HR: 4.2, 95% CI: 1.0-16.8). In conclusion, our results suggest that D-dimer measured at diagnosis may serve as a predictive biomarker of major bleeding after VTE, especially within the initial 3 months.

Heparin induces mobilization of osteoprotegerin into the circulation.

Heparin treatment may induce osteoporosis by an unknown mechanism. Osteoprotegerin (OPG), a glycoprotein with a heparin-binding site, is a decoy receptor for RANKL which is responsible for osteoclast development. The objective was to investigate the effect of unfractionated heparin (UFH) and lowmolecular-weight heparin (LMWH; dalteparin) on plasma levels of OPG. Twenty-two male students were allocated to the following treatment regimens; A) one bolus of 5,000 IU UFH iv followed by infusion of 450 IU/kg/24 h for 72 hours (n = 7), B) sc administration of LMWH (200 IU/kg) once daily for 72 hours (n = 8), C) sc administration of 100 IU/kg LMWH once (n = 8), D) sc administration of 250 IU/kg UFH once (n = 7), E) control infusion of saline for 12 hours (n = 7). UFH boluses of 5,000 IU were given 4 and 24 hours after cessation of regimens A and B. Bolus injection of UFH iv caused a prompt increase in plasma OPG from 0.68 ng/ml (SD = 0.09) to 1.13 ng/ml (SD = 0.30) (p = 0.003) which declined during the continuous UFH infusion and reached baseline values after 8 hours (regime A). Similar increases in plasma OPG was obtained by repeated UFH boluses after cessation of treatment. Subcutaneous administration of LMWH (200 IU/kg) caused a modest, but significant (p = 0.002) increase in plasma OPG similar to the mobilization by 250 IU/kg UFH sc, but the LMWH treatment caused a three-fold higher anti-Xa activity (p < 0.001). We conclude that UFH causes a more pronounced vascular mobilization of OPG than LMWH, indicating that UFH has a higher affinity for OPG than LMWH.

Associations between serum levels of calcium, parathyroid hormone and future risk of venous thromboembolism: the Tromsø study.

OBJECTIVE: The relationship between serum levels of calcium, parathyroid hormone (PTH) and risk of venous thromboembolism (VTE) has not been addressed in population-based cohorts. We investigated the associations between serum levels of calcium and PTH, with future risk of VTE in a general adult population. DESIGN: Population-based cohort. METHODS: A total of 27 712 subjects (25-87 years) who participated in Tromsø 4 (1994-1995) and Tromsø 5 (2001-2002) surveys were included in the study, and total calcium and PTH were measured in 27 685 and 8547 subjects respectively. Incident VTE was recorded through December 31, 2012. Cox-regression models with calcium and PTH as time-varying exposures were used to calculate hazard ratios (HR) of VTE by quartiles of calcium and PTH. Quartiles of calcium and PTH were also combined to assess the effect of discordants of both PTH and calcium (e.g. highest and lowest quartiles of both calcium and PTH) on VTE risk using the middle two quartiles as reference. RESULTS: There were 712 VTEs during 15.0 years of median follow-up. Serum levels of calcium and PTH were not associated with risk of VTE. However, subjects with discordant high serum levels of both calcium and PTH (calcium ≥2.45 mmol/L and PTH ≥4.0 pmol/L) had increased risk of VTE compared to those in subjects with normal calcium and PTH (multivariable HR: 1.78, 95% CI: 1.12-2.84). CONCLUSIONS: Serum levels of calcium and PTH separately were not associated with future risk of VTE, but subjects with high levels of both calcium and PTH had increased risk of VTE compared to those in subjects with normal levels.

Serum osteoprotegerin and renal function in the general population: the Tromsø Study.

BACKGROUND: Serum osteoprotegerin (OPG) is elevated in patients with chronic kidney disease (CKD) and increases with decreasing renal function. However, there are limited data regarding the association between OPG and renal function in the general population. The aim of the present study was to explore the relation between serum OPG and renal function in subjects recruited from the general population. METHODS: We conducted a cross-sectional study with 6689 participants recruited from the general population in Tromsø, Norway. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equations. OPG was modelled both as a continuous and categorical variable. General linear models and linear regression with adjustment for possible confounders were used to study the association between OPG and eGFR. Analyses were stratified by the median age, as serum OPG and age displayed a significant interaction on eGFR. RESULTS: In participants ≤62.2 years with normal renal function (eGFR ≥90 mL/min/1.73 m2) eGFR increased by 0.35 mL/min/1.73 m2 (95% CI 0.13-0.56) per 1 standard deviation (SD) increase in serum OPG after multiple adjustment. In participants older than the median age with impaired renal function (eGFR <90 mL/min/1.73 m2), eGFR decreased by 1.54 (95% CI -2.06 to -1.01) per 1 SD increase in serum OPG. CONCLUSIONS: OPG was associated with an increased eGFR in younger subjects with normal renal function and with a decreased eGFR in older subjects with reduced renal function. Our findings imply that the association between OPG and eGFR varies with age and renal function.