Plasma hemostasis in patients with coronavirus infection caused by SARS-CoV-2.

2020 ◽  
Author(s):  
О.Ю. Матвиенко ◽  
Н.Е. Корсакова ◽  
А.А. Лернер ◽  
Т.Н. Шведова ◽  
Л.П. Папаян
Keyword(s):  
Von Willebrand Factor ◽  
Protein C ◽  
Thrombin Generation ◽  
Disease Course ◽  
Anticoagulant Treatment ◽  
Coronavirus Infection ◽  
High Level ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
D Dimer

Введение. Пандемия COVID-19 стала глобальной проблемой мирового сообщества. Основным патогенетическим механизмом заболевания представляется развитие иммунного тромбоза, результатом которого являются нарушение микроциркуляции, артериальные и венозные тромбозы, респираторный дистресс-синдром, полиорганная недостаточность. Изучение механизмов развития гиперкоагуляционных изменений у пациентов с COVID-19 вызывает огромный интерес и позволит улучшить исходы заболевания. Цель исследования: оценка состояния плазменного звена гемостаза у пациентов с коронавирусной инфекцией в остром периоде заболевания. Материалы и методы. Обследованы 59 пациентов с тяжелым и среднетяжелым течением коронавирусной инфекции, получавшие антикоагулянтную профилактику. Определяли следующие параметры системы гемостаза: активированное парциальное тромбопластиновое время, протромбиновый тест, концентрацию фибриногена, активность фактора VIII, антитромбина, протеинов C и S, содержание D-димера, фактора Виллебранда и гомоцистеина, а также генерацию тромбина методом калиброванной автоматизированной тромбинографии. Результаты. У пациентов с COVID-19 по сравнению со здоровыми лицами было выявлено увеличение концентрации фибриногена, уровня фактора Виллебранда, гомоцистеина и D-димера, значительное снижение уровня свободного протеина S, усиление генерации тромбина, снижение чувствительности к тромбомодулину. Была выявлена прямая корреляция между тяжестью состояния пациентов и уровнями фактора Виллебранда и гомоцистеина. Заключение. Несмотря на проводимую антикоагулянтную терапию, у пациентов с коронавирусной инфекцией отмечены выраженные признаки активации системы гемостаза, которые характеризуются как повышением отдельных маркеров гиперкоагуляции, так и значимым усилением генерации тромбина на фоне угнетения работы системы протеина С. Повышенный уровень гомоцистеина плазмы крови является дополнительным фактором риска, ухудшающим течение заболевания. Значительное повышение уровня фактора Виллебранда может быть неблагоприятным прогностическим признаком течения заболевания. Background. The COVID-19 pandemic is a global health care challenge. The concept of immunothrombosis has established as a central pathogenic factor leading to thrombosis complications, respiratory insufficiency and multiple organ failure. The study of hypercoagulability mechanisms in patients with COVID-19 may be useful for improving disease’s outcomes. Objectives: to evaluate plasma hemostasis in patients with coronavirus infection at the acute period of the disease. Patients / Methods. We examined 59 patients with severe and moderate coronavirus infection who received anticoagulant treatment. The following hemostasis parameters were determined: activated partial thromboplastin time, prothrombin test, fibrinogen, factor VIII, von Willebrand factor, D-dimer, protein C and S, homocysteine, and thrombin generation. Results. Fibrinogen, von Willebrand factor, D-dimer, homocysteine, and thrombin generation were higher in patients with COVID-19 than in healthy people, protein S was reduced. The direct correlation between the severity of the patient’s condition and the levels of von Willebrand factor and homocysteine was found. Conclusions. Patients with COVID-19 had significant hypercoagulability despite of the anticoagulant treatment. Signs of hemostasis activation are characterized by both increasing of hypercoagulation individual markers and thrombin generation with inhibition of protein C system. High level of plasma homocysteine is an additional risk factor that worsens the disease course. High level of von Willebrand factor may be an unfavorable prognostic sign of the disease course.

scholarly journals Post-Covid-19 Hemostatic Characteristics of Convalescent Patients: The Bergamo Experience

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1054-1054
Author(s):  
Carmen Julia J Tartari ◽  
Giulia Milani ◽  
Francesco Salvetti ◽  
Marina Marchetti ◽  
Laura Russo ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Protein C ◽  
Severe Disease ◽  
Protein S ◽  
Demographic Characteristics ◽  
Increased Risk ◽  
Antibody Levels ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
D Dimer

Abstract Introduction: Severe COVID-19 patients present with a hypercoagulable state, complement activation and endothelial perturbation, which result from an excessive inflammatory response. Thromboinflammation is one important mechanism underlying the COVID-19-associated coagulopathy and the increased risk of thrombosis. Bergamo city is one of the first and most affected area by SARS-CoV-2 infection in the world. For this reason, since the beginning we were actively involved in recruiting convalescent COVID-19 patients, in a program of selection of candidates for convalescent plasma donation. In a large cohort of convalescent COVID-19 patients, we aimed to characterize markers of coagulation activation and endothelial perturbation, in order to explore whether the COVID-19-related hemostasis activation might persist afterwards and evaluate its possible association with the degree of severity of the previous infection, and/or with demographic characteristics, or anti-SARS-CoV-2 antibody levels. Methods: In 392 convalescent COVID-19 patients (216M/176F, median age: 46 years) plasma levels of fibrinogen, protein C, protein S, factor V, factor VIII, factor XIII, D-dimer, von Willebrand factor (vWF), prothrombin fragment F1+2 were measured at the recruitment, i.e. 1-5 months from recovery. Samples were tested for the anti-SARS-CoV-2 antibodies, including anti-S IgG (Anti-S Ab) and anti-N IgG (Anti-N Ab) antibodies at enrollment and at each scheduled subsequent visits. Results: Levels of fibrinogen, D-dimer, von Willebrand factor, protein S and protein C were significantly higher (p<0.05) in patients who were hospitalized for severe COVID-19 as compared to patients who were treated at home. There was no correlation between levels of coagulation biomarkers and days from end of symptoms. Male gender, age > 40 years, and severe form of COVID-19 were identified as independent predictors of high levels of both anti-S and anti-N Ab (p<0.001). Among hemostatic biomarkers, fibrinogen (p<0.01) and vWF (p<0.05) independently predict high levels of anti-S Ab. In particular, vWF levels positively correlated with anti-S Ab levels (vWF-antigen r=0.188; vWF-activity r=0.241 and vWF-RiCof r=0.223, p<0.01). Evaluation of anti-SARS-CoV2 antibody levels at different time points during follow up revealed that 30% of patients displayed high levels of anti-S Ab until more than 8 months from the end of symptoms. Conclusions: Convalescent patients, with a history of severe COVID-19 had a persistent endothelium activation, despite of disease clinical remission even after 9 months from end of symptoms. Furthermore, fibrinogen and vWF levels predicted high levels of Anti-S Ab. Among demographic characteristics, gender, age and severe disease can be predictors of increased antibody response. These findings suggest that inflammation, coagulation and endothelial dysfunction may persist after recovery and may explain the findings of persistent clinical symptoms reported in these patients after healing from COVID-19. Disclosures Falanga: Bayer: Honoraria; Leo Pharma: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria.

Effects of Pentasaccharide (Fondaparinux) and Direct Thrombin Inhibitors on Coagulation Testing

2004 ◽  
Vol 128 (10) ◽  
pp. 1142-1145
Author(s):  
Robert C. Gosselin ◽  
Jeffrey H. King ◽  
Kim A. Janatpur ◽  
William H. Dager ◽  
Edward C. Larkin ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Protein C ◽  
Protein S ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Coagulation Tests ◽  
Von Willebrand ◽  
The Impact ◽  
Willebrand Factor ◽  
D Dimer

Abstract Context.—Direct thrombin inhibitors (DTIs) and fondaparinux represent a new class of anticoagulants. The effects of DTIs on activated partial thromboplastin time and prothrombin time measurements have been reported previously, but there are limited data on the impact of these anticoagulants on other coagulation tests. Objective.—To determine the effects of fondaparinux and 3 DTIs (argatroban, bivalirudin, and lepirudin) on miscellaneous coagulation tests. Design.—Bivalirudin, lepirudin, argatroban, and fondaparinux were added to pooled normal plasma and tested for fibrinogen, antithrombin (thrombin and Xa substrate methods), plasminogen, protein C (clot and chromogenic methods), protein S, von Willebrand factor, D-dimer, lupus anticoagulant testing (dilute Russell viper venom test [DRVVT] with ratio), and factors II, IX, and X activities. Results.—We found no drug interference on antithrombin, plasminogen, chromogenic protein C, von Willebrand factor, or D-dimer results. All DTIs falsely decreased fibrinogen values, while falsely increasing protein C and protein S levels. All DTIs prolonged the DRVVT, and only argatroban yielded DRVVT ratios less than 1.2. Lepirudin demonstrated no effect on factor II activity, and only argatroban demonstrated decreased factor X activity. All DTI samples demonstrated a linear, dose-dependent, false decrease of factor IX activity. Conclusions.—Using in vitro methods, we demonstrated DTI effects on numerous clot-based assays, but we found no interference with latex agglutination, chromogenic, or platelet aggregation methods. Fondaparinux only affected measurement of protein S activity. Caution must be used when interpreting coagulation test results on patients receiving these drugs.

Pro-coagulant imbalance in patients with community acquired pneumonia assessed on admission and one month after hospital discharge

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Armando Tripodi ◽  
Simona C. Rossi ◽  
Marigrazia Clerici ◽  
Giuliana Merati ◽  
Erica Scalambrino ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cardiovascular Diseases ◽  
Hospital Discharge ◽  
Von Willebrand Factor ◽  
Healthy Subjects ◽  
Protein C ◽  
Thrombin Generation ◽  
Community Acquired Pneumonia ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Objectives Patients hospitalized because of community-acquired-pneumonia (CAP) are at risk of cardiovascular diseases. Although plasma procoagulant imbalance play a role, mechanisms are not completely understood. We aimed to investigate whether there is a measurable state of procoagulant imbalance following inflammation determined by CAP. Methods We analyzed blood from 51 CAP patients at admission and 51 healthy-subjects (HS) for (i) pro and anticoagulants, (ii) thrombin generation (TG) with or without thrombomodulin (TM), which is the physiologic activator of the protein C anticoagulant pathway and(iii) by assessing the ratio between von Willebrand-factor (VWF) and its protease ADAMTS13. Thirty patients were re-analyzed one month after discharge when CAP was resolved. Results Median levels of TG parameters, including the endogenous thrombin potential (ETP), the ETP-TM-ratio (with/without TM), peak-thrombin and velocity index were higher in patients at baseline than HS. In particular, the median (IQR) ETP-TM-ratio in patients vs. HS was 0.88 (0.83–0.91) vs. 0.63(0.48–0.71), p<0.001. Factor (F)VIII, a potent procoagulant involved in TG was higher in patients at baseline than HS [195 U/dL (100–388) vs. 127(108–145)], p<0.001]. The ratio of VWF/ADAMTS13 was higher at baseline than HS. Cumulatively, the findings indicate a state of pro-coagulant imbalance, which (although reduced), remained high [i.e., ETP-TM-ratio, 0.80 (0.74–0.84); FVIII, 152 U/dL (122–190)] one month after discharge when the infection was resolved. Conclusions Patients with CAP possess a state of pro-coagulant imbalance, which remains substantially high, even when the infection is resolved. The findings suggest CAP patients as candidates for antithrombotic prophylaxis even after the resolution of infection. Clinical trials are warranted to assess the benefit/risk ratio of prophylaxis extension.

scholarly journals Comparative analysis of prothrombotic activity in patients with myocardial infarction with non-obstructive and obstructive atherosclerotic lesions of the coronary arteries

2021 ◽  
Vol 10 (Supplement_1) ◽  
Author(s):  
VV Ryabov ◽  
D Vorobyeva ◽  
YUG Lugacheva ◽  
IV Kulagina
Keyword(s):  
Myocardial Infarction ◽  
Coronary Arteries ◽  
Von Willebrand Factor ◽  
Protein C ◽  
Control Group ◽  
Moderate Correlation ◽  
Blood Tests ◽  
Group A ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The reported study was funded by RFBR, project number №19-315-90106 Aim To compare indicators of blood prothrombotic activity in patients with myocardial infarction with and without coronary arteries obstruction Material and methods. The study included 40 patients with AMI (19 patients in the main group and 21 patients in the control group). Three patients (15.7%) with acute myocarditis were excluded from the analysis. Hemostasiological and hematological blood tests were studied upon admission, on the 2nd, 4th, 7th days from hospitalization. Blood samples for protein C, antithrombin, von Willebrand factor (WF), plasminogen, homocysteine were performed on 4th ± 1 day from hospitalization. To determine the IgG / IgM antibodies to cardiolipin and β2-glycoprotein for the diagnosis of APS, the ORGENTEC Anti-β2-Glycoprotein I IgG / IgM ELISA enzyme immunoassay was used. Blood tests for lupus anticoagulant were performed using an ACL-Top 700 analyzer (Werfen) with HemosIL SynthASil dRVVT screen reagents / dRVVT confirm  and with a SCT screen / SCT confirm quartz activator. Results In patients with MINOCA a statistically higher level of homocysteine (p = 0.03) and a lower level of plasminogen (p = 0.007) are determined. Protein C, antithrombin, WF the presence of lupus anticoagulant, antibodies to cardiolipin and β2-glycoprotein no differences between the groups were detected, p &gt;0.05. MINOCA patients have a statistically higher platelet level on the 2nd and 4th day of AMI (p = 0.046 and p = 0.01 ) however the level of hemoglobin and hematocrit was statistically lower on the 4th day of AMI, (p = 0.008). In the main group, a moderate correlation was found between protein C and antithrombin (r = 0.65, p = 0.0001), antithrombin and von Willebrand factor (r = 0.54, p = 0.0001), between protein C and platelet level by 4th day (r = - 0.49, p = 0.04). In MINOCA patients a moderate negative correlation was found between homocysteine and plasminogen (r = -0.69, p = 0.002). In the control group, a high correlation was found between protein C and antithrombin (r = 0.96, p = 0.0001), a moderate correlation between protein C and plasminogen (r = 0.47, p = 0.03). In addition, a relationship was revealed between the presence of thrombosis according to ICAG data and the level of ejection fraction (r = 0.46, p = 0.04) in the control group, as well as between the presence of thrombosis and the level of fibrinogen upon admission (r = 0.55, p = 0.008). Conclusions Patients with MINOCA have a higher level of homocysteine and a lower level of plasminogen. For such indicators as protein C, antithrombin III, WF the presence of antibodies on the APS is not defined differences between groups. According to laboratory data patients with MINOCA showed higher levels of platelets but lower levels of hemoglobin and hematocrit in the early post-infarction period.

scholarly journals Quantification of von Willebrand factor and ADAMTS-13 after traumatic injury: a pilot study

2021 ◽  
Vol 6 (1) ◽  
pp. e000703
Author(s):  
Taleen A MacArthur ◽  
Julie Goswami ◽  
Laurie Moon Tasson ◽  
Alexander Tischer ◽  
Kent R Bailey ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Acute Phase ◽  
Von Willebrand Factor ◽  
Thrombin Generation ◽  
Trauma Patients ◽  
Phase Reaction ◽  
Time Points ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor

BackgroundVon Willebrand factor (VWF) is an acute phase reactant synthesized in the megakaryocytes and endothelial cells. VWF forms ultra-large multimers (ULVWF) which are cleaved by the metalloprotease ADAMTS-13, preventing spontaneous VWF–platelet interaction. After trauma, ULVWF is released into circulation as part of the acute phase reaction. We hypothesized that trauma patients would have increased levels of VWF and decreased levels of ADAMTS-13 and that these patients would have accelerated thrombin generation.MethodsWe assessed plasma concentrations of VWF antigen and ADAMTS-13 antigen, the Rapid Enzyme Assays for Autoimmune Diseases (REAADS) activity of VWF, which measure exposure of the platelet-binding A1 domain, and thrombin generation kinetics in 50 samples from 30 trauma patients and an additional 21 samples from volunteers. Samples were analyzed at 0 to 2 hours and at 6 hours from the time of injury. Data are presented as median (IQR) and Kruskal-Wallis test was performed between trauma patients and volunteers at both time points.ResultsREAADS activity was greater in trauma patients than volunteers both at 0 to 2 hours (190.0 (132.0–264.0) vs. 92.0 (71.0–114.0), p<0.002) and at 6 hours (167.5 (108.0–312.5.0) vs. 92.0 (71.0–114.0), p<0.001). ADAMTS-13 antigen levels were also decreased in trauma patients both at 0 to 2 hours (0.84 (0.51–0.94) vs. 1.00 (0.89–1.09), p=0.010) and at 6 hours (0.653 (0.531–0.821) vs. 1.00 (0.89–1.09), p<0.001). Trauma patients had accelerated thrombin generation kinetics, with greater peak height and shorter time to peak than healthy volunteers at both time points.DiscussionTrauma patients have increased exposure of the VWF A1 domain and decreased levels of ADAMTS-13 compared with healthy volunteers. This suggests that the VWF burst after trauma may exceed the proteolytic capacity of ADAMTS-13, allowing circulating ULVWF multimers to bind platelets, potentially contributing to trauma-induced coagulopathy.Level of evidenceProspective case cohort study.

Multi-Cellular Activation In Vivo by Endotoxin in Humans – Limited Protection by Adenosine Infusion

2000 ◽  
Vol 84 (09) ◽  
pp. 381-387 ◽  
Author(s):  
Nailin Li ◽  
Anne Soop ◽  
Alf Sollevi ◽  
Paul Hjemdahl
Keyword(s):  
Von Willebrand Factor ◽  
Thrombin Generation ◽  
Platelet Reactivity ◽  
Adenosine Infusion ◽  
Cellular Activation ◽  
Soluble P ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Secretion

SummaryThe influence of adenosine infusion (40 µg/kg/min for 4 h) on inflammatory and hemostatic parameters was investigated in healthy males without (n = 10) or with (n = 11) intravenous endotoxin injection (4 ng/kg). Without endotoxin, adenosine elevated circulating leukocytes and circulating platelet-leukocyte aggregates. Endotoxin activated platelets and leukocytes in vivo. Platelet activation was seen as slightly increased platelet P-selectin expression, decreased platelet counts, and elevated plasma soluble P-selectin (from 39.6 ± 3.4 to 68.9 ± 6.6 ng/ml; P <0.01). Leukocyte activation was evidenced by increased CD11b expression (from MFI of 0.54 ± 0.02 to 2.21 ± 0.17; P <0.01) and plasma elastase levels (from 25.3 ± 2.5 to 169.3 ± 22.5 ng/ml; P <0.01). Endotoxin also enhanced platelet and leukocyte responsiveness to in vitro stimulation. Endotoxin induced von Willebrand factor secretion (from 92 ± 8 units to 265 ± 19 units at 4 h; P <0.001) and enhanced thrombin generation in vivo. Endotoxin induced leukocytosis and thus increased circulating platelet-leukocyte, mainly platelet-neutrophil, aggregates. Adenosine caused slight attenuation of platelet reactivity to agonist stimulation, enhanced the endotoxin-induced leukocytosis, and detained more platelet-leukocyte aggregates in circulation, but did not attenuate endotoxin-induced neutrophil elastase secretion, von Willebrand factor secretion, or thrombin generation. Thus, endotoxemia induces multi-cellular activation in vivo. Adenosine inhibits leukocyte adhesion and extravasation, and mildly attenuates platelet responsiveness and soluble P-selectin release. Adenosine has the potential of becoming a therapeutic antiinflammatory drug, but an optimal treatment strategy needs to be developed.

scholarly journals von Willebrand factor binding to myosin assists in coagulation

2020 ◽  
Vol 4 (1) ◽  
pp. 174-180 ◽  
Author(s):  
Veronica H. Flood ◽  
Tricia L. Slobodianuk ◽  
Daniel Keesler ◽  
Hannah K. Lohmeier ◽  
Scot Fahs ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Thrombin Generation ◽  
Platelet Rich Plasma ◽  
Factor V ◽  
Factor X ◽  
Skeletal Muscle Myosin ◽  
Myosin Binding ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract von Willebrand factor (VWF) binds to platelets and collagen as a means of facilitating coagulation at sites of injury. Recent evidence has shown that myosin can serve as a surface for thrombin generation and binds to activated factor V and factor X. We studied whether VWF can also bind myosin as a means of bringing factor VIII (FVIII) to sites of clot formation. A myosin-binding assay was developed using skeletal muscle myosin to measure VWF binding, and plasma-derived and recombinant VWF containing molecular disruptions at key VWF sites were tested. Competition assays were performed using anti-VWF antibodies. FVIII binding to myosin was measured using a chromogenic FVIII substrate. Thrombin generation was measured using a fluorogenic substrate with and without myosin. Wild-type recombinant VWF and human plasma VWF from healthy controls bound myosin, whereas plasma lacking VWF exhibited no detectable myosin binding. Binding was multimer dependent and blocked by anti-VWF A1 domain antibodies or A1 domain VWF variants. The specific residues involved in myosin binding were similar, but not identical, to those required for collagen IV binding. FVIII did not bind myosin directly, but FVIII activity was detected when VWF and FVIII were bound to myosin. Myosin enhanced thrombin generation in platelet-poor plasma, although no difference was detected with the addition of myosin to platelet-rich plasma. Myosin may help to facilitate delivery of FVIII to sites of injury and indirectly accelerate thrombin generation by providing a surface for VWF binding in the setting of trauma and myosin exposure.

Associations of von Willebrand factor, fibrin D-dimer and tissue plasminogen activator with incident coronary heart disease: British Women's Heart and Health cohort study

2007 ◽  
Vol 14 (5) ◽  
pp. 638-645 ◽  
Author(s):  
Margaret May ◽  
Debbie A. Lawlor ◽  
Rita Patel ◽  
Ann Rumley ◽  
Gordon Lowe ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Von Willebrand Factor ◽  
Incident Coronary Heart Disease ◽  
Tissue Plasminogen ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
D Dimer

Background Associations of three markers of thrombotic tendency, von Willebrand factor, tissue plasminogen activator antigen and fibrin D-dimer, with coronary heart disease have been reported in meta-analyses. It is not known, however, whether findings are generalizable to older women. Design Prospective cohort of 3582 women aged 60-79 years randomly selected from 23 towns without evidence of cardiovascular disease at entry into the British Women's Heart and Health Study. Methods Women were followed for 4.7 years for incident coronary heart disease. Cox proportional hazard models were used to compare the hazard ratio of coronary heart disease per doubling for each thrombotic factor. Results In models adjusting for age and town only there was no association between von Willebrand factor or D-dimer and incidence of coronary heart disease, but there was a positive association of tissue plasminogen activator: coronary heart disease hazard ratio per doubling was 1.37 (95% confidence interval: 1.08-1.75). Adjustment for potential confounders (socio-economic position, smoking, lung function, physical activity, alcohol consumption, body mass index, waist-to-hip ratio) attenuated association to 1.20 (0.92-1.58). Further adjustment for risk factors that may be part of the same pathophysiological process linking tissue plasminogen activator to coronary heart disease (high density lipoprotein cholesterol, triglycerides, blood pressure, fasting glucose, insulin, C-reactive protein, fibrinogen) attenuated the hazard ratio to 1.05 (0.79-1.40). Conclusion In older women, tissue plasminogen activator was associated with incident coronary heart disease, but does not appear to be an independent risk factor for coronary heart disease as the association was attenuated by adjustment for confounding and other metabolic and vascular risk factors. Eur J Cardiovasc Prev Rehabil 14:638-645 © 2007 The European Society of Cardiology

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