B blood group: A strong risk factor for venous thromboembolism recurrence Delphine Baudouy, Pamela Moceri, Olivier Chiche, Priscille Bouvier, Elie-Dan Schouver, Pierre Cerboni, Pierre Gibelin, Emile Ferrari PII: DOI: Reference:
S0049-3848(15)00227-3 doi: 10.1016/j.thromres.2015.05.002 TR 5949
To appear in:
Thrombosis Research
Received date: Revised date: Accepted date:
12 December 2014 23 March 2015 4 May 2015
Please cite this article as: Baudouy Delphine, Moceri Pamela, Chiche Olivier, Bouvier Priscille, Schouver Elie-Dan, Cerboni Pierre, Gibelin Pierre, Ferrari Emile, B blood group: A strong risk factor for venous thromboembolism recurrence, Thrombosis Research (2015), doi: 10.1016/j.thromres.2015.05.002
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT B blood group: a strong risk factor for venous thromboembolism
SC RI
PT
recurrence
Delphine Baudouy, MD*; Pamela Moceri, MD*; Olivier Chiche, MD*; Priscille Bouvier, MD*; Elie-Dan Schouver, MD*; Pierre Cerboni, MD*; Pierre Gibelin, MD, PhD*; Emile
NU
Ferrari, MD*.
MA
* Cardiology Department, Pasteur University Hospital, CHU de Nice, France
ED
Running head: Blood-group and thrombosis
PT
Total word count : 2744 (excluding abstract and references)
CE
Corresponding Author: Dr Pamela Moceri Cardiology Department, Hôpital Pasteur, CHU de Nice
AC
30 Voie Romaine, CS 51069 06001 Nice Cedex 1, France
Phone number +33 492037734 / Fax number +33 492037872 E-mail: [email protected]
Conflicts of interest: none Acknowledgement of grant support: No source of funding
1
ACCEPTED MANUSCRIPT ABSTRACT Background: Non-O blood group patients are at higher risk of first episode of venous
PT
thromboembolism (VTE). However, only little is known about the risk of recurrence according to the blood group. In this study, we aimed to determine the impact of ABO blood
SC RI
group on VTE recurrence.
Methods: We prospectively recruited 106 consecutive patients with a first documented episode of pulmonary embolism (PE). Patients were followed at least 12 months after
NU
anticoagulation discontinuation. The main endpoint was recurrence of symptomatic VTE.
MA
Results: Data from 100 patients were analyzed. Median follow-up was 28 months [24-34.8]. PE was unprovoked in 48 patients. Mean anticoagulation duration was 5.3 ± 2.2 months. The
ED
rate of VTE recurrence was 12.7 per 100 patient-years (30 recurrences). B blood group patients had a 2.7-fold increased risk of VTE recurrence (95%CI 1.1-6.2, p=0.03). On
PT
multivariate analysis, B blood group was the strongest independent predictor of VTE recurrence (Hazard Ratio (HR) 2.6, 95%CI 1.1-6.1, p=0.04). In contrast, A and AB blood
CE
groups were not associated with VTE recurrence. VTE recurrences were less frequent in O
AC
blood group compared to non-O patients (HR 0.5, 95%CI 0.2-1.1, p=0.09). O blood group women had a 5-fold decreased risk of VTE recurrence (HR 0.2, 95%CI 0.1-0.8, p=0.01). Conclusions: Non-O blood groups, beyond being involved in the occurrence of a first VTE event, also contribute to VTE recurrence. B blood group is strongly associated with VTE recurrence, thus high-risk B blood group patients could benefit from long-term anticoagulation therapy after a first VTE event.
Keywords: ABO Blood-Group System, Pulmonary embolism, Venous Thromboembolism.
2
ACCEPTED MANUSCRIPT INTRODUCTION Venous thromboembolism (VTE) is a common disease influenced by multiple genetic
PT
and environmental risk factors.[1-4] The risk of VTE recurrence is a major concern in daily practice.[5] An unprovoked first thromboembolic event, male gender and cancer are well-
SC RI
known risk factors for VTE recurrence.[6-9] Residual venous obstruction and D-dimer elevation after anticoagulation therapy discontinuation might also increase the recurrence of VTE.[10,11] Despite being known as a risk factor of first VTE event, the majority of
NU
thrombophilia factors are not recognized as a recurrence risk factor.[12] In parallel, while
MA
ABO phenotype is recognized as a first VTE event risk factor, only little is known about its contribution in VTE recurrence, particularly after a first episode of pulmonary embolism (PE).[13-15]
ED
In this study, we aimed to investigate the effect of each ABO blood group on VTE
AC
CE
PT
recurrence after a first episode of PE.
3
ACCEPTED MANUSCRIPT METHODS Study design
PT
We performed a prospective longitudinal cohort study in the University Hospital of Nice (France). We included consecutive patients presenting with a first documented episode
SC RI
of PE, with or without clinical manifestation of deep vein thrombosis (DVT) between July 2008 and July 2010. Indices PE were confirmed in all patients with a computed tomography pulmonary angiogram. VTE recurrences were also confirmed with a computed tomography
NU
pulmonary angiogram for PE and with venous Doppler ultrasound for DVT. Anticoagulation
MA
therapy duration was decided according to guidelines.[16] The diagnosis of VTE recurrence (DVT or PE) required the identification of a thrombus in a new localization, or in the same localization if proof of its disappearance was provided in the meantime. Patients were
ED
followed on a regular basis, every 3 to 6 months and clinical events were prospectively
PT
collected. The main outcome in this study was the recurrence of any VTE event. The main endpoint was the occurrence of an objectively proven symptomatic recurrence of VTE during
CE
the follow-up after anticoagulation therapy discontinuation. VTE recurrence status was
AC
determined at the end of the follow-up period, in September 2011. We excluded patients who required long-term anticoagulation therapy for reasons other than VTE and patients lost to follow-up in whom the VTE recurrence status was unknown in September 2011. A minimum follow-up of 12 months after anticoagulation discontinuation was required to sort out patients according to their VTE recurrence status. After patients provided written informed consent, data were collected, including demographic characteristics, known risk factors for VTE, clinical and biological characteristics of PE at the time of index event, ongoing medications and imaging reports confirming the index VTE event. According to the guidelines,[17] patients were tested for thrombophilia when indicated. In particular, we discussed screening if moderate or minor
4
ACCEPTED MANUSCRIPT triggering circumstances were found and in patients younger than 40 years old or with a familial history of VTE. Patients classified in the cancer group were either treated with an
PT
active anticancer therapy, or were in a follow-up period too short to consider complete recovery (without any specific therapy).
SC RI
ABO phenotype was determined from the French Blood Establishment database. We conducted our study in compliance with the ethical principles of the declaration of Helsinki. Approval by the local ethic committee was obtained for this observational study and
MA
NU
informed consent was obtained from each patient (CNIL registration number: 1770593).
Statistical analysis
Statistical analyses were performed using MedCalc (MedCalc Software, version
ED
12.7.3.0, Mariakerke, Belgium). Data are presented as mean ± SD for normally distributed
PT
data or median and interquartile range for skewed data. Chi-squared test was used for
comparisons.
CE
comparison of qualitative data. Mann & Whitney and Student’s t-tests were used for other
AC
The main outcome was objectively proven symptomatic recurrent VTE. Date of admission for the first VTE event was used to determine the beginning of the follow-up period. Follow-up ended with either death, VTE recurrence or at the end of the study. Patients who died of VTE recurrence were included in the recurrent group. We used the Kaplan-Meier method to estimate the risk of recurrent VTE after the index PE. A second or third recurrent event after the index PE was not included in the cumulative incidence analyses, patients were censored after their first event. The relation between baseline patient’s characteristics and recurrence of VTE was assessed with the use of univariate and multivariate Cox proportional hazard regression analysis. Variables identified by the univariate analysis as potential risk factors and achieving a significance level of p
S0049-3848(15)00227-3 doi: 10.1016/j.thromres.2015.05.002 TR 5949
To appear in:
Thrombosis Research
Received date: Revised date: Accepted date:
12 December 2014 23 March 2015 4 May 2015
Please cite this article as: Baudouy Delphine, Moceri Pamela, Chiche Olivier, Bouvier Priscille, Schouver Elie-Dan, Cerboni Pierre, Gibelin Pierre, Ferrari Emile, B blood group: A strong risk factor for venous thromboembolism recurrence, Thrombosis Research (2015), doi: 10.1016/j.thromres.2015.05.002
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT B blood group: a strong risk factor for venous thromboembolism
SC RI
PT
recurrence
Delphine Baudouy, MD*; Pamela Moceri, MD*; Olivier Chiche, MD*; Priscille Bouvier, MD*; Elie-Dan Schouver, MD*; Pierre Cerboni, MD*; Pierre Gibelin, MD, PhD*; Emile
NU
Ferrari, MD*.
MA
* Cardiology Department, Pasteur University Hospital, CHU de Nice, France
ED
Running head: Blood-group and thrombosis
PT
Total word count : 2744 (excluding abstract and references)
CE
Corresponding Author: Dr Pamela Moceri Cardiology Department, Hôpital Pasteur, CHU de Nice
AC
30 Voie Romaine, CS 51069 06001 Nice Cedex 1, France
Phone number +33 492037734 / Fax number +33 492037872 E-mail: [email protected]
Conflicts of interest: none Acknowledgement of grant support: No source of funding
1
ACCEPTED MANUSCRIPT ABSTRACT Background: Non-O blood group patients are at higher risk of first episode of venous
PT
thromboembolism (VTE). However, only little is known about the risk of recurrence according to the blood group. In this study, we aimed to determine the impact of ABO blood
SC RI
group on VTE recurrence.
Methods: We prospectively recruited 106 consecutive patients with a first documented episode of pulmonary embolism (PE). Patients were followed at least 12 months after
NU
anticoagulation discontinuation. The main endpoint was recurrence of symptomatic VTE.
MA
Results: Data from 100 patients were analyzed. Median follow-up was 28 months [24-34.8]. PE was unprovoked in 48 patients. Mean anticoagulation duration was 5.3 ± 2.2 months. The
ED
rate of VTE recurrence was 12.7 per 100 patient-years (30 recurrences). B blood group patients had a 2.7-fold increased risk of VTE recurrence (95%CI 1.1-6.2, p=0.03). On
PT
multivariate analysis, B blood group was the strongest independent predictor of VTE recurrence (Hazard Ratio (HR) 2.6, 95%CI 1.1-6.1, p=0.04). In contrast, A and AB blood
CE
groups were not associated with VTE recurrence. VTE recurrences were less frequent in O
AC
blood group compared to non-O patients (HR 0.5, 95%CI 0.2-1.1, p=0.09). O blood group women had a 5-fold decreased risk of VTE recurrence (HR 0.2, 95%CI 0.1-0.8, p=0.01). Conclusions: Non-O blood groups, beyond being involved in the occurrence of a first VTE event, also contribute to VTE recurrence. B blood group is strongly associated with VTE recurrence, thus high-risk B blood group patients could benefit from long-term anticoagulation therapy after a first VTE event.
Keywords: ABO Blood-Group System, Pulmonary embolism, Venous Thromboembolism.
2
ACCEPTED MANUSCRIPT INTRODUCTION Venous thromboembolism (VTE) is a common disease influenced by multiple genetic
PT
and environmental risk factors.[1-4] The risk of VTE recurrence is a major concern in daily practice.[5] An unprovoked first thromboembolic event, male gender and cancer are well-
SC RI
known risk factors for VTE recurrence.[6-9] Residual venous obstruction and D-dimer elevation after anticoagulation therapy discontinuation might also increase the recurrence of VTE.[10,11] Despite being known as a risk factor of first VTE event, the majority of
NU
thrombophilia factors are not recognized as a recurrence risk factor.[12] In parallel, while
MA
ABO phenotype is recognized as a first VTE event risk factor, only little is known about its contribution in VTE recurrence, particularly after a first episode of pulmonary embolism (PE).[13-15]
ED
In this study, we aimed to investigate the effect of each ABO blood group on VTE
AC
CE
PT
recurrence after a first episode of PE.
3
ACCEPTED MANUSCRIPT METHODS Study design
PT
We performed a prospective longitudinal cohort study in the University Hospital of Nice (France). We included consecutive patients presenting with a first documented episode
SC RI
of PE, with or without clinical manifestation of deep vein thrombosis (DVT) between July 2008 and July 2010. Indices PE were confirmed in all patients with a computed tomography pulmonary angiogram. VTE recurrences were also confirmed with a computed tomography
NU
pulmonary angiogram for PE and with venous Doppler ultrasound for DVT. Anticoagulation
MA
therapy duration was decided according to guidelines.[16] The diagnosis of VTE recurrence (DVT or PE) required the identification of a thrombus in a new localization, or in the same localization if proof of its disappearance was provided in the meantime. Patients were
ED
followed on a regular basis, every 3 to 6 months and clinical events were prospectively
PT
collected. The main outcome in this study was the recurrence of any VTE event. The main endpoint was the occurrence of an objectively proven symptomatic recurrence of VTE during
CE
the follow-up after anticoagulation therapy discontinuation. VTE recurrence status was
AC
determined at the end of the follow-up period, in September 2011. We excluded patients who required long-term anticoagulation therapy for reasons other than VTE and patients lost to follow-up in whom the VTE recurrence status was unknown in September 2011. A minimum follow-up of 12 months after anticoagulation discontinuation was required to sort out patients according to their VTE recurrence status. After patients provided written informed consent, data were collected, including demographic characteristics, known risk factors for VTE, clinical and biological characteristics of PE at the time of index event, ongoing medications and imaging reports confirming the index VTE event. According to the guidelines,[17] patients were tested for thrombophilia when indicated. In particular, we discussed screening if moderate or minor
4
ACCEPTED MANUSCRIPT triggering circumstances were found and in patients younger than 40 years old or with a familial history of VTE. Patients classified in the cancer group were either treated with an
PT
active anticancer therapy, or were in a follow-up period too short to consider complete recovery (without any specific therapy).
SC RI
ABO phenotype was determined from the French Blood Establishment database. We conducted our study in compliance with the ethical principles of the declaration of Helsinki. Approval by the local ethic committee was obtained for this observational study and
MA
NU
informed consent was obtained from each patient (CNIL registration number: 1770593).
Statistical analysis
Statistical analyses were performed using MedCalc (MedCalc Software, version
ED
12.7.3.0, Mariakerke, Belgium). Data are presented as mean ± SD for normally distributed
PT
data or median and interquartile range for skewed data. Chi-squared test was used for
comparisons.
CE
comparison of qualitative data. Mann & Whitney and Student’s t-tests were used for other
AC
The main outcome was objectively proven symptomatic recurrent VTE. Date of admission for the first VTE event was used to determine the beginning of the follow-up period. Follow-up ended with either death, VTE recurrence or at the end of the study. Patients who died of VTE recurrence were included in the recurrent group. We used the Kaplan-Meier method to estimate the risk of recurrent VTE after the index PE. A second or third recurrent event after the index PE was not included in the cumulative incidence analyses, patients were censored after their first event. The relation between baseline patient’s characteristics and recurrence of VTE was assessed with the use of univariate and multivariate Cox proportional hazard regression analysis. Variables identified by the univariate analysis as potential risk factors and achieving a significance level of p
