Thrombosis Research 133 (2014) 322–326

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Regular Article

Apolipoprotein M and the risk of unprovoked recurrent venous thromboembolism Ashfaque A. Memon a,⁎, Jan Sundquist a,b, Bengt Zöller a, Xiao Wang a, Björn Dahlbäck c, Peter J. Svensson d, Kristina Sundquist a,b a

Center for Primary Health Care Research, Department of Clinical Sciences, Skåne University Hospital, Lund University, Sweden Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA, United States Department of Laboratory Medicine, Skåne University Hospital, Lund University, Sweden d Department of Coagulation Disorders, Skåne University Hospital, Lund University, Sweden b c

a r t i c l e

i n f o

Article history: Received 26 August 2013 Received in revised form 25 November 2013 Accepted 4 December 2013 Available online 10 December 2013 Keywords: Apolipoprotein M Recurrence Risk factors Venous thrombosis

a b s t r a c t Introduction: Apolipoprotein M (ApoM) protects against atherosclerosis; however, it is unknown whether it also protects against recurrent venous thromboembolism (VTE). Material and Methods: Patients in the Malmö Thrombophilia Study (MATS) were followed post-anticoagulant treatment until the diagnosis of recurrent VTE or the end of the study (mean follow-up 36 months). Among patients with a first episode of unprovoked VTE, we identified 43 patients (9.7%) with recurrent VTE during the follow-up period. Three age- and sex-matched control subjects without recurrent VTE were selected for each case (n = 129). Plasma levels of ApoM were quantified by a sandwich ELISA method. Results: Among all patients, the plasma levels (mean ± SD) of ApoM were not significantly different between patients with recurrent (0.70 ± 0.2) and non-recurrent VTE (0.74 ± 0.2), p = 0.2. However, after stratification of data according to gender, male patients with recurrent VTE showed significantly (p = 0.02) lower ApoM levels (0.63 ± 0.2) as compared to those with non-recurrent VTE (0.74 ± 0.2). No significant differences in ApoM levels were found between recurrent (0.8 ± 0.2) and non-recurrent VTE (0.75 ± 0.2) in female patients, p = 0.3. Cox-regression analysis showed that the risk of recurrent VTE was 0.98 (95% CI, 0.96-0.99) for each 0.01 μM increase in ApoM level in male patients (p = 0.042), and this risk remained unchanged after adjusting for inherited thrombophilia and body mass index (p = 0.027). ApoM levels were not associated with the risk of recurrent VTE in female patients. Conclusion: Our results show that levels of ApoM in recurrent VTE may differ according to gender and lower levels of ApoM may predict VTE recurrence in male patients. © 2013 Elsevier Ltd. All rights reserved.

Introduction Venous thromboembolism (VTE) is a common cardiovascular disease (CVD) that frequently recurs and is associated with significant numbers of deaths annually [1]. Multiple acquired factors (older age, malignancy, trauma, major surgery, immobilization, female hormone therapy, pregnancy) [2,3] and genetic factors (Factor V Leiden (rs6025) and prothrombin G20210A (rs1799963) mutations, protein C, protein S and antithrombin deficiencies) [4,5] have been identified as risk factors for VTE. However, there is an increased risk of recurrence in patients with no identifiable acquired risk factor associated with the first event (unprovoked recurrence), compared to patients with known risk factors (provoked) [6]. The cumulative risk of recurrent VTE after a first episode of deep vein thrombosis (DVT) has been shown to be about 17% after ⁎ Corresponding author at: Center for Primary Health Care Research, Wallenberg Laboratory, 6th floor, Inga Marie Nilsson’s gata 53, Skåne University Hospital, S-205 02 Malmö, Sweden. Tel.: +46 40331465; fax: +46 40391370. E-mail address: [email protected] (A.A. Memon). 0049-3848/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.thromres.2013.12.006

2 years of follow-up and 30% after 8 years [7]. Treatment with oral anticoagulants such as vitamin K antagonists prevents most episodes of recurrence, albeit at the cost of an increased risk of uncontrolled bleeding [8]. Therefore, thrombotic risk assessment is necessary before continuation of anticoagulant treatment in patients with high risk of recurrence and to limit the treatment duration in patients with a lower risk of recurrence. However, the risk of recurrent thrombosis after stopping treatment is not easily predicted, in spite of a number of identified risk factors, such as male sex, elevated D-dimer levels and residual thrombosis [9,10]. An association between VTE and risk factors for atherosclerotic vascular diseases is emerging and may help in identifying new risk factors for venous thrombosis [11]. Apolipoprotein M (ApoM), a member of the lipocalin protein family, is a 25 kDa plasma protein [12]. In circulation, ApoM is predominantly associated with high-density lipoprotein (HDL) [13]. ApoM is the carrier of the biologically active lipid mediator sphingosine-1-phospate (S1P) in HDL, which exerts endothelial protective functions [14]. Studies suggest a protective role for ApoM against arterial CVDs. For example, pre-clinical animal studies suggest an anti-

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atherosclerotic role for ApoM [15]. Lower levels of ApoM have been observed in patients with critical limb ischemia [16] and abdominal aortic aneurysms [17]. Lower level of HDL has been shown to be associated with lower risk of recurrent VTE [18]. However, to our knowledge the role of ApoM in VTE has not been investigated yet. In this study we analyzed and compared the level of ApoM in patients with recurrent and non-recurrent VTE from the Malmö Thrombophilia Study (MATS).

prothrombin G20210A mutation (rs1799963), or levels below the laboratory reference range of free protein S (women b0.5 kIE/L, men b 0.65 kIE/L), protein C (b 0.7 kIE/L) or antithrombin (b 0.82 kIE/L). All participants provided written informed consent and the study was approved by the ethics committee of Lund University.

Material and Methods

Non-fasting whole blood samples were collected between 14–90 days (mean ± SD, 32 ± 19.0) after anticoagulation withdrawal into citrate-treated tubes and were centrifuged at 2000 ×g for 15 min at 4 °C to collect plasma. The samples were then aliquoted and stored at −80 °C prior to analysis. ApoM levels were measured by a sandwich ELISA method, which has been described previously [20]. Briefly, 96well Costar plates (Corning, Inc., Lowell, MA, USA) were coated with a catching monoclonal ApoM antibody (mAb 58) and blocked with quenching buffer. The samples were diluted and incubated overnight. The bound ApoM was detected by using a biotinylated secondary ApoM antibody (mAb42) in combination with streptavidin-avidinhorseradish peroxidase and 1,2-phenylenediamine dihydrochloride (Dako, Glostrup, Denmark). The 490-nm absorbance was measured and compared with a plasma standard curve having known amounts of ApoM. DNA mutations for factors II and V were analyzed by TaqMan allele discrimination using gene-specific assays for these two factors (Applied Biosystems, Life Technologies Corporation, Carlsbad, CA, USA) [21].

Study Population Participants were selected from the Malmö Thrombophilia Study (MATS), a prospective population-based study conducted at Skåne University Hospital in Sweden [19] from March 1998 to December 2008 on 1465 consecutive patients diagnosed with VTE. Patients for whom complete information on recurrence was missing (n = 51), who had thrombotic events before inclusion (n = 25), who had recurrence during anticoagulant therapy (n = 281) or who gave samples during treatment, (n = 382) were excluded. Of the remaining 726 patients, those who had a recorded history of an acquired risk factor for VTE, such as surgical intervention, immobilization or cast therapy within the last month, malignancies diagnosed prior to or at diagnosis of the first VTE event, use of contraceptives pills, hormonal therapy, pregnancy and postpartum period (first 6 weeks after delivery) were excluded (n = 283). Among the remaining 443 patients (unprovoked VTE without any acquired risk factors at the time of inclusion), 43 (9.7%) suffered from recurrent VTE. Control samples were selected from the remaining patients at a ratio of 1:3 and were matched for age and sex. The primary end-point of the study was confirmed diagnosis of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) during the follow-up period. Patients were censored if they were free of DVT and/or PE throughout the follow-up period. The follow-up period (mean ± SD, 36 ± 25 months) was counted from the time of the blood sample collection (see below) until the diagnosis of recurrent VTE or the end of the study. Diagnosis of DVT and PE was objectively confirmed by phlebography, duplex ultrasonography, computed tomography (CT), lung scintigraphy or magnetic resonance imaging (MRI) [19]. All patients were initially treated with low molecular weight heparin (LMH) or unfractionated heparin (UFH) and then with warfarin as an oral anticoagulant (OAC) for 3–6 months. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared (kg/m2). Thrombophilia was defined as presence of the Factor V Leiden mutation (rs6025) or the

Laboratory Methods

Statistical Analysis Continuous variables were compared by a t-test and dichotomous variables with Chi-square test and Fisher's exact test where appropriate. Uni- and multivariate regression analyses were performed using Cox proportional hazards models. Statistical analyses were performed using IBM SPSS 21 (IBM, Armonk, NY, USA). Data are presented as the mean ± standard deviation (SD). Results In total, 443 patients with first unprovoked venous thromboembolism (VTE) were followed and a total of 43 unprovoked recurrent VTE patients were identified during the follow-up and 129 controls (1:3) matched for age and sex were selected from patients with no recurrent VTE during the follow-up. Baseline characteristics are presented in Table 1. In 36% of patients with thrombophilia, recurrent VTE developed,

Table 1 Baseline characteristics of the study population.

Age (Years), mean ± SD Sex, n (%) Male, n = 104 (60) Female, n = 68 (40) BMI (kg/m2), mean ± SD Thrombophilia, n (%)¶ Yes, n = 67 (39) No, n = 105 (61) Duration of anticoagulant (days), mean ± SD Thrombosis location, n (%) DVT, n = 123 (71) PE, n = 36 (21) DVT + PE, n = 13 (8)

Non-recurrent VTE (n = 129)⁎

Recurrent VTE (n = 43)

p-value

64.0 ± 13.1

64.0 ± 13.0

1.0†

78 (60) 51 (40) 27.6 ± 4.9

26 (60) 17 (40) 27.4 ± 4.6

1.0‡

43 (33) 86 (67) 170 ± 64

24 (56) 19 (44) 173 ± 67

0.01‡

91 (71) 29 (22) 09 (07)

32 (75) 07 (16) 04 (09)

0.6§

DVT: deep venous thrombosis; PE: Pulmonary embolism. BMI: Body mass index. ⁎ Non-recurrent VTE: Patients with no recurrent venous thromboembolism during follow-up, matched for age and sex. † Mann Whitney U test. ‡ Fisher exact test. § Chi-square test. ¶ Thrombophilia: Factor V Leiden and Factor II mutations, protein S, protein C and antithrombin deficiency.

0.91†

0.4†

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location of first thrombosis (p = 0.6) between patients with and without recurrent VTE (Table 1). Recurrent VTE and Apolipoprotein M Among all patients, levels of ApoM were not significantly different between patients without (0.74 μM ± 0.2; mean ± SD) and those with recurrent VTE (0.70 μM ± 0.2), p = 0.22 (Fig. 1A). However, after stratification of data according to gender, significantly lower levels of ApoM were found in men with recurrent VTE (mean ± SD, 0.63 μM ± 0.2), as compared to men without recurrence (0.74 μM ± 0.2) p = 0.02 (Fig. 1B). In contrast, the levels of ApoM in women with recurrent VTE (0.80 μM ± 0.2; mean ± SD) were not significantly different from the ApoM levels in women without recurrence (0.75 μM ± 0.2), p = 0.31 (Fig. 1B). Men with recurrent VTE had significantly lower levels of ApoM than women with recurrent VTE (0.63 μM ± 0.2 vs 0.80 μM ± 0.2, respectively), p = 0.008. In contrast, no significant differences in ApoM levels were found between men and women with non-recurrent VTE (0.74 μM ± 0.2 vs 0.75 μM ± 0.2 respectively), p = 0.88 (Fig. 1B). Apolipoprotein M and Risk of Recurrent VTE

Fig. 1. Levels of ApoM in the overall population (A) and in male and female patients (B) with and without recurrent VTE. No significant difference was found in ApoM levels between recurrent and non-recurrent VTE in the overall population (P = 0.22). Males with recurrent VTE had significantly lower levels of ApoM than males without recurrent VTE (p = 0.02). No significant difference was found in ApoM levels between nonrecurrent and recurrent VTE in female patients (p = 0.31). Males with recurrent VTE had significantly lower levels of ApoM compared to females with recurrent VTE (P = 0.008). No difference was found in ApoM levels between males and females without recurrent VTE (p = 0.88). Sold line represents mean, *p = b0.05 and **p = b0.01.

as compared to 18% among those without thrombophilia (p = 0.01). There were no significant differences in age (p = 1.0), sex (P = 1.0), BMI (p = 0.91), duration of anti-coagulant treatment (P = 0.4), or

ApoM was entered as a continuous variable in a Cox proportional hazards model. The hazard ratio (HR) was 0.98 (95% CI, 0.96-0.99), for each 0.01 μM increase in ApoM level in male patients (p = 0.042) and this HR remained unchanged 0.98 (95% CI, 0.96-0.99) in the multivariate analysis including thrombophilia and BMI (p = 0.027) (Table 2). In male patients, thrombophilia was neither associated with risk of recurrence in the univariate analysis [HR (95% CI); 1.44 (0.673.1)], p = 0.35, nor in the multivariate analysis [HR (95% CI); 1.63 (0.72-3.7)], p = 0.24. In female patients, an increase of 0.01 μM in the level of ApoM was neither associated with the risk of recurrent VTE in the univariate analysis [HR (95% CI); 1.01 (0.99-1.04)], p = 0.46, nor in the multivariate analysis [HR (95% CI); 1.0 (0.98-1.03)], p = 0.70 (Table 2). However, in female patients, thrombophilia was significantly associated with higher risk of recurrence in both the univariate [HR (95% CI); 3.76 (1.36-10.4)], p = 0.01, and the multivariate analysis [HR (95% CI); 3.53 (1.3-9.87)], p = 0.017 (Table 2). Among all patients, thrombophilia was associated with higher risk of recurrent VTE [HR (95% CI); 2.25 (1.21-4.16.4)], p = 0.01. No association between risk of recurrent VTE and ApoM levels was found among all patients (data not shown). Discussion The present study suggests an association between low levels of ApoM and increased risk of unprovoked recurrent VTE in men but not in women. During recent years, efforts have been made to identify risk factors for thrombotic risk assessment. However, it remains a challenge to predict the individual risk for recurrence of VTE, especially in unprovoked VTE. Recent epidemiological studies suggest that arterial and

Table 2 Gender specific hazard ratios (HRs) with 95% confidence intervals (CIs) in unprovoked recurrent VTE. Men Univariate

Women P

HR (95% CI) ApoM (0.01 μM) Thrombophilia⁎ (yes/no)

0.98 (0.96-0.99) 1.44 (0.67-3.1)

Multivariate

P†

HR (95% CI) 0.042 0.35

0.98 (0.96-0.99) 1.63 (0.72-3.7)

Univariate

P

HR (95% CI) 0.027 0.24

1.01 (0.99-1.04) 3.76 (1.36-10.4)

⁎ Thrombophilia: Factor V Leiden and Factor II mutations, protein S, protein C and antithrombin deficiency). † Adjusted for body mass index (BMI).

Multivariate

P†

HR (95% CI) 0.46 0.01

1.00 (0.98-1.03) 3.53 (1.3-9.87)

0.70 0.017

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venous cardiovascular diseases share common risk factors [22,23]. ApoM was first found in chylomicrons and in circulation it is preferentially associated with HDL and only to a minor extent to other lipoproteins [12,13]. It plays an important role in lipid metabolism and has been shown to protect against atherosclerosis [24]. Higher levels of HDL have been associated with lower risk of recurrent venous VTE [18]. However, the role of ApoM in recurrent VTE is not known. We quantified plasma level of ApoM in patients with first episode of unprovoked venous thromboembolism (VTE) and investigated its association with the risk of recurrent VTE. Men with recurrent VTE had significantly lower levels of ApoM as compared to women. Interestingly, ApoM levels were nearly identical in both men and women with no recurrent VTE. These results suggest that ApoM could be a biomarker of recurrence of VTE in men but not in women. It should be noted, however, that ApoM levels may change during the follow-up period. Although inconsistently found in different studies [25], male sex is associated with a 1.6 fold increased risk of recurrent VTE [26]. However, this potential sex difference remains, so far, unexplained. Dyslipidemia, such as lower HDL and higher LDL levels, has been associated with VTE risk [27,28] and stratification of data according to sex shows that the association between dyslipidemia and VTE is stronger in men compared to women [29]. Therefore, based on our results one may speculate that lower levels of ApoM in recurrent VTE in men may contribute, at least in part, to the higher risk of recurrence in men. VTE recurrence rates are reported to be higher in patients with inherited thrombophilic defects [30,31]. However, the clinical importance of these inherited genetic defects in recurrent VTE risk is controversial [9,10,32,33]. Consistent with previous studies, we also found an increased risk of recurrent VTE in all patients with thrombophilia as compared to those without thrombophilia. Multivariate Cox regression analysis showed that the association between ApoM level and risk of recurrent VTE was independent of thrombophilia and BMI in men, whereas thrombophilia remained a significant risk factor of recurrent VTE in women. These results further support the previous observations that men and women do not share the same risk factors for recurrent VTE [34]. The main limitation of the study is the low number of patients. This was due to a lower rate of VTE recurrence in the present study as compared to other studies [7,35] and, additionally, because we excluded patients with known acquired risk of recurrent VTE (see above). Other potential limitations of the study are the non-fasting measurements of ApoM (if ApoM varies with food intake) and the time period between anticoagulation withdrawal and sample collection. It should be noted, however, that this study was performed as a hypothesis generating study. And our findings justify further clinical studies on the role of ApoM in recurrent VTE in larger populations and in other settings. Additional studies are needed to determine whether ApoM level might be of value in predicting recurrent VTE. In conclusion, male patients with recurrent VTE had significantly lower levels of ApoM compared to those with non-recurrent VTE. In addition, lower levels of ApoM were associated with higher risk of recurrent VTE in male patients. Funding This work was supported by grants from the Swedish Research Council (#K2012-70X-15428-08-3) to Kristina Sundquist and #7143 to Björn Dahlbäck), The Swedish Heart-Lung Foundation (Bengt Zöller and Björn Dahlbäck), FORTE, Swedish Research Council for Health, Working Life and Welfare, as well as ALF funding from Region Skåne awarded to Kristina Sundquist, Bengt Zöller, Jan Sundquist and Björn Dahlbäck. Conflict of Interest Statement Authors declare no conflict of interest.

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Apolipoprotein M and the risk of unprovoked recurrent venous thromboembolism.

Apolipoprotein M (ApoM) protects against atherosclerosis; however, it is unknown whether it also protects against recurrent venous thromboembolism (VT...
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