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Keywords:

  • anticoagulation;
  • blood coagulation;
  • deep vein thrombosis;
  • pulmonary embolus;
  • risk factors;
  • venous thrombosis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. Acknowledgements
  9. References

Summary. Background: Elevated plasma D-dimer and factor VIII coagulant activity (FVIIIc) may be associated with the risk of recurrent venous thromboembolism (VTE). Objectives: To evaluate D-dimer and FVIIIc as risk factors for recurrent VTE and assess the efficacy of extended low-intensity warfarin (target International Normalized Ratio 1.5–2.0) in preventing recurrence by biomarker level. Patients and methods: In the Prevention of Recurrent Venous Thromboembolism trial, 508 idiopathic VTE patients treated for ≥ 3 months with full-intensity warfarin, and who had stopped warfarin for 7 weeks on average, were randomized to low-intensity warfarin or placebo and followed for 2.1 years for recurrent VTE. Prerandomization blood samples were analysed for D-dimer and FVIIIc. Results: One-third of participants had elevated baseline D-dimer (≥ 500 ng mL−1) and one-fourth, elevated FVIIIc (≥ 150 IU dL−1). Adjusting for other risk factors, the hazard ratios (HRs) for recurrent VTE with elevated D-dimer or FVIIIc were 2.0 [95% confidence interval (CI) 1.2–3.4] and 1.5 (95% CI 0.8–2.8), respectively. The association of elevated D-dimer with recurrence was larger among patients with one prior VTE (HR 3.2, 95% CI 1.3–8.0) than in patients with more than one event (HR 1.4, 95% CI 0.7–2.2). For patients with one prior VTE on placebo, the annual recurrence incidence was 10.9% with elevated D-dimer and 2.9% with normal values. Low-intensity warfarin was equally effective in recurrence risk reduction in those with normal or elevated biomarkers. Conclusions: Among patients with idiopathic VTE, measurement of D-dimer, but not FVIIIc, might be useful for risk stratification. The efficacy of extended low-intensity warfarin therapy did not vary by biomarker level.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. Acknowledgements
  9. References

Deep vein thrombosis (DVT) and pulmonary embolus are common, with an age-adjusted incidence of approximately two cases per 1000 person-years in middle and older age [1]. Idiopathic venous thromboembolism (VTE) implies the occurrence of VTE in the absence of triggering factors such as immobilization, trauma, surgery or cancer. The proportion of cases of VTE classified as idiopathic varies from 26% to 48% in different studies [1,2]. After completing initial anticoagulation, recurrence rates of up to 10% per year have been reported in patients with idiopathic VTE. This contrasts with a much lower yearly recurrence risk in patients who experience VTE in the presence of a transient risk factor [1,3].

Recent trials among patients with idiopathic VTE demonstrated efficacy of longer duration of either full- or low-intensity warfarin continued for two or more years [4,5]. However, treatment with warfarin is complicated, variably accepted by patients and associated with hemorrhagic complications [6]. Identification of subgroups with particularly high recurrence risk might allow better tailoring of this treatment. Higher levels of plasma D-dimer and factor VIII coagulant activity (FVIIIc) are risk factors for a first VTE [7–9]. Further, after stopping full-intensity oral anticoagulation for a first VTE, higher D-dimer [10,11] may identify a subset of idiopathic VTE patients with an increased risk of recurrence. Similarly, elevated FVIIIc may predict recurrent VTE, but this has not been confirmed in all studies [12–15].

Despite possible associations of increased D-dimer and FVIIIc with the risk of recurrent VTE, the efficacy of long-term oral anticoagulation in preventing recurrence in those with high levels of these factors has not been evaluated. We evaluated higher D-dimer and FVIIIc as risk factors for recurrent VTE and studied the efficacy of long-term low-intensity warfarin [target International Normalized Ratio (INR) 1.5–2.0] in preventing recurrence in patients with elevated D-dimer and/or FVIIIc.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. Acknowledgements
  9. References

Participants and study design

The Prevention of Recurrent Venous Thromboembolism (PREVENT) clinical trial was a double-blind randomized trial testing the hypothesis that long-term low-intensity warfarin therapy (target INR, 1.5–2.0) might be safe and effective in reducing risk of recurrent VTE in patients with one or more previous idiopathic VTE [4]. Idiopathic VTE was defined as the occurrence of VTE in the absence of surgery or trauma within 90 days. Men and women older than 30 years of age with documented idiopathic VTE were eligible to participate if they had completed at least 3 months of full-intensity warfarin with a target INR of 2.0–3.0. To be eligible to participate, patients should have completed a standard course of full-intensity warfarin within the preceding 2 years (duration determined by their physician) but no sooner than 21 days prior to enrollment. Exclusion criteria included a history of metastatic cancer or active cancer, major gastrointestinal bleeding, hemorrhagic stroke, life expectancy < 3 years or known antiphospholipid syndrome.

There were 508 patients with prior idiopathic VTE randomized at 52 centers in the USA, Canada and Switzerland; 253 to placebo and 255 to low-intensity warfarin. Median duration of full-intensity warfarin prior to randomization was 6.5 months. After randomization, office visits were scheduled every 2 months for blinded determinations of the INR to adjust the warfarin dose and to ascertain occurrence of clinical events. Confirmation of the end point of recurrent VTE required a positive imaging study such as duplex ultrasonography, computed tomography or ventilation perfusion scanning. Major hemorrhage was defined as any bleeding that led to hospitalization or transfusion. For the duration of the trial, the median INR in the placebo group was 1.0 (interquartile range, 1.0–1.1) and 1.7 (interquartile range 1.4–2.0) in the warfarin group. The trial was terminated in December 2002, due to a large clinical benefit of low-intensity warfarin. The median duration of follow-up at the time of termination of the trial was 2.1 years, with a range of 12 days to 4.3 years.

Laboratory analysis

At the time of enrollment, a median of 7 weeks (range 12 days to 2 years) after stopping anticoagulation, blood samples were obtained and centrifuged at 4 °C, with samples shipped to a central laboratory on cold packs by overnight courier. Plasma was stored in liquid nitrogen at −80 °C. After completion of the trial, citrate plasma samples were thawed and analyzed for D-dimer and FVIIIc on the STA-R analyzer (Diagnostica Stago, Parsippany, NJ, USA). D-dimer was assessed using an immuno-turbidometric assay (Liatest D-Di; Diagnostica Stago) and FVIIIc was determined by measuring the clotting time of the sample in FVIII-deficient plasma in the presence of activators (STA-Deficient VIII; Diagnostica Stago). The coefficients of variation for these assays were 3.0% and 3.85%, respectively. DNA was analysed for FV Leiden and the prothrombin 20210A variant [16,17].

Elevated D-dimer was defined as ≥ 500 ng mL−1 [10]. We defined elevated FVIIIc as values in the top quartile for the PREVENT study population [7,14].

Statistical analysis

All analyses were based on intention to treat. To compare distributions of baseline characteristics and inherited thrombophilic states in different plasma biomarker groups, we utilized Wilcoxon's rank sum tests for continuous variables and chi-squared tests for categorical variables. The cumulative probability of recurrent VTE was estimated using the method of Kaplan–Meier. Homogeneity between patient groups was tested using a two-sided log-rank test. To evaluate the risk of recurrent VTE associated with elevated plasma biomarkers and the efficacy of low-intensity warfarin, we estimated incidence rates for recurrence in groups defined by randomized treatment assignment and elevated coagulation factors. Incidence rates for recurrent VTE (events per 100 person-years) were reported as yearly incidence proportions (% per year). Plasma markers were entered as binary variables into Cox proportional hazard models to estimate the hazard ratios (HR) with 95% confidence intervals (CIs) for recurrence. These HRs were then adjusted for age, gender, treatment assignment, time from index event and number of pre-enrollment VTE. The hypotheses of varying associations of hemostatic factors with recurrence risk by treatment assignment or number of prior VTE were tested in proportional hazards models that included interaction terms between these variables. Differences by number of prior VTE were sought because a biomarker might be less useful for decision-making among patients with more than one prior VTE, as they are often prescribed long-term oral anticoagulation. SAS software version 8 (SAS institute, Cary, NC, USA) was used and a P-value of < 0.05 was considered significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. Acknowledgements
  9. References

Patients

Of the 508 participants, D-dimer and FVIIIc were measured in 501 and 503 patients, respectively. Using threshold values of 500 ng mL−1 for D-dimer and 150 IU dL−1 for FVIIIc, 167 (33.3%) and 123 (24.5%) had elevated baseline levels, respectively. Patients with elevated D-dimer were older, more likely to have prior malignancy and had a longer time interval from their index event to randomization. Those with elevated FVIIIc were more likely to be older, women and less likely to smoke (Table 1).

Table 1.   Baseline characteristics by plasma biomarker levels
CharacteristicD-dimerFVIIIc
< 500 ng mL−1 (n = 334)≥ 500 ng mL−1 (n = 167) P-value< 150 IU dL−1 (n = 380)≥ 150 IU dL−1 (n = 123) P-value
  1. FVIIIc, factor VIII coagulant activity; VTE, venous thromboembolism.

  2. *Information on smoking status was not available in 18 participants.

  3. There were three patients homozygous for factor V Leiden: one in the normal and two in the high D-dimer groups, three in the low FVIIIc group.

Median age (years) (interquartile range)51 (44–59)61 (49–70)< 0.000152 (45–64)56 (49–67)0.007
Female gender (%)157 (47.0)79 (47.3)0.95163 (42.9)74 (60.2)0.001
Women taking exogenous hormones at index VTE (%)87 (55.4)35 (44.3)0.1089 (54.6)33 (44.6)0.15
Race
 Non-Hispanic white297 (88.9)143 (85.6)0.29339 (89.2)102 (82.9)0.07
 Other37 (11.1)24 (14.4) 41 (10.8)21 (17.1)
Body mass index ≥ 30 kg m−2 (%)167 (50.2)80 (47.9)0.64183 (48.3)64 (52.0)0.47
Prior malignancy (%)23 (6.9)22 (13.2)0.0234 (9.0)11 (8.9)0.99
Current smoking (%)*41 (12.7)19 (11.8)0.7754 (14.8)6 (5.0)0.005
Number of pre-enrollment VTE (%)
 One212 (63.5)96 (57.5)0.19241 (63.4)68 (55.3)0.08
 Two92 (27.5)59 (35.3) 112 (29.5)39 (31.7)
 Three or more30 (9.0)12 (7.2) 27 (7.1)16 (13.0)
Months from index event to randomization (interquartile range)10.9 (8.2–18.7)13.6 (8.7–20.1)0.0112.3 (8.3–19.5)10.8 (8.4–17.6)0.45
Factor V Leiden (%)83 (24.9)38 (22.8)0.6189 (23.4)33 (26.8)0.44
Prothrombin 20210A heterozygote (%)12 (3.6)12 (7.2)0.0821 (5.5)3 (2.4)0.16

D-dimer and recurrent VTE

The median baseline plasma D-dimer in patients with recurrent VTE was higher than in those without recurrence (460 vs. 350 ng mL−1, P = 0.05). Elevated D-dimer (≥ 500 ng mL−1) was associated with a 2-fold (95% CI 1.2–3.4) increased risk of recurrent VTE. After adjustment for age, gender, time from index event, treatment assignment and number of pre-enrollment VTE, elevated D-dimer remained an independent risk factor for recurrence (HR 2.0, 95% CI 1.1–3.7). The cumulative risk of recurrence by plasma D-dimer is shown in Fig. 1. In participants assigned to placebo, elevated D-dimer was associated with a recurrence rate of 12.3% per year compared with a rate of 5.6% per year for patients with normal levels (Fig. 2). Although the overall rate was lower, a similar doubling of recurrence rates was observed with elevated D-dimer in the warfarin group.

image

Figure 1.  Recurrent venous thromboembolism (VTE) by plasma D-dimer concentration.

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image

Figure 2.  Annual incidence of recurrent venous thromboembolism by plasma biomarkers and treatment assignment. Dark bars represent those randomized to warfarin and open bars, placebo. n refers to sample size in each group.

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The recurrence risk with elevated D-dimer among patients with one prior VTE was higher than among those with two or more prior VTE. In those with one prior event, the adjusted HR was 3.2 (95% CI 1.3–8.0), while this was 1.4 (95% CI 0.7–2.2) in those with more than one prior VTE. The difference between these two HRs was not statistically significant on the multiplicative scale (P = 0.16). Among patients with a single prior VTE randomized to placebo, with normal D-dimer the recurrence rate was 2.9% per year, compared with 10.9% per year with elevated D-dimer (Fig. 3). Among patients with one previous VTE assigned to warfarin, the recurrence rate was also higher for those with elevated (1.8% per year) compared with normal D-dimer (0.9% per year). Among patients with two or more prior VTE, who were randomized to placebo, the recurrence rate was 10.8% per year for those with normal D-dimer compared with 14.1% per year for those with elevated D-dimer (Fig. 3). In patients with more than one prior VTE randomized to warfarin, recurrence rates were also higher for those with elevated D-dimer (6.9% per year) compared with those with normal levels (3.8% per year).

image

Figure 3.  Recurrence rates by D-dimer, number of prior venous thromboembolism (VTE) and treatment assignment. Dark bars represent those randomized to warfarin and open bars, placebo. n refers to sample size in each group.

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As prior cancer (history of cancer in the absence of active disease at enrollment) was more common in those with elevated D-dimer, we repeated the analysis excluding these participants. Overall, 45 confirmed VTE occurred during follow-up in 456 participants without prior cancer and the risk of recurrence in these participants did not differ appreciably from the overall risk (HR 1.9, 95% CI 1.0–3.3). We explored the possibility that elevated D-dimer may be a result of occult malignancy by studying the association of D-dimer and incident cancer during follow-up. There were 13 new cases of cancer diagnosed during follow-up with a HR of 1.8 (95% CI 0.6–5.4) for elevated compared with normal D-dimer.

As time from cessation of full-intensity warfarin might affect the association of elevated D-dimer and recurrent VTE, we adjusted our HRs for time from index event to randomization and results did not change. We also repeated the analysis including only those participants who were randomized after 4 weeks of stopping full-intensity warfarin. This cohort of 339 patients had 33 recurrent VTE during follow-up and the HR for recurrence associated with elevated D-dimer did not differ appreciably from the overall relative risk (HR 1.8, 95% CI 0.9–3.7).

FVIIIc and recurrent VTE

The median FVIIIc was similar in those with and without recurrent VTE (122 vs. 116 IU dL−1, P = 0.55). Those with elevated FVIIIc (≥150 IU dL−1) had an increased recurrence risk in both crude (HR 1.5, 95% CI 0.8–2.7) and adjusted analyses (HR 1.5, 95% CI 0.8–2.7), but this was not statistically significant. After 3.5 years of follow-up, participants with higher FVIIIc had a cumulative probability of recurrence of 21% compared with 13% for those with lower levels, but this difference was not statistically significant (Fig. 4). Incidence rates for recurrent VTE by treatment assignment and FVIIIc are shown in Fig. 2. Participants with elevated FVIIIc had higher recurrence rates in both the warfarin and placebo groups compared with normal FVIIIc. Elevated FVIIIc was also associated with a higher hazard of recurrence in those with one compared with more than one prior VTE (HR 2.0, 95% CI 0.8–5.3 and HR 1.3, 95% CI 0.4–2.1 respectively; P > 0.05 for the difference).

image

Figure 4.  Recurrent venous thromboembolism by factor VIII coagulant activity (FVIIIc).

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We evaluated different thresholds for defining elevated FVIIIc on recurrence risk by repeating our analysis using cut points of the 50th (≥ 116 IU dL) and 90th percentile (≥ 202 IU dL−1) for our study population. There were weaker associations of elevated FVIIIc and recurrent VTE with cut points of 50th (HR 1.01, 95% CI 0.6–1.8) and 90th percentile (HR 1.3, 95% CI 0.5–3.0).

Combined effects of elevated FVIIIc and D-dimer on recurrent VTE

Eighteen per cent of the 53 participants who had both elevated D-dimer and FVIIIc had recurrent VTE compared with 11% of those with one elevated biomarker and 8% with both normal. For patients with both elevated D-dimer and FVIIIc (compared with both normal), the HR of recurrent VTE was 2.6 (95% CI 1.2–5.6).

Efficacy of low-intensity warfarin by D-dimer and FVIIIc

Overall, there were 52 VTE recurrences after randomization. Recurrence rates and HRs by treatment assignment and plasma biomarker levels are summarized in Fig. 2 and Table 2. The magnitude of risk reduction with low-intensity warfarin was similar at more than 60% in patients with elevated or normal D-dimer and FVIIIc. There were no significant differences in the magnitude of risk reduction with low-intensity warfarin in categories of D-dimer (P = 0.95) or FVIIIc (P = 0.78). Further, the efficacy of low-intensity warfarin did not vary by combinations of elevated D-dimer or FVIIIc and number of prior VTE (P for interaction = 0.43 and 0.42, respectively).

Table 2.   Rates and hazard ratios by treatment assignment and biomarker levels
BiomarkerPlaceboWarfarinHazard ratio of recurrence with warfarin (95% CI)P for interaction*
Number of eventsIncidence rate (%/year)Number of eventsIncidence rate (%/year)
  1. *Null hypothesis for the test is no interaction between treatment and plasma biomarker level.

D-dimer (ng mL−1)
 < 500205.671.90.35 (0.15–0.83)0.95
  ≥ 5001812.373.90.34 (0.14–0.82)
Factor VIII coagulant (IU dL−1)
 < 150276.792.10.33 (0.16–0.7)0.78
  ≥ 1501110.253.90.39 (0.14–1.1)

Major hemorrhage was rare in those randomized to low-intensity warfarin or placebo and there was no association of either biomarker with risk of major hemorrhage (data not shown).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. Acknowledgements
  9. References

In this trial of 508 patients with prior idiopathic VTE, plasma D-dimer ≥ 500 ng mL−1, measured a median of 7 weeks after cessation of full-intensity anticoagulation was an independent risk factor for recurrent VTE. Although elevated FVIIIc (≥ 150 IU dL−1) correlated with recurrent VTE, the association of FVIIIc was not as robust as that of D-dimer. These results support the potential utility of D-dimer, but not FVIIIc, in risk assessment of patients with previous idiopathic VTE. Although the absolute recurrence rate for patients with elevated D-dimer randomized to warfarin was higher than those with lower D-dimer treated with warfarin, the use of long-term low-intensity warfarin resulted in similar relative risk reduction in both high- and low-risk subsets of patients.

In our study, the 3-fold higher recurrence risk with elevated D-dimer in patients with one prior VTE is similar to findings of a prospective Italian cohort study of 396 patients with first idiopathic or secondary VTE where D-dimer (> 500 ng mL−1) measured 3 months after completing full-intensity oral anticoagulation, was associated with a 2.45 higher risk of recurrent VTE [10]. That study had fewer patients with idiopathic VTE than ours (166 vs. 508) and did not evaluate the role of warfarin in preventing recurrent events. In a cohort study of 610 Austrian patients with first idiopathic VTE, D-dimer < 250 ng mL−1, measured 3 weeks after discontinuing oral anticoagulation, was associated with a 60% lower risk of recurrent VTE compared with higher levels [11]. Our finding was similar, with a 59% lower risk of recurrent VTE associated with D-dimer < 500 ng mL−1 in patients with first idiopathic VTE.

Our findings are similar to those of a recent study of Dutch patients with first DVT that suggested a weak association between higher FVIIIc (> 166 IU dL−1; measured 19 months after thrombosis) and recurrent VTE (HR 1.3, 95% CI 0.8–2.1) [15] but differ from two prior prospective studies that used a threshold of the 90th percentile to define elevated FVIIIc [12,13]. Compared with our study, in the Austrian study, the mean FVIIIc was higher in participants with (182 ± 66 vs. 135 ± 76 IU dL−1) and without recurrent VTE (157 ± 54 vs. 132 ± 80 IU dL−1). Median levels were also much higher in the Italian study, 215 vs. 122 IU dL−1 among those with recurrence and 190 vs. 116 IU dL−1 in those without recurrence. Utilizing a higher threshold of the 90th percentile (≥ 202 IU dL−1) in our study did not alter the weak association between elevated FVIIIc and recurrent VTE (HR 1.3, 95% CI 0.5–3.0). These two studies measured FVIIIc closer to the time of stopping warfarin (3–4 weeks). FVIIIc increases acutely after thrombosis and may vary with the time interval between VTE and obtaining blood samples [18]. A more standardized time interval between cessation of anticoagulation and measurement of FVIIIc in previous studies compared with this and the Dutch study might explain differences in findings. However, adjustment for time between stopping warfarin and laboratory assessment did not alter interpretation of our results (data not shown). It is possible that other characteristics of patients (e.g. prevalence of other genetic traits) might differ by country and explain these differences. Methodological differences in FVIIIc assays cannot be ruled out.

In most studies, common hereditary thrombophilias have not predicted risk of recurrent VTE [15,19,20]. Markers of global hemostasis activation, such as D-dimer, might be more useful clinically [20]. Although our primary analysis was the overall association of elevated hemostatic markers and recurrent VTE, we also evaluated this association in participants with only one VTE at baseline as a secondary analysis. We observed an appreciable difference in absolute recurrence rates in patients with first VTE and normal (2.9% per year) compared with high levels of D-dimer (10.9% per year). However, elevated D-dimer did not add substantially to the estimation of recurrence risk in those with two or more pre-enrollment VTE and our findings suggest that D-dimer measurement may not be helpful in managing such patients. Biases in selection of such patients for participation in this randomized trial might explain this finding.

This study was a secondary analysis of a randomized double-blind placebo controlled trial of low-intensity anticoagulation where the outcome of recurrent symptomatic VTE was objectively confirmed using prespecified criteria and imaging studies. Plasma samples for biomarkers were obtained at enrollment and did not influence the randomization of participants. As blood was obtained on average 7 weeks after cessation of full-intensity anticoagulation, it is unlikely that preceding anticoagulation influenced D-dimer and FVIIIc. However, a limited number of recurrent VTE may have limited our power to evaluate FVIIIc. Conclusions regarding the efficacy of low-intensity warfarin in a high-risk subset of idiopathic VTE patients are based on a 2-year average follow-up; extending anticoagulation beyond this duration based on biomarkers requires further study.

In conclusion, after cessation of full-intensity warfarin for idiopathic VTE, one-third of patients had elevated D-dimer and this was independently associated with a higher risk of recurrent thrombosis. Treating these high-risk patients with long-term low-intensity warfarin is effective in lowering the risk of recurrent VTE. Further study of the effect of long-term anticoagulation, including that of higher intensity treatment, among those with low or high D-dimer is needed.

Conflict of interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. Acknowledgements
  9. References

Dr Cushman received an investigator-initiated grant from Astra-Zeneca and one consultant fee from Bristol-Myers-Squibb. Dr Ridker has received research grant funding from Bristol-Myers-Squibb. Dr Goldhaber has received research grant funding from Bristol Myers Squibb, Sanofi-Aventis and GlaxoSmithKline, and consulting fees from Emisphere, Bayer, and Duramed.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. Acknowledgements
  9. References

Supported by grants (HL-57951 and HL-58036) from the National Heart Lung and Blood Institute (Bethesda, MD, USA), the Leducq Foundation (Paris, France), the Doris Duke Charitable Foundation (New York, NY, USA), and the Donald W Reynolds Foundation (Las Vegas, NV, USA). SS is supported by an institutional NRSA grant (HL 007575) from the National Heart Lung Blood Institute (Bethesda, MD, USA).

We thank Ms Ellie Danielson, Ms Jean MacFadyen and Ms Elaine Cornell for logistical support and Ms Nora Sullivan for her laboratory work.

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  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflict of interest
  8. Acknowledgements
  9. References
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