Abstract
Objective:
To determine the frequency of elevated D-dimer plasma concentration (>500 ng/mL) in patients with systemic sclerosis and evaluate its association with systemic sclerosis–specific microvascular and macrovascular complications.
Methods:
Retrospective observational study of patients with systemic sclerosis followed in a tertiary referral center with at least one measurement of D-dimer between 2010 and 2018.
Results:
A total of 214 patients were analyzed. Mean age at inclusion was 55.1 ± 14.7 years; 180 (84.1%) were female; 74 (34.6%) had diffuse cutaneous systemic sclerosis. Anti-Scl70 and anti-centromere antibodies were positive in 74 (34.6%) and 75 (35.0%) patients, respectively. D-dimer level was elevated in 93 (43.5%) patients, independently of cutaneous subtype (44.6% in diffuse cutaneous systemic sclerosis vs 42.9% in limited cutaneous systemic sclerosis, p = 0.81). At least one microvascular complication was found in 108 (50.5%) patients: 105 (49.1%) with previous or current digital ulcers, 6 (2.8%) with renal crisis, and 4 (1.9%) with pulmonary arterial hypertension. Microvascular complications were more frequent in patients with elevated D-dimer (57.0% vs 45.5%, p = 0.09), significantly so after exclusion of patients with a history of cancer and/or venous thromboembolism (60.5% vs 44.8%, p = 0.04). Macrovascular complications were detected in 15 (7.0%) patients and were associated with a high D-dimer level (11.8% vs 3.3%, p = 0.03). Over a median follow-up of 2.3 years [1.1–3.3] after D-dimer measurement, new macrovascular complications occurred only in patients with high D-dimer (n = 8).
Conclusion:
High D-dimer levels are frequently found in systemic sclerosis patients and seem to be associated with the occurrence of macrovascular and microvascular complications after adjustment for confounding factors.
Keywords: Systemic sclerosis, plasma D-dimers, microvascular complications, macrovascular complications
Introduction
Systemic sclerosis (SSc) is a systemic autoimmune disorder characterized by endothelial dysfunction and vascular hyperreactivity, fibroblast activation and accumulation of extra-cellular matrix and dysregulation of the immune system with autoimmunity.1,2 Clinical presentation of patients with SSc is diverse, with two main clinical subtypes based on the extent of skin involvement: diffuse cutaneous SSc (dcSSc) with skin sclerosis extending beyond the elbows and knees, and limited cutaneous SSc (lcSSc) 3 with only distal skin involvement.
Vasculopathy is a hallmark of the disease, characterized by microvascular involvement.3,4 In fact, most patients with SSc complain of Raynaud’s phenomenon and 40%–50% of them develop at least one digital ulcer due to microvascular disease, with recurrences of ulcers in 2/3 of the cases.5–8 Other more rare but life-threatening microvascular complications include pulmonary arterial hypertension (PAH), which occurs in approximately 5%–12% of patients 9 and is one of the two main causes of death in SSc,10–12 as well as scleroderma renal crisis (SRC) which affects 4%–5% of patients with SSc and can lead to end-stage renal disease or death. 13
Alongside microvascular disease, a significant proportion of patients with SSc develop macroangiopathy, especially in the form of peripheral vascular occlusive disease.2,14 Ulnar artery occlusion is found to be present in 37% of patients with SSc. 15 Other cardiovascular (CV) events such as myocardial infarction and stroke are less frequent, but their occurrence is increased twofold in SSc patients as compared to the general population.16–18 Furthermore, 5%–14% of deaths in SSc patients are due to heart involvement.14,19–22
SSc vasculopathy is characterized by ischemia-reperfusion injury. Local thrombotic events in small arteries and capillaries are frequent and reflect the imbalance between the coagulation and fibrinolytic systems.1,23,24 Interestingly, plasma levels of D-dimer (DD), the terminal degradation product of cross-linked fibrin, have been reported to be elevated in SSc patients as compared to healthy controls, suggesting an excess of fibrin formation and degradation in patients with SSc. 25
Plasma concentration of DD is regularly measured in order to identify patients at risk for pulmonary embolism.26–28 In a population-based study, 29 the incidence rate of pulmonary embolism and deep venous thrombosis in SSc patients was 3.47 and 3.48 per 1000 person-years, respectively, compared to 0.78 and 0.76 per 1000 person-years among non-SSc individuals. However, in patients with SSc, the use of DD in the diagnosis of thromboembolic events can lead to burdening, time-consuming exams with unnecessary contrast or radiation exposure, since DD levels seem to be often elevated. 30 In fact, elevated DD levels have been associated with macrovascular disease in small open series30,31 and data are inconsistent regarding SSc-specific microvascular complications.
Given the burden of vascular complications in SSc, reliable predictive biomarkers are essential, but lacking. The primary aim of this study was to determine the frequency of elevated DD levels (⩾500 ng/mL) in patients with SSc, and to evaluate the association between elevated DD levels and vascular complications in these patients including both macrovascular and SSc-specific microvascular complications.
Patients and methods
Study population and follow-up
We conducted a retrospective observational study of patients with SSc that were referred at least once to our tertiary national referral center for Scleroderma (Reference Centre for Rare Systemic Autoimmune Diseases of Ile de France) in the Department of Internal Medicine at Cochin Hospital (Assistance Publique-Hôpitaux de Paris, France) between 2010 and 2018.
Inclusion criteria were a definite diagnosis of SSc based on the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria of 2013 32 and at least one measurement of DD. Included patients were followed mostly by one of the investigators (L.M.). Time of the first DD measurement was considered as the baseline (which was chronologically different for each patient). Clinical charts for variables of interest were reviewed at baseline and until the last follow-up visit.
DD measurement
Venous blood samples were collected into 0.109-M buffered trisodium citrate (9:1 v/v) tubes (Greiner Bio One, Courtabœuf, France). Platelet-poor plasma (PPP) was obtained after a double centrifugation at 2500g for 15 min at room temperature then processed within 2 h. DD were measured by enzyme-linked immunosorbent assay (ELISA, Vidas® D-Dimer Exclusion II™, Biomerieux, Paris, France) on VIDAS analyser according to the manufacturer instructions. Plasma DD level was considered elevated when it was above the normal level observed in healthy adult population thus >500 ng/mL.27,33
Data collection and definition of variables of interest
Demographic and clinical variables of interest were collected retrospectively from the digital clinical files and from the center database.
SSc-specific microvascular complications included at least one of the following: digital ulcers or pitting scars; SRC, defined by rapidly progressive oliguric renal insufficiency with no other explanation and/or rapidly progressive hypertension occurring during the course of SSc (in case of normotensive SRC, it was defined by an increase in serum creatinine >50% over baseline or ⩾20% of the upper limit of the normal and one of the following five features: (a) proteinuria ⩾2+ by dipstick, (b) hematuria ⩾2+ dipstick or ⩾10 red blood cell/hpf, (c) thrombocytopenia <100,000/mm³, (d) hemolysis defined as anemia not due to others causes and either schistocytes or other red blood cell fragments seen on blood smear, or increased reticulocyte count, (e) renal biopsy findings consistent with SRC) 34 ; or PAH, defined as the presence of a mean pulmonary arterial pressure (PAP) equal or greater than 25 mm Hg at rest or 30 mm Hg with exercise at right-heart catheterization, low pulmonary artery wedge pressure (≦15 mm Hg) and a high pulmonary vascular resistance (>3 WU), considered due to vasculopathy and not secondary to pulmonary fibrosis. 28 Patients were divided in group 1 corresponding to PAH (pre-capillary arterial hypertension due to vasculopathy), group 2 (post-capillary pulmonary hypertension (PH)), group 3 (pre-capillary PH due to pulmonary fibrosis with hypoxemia), and group 4 (chronic thromboembolic PH). PAH definition was revised in 2018; since the study started in 2010 and ended up in 2018, we decided to keep the former threshold of 25 mm Hg of mean PAP and not the new threshold of 20 mm Hg for the definition of PAH. We also analyzed the estimated systolic PAP (sPAP) measured by transthoracic Doppler echocardiography, which was considered elevated when greater than 40 mm Hg at rest.2,30
New microvascular complications were defined as at least one new microvascular event (as defined above), occurring after the first DD measurement until the last follow-up visit.
Macrovascular complications included at least one of the following: non-cardioembolic ischemic stroke, coronary artery disease/myocardial infarction, and peripheral artery disease.
New macrovascular complications were defined as at least one new macrovascular complication (as defined above), occurring after the first DD measurement until the last follow-up visit.
Other variables that could affect DD levels and vascular events were collected; they included age (in years), sex, disease duration (in years), clinical subtype (dcSSc or lcSSc), medical history (solid cancer/hematological cancer within the last 5 years; venous thrombotic events (deep and/or superficial venous thrombosis or pulmonary embolism); hypertension; diabetes mellitus; dyslipidemia; smoking status (current, past, or never)); a concurrent venous thrombotic event (at the time of first DD evaluation); current treatment, including immunosuppressive treatment (methotrexate, mycophenolate mofetil, cyclophosphamide, rituximab), corticosteroids, anticoagulation therapy, antiplatelet therapy, and calcium channel blockers; clinical manifestations, such as Raynaud’s phenomenon, telangiectasia, interstitial lung disease, carbon monoxide diffusion capacity (DLCO), forced vital capacity (FVC), dysphagia/gastro-esophageal reflux, subcutaneous calcinosis, modified Rodnan skin score; and complementary data, including presence of anti-nuclear, anti-centromere, anti-topoisomerase 1, anti-phospholipid antibodies, levels of serum N-terminal pro-brain natriuretic peptide (NT-proBNP, in pg/mL), serum creatinine (in µmol/L), hemoglobin (in g/dL), platelet count (in 109/L), activated partial thromboplastin time (APTT, in seconds), leucocyte count (in 109/L), and C-reactive protein (CRP) levels (in mg/L).
Statistical analysis
Continuous variables were expressed as mean ± standard deviation (SD) if normally distributed or otherwise as median with interquartile range (IQR). Categorical variables were expressed as count (percentages).
First, we analyzed the frequency of elevated DD in SSc patients. We used the first available measurement performed in our center as baseline and analyzed the clinical context of measurement. The majority (69%) of DD measurements were ordered as routine laboratory analysis in patients electively hospitalized for an annual/biannual check-up. DD variation was checked, and consistency was assessed when a second DD value was available. We then performed a descriptive analysis of the study population at the time of first DD measurement, which was chronologically different for each patient. We compared subjects with increased DD levels to the others, with respect to socio-demographic and clinical variables at baseline, using t-student test or Wilcoxon rank-sum test for continuous variables and chi 2 test or Fisher’s exact test for dichotomous variables, as appropriate.
Second, we described the proportion of patients with vascular complications at baseline and evaluated whether there was an association with a high DD level, using Fisher’s exact test. Logistic regression was used to estimate the risk and adjust for covariates when feasible. Goodness-of-fit was evaluated using the Hosmer–Lemeshow test, and discrimination was assessed with the area under the ROC curve (AUC) for each model. We performed the same associative analysis excluding SSc patients with history of malignancy, current or past thromboembolic events, and presence of signs of current inflammation (defined as both leucocytes >10 × 109/L and CRP >5 mg/L). We also analyzed the proportion of patients with new vascular complications from baseline until the last follow-up visit and assessed whether they were associated with a high DD level. Significance level was set at 0.05. All analyses were performed using STATA IC V 14.2 (StataCorp. 2015).
Ethical issues
Blood collection was performed independently of the study purpose. This retrospective observational study was performed in conformity with the principles of the Declaration of Helsinki and national research ethical standards and was approved by the local Ethics Committee.
Results
DD plasma levels in patients with SSc
Out of the 1016 patients followed in our center who met the ACR/EULAR criteria for SSc entered in our database at the time of study, 214 had had at least one measurement of DD (Figure 1). Ninety-three out of these 214 patients (43.5%) had elevated DD levels, independently of cutaneous subtype (44.6% vs 42.9%, in patients with dcSSc or lcSSc, respectively, p = 0.81). Median DD level was 440.5 ng/mL [IQR: 280–760] (Figure 2). Demographic and clinical characteristics of the study population, which were consistent with those of the rest of our SSc cohort (Supplementary Table 1), are described in Table 1. Patients with increased DD levels were compared to those having normal DD (Table 1).
Figure 1.
Flowchart of the study population.
DD: D-dimer plasma concentration; SSc: systemic sclerosis.
Figure 2.
Distribution of D-dimer plasma concentration in 214 patients with systemic sclerosis. D-dimer plasma concentrations are represented globally (a) or with regard to the presence or absence of microvascular (b) or macrovascular (c) complications in a total of 214 patients with systemic sclerosis. Data are shown as box and whisker plots. Extreme outliers were excluded from the graphs.
Table 1.
Baseline characteristics of 214 patients with systemic sclerosis having high (defined as >500 ng/mL) or normal D-dimer plasma concentration.
| Total (n = 214) | High DD (n = 93) | Normal DD (n = 121) | P-value | |
|---|---|---|---|---|
| General | ||||
| Age (mean ± SD) | 55.1 ± 14.7 | 59.5 ± 14.5 | 51.6 ± 13.9 | <0.001 |
| Sex | 0.11 | |||
| Female | 180 (84.1) | 74 (79.6) | 106 (87.6) | |
| Male | 34 (15.9) | 19 (20.4) | 15 (12.4) | |
| Disease duration (time from diagnosis in years) (median [IQR]) | 7 [3–12] | 7 [3–12] | 7 [4–12] | 0.85 |
| Disease duration (time from first non-RP symptom in years) (median [IQR]) (n = 175) | 9 [5–14] | 9 [6–14] | 8 [5–14] | 0.25 |
| Cutaneous clinical type of SSc | 0.81 | |||
| Diffuse | 74 (34.6) | 33 (35.5) | 41 (33.9) | |
| Limited | 140 (65.4) | 60 (64.5) | 80 (66.1) | |
| Past medical history other than SSc-related | ||||
| Solid or hematological cancer within 5 years | 12 (5.6) | 9 (9.7) | 3 (2.5) | 0.03 |
| Venous thromboembolic disease | 20 (9.3) | 8 (8.6) | 12 (9.9) | 0.82 |
| Diabetes mellitus | 6 (2.8) | 3 (3.2) | 3 (2.5) | 1.00 |
| Dyslipidemia | 28 (13.1) | 11 (11.8) | 17 (14.1) | 0.63 |
| Hypertension | 48 (22.4) | 30 (32.3) | 18 (14.9) | 0.003 |
| Smoking (n = 194) | 0.85 | |||
| Present | 28 (14.4) | 13 (16.1) | 15 (13.3) | |
| Past | 50 (25.8) | 21 (25.9) | 29 (25.7) | |
| Never | 116 (59.8) | 47 (58.0) | 69 (61.1) | |
| Thrombotic event at the time of DD measurement | ||||
| Pulmonary embolism | 4 (1.9) | 3 (3.2) | 1 (0.8) | 0.32 |
| Treatment | ||||
| Immunosuppressants | 61 (28.5) | 21 (22.6) | 40 (33.1) | 0.09 |
| Corticosteroids | 70 (32.7) | 27 (29.0) | 43 (35.5) | 0.51 |
| Anticoagulant | 20 (9.3) | 11 (11.8) | 9 (7.4) | 0.34 |
| Antiaggregant | 32 (15.0) | 23 (24.7) | 9 (7.4) | 0.001 |
| Calcium channel blockers | 164 (76.6) | 74 (79.6) | 90 (74.4) | 0.43 |
DD: D-dimers plasma concentration; SD: standard deviation; IQR: interquartile range; RP: Raynaud’s phenomenon; SSc: systemic sclerosis.
Results are expressed as counts (percentage) unless otherwise specified. Significance level was set at 0.05.
p < 0.05.
A second DD measurement was available for 112 (52.3%) patients. DD levels remained elevated in 29/38 patients (76.3%). Furthermore, the medians of the first and second measurements did not differ significantly (441 ng/mL [IQR: 280–760] vs 400 ng/mL [IQR: 281–624], p = 0.96).
Clinical manifestations of SSc associated with high DD plasma concentrations
Patients with high DD levels were older (mean age was 59.5 ± 14.5 years vs 51.6 ± 13.9 years, p < 0.001) and had a higher frequency of malignancy (9.7% vs 2.5%, p = 0.03) and hypertension (32.3% vs 14.9%, p = 0.003) (Table 1). They were also more frequently on antiplatelet therapy (24.7% vs 7.4%, p = 0.001). There were no differences between the two groups regarding gender, disease duration, cutaneous subtype, other CV risk factors (diabetes, dyslipidemia, and smoking), and previous or concurrent venous thromboembolic events.
The type of autoantibodies and specific nonvascular SSc visceral manifestations did not differ between those with high DD levels and those with normal DD levels, except for telangiectasia which was more frequent in patients with high DD levels (75.3% vs 61.2%, p = 0.03) (Table 2). The median modified Rodnan skin score was mildly but significantly higher in those with high DD (6 vs 4, p = 0.04). There was also a higher percentage of patients with an elevated sPAP as measured by echocardiogram in the high DD group (19.2% vs 7.3%, p = 0.02).
Table 2.
Clinical, biological, and functional characteristics of 214 patients with systemic sclerosis having high (defined as >500 ng/mL) or normal D-dimers plasma concentration.
| Total (n = 214) | High DD (n = 93) | Normal DD (n = 121) | P-value | |
|---|---|---|---|---|
| Clinical manifestations | ||||
| Raynaud’s phenomenon | 205 (95.8) | 88 (94.6) | 117 (96.7) | 0.51 |
| Telangiectasia | 144 (67.3) | 70 (75.3) | 74 (61.2) | 0.03 |
| Dysphagia/reflux | 165 (77.1) | 73 (78.5) | 92 (76.0) | 0.67 |
| Arthralgia | 103 (48.1) | 47 (50.5) | 56 (46.3) | 0.54 |
| Calcinosis | 75 (35.0) | 35 (37.6) | 40 (33.1) | 0.49 |
| Sicca syndrome | 95 (44.4) | 39 (41.9) | 56 (46.3) | 0.53 |
| Modified Rodnan skin score (median [IQR]) (n = 202) | 5 [2–12] | 6 [2–15] | 4 [2–10] | 0.04 |
| Interstitial lung disease | 113 (52.8) | 56 (60.2) | 57 (47.1) | 0.06 |
| Low DLCO (<70%) (n/n total, %) | 135/197 (68.5) | 61/81 (75.3) | 74/116 (63.8) | 0.09 |
| Low FVC (<80%) (n/n total, %) | 47/194 (24.2) | 23/79 (29.1) | 24/115 (20.9) | 0.19 |
| Antibodies | ||||
| Anti-topoisomerase 1 | 74 (34.6) | 31 (33.3) | 43 (35.5) | 0.74 |
| Anti-centromere | 75 (35.0) | 31 (33.3) | 44 (36.4) | 0.64 |
| Anti-phospholipid (n = 127) | 14 (11.0) | 7 (13.5) | 7 (9.3) | 0.57 |
| Laboratorial and complementary data | ||||
| Hemoglobin (g/dL) (mean ± SD) | 12.7 ± 1.5 | 12.3 ± 1.7 | 13.1 ± 1.3 | <0.001 |
| Platelets (109/L) (mean ± SD) | 259 ± 84 | 270 ± 104 | 250 ± 65 | 0.10 |
| APTT (in seconds) (mean ± SD) | 35.0 ± 5.8 | 36.1 ± 6.8 | 34.1 ± 4.8 | 0.01 |
| Leucocytes a (×109/L) (median [IQR]) | 7.3 [5.8–9.1] | 7.3 [6.2–9.3] | 7.3 [5.4–9.0] | 0.22 |
| CRP a (mg/L) (median [IQR]) (n = 205) | 2.3 [1.0–7.0] | 6.6 [2.2–15.4] | 1.5 [0.0–4.2] | <0.001 |
| CRP > 5 mg/L (n/n total, %) | 71/205 (34.6) | 49/88 (55.7) | 22/117 (18.8) | <0.001 |
| Creatinine (µmol/L) (median [IQR]) | 66 [55–81] | 63 [54–88] | 68 [56–80] | 0.62 |
| sPAP b (mm Hg) (median [IQR]) (n = 183) | 29 [25–35] | 30 [25–39] | 28 [25–31] | 0.02 |
| sPAP ⩾ 41 mm Hg (n/n total, %) | 22/183 (12.0) | 14/73 (19.2) | 8/110 (7.3) | 0.02 |
| NT-proBNP (ng/L) (median [IQR]) (n = 205) | 93 [55–197] | 159 [82–313] | 73 [0–128] | <0.001 |
DD: D-dimers plasma concentration; DLCO: carbon monoxide diffusion capacity; FVC: forced vital capacity; SD: standard deviation; APTT: activated partial thromboplastin time; IQR: interquartile range; CRP: C-reactive protein; sPAP: systolic pulmonary artery pressure; NT-proBNP: N-terminal pro-brain natriuretic peptide.
Results are expressed as count (percentage) unless otherwise specified. Significance level was set at 0.05.
20 patients had both leucocytes >10 × 109/L and CRP >5 mg/L.
Estimated by echocardiography.
p < 0.05.
Signs of systemic inflammation were more frequent in patients with high DD levels, with 55.7% of patients having elevated CRP compared to 18.8% with normal DD levels (p < 0.001). Other differences in the laboratory values analyzed are shown in Table 2.
SSc-related vascular manifestations associated with high DD plasma concentrations
Microvascular manifestations were present in 108 (50.5%) patients (Table 3). There were 14 patients (6.5%) with PH confirmed by right-heart catheterization: 4 of group 1; 7 of group 3; and 3 of group 2.
Table 3.
Microvascular and macrovascular complications in 214 patients with systemic sclerosis having high (defined as >500 ng/mL) or normal D-dimer plasma concentration at baseline.
| Total (n = 214) | High DD (n = 93) | Normal DD (n = 121) | P-value | |
|---|---|---|---|---|
| Microvascular complications (⩾1) (n, %) | 108 (50.5) | 53 (57.0) | 55 (45.5) | 0.09 |
| Pulmonary arterial hypertension | 4 (1.9) | 2 (2.2) | 2 (1.7) | |
| Scleroderma renal crisis | 6 (2.8) | 5 (5.4) | 1 (0.8) | |
| Digital ulcers | 105 (49.1) | 50 (53.8) | 55 (45.5) | 0.23 |
| Macrovascular complications (⩾1) (n, %) | 15 (7.0) | 11 (11.8) | 4 (3.3) | 0.03 |
| Non-cardioembolic ischemic stroke | – | – | – | |
| Coronary artery disease/myocardial infarction | 7 (3.3) | 5 (5.4) | 2 (1.7) | |
| Peripheral artery disease | 10 (4.7) | 7 (7.5) | 3 (2.5) |
DD: D-dimer plasma concentration.
There was a tendency to a higher frequency of microvascular complications in patients with high DD levels (57.0% vs 45.5%, p = 0.09) (Table 3). After exclusion (Supplementary Tables 2 and 3) of patients with a history of cancer and/or venous thromboembolic disease (considered confounding factors for elevated DD levels), a significantly higher frequency of microvascular complications was observed in patients with high DD levels (60.5% vs 44.8%, p = 0.04) (Supplementary Table 4). After additionally excluding patients with concurrent signs of inflammation, the association between high DD levels and microvascular complications seemed even more significant (p = 0.014, total number = 166). Of note, there was also a higher frequency of active or previous digital ulcers in patients with high DD levels, that only reached significance after excluding patients with a history of cancer, venous thromboembolic disease or current signs of inflammation (p = 0.02, total number = 166).
Macrovascular manifestations were less frequent (15 patients, 7.0%) but were significantly associated with high DD level (11.8% vs 3.3%, p = 0.03) (Table 3), even after adjusting for significant covariates (Supplementary Table 5): crude OR: 3.9 [95% confidence interval (CI): 1.2–12.8], p = 0.023; adjusted OR for sex, age, and CRP: 4.0 [95% CI: 1.0–16.2, p = 0.049]; AUC = 0.84 (Supplementary Table 6). The association between high DD levels and macrovascular complications remained statistically significant (p = 0.049, total number = 166) after excluding patients with history of cancer, venous thromboembolic disease, or current signs of inflammation. Moreover, the median DD level in patients with macrovascular complications was significantly higher than in patients without (644 ng/mL [IQR: 426–939] vs 431 ng/mL [IQR: 277–749], p = 0.03) (Figure 2).
Regarding new vascular complications following the first DD measurement till the last follow-up visit (with a median follow-up period of 2.3 years [IQR: 1.1–3.3]), there were new microvascular events in 52 (24.3%) patients, with no difference between those with high or normal DD levels (p = 0.85) (Table 4). Macrovascular events, however, occurred in 8.6% of those with high DD levels, while no events occurred in the group with normal DD levels. The occurrence of new venous thromboembolic events was similar between the two groups (p = 0.47).
Table 4.
New microvascular/macrovascular complications and thromboembolic events occurring during the follow-up in 214 patients with systemic sclerosis with high (defined as >500 ng/mL) or normal D-dimer plasma concentration.
| Total (n = 214) | High DD (n = 93) | Normal DD (n = 121) | P-value | |
|---|---|---|---|---|
| New microvascular complications (⩾1) a (n, %) | 52 (24.3) | 22 (23.7) | 30 (24.8) | 0.85 |
| Pulmonary arterial hypertension | 1 (0.5) | 1 (1.1) | – | |
| Scleroderma renal crisis | – | – | – | |
| Digital ulcers | 51 (23.8) | 21 (22.6) | 30 (24.8) | 0.71 |
| With no previous digital ulcers (n/n total) | 6/51 | 1/21 | 5/30 | |
| New macrovascular complications (⩾1) a (n, %) | 8 (3.7) | 8 (8.6) | – | 0.001 |
| Non-cardioembolic ischemic stroke | 1 (0.5) | 1 (1.1) | – | |
| Coronary artery disease/myocardial infarction | 1 (0.5) | 1 (1.1) | – | |
| Peripheral artery disease | 6 (2.8) | 6 (6.5) | – | |
| In patients without history of macrovascular event (n/n total) | 5/8 | 5/8 | – | |
| Venous thromboembolism (⩾1) a (n, %) | ||||
| Venous thrombosis and/or pulmonary embolism | 7 (3.3) | 4 (4.3) | 3 (2.5) | 0.47 |
DD: D-dimer plasma concentration.
Median time of follow-up after D-dimer plasma level measurement was 2.3 years [IQR: 1.1–3.3].
Discussion
We have found that plasma DD are increased in approximately half of patients with SSc and that a high DD level was significantly associated with macrovascular complications. Furthermore, after excluding patients with confounding factors for high DD levels (history of cancer and/or venous thromboembolism), a high DD level was also associated with a higher frequency of microvascular complications.
Our findings are similar to most previous studies regarding the prevalence of high DD levels in SSc patients. Ames et al. 1 showed that DD, fibrinogen, and von Willebrand factor were higher in 26 SSc patients (11 lcSSc, 15 dcSSc) compared to 22 healthy controls (p < 0.001). However, they reported a mean DD level of 112 ± 7.6 ng/mL, which was lower than in our study, while more recent studies showed values similar to ours. In a French study, Marie et al. 30 confirmed that DD levels were significantly increased in 69 patients with SSc compared with age and sex-matched controls (506 vs 211 ng/mL, p < 0.001) and found a similar percentage of SSc patients with high DD (47.8% vs 4.5% in healthy controls, p < 0.001).
Another interesting finding in our study was that patients with high DD levels often kept an increased level whenever measurements were repeated, suggesting an ongoing underlying process, rather than a transient acute event. As already suggested by Ames et al., 1 hypo-fibrinolysis and increased thrombin generation could be viewed as an active intravascular amplification system that could significantly contribute to the progression of micro- and/or macrovascular complications.
Regarding the possible association between high DD levels and clinical cutaneous subtypes, we did not find a significant difference in DD levels between lcSSc and dcSSc. Results from previous studies have so far been heterogeneous on this matter. Marie et al. 30 found results similar to ours, while two other studies1,35 found higher DD levels in patients with dcSSc compared to lcSSc. However, in one of these, although a significant difference was reported, both subtypes had DD levels below 500 ng/mL (131 ± 10 ng/mL vs 91 ± 6.9 ng/mL), which may not be clinically relevant. Second, in the other study, 35 77% of the 56 included patients had dcSSc, which was a much higher prevalence than in our study, and may have biased the results.
Concerning microvascular complications, Marie et al. 30 found no association with high DD levels. In contrast, Alegre-Sancho et al. 31 found an association between high DD levels and low DLCO and ischemic digital ulcers in 115 SSc patients. Similar baseline associations were found in our study (such as advanced age, inflammation biomarkers, hypertension, sPAP). A low prevalence of PAH (1.9%) was observed, which could be due to selection bias, with a higher prevalence of PH (6.5%) if subtypes were considered all together. In our study, microvascular complications were more frequent in patients with high DD levels, although not significantly when analyzing the whole study population. However, after excluding patients with confounding factors for high DD levels (i.e. a history of cancer and/or venous thromboembolism) microvascular complications did seem to occur significantly more frequently in patients with high DD levels, suggesting a possible association.
Regarding the association between macrovascular disease and high DD levels in SSc patients, which has been consistently shown in small studies, our results, despite the small number of events, also confirm this association. Marie et al. 30 showed that macrovascular impairment is more frequent in SSc patients with high DD levels compared to those with normal DD (21% vs 6%, p = 0.05). More recently, Alegre-Sancho et al. 31 evaluated macrovascular damage in SSc patients, using intima media thickness of the extracranial branches of the carotid artery, the presence or absence of atheroma plaques, and the ankle-brachial index. They showed that macrovascular damage was associated with high DD baseline levels, even after adjustments (for age or any coexistent inflammatory disease). The low prevalence of macrovascular complications in our study may be due to the low burden of CV risk factors in our patients, as well as the regular and close follow-up of SSc patients in our referral center, which enables effective preventive measures.
Our study has several limitations that need to be addressed: first, it is a retrospective monocentric study; second, patient selection was restricted to those who had a DD measurement resulting therefore in some selection bias, although our study population was comparable to the rest of our SSc cohort; third, given the low incidence and prevalence of vascular manifestations, multiple adjustments for covariates were not feasible; finally, although some unreported factors could contribute to explain the higher frequency of macrovascular complications, such as genetic, diet, and exercise habits, previous studies suggested that CV risk factors do not seem to explain the excessive CV risk in SSc patients.13,30
Despite these limitations, this study is innovative because it evaluates the association of DD levels with SSc-specific microvascular and macrovascular complications in a large cohort of SSc patients. While it confirmed the results of recent published studies regarding the association of high DD levels with macrovascular manifestations in SSc patients, it also showed a possible association with microvascular complications.
In conclusion, DD plasma levels are frequently elevated, roughly in half of patients with SSc, independently of cutaneous subtype or visceral involvement, previous history or concurrent venous thromboembolic events. In patients with SSc, a high DD level seems to be associated with the occurrence of macrovascular and SSc-specific microvascular complications. Further prospective studies are nonetheless needed to clarify the potential impact of DD level measurement in patients with SSc.
Supplemental Material
Supplemental material, Supplementary_tables-final for High D-dimer plasma concentration in systemic sclerosis patients: Prevalence and association with vascular complications by Sofia Furtado, Bertrand Dunogué, Georges Jourdi, Benjamin Chaigne, Aziza Chibah, Paul Legendre and Luc Mouthon in Journal of Scleroderma and Related Disorders
Acknowledgments
The Editor/Editorial Board Member of JSRD is an author of this paper, therefore, the peer review process was managed by alternative members of the Board and the submitting Editor/Board member had no involvement in the decision-making process.
Footnotes
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iDs: Sofia Furtado 
https://orcid.org/0000-0003-1557-2020
Paul Legendre
https://orcid.org/0000-0003-2787-5491
Supplemental material: Supplemental material for this article is available online.
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Supplementary Materials
Supplemental material, Supplementary_tables-final for High D-dimer plasma concentration in systemic sclerosis patients: Prevalence and association with vascular complications by Sofia Furtado, Bertrand Dunogué, Georges Jourdi, Benjamin Chaigne, Aziza Chibah, Paul Legendre and Luc Mouthon in Journal of Scleroderma and Related Disorders