C-reactive protein and red cell aggregation correlate with late venous function after acute deep venous thrombosis
Article Outline
Objective
Risk factors leading to development and subsequent progression of chronic venous insufficiency after acute deep venous thrombosis (DVT) are only partially identified. Inflammation and rheologic abnormalities might have a causative role. The purpose of this study was to investigate C-reactive protein (CRP), D-dimer, and blood rheologic parameters in patients after acute DVT in relation to clinical outcome.
Subjects and methods
Patients with a history of acute proved DVT underwent clinical examination and duplex ultrasound scanning of the veins, and Venous Clinical Severity Score (VCSS) and Venous Segmental Disease Score (VSDS) were calculated. Further, CRP, D-dimer, and several rheologic parameters were determined and related to outcome as assessed with venous scores.
Results
Forty-three patients were examined 28 (median) months after the index event. Patients had higher CRP (P < .001), D-dimer (P < .001), red blood cell aggregation (P < .01), fibrinogen concentration (P < .01), and leukocyte count (P < .05) than did healthy control subjects. CRP and red blood cell aggregation were positively correlated with VCSS (r = 0.42 and P < .01, and r = 0.30 and P < 0.05, respectively). Multivariate regression analysis showed that the relation between CRP and VCSS was independent of other laboratory and rheologic parameters and of age, total thrombus load, duration of compression therapy after the index event, recurrence, recanalization, and presence of comorbid conditions (P < .05).
Conclusions
CRP is independently related to the severity of venous dysfunction in patients after acute DVT. Chronic inflammation as well as changes in blood rheologic parameters may be causally involved in the development of chronic venous insufficiency occurring in the medium-term and long-term course after acute DVT.
After acute deep venous thrombosis (DVT) patients are at increased risk for development of chronic venous insufficiency (CVI) due to post-thrombotic syndrome. Factors that contribute to development and progression of the disease include chronic venous hypertension, ultimately leading to disturbances in the microcirculation (eg, capillary damage) and changes in blood viscosity.1
A low incidence of post-thrombotic syndrome, as a result of administration of oral anticoagulant agents and regular compression therapy, has been demonstrated in patients at low risk in a long-term follow-up study after DVT (Zurich study).2 In this study only 5% of patients developed marked trophic changes. However, the rate of recurrence was 24%. Several clinical, acquired, and inherited risk factors for development of post-thrombotic syndrome, such as the initial extent of thrombus (total thrombus load),3 ipsilateral recurrent DVT,4 and thrombophilia-associated genetic disorders including activated protein Cresistance caused by factor V Leiden mutation,5 have been identified. Furthermore, both increased serologic markers of activated coagulation, such as prothrombin fragments 1 and 2 and markers of inhibited fibrinolysis, such as antigen levels against tissue plasminogen activator, after acute DVT are inversely related to the extent of recanalization.6 Red blood cell aggregability, another crucial determinant of blood viscosity, also is increased in patients with a history of unexplained DVT, which suggests a causal relationship between alterations in blood rheologic parameters and thromboembolic events.7
There is increasing clinical and experimental evidence that inflammatory processes, in combination with alterations in blood rheologic parameters, might also have a pivotal role in the setting of acute DVT. In a recent study plasma C-reactive protein (CRP) was significantly increased in patients with acute DVT,8 which suggests a role for an inflammatory component in the pathogenesis of CVI after DVT. In another study, increased expression of vascular cell adhesion molecule-1, a ligand expressed by cytokine-stimulated endothelium, was significantly linked to the occurrence of venous thromboembolism.9
However, to date, markers of inflammation have not yet been thoroughly investigated in patients after DVT in relation to their clinical mid-term to long-term outcome.
Therefore the purpose of our study was to investigate CRP, D-dimer, and rheologic parameters in patients after acute DVT. Furthermore, we wanted to examine in particular the relationship of these parameters to clinical outcome and recanalization, as verified at duplex ultrasound scanning. To this end we used the recently established new scoring system for evaluation of chronic venous disease.10
Patients and methods
Patients
Allpatients who had been referred to the Division of Angiology, University Hospital Zurich, between Jan 1, 1994, and Sep 30, 2001, for evaluation of suspected DVT were identified by review of patient charts. All patients with DVT of the lower extremities, proved with duplex ultrasound scanning or ascending phlebography, were invited by telephone to participate in the study. Patients who consented were invited to return to the hospital for a clinic visit, which consisted of a medical interview, physical examination, color-coded duplex ultrasound scanning of the veins, and determination of CRP, D-dimer, and several rheologic variables.
After written informed consent was obtained, a precise medical history was taken, with particular attention to questions about the presence of thrombotic risk factors at the onset of acute DVT, duration of anticoagulant therapy after DVT, compression therapy, and eventual recurrent thromboembolic events. In addition, particular attention was paid to present comorbid conditions that may have influenced inflammatory and rheologic parameters, such as recent surgery or recent acute illness. Symptoms of CVI were asked about according to a standardized questionnaire.
At clinical examination, signs of CVI were exactly recorded, and patients were classified according to the clinical component (C) of the CEAP classification.3 Furthermore, the Venous Clinical Severity Score (VCSS), as described by Rutherford et al, was calculated.10 This score includes 9 clinical characteristics, and has been proposed by a Committee of the American Venous Forum as a quantitative measure for clinical characterization of the severity of venous dysfunction. A thrombus score, as described by Porter et al,3 was also calculated for each patient.
Methods
All patients underwent color-coded duplex ultrasound scanning (Acuson 128XP) of the veins in the affected leg.
For duplex ultrasound scanning, patients were placed in a 15-degree reverse Trendelenburg position. The inferior vena cava, iliac veins, common and superficial femoral veins, popliteal veins, tibial-soleal veins, and greater and minor saphenous veins were examined on the basis of standard ultrasound criteria, including visibility of thrombi, compressibility with external pressure, and presence of spontaneous or augmented flow. Each segment was accordingly classified as patent, partially occluded, or completely occluded. Insufficient venous valves were identified according to venous reflux during the Valsalva maneuver or with distal manual compression. From these data the Venous Segmental Disease Score (VSDS), as described by Rutherford et al,10 was calculated. This score is based on a combination of anatomic and pathophysiologic components. On the basis of appropriate venous imaging (duplex ultrasound scanning or phlebography), 11 major venous segments are graded according to the presence of reflux or obstruction. The segments are weighed with respect to their relative importance when involved in reflux or obstruction, with a maximum score of 10.
Blood was drawn from the antecubital vein without veno-occlusion, for determination of CRP concentration, D-dimer, platelet count, white blood cell count, and rheologic variables including fibrinogen, plasma viscosity, red blood cell aggregation, whole blood viscosity, hematocrit, and platelet aggregation.
Citrated plasma was used for the determination of plasma fibrinogen, with the method of Clauss.11 Plasma viscosity was determined in ethylenediamine tetraacetic acid (EDTA) plasma with a viscometer of the capillary type at 25°C (Processer viscosity system, PVS 1). Whole blood viscosity was measured in EDTA plasma with a rotational viscometer (Contraves LS 30) at a medium shear rate (2.37/s) and a low shear rate (0.695/s) at 37°C.12 Red cell aggregation in EDTA blood was determined at a low shear rate (3/s) with a photometric rheoscope (MA1-Aggregometer; Myrenne).13 EDTA blood was centrifuged at 15,000g for 5 minutes for determination of microhematocrit levels. Platelet aggregation was assessed by centrifuging (10 minutes, 1000g, room temperature) fresh citrated plasma (3.8%, 1:10) to obtain platelet-rich plasma concentration. The remaining sample was recentrifuged (15 minutes, 3000g, room temperature) to obtain platelet-poor plasma. Platelet-rich plasma was then adjusted with platelet-poor plasma to achieve a final platelet count of 250 × 109/L. After stimulation with epinephrine (final concentration, 0.1 mmol/L), collagen (final concentration, 5 mg/L), and adenosine diphosphate (final concentration, 0.002 mol/l), maximal aggregation was measured with an APACT 4 aggregometer. Platelet aggregation was registered photometrically as a change in light transmission over time. Platelet aggregation studies were performed within 30 minutes after blood collection. All blood cell counts were assessed with a semiautomated Sysmex K-1000 hematology analyzer (Toa Medical Electronics).
Twenty-nine clinically healthy age-matched and sex-matched subjects (12 men, 17 women; mean age, 52 ± 8 years) served as control subjects. None had a history of venous disease or any other serious disease. All were non-smokers, and none were taking any medication. At clinical examination none showed signs of venous disease or any other disease, and results of routine laboratory studies were normal.
Statistical analysis
All statistical analyses were performed with Statview 5.0 software. Continuous variables are reported as mean ± SD, and categorical variables as percentage. Two group comparisons for continuous variables were performed with the Mann-Whitney U test, and for categorical variables with the χ2 test.
Regression analysis was used to investigate the relation between laboratory and rheologic variables, and venous scores. Multivariate regression analysis was applied to account for the effect of possible confounders, including laboratory and rheologic variables with imbalances (P < .1) between patients and control subjects, and clinical factors such as age, total thrombus load, duration of compression therapy, recurrence, recanalization, presence of comorbid conditions. For the purpose of analysis, comorbid conditions were grouped together and run as a variable. P < .05 was considered statistically significant.
Results
Patients
Six hundred fourteen patients who had been referred for evaluation of suspected DVT from Jan 1,1994, to Sep 30, 2001, were identified by chart review. In 181 patients (29%) DVT was proved at color-coded duplex ultrasound scanning or phlebography. Of those, 170 (94%) patients had DVT in lower extremities, and 11 (6%) patients had DVT in upper extremities. One hundred seven patients (63%) refused to participate either because they were unable or unwilling to return to the hospital, had acute illnesses, or had undergone recent surgery, and were excluded. Twenty patients (12%) had died meanwhile, none because of venous thromboembolism. Finally, 43 (25%) patients with DVT in lower extremities were included in the study.
Retrospective analysis of patient charts revealed that patients who did not participate (n = 127) and those who eventually participated (n = 43) did not differ with respect to age (57.8 ± 20 years vs 58 ± 16 years; not significant [NS]), sex (male-female ratio, 58:69 vs 15:28; NS), and location of DVT (proximal-distal ratio, 68:59 vs 21:22; NS).The mean number of risk factors was 2.5 ± 1.8 versus 2.9 ± 1.5 in patients who did not enter the study compared with those who participated.
Characteristics of the 43 patients who eventually participated are shown in Table I.
Table I. Patient characteristics
| n | % | |
|---|---|---|
| Age (y) (mean ± SD) | 58 ± 16 | |
| Sex | ||
 Male | 15 | |
| Female | 28 | |
| Thrombosis risk factors at acute DVT event | ||
| Age >40 years | 37 | 86.0 |
| Malignancy | 6 | 14.0 |
| Immobilization | 10 | 23.3 |
| Estrogen therapy | 8 | 18.6 |
| Surgery | 10 | 23.3 |
| Cardiac disease | 7 | 16.3 |
| Prolonged travel (>6 h) | 4 | 9.3 |
| Limb trauma | 3 | 7.0 |
| Family history | 17 | 39.5 |
| Previous DVT | 6 | 14.0 |
| Pregnancy | 1 | 2.3 |
| Known prothrombotic state | 10 | 23.3 |
| Obesity | 5 | 11.6 |
| Proximal/distal DVT (n) | 21/22 | |
| Duration of anticoagulation therapy (mo) (mean ± SD) | 6.2 ± 5.8 | |
| Compression therapy | 35 | 81 |
| Duration (mo) (mean ± SD) | 9.8 ± 10.3 | |
| Time since acute DVT (mo) (mean ± SD) | 28 ± 19 | |
| Recurrent DVT since acute event | 6 | 14 |
The mean number of risk factors per patient for development of thrombosis at the time of acute DVT was 2.9 ± 1.5. Thirty-four patients (79%) had permanent risk factors (malignant tumor, inherited thrombophilia, advanced age), and 9 patients (21%) had transient risk factors (travel of long duration, immobilization). Twenty-one patients (49%) had proximal DVT (thrombosis involving the popliteal or more proximal veins), and 22 patients (51%) had distal DVT. DVT occurred more often in the left leg (58%) than in the right leg (42%).
All patients had initially been treated with therapeutic doses of low molecular weight heparin (LMWH). Forty-one patients subsequently were switched to coumarin; 2 patients continued LMWH because of contraindications to coumarin therapy.
Compression therapy was classified as regular when compression was applied at least 4 times per week during the daytime.
After discontinuation of anticoagulant therapy, 6 patients (14%) had recurrent DVT (18.7 ± 14.4 months after the first DVT event), in the ipsilateral leg in 3 patients. Recurrence in these patients occurred at least 8 months before performance of the present study.
Findings at clinical examination and duplex ultrasound scanning
Clinical findings, summarized as CEAP class, were related to findings obtained at duplex ultrasound scanning, and are shown in Table II. At clinical examination, most patients had CEAP class 1 to 3 disease, and only 1 patient had CEAP class 5 disease.
Table II. Clinical findings in relation to duplex ultrasound scanning in 43 patients after acute deep venous thrombosis
| CEAP clinical stage | No. of patients | Duplex ultrasound scanning | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Normal | Reflux | Obstruction | Obstruction + reflux | ||||||
| n | % | n | % | n | % | n | % | ||
| C0 | 4 | 3 | 75 | 1 | 25 | ||||
| C1 | 9 | 7 | 77 | 1 | 11 | 1 | 11 | ||
| C2 | 8 | 6 | 75 | 1 | 12.5 | 1 | 12.5 | ||
| C3 | 19 | 10 | 53 | 3 | 16 | 4 | 21 | 2 | 10 |
| C4 | 2 | 1 | 50 | 1 | 50 | ||||
| C5 | 1 | 1 | 100 | ||||||
Color-coded duplex ultrasound scans revealed complete recanalization in 29 patients (67%), and obstruction with or without reflux in 14 patients (33%). All patients with complete recanalization had no or only mild CVI (CEAP 0-3; Table II).
The mean value for all patients was 3.5 ± 2.6 for VCSS, and 0.7 ± 1.6 for VSDS. The mean thrombus score was 1 ± 1.9 (data not shown).
Patients with proximal DVT had higher VSDS scores (1.2 ± 2.1 vs 0.3 ± 0.6; P < .05) and also higher thrombus scores (1.6 ± 2.4 vs 0.5 ± 0.9; P < .05) compared with patients with distal DVT. Furthermore, we found that patients with severe CVI (class 4 or 5) had higher VCSS scores (9.7 ± 4.7 vs 3.0 ± 1.8; P < .001) and VSDS scores (3.3 ± 3.5 vs 0.6 ± 1.3; P < .005) compared with patients with no or mild CVI (class 0-3).
CRP, D-dimer, and rheologic variables
Patients had higher values for CRP, D-dimer, plasma fibrinogen, red blood cell aggregation, and white blood cell counts than did control subjects (Table III).
Table III. C-reactive protein, D-dimer, and rheologic variables
| Patients | Control subjects | P | |
|---|---|---|---|
| C-reactive protein (mg/L) | 6.11±7.3 | 3±2.1 | <.01 |
| D-Dimer (mg/L) | 0.4±0.2 | 0.25±0.15 | <.05 |
| Fibrinogen (mg/dL) | 339±77 | 293±48 | <.01 |
| Plasma viscosity (mPa.s) | 1.6±0.2 | 1.58±0.9 | NS |
| RCA low shear (AU) | 47.7±10 | 40.2±10 | <.01 |
| WBV low shear (mPa.s) | 25.5±7.8 | 26.0±6.5 | NS |
| WBV medium shear (mPa.s) | 14.9±3.3 | 14.9±5.4 | NS |
| Hematocrit (%) | 36.7±3.4 | 37.4±2.6 | NS |
| Platelet aggregation | |||
| ADP-induced (%) | 46.1±25.1 | 48.4±24.9 | NS |
| Epinephrine-induced (%) | 63.6±19.4 | 62.3±16.9 | NS |
| Collagen (%) | 70.1±14.9 | 71.1±19.7 | NS |
| Leukocytes (×103/μL) | 6.56±2.8 | 5.26±1.2 | <.01 |
| Platelets (×103/μL) | 224.5±62.6 | 229.3±62 | NS |
We found a significant correlation between CRP and VCSS (r = 0.42; P < .01), and red blood cellaggregation and VCSS (r = 0.30; P < .05; Fig 1, Fig 2).
Fig 1.
Correlation between C-reactive protein and Venous Clinical Severity Score (VCSS).
Fig 2.
Correlation between red blood cell aggregation and Venous Clinical Severity Score (VCSS).
There was a tendency for D-dimer to increase with VCSS; however, significance was not reached (r = 0.28; P = .07; Fig 3.
Fig 3.
Correlationbetween D-dimer and Venous Clinical Severity Score (VCSS).
For VSDS, we observed a trend to increase both with VCSS (r = 0.26; P = .09) and with CRP (r = 0.26; P = .09); no correlations were seen between VSDS and other laboratory or rheologic variables (all NS).
We found no differences in laboratory and rheologic variables between patient subgroups according to total thrombus load at the index event (proximal or distal DVT), recurrence and recanalization as verified at duplex ultrasound scanning (all NS).
Comorbid conditions present at follow-up are shown in Table IV. CRP was not different in patients without comorbid conditions and those with 1 or more comorbid conditions: 5.2 ± 7 mg/L (range, 2-37 mg/L) versus 8.0 ± 7.8 mg/L (range, 2-26 mg/L; P = .17).
Table IV. Comorbid conditions present at follow-up
| Comorbid condition | n | % |
|---|---|---|
| History of malignant disease; no active cancer | 6 | 14 |
| Cardiac disease: history of PCI; valvular heart disease | 7 | 16 |
| Arterial hypertension | 5 | 12 |
| Peripheral polyneuropathy | 1 | 2 |
| Osteoarthrosis | 6 | 14 |
| Depression | 1 | 2 |
| Epilepsy | 1 | 2 |
| Cystic kidney disease | 1 | 2 |
| Thrombophilia: heterozygous factor V Leiden mutation; increased thrombin-antithrombin III complex; heparin co-factor II deficiency | 5 | 12 |
Multivariate regression analysis showed that the relation between CRP and VCSS was independent of other laboratory and rheologic variables, and of age, total thrombus load, duration of compression therapy, recurrence, recanalization, and presence of comorbid conditions (P = .02).
Discussion
In the current work, we for the first time investigated inflammatory parameters in conjunction with rheologic variables in patients during the medium-term and long-term course after acute DVT, and correlated those parameters with recently established clinical scores for assessment of severity of venous dysfunction. VCSS has been established as a quantifiable measure for severity of venous dysfunction. We found that CRP, D-dimer, fibrinogen, red blood cell aggregation, and leukocyte count were increased in patients compared with control subjects. Furthermore, both CRP and red blood cell aggregation were significantly correlated with the clinical severity of CVI as assessed with VCSS.
CRP is a marker of systemic inflammation, and has been associated with increased risk for cardiovascular disease.14, 15, 16 CRP levels also predict future risk for development of symptomatic peripheral artery disease.17 Both CRP and D-dimer are inversely correlated with ankle-brachial index in patients with a history of cardiac or cerebrovascular disease,18 and are independently associated with altered walking performance in patients with PAD.19 Mechanisms that have been proposed to explain the effect of the inflammatory response, with CRP directly or indirectly contributing to the pro-inflammatory state, include impairment of endothelial function20, 21, 22 and migration of leukocytes mediated by adhesion molecules.23 Recently, increased attention in clinical8 and experimental studies24 has been on not only the involvement of inflammation in the pathogenesis of arterial atherogenesis but also its association with venous thrombogenesis. Studies in a mouse model of DVT recently provided strong evidence for a causal relationship between an inflammatory process and the development of DVT.24 High circulating levels of pro-inflammatory adhesion molecule P-selectin were associated with increased thrombosis. In addition, leukocyte-derived microparticles, which may be released after binding of P-selectin to its receptor, were also associated with increased thrombus formation.24 P-selectin expression on endothelial cells and platelets may be increased when stimulated by cytokines, which in turn are released from monocytes after CRP stimulation. That the link between inflammation and thrombosis might be a causal centerpiece in the pathogenesis of venous thrombosis is further supported by a recent observational study in men that demonstrated increased CRP levels in patients with acute DVT.8 We are the first to show that this inflammatory response is not only associated with the acute event, but may also be crucially involved in development of CVI in the context of post-thrombotic syndrome. Therefore, on the basis of our current data, we postulate that inflammation and its pathophysiologic consequences may well persist far beyond the acute event. However, this may not yet necessarily imply causality. In this context, that CRP levels were significantly associated with CVI independent of ongoing chronic disease should be emphasized. It remains unclear what determines clinical outcome after the index DVT event, in particular, why the inflammatory response apparently persists in some patients in whom post-thrombotic CVI will develop. One possibility might be the concomitant occurrence of changes in both inflammatory and rheologic status. Furthermore, although not verified in our population, the presence or persistence of other risk factors may contribute.
To the best of our knowledge, only 1 other study25 examined changes in coagulatory and pro-inflammatory parameters in the setting of CVI. However, this study included only consecutive patients with varicose veins in whom CVI developed, whereas our study included patients during the medium-term and long-term course after acute DVT. However, in contrast to our study, no significant increase in CRP or fibrinogen was found in those patients with varicose veins and CVI.25 Therefore we may hypothesize that the acute index event (DVT) must occur to trigger the pathophysiologic events associated with post-thrombotic CVI.
Although D-dimer level as a marker for ongoing fibrin formation and degradation was significantly increased in patients compared with control subjects, no significant correlation could be established between D-dimer and VCSS, even if there was a strong trend. This seems all the more surprising because D-dimer induces the synthesis and release of pro-inflammatory cytokines26 and may therefore fit very well into the “inflammation-thrombosis hypothesis” at the origin of DVT and post-thrombotic syndrome. Mechanisms proposed for the relation between CRP and CVI in the context of post-thrombotic syndrome may in principle also apply for D-dimer. However, the size of the patient group in our study may have been too small to establish significance. Furthermore, during the long period after the acute index event, other, non-DVT-related sources of inflammatory stimulation might have occurred. However, by taking an exact medical history, we strongly believe we minimized, although not completely ruled out, this possibility. The overall clinical classification of CVI in the limbs was low, inasmuch as only 3 patients (7%) had CEAP class 4 or 5 disease. Advanced grades of CVI are more likely to entail an intrinsic inflammatory component. Therefore an important possible confounder in this particular context seems unlikely to have relevantly contributed.
Despite a persistent inflammatory and pro-coagulant state, as demonstrated by increased levels of CRP, fibrinogen, and leukocytes on the one hand, and D-dimer and red blood cell aggregation on the other hand, duplex ultrasound scans in more than two thirds of our patients revealed complete recanalization. This may well be due to the use of potent drugs (LMWH, coumarin) and regular use of compression stockings.
Limitations of our study include the relatively small number of patients, in particular the small number of patients with severe venous insufficiency. Furthermore, although significance could be statistically documented, the correlations are rather weak, which might, at least in part, be due to the small number of patients. And last, definitive proof of causality and a cause-effect relationship cannot be established.
Recently the VCSS proposed by the American Venous Forum has been validated against an objective test (duplex ultrasound scanning).27 In our study it also proved to be a reliable and useful score for assessing venous outcome. That some of the parameters, CRP and red blood cell aggregation, were particularly well correlated with the clinical assessment of venous outcome, as evaluated by the recently established VCSS, may make them attractive markers for follow-up of patients in the future.
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Competition of interest: none.
PII: S0741-5214(04)00919-X
doi:10.1016/j.jvs.2004.07.004
© 2004 The Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.
