Risk assessment of deep vein thrombosis with D-dimer level in patients eligible for vascular surgery

Introduction

D-dimer (DD) is the end product of fibrin degradation by plasmin [1], and an increased level of DD indicates activation of the coagulation system and fibrinolysis. The main diagnostic value of DD is its ability to indirectly assess the intensity of thrombin generation and the conversion of fibrinogen to fibrin catalysed by thrombin in both arteries and veins. The upper limit of DD is usually set at 500 ng/ml fibrinogen equivalent units (FEU) [2].
It is estimated that about 40% of patients with elevated DD levels are at risk of developing venous thromboembolism, which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). However, many other clinical states are associated with elevated DD, including disseminated intravascular coagulation, myocardial infarction, ischaemic stroke, neoplasm, patients after surgical procedures and trauma, inflammatory pathologies such as inflammatory bowel disease, infections (particularly bacterial ones), and severe post-thrombotic syndrome with large varicose veins or ulcerations [3-6]. Thromboembolic complications represent a major problem in general surgery patients. Vascular surgery patients are at even higher risk. Up to 15-25% of patients not receiving thromboprophylaxis can postoperatively develop DVT [7]. This concerns particularly patients after major general surgical interventions and patients presenting with risk factors for thromboembolism. The risk of thrombotic complications seems to be even higher in patients with initially high levels of DD [8].
Atherosclerotic peripheral arterial occlusive disease, which in some patients requires surgical reconstruction, is a relatively common disease. Prevalence of peripheral arterial occlusive disease is estimated to be at the level of 3-10% of adults and it increases with age. As many as 15-20% individuals older than 70 years present with clinical signs of peripheral arterial occlusive disease [5]. In Poland 40,000 new cases are noted each year [9]. Immobility, which is due to severe occlusive atherosclerosis, is often associated with increased risk of venous thromboembolism. In spite of the fact that patients scheduled for vascular reconstructions present with risk of thromboembolism, current guidelines do not recommend routine thromboprophylaxis [7, 10].
The aim of this study was to assess D-dimer levels in a group of patients scheduled for femoropopliteal bypass and to compare results of this laboratory test to those obtained in a group of volunteers without lower limb ischaemia.

Material and methods

We included two research groups and one control group in our study. Group I (n = 50) suffered from stage IIb lower-limb ischaemia according to Fontaine’s classification, and group II (n = 52) from stage III lower-limb ischaemia. The control group (n = 49) consisted of persons without ischaemia of lower extremities but with comorbidities typical for their age group, who spend their free time in one of Wroclaw’s senior clubs.
Inclusion criteria for groups I and II: stage IIb or III lower limb ischaemia according to Fontaine’s classification.
Relative criteria for groups I, II, and control groups (at least one of the listed below):
• type 2 diabetes mellitus,
• qualification for femoropopliteal bypass surgery,
• history of myocardial infarction,
• history of ischaemic stroke without subsequent motor disability,
• hypertension controlled with pharmacotherapy.
Exclusion criteria:
• trophic changes in the lower limbs,
• sensory disturbances resulting from ischaemia (sensory neuropathy) without intermittent claudication,
• comorbidities that permanently impair motor function,
• diagnosed mental illness,
• lack of an informed and voluntary consent to participate in the study,
• neoplastic disease.
The numbers of participants in each arm of the study are presented in Figure 1.
Samples of venous blood were collected to determine levels of DD. Levels of DD were measured using quantitative agglutination and immunoassay tests. These laboratory investigations were performed in the laboratory of University Teaching Hospital in Borowska Street, Wroclaw. Demographic and clinical characteristics of patients and controls are presented in Table 1.

Statistical methods

In a case of nonrepudiation of the hypothesis on normal distribution, the distributions were compared using the one-way analysis of variance (ANOVA). The F-test that was used in the analysis when comparing two means consisted of Student’s t-test squared. The correlations of categorised variables (of discrete distribution) were evaluated using the chi-squared test (χ2). The statistical significance was determined with the significance level set at α = 0.05. The calculations were performed using Statistica 8.0 and GNU Octave 4.0.0 software.

Results

DD levels did not significantly differ between patients presenting with stage IIb and stage III of lower limb ischaemia. However, values of DD differed significantly between patients and controls (Table 2). There was no monotonic relationship between DD levels and patient’s age. A rising trend was noted in group I, while simultaneously, a significant decrease was observed in the group of patients from 56 to 65 years of age (0.7 µg/ml). On the other hand, in the age group over 66 years, the mean DD value increased to 1.1 µg/ml. The situation is slightly different in the second group, with DD value decreasing from 1.3 to 0.8 µg/ml with the age of the patients, but still remaining high in the last subgroup. In the control group, a strong growing tendency can be observed when comparing the medians of the DD level between the age groups; the DDr level doubles between the age groups from 58 to 60 years and 65 to 69 years (from 0.2 to 0.4) (Table 3, Fig. 2).

Discussion

Atherosclerotic peripheral arterial occlusive disease chronically impairs patient’s mobility. In addition, comorbidities such as diabetes and hypertension contribute to the unfavourable clinical prognosis. In this paper we analysed one of the risk factors for thromboembolism. We tried to assess whether chronic ischaemia of the lower limbs influences DD levels.
Our study demonstrated that DD levels were elevated in comparison with the control group. Our research also indicated that while D-dimer levels decreased with age from 1.3 µg/ml to 0.8 µg/ml while still being elevated in one of the groups (group II), they had a tendency to increase in the other group (group I) from 0.9 µg/ml to 1.1 µg/ml. Ntourakis et al. [11] observed high D-dimer levels in patients over 70 years of age, and the difference between the age groups was statistically significant. Natkaniec et al. [12], however, did not observe a correlation between the age of the patient and coagulation parameters, including D-dimer levels [13]. Känel et al. [14] in their study on 116 persons also noted a statistically significant correlation between the age and D-dimer levels, which probably increases the risk of myocardial infarction, unstable angina pectoris, or vascular disorders [9].
Garg et al. [15] assessed the risk factors of thromboembolic events depending on age, gender, and BMI. Although the BMI differences between the groups were small and not statistically significant, there was a positive correlation between the BMI and D-dimer levels; a D-dimer level increase was noted with the increase of BMI (Figs. 3 and 4). A similar study by Grygiel-Górniak [16] assessed patients with diabetes and high BMI, particularly with abdominal fat distribution. The patients had high D-dimer levels and elevated thromboembolic risk. Nwose et al. [17], who sought to correlate the D-dimer levels with diabetes progression in overweight patients, managed to observe a correlation between these variables. Moreover, prolonged duration of the disease also proved to increase the prothrombotic markers [18].
Ambiguity of the results encourages closer examination of patients with lower-limb ischaemia in the context of D-dimer levels.

Conclusions

DD levels are higher in patients presenting with chro­nic lower-limb ischaemia, but the clinical stage of ischae­mia does not correlate with the levels of DD.
No strong correlation between the age of patients or controls and DD levels was revealed.

The authors declare no conflict of interest.

References

1. Reber G, de Moerloose P. Standardization of D-dimer testing. In: Kitchen S, Olson JD, Preston FE (Eds.). Quality in laboratory hemostasis and thrombosis. Wiley-Blackwell, Oxford, 2009: 99-109.
2. Bruinstroop E, Van de Ree MA, Huisman MV. The use of D-dimer in specific clinical conditions: a narrative review. Eur J Intern Med 2009; 20: 441-446.
3. Kovac M, Mikovic Z, Rakicevic L, Srzentic S, Mandic V, Djordjevic V, Radojkovic D, Elezovic I. The use of D-dimer with new cutoff can be useful in diagnosis of venous thromboembolism in pregnancy. Eur J Obstet Gynecol Reprod Biol 2010; 148: 27-30.
4. Morse M. Establishing a normal range for D-dimer levels through pregnancy to aid in the diagnosis of pulmonary embolism and deep vein thrombosis. J Thromb Haemost 2004; 2: 1202-1204.
5. Olson JD, Cunningham MT, Higgins RA, Eby CS, Brandt JT. D-dimer: simple test, tough problems. Arch Pathol Lab Med 2013; 137: 1030-1038.
6. Oude Elferink RF, Loot AE, Van De Klashorst CG, Hulsebos-Huygen M. Clinical evaluation of eight different D-dimer tests for the exclusion of deep venous thrombosis in primary care patients. Scand J Clin Lab Invest 2015; 75: 230-238.
7. Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW. Prevention of venous thromboembolism. Chest 2008; 133: 381-453.
8. Burns A, Rabins P. Career burden in dementia. Int J Geriatr Psychiatry 2000; 15: 9-13.
9. Tripodi A. D-dimer testing in laboratory practice. Clin Chem 2011; 57: 1256-1262.
10. Cosmi B, Palareti G. Update on the predictive value of D-dimer in patients with idiopathic venous thromboembolism. Thromb Res 2010; 125 (Suppl. 2): S62-65.
11. Ntourakis D, Sergentanis TN, Georgiopoulos I, Papadopoulou E, Liasis L, Kritikos E. Subclinical activation of coagulation and fibrinolysis in laparoscopic cholecystectomy: do risk factors exist? Int J Surg 2011; 9: 374-377.
12. Natkaniec M, Szczupak K, Ostachowski M, Matłok M, Migaczewski M, Pędziwiatr M. Coagulation profile in patients undergoing elective laparoscopic surgery. Przegl Lek 2014; 71: 528-531.
13. Taira T, Taira BR, Carmen M, Chohan J, Singer AJ. Risk of venous thromboembolism in patients with borderline quantitative D-dimer levels. Am J Emerg Med 2010; 28: 450-453.
14. Känel R, Dimsdale JE, Mills PJ, Ancoli-Israel S, Patterson TL, Mausbach BT, Grant I. Effect of Alzheimer caregiving stress and age on frailty markers interleukin-6, C-reactive protein, and D-dimer. J Gerontol A Biol Sci Med Sci 2006; 61: 963-969.
15. Garg PK, Teckchandani N, Hadke NS, Chander J, Nigam S, Puri SK. Alteration in coagulation profile and incidence of DVT in laparoscopic cholecystectomy. Int J Surg 2009; 7: 130-135.
16. Grygiel-Górniak B. Oxidative stress as a cardio-diabetologic risk factor – facts and myths. Bromat Chem Toksykol 2010; 43: 109-117.
17. Nwose EU, Jelinek HF, Richards RS, Kerr PG. Erythrocyte oxidative stress in clinical management of diabetes and its cardiovascular complications. Br J Biomed Sci 2007; 64: 35-43.
18. Keeling DM, Mackie IJ, Moody A, Watson HG. The diagnosis of deep vein thrombosis in symptomatic outpatients and the potential for clinical assessment and D-dimer assays to reduce the need for diagnostic imaging. Br J Haematol 2004; 124: 15-25.