Introduction. Deep venous thrombosis (DVT) is a common disease which affects 1−2 out of 1000 people every year. In Slovenia, approximately 3000 people are yearly diagnosed with DVT, which makes it an important health problem. Post-thrombotic syndrome (PTS) is a chronic complication, which occurs in 20 to 50% of the DVT patients. PTS reduces the quality of life and significantly increases healthcare-related costs.
Pathophysiology of PTS is complicated and not entirely understood; increased venous pressure plays the main role and is caused by chronic vein occlusion and retrograde blood flow. PTS can be defined as a combination of different symptoms and signs that appear in patients with a history of DVT. Several risk factor have been discovered, such as older age, higher body mass, more proximal thrombosis, chronic venous insufficiency, recurrent DVT, smoking, and subtherapeutic anticoagulation.
Pathophysiology of arterial atherosclerotic disease and venous thrombosis used to be interpreted as two distinct mechanisms, however, a lot of data show a relationship between the two in their etiology. A relationship between blood levels of systemic inflammatory markers and atherosclerosis is known; inflammatory markers are sometimes designated as novel risk factors for cardiovascular disease. The relationship between inflammation and venous thrombosis is less understood, however, studies show that inflammatory markers are probably important in the pathophysiology of DVT. Some studies also investigated the relationship between inflammation and PTS, however, the results are not conclusive.
Aim. We aimed to investigate different factors related to DVT and PTS: deteriorated vessel wall function, inflammatory and fibrinolytic markers, and recanalization. Additionally, we evaluated the incidence and forms of PTS among our DVT patients and compared different types of treatment.
Methods. We included 120 consecutive patients treated for DVT in the outpatient clinic of the Department of Vascular Disease, University Medical Centre Ljubljana. Inclusion criteria were the following: proximal DVT of lower extremities (V. femoralis communis, V. femoralis and/or V. poplitea) and age between 35 and 75 years. Patients with active cancer, symptomatic arterial disease, diseases, that would significantly influence levels of systemic inflammatory markers, and those unwilling to participate were excluded. Additionally, we included a control group of 40 anthropometrically comparable subjects without a history of DVT.
The research was approved by the Republic of Slovenia National Medical Ethics Committee (reference number 121/08/14). Written informed consent was obtained from all patients before inclusion in the study.
Patients were invited for a check-up visit at the clinic in the period between 12 and 36 months after the DVT diagnosis. A thorough medical history was obtained, focusing on the DVT diagnosis and treatment. A clinical examination was performed, specifically searching for signs of PTS. Blood for laboratory analyses of the selected systemic inflammatory and fibrinolytic markers was collected and blood pressure, body mass and body height measured. Properties of the arterial wall were investigated using several techniques (ultrasound assessment of endothelial function of the brachial artery, peripheral tonometry, arterial stiffness). Patients answered a questionnaire about leg symptoms. The data was organized and statistically analysed.
Results. Median age of the DVT patients was 60.5 years, a majority of them were men (58%) and had increased body mass index (28.7 kg/m2). Out of 120 DVT patients, 34% had a Villalta score of 5 or more, fulfilling the criteria for PTS. These patients were older and more often had recurrent DVT. The most common symptoms and signs of PTS were leg pain, heaviness, cramps and swelling.
At the time of the ultrasound vein examination, the thrombus was still visible in 72% of the DVT patients – in 14% the vein was completely occluded, while in 58% it was partially occluded. The group of patients who developed PTS had a lower recanalization rate in comparison to the group without PTS; complete recanalization was more often seen in patients without PTS (6% vs. 29%, p = 0.001). There were no significant differences in the presence of reflux between the groups.
According to the type of treatment, DVT patients were divided into two groups: 77 patients were treated with rivaroxaban and 43 with warfarin combined with a low molecular weight heparin in the initial period. Even when adjusted for other factors, such as age, patients treated with warfarin had an odds ratio of 4.2 for PTS development (p = 0.005) in comparison to the patients treated with rivaroxaban. A great majority of all DVT patients used compression therapy at least in the initial period of the treatment.
We found statistically significant differences in the endothelial function of the brachial artery between patients after DVT and the control group in the period 12 to 36 months after the acute DVT. Patients after DVT had decreased FMD (0.04 vs. 0.08, p = 0.001) and NMD (0.12 vs. 0.19, p = 0.001). An increased brachial artery diameter was found in the DVT group. Using peripheral arterial tonometry, we found significantly increased augmentation index (AI) and augmentation index, adjusted to the heart rate of 75/minute, (AI75) in patients after DVT in comparison to the control group (22.0 vs. 6.0, p = 0.004 and 16.0 vs. 1.5, p = 0.001, respectively). No significant differences in the endothelial function of the brachial artery and arterial stiffness between PTS-positive and PTS-negative patients were found.
In laboratory blood analyses, we found important differences in the values of CRP, leukocytes, D-dimer, PAI-1 and t-PA in patients more than one year after acute DVT in comparison to the control group. No significant differences in blood markers between PTS-positive and PTS-negative patients were found.
Conclusions. PTS occurs in about 34% of our DVT patients. Patients with PTS have a reduced function of lower limbs, therefore PTS prevention and symptom reduction are necessary in DVT treatment. Patients who develop PTS had a lower rate of venous recanalization in comparison to DVT patients who do not develop PTS; early recanalization is probably important. Patients treated with rivaroxaban had a lower incidence of PTS in comparison to the patients treated with warfarin, however, larger randomized study would be needed for stronger evidence. Patients with DVT assessed 12 to 36 months after the acute DVT had increased diameter of the brachial artery, more deteriorated endothelial function and more expressed arterial stiffness in comparison to the control group, indicating an association between venous disease and arterial wall function. DVT patients had higher levels of inflammatory and fibrinolytic markers measured 12 to 36 months after acute DVT in comparison to the control group, indicating increased inflammatory and fibrinolytic activity years after acute DVT. No significant differences in the arterial wall function and levels of systemic inflammatory and fibrinolytic markers between PTS-positive and PTS-negative patients were found.