FACTORS RELATED TO THE POST-THROMBOTIC SYNDROME IN PATIENTS WITH DEEP VENOUS THROMBOSIS

Uvod. Globoka venska tromboza (GVT) je pogosta bolezen, ki prizadane 1-2 na 1000 prebivalcev letno. V Sloveniji je z GVT vsako leto diagnosticiranih približno 3000 bolnikov, kar predstavlja pomemben zdravstveni problem. Potrombotični sindrom (PTS) je kronični zaplet, ki se pojavi pri 20-50 % bolnikov z GVT. PTS zmanjša kakovost življenja in poveča z zdravljenjem povezane stroške. Patofiziologija PTS je zapletena in ne popolnoma raziskanapomembno vlogo igra povišan venski pritisk, ki ga povzroča kronična zapora vene in retrogradni tok krvi. PTS je definirana kot kombinacija simptomov in znakov, ki se pojavijo mesece ali leta po akutni GVT. Znanih je več dejavnikov tveganja, kot so višja starost, povišana telesna teža, bolj proksimalna tromboza, kronična venska insuficienca, ponavljajoča GVT, kajenja in subterapevtska antikoagulacija. Arterijska aterotrombotična bolezen in venska tromboza sta bili nekoč smatrani kot dve popolnoma ločeni bolezni, vendar več raziskav kaže na povezavo v etiologiji. Povezava med sistemskimi vnetnimi pokazatelji in aterosklerozo je znanaza vnetne dejavnike se pojavlja celo izraz novi dejavniki tveganja za kardiovaskularno bolezen. Povezava vnetja in venske bolezni je manj raziskana, vendar študije kažejo na pomembnost vnetnih dejavnikov pri patofiziologiji GVT. Prav tako so nekatere študije raziskovale povezavo med sistemskimi vnetnimi dejavniki in PTS, vendar so rezulatati zaenkrat večinoma nasprotujoči. Cilj. Naš cilj je bil raziskati različne dejavnike, povezane z GVT in PTS: spremembe v funkciji žilne stene, plazemske nivoje sistemskih vnetnih in fibrinolitičnih markerjev ter rekanalizacijo. Dodatno smo želeli ugotoviti pogostost in oblike PTS med našimi bolniki z GVT ter primerjati načine zdravljenja. Metode. Vključili smo 120 zaporednih bolnikov, zdravljenih zaradi GVT v Dnevni bolnišnici Kliničnega oddelka za žilne bolezni, Univerzitetni klinični center Ljubljana. Vključitvena kriterija sta bila: proksimalna GVT spodnjih okončin (V. femoralis communis, V. femoralis in/ali V. poplitea) in starost med 35 in 75 let. Izključili smo bolnike z aktivnim malignim obolenjem, simptomatsko arterijsko boleznijo, boleznimi, ki bi lahko pomembno vplivale na nivoje sistemskih vnetnih markerjev, ter bolnike, ki niso želeli sodelovati. Dodatno smo vključili kontrolno skupino 40 antropometrično podobnih preiskovancev, ki niso nikoli preboleli GVT. Raziskavo je odobrila Komisija Republike Slovenije za medicinsko etiko (soglasje številka 121/08/14). Pred vključitvijo v raziskavo so vsi preiskovanci podpisali pisno soglasje. Bolniki so bili 12 do 36 mesecev po diagnozi GVT povabljeni na kontrolni pregled. Pregledali smo zdravsteno dokumentacijo, se pogovorili z bolniki in naredili klinični pregled, pri čemer smo se osredotočili na znake in simptome PTS. Odvzeli smo kri za krvne preiskave sistemskih vnetnih in fibrinolitičnih markerjev, izmerili krvni tlak, telesno težo in telesno višino. Z različnimi metodami smo merili smo lastnosti arterijske žilne stene (ultrazvočna ocena endotelijske funkcije brahialne arterije, periferna tonometrija, togost arterij). Preiskovaci so izpolnili vprašalnik o težavah z nogo. Podatke smo organizirali in jih statistično obdelali. Rezultati. Mediana starosti bolnikov z GVT je bila 60,5 let, večji del je bilo moških (58 %), v povprečju so imeli povišan indeks telesne mase (28,7 kg/m2). Izmed 120 bolnikov po GVT jih je 34 % zbralo 5 ali več točk po točkovniku Villalta, s čimer so izpolnjevali kriterije za PTS. Bolniki s PTS so bili starejši in so pogosteje imeli ponavljajoče GVT. Najpogostejši simptomi in znaki so bili bolečina, teža in krči v nogi ter otekanje noge. Ob ultrazvočnem pregledu ven je bil tromb še vedno viden pri 72 % bolnikov z GVT – v 14 % je bila vena popolnoma okludirana, medtem ko je bila v 58 % le delno okludirana. Bolniki, ki so razvili PTS, so imeli nižjo stopnjo rekanalizacije v primerjavi z bolniki brez PTSpopolna rekanalizacija je bila pogostejša pri bolnikih brez PTS (6 % proti 29 %, p=0,001). V prisotnosti refluksa statistično pomembnih razlik med skupinama nismo opažali. Glede na način zdravljenja smo bolnike razdelili na dve skupini – 77 bolnikov je bilo zdravljenih z rivaroksabanom, 43 pa z varfarinom v kombinaciji z nizkomolekularnim heparinom ob začetku zdravljenja. Tudi ko smo rezultate vključili v multiplo analizo z ostalimi dejavniki, kot je starost, so imeli bolniki zdravljeni z varfarinom 4,2-krat višje obete za razvoj PTS v primerjavi z bolniki, zdravljenimi z rivaroksabanom (p=0,006). Velika večina vseh bolnikov je vsaj v začetnem obdobju redno uporabljala kompresijsko terapijo. Našli smo statistično značilno razliko v endotelijski funkciji brahialne arterije med bolnikih 12 do 36 mesecev po GVT in kontrolno skupino. Bolniki po GVT so imeli nižjo od pretoka odvisno vazodilatacijo - FMD (0,04 proti 0,08, p=0,001) in od endotelija neodvisno vazodilatacijo - NMD (0,12 proti 0,19, p=0,001). Bolniki po GVT so imeli tudi povišan premer brahialne arterije. S pomočjo periferne arterijske tonometrije smo izmerili statistično značilno povišan augmentacijski indeks (AI) in augmentacijski indeks, prilagojen na frekvenco 75 utripov/minuto (AI75) pri bolniki po GVT v primerjavi s kontrolno skupino (22,0 proti 6,0, p=0,004 ter 16,0 proti 1,5, p=0,001). Med bolniki z in brez PTS pomembnih razlik v endotelijski funkciji brahialne arterije ter meritvah periferne tonometrije nismo izmerili. Izmerili smo pomembne razlike v laboratorijskih vrednostih CRP, levkocitov, D-dimerja, PAI-1 in t-PA pri bolnikih več kot eno leto po akutni GVT v primerjavi s kontolno skupino. Med bolniki z in brez PTS pomembnih razlik v nivojih sistemskih vnetnih in fibrinolitičnih markerjev nismo izmerili. Zaključki. PTS se je pojavil pri 34% naših bolnikov z GVT. Bolniki s PTS imajo zmanjšano funkcijo nog, zato je pri zdravljenju GVT potrebno preprečevanje in zmanjševanje simptomov PTS. Bolniki s PTS so imeli nižjo stopnjo rekanalizacije prizatedih ven v primerjavi z bolniki po GVT, ki PTS niso razvilizgodnja rekanalizacija je verjetno pomembna pri zdravljenju GVT. Bolniki, zdravljeni z rivaroksabanom, so imeli nižjo incidenco PTS v primerjavi z bolniki, zdravljenimi z varfarinom, vendar bi bila za zanesljiv dokaz potrebna večja randomizirana raziskava. Bolniki po GVT so imeli 12 do 36 mesecev po akutni GVT večji premer brahialne arterije ter bolj izraženo endotelijsko disfunkcijo in togost arterij v primerjavi s kontrolno skupino, kar nakazuje povezavo med vensko boleznijo in funkcijo arterijske žilne stene. Bolniki z GVT so imeli v primerjavi s kontrolno skupino 12 do 36 mesecev po akutni GVT višje nivoje sistemskih vnetnih in fibrinolitičnih markerjev, kar kaže na povečano vnetno in fibrilnolitično aktivnost tudi več kot eno leto po akutni GVT. Pomembnih razlik v lastnostih arterijske žilne stene ter nivojih sistemskih vnetnih in fibrinolitičnih markerjev med bolniki z in brez PTS nismo našli.Introduction. Deep venous thrombosis (DVT) is a common disease which affects 1&#87222 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 understoodincreased 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 knowninflammatory 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 PTScomplete 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 PTSearly 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