Povezanost deplecije limfocita i trombocita nakon indukcijske terapije Thymoglobulinom s razvojem vaskulopatije presatka nakon transplantacije srca

master's thesis

• Title (english): Association of lymphocyte and platelet depletion after Thymoglobulin induction therapy with the development of cardiac allograft vasculopathy after heart transplantation
• Author: Marija Doronjga
• Mentor: Boško Skorić (mentor)
• Committee member: Davor Miličić (predsjednik povjerenstva)
• Committee member: Martina Lovrić Benčić (član povjerenstva)
• Committee member: Boško Skorić (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; (Department of Internal Medicine); Zagreb
• Defense date and country: 2024-07-12, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Clinical Medical Sciences; Internal Medicine

Abstract

Uvod: Vaskulopatija srčanog presatka (engl. cardiac allograft vasculopaty, CAV) je jedan od glavnih uzroka posttransplantacijskog morbiditeta i mortaliteta. Premda je imunološki-posredovano oštećenje ključno i specifično za nastanak CAV-a, korist od snažne indukcijske imunosupresije kunićjim antitimocitnim globulinom (rATG, Thymoglobulin) u prevenciji CAV-a nakon transplantacije srca (HTx) ostaje kontroverzna i slabo istražena. Dok limfopeniju smatramo odrazom terapijskog učinka, popratni pad broja trombocita u perifernoj krvi nakon primjene rATG-a držimo neželjenom nuspojavom iako postoje pokazatelji da upravo trombociti igraju ulogu u patogenezi CAV-a. Hipoteza ovog istraživanje je da bolesnici nakon HTx i indukcije rATG-om sa snažnijim padom limfocita i trombocita imaju nižu incidenciju vaskulopatije presatka tijekom trogodišnjeg praćenja.

Metode: U ovu retrospektivnu studiju uključili smo 94 bolesnika kojima je učinjena HTx u Kliničkom bolničkom centru Zagreb u razdoblju od siječnja 2010. do prosinca 2017. godine. Svi bolesnici su primili indukcijsku terapiju rATG-om tijekom 5 dana nakon HTx u dnevnoj dozi od 1,5 mg/kg. Svim bolesnicima smo određivali kompletnu krvnu sliku s diferencijalnim brojem leukocita 0. dan, te 7., 14. i 21. poslijetransplantacijski dan. Primarni ishod bila je dijagnoza CAV stupnja ≥1 tijekom 3 godine nakon HTx.

Rezultati: Tijekom perioda praćenja 26,6% bolesnika je razvilo CAV. Ovi bolesnici su imali značajno starije darivatelje (47 (IQR 40-49) naspram 37 (IQR 28-49) godina; p=0,02), veći broj trombocita 7. dan (140 x 109/L (IQR 103-156 x 109/L) naspram 105 x 109/L (IQR 68-147 x 109/L); p=0,04), veći apsolutni broj limfocita 14. dan (335 x 109/L (IQR 184-314 x 109/L naspram 215 x 109/L (IQR 105-401 x 109/L); p=0,02) i veći broj trombocita 21. dan nakon transplantacije (237 x 109/L (IQR 195-278 x 109/L) naspram 193 x 109/L (IQR 148-226 x 109/L); p=0,03). Univarijatna binarna logistička regresija pokazala je povezanost CAV-a sa starijom dobi darivatelja, apsolutnim brojem limfocita ≥200 x 109/L 7. dana i većim brojem trombocita 7. i 21. dan nakon HTx. U multivarijabilnoj binarnoj logističkoj regresiji, prilagođeni rizik od CAV-a ostao je značajan za bolesnike koji su imali starijeg darivatelja (p=0,027) i veći broj trombocita 21. dan (p=0,04).

Zaključak: Niži broj trombocita nakon indukcije rATG-om je povezan s manjom incidencijom CAV-a tijekom 3 godine nakon HTx. Varijabilni odgovor trombocita na primjenu rATG mogao bi objasniti proturiječne rezultate dosadašnjih studija na način da korist od rATG-a u prevenciji CAV-a imaju upravo oni bolesnici koji na ovaj lijek reagiraju većim padom broja trombocita.

Abstract (english)

Background: Cardiac allograft vasculopathy (CAV) is one of the main causes of morbidity and mortality after heart transplantation (HTx). Although immune-mediated mechanisms are pivotal and specific for the development of CAV, the benefit of intense induction immunosuppression with rabbit antithymocyte globulin (rATG, Thymoglobulin) in the prevention of CAV after HTx remains controversial and understudied. While lymphopenia is considered a therapeutic effect, the accompanying drop in the number of platelets in the peripheral blood after the administration of rATG is considered an unwanted side effect, even though there are reasonable implications that platelets could play a role in the pathogenesis of CAV. This study hypothesizes that patients with a stronger decrease in lymphocyte and platelet count after rATG induction have a lower incidence of CAV during the 3-year follow-up.

Methods: In this retrospective study, we included 94 patients receiving heart transplantation between January 2010 and December 2017. All patients received rATG induction therapy for 5 days after HTx at a daily dose of 1.5 mg/kg. Absolute lymphocyte count (ALC) and platelet counts were assessed on days 0, 7, 14, and 21 following HTx. The primary outcome was the diagnosis of grade ≥1 CAV during 3 years of follow-up.

Results: During the follow-up period, 26.6% of patients developed CAV. These patients had significantly older donors (47 (IQR 40-49) vs 37 (IQR 28-49) years; p=0.02), higher platelet count on day 7 (140 x 109/L (IQR 103-156 x 109/L) vs 105 x 109/L (IQR 68-147 x 109/L); p=0.04), higher ALC on day 14 (335 x 109/L (IQR 184-314 x 109/L vs 215 x 109/L (IQR 105-401 x 109/L); p=0.02), and higher platelet count on day 21 post-HTx (237 x 109/L (IQR 195-278 x 109/L) vs 193 x 109/L (IQR 148-226 x 109/L); p=0.03). Univariate binary logistic regression showed that CAV was associated with older donor age, ALC ≥200 x 109/L on day 7, and higher platelet count on days 7 and 21. In multivariable binary logistic regression, the adjusted risk of CAV remained significant for patients with older donors (p=0.027) and higher platelet count on day 21 (p=0.04).

Conclusion: Lower platelet count after rATG induction was associated with a lower incidence of CAV during the first 3 years after HTx. The inconsistent findings of earlier research examining the impact of rATG induction in CAV prevention may be explained by the varying platelet response to rATG, with recipients exhibiting a stronger decrease in platelet count benefiting from the treatment.

• Keywords: kunićji antitimocitni globulin; vaskulopatija srčanog presatka; transplantacija srca
• Keywords (english): cardiac allograft vasculopathy; rabbit antitymocite globuline; heart transplantation
• Language: croatian
• URN:NBN: urn:nbn:hr:105:281894
• Study programme: Title: Medicine; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: doktor/doktorica medicine (doktor/doktorica medicine)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2024-07-01 07:34:35