Effect of oral contraceptives on factors of coagulation and fibrinolysis

Oralni kontraceptivi imaju brojne učinke na organizam žene poput poželjnog smanjenja pojavnosti zloćudnih bolesti jajnika i endometrija, ali i nepoželjne učinke od kojih je najpoznatiji povišeni trombotički rizik. Činjenica je da su oralni kontraceptivi jedan od rizika za razvoj trombo-embolijskih bolesti, s relativnim rizikom od 1,15 do 8,5 ovisno o formulaciji pripravka i obliku trombo-embolijske bolesti. Razvoj laboratorijske dijagnostike, molekularnih ispitivanja i koagulacijskih pretraga, dao je novi zamah istraživanjima povezujući epidemiološke podatke o trombotičkim rizicima poput pušenja, debljine, dobi, tjelovježbe i drugih s biološkom osnovom. Istovremeno, razvoj sintetičnih estrogena i progesterona, njihovih doza i kombinacija, dodatan su poticaj studijama učinka pojedine formulacije na koagulacijski odgovor. Cilj istraživanja bio je utvrđivanje utjecaja oralnih kontraceptiva na čimbenike zgrušavanja i fibrinolize u lokalnoj populaciji, ovisno o: količini i hormonalnom sastavu korištenog pripravka, postojanju nasljednih trombofilija te razlici među ispitanicama u dobivenim vrijednostima aktivnosti čimbenika hemostaze u odnosu na dodatne čimbenike rizika za trombo-embolijske bolesti. U istraživanje su uključeni rezultati 195 žena koje su uzimale 6 ciklusa oralnu kontracepciju. Određivani su čimbenici nasljedne trombofilije (FV Leiden, FIIG20210A i PAI-1 5G/4G) i parametri hemostaze (PV, APTV, fibrinogen, aPCR, protein C i S, FVIII, antitrombin, plazminogen, inhibitor plazmina, PAI-1 i d-dimeri) mjereni u 3 vremenske točke: osnovni - prije uzimanja oralne kontracepcije, nakon 3 i nakon 6 ciklusa. Rezultati istraživanja pokazuju da su pod utjecajem oralnih kontraceptiva promijenjeni svi koagulacijski parametri osim aktivnosti FVIII. Analizom rezultata formulacija pripravaka, najveće razlike nađene su u kombinacijama s 20μg EE2 GSD vs DRSP za koagulacijske pretrage protein C i S, plazminogen i PAI-1. U istraživanju je potvrđena jednaka učestalost trombofilnih mutacija među ispitanicama kao u općoj populaciji. Polimorfizam PAI-1 5G/4G nije imao utjecaja na aktivnost PAI-1 kod mladih žena, niti je uzimanje oralnih kontraceptiva imalo učinka na aktivnost PAI-1. Istraživanje je potvrdilo utjecaj oralne kontracepcije na koagulacijske pretrage, ali i nastojanje sustava hemostaze za stjecanjem nove točke ravnoteže. Gestageni također utječu na koagulacijski odgovor žena. Patološke vrijednosti pretraga aktivnosti proteina S i određivanja koncentracije d-dimera mogu pomoći kliničarima u odluci o nastavku ili prekidu oralne kontracepcije kod žena s drugim visokim rizikom i/ili sumnjom na trombo-embolijski događaj.Oral contraceptives have numerous effects on women’s body like favorable decrease of prevalence risk for ovarian and endometrial cancer, but also undesirable increase of thrombotic events. The fact is that oral contraceptives are one of the reasons for increased risk for venous thromboembolism, with relative risk is 1.15- 8.5, depending on the drug formulation and type of thromboembolic disease. The development of laboratory diagnostics, molecular tests and coagulation tests, gave a new momentum to the researches linking epidemiological data on thrombotic risks such as smoking, obesity, age, exercise, and others with a biological basis. Simultaneously, development of synthetic estrogen and progesterones are an additional stimulus for new studies of the effect of oral contraceptive formulations on the coagulation response. The aim of the study was to determine the influence of oral contraceptives on factors of coagulation and fibrinolysis in the local population, depending on: the amount and composition of used drug, the presence of hereditary thrombophilia and the difference among study subjects in the obtained values of factors of coagulation and fibrinolysis in relation to the presence of additional risk factors for thromboembolic diseases. The study included the data results of 195 women, who took six cycles of oral contraceptives. Tests for hereditary thrombophilia (FV Leiden, FIIG20210A and PAI-1 5G/4G) were performed, as well as tests of hemostasis (PT, APTT, fibrinogen, APCR, protein C and S, FVIII, antithrombin, plasminogen, plasmin inhibitor, PAI-1 and d-dimer) measured at three time points: basic - before taking oral contraceptives after three and after six cycles of their use. The results showed that oral contraceptives have changed all measured parameters except activity of FVIII. Analyzing the results by formulation of drug, the greatest differences were found in combination with 20μg EE2 GSD vs. DRSP for coagulation tests protein C and S, plasminogen and PAI-1. Data confirmed the same frequency of FV Leiden, FII G2021A i PAI-1 5G/4G among study subjects as in general population. Polymorphism of PAI-1 5G/4G had no influence on PAI-1 activity, nor the use of oral contraceptives. This study confirmed impact of oral contraceptives on coagulation tests and tendency of hemostasis to reach new equilibrium. Gestagens also have impact on coagulation response. Pathological test results of protein S activity and d-dimers may help clinicians in the decision on continuation or discontinuation of oral contraceptives in women with other high-risk and / or suspected thromboembolic event