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Anticoagulation in Pregnancy and A ISSN 2334-9492 (Online) Hospital Pharmacology. 2016; 3(1):328-340 UDC: 615.273-055.26 doi:10.5937/hpimj1601328A Anticoagulation in Pregnancy and Puerperium: With a Focus on the Benefi ts and Risks of the Applications of Vitamin K Education article Antagonists on the Prevention of MECHANICAL Heart Valves Thrombosis A Nebojša M. Antonijević1,2, Ljubica M. Jovanović2, Branka M. Terzić2, Mirjana K. Kovač1,3, Tatjana Ž. Ilić Mostić4, Ivana D. Živković2, Dragan M. Matić2, Ratko M. Lasica1,2, Ivan V. Ranković5, Nebojša L. Radovanović1,2, Milika R. Ašanin1,2, Vladimir I. Kanjuh6 1 Medical Faculty, University of Belgrade, Belgrade, Serbia 2 Clinic of Cardiology, Clinical Centre of Serbia, Belgrade, Serbia 3 Transfusion Institute of Serbia, Belgrade, Serbia 4 Clinic of Gynecology and Obstetrics, Clinical Centre of Serbia, Belgrade, Serbia 5 Clinic of Gastroenterology and Hepatology, Clinical Centre of Serbia, Belgrade, Serbia 6 Department of Cardiovascular Pathology, Serbian Academy of Science and Art, Belgrade, Serbia SUMMARY Introduction: The current number of women in the reproductive phase (from 15 to 45 years) in Europe is estimated at about 105 million, with about 5 million children annually born in average. About 1% of pregnancies among women in Europe are com- plicated by heart disease, the risk of cardiovascular disease in pregnant women being further increased by the fact that ever older women are giving birth. Methods: Preparing this paper is based on a systematic PubMed search of existing professional databases and accessible medical journals and textbooks dealing with this subject matter. Topic: Being certainly drugs with the best anticoagulant eff ect in situations of high risk for thrombosis, especially in patients with mechanical prosthetic heart valves during pregnancy, vitamin K antagonists (VKA) on the other hand also entail a well- known dose-related risk of embryo toxicity, genotoxicity, and hemorrhage in the fetus and in the mother. The choice of appropriate anticoagulant depends on the stage of pregnancy. In accordance with the North-American guidelines (American College of Chest Physicians - ACCP) for women already on oral vitamin K antagonists actively try- ing to conceive frequent pregnancy tests, and substitution of VKA with heparin drugs when pregnant are recommended rather than VKA replacement with low molecular weight heparin (Low Molecular Weight Heparin - LMWH) when planning a pregnancy. Heparin derivatives have no embryo toxic and fetotoxic characteristic eff ects of VKA but they are less eff ective at preventing valve thrombosis, due to which they have Corresponding author: Assistant Professor Nebojša M. Antonijević, MD, PhD, © The Serbian Medical Society 2014 Specialist in Internal Medicine, Subspecialist in Cardiology Clinic of Cardiology, Clinical Centre of Serbia, 11000 Belgrade, Serbia E-mail: [email protected] 328 Antonijević NM et al: Anticoagulation in Pregnancy and Puerperium: With a Focus on the Benefi ts and Risks of the Applications of Vitamin K Antagonists on the Prevention of MECHANICAL Heart Valves Thrombosis recently been superseded by improved techniques for monitoring eff ects of heparin, with a mentioned made that low molecular weight heparin used in high therapeutic doses requires obligatory (on a weekly basis) monitoring of anti-factor Xa coagulation activities. Conclusion: Adequate anticoagulant therapy during pregnancy requires an analysis of risk factors for thrombosis, hemorrhage risk, consideration of comorbidities in preg- nant women, especially renal function, especially taking into account the gestational age. Though it must be admitted that there is no absolutely safe anticoagulant ther- apy during pregnancy, a choice of the safest option regarding the stated risks for the mother and the child is of paramount importance. Keywords: pregnancy, anticoagulant therapy, mechanical prosthetic valves A INTRODUCTION and legs. Consequently, in certain conditions during pregnancy there is a need for admin- Th e current number of women in the repro- istering adequate anticoagulant therapy. Some ductive phase (from 15 to 45 years) in Europe diseases and conditions require the use of vita- is estimated at about 105 million, with about min K antagonists (VKA), whose teratogenic 5 million children annually born in average. potential presents a signifi cant safety issue [2]. About 1% of pregnancies among women in Th ough VKA administration represents the Europe are complicated by heart disease, the most eff ective anticoagulant therapy for the risk of cardiovascular disease in pregnant prevention of thrombosis in pregnant women women being further increased by the fact that with mechanical heart valves, at the same time ever older women are giving birth [1]. it may lead to serious birth defects, embryopa- Pregnancy is a condition of increased thy, even stillbirth [8]. Th erapy with heparin risk of thrombosis due to synergy of all the drugs, especially with low molecular weight three components of the Virchow’s triad [2]. heparins (LMWH) has reduced adverse fe- Due to altered physiology in pregnant women tal outcomes, but, on the other hand was ac- and hormonal status procoagulant factors and companied by a higher incidence of prosthetic the procoagulant state dominates. Levels of fi - valve thrombosis in patients with prosthetic brinolysis inhibitor (PAI-1 or PAI-2) produced heart valves. Th e risk of thrombosis in prac- by the placenta are elevated, causing a decrease tice may be reduced by using higher doses of in fi brinolytic activity during pregnancy. On LMWH, more frequent testing and adjusting the other hand, additional thrombogenic ef- not only peak anti-Xa activity levels analyzed fect is associated with changes in the levels of from a blood sample 4 h aft er subcutaneous natural anticoagulants, namely, a reduction in injection of LMWH, but also trough anti-Xa protein S levels is recorded as early as the fi rst activity levels, analyzed in the blood sample trimester; the concentration of antithrombin immediately prior to the administration of (AT) decreases in case of a caesarean delivery. subcutaneous injections of LMWH. When A series of homeostatic changes induced in administering LMWH in order to prevent pregnancy is associated with activated protein thrombosis prosthetic valves, it is advised to C resistance registered in a number of preg- maintain anti Xa activity values at a high ther- nant women [3-5]. Also, there is an increase apeutic level [2]. in platelet-endothelial adhesion molecules as well as endothelial cell activation associated METHODS with a proinfl ammatory state, especially dur- ing labour or caesarean section when damage Preparing this paper is based on a systematic to blood vessels is incurred [2,6,7]. PubMed search of existing professional data- In addition, the gravid uterus com- bases and accessible medical journals and text- presses major blood vessels of the abdomen books dealing with this subject matter. and pelvis, this resulting in venous dilata- tion and slowed venous fl ow, which poses a risk of deep venous thrombosis of the pelvis www.hophonline.org 329 Hospital Pharmacology. 2016; 3(1):328-340 ORAL ANTICOAGULANTS DURING been described as well as agenesis of the cor- PREGNANCY pus callosum, Dandy-Walker malformation, mid line cerebellar atrophy, ventral middle Anticoagulant therapy is indicated in preg- line dysplasia which may lead to atrophy of nancy in women with mechanical prosthetic the nervus opticus. Blindness, epilepsy, deaf- valves, with previous or current venous throm- ness, respiratory distress, kidney agenesis or bosis and thromboembolism as well as in pres- hypofunction, anal dysplasia, cleft lip and soft ence of a thrombus in the cardiac chambers, palate may likewise occur [10,13]. Th e risk of atrial fi brillation with a high thromboembolic developing embryopathy is estimated at 5-7%, risk, in pulmonary hypertension due to severe this percentage being higher when broadened thrombophilia or if there is a history of recur- to include the less pronounced CNS disorders rent miscarriage. Besides thrombophilia with induced by warfarin [9]. recurrent miscarriage, anticoagulant therapy Due to the transfer of VKA through is also considered in cases of stillbirth, pre- the placenta, the fetus is at signifi cantly in- eclampsia, post-thrombotic syndrome, ovar- creased risk of hemorrhage. Th e immaturity of ian hyperstimulation syndrome in the fi rst the fetal liver is a major cause of slow warfarin trimester, known to be likely associated with a metabolism and low clotting factor levels in hypercoagulable state [2,9]. the fetus itself, the anticoagulant eff ect thus be- Oral anticoagulation with vitamin K ing markedly greater than in the mother. Fur- antagonists provides better maternal protec- thermore, there is a high risk of hemorrhage in tion against thrombosis than heparin prepa- newborns during childbirth, sometimes with a rations, though its administration may be as- possible fatal outcome. Th erefore, interruption sociated with a potential risk of embryopathy, of VKA therapy at 34-36 weeks of gestation is fetal malformation as well as loss, especially in recommended or a cesarean section suggested the period of 6-12 weeks of gestation and prior reducing the possibility of hemorrhage in the to delivery [8,10]. It being considered by au- child due to birth trauma [9]. Some authors thors such as Dr. Celine Montovan that VKA specifi cally point out the development of ret- administration, particularly between 6-12 roplacental hematoma
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