DOI: 10.1161/CIRCULATIONAHA.113.001145 Thrombolytic Therapy for the Treatment of Prosthetic Heart Valve Thrombosis in Pregnancy with Low Dose, Slow Infusion of t-PA Running title: Özkan et al.; Lysis of prosthetic valve thrombus in pregnancy Mehmet Özkan, MD1; Beytullah Çakal, MD1; Süleyman Karakoyun, MD1; Ozan Mustafa Gürsoy, MD1; Cihan Çevik, MD2; Macit KalçÕk, MD1; Ali Emrah O÷uz, MD1; Sabahattin Gündüz, MD1; Mehmet Ali Astarcioglu, MD1; Ahmet Ça÷rÕ Ayk Aykan, kan an,, MD1; Zübeyde Bayram, MD1; Murat Biteker, MD1; Evren Kaynak, MD3; Gökhan Kahveci, Kah ahve veecii, MD1; Nilüfer Ekúi Duran, MD1; Mustafa YÕldÕz, MD1 ¹Kosuyolu ¹Kos ¹K osuyol oluu Kartal K rt Ka rtal al Heart Hea eart rt Training Tra rain iniingg and and Research Res esea earc rchh Hospital, Hosppit Ho ital al,, Department D paartme De rtment nt of of Cardiology, Card Ca rdio iolo logy gy,, øøstanbul, stan st anbu bul, Turkey; Tu ²Texa ²Texas as H Heart eaartt IInstitute nssti titu tu ute aatt St St.L St.Luke’s .Luuke’’s Epi Episcopal isccopa paal Ho Hosp Hospital, pit itaal, Baylor Bayylor College Collle lege ge off Med M Medicine, edici dicine nee, Division Divi Divi visi sionn ooff Ad Adult dullt C Cardiology, ardio iolo ogy gy,, Ho Hou Houston, uston, ust ton, T TX; X;; ³³The Th he Univ U University niv iver ersiity ooff Te er Texa Texas xaas He Health eal alth t S th Science cieencce C ci Center, en nteer, Divi Di visi vi sion si on of of Adult Adul Ad ultt Cardiology, ul Card Ca rdio rd iolo io logy lo gy,, Ho gy Hous usto us ton, to n, TX TX Division Houston, Address for Correspondence: Mehmet Özkan, MD Department of Cardiology Koúuyolu Kartal Heart Training and Research Hospital Denizer Caddesi, Cevizli Kavúa÷Õ, No: 2 34846, østanbul, Turkey Tel: +90 532 2551513 Fax: +90 216 4596321 E-mail: [email protected] Journal Subject Codes: Diagnostic testing:[31] Echocardiography, Hypertension:[19] Valvular heart disease, Thrombosis:[160] Fibrinolysis 1 DOI: 10.1161/CIRCULATIONAHA.113.001145 Abstract: Background—Prosthetic valve thrombosis (PVT) during pregnancy is life-threatening for mother and fetus, and the treatment of this complication is unclear. Cardiac surgery in pregnancy is associated with very high maternal and fetal mortality and morbidity. Thrombolytic therapy (TT) has been rarely used in these patients. The aim of this study is to evaluate the safety and efficacy of low-dose (25 mg), slow infusion (6 hours) of t-PA (tissue plasminogen activator) for the treatment of PVT in pregnant women. Methods and Results—Between 2004 and 2012, t-PA was administered to 24 consecutive non-obstructive n=13). Mean women in 25 pregnancies with 28 PVT episodes (obstructive n=15; non-obstruc ctiivee n=1 =13) =1 3).. Me 3) M ean age of the patients was 29±6 years. TT sessions were performed under transesophageal echocardiography 48.7±29.5 ec cho hoca card ca rdio rd iogr io g aphy hy gguidance. uidance. The mean dose of ttt-PA PA used was 48 8.7 7±2 29. 9 5 mg m (range 25-100mg). All A ll episodes e isodes resulted ep res esuultedd in i complete com ompl plet pl etee thrombus thro th romb mbus lysis lyysis following followi wing wi ngg TT. TT. T One One ne patient patientt had had placental pla lace c ntal ce al hemorrhage with preterm hemo he morr mo rrha rr hage ge w ithh pr it pret eteerm m li llive vee bbirth irth ir th ooccurred cccur urre redd at 330 re 0thh w week, eek, ee k, aand ndd oone ne ppatient atiiennt at nt hhad ad m minor inoor bbleeding. in leeed edin in ng.. Conclusionss—Lo Loww do wdose s , slow s ow sl o infusion inf n us usio on of t-PA t-P PA with w th repeated wi rep epeeat ep ated ed doses dos o es as as needed need ne e ed ed d is is an effective effective Conclusions—Low-dose, therapy with excellent thrombolytic success rate for the treatment of PVT in pregnant women. This protocol also seems to be safer than cardiac surgery or any alternative medical strategies published to date. TT should be considered as first-line therapy in pregnant patients with PVT. Key words: pregnancy, thrombolysis, transesophageal echocardiography, prosthetic valve thrombosis 2 DOI: 10.1161/CIRCULATIONAHA.113.001145 Introduction Pregnancy is associated with increased risk of thrombosis among women with mechanical prosthetic heart valves (PHV).1 The largest literature review of women with PHV who were on anticoagulation during pregnancy reported thromboembolic complications occurred in 3.9% of women taking only warfarin, 9.2% of women who received unfractionated heparin (UFH) in the ¿rst trimester followed by warfarin, and one-fourth of women treated with UFH throughout their pregnancy. Maternal death was observed in these groups in 2%, 4%, and 15%, respectively, and was usually related to prosthetic valve thrombosis.2 Similarly, fifteen percent of pregnant women developed prosthetic valve thrombosis (PVT) while using low molecular weight heparin (LMWH) LMWH)3. PVT during pregnancy requires immediate therapy such as valve replacement, thrombolytic hro ombol olyt lyt ytic ic the therapy era rapy py (TT), or surgical thrombec thrombectomy. ctom tomy. Recommen Recommendations en nda d tiion onss of guidelines regarding this hiss complication complicattio ionn are aree similar s mi si mila larr too the la the management mana anageme ment of me of PVT PV VT in non-pregnant non on-p -prregn gnaantt pa patients. atien tients tss.4,5 Th Thee guidelines guid gu idel id elin el i es suggest in sug ugge geest to to optimize opti op timi mizze ze aanticoagulation ntic nt icoa ic oagu gula gu lati la tionn iin ti n no non-critically on--cri -cri riti ticcall ti llyy ill ll il pa pati patients tieents ents w with itth re recent ece centt su subub ubtherapeutic herapeutic an anticoagulation. nti tico coag co agul ag ulat ul atio at i n. S Surgery urrge gery ry y iss re reco recommended comm co mmen mm en nde dedd wh when en aanticoagulation ntic nt icoa ic oaagu gula lati la tion ti on ffails, ails ai ls,, or ffor ls o criticallyy or ill patients with obstructive thrombosis, or large ( 10 mm) non-obstructive PVT complicated by embolism. Fibrinolysis is recommended for either critically ill patients when surgery is not immediately available or when PVT is right-sided. However, cardiac surgery in pregnancy is associated with very high maternal and fetal mortality (6% and 9%, respectively), and morbidity (24% and 30%, respectively) 6. These patients are rarely considered for thrombolytic therapy because of the concerns about bleeding, fetal harm, and apprehension that thrombolytic agents are absolutely contraindicated in pregnancy. Recently, transesophageal echocardiography (TEE)guided low-dose (25 mg), slow infusion (6 hours) of t-PA was demonstrated to be a safe and 3 DOI: 10.1161/CIRCULATIONAHA.113.001145 effective strategy for the treatment of PVT in a large, prospective study 7. This trial involved 182 patients with 220 episodes of PVT. Low-dose, slow infusion of t-PA protocol was associated with highest (86%) thrombolytic success and lowest (10.5%) complication rates with no mortality, suggesting that guidelines regarding the treatment of PVT might need to be updated to reflect the utility of thrombolysis for all patients. In this study, we evaluated the safety and efficacy of this particular therapy in pregnant women with PVT. Methods Rationale of the study methods 1. Surgery vs. Thrombolytic Therapy This study is the subgroup of TROIA Trial which was published earlier 7. The study is nonanddom mized ized ddue uee tto o rrelatively elatively small number of pa ati t ents with highly ly y spe eci ciffic fi clinical condition, randomized patients specific very very y high morb morbidity rb bid iditty an andd mo mor mortality rtalit rtal ityy asso aassociated ssoociateed w with ithh ssurgery urg gery ery fr ffrom om th om the he aavailable vaillab able le data, dat ataa, a, and and lack laack ack off evidence ev vid iden ence en c ssupporting ce uppo up port rttin ng ssuperiority upe peri riorrit ityy off eeither ith it her th her the therapy. erap apy. y. F Furthermore, urth ur t er th erm more re, TT aand re ndd ssurgery urge ur gery ge ry w were erre nnot ott considered as as al alte alternative teern rnat a iv at ivee tr treatment rea eatm tmen tm entt op en ooptions; tiion ons; s; instead, instteaad, d they the heyy were were considered con o si side dere de redd as re a complimentary com ompl plim pl im mentary treatments to each other from the beginning of the study. Hence, TT was the first treatment option to virtually all pregnant patients with PVT, and surgery was only considered in patients who had an absolute contraindication to TT, failed thrombolysis, or refused to receive TT. The same thrombolytic protocol used in TROIA trial (25 mg of t-PA infusion in 6 hours/each thrombolytic session) was used in this study. We conducted a prospective audit of pregnant women with PVT treated with TT at any stage during pregnancy. 2. Why low dose, slow infusion t-PA? T-PA is a highly fibrin-specific drug and does not cause systemic thrombolytic effect. T-PA’s 4 DOI: 10.1161/CIRCULATIONAHA.113.001145 placental passage is minimal and not sufficient to cause unwanted fibrinolytic effect in the fetus 8 . It has short biological half-life and do not induce antigenic reaction. We hypothesized that t- PA could be an ideal agent for pregnant patients with PVT compared to streptokinase and urokinase. We also hypothesized that low-dose, slow infusion of t-PA would lyse the clot gradually with reduced risk of thromboembolism and without compromising the success rates. Furthermore, we thought that bleeding risk could be reduced since t-PA infusion would be stopped immediately with a slow infusion protocol. 3. Thrombolytic therapy protocol and dosing regimen Six-hour infusion of 25 mg t-PA without a bolus (repeat once after 24 hours, up to 6 times if needed, maximum total dose of 150 mg) was used in all pregnant patients with P VT. We ddid VT id nnot ot PVT. use intravenous heparin during t-PA infusions to minimize bleeding risk. Heparin 70 IU/kg bolus an and nd 16 IIU/kg U/kg U/ kg per err hhour o r (up to 1000 IU/hour) infusion ou infu usio sion with a target ett act activated tiv vat ated e partial thromboplastin hro omb m oplastin in time tim me (aPTT) ( PT (a PTT T) of T) of 1.5-2.0 1.51. 5 2.0 times 5timess the th me mean n ooff th the he re ref reference ferenc fer ncee ra range angge wa wass st started tar a ted immediately mme medi d at di atel elly after afte af teer the t e t-PA th t-P PA infusion. PA innfus nfussio ion. n. If If repeat reepe peaat thrombolytic thro th ro ombo mbolyt ytic yt ic infusion inf nfus nf usio us ionn was waas needed, neeeded ne eded e , heparin hepa he parrinn was waas hold again until unttil aPTT aPT PTT T wa w wass le less s tthan hann 500 sseconds ha econ ec onds on ds and and then t en th n t-PA t-P PA infusion infu in fusi sion si on w was as sstarted. taart rted ed.. If ed I the TT wa was as successful, we started anticoagulation with heparin and warfarin. Warfarin was used when its daily dose was equal or less than 2.5 mg during the first trimester after obtaining informed consent from the patient. Otherwise enoxaparin was used to achieve peak anti-Factor Xa activity of. 0.7 to 1.2 IU/ml. Study patients with rethrombosis and patients with multiple mechanical valves were started on aspirin 300 mg daily in addition to anticoagulation. Patients received warfarin in second and third trimester up to the end of 35th week of pregnancy (INR=2.5-4). They were hospitalized after that and intravenous heparin started until cesarean section. All pregnant patients underwent TTE and TEE immediately if they had any signs or symptoms 5 DOI: 10.1161/CIRCULATIONAHA.113.001145 suggesting PVT and every 12 weeks following the TT until delivery. 4. Inclusion and exclusion criteria All pregnant patients with obstructive PVT, non-obstructive PVT with recent systemic thromboembolism and thrombus diameter of >5 mm, asymptomatic mobile non-obstructive PVT with thrombus diameter of at least 10 mm were included in this study. Patients with an absolute contraindication to TT, asymptomatic non-obstructive PVT patients without a history of recent thromboembolism and with thrombus diameter of smaller than 10 mm7, and patients with imminent abortion or placenta previa were excluded. Patients with prosthetic valve obstruction who had no thrombus/mass/pannus in TEE study and normal prosthetic valve leaflet motion were considered as patient-prosthesis mismatch and also excluded from the stud dy. study. Twenty-four consecutive pregnant patients with twenty-eight episodes of PVT between De Dece cemb ce mber mb err 2004 200 0 4 to March March 2012 were included inn this this study. A “PVT “P PVT V episode” epi pissode” so refers the entire December reaatm tment peri iod d of of a pati ppatient ati tien entt wh en w adm dmittedd to to the thhe he hospital hoospita pitaal with with h a PVT PVT VT aand ndd iincludes nclu nc lu udees aall ll t-PA t-PA treatment period whoo is admitted nfu fusi siion o s per per thrombolytic thrrombo th mbolyt olyttic regimen reg egim eg imen im en whether wheth heth ther er or or not no ot each eacch ch infusion inf nfus ussio ionn iss successful. succceess ssfu ful. fu l If l. If th thee sa ame me infusions same patient is readmitted reaadm dmit itte tedd at a different te dif iffe fereent ttime fe imee with im with rethrombosis reth t ro romb m ossis mb i of of th he pr pros o th os thet etic et ic hheart eaart vvalve a ve al v during the prosthetic pregnancy, this was considered a separate PVT episode. Clinical characteristics including New York Heart Association (NYHA) functional class, demographics, and medications of the patients were recorded into a database. All pregnant patients with mechanical heart valves routinely underwent 2D TEE, (GE Medical Systems, Milwaukee, WI, USA) between 2004-2008 and Philips IE33 2D TEE and RT 3D TEE (Philips Medical Systems, Andover, MA, USA) between 2008-2012 when they were presented with thromboembolism or worsening NYHA functional class, and/or TTE demonstrated prosthetic valve dysfunction or thrombus or any echodensity suspicious of thrombus. Thrombus was 6 DOI: 10.1161/CIRCULATIONAHA.113.001145 recognized as a homogeneous, mobile or ¿xed mass with similar echodensity to the myocardium located at the valve occluder and/or valve struts and was visualized in all patients with PVT by echocardiography. All patients also underwent TTE and TEE examination within an hour after the thrombolytic sessions. Fetal assessment was performed by an obstetrician after admission and following every TT episode. Finally, fetal ultrasounds were obtained following TT and every four weeks till delivery. Fetal outcome was classi¿ed as either a termination of pregnancy before 20 weeks’ gestation, miscarriage (spontaneous fetal loss < 20 weeks’ gestation), stillbirth (fetal death > 20 weeks gestation), baby death (neonatal or infant death), or a live birth. Preterm birth was delivery before 37 weeks’ gestation and included both spontaneous and iatrogenic preterm births. All the risks, bene¿ts, and alternatives of TT were explained to the patients in detail. Each Ea ach patient pat atie ient ie nt gave gav ve written written informed consent andd the the study is appr approved rov o ed d bby y local ethics committee. C riiter ite ia for tthrombolytic hrom hr om mbo boly yti ticc su suc ccesss cces Criteria success In PVT, major complications, n ppatients atie at ient ie ntss wi with th oobstructive bstruucttive bstr tive P VT, in tthe VT he aabsence he bsen bs e ce ooff fa en ffatal tal or nnonfatal tal onfa on faataal ma majo or co omp mpli liica cattioons, aa)) Doppler documentation docu cu ume ment ntat nt atio at io on off the the resolution res esoolu lution on of of increased in ncr crea e se ea sedd gradient grrad adie ient ie nt an and de decr decreased crea cr ease ea sedd va se valv valve lvee ar lv aarea, ea, b) Reduction by 75% in major diameter and/or area of the thrombus, and c) Clinical improvement in symptoms were considered the major criteria for thrombolytic therapy success. Complete success was defined when all three criteria were met, and partial success was defined when less than three criteria were met. In patients with non-obstructive PVT, in the absence of fatal or nonfatal major complications, complete success was defined as 75% reduction in thrombus area and/or length. Partial success was defined as 50%-75% reduction in thrombus area and/or length. For the interpretation of results in patients with PVT, partial and complete success rates were combined. 7 DOI: 10.1161/CIRCULATIONAHA.113.001145 Definition of complications Major fatal complication was defined as all cause in-hospital mortality. Nonfatal major complications included ischemic stroke, intracranial hemorrhage, systemic thromboembolism, bleeding including placental hemorrhage requiring transfusion or surgery, and t-PA related preterm delivery. Nonfatal minor complications were defined as bleeding without need for transfusion and transient ischemic attack (TIA). Statistical analysis Statistical analysis was performed using SPSS 19.0. All analysis was done based on episodes. The variables were investigated using analytical methods (Kolmogorov-Smirnov/ Shapiro-Wilk test) Descriptive est) to determine whether or not they are approximately normally distributed. De esccript ptiv pt ivee iv statistics tatistics were reported as mean, standard deviation, median, minimum and maximum values for continuous percentages co ont ntin inuuous in uous vvariables ariaabl bles es and as frequencies with pe erc rcen ntages for the ca ccategorical tego gooric ical variables. The paired compare post pair red e t-test was was used used d too co omp mpar aree pr pree an and po ostt TT T prosthetic prossth stheti hetiic valve vallve area, va a eaa, peak ar peak and and d mean mea eann gradients. p=0.05. grad gr adie ad ient ie n s. The nt The he significance sig igni nifi fica caanc nce level leve le veel was w s set wa set at p=0 =0.0 =0 .005. Results Over an 8 year-period, 24 women received t-PA during 25 pregnancies with 28 episodes of PVT. Their mean age was 29±6 (19-42) years. The demographic and clinical characteristics are reported in Table 1. The mean gestational age on admission was 19±11 weeks (range between 636). The most common symptom was dyspnea (n=18, 64%). Three patients were asymptomatic. Only one episode presented with TIA. Patients had atrial fibrillation in 14% (n=4) of PVT episodes. Two patients were using low-dose aspirin (100mg) on admission (7%). None of the patients had hypertension or diabetes. There was no medication use other than warfarin, aspirin, 8 DOI: 10.1161/CIRCULATIONAHA.113.001145 and prenatal vitamins. Twenty-three women had only mechanical mitral valves and one patient had mechanical mitral and normally functioning aortic valve. All PVT episodes involved mitral prosthesis only. Poor compliance with warfarin, sub-therapeutic anti-Xa, or INR level was detected in 26 of 28 (93%) episodes on admission. Fifteen episodes occured on warfarin therapy (INR levels on admission were <2 in all except one of them), and ten episodes occurred in patients who were on enoxaparin. Three patients had rethrombosis during the same pregnancy; one woman had PVT on her second pregnancy. Fourteen (50%) episodes occurred in during the first trimester, 4 (14 %) second trimester, and 10 (36 %) in the third trimester. Three patients declined TT and wished to proceed with surgery. One of these patients (28 weeks pregnant) and the he fetus died during surgery. Echocardiographic results In mean was 1.2±0.2 n oobstructive bstr bs truc tr uccti tive vee PVT VT episodes (n=15, 54%), the m e n valve area w ea a 1.2 as .22±0.2 ±0 cm²; the average mean mmHg, respectively. Following peak ak k and mea an ggradients raadie adie i nt ntss we were re 225.6±5.3 5.6± 5. 6±55.3 mmHg; 6± mm mHg; 17.8±4.4 17.8± 17. ±4.4 m ±4.4 mHg, res mHg esppecctiv iv vel ely. y. F ollo ol low lo wing thrombolytic mean valve peak mean gradient improved hro omb mbol olyt ytic yt ic pprotocol, ro oto oco coll, l, m eann va ea valv lvee area lv aarea, reaa, pe pea ak aand nd m eaan gr gra adie adie ient ntt imp mpro mp ro oveed si ssignificantly gnif gn iffica icantl tlly (m ((mean eann valve area: 2.3±0.3 2.3± 2. 3±0. 3± 0..3 cm², cm , peak pea eakk gradient grrad adie ieent 12.2 12. 2.22 ± 2.9 2 9 mmHg, 2. mmH mm Hg, g mean mea eann gradient g ad gr adie ient ie nt 55.3 .3 ± 11.4; .4;; pp<0.01 .4 < .01 for <0 each). In non-obstructive PVT episodes (n=13, 46%), the mean valve area was 2.4±0.2 cm²; and the average peak and mean gradients were 11.1±1.7 mmHg; 4.7±1.09 mmHg, respectively. Following thrombolytic protocol, mean valve area, peak and mean gradient remained similar (mean valve area 2.5±0.2 cm²; p= 0.96, peak gradient 10.8±3.4 mmHg; p=0.78, mean gradient 4.2±1.3 mmHg; p= 0.24). The thrombus area could be measured in all (100%) of the episodes (n= 15, mean 1.7±1.2cm2, range between 0.8-6 cm2 in obstructive PVT group, and n=13, 0.9±0.4 cm2, range between 0.4-1.8 cm2, in non-obstructive PVT group, p: 0.022). There was no remaining thrombus following TT on TEE. Figure 1 demonstrates Doppler tracing (A), 2-D (B), 9 DOI: 10.1161/CIRCULATIONAHA.113.001145 and 3-D TEE (C) images and movie clip (Movie Clip 1A and 1B) of one of the study patients with obstructive thrombus. Maternal and fetal outcomes There were twenty live births including one delivery which occurred on the 30th week of pregnancy in a 42 year-old woman due to placental hemorrhage following three TT sessions (total of 75 mg t-PA). This woman had received 7.5 mg/day warfarin throughout the entire pregnancy. Both mother and fetus were healthy following preterm delivery. However, this baby was found to have complete hearing loss (patient #14). Overall, there were 5 (20%) miscarriages (two in the first trimester, three in the second trimester). Miscarriages occurred one to five weeks following TT. None of the pregnant patients developed systemic thromboemboli lism sm aft fter ft er T T. thromboembolism after TT. Thrombolytic therapy outcomes The Th he av average verag erag agee ddose ose see ooff TT per PVT episode used w was as 48.7±29.5 mgg (med (median ed dia iann 27.5 mg, range bbetween etw ween 25-100 00 0 mg). mg)). All Alll episodes epis ep isoodes is odess resulted resuulted iin n comp complete mplete mp tee tthrombolytic hrom hr ombo om booly yti ticc ssuccess. ucces ccesss.. T The he iinitial niti ni tiall rrate ti atte ooff success after PVT 61% ucc cces esss af es afte terr th te thee ¿rst ¿rs r t dose dose off t-PA t-PA thrombosis throm hrom ombo bossiss was bo was 47% 47% (7/15) (7/ 7/15 155) inn obstructive obs b trruccti tive vee P VT T ggroup, ro oup up,, 61 1% (8/13) 8/13) in nonnon-obstructive n-ob obst ob sttru ruct ctiv ct ivee PV iv PVT T gr grou group. oup. ou p T The he aaverage vera ve raage ddose o e to oobtain os btai bt ainn co ai complete omp mple lete le te tthrombus hrrom ombu buss lysis was bu similar between obstructive PVT group and non-obstructive PVT group (54.3±30.8 mg in obstructive PVTs vs. 42.3±27.7 mg in non-obstructive PVTs, p= 0.23) (Figure 2). Discussion This single center, prospective study including a relatively large number of pregnant patients with PVT demonstrated that low-dose, slow infusion of t-PA was associated with successful thrombus lysis in all episodes. Our findings also indicated that the incidence of maternal and fetal adverse events with this protocol was lower than surgery or medical therapy based on the 10 DOI: 10.1161/CIRCULATIONAHA.113.001145 available published data. Therefore, low-dose, slow infusion of t-PA with repeated doses as needed under TEE guidance seems to be effective and relatively safe for both mother and fetus, and we suggest that it should be used as first-line therapy for PVTs in pregnant women. Currently, there are no evidence-based guidelines for the pregnancies complicated with PVT. We performed a comprehensive literature review on papers discussing TT in pregnant patients with PVT (Table 2) and compared the TT outcome results of our study with the published articles9-34 (Table 3). Overall, TT has been administered in 32 pregnancies (38 episodes) complicated with PVT. These reports yielded an average thrombolytic success, maternal mortality, major complication, and minor complication rates of 76%, 10%, 14%, and 32%, respectively. Fetal/neonatal mortality was 28 %. Similarly, Leonhardt repo orted ed d a lliterature itter erat atur at ure reported eview on TT with t-PA (reteplase or alteplase) used in 21 pregnant patients for the treatment of review no onn-PV PVT PV T ca cau usess, such su as stroke (n: 10), pulmon nary embolism (n:: 7), 7 , deep 7) deeep de ep venous thrombosis non-PVT causes, pulmonary 3 n:3 3), ) and myo ocaard diaal in nfa farrcti rcti tioon on ((n:1) n 1) n: 1 35 . Thee rreport eporrt did d nnot ot in include nclude nclu dee ccase ase rreports ep por ortts ts aafter fter ft err ddelivery e iv el iver eryy aand nd (n:3), myocardial infarction usage usag us agee of ag o other oth theer er thrombolytic thro hromb omboly boly yti tic drugs. d ug dr ugss. Thrombolytic Thrrom mbo boly yti t c su success, ucccesss, s, maternal mat ater e na er nall mo mort mortality, tal alit itty, y aand ndd m morbidity orrbi bidi d ty di y were 71%, 5% 5%, %, an and nd 24 24%, % rrespectively. %, espe es p ct pe ctiv i el iv ely. y. F Fetal/neonatal etal et al/n al /n neonnat a al a m mortality orta or tali ta l ty w li was ass 224%. 4%.. In oour 4% ur sstudy, tudy tu dy, TEEdy guided low-dose, slow infusion t-PA protocol was associated with 100% thrombolytic success with no maternal mortality. Fetal mortality was 20%. In general, TT for the treatment of PVT in non-pregnant patients is successful in approximately 85% of patients 36-43. On the other hand, our protocol demonstrated complete success rate among all pregnant patients with PVT. This could be explained by the fresh and rapid development of clot in this specific patient population compared to non-pregnant patients with gradually developed and organized thrombus. These findings suggest that low-dose, slow infusion of t-PA can dramatically improve maternal and/or fetal outcomes in pregnant patients with PVT and this effect may be more pronounced due to the 11 DOI: 10.1161/CIRCULATIONAHA.113.001145 thrombus nature in pregnant patients compared to non-pregnant patients. Administration of thrombolytic therapy is considered as a relative contraindication during pregnancy 4,5. Therefore, clinicians hesitate to use TT during pregnancy due to the anticipated maternal and fetal risk of hemorrhagic and thromboembolic complications. The risks of TT during pregnancy have never been evaluated with randomized trials. The best level of evidence comes from case reports or case series. Even though TT in these reports were performed with a different drug, a different protocol, and various indications, the overall complication rates of TT in these patients are not worse than the complication rates in the large randomized TT trials on stroke, myocardial infarction, and pulmonary embolism.44-47 PVT during pregnancy is uncommon but requires urgent therapy. Among 172 pregnancies with thrombotic icc disorders, dis i orde ders rs,, there rs th were only four cases of PVT, and the most commonly used regimen in these patients was streptokinase treept ptok okin ok inas in asee which as whhic ichh was initiated for mostly deep deeep vvenous enous thrombo thrombosis bo osis or ppulmonary ulmonary embolism. Only these women received t-PA treatment O nlly ly five out off th hese se 172 72 ppregnant reggnan re gnan nt w omen re eceiv ved t-P -PA -P A fo fforr th the tr trea eattmen tmentt of aacute cu utee thrombosis. hro omb mbos osis iss.47 There Therre re was wass no no maternal mate mate tern rnal rn al death deaath from fro om any any thrombolytic thro thro rom mbol mbol olyt yttic therapy the h rappy py in in that thatt report. repo eport. or . However, surgery sur urge gery ge ry is is traditionally trrad ditio iona io n llly considered na co ons n id ider ered er ed as as a first firs fi rstt line rs liine therapy the h ra rapy p in py in patients pati pa tiien ents ts with wit ithh PVT. PV Cardiac Cardiaac surgery exposes mother and the child to a greater risk than thrombolytic therapy does6. It is associated with very high maternal and fetal mortality (6% and 9%, respectively), and morbidity (24% and 30%, respectively) suggesting the risk might exceed the risk of administration of TT. A specific concern with TT in pregnancy is increased risk of spontaneous abortion. The incidence of this complication with different anticoagulant regimens is up to 37.5% in patients with prosthetic heart valve.2,3 Mc Lintock reported 26% spontaneous abortion rate with only oral anticoagulation; 23% with heparin in first trimester followed by oral anticoagulation, and 9% with LMWH in first trimester followed by oral anticoagulation during pregnancy3. 12 DOI: 10.1161/CIRCULATIONAHA.113.001145 Approximately one quarter of pregnant patients on oral or intravenous anticoagulation develop miscarriage. The incidence of spontaneous miscarriage in Turkish pregnant women who were not on oral anticoagulants was reported as 20%48. In our study, spontaneous miscarriages occurred in five episodes (20%). Although the total number of miscarriages was low to make a definite conclusion, it was similar to the expected rate among this specific patient population suggesting that our protocol did not increase the baseline miscarriage rate. This observation seemed robust especially in patients who received fewer TT sessions and small doses of oral anticoagulation. One woman who was on warfarin 7.5mg/day developed placental hemorrhage following TT. She had received three sessions of heparin following three doses of t-PA which could have caused the development of placental hemorrhage. Her baby had totall hhearing eaariing lloss osss os which could be also secondary to the high dose warfarin rather than t-PA. Nevertheless, our find nd din inggs gs iindicate ndic nd icatee th ic that a this TT protocol is associat ated at e with a succes ed ssf sful tthrombus hroombus lysis in pregnant hr findings associated successful PV T patients w ithoout iincreasing it nccreeassin ing ng th he co ompliicat cation n rrates atess ffor or mother mot othe herr and and fetus. feetu tuss. PVT without the complication Stud St udyy li ud limi miita tati tion on ns Study limitations Our study is a single sin i gl glee center, c nt ce n err, non-randomized n nno n ra r nd n om omiz ized iz ed observational obs bser errva vati t on onal al study. stu udy dy. However, Howe Ho weve we ver, ve r itt ha r, hass re rema m rkable remarkable size for this specific study population. All pregnant patients with PVT were treated similarly in our hospital. All patients had thrombosed mitral mechanical valves. Therefore, the applicability of our findings to other mechanical and bioprosthetic valves may be questionable. Finally, this study is not a head to head comparison of thrombolytic therapy to surgery for the treatment of PVT in pregnant patients. However, among three patients who underwent surgery in our patient population, one patient (and fetus) died which may reflect the high mortality of this strategy. Conclusion Low-dose, slow infusion of t-PA with repeat doses as needed is an effective therapy with very 13 DOI: 10.1161/CIRCULATIONAHA.113.001145 high thrombolytic success rate for the treatment of PVT in pregnant women. This protocol also seems to be safer than cardiac surgery or alternative medical strategies published to date. TT should be considered as first-line therapy in pregnant patients with PVT. Acknowledgments: We thank the physicians who participated at the study: Cihangir Kaymaz, Nihal Özdemir, Ali Metin Esen, Yusuf Karavelio÷lu, Ruken Bengi Bakal, Emre Ertürk, Tayyar Gökdeniz, Hasan Kaya. We also thank to Dr.Ubeydullah Deligönül, Jefferson City Medical Group, Jefferson City, Missouri, USA; for his critical revision of the manuscript. Conflict of Interest Disclosures: None. References: 1. Elkayam U, Singh H, Irani A, Akhter MW. Anticoagulation in pregnant women with prosthetic heart valve. J Cardiovasc Pharmacol Ther. 2004;9:107-115. 2. C ha WS han WS,, An Anan andd S,, G an insb in sber errg JS JJS.. An Anti tico coag ag gul ulat attioon ooff pr preg egnaant w eg omen om en w ithh me it mech chan anic iccal hheart e rt ea r Chan Anand Ginsberg Anticoagulation pregnant women with mechanical vvalves: alv ves e : a system emat atiic rreview evie evie iew w of tthe hee lliterature. iterratture.. A iter rch h IIntern nterrn Med. Med. Med d. 2000;160:191-196. 200 000; 0;16 160:199116 1-19 196. 6 6. systematic Arch 3.. McLintock McL cLin into to ock C, C, McCowan McCow McC wan LM, wan LM North Nort No rthh RA. RA. A. 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Thrombosis valvular prosthesis of 16 DOI: 10.1161/CIRCULATIONAHA.113.001145 Starr treated successfully by tenecteplase during pregnancy. Ann Fr Anesth Reanim. 2010;29:500-501. 32. Kaya EB, Kocabaú U, Aksoy H, Aytemir K, Tokgözo÷lu L. Successful fibrinolytic treatment in a pregnant woman with acute mitral prosthetic valve thrombosis. Clin Cardiol. 2010;33:E101103. 33. Ozer O, Davutoglu V, Soydinc HE, Cebesoy FB, Sari I, Akcay M. Fibrinolytic therapy of prosthetic mitral valve thrombosis during pregnancy: three case reports and review of the literature. Clin Appl Thromb Hemost. 2010;16:406-413. 34. Srinivas BC, Moorthy N, Kuldeep A, Jeevan H, Chandrasekaran D, Manjunath CN. Thrombolytic therapy in prosthetic valve thrombosis during early pregnancy. Indian Heart J. 2012;64:74-76. 35. Leonhardt G, Gaul C , Nietsch HH , Buerke M, Schleussner E. Thrombolytic therapy in pregnancy. J Thromb Thrombolysis. 2006;21:271-276. 36. 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Menon V, Harrington RA, Hochman JS, Cannon CP, Goodman SD, Wilcox RG, myocardial Schünemann HJ, Ohman EM. Thrombolysis and adjunctive therapy in acute myoc car ardi d al di infarction: Therapy. Chest. nfarction: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Th Ther e ap apy. y. Ch Ches est. 2004;126:549S-575S. GS, 47. Ahearn G S, Hadjiliadis D, Govert JA, Tapson VF. Massive pulmonary embolism during pregnancy recombinant plasminogen pr reg egna naancy ncy su ssuccessfully cces esssful sfu ly treated with recombinan nt ttissue isssue plasminog oggen aactivator: ctiivator: ct iv a case report and review treatment options. Arch Med. 2002;162:1221-1227. evi vieew of tr trea eatm ea men entt op pti tion onns. s Ar rch IIntern nter nt ernn Me Med d. 20 2002 02;162 02 622:1 :122 2 1-12 22 12227. 12 27. 48. Sezer Kamel N,, U Unlu C,, Ce Celik HK. Impact 48 8. S ezer K,, K am mel N nlu lu uC C liik HK K. Im mpactt of of ffirst irst ir st ttrimester r messterr andd ppostpartum ri ostp os tpar artu t m per pperiod eriood thyroid Gynecol hyr yroi oidd autoantibodies oi auto au toaanti to antibo bodi bo dies ess on on abortus aboortu ab tuss incidence inci in ciddenc denc ncee inn Turkish Turkkish ki h pregnant pre regn gnan gn antt women. an wome wo men.. Gy me yneeco coll Endocrinol. Enddoc docrin crinool. ol. 2009;25:387-391. 2009 09;2 ;255:38 3877 39 391. 18 DOI: 10.1161/CIRCULATIONAHA.113.001145 Table 1. Demographic and clinical characteristics of the pregnant patients with prosthetic valve thrombosis. No Age Prosthetic Thrombus Elapsed time since valve Valve Type surgery (months) 1 2 3 4 5 6 7¥ 8¥ (Re) 9 22 31 38 38 35 26 19 21 22 Mitral Mitral Mitral Mitral Mitral Mitral Mitral Mitral Mitral Aortic:N/F Mitral Mitral Mit itra r l ra Mitral Mitrall Mitral Mitral Mitral Mitral Mitral Mi l Mit Mi Mitral tral al NOT OT OT OT NOT NOT NOT NOT NOT 67 124 11 74 56 36 27 58 13 NYHA Class I-II III-IV + Clinical Presentation Warfarin-2,5 mg 50 11 A S None Warfarin-5 mg 50 20 H S None Warfarin-5 mg 25 34 H S None Warfarin-7,5# 25 18 H S None + N 100 6 A S N None N + Warfarin-10 mg 50 25 H S None + LMWH-4000 IU 100 6 A S N None + Warfarin-7,5 mg 25 11 H S None N + Warfarin-2,5 50 11 H S None N ASA 100mg 10€ 25 OT 18 + LMWH-6000 IU 75 14 H S None N 11€(Re) 25 NOT NO O 21 + Warfarin-5 mg 500 35 H S None N 12§ OT 26 + LMWH-6000 IU 100 6 H None 25 1000 S N 13§ (Re) 2255 NOT NOT T 3322 + N 225 5 122 H S N None 14 442 2 O OT T 47 + Warf Warfarin-7,5 rfar f in in-7,5 5m mg g 755 330 0 H** S S* * PH 15 38 OT OT 56 + Warfarin-5 Waarf rfar fa in in-5 -5 mg mg 100 9 H S None N 16 LMWHNone 221 1 NOT O 77 + L MWHMW H 66000 H0000 IU 00 U ** 25 335 5 H S N 17 23 23 OT OT 37 + Warfarin-5 Warfar Wa arin in-5 -5 mg mg 100 1 0 10 33 H S None N 18 225 5 O OT T 27 + W Wa Warfarin-5 rfar rf a in in-5 -5 5m mg, g, g, 255 32 32 H S None N ASA AS A 100mg 100m 10 0mgg 19 334 4 Mit Mi Mitral trall O OT T 76 + D Dyspnea yspnea W Warfarin-7,5 arfari f in-7 7,5 5 mg 75 110 0 H S N None 20 35 Mitral NOT NOT 15 15 + Palpitation Pal alpi pita tati tion on L LMWH-4000 M HMW H 40 4000 000 IIU U 25 9 H S N None 33 Mittrall Mi NOT 45 Asympttomattic LMW MWH H 60 6000 00 IU IU 11 A S N 21 33 Mitral NOT 45 + Asymptomatic LMWH-6000 25 11 None 22 36 Mitral NOT 17 + Dyspnea Warfarin-2,5 mg 25 36 H S None 23 27 Mitral OT 16 + Dyspnea Warfarin- 10 mg 50 9 A S None 24 28 Mitral OT 23 + Dyspnea LMWH-6000 IU 25 36 H S None 25 35 Mitral OT 60 + Dyspnea N 25 8 H S None 26£ 30 Mitral OT 28 + Dyspnea LMWH-6000 IU 25 22 H S None 27£(Re) 30 Mitral OT 38 + Dyspnea LMWH-4000 IU 25 32 H S None 28 28 Mitral NOT 28 + Asymptomatic LMWH-6000 IU 25 9 H S Epis. Re=Rethrombosis; ASA= Acetyl salicylic acid, OT=Obstructive thrombus, NOT=Non-obstructive thrombus; N/F=Normally Functioning;, NYHA= New York Heart Association, H= Healthy, A= Abortion, Epi= Epistaxis; PH=Placental hemorrhage,**= additional aspirin use; ¥,€,§,£= the same sign represents the same patient, S= success, S*=This patient developed placental hemorrhage and preterm delivery. H*=Baby had complete hearing loss. + + + Palpitation Dyspnea Dyspnea Dyspnea Palpitation Dyspnea Palpitation Asymptomatic Transient ischemic attack Dyspnea Dyspnea Dyspnea Palpitation Pal alpi p ta pi tati tion on Dy Dyspnea spnea sp e Dyspnea Dysp spnea e Palpitation Pal pita it tion io Dyspnea Dyysp s nea ea Dy Dyspnea spne sp pne neaa Maternal Anticoagulation at Tissue Prosthetic valve plasminogen Gestational Fetal week Status Final thrombosis activator dose Complication diagnosis-Dose Results 19 DOI: 10.1161/CIRCULATIONAHA.113.001145 Table 2. Published Case Reports Regarding Thrombolytic Therapy of Prosthetic Valve Thrombosis During Pregnancy. Patient no Year Age Moisson et al9 1 1979 25 9 mo Streptokinase Witchitz et al10 1 1980 26 8 mo Streptokinase Jimenez et al11 1 1988 36 14 Urokinase 36 Urokinase 14 Urokinase 2000 U/kg/hr 28 Streptokinase Authors p Same pt Tissot et all12 1 1991 32 Same pt Gestational Thrombolytic week agent Dose Valve position 750000 U/12 hr Mitral (SE) 500000 bolus+ Mitral (SE) 1200000 U/12hr 2000 U/kg/h, 24 hr Aortic (SJM) 2000 U/kg/hrX3+4000 Aortic ((SJM)) U/kg/hr None Success Healthy Mitral (SJM) Uterine Uterin ne hemorrhage hemorrha hage g Success Succ Su cces cc esss es Healthy H a He 250000 U+ 500000 U/1hr Aortic (SJM) None Success Success Healthy Hea e Mitral (BS) Death Spontaneous Sponta abortus abo Success Hea Healthy Success Succ Su cces esss Healthy H a He Souto et all13 1 1991 35 First trimester Streptokinase 1500000 U/1hr Ramamurthy thyy et et al14 1 1994 19 28 28 Streptokinase 250000 2500 25 0 00 bolus+ 2400000 2400 24 0 000 /24 hr Azzano et al15 1 1995 1995 38 38 17 tPA tPA 50 50 mg/2 mg g/2 hhrr Di Rio et al a 16 Same pt pt 17+4 7+4 day day y tPA tPA 0.1 . m mg/kg/hr, g/kg kg/h g/h /hr, r, 8 hhrr Rinaldi et al al17 1 1999 1999 9 28 15 tPA tPA 500 m mg g 18 1 1997 1 977 19 332 2 28 8 tPA tPA 50 m mg g 1 2001 2001 27 1 14 tPA PA 1 2001 2001 28 8 St Streptokinase rept re p ok okin in nas ase 1 2001 2001 443 3 25 tPA PA 1 2001 37 13 Streptokinase N N/a / /a 250000 2500 25 000 0 bolus+ bol olus us+ 1400000 1400 14 0000 00 000 U/14 00 U/14 1 hr hr 100 100 mg 250000 bolus + 7200000 U/72 hr 50 mg/2 hr Fleyfel et aall Sanchez ett al19 20 Anbarasann et al 21 Nanas et all Abbadi22 23 Behrendt et al 1 2002 33 17 24 Nassar et al 1 2003 20 26 Sahnoun-Trabelsi et al25 1 2004 37 14 tPA Streptokinase +tPA Urokinase Same pt 2004 38 32 Urokinase 2 2004 31 14 Urokinase Maternal status Fetal status Complications Results Uterine Success Healthy hemorrhage Uterine Success Healthy hemorrhage None Success Healthy Uterine hemorrhage Tricuspid Uterine T Tr icuspi ic pidd U er Ut erin inee (SJM) hemorrhage (SJM SJM JM)) hemo he m rr mo rrha hage ha gee Tricuspid Uterine T Tr icusspi ic pidd U er Ut erin inee (SJM) S hhemorrhage* he morrhage* mo e A Ao Aortic ortticc (SJM) M N No None n ne Plasental P asen Pl assenta tall Mitral Mi i all ((SJM) SJM) SJ M M) hematoma hema he mato ma toma to m ma Mit Mitral itrall (C (CM) M) Thromboembolism Thromboemb Th b m olism m Mitral (BS) (BS BS)) Healthy H a He Failure Faiilure Healthy Heaa None No ne Success Healthy Heaa M Mitral it l (S (SJM (SJM) JM)) N None S Success H Healthy Mitral (SJM) Thromboembolism Failure Healthy AEMI Mitral (CM) None 2000 U/kg/12 hr Aortic (SJM) 4500 U/kg, 24 hr+2000 Aortic (SJM) U/kg/hr 4500 U/kg/24 hr Mitral (SJM) 20 Success S cc Su cces esss Mitral Mitr Mi t all (SJM) (SJ SJM) M) Aortic (SJM) 6650000 U+100 mg S Success ucce cc ss Medical Med abortus abo Hea Healthy F Fa Failure ilur il ue None Failure Partial success Success IUFD Healthy None Success Healthy None Success Healthy Healthy DOI: 10.1161/CIRCULATIONAHA.113.001145 500000 bolus+ 1500000 U 2000U/kg/12 hr, 500000 bolus + 1500000 U Aortic (SJM) Metrorrhagia Success Spontaneous abortus Mitral (BS) Hematoma Success Spontaneous abortus Same pt 2004 31 28 Streptokinase 3 2004 17 35 Urokinase + Streptokinase 4 2004 34 12 tPA 0.75/ mg/kg/2 hr Mitral (SJM) Death 5 2004 20 8 tPA 0.75/mg/kg/2 hr Mitral (SJM) Death Varadarajan et al26 1 2006 28 tPA 50 mg g Mitral ((SJM)) Sandset PM M et al. 27 1 Same pt 2007 tPA+UFH tPA N/a N/a tPA N/a Early second trimester 6 Same pt 28 Choi et al 29 Wei A et al 300 Maegdefessel ssel ss el all Slaoui M eett al311 32 Kaya EB at a al32 33 a Ozer O at al Srinivas BC ett all344 1 2007 36 14 tPA 100 mg/2 hr 1 2008 20 37 13 tPA 1100 00 mg+100mg 1 1 1 2008 20 2010 2010 2010 010 27 444 4 26 32 1 17 Tenecteplase Tenecteplase Ten enec ecte tepl p as pl asee tPA tPA 1 20100 24 34 2 3 2010 201 0100 2010 201 0100 211 20 8 28 1 2012 2012 25 10 7000 U 60 mg mg 100 100 m mg/3hr g/3h g/ 3 r 3h 50 mg/6 mg/4 mg/ g 6 hr+25 hr+2 hr + 5 mg +2 m /4 4 tPA t A tP hr+25 hr+2 r+25 mg mg/4 /4 hhrr tPA 50 mg/4 tPA 50 mg/4 m /4 mg /4 hr+25 hr+ r 25 r+ 25 m g/4 hr g/ h tPA 50 m mg/4 hr+25 tP PA g/44 hr g/ hr+2 + 5 mg +2 mg/4 / hhrr /4 250000 25500 0000 00 U Strep Streptokinase pto toki kinase se +2400000U/24 +240 +2 4000 40 0000 00 00U/ 00 U/24 U/ 24 hhrr None Spontaneous abortus Spontaneous abortus Success Healthy N/a N/a Succ Su Success ucc cces esss es S Success ucce uc cess ce s ss N/a Success Medical M d Me abortus abo Healthy Hea SAVP (SJM) Thromboembolism Success Pulmonaryy Hematoma Failure (MAP) ( AP)) (M Aortic Aoort r ic (SJM) (SJJM) None Success Mitral Mit itra rall None Noone Success Suc ucce cess ss M Mi Mitral tral a ((SJM) al SJM) SJ JM Epistaxis E is Ep i taxi xis is S Su Success cces cc es es Hea Healthy Healthy Hea H Healthy ea Healthy Hea Mitral M tral Mi ra (SJM) M None N ne No Success Succe cc ss Healthy Hea Mitral (SJM) Mitral (S JM M) Mitral Mitr Mi itral al ((SJM) SJM) SJ M M) T TIA IA Epistaxis Epis Ep ista taxi ta xiss xi Success S ucce ccess ss Success Su S cces cc ces esss Healthy Hea Healthy H a He Mitral Mitr Mi tral al (SJM) (SJ SJM) M)) None No ne Success Suc uccess ss Healthy Hea *=Uterine hemorrhage requiring requirin ingg surgery; surg su rger rg ery; y; AEMI=acute AEMI AE MI=a MI =acu acute embolic emb mbol o ic myocardial myo yoca card rdia di l in iinfarction; f rcti fa tion o ; BS B BS=Bjork-Shiley; =Bjo =B jo ork k-S -Shhile hil y; y C CM=Carbomedics; M Ca M= Carb r om rb omed edic ed i s; MAP=Medtronic MAP AP=M =Med =M edttro ed ronnicc Ad Advantage Adva vant va ntag nt ag ge Pr Prosthesis; Mo = m months; on on N/a=Not available; vai aila labl ble; e; S SAVP=systemic AVP= AV P sy syst stem emiic at atri atrioventricular riov oven entr tric icul ular ar pposition; osit os itio ion; n; S SE=Starr-Edwards; E=S Sta tarr rr-E Edw dwar ards ds;; SJ SJM= SJM=St. M St St.. Ju Jude de M Medical; edi dica cal; l; ttPA=Tissue PA=T PA Tis issu suee pl plas plasminogen asmi mino noge genn ac acti activator; tiva vato tor; r; U UFH=Unfractionated FH=U FH Unf nfra ract ctio iona nate tedd he hepa heparin; pari rin; n; P Pt=Patient; t= = IUFD= intrauterine fetal death. 21 DOI: 10.1161/CIRCULATIONAHA.113.001145 Table 3. Comparison of our study with the published articles with regards to maternal and fetal success, major and minor complications and mortality. Patients Pregnancies Thrombolytic therapy episodes Fetal anomalies Fetal Status Healthy Miscarriage Medical abortion Intrauterine fetal death Hysterectomy* Thromboembolism Major Acute embolic myocardial Complications infarction Placental hemorrhage Total Mate Maternal M ateern rnal status tattus Ep Epistaxis ista is staxi xs xi H em mat ma mato Hematoma Ut Uterine ter e in inee he hhemorrhage morr mo rrha rr hage ha gee *** * Minor M Mi no or Complications C Co mp pliica cati tions Pl Placental laccen e ta t l hemorrhage hemo morr r ha hage g ** ge Metr Me Metrorrhagia** ror orrh rhaagia rh ia** *** T Transient i iischemic h i attack k Total Fetal Death Maternal Death Thrombolytic therapy success Maternal Success TROIA-PREG N (%) 24 25 28 0 (0) Literature (1979-2012) N (%) 31 32 38 0 (0) 20 (80) 5 (20) 0 (0) 0 (0) 24(75) 5(16) 2(6) 1(3) 0 (0) 0 (0) 0 (0) 1(3) 3(8) 3( 8) 1(3) 1( 3) 1 (4) 1 (4)) 0(0) 5(14) 1 (4 ((4) 4) 0 ((0) 0) 0 (0 (0) 0) 0 (0 ((0)) 0 (0) (0 0 (0) 1 (4) 5( 20) 0 (0) 28 (100) 27 (96) 2(5)) 2(5) 22(5) (5) 5(16 5( 5(16) 6) 1( 1(3) (3)) 11(3) 1( 3) 1(3) 12(32) 8(25) 3(10) 30 (76) 30 (76) *=Secondary to uterine hemorrhage; **=Accepted as major complication if blood transfusion, surgery, or preterm delivery was necessary. 22 DOI: 10.1161/CIRCULATIONAHA.113.001145 Figure Legends: Figure 1. A study patient with obstructive prosthetic valve thrombosis. Doppler image demonstrates increased transprosthetic gradient and decreased valve area (Figure 1A). The 2DTEE image of the bileaflet mechanical valve with obstructive thrombus measuring 0.95x2 cm with an area of 1.8 cm2 (arrows) and the immobile medial leaflet (Figure 1B). RT-3D-TEE view also demonstrates the thrombus and the immobile medial leaflet (arrows) (Figure 1C). (Ant: Anterior, LA: Left atrium, LAA: LA appendage, LV: Left ventricle, THR: Thrombus) ndd nnono on Figure 2. T-PA doses required for complete thrombolysis in both obstructive and obstructive prosthetic valve thrombosis in pregnant patients. (THR: Thrombus) 23 Figure 1 Figure 2