Thrombolytic Therapy for the Treatment of Prosthetic Heart Valve

Transcription

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
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
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
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
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
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
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
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
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
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
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
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
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
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.
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22
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12
27.
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Sezer
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Unlu
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Celik
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Impact
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8. S
ezer K,, K
am
mel N
nlu
lu
uC
C
liik HK
K. Im
mpactt of
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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
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2009
09;2
;255:38
3877 39
391.
18
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
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
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
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
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

Thrombolytic Therapy for the Treatment of Prosthetic Heart Valve

Transcription

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