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Massive Pulmonary Embolism During Pregnancy Successfully Treated With Recombinant Tissue Plasminogen Activator
A Case Report and Review of Treatment Options
Gregory S. Ahearn, MD;
Denis Hadjiliadis, MD;
Joseph A. Govert, MD;
Victor F. Tapson, MD
Arch Intern Med. 2002;162:1221-1227.
INTRODUCTION
Thromboembolic disease is an important cause of morbidity and mortality
during pregnancy.1 Berg and colleagues2 found that 11% of maternal deaths during pregnancy
were related to pulmonary embolism (PE). Another study revealed that up to
40% of pregnant women with asymptomatic deep vein thrombosis (DVT) may also
have concurrent PE.3 Women are at increased
risk for DVT and PE during pregnancy for several reasons. Pregnancy is a thrombophilic
state; fibrinogen levels are increased, and during the final trimester there
is a decrease in fibrinolytic activity. In addition, the gravid uterus causes
compression and stasis in the lower extremities and pelvic veins favoring
thrombosis.3 Finally, women with a history
of thrombotic complications during pregnancy have an increased prevalence
of genetic mutations related to coagulation.4
Traditionally, thromboembolic disease during pregnancy has been treated
with unfractionated5 and, more recently, low-molecular-weight
heparin.1, 6 A strong negative
charge keeps heparins from crossing the placenta and affecting the fetus.
The treatment options available for patients with massive, life-threatening
PE in whom conservative heparin therapy has failed include embolectomy, thrombolytic
therapy, and localized catheter-directed thrombolytic therapy. Inferior vena
cava (IVC) filters are often part of the management of severe PE and have
been used safely during pregnancy, although their long-term safety remains
uncertain. Thrombolytic agents are relatively contraindicated during pregnancy
because of the presumed risk of maternal bleeding and fetal loss. The teratogenicity
for these agents in humans is also uncertain. There is some concern that increased
levels of plasmin may precipitate premature labor, although this has never
been convincingly demonstrated in clinical practice.7
The risk of bleeding post partum may be further increased after thrombolytic
therapy because of uterine atony induced by elevated levels of fibrin split
products, which are present after thrombolytic therapy.7
The decision to embark on high-risk therapy for PE is difficult because of
early observations that patients who do not die immediately usually do well
once adequate anticoagulant therapy has been started.8
Treatment decisions are further complicated by pregnancy, in which the outcome
of the fetus is also at stake. This article will discuss each of these treatment
modalities and relate them to the pregnant patient.
REPORT OF A CASE
A 12-week pregnant, 36-year-old African American woman with acute dyspnea
and substernal chest pain was brought to the emergency department by ambulance.
She was having dyspnea on exertion and trouble climbing stairs for the past
week. She had been seen the day prior for pain in her left leg, which was
treated with acetaminophen. She was diaphoretic and lethargic with a systolic
blood pressure of 82/50 mm Hg and a pulse rate of 135/min. Her neck veins
were not visible, and her lung fields were clear. Findings from cardiac examination
were remarkable for tachycardia with a 2/4 high-pitched systolic murmur heard
along the upper left sternal border. An intermittent third heart sound along
the left sternal border was also present. Abdominal examination findings were
benign, with the uterine fundus barely palpable. There was no peripheral edema.
Pelvic and neurologic examination results were normal. Initial pulse oximetry
on room air was 80%, which increased to 95% on 100% oxygen by face mask. Her
electrocardiogram revealed sinus tachycardia at a rate of 120 beats per minute
with a Q wave and inverted T wave in lead III. Because of the high suspicion
for PE, therapeutic intravenous heparin was begun immediately. The ventilation-perfusion
scan was consistent with massive PE, with almost no perfusion to the left
lung and multiple filling defects in the right lung. Radioactive tracer was
also noted in the brain and kidney, suggestive of a right to left shunt (Figure 1). Echocardiography with a bubble
study confirmed the presence of a right to left shunt through a patent foramen
ovale as well as a dilated, hypokinetic right ventricle. Her left ventricular
function was normal. A Doppler ultrasound study of her lower extremities revealed
acute DVT in the left leg, extending from the popliteal vein proximally through
the common femoral vein.
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High-probability perfusion scan showing bilateral defects as well
as evidence of right to left shunting. A, Intense tracer uptake in the head
consistent with a right to left shunt. B, Bilateral perfusion defects as well
as uptake in the kidneys, which is indicative of right to left shunting. The
uptake in the kidneys is more pronounced in the posterior view.
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The patient was brought to the medical intensive care unit. Despite
aggressive fluid resuscitation, she remained hemodynamically tenuous with
systolic blood pressures ranging from 80 to 89 mm Hg. Because of the perceived
high risk of a fatal PE and the possibility of paradoxical emboli through
her patent foramen, she was given 100 mg of recombinant tissue plasminogen
activator (rtPA) over 2 hours. The patient had an excellent response to thrombolytic
therapy. After several hours, supplemental oxygen was discontinued, the chest
pain and tachycardia resolved, and her blood pressure stabilized. She had
no clinically apparent bleeding complications, no evidence of fetal compromise,
and was discharged home in good condition on hospital day 4 with a prescription
for subcutaneous enoxaparin sodium, 1 mg/kg every 12 hours. She subsequently
delivered a normal-term infant without complication.
EMBOLECTOMY
Early experience with embolectomy was associated with exceedingly high
mortality and neurologic complications.9 Technological
advances such as extracorporeal bypass significantly reduced the morbidity
and mortality from the procedure.8 Since the
development of extracorporeal bypass, several series have been reported, with
mortality rates ranging from 0% to 86%.10-21
The variability in these series stems from variable patient populations and
selection criteria for surgery.
Recommendations and criteria for patients suitable for embolectomy have
been controversial, with some authors advocating a conservative approach of
maximizing medical therapy8, 22-23
and other authors proposing early and aggressive surgical management12 of patients with PE. In a more contemporary review,
the role of embolectomy9 was downplayed in
favor of making every effort to maximize medical therapy. With several randomized
trials demonstrating the efficacy of thrombolytic therapy in the reduction
of acute clot burden and restoration of hemodynamics,24-29
the role of embolectomy has been relegated to those in whom heparin therapy
has failed and have strong contraindications to the use of thrombolytic therapy.
In pregnancy, however, the role of embolectomy is more problematic because
pregnancy is a relative contraindication to the use of thrombolytics because
of the risk of hemorrhage and fetal loss. An emergent surgical procedure is
clearly associated with risk of maternal and fetal morbidity and mortality
as well as the risk of fetal loss.30
Pregnant patients with massive embolism may make more reasonable surgical
candidates because they are generally younger than the general medicine population
and have limited comorbid illness. While there have been no large case series
reporting outcomes of embolectomy during pregnancy, Becker30
reported the results of 68 pregnant women undergoing cardiopulmonary bypass.
There was an approximately 20% incidence of fetal loss. Only 3 of these 68
cases were embolectomies with no maternal deaths and 1 fetal death.
Published experience with emergent embolectomy in pregnancy is limited
to case reports.31-33
In 1989, Blegvad et al33 reported a case of
successful embolectomy in a patient during the second trimester and reviewed
the predominantly European literature up until that time. They found 10 reported
cases with no maternal deaths but 4 fetal deaths. In summary, based on the
available evidence, it seems the operative risk to the mother is reasonable;
however, the fetal death rate is substantial, ranging from 20% to 40%.
THROMBOLYTIC THERAPY
Up until the early 1970s, surgical embolectomy was the only alternative
to heparin therapy for patients with massive PE. In 1970, the Urokinase Pulmonary
Embolism Trial (UPET) demonstrated that urokinase was more effective than
heparin for thrombolysis over the first 24 hours of treatment for massive
PE.34 Because of concerns about bleeding and
teratogenicity, pregnant patients were excluded from UPET and other clinical
trials of thrombolytics in PE. Thus, the risks of thrombolytic therapy in
pregnancy have not been adequately delineated by randomized trials and are
unlikely to be in the future.
Currently used thrombolytic agents are streptokinase and rtPA. Both
agents activate plasminogen to form the fibrinolytic enzyme plasmin. In addition
to cleaving fibrin, plasmin cleaves fibrinogen, factor V, and factor VIII,35 resulting in a systemic "lytic" state. One potential
advantage of rtPA over the other 2 agents is that it has a high affinity for
plasminogen only in the presence of fibrin.36-37
This specificity theoretically results in more localized thrombolysis at the
site of thrombosis and less generalized coagulopathy. Animal models suggest
that for a given level of fibrinolytic activity, rtPA results in less hypofibrinogenemia
and fewer hemorrhagic complications than streptokinase.38-40
This localized activity may also account for the observation that the thrombolytic
activity of rtPA persists after it has been cleared from the general circulation.
However, a clinical advantage of rtPA has not been clearly demonstrated with
regard to this fibrin specificity.
Recombinant tissue plasminogen activator is a large polypeptide (72 000
kd) that does not cross the placenta. It is not antigenic, thus patients may
receive repeated doses.22 Streptokinase is
also a large molecule derived from group C streptococci that does not cross
the placenta in sufficient amounts to cause fibrinolysis in the fetus.41-42 It is, however, antigenic, and after
the first dose, patients should not receive it again for 6 months after the
last use. Urokinase is a small nonantigenic molecule purified from human urine
that crosses the placenta. At present, limited evidence has not shown coagulopathy
in the fetus, although it could be a concern. Tenecteplase has recently become
available and appears to be as safe and effective as rtPA in myocardial infarction;
however, it has not been studied in thromboembolic disease or in pregnancy.20
Several randomized trials using thrombolytic agents in PE have established
that thrombolytic therapy more effectively reduces clot burden and improves
hemodynamics more rapidly compared with heparin therapy,24, 26-28,34, 43
but without evidence of long-term survival advantage. No agent has been proven
to be clearly superior to the others.9, 29, 44-46
Current recommendations suggest reserving thrombolytic therapy for patients
with severe PE with hemodynamic compromise.23
Others have suggested that evidence of right ventricular dysfunction on echocardiogram
should be an indication for thrombolytic therapy. This remains controversial.47
The literature on the use of thrombolytic therapy during pregnancy is
limited to case reports and case series.7, 42, 44, 48-60 Table 1 summarizes reports in the English
literature. In 172 women 14- to 40-weeks' pregnant who were treated with thrombolytic
therapy (164 were treated with streptokinase; 3, urokinase, and 5, rtPA),
there have been 5 nonfatal maternal bleeding complications (2.9%) and 3 fetal
deaths (1.7%). No maternal deaths from thrombolytic therapy have been reported.
Most reported experience with streptokinase comes from 2 series reported by
Ludwig and Genz50 and Ludwig.61
In 1973, Ludwig61 reported the results in 24
patients who had received streptokinase for DVT or PE. He reported a good
clinical response with no maternal or fetal complications. In 1981, Ludwig
and Genz50 reported a series of 122 pregnant
patients who had received streptokinase for acute DVT. There was a favorable
clinical response in 90% of the patients treated; however, 2 women had significant
bleeding requiring emergent cesarean section; there was 1 premature rupture
of membranes with a good outcome and 1 fetal death.
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Thrombolytic Therapy in Pregnancy*
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There is substantially less reported experience with both urokinase
and rtPA in pregnancy. It has been reported that 3 pregnant patients have
received urokinase for DVT or PE with favorable clinical outcomes and no reported
complications.51, 58 Similarly,
there are 6 published reports of pregnant women who have received rtPA for
thrombosed prosthetic valves, myocardial infarction, and PE.52-54,57, 59-60
In these reports there were no adverse maternal outcomes and 1 fetal death
that was related to the rethrombosis of a prosthetic valve 2 weeks after treatment
with rtPA.
In 1997, Turrentine et al62 published
a review of thrombolytic therapy in 172 pregnant patients, which included
substantial experience from European literature. They reported an overall
rate of maternal hemorrhagic complications of 8.1%. Most of these complications
occurred with streptokinase, though there were very few patients treated with
either urokinase or rtPA. There were 2 maternal deaths (1.2%). However, after
careful review of the cases, they were not direct complications of thrombolytic
therapy. One developed pyelonephritis and sepsis, and the other had a cardiac
arrest attributed to a thrombosed mitral valve. Turrentine et al62
reported a 5.8% rate of pregnancy loss and a 5.8% rate of preterm delivery.
Any conclusions about the efficacy and safety of thrombolytic therapy
in pregnancy must be drawn with extreme caution. From the available evidence
it seems that the maternal bleeding complication rate ranges from 1% to 6%,
which is comparable to that of nonpregnant patients who receive thrombolytics.
Reported rates of "major bleeding" following thrombolytic therapy in patients
with myocardial infarction and DVT and PE have ranged from 1% to 29%, 4% to
25%, and 6% to 45%, respectively.63 Most of
these bleeding events occurred around catheter and puncture sites. Importantly,
among case reports in pregnant women, there were no intracranial bleeds, and
the 2 deaths reported were not secondary to hemorrhage.
CATHETER-DIRECTED THROMBOLYTIC THERAPY
Potential advantages of catheter-directed thrombolytic therapy are more
rapid clot lysis because of a higher local concentration drug and less systemic
fibrinolysis, thus a lower risk of bleeding complications. Disadvantages are
the need for pulmonary artery catheterization with the potential risks of
arrhythmia and myocardial rupture.64 Another
concern unique to pregnancy is the radiation exposure associated with fluoroscopy.
Several reports have demonstrated the feasibility of locally delivered
low-dose thrombolytic therapy;25, 64-66
however, there is no convincing evidence that catheter-directed thrombolytic
therapy is superior to treatment with systemic thrombolytics or standard heparin.
To our knowledge, there is a single report of catheter-directed thrombolytic
therapy for the treatment of thromboembolic disease during pregnancy. Krishnamurthy
et al67 reported a series of 3 patients, 1
with hemodynamically significant PE and 2 with iliofemoral DVT that had not
responded to standard heparin therapy. All patients received 2200 U/kg per
hour of urokinase directed at the thrombus with concurrent intravenous heparin.
All 3 patients had marked clinical improvement, and their pregnancies proceeded
normally.
In summary, local therapy is feasible but requires specialized facilities
and expertise. There is no evidence that it is superior to systemic therapy.
Further studies examining different dosing strategies are required to determine
its role in the management of massive PE. More experience is needed before
catheter-directed therapy can be recommended for pregnant patients.
VENA CAVA FILTERS
In the 1960s percutaneous filter devices supplanted surgical interruption
of the vena cava as a mode of PE prevention in high-risk patients. This important
advance removed the risk of general anesthesia and an operative procedure
in patients who are critically ill. Traditional indications for the placement
of a vena cava filter are (1) recurrent embolism on adequate medical therapy,
(2) strong contraindications to full anticoagulation after a thromboembolism,
and (3) critically ill patients at high risk for recurrent embolism in whom
it is believed that a recurrent embolism would likely be fatal. Some authors
have advocated prophylactic placement of vena cava filters in trauma patients
believed to be at very high risk for thromboembolism; however, this recommendation
has not become general practice.68-69
Early experience found that these devices were effective in preventing
recurrent thromboembolism, but there were several complications. Up to 85%
of patients developed caval thrombosis,70 with
many of these patients developing chronic venous stasis. In addition, several
deaths were attributed to filter migration. Refinements in design culminated
in the Greenfield filter, which is currently the most widely used device.
Its more conical design allows clot to be funneled to the apex of the device,
allowing free blood flow though the cava. Experimental and clinical evidence
suggest that free-flowing blood around trapped clot allows for clot lysis
and perpetual cleaning of the filter.70 Multiple
series have documented long-term patency rates in excess of 95% and a rate
of recurrent PE of 2% to 4%.71-72
With widespread use of Greenfield filters, case reports of late complications
have emerged21, 73-89:
- Duodenal perforation21, 73-74
- Caval rupture in aortic mural thrombus77-78
- Penetration into vertebral bodies79-80
- Strut failure resulting in penetration into the retroperitoneum81
- Distal migration resulting in poor alignment and pulmonary emboli76
- Acute myocardial infarction from migration to the right atrium82
- Migration into pulmonary artery83
- Aortic perforation77, 85
- Tricuspid insufficiency from intracardiac migration87
- Renal pelvis perforation88
- Penetration into an aortic aneurysm89
In addition, severe complications during filter placement may occur,
including intracardiac and intrapulmonary migration.90-91
The exact incidence of such complications is unknown, but they serve as a
reminder of the potential long-term morbidity associated with filter placement.
The first report of the successful use of a vena cava filter during
pregnancy was in 1981.91 Several case reports
and series have reported favorable results using IVC filters.92-94
In 1986, Hux et al94 described 6 pregnant patients
with thromboembolic disease who had good maternal and fetal outcomes after
Greenfield filter placement.94 Thomas et al95 described 8 pregnant patients at risk for PE prophylactically
treated with Greenfield filters with similarly good outcomes.95
Most recently, Aburahma and Boland96 published
a series of 11 pregnant patients who had filters placed for the management
of DVT. There were no serious maternal or fetal complications; however, at
a mean follow-up of 61 months, 27% of patients who had filters placed still
had significant lower extremity edema.
The indications for IVC filter placement during pregnancy are the same
as for the nonpregnant patient. The incidence of late complications of IVC
filter placement during pregnancy is unknown because there are limited long-term
follow-up data addressing this point. To our knowledge, there is only 1 report
of a woman who, 7 years after the placement of a Greenfield filter, developed
thrombosis involving her IVC, bilateral common iliac veins, and right renal
vein after delivery of a healthy child.97 When
considering IVC filter placement in a young and otherwise healthy patient,
the physician must be mindful of the many potential complications that may
occur over the patient's lifetime. Additionally, compression from the gravid
uterus during the current and future pregnancies may increase the risk for
complications. One potential option is to place the filter above the renal
veins, which prevents contact with gravid uterus. The concern with this approach
is the possibility of clot forming on the filter and propagating proximally
with subsequent compromise of the renal veins. One series reports favorable
results in 11 patients with this approach;98
however, the risk of renal compromise remains a concern.
Because of long-term safety concerns, an attractive alternative to permanent
IVC filters is to place a retrievable filter. Such a device would protect
the patient from thromboembolism during the high-risk period around the acute
event. Over time, clot lysis as well as organization occur, and the risk of
embolism is substantially reduced. At this time the device could be removed.
Two case reports have emerged from European literature in which pregnant women
with PE and DVT have had such filters placed to prevent thromboembolism during
delivery or cesarean section.99-100
One limitation is that the device must be removed within 10 days, which limits
its usefulness in situations that need long-term protection from PE.
Another potential disadvantage of IVC filters is their inability to
block small communicating veins between the upper and lower parts of the body.
Small emboli can still occur. These emboli can have devastating consequences
in patients with a patent foramen ovale. After an initial pulmonary embolus,
the closed patent foramen ovale frequently opens because of the pulmonary
hypertension that follows the embolus. This in turn causes blood to shunt
from right to left in the heart. Subsequent emboli have a significant chance
of traveling to the brain or coronary arteries via the systemic circulation,
causing devastating strokes or myocardial infarction.
CONCLUSIONS
Pulmonary embolism in pregnancy remains a rare but significant cause
of morbidity and mortality among pregnant women. Most patients with DVT and/or
PE can be safely and successfully treated with unfractionated or low-molecular-weight
heparin for the duration of the pregnancy. Unfortunately, there are no conclusive
data on the appropriate treatment of massive PE. Our current review summarizes
the data supporting each of the different treatment modalities. Embolectomy
appears to be safe for the mother, but is associated with a high rate of fetal
loss (about 20%). Pregnancy is a relative contraindication to thrombolytic
therapy, but a careful review of the literature reveals that approximately
200 patients were successfully treated, with a very low maternal mortality
(approximately 1%) and a low rate of fetal loss (6%) or premature delivery
(6%). Thrombolytic therapy appears to be the more easily and safely administered
treatment when medical therapy fails or when there is a patent foramen ovale
with a right to left shunt. The use of IVC filters appears to be the safest
short-term method of treating massive PE during pregnancy, but it can have
significant future complications.
AUTHOR INFORMATION
Accepted for publication October 15, 2001.
Corresponding author and reprints: Victor F. Tapson, MD, Department
of Medicine, Division of Pulmonary and Critical Care Medicine, Duke University
Medical Center, Box 31175, Durham, NC 27710 (e-mail: taps001{at}mc.duke.edu).
From the Department of Medicine, Division of Pulmonary and Critical
Care, Duke University Medical Center, Durham, NC.
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