Article type : Review of Therapeutics

Accepted Article
Title Page

Title: Thrombolysis for Massive Pulmonary Embolism in Pregnancy

Authors:

1. Mojdeh S. Heavner
Department of Pharmacy Practice and Science
University of Maryland School of Pharmacy
2. Min Zhang
Department of Pharmacy Services
Yale-New Haven Hospital
3. Chelsea E. Bast
Department of Pharmacy
Baylor University Medical Center
4. Lindsey Parker
Department of Pharmacy
The Johns Hopkins University Hospital
5. Rachel F. Eyler
Department of Pharmacy Practice
University of Connecticut School of Pharmacy

Address for correspondence: Mojdeh S. Heavner

Assistant Professor, Critical Care
Department of Pharmacy Practice and Science
University of Maryland School of Pharmacy
20 North Pine Street, N427
Baltimore, MD 21201
mheavner@rx.umaryland.edu

Key Words: alteplase, thrombolysis, pulmonary embolism, pregnancy

Funding: none

Running Head: Thrombolysis for Massive Pulmonary Embolism in Pregnancy

Abstract

Pregnant women are at high risk for venous thromboembolism, including pulmonary embolism (PE),

given expected changes in coagulation, fibrinolysis, and venous blood flow. In fact, PE is the leading
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 cause of maternal death in the United States. Non-pregnant patients who develop PE with hypotension
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or showing signs of deterioration after anticoagulation receive thrombolytics as a standard of care.

Pregnant women, however, have been excluded from clinical trials with thrombolytics and all data

available in this population is published as case reports or case series. We reviewed all reports of

thrombolytics, systemic or catheter-directed, used in pregnant patients with massive PE. This article

summarizes the risks for thromboembolism in pregnancy, compares and contrasts thrombolytic agents

in this setting, and provides a recommendation for management of massive PE in this special

population. Overall, reports suggest that the use of these agents is associated with beneficial outcomes

and relatively low risk of complications. The quality of this evidence is low and clinical judgment is

required to assess individual patients for risks versus benefits of thrombolysis.

Introduction

Pregnancy causes a hypercoagulable state that puts pregnant patients at a higher risk for thrombotic

complications such as venous thromboembolism (VTE), including pulmonary embolism (PE) and deep

vein thrombosis (DVT).1 Current guidelines on thrombolytic use in PE state that systemic thrombolytics

are indicated in patients presenting with associated hypotension, defined as a systolic blood pressure

<90 mmHg, who do not have a high bleeding risk. Systemic thrombolytic therapy can also be considered

in patients with a low bleeding risk who deteriorate after starting anticoagulant therapy, prior to the

development of hypotension.2 While pregnancy is listed as a relative contraindication to systemic

thrombolytic therapy, the high mortality rates associated with PE may necessitate intervention. In the

general population, acute PE has an estimated mortality of approximately 15% at 3 months. This

number climbs to approximately 50% in patients hospitalized with massive PE.3 The literature

surrounding the use of thrombolytic therapy in pregnancy is sparse, as pregnant women are excluded

from clinical trials and no controlled studies have been performed. This review summarizes the risks for

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 thromboembolism in pregnancy, compares and contrasts different thrombolytic agents in this setting,
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and provides a recommendation for management of massive PE in this special population.

Literature Review

Published reports concerning safety and efficacy of thrombolytics in pregnant patients with PE were

considered for this review. The PubMed and Embase databases were used to search and identify

reports. The following keywords were used: thrombolytics AND pregnancy, pulmonary embolism AND

pregnancy, fibrinolytics AND pregnancy, thrombolytics AND pulmonary embolism. The search was

performed from February 7th through March 22nd, 2017 and yielded primary research articles as well as

relevant review articles on the topic. Pertinent reports identified in the review articles that did not

appear in the initial search were retrieved as well. The publication dates of reports used in this review

spanned from 1972 - 2015.

Pulmonary Embolism in Pregnancy

Pulmonary embolism is the leading cause of maternal death in the United States, contributing to 9.6% of

maternal deaths from 2006-2010.4 The incidence of VTE ranges from 0.76 to 1.72 per 1000 pregnancies,

which is 4 to 5 times higher than in non-pregnant women. Additionally, nearly 3 quarters of pregnancy-

related DVTs occur during the antepartum period compared with the postpartum period. Among

patients with antepartum DVT, the rates are distributed similarly among all 3 trimesters.1, 5 The risk of PE

during pregnancy is 10.6 per 100,000 woman-years .6 Approximately 45% to 60% of PEs are diagnosed in

the postpartum period, occurring more commonly after cesarean delivery compared to vaginal delivery.1

Pregnancy-associated DVT is most commonly left-sided, which is likely related to compression of the left

iliac vein by the right iliac artery and the enlarging gravis uterus.7 The key elements of Virchow’s triad,

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 including venous stasis, hypercoagulability, and vascular damage, are all present during pregnancy and
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6-weeks postpartum. Venous stasis typically begins in the first trimester and reaches its peak around 36

weeks gestation. It is manifested through dilation of capacitance vessels and diminished venous return

due to pressure of the gravid uterus on the iliac veins.1 Additionally, both vaginal and cesarean deliveries

lead to tissue damage around the pelvic vessels and subsequent alteration of the vascular

endothelium.7, 8

Coagulation and fibrinolytic changes during pregnancy result in a hypercoagulable state that has likely

evolved to protect women from hemorrhage secondary to childbirth and miscarriage. Coagulation

factors II, IV, VII, VIII, XII and fibrinogen are elevated by the end of the first trimester under the influence

of estrogen (Figure 1).7, 8 This leads to enhanced thrombin production, which is measured through the

concentration of either fibrinopeptide A or the thrombin-antithrombin complex. There are also changes

in physiological anticoagulants including reduced free protein S levels and acquired resistance to

activated protein C. Additionally, the venous flow velocity is decreased by 50% by the end of the second

trimester until about 6 weeks after delivery. Increased activity of plasminogen activator inhibitor type 1

and type 2 and decreased activity of tissue plasminogen activator lead to increased fibrin generation and

inhibition of fibrinolytic activity.7, 8

Thrombolytic Agents

Thrombolytics can be classified into 3 groups based on similar characteristics. First generation agents,

including urokinase and streptokinase, are not fibrin-specific and work by converting plasminogen to

plasmin. These agents also have shorter half-lives compared to later agents, necessitating longer

infusion times of 12-24 hours for treatment of PE. Alteplase, a second generation agent, is fibrin-

specific, meaning it works in the presence of fibrin. Its longer half-life allows for administration over 2

hours. Third generation agents, including reteplase and tenecteplase, are fibrin-specific as well.

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 Additionally, their longer half-lives allow for convenient bolus administration in patients with myocardial
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infarction (MI). However, these agents are not currently approved by the Food and Drug Administration

(FDA) for the treatment of PE.9 Studies in non-pregnant patients with MI also suggest that fibrin

specificity may be associated with bleeding, with the most bleeding occurring with the first generation

agents and the least bleeding occurring with the third generation agents, although procedure type and

patient demographics (gender, weight, and age) play a stronger role in determining bleeding risk.9-11

Drugs with molecular weights greater than 1000 Da cross poorly into the placenta by passive diffusion.

Thus, it is unlikely that any thrombolytics will reach the fetus directly because they are all larger than

1000 Da. However, agents with larger molecular weights could presumably be preferred because the

risk of reaching the fetus would be lowest.12 There is no registry to monitor pregnancy outcomes in

women exposed to thrombolytics. However, the use of thrombolytics in existing animal and limited

human exposures do not suggest significant fetal harm with regards to teratogenicity or other risks.13-15

Hemorrhage resulting from placental separation is a possible risk of therapy at any time during

pregnancy; careful monitoring of the mother is recommended to prevent this from causing a significant

risk to the fetus.

First Generation

Urokinase, which was originally isolated from human urine, enacts its thrombolytic effects through

direct activation of plasminogen to form plasmin. Placental passage in humans has not been studied,

although the placenta contains proteinase inhibitors that can inactivate the drug, even if it does cross

the placental membrane.16 Urokinase treatment did not increase malformations in mice and rats

receiving supra-therapeutic doses of the drug.17

In contrast to urokinase, streptokinase works by activating circulation and clot-bound plasminogen

through the formation of streptokinase-plasminogen complexes. These complexes convert circulating

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 plasminogen to plasmin, which initiates fibrinolysis. Streptokinase undergoes insignificant placental
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transfer18, however a disadvantage of this agent is that it must be administered over 24 hours.12

Streptokinase is also associated with antibody development due to its nonspecific plasminogen binding,

provoking allergic reactions and hypotension.9 These antibodies can be transferred to the fetus,

although this would only be clinically concerning if the fetus needed subsequent treatment with a

thrombolytic.19

Pfeifer and colleagues analyzed the effects of streptokinase on umbilical cord blood. A “double dose” of

streptokinase was given to 11 women during delivery, and umbilical vein blood was obtained and

analyzed at 5, 10, and 15 minutes after administration. No fibrinolysis of umbilical cord blood was

observed in these patients. However, in two patients receiving a “10-fold dose” of streptokinase,

evidence of umbilical cord blood fibrinolysis was reported 10 minutes after administration. Overall, the

study concluded that single “therapeutic” doses of streptokinase have no detectable thrombolytic effect

on umbilical cord blood.20, 21

Second Generation

Alteplase was developed through molecular cloning techniques. It is also fibrin-specific and works by

converting plasminogen to plasmin in the presence of fibrin. Clearance of alteplase is similar to hepatic

blood flow and is dependent on liver perfusion.22 Like streptokinase, alteplase undergoes insignificant

placental transfer. However, alteplase has been associated with subplacental bleeding in pregnant

women.18 Additionally, no teratogenicity was found in the rat and rabbit models for doses up to 10

mg/kg/day and no problems were observed with postnatal development with doses up to 3

mg/kg/day.23 In contrast to streptokinase, alteplase is not associated with allergic or febrile reactions9

and is administered over a shorter time period of 2 hours.13

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 Third Generation
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Reteplase, a third generation agent approved by the FDA in 1996, has a longer half-life compared to

alteplase. It works by facilitating the conversion of plasminogen to plasmin. Like alteplase, reteplase is

fibrin-specific, however modifications to its molecular structure allow reteplase to bind fibrin with

higher specificity and 5-times lower affinity, improving its ability to penetrate into clots. Reteplase is

cleared both renally and hepatically.22 Reteplase also has a longer half-life, allowing for bolus

administration in the treatment of acute MI.9 However, reteplase is not currently FDA approved for

treatment of PE, making dosing unclear in this population.15

Lastly, tenecteplase is a newer third generation thrombolytic agent derived through modifications of

tissue plasminogen activator at 3 sites.9 Advantages of tenecteplase include its greater potency,

increased fibrin specificity, and longer duration due to decreased clearance from plasma. Tenecteplase

is hepatically eliminated; however, it undergoes slower clearance than alteplase,24 which explains its

longer duration of action..24 A phase II pharmacokinetic study showed a biphasic or two-part

compartmental profile with a mean initial half-life of 22 minutes and terminal half-life of 115 minutes.24

According to the tenecteplase package insert, multiple intravenous administrations resulted in toxicity

to both the mother and embryo in the rabbit model without evidence of toxicity following a single

intravenous administration.14 Similar to reteplase, tenecteplase is administered as a single bolus dose in

patients with acute MI9, however because tenecteplase does not have FDA approval for treatment of PE,

dosing for this indication remains unclear.14

Pharmacokinetics and Pharmacodynamics of Thrombolytic Agents

The basic pharmacokinetic characteristics of the thrombolytic agents are summarized in Table 1.12-15, 22,
24-30
The thrombolytics are similar in that pharmacokinetic drug-drug interactions do not appear to be

clinically relevant. Thrombolytic agents are not metabolized through the cytochrome P450 system, and

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 therefore, common cytochrome P-450 (CYP) inhibitors and inducers are not reported to affect their
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pharmacokinetics. However, a possible pharmacokinetic interaction between thrombolytics and agents

that impact hepatic blood flow may exist. One study of 60 patients with acute MI found that patients

receiving alteplase plus nitroglycerin had decreased evidence of reperfusion, increased reperfusion

time, and increased evidence of reocclusion compared with patients receiving alteplase alone.31

Evidence of this type of interaction was not seen in a controlled study of nifedipine and alteplase

coadministration, despite a 95% increase in hepatic blood flow; plasma concentrations and activity of

alteplase remained the same in study participants.32

There is concern regarding the pharmacodynamic interactions between thrombolytic agents and

anticoagulant and/or antiplatelet drugs such as heparin, oral anticoagulants, platelet inhibitors, and

contrast media. Although no clear guidance exists outlining the risks and benefits of possible synergistic

or additive interactions between these agents, patients should be monitored frequently for signs of

bleeding. In the non-pregnant patient population, avoiding activated partial thromboplastin time (aPTT)

values >2.5-fold normal has been suggested during coadministration with unfractionated heparin.33

Additionally, 1 study of non-pregnant patients demonstrated that streptokinase might cause a partial

resistance to anticoagulation, necessitating higher heparin doses and more frequent dosage

adjustments.33, 34 The European Society of Gynecology guidelines on the management of cardiovascular

diseases during pregnancy offer guidance regarding heparin coadministration with thrombolytic agents

in pregnant women. The guideline states that “when thrombolysis has been given, the loading dose of

unfractionated heparin should be omitted and an infusion started at a rate of 18 units/kg/h. After

stabilization of the patient, unfractionated heparin can be switched to a low molecular weight heparin

for the residual duration of pregnancy.” 18

In general, coadministration of thrombolytic agents and anticoagulant and/or antiplatelet drugs should

be done with caution. Data have shown mixed results regarding the risk of bleeding versus benefit

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 depending on the type of drug being coadministered and the patient population.33 Differences exist
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among thrombolytic agents that need to be considered as well.

Current Recommendations

Thrombolytics in Pregnancy

Currently, no guidelines exist to define the role of thrombolytic therapy in pregnant patients with PE. In

the general population, systemic thrombolytic therapy has shown benefit over anticoagulation alone for

the treatment of PE in patients at high risk for mortality. The 2016 CHEST Guideline and Expert Panel

Report on Antithrombotic Therapy, published by The American College of Chest Physicians, for VTE

Disease provides the following recommendations:2

1. In patients with acute PE associated with hypotension (systolic blood pressure <90 mm Hg) who

do not have a high bleeding risk, we suggest systemically administered thrombolytic therapy over no

such therapy (Grade 2B).

2. In most patients with acute PE not associated with hypotension, we recommend against

systemically administered thrombolytic therapy (Grade 1B).

3. In selected patients with acute PE who deteriorate after starting anticoagulant therapy but have

yet to develop hypotension and who have a low bleeding risk, we suggest systemically administered

thrombolytic therapy over no such therapy (Grade 2C).

Pulmonary emboli can be described as massive, submassive, and nonmassive. Massive PE is defined as

an acute PE with sustained systemic hypotension or cardiogenic shock.35 Submassive PE is associated

with hemodynamic stability, but with right ventricular dysfunction confirmed by echocardiography or

elevated cardiac biomarkers. The role of thrombolytics even in non-pregnant patients with submassive

PE remains controversial. The MOPPET (Moderate pulmonary embolism treated with thrombolysis)

study concluded that low-dose alteplase plus anticoagulation reduced the incidence of the composite

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 outcome of pulmonary hypertension or recurrent PE compared to anticoagulation alone in patients with
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moderate PE. However, because the definition of moderate PE (>70% involvement of thrombus in ≥ 2

lobar or either the left or right main pulmonary arteries and high probability ventilation-perfusion (V/Q)

scan with V/Q mismatch in ≥2 lobes) differs from the definition of submassive PE, it is difficult to

extrapolate its findings to patients with submassive PE.35, 36

Risks Associated with Thrombolysis

In the general population, thrombolytic therapy in acute PE has been demonstrated to reduce all-cause

mortality and recurrent PE.2 However, these agents are also associated with safety risks including major

bleeding and intracranial hemorrhage.2 In a retrospective, multi-center analysis, the frequency of

intracranial hemorrhage after thrombolysis was 1.9% (95% confidence interval, 0. 7 to 4.1 %). Of the 6

patients who experienced intracranial hemorrhage, 2 died due to complications. Additionally, diastolic

blood pressure at hospital admission was significantly higher in patients who experienced intracranial

hemorrhage (90.3±15.1 mm Hg) compared with patients who did not (77.6±10.9 mm Hg; p=0.04).37

Ahearn and colleagues evaluated 172 case reports and concluded that the maternal bleeding

complication rate following systemic thrombolysis mirrors that of the general population, ranging from

1% to 6%. Most bleeding is reported to occur around catheter and puncture sites.38 To our knowledge,

there have been no reports of intracranial bleeds in pregnant women who received systemic

thrombolysis.

Review of Evidence for Thrombolysis for Massive PE in Pregnancy

There is currently a lack of large clinical trials and prospective data looking at thrombolytic use for

massive PE in pregnancy, and use is a relative contraindication in the guidelines.2 However, despite

limited experience with thrombolytics in pregnancy, this therapy may be lifesaving in pregnant patients

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 with massive PE and severe hemodynamic compromise. Table 2 provides a review of 23 case reports of
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thrombolytic use in pregnant patients with PE, excluding postpartum reports and non-English language

reports.38-58 Patient age and gestational period ranged from 19-34 years and 8-35 weeks, respectively.

All patients presented with significant hypotension and massive PE. Of the 23 case reports, alteplase use

was described most frequently (48%), followed by streptokinase (35%), urokinase (13%), and reteplase

and tenecteplase least commonly (4% each). In one case report, 39 both urokinase and alteplase were

used. Bleeding complications were reported in 9/23 (39%) cases. These complications ranged from

minor, such as slight bleeding from a puncture site, to major complications involving severe vaginal

bleeding requiring transfusion. One case report by Huang and colleagues documents placental

abruption, otherwise known as the premature separation of the placenta from the wall of the uterus,

following alteplase use. The authors speculated that prolonged heparin anticoagulation may have

played a role in the placental abruption, and suggested that alteplase could have interfered with

placental implantation.41

There were no reports of maternal death following thrombolytic use, and 2/23 (9%) reports document

fetal death. In one of these cases, the baby passed away after birth due to complications associated with

acute respiratory distress syndrome (ARDS). The autopsy showed hemorrhages commonly found in

premature infants who die of ARDS, and the authors stated that the death was unrelated to the

thrombolytic therapy.40 In the other case, fetal death occurred prior to birth, and the authors concluded

that the cause was likely maternal anoxia from the massive PE. The authors also mentioned that at

autopsy there was no evidence of fetal hemorrhagic complications.50

Catheter-Directed Thrombolysis

Catheter-directed thrombolysis (CDT) offers several advantages over systemic thrombolysis, the most

significant of which is a reduced risk of bleeding.2 Because thrombolysis is performed locally, only

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 approximately one-third of the dose necessary for systemic thrombolysis is required during CDT.
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Reducing the thrombolytic dose is expected to result in less remote bleeding, protecting patients from

intracranial and gastrointestinal bleeds. Clot fragmentation also occurs through the physical act of

placing the infusion catheter and performing additional maneuvers, thereby enhancing pharmacologic

and endogenous thrombolysis. Oftentimes CDT is combined with other techniques, such as active

thrombus fragmentation and aspiration.2

Even in the general population there have been no randomized controlled trials or observational studies

comparing CDT to systemic thrombolysis. The current guideline recommendation is to use systemic

thrombolysis over CDT in patients without a high risk of bleeding due to the higher quality of available

evidence. However, in patients with a higher risk of bleeding, the guideline states that CDT is preferred

over systemic thrombolysis. Lastly, guidelines suggest catheter-assisted thrombus removal over no such

intervention in hypotensive patients with acute PE who have (1) a high bleeding risk, (2) failed systemic

thrombolysis, or (3) shock that is likely to cause death before systemic thrombolysis can take effect.

Catheter-based thrombus removal is defined as mechanical interventions with or without CDT. Although

no recommendation is made regarding the use of catheter-based thrombus removal in pregnancy,2

many pregnant patients with massive PE meet this criteria.

Table 3 provides a review of 4 cases of CDT use in pregnancy.59-62 Two cases included mechanical

fragmentation of the thrombus along with CDT.60, 61 Alteplase was used in 3 cases and urokinase was

used in one case. Major bleeding complications were reported in 1 of the 4 cases and involved a

hemoglobin drop of 2 g/dL occurring 24 hours after CDT and a hematoma, which developed at the site

of the patient’s recent episiotomy.60 Improvement in pulmonary blood flow was observed in 2 of the 3

cases. No maternal deaths and one fetal death occurred. The authors speculated that the fetal death

was unrelated to alteplase therapy, as the drug was administered locally and theoretically should have

been metabolized before reaching the placenta.60

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Accepted Article
Discussion

As evidenced by the case reports and case series describing the use of thrombolysis for massive PE in

pregnancy, patients are receiving thrombolytics for massive PE in practice, despite a lack of randomized

controlled trials in this special population. After reviewing the pharmacokinetic and pharmacodynamic

studies available, and case series published thus far, it appears that thrombolytic therapy can be safely

considered in pregnant patients with massive PE. This suggests that the current guideline

recommendations of using thrombolytics in patients with associated hypotension (systolic blood

pressure <90 mmHg) or patients who deteriorate after starting anticoagulant therapy with a low risk of

bleeding may also apply to pregnant women.2 Overall, alteplase appears to be a superior option for

systemic thrombolysis in pregnancy due to its availability, properties, and pharmacokinetic profile.

Compared to first generation agents, alteplase may be administered over a shorter duration of time and

is associated with a lower risk of allergic and febrile reactions. Furthermore, because alteplase acts only

in the presence of fibrin, there is a theoretical advantage of a decreased hemorrhage risk compared to

first generation agents. However, prospective, randomized controlled trials are necessary to determine

the true safety and efficacy of alteplase in pregnancy. There is also an inherent publication bias

whenever utilizing case reports as evidence, as healthcare professionals are more likely to publish

successful cases.

While reteplase and tenecteplase were each used with success in 1 case report48, 56, neither agent is

currently approved for the treatment of PE, and data surrounding their safety and efficacy in pregnant

patients is lacking. Additionally, despite bleeding risks associated with thrombolytic use, it is imperative

not to delay therapy in indicated individuals, as hypotension and hypoperfusion in pregnancy can lead to

fetal demise. Catheter-directed thrombolysis is an alternative to systemic thrombolysis for both

pregnant and non-pregnant patients, and may be considered for patients with high risk for bleeding.

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 Although there is mounting evidence to support the use of CDT in pregnant patients, there is no data to
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suggest that it should be preferred over systemic therapy. While outside the scope of this review,

providers may also consider alternatives to systemic thrombolysis such as surgical embolectomy,

although this carries other unique risks from general anesthesia and surgery that can adversely impact

the mother and fetus.

Conclusions

Overall, available case reports documenting thrombolytic use for treatment of massive PE in pregnant

women suggest that use of these agents is associated with beneficial outcomes and a relatively low risk

of complications. However, the quality of evidence remains low and there is potential for publication

bias. Current guideline recommendations of using thrombolytics in patients with associated

hypotension or patients who deteriorate after starting anticoagulant therapy with a low risk of bleeding

may benefit from thrombolytic therapy should also be applied to pregnant women with PE. Overall,

alteplase appears to be the best option for systemic thrombolysis in pregnancy due to its availability,

properties, and pharmacokinetic profile. Clinical judgment is always required when weighing the risks

and benefits of thrombolytic therapy.

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Accepted Article
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 Table 1. Comparison of Thrombolytic Agents
Accepted Article
Urokinase Streptokinase Alteplase Reteplase Tenecteplase

Generation First First Second Third Third

Half-Life (min)14, 25, 26 15 Initial: 16 4-8 14-18 Initial: 20-24

Terminal: 90 Terminal: 90-130

Molecular Weight12 31126.5 47286.7 59042.3 39589.6 58951.2

(Daltons)

Clearance22, 24, 27, 28 Rapid hepatic Hepatic Hepatic Renal/hepatic Hepatic

clearance

Pregnancy B C C C C
Category13-15, 27, 29

Pregnancy Risk30 Limited human Information not Compatible Compatible: Compatible:

data: animal data available maternal benefit > maternal benefit >
suggest low risk embryo-fetal risk embryo-fetal risk

FDA Approved for Yes No longer Yes No No

Treatment of PE13-15, available on the
27
U.S. market

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 Table 2. Summary of Case Reports Describing Thrombolysis for Pulmonary Embolism in Pregnancy
Accepted Article Gestational
Publication Year Maternal Gestational Bleeding Maternal
Severity Thrombolytic Regimen Age at Fetal Death
& Author Age Period Complications Death
Delivery
Alteplase
(Urokinase initially)
1990
27 31 weeks Massive 10 mg/hr x 4 hrs + 2 mg/hr x Minor Preterm No No
Flossdorf39
1.5 hrs
1990
29 35 weeks Massive 100 mg over 3 hrs No Preterm No Yes
Baudo40
2000
31 12 weeks Massive 100 mg over 2 hrs Major Preterm No No
Huang41
2002
36 12 weeks Massive 100 mg over 2 hrs No Full term No No
Ahearn38
2003
36 20 weeks Massive 10 mg + 90 mg over 2 hrs No Full term No No
Patel42
2005
34 23 weeks Massive 10 mg + 90 mg over 1.5 hrs No Full term No No
Trukhacheva43
2011
No
Fasullo44 42 14 weeks Massive 10 mg + 90 mg over 2 hrs No No No
information
2011
33 31 weeks Massive 10 mg + 90 mg over 1.5 hrs Minor Full term No No
Lonjaret45
2011
27 11 weeks Massive 10 mg + 90 mg over 2 hrs No Full term No No
Holden46
2011
33 8 weeks Massive 10 mg + 90 mg over 2 hrs No Preterm No No
Holden46
2012
34 10 weeks Massive No details provided No Preterm No No
Plesinac47
Reteplase
2002
28 30 weeks Massive 10 mg + 90 mg over 2 hrs No Preterm No No
Yap48
Streptokinase
1972 600,000 units over 30 min +
29 32 weeks Massive Major Preterm No No
Hall49 100,000 units/hr x 40 hrs
1977 Yes
24 34 weeks Massive No details provided Major N/A No
McTaggart50
1990
21 28 weeks Massive No details provided Major Preterm No No
Fagher51
1994 200,000 units over 20 min +
34 25 weeks Massive Minor Full term No No
Mazeika52 100,000 units/hr x 2 hrs
2009 250,000 units + 100,000 Full term
34 25 weeks Massive Major No No
Te Raa53 units/hr x 24 hrs
2011 250,000 units + 100,000
44 25 weeks Massive No Full term No No
Holden46 units/hr x 24 hrs
rd
2013 3 250,000 units over 30 min +
29 Massive No N/A No Yes
Tawfik54 Trimester 100,000 units/hr x 12 hrs
2013
27 8 weeks Massive No details provided No Full term No No
Beebeejaun55
Tenecteplase
2012 No No
37 29 weeks Massive 40 mg over 5 min No No
dos Santos56 information information
Urokinase
1986 4,400 IU/kg over 10 min +
19 28 weeks Massive Minor Full term No No
Delclos 57 4,400 IU/kg/hr x 12 hrs
1990 27 31 weeks Massive Urokinase 200,000 IU initial Minor Preterm No No

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 Flossdorf 39 treatment
(followed by alteplase)
Accepted Article
1995
4,400 IU/kg over 10 min +
Kramer58 20 21 weeks Massive No Full term No No
4,400 IU/kg per hr x 12 hrs
N/A=not applicable.

Table 3. Summary of Case Reports Describing Catheter-Directed Thrombolysis for Massive Pulmonary
Embolism in Pregnancy

Mechanical Pulmonary
Publication Year Maternal Gestational Thrombolytic Bleeding Gestational Age Maternal Fetal
Thrombus Blood Flow
& Author Age Period Agent Complications at Delivery Death Death
Removal Improved

1999
No 31 26 weeks Urokinase Yes No Full term No No
Krishnamurthy59

2001
Yes 19 15 weeks Alteplase No Major N/A No Yes
Sofocleous60

2005
Yes 29 30 weeks Alteplase Yes No Full term No No
Bechtel61

2015
No 34 33 weeks Alteplase Yes No Preterm No No
Pick 62

Figure Legends

Figure 1 Title: Changes in Coagulation Pathway during Pregnancy.

Figure 1 Footnote: Clotting factors that have significant changes are displayed with arrows.

Figure 1 Legend: TF = Tissue Factor

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Accepted Article

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