The n e w e ng l a n d j o u r na l
Case Records of the Massachusetts General Hospital
From the Department of Medicine, Bos‑
ton Medical Center (H.W.F.), the Depart‑
ment of Medicine, Boston University
School of Medicine (H.W.F.), the Depart‑
ments of Radiology (S.M.), Medicine
(A.S.W., N.P.K., E.M.M.), and Pathology
(J.R.S.), Massachusetts General Hospi‑
tal, and the Departments of Radiology
(S.M.), Medicine (A.S.W., N.P.K., E.M.M.),
and Pathology (J.R.S.), Harvard Medical
School — all in Boston.
N Engl J Med 2018;378:1430-8.
DOI: 10.1056/NEJMcpc1800323
Copyright © 2018 Massachusetts Medical Society.
1430
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of m e dic i n e
Founded by Richard C. Cabot
Eric S. Rosenberg, M.D., Editor
Virginia M. Pierce, M.D., David M. Dudzinski, M.D., Meridale V. Baggett, M.D.,
Dennis C. Sgroi, M.D., Jo‑Anne O. Shepard, M.D., Associate Editors
Allison R. Bond, M.D., Case Records Editorial Fellow
Emily K. McDonald, Sally H. Ebeling, Production Editors
Case 11-2018: A 48-Year-Old Woman
with Recurrent Venous Thromboembolism
and Pulmonary Artery Aneurysm
Harrison W. Farber, M.D., Shaunagh McDermott, M.D., Alison S. Witkin, M.D.,
Noreen P. Kelly, M.D., M.B.A., Eli M. Miloslavsky, M.D.,
and James R. Stone, M.D., Ph.D.​​
Pr e sen tat ion of C a se
Dr. Samir Zaidi (Medicine): A 48-year-old woman with a history of venous thrombo-
embolism was seen in the pulmonary clinic of this hospital because of cough and
decreased exercise tolerance.
Fifteen months before this presentation, at another hospital, the patient re-
ceived a diagnosis of deep venous thrombosis of the right leg and segmental and
subsegmental pulmonary embolism in both lower lobes. Blood tests for a factor V
Leiden mutation and a prothrombin gene mutation were reportedly negative, as
were tests for antiphospholipid, anticardiolipin, and β2-glycoprotein antibodies;
the blood level of protein S was reportedly low. Treatment with warfarin was initi-
ated. After 3 months of treatment, the patient had persistent cough and dyspnea
on exertion, and repeat imaging studies were obtained.
Dr. Shaunagh McDermott: Twelve months before this presentation, computed tomo-
graphic (CT) angiography of the chest was performed at the other hospital. There
was pulmonary embolism in the right lung, with occlusion of the interlobar pul-
monary artery that extended into the middle and lower lobes, including segmental
arteries. There was also a new focal dilatation (1.1 cm in diameter) of the pulmo-
nary artery in the left lower lobe, as well as a new small right pleural effusion
(Fig. 1).
Dr. Zaidi: Warfarin was discontinued, and treatment with apixaban was initiated.
After 6 months of treatment, additional imaging studies were obtained.
Dr. McDermott: Six months before this presentation, CT angiography of the chest
was performed at the other hospital. A large pulmonary embolus occluded the
distal right main pulmonary artery, and the previously identified pulmonary em-
boli had not resolved. The dilatation of the pulmonary artery in the left lower lobe,
which contained a thrombus, had not changed.
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 Case Records of the Massachuset ts Gener al Hospital

A B C

Figure 1. CT Angiogram of the Chest.

A CT angiogram of the chest was obtained 12 months before this presentation. There is an occlusive filling defect in
the right interlobar pulmonary artery (Panel A, arrow), a finding consistent with a pulmonary embolus. The embolus
extends into the right middle and lower lobes (Panel B, arrow). There is a focal dilatation (1.1 cm in diameter) of the
pulmonary artery in the left lower lobe (Panel C, arrow).

Dr. Zaidi: Because additional thromboembolic
events had occurred while the patient was receiv-
ing apixaban, this medication was discontinued.
Treatment with therapeutic subcutaneous enoxa-
parin sodium was initiated, after which the re-
sults of an anti–factor Xa assay were reportedly
within the therapeutic range. After 4 months of
treatment, repeat imaging studies were obtained.
Dr. McDermott: Two months before this presen-
tation, CT angiography of the chest was per-
formed at the other hospital. The right main
pulmonary artery was completely occluded by
thromboembolic material. There were several
areas of consolidation that most likely represent-
ed evolving infarcts, as well as a thrombosed
subsegmental artery in the left lower lobe in the
area of the previously identified dilatation.
Dr. Zaidi: Transthoracic echocardiography was
performed. The left ventricular ejection fraction
was 55%, and the atria and right ventricle were
of normal size and function. A ventilation–perfu-
sion scan revealed a complete absence of perfu-
sion to the right lung and multiple wedge-shaped
perfusion defects at the left lung base. The pa-
tient was referred to the pulmonary clinic of this
hospital for further evaluation.
On evaluation, the patient reported weight
loss of 18 kg during the previous 3 months but
no fever, night sweats, hemoptysis, oral ulcers,
genital ulcers, rashes, or eye pain or redness. She
had no known exposures to tuberculosis. She had
a history of hypothyroidism and seizure disorder.
Medications included subcutaneous enoxaparin
sodium, levothyroxine, levetiracetam, and phe-
nytoin. The patient reported consistent use of
subcutaneous enoxaparin sodium, and the re-
sults of an anti–factor Xa assay were reportedly
in the therapeutic range.
The patient resided in New England and had
traveled to Florida during the year before this
evaluation. She did not smoke tobacco, drink
alcohol, or use illicit drugs. Her mother had dia-
betes; there was no family history of pulmonary
disease, lung cancer, pulmonary embolism, or
deep venous thrombosis.
On physical examination, the temperature was
36.9°C, the blood pressure 102/62 mm Hg in both
arms, the pulse 96 beats per minute, the respira-
tory rate 20 breaths per minute, and the oxygen
saturation 96% while the patient was breathing
ambient air. The weight was 48 kg, and the
body-mass index (the weight in kilograms di-
vided by the square of the height in meters) 17.5.
The patient was breathing comfortably. Both
lungs were clear. The first and second heart
sounds were normal, without murmurs. The ra-
dial and dorsalis pedis pulses were normal. There
was no clubbing or edema. The remainder of the
physical examination was normal. Imaging stud-
ies were obtained to further evaluate the throm-
bus of the right main pulmonary artery.
Dr. McDermott: Magnetic resonance imaging of
the chest was performed before and after the
administration of gadolinium. There was almost
complete occlusion of the distal right main pul-
monary artery and bilateral segmental and sub-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A
B tests for human immunodeficiency virus type 1
Figure 2. MRI of the Chest.
T1-weighted images were obtained after the administra‑
tion of gadolinium. There is a filling defect in the right
main pulmonary artery that does not show enhance‑
ment (Panel A, arrow), a finding consistent with a pul‑
monary embolus. In this area, there is enhancement of
the wall of the pulmonary artery, which is smooth and
2 mm in thickness. There is also an infarct in the periph‑
ery of the right lower lobe (Panel A, arrowhead). There
is a new aneurysm (2.4 cm in diameter) of the pulmonary
artery in the lateral basal segment of the left lower lobe
(Panel B, arrow) that contains an eccentric thrombus.
segmental pulmonary arteries that was consis-
tent with thromboembolism. In the area of the
occlusive thromboembolic material, there was
enhancement of the wall of the main pulmonary
artery, which was smooth and 2 mm in thick-
ness (Fig. 2). The main pulmonary artery was
not dilated, and there was no evidence of strain
on the right side of the heart. A new aneurysm
(2.4 cm in diameter) of the pulmonary artery in
the lateral basal segment of the left lower lobe
contained a small amount of eccentric thrombo-
embolic material. There were enlarging pulmo-
nary infarcts in the right lung with a small
amount of adjacent loculated pleural fluid.
Dr. Zaidi: The patient was admitted to this
hospital for further evaluation. Blood levels of
electrolytes and glucose, the complete blood
count and differential count, and results of
renal- and liver-function tests were normal. As-
says for antinuclear antibodies and antineutro-
phil cytoplasmic antibodies were negative, as were
and type 2 antibodies and type 1 p24 antigen.
Blood cultures showed no growth. Screening for
antitreponemal antibodies and an interferon-γ re-
lease assay for tuberculosis were negative, as were
the results of a blood test for galactomannan
antigen (negative index value, <5.0). The 1,3-beta-
d-glucan level was less than 31 pg per milliliter
(reference range, <60), the erythrocyte sedimen-
tation rate was 69 mm per hour (reference range,
0 to 20), and the C-reactive protein level was
106 mg per liter (reference range, <8). Venous
ultrasonography of both legs showed a partially
occlusive deep venous thrombus (1.0 cm in
length) in the right popliteal vein.
A procedure was performed, and a diagnosis
was made.
Differ en t i a l Di agnosis
Dr. Harrison W. Farber: This 48-year-old woman
had progressive fatigue and dyspnea on exertion
that developed during the 15 months after she
received a diagnosis of deep venous thrombosis
and pulmonary embolism. These symptoms could
be consistent with the development of chronic
thromboembolic pulmonary hypertension.
Chronic Thromboembolic Pulmonary
Hypertension
A small percentage of patients with acute pul-
monary embolism have chronic thromboembolic
pulmonary hypertension, a condition in which
thromboembolic obstruction of the pulmonary

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 Case Records of the Massachuset ts Gener al Hospital
arteries is associated with the development of a
vascular arteriopathy that results in vascular re-
modeling and pulmonary hypertension.1-7 If this
condition goes untreated, it can lead to progres-
sive right ventricular failure and death.8 Although
chronic thromboembolic pulmonary hyperten-
sion is a potential explanation for this patient’s
progressive symptoms, several features of her
presentation are not consistent with this diagno-
sis. First, despite the extensive compromise of
the pulmonary vasculature and the development
of dyspnea on exertion, it seems unlikely that
she had clinically significant pulmonary hyper-
tension, since the right ventricle and right atrium
appeared normal on echocardiography. Second,
if she had adhered to the various anticoagulant
therapies that had been prescribed, continued
development of thromboembolic disease would
be unusual without a concurrent clotting dis­
order. Third, given her weight loss of 18 kg
and elevated erythrocyte sedimentation rate
and C-reactive protein level, a systemic disease
seems more likely.
Overall, I think chronic thromboembolic pul-
monary hypertension is unlikely to explain her
clinical presentation. The finding of a pulmonary
artery aneurysm on CT is a unique aspect of this
patient’s presentation and may provide an impor-
tant clue to help us arrive at the diagnosis. There-
fore, I will construct my differential diagnosis
around the presence of a pulmonary artery an-
eurysm and see whether that unusual finding will
help to explain the other features of this case.
Pulmonary Artery Aneurysms
A pulmonary artery aneurysm is a focal dilata-
tion of all three layers of the vessel wall, where-
as a pseudoaneurysm does not involve all the
layers. It is important to distinguish pulmonary
artery aneurysms from pseudoaneurysms because
of the risk associated with rupture that is more
common in pseudoaneurysms.9 Although pul-
monary artery aneurysms are rare, several well-
described conditions are associated with their
development, including trauma, infection, con-
genital heart disease, lung cancer, pulmonary hy-
pertension, and systemic inflammatory diseases.
This patient had no history of trauma that
could have led to the development of a pulmo-
nary artery aneurysm, specifically no previous
pulmonary artery catheterization. The infections
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that are most likely to cause pulmonary artery
aneurysms are syphilis and tuberculosis; the
negative screening test for antitreponemal anti-
bodies essentially rules out late syphilis infec-
tion, and the negative interferon-γ release assay
makes tuberculosis unlikely. Endocarditis with
septic emboli to the pulmonary arterial system
can cause pulmonary artery aneurysms, but this
condition is not likely to be present in a patient
with no fever, negative blood cultures, and no
evidence of valvular vegetations on echocardiog-
raphy. Pulmonary artery aneurysms can be as-
sociated with congenital heart disease, such as
patent ductus arteriosus, but this patient had no
known history of such a condition. On rare oc-
casions, pulmonary artery aneurysms have been
associated with lung cancer; this patient had
weight loss during the 3 months before presen-
tation but had no other signs or symptoms of
cancer and no evidence of a mass lesion on mul-
tiple imaging studies of the chest. Pulmonary
hypertension can lead to pulmonary artery aneu-
rysms, but echocardiography revealed a normal
right atrium and normal right ventricular size and
function, findings that are not consistent with
this diagnosis. Moreover, pulmonary artery an-
eurysms that are associated with pulmonary hy-
pertension are usually observed in long-standing,
severe disease, which this patient did not have.10
Systemic Inflammatory Diseases
The inflammatory diseases that are associated
with pulmonary artery aneurysms are rare and
include Takayasu’s arteritis, Behçet’s disease, and
the Hughes–Stovin syndrome. Takayasu’s arteritis,
which is a large-vessel vasculitis, is unlikely in
this patient who has no evidence of pulmonary
vascular stenosis, since the pulmonary artery
aneurysms that develop in patients with Takaya-
su’s arteritis are usually poststenotic dilatations.11
In addition, this patient did not have signs of
involvement of any arteries outside the pulmo-
nary circulation. Although Takayasu’s arteritis
can occasionally be isolated in the pulmonary
circulation,12 it more commonly also affects the
systemic large vessels.
Behçet’s Disease and the Hughes–Stovin
Syndrome
Behçet’s disease and the Hughes–Stovin syndrome
are the two vasculitides that are most commonly
1433
 The n e w e ng l a n d j o u r na l
associated with the development of pulmonary
artery aneurysms.13-15 These two diagnoses share
many characteristics, and it has been suggested
that the Hughes–Stovin syndrome is a partially
manifested form of Behçet’s disease15; indeed,
the Hughes–Stovin syndrome has been referred
to as “a cardiovascular manifestation of Behçet’s
disease”16 and “incomplete Behçet’s.”17 This pa-
tient did not have other clinical manifestations
of Behçet’s disease, such as recurrent oral ulcers,
genital ulcers, or eye or skin lesions,18-21 and
therefore, classic Behçet’s disease is unlikely. I
suspect that the Hughes–Stovin syndrome is the
diagnosis in this case, even though it is an ex-
tremely rare disease, with fewer than 40 cases
reported in the literature.22
Aneurysms in the Hughes–Stovin syndrome
can be single or multiple and can be unilateral
or bilateral; they usually involve the pulmonary
and bronchial arteries but can occur anywhere
in the systemic circulation.15 Three phases are
described in the Hughes–Stovin syndrome: an
initial phase characterized by venous thrombo-
phlebitis, a second phase characterized by for-
mation of large pulmonary and bronchial aneu-
rysms, and a third phase characterized by
aneurysmal rupture that leads to massive hemop-
tysis and death.23 This patient had evidence of
the first and second phases of disease. The third
phase is the leading cause of death in untreated
patients with the Hughes–Stovin syndrome.15
This patient did not have hemoptysis, which, in
the Hughes–Stovin syndrome, can be caused by
aneurysmal rupture and erosion into a bron-
chus, active vasculitis resulting in thrombosis,
or bronchial artery hypertrophy due to ischemia
from a pulmonary artery occlusion.
There are no diagnostic tests for the Hughes–
Stovin syndrome, and I suspect that the proce-
dure performed in this patient was related to
management of the aneurysm of the left pulmo-
nary artery. However, the completely occluded
right pulmonary artery presents two complicat-
ing issues. First, since most of the cardiac output
was to the left lung, which was the site of both
the 1.1-cm dilatation of the pulmonary artery
and the 2.4-cm aneurysm of the pulmonary ar-
tery, risk of rupture was most likely higher be-
cause of pressure from this increased flow.
Second, because there was essentially no blood
flow to the right lung and compromised blood
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of m e dic i n e
flow to the left lung, problems during an embo-
lization procedure to the left lung could be cata-
strophic. I suspect that the procedure was a
pulmonary thromboendarterectomy to reestab-
lish pulmonary circulation to the right lung be-
fore managing the aneurysm of the left pulmo-
nary artery.
Dr. Meridale Baggett (Medicine): Dr. Witkin, what
was your initial approach in the management of
this patient’s pulmonary artery aneurysm?
Dr. Alison S. Witkin: At the time of the patient’s
admission to this hospital, we were most con-
cerned about the potential for rupture of the
pulmonary artery aneurysm. We considered sev-
eral potential treatment options, including im-
mediate surgical intervention, embolization, and
observation with management of the underlying
disease. For aneurysms in the proximal main
pulmonary artery, primary surgical repair may
be feasible.24 Lobectomy may be performed when
the aneurysm is confined to one region of the
lung.25 However, this patient’s aneurysm was too
distal for a primary repair, and a left lower lo-
bectomy was considered to be nonfeasible, since
the only remaining perfusion would be to the
left upper lobe, given the absence of perfusion to
the right lung. Embolization of the pulmonary
artery aneurysm in this patient would require
complete embolization of the left lower lobe,
leading to consequences similar to those associ-
ated with a lobectomy.23,26 However, given the
rapid progression of the size of the aneurysm in
this patient, observation alone would carry a
considerable risk of life-threatening rupture.
The decision was made to first attempt to
restore perfusion to the right lung with a pulmo-
nary thromboendarterectomy and then to pur-
sue management of the aneurysm of the left
pulmonary artery.
Dr . H a r r ison W. Fa r ber’s
Di agnosis
Hughes–Stovin syndrome.
In t r aoper at i v e C our se
Dr. Noreen P. Kelly: Before the start of the pulmo-
nary thromboendarterectomy, transesophageal
echocardiography was performed. The study re-
vealed an echogenic mass in the proximal por-
 Case Records of the Massachuset ts Gener al Hospital

tion of the right pulmonary artery that occluded ease, a definitive active vasculitis is often not
the lumen of the artery (see Videos 1 and 2, identified and the inflammatory infiltrates in the
Videos showing
available with the full text of this article at pulmonary arteries are typically primarily lym- transesophageal
NEJM.org). The appearance of the mass on echo- phoplasmacytic with foamy hemosiderin-laden echocardiography
cardiography was consistent with a thrombus, macrophages.22,32,33 Thus, although these two are available at
tumor, or vegetation. The patient underwent conditions appear to be closely related, they may NEJM.org
thromboendarterectomy with the use of cardio- be distinct entities. In this patient, the patho-
pulmonary bypass and hypothermic circulatory logical features were more consistent with the
arrest. Pluglike material was removed from the Hughes–Stovin syndrome.
right pulmonary artery, and on examination of
an intraoperative frozen section, the material was Discussion of M a nagemen t
consistent with a thrombus. Postoperative trans-
esophageal echocardiography revealed no evi- Dr. Eli M. Miloslavsky: The treatment strategy for
dence of a residual thrombus in the proximal this patient with the Hughes–Stovin syndrome
portion of the right pulmonary artery. However, was derived from experiences with the manage-
the arterial wall appeared abnormally thickened, ment of Behçet’s disease, given the rarity of the
a finding suggestive of a possible underlying in- Hughes–Stovin syndrome and its similarity to
flammatory process (Fig. 3). A biopsy specimen Behçet’s disease. Because there is considerable
was obtained from the right pulmonary artery. evidence that formation of both thrombosis and
aneurysm in Behçet’s disease is caused by in-
flammation rather than a hypercoagulable state,
Pathol o gic a l Discussion
immunosuppression is the cornerstone of treat-
Dr. James R. Stone: The biopsy specimen was com- ment.34-38 The role of anticoagulation in Behçet’s
posed primarily of an organizing thrombus with disease is uncertain.34,35
extensive chronic inflammation (Fig. 4). The Pulmonary artery aneurysms are treated ag-
inflammation in the thrombus consisted primar- gressively because of the morbidity and mortal-
ily of CD3+ T lymphocytes and CD68+ macro- ity associated with rupture. This patient was
phages. Plasma cells were also present, but in treated with a combination of glucocorticoids
smaller numbers. There were occasional IgG4+
plasma cells, which is a nonspecific finding.
Many of the macrophages contained hemosid-
erin. There was a focal adherent pulmonary ar-
tery wall in the specimen, which showed healing
injury in the media, with both T lymphocytes
and macrophages. No microorganisms were pres-
ent on special stains, and definitive features of
an active vasculitis were not identified.
It is important to consider whether the patho-
logical features seen in this case are more con-
sistent with Behçet’s disease or the Hughes–Stovin
syndrome, since both conditions are character-
ized by injury and inflammation of the pulmo-
nary vascular wall. Behçet’s disease is character-
ized by necrotizing vasculitis, which often shows
a mixture of inflammatory cells, including neu-
trophils, lymphocytes, macrophages, eosinophils,
Figure 3. Postoperative Transesophageal Echocardiogram.
and plasma cells.27-29 Behçet’s disease may also
A transesophageal echocardiogram was obtained in the upper esophageal
be characterized by a lymphocytic vasculitis or a window at 0 degrees omniplane after thromboendarterectomy. There is
neutrophilic leukocytoclastic vasculitis.28,30,31 In unobstructed flow through the right pulmonary artery, but the walls of the
patients with the Hughes–Stovin syndrome who artery appear thickened (arrows).
do not meet the clinical criteria for Behçet’s dis-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

CI

TH

C D

E F CD3 CD68

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Copyright © 2018 Massachusetts Medical Society. All rights reserved.
 Case Records of the Massachuset ts Gener al Hospital

Figure 4 (facing page). Thromboendarterectomy

­Specimens.
A photograph of the thromboendarterectomy specimen
from the right lung (Panel A) shows successful removal
of the thrombotic material. On hematoxylin and eosin
staining (Panel B), there is a residual organizing throm‑
bus (TH) and extensive chronic inflammation (CI). At
high magnification (Panel C), the inflammation is com‑
posed of mononuclear cells (arrowheads) and foamy
macrophages (arrows) that contain hemosiderin on
iron staining (inset, in blue). On immunohistochemi‑
cal staining, the inflammatory cells are primarily CD3+
T lymphocytes (Panel D, in brown) and CD68+ macro‑
phages (Panel E). There is a healing injury in the media
of the pulmonary artery wall (Panel F, arrow), with inflam‑
mation composed of CD3+ T lymphocytes (left inset)
and CD68+ macrophages (right inset). Elastic staining
shows disruption of the elastic lamina (Panel G, arrows).
and cyclophosphamide.37,39,40 Despite this regimen,
the aneurysm did not decrease in size. More re-
cently, several small case series have showed the
efficacy of tumor-necrosis-factor–α inhibitors
in patients with arterial aneurysms related to
Behçet’s disease. Therefore, infliximab was start-
ed in place of cyclophosphamide.41,42
Dr. Witkin: After the thromboendarterectomy,
the patient recovered well. She was discharged
home on postoperative day 10 with the ability to
walk and with no need for supplemental oxygen.
Unfortunately, a postoperative ventilation–perfu-
sion scan showed no reperfusion to the right
lung, and therefore, interventions for the aneu-
rysm of the left pulmonary artery were not fea-
sible. Her dyspnea on exertion and intermittent
cough remained stable. The patient was treated
with prednisone therapy for 6 weeks after the
procedure, at which time, cyclophosphamide was
added. However, her C-reactive protein level and
erythrocyte sedimentation rate remained elevated,
and repeat CT of the chest showed an increase
in the size of the aneurysm. After treatment
with infliximab, the patient’s inflammatory
markers improved and repeat imaging showed a
slight decrease in the size of the aneurysm.
A nat omic a l Di agnosis
Pulmonary artery aneurysm that was most likely
due to the Hughes–Stovin syndrome.
This case was presented at the Medical Case Conference.
Dr. Farber reports receiving grant support, advisory-board
fees, and fees for serving on a speakers’ bureau from Actelion
and Gilead, advisory-board fees from Arena and Boehringer In-
gelheim, fees for serving on a steering committee from Bellero-
phon, advisory-board fees and fees for serving on a speakers’
bureau from Bayer, and grant support and advisory-board fees
from United Therapeutics; Dr. Witkin, receiving travel support
from Actelion; and Dr. Stone, receiving consulting fees from
GlaxoSmithKline, fees for providing expert testimony from USP
Labs, and lecture fees from Alnylam. No other potential conflict
of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Dr. Cameron Wright and Dr. Gus Vlahakes for pro-
viding the photograph of the pulmonary thromboendarterecto-
my specimen.

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