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Primary idiopathic pulmonary hypertension complicated by pulmonary arterial thrombosis. Association with antiphospholipid antibodies

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Association with Antiphospholipid Antibodies
Objective. We report an unusual case of primary
pulmonary hypertension and review the pertinent
Methods. A 25-year-old Caucasian woman presented with progressive dyspnea and was found to have
pulmonary hypertension. Antiphospholipid antibodies
were present. The patient had a prolonged hospital
course, was unresponsive to therapy, and died suddenly.
Results. Postmortem examination revealed a
large thrombus affecting the right main pulmonary
artery, with plexogenic arteriopathy bilaterally.
Conclusion. This appears to be the first reported
case of primary pulmonary hypertension complicated by
thrombosis of a main pulmonary artery in association
with antiphospholipid antibodies.
Primary pulmonary hypertension (PHT) has
been defined by the World Health Organization as
pulmonary arterial hypertension of unknown cause
(1). It may be subdivided into two major types histopathologically: thromboembolic and plexogenic (2).
Both groups are similar with respect to their clinical
and hemodynamic features, as well as the short survival time for patients thus affected. The two types
may be distinguished by the presence or absence of an
embolic source, for example, the microthrombi origiFrom the Division of Rheumatology , Department of Medicine, St. Luke’s/Roosevelt Hospital, Columbia University, New
York, New York.
Monica E. Luchi, MD; Ronald A. Asherson, MD; Robert
G. Lahita, MD, PhD.
Address reprint requests to Monica E. Luchi, MD, Department of Rheumatology, Antenucci Building, St. Luke’s/Roosevelt
Hospital Center, 432 West 58th Street, New York, NY 10019.
Submitted for publication June 14. 1991; accepted in revised form January 29, 1992.
Arthritis and Rheumatism, Vol. 35, No. 6 (June 1992)
nating in the pelvis in patients with thromboembolic
PHT, or primary plexogenic PHT in patients with
radiologically clear lung fields. In some patients, however, it might be difficult to distinguish between the
two types without open lung biopsy and histopathologic examinations. The problem is even more complicated in the plexogenic type, since pulmonary thrombosis may develop secondarily because of low cardiac
Both types, however, may be associated with
antiphospholipid antibodies (aPL)-those
for the “lupus anticoagulant,” as well as those directed against negatively charged phospholipids, of
which anticardiolipin is one.
We describe here the case of a patient who
presented with the clinical picture of primary, nonthromboembolic PHT, in whom both types of aPL
were demonstrated. The patient’s clinical course was
complicated by the development of a proximal thrombosis in one of the major arteries, with secondary
pulmonary infarctions peripherally. This appears to be
the first reported case of a patient with “primary”
idiopathic plexogenic PHT in whom aPL-associated
thrombosis developed in a major pulmonary vessel,
associated with the antiphospholipid coagulopathy.
This case conforms to a diagnosis of “primary” antiphospholipid syndrome (3,4).
A 25-year-old white woman presented to our emergency room because of shortness of breath, progressive
dyspnea and chest pain over the previous 2 months, and
2-pillow orthopnea. Pertinent medical history included a
diagnosis of “seizure disorder,” based on the findings of an
evaluation at another hospital 2 months previously because
of 2 episodes of dyspnea with syncope. A nonspecific heart
murmur had been noted 2 years earlier, but no diagnostic
procedure was performed at that time. Four years earlier,
the patient gave birth to a healthy infant; the pregnancy and
vaginal delivery were uncomplicated.
On initial examination, the patient was afebrile, with
a pulse rate of 120 beats/minute, blood pressure level of
120/75 mm Hg, and respiratory rate of 24/minute. Her lungs
were clear. Cardiac examination revealed a normal first
heart sound, an accentuated P, (pulmonic valve component
of second heart sound), and a grade II/VI systolic murmur,
heard best at the left sternal border. There was no clubbing
of the fingers or toes.
Electrocardiography revealed a sinus Ldchycardiaof
110 bpm, right axis deviation of + 1lo”, and right ventricular
hypertrophy. Chest radiography showed enlargement of the
right heart chambers and enlargement of the pulmonary
arteries, with attenuation of the distal branches, suggestive
of pulmonary hypertension (Figure 1).
An echocardiogram, with contrast medium injection,
demonstrated a right-to-left atrial shunt. The right-sided
chambers were dilated (Figure 2). There was severe tricuspid regurgitation, and the pulmonary systolic pressure was
estimated to be 91 mm Hg.
Laboratory examination revealed a white blood cell
count of 12.8 x I09/liter, without shift, a hemoglobin value of
14.1%, and a platelet count of 268.0 x 109/liter. The prothrombin time (PT) was 13.2 seconds, and the baseline
partial thromboplastin time (PIT) was 29.6 seconds.
A diagnosis of pulmonary hypertension of uncertain
etiology was made.
Results of the following pulmonary function tests
Figure 1. Posteroanterior radiographic view of the patient’s chest,
revealing enlarged right heart chambers, enlarged pulmonary arteries, and distal arterial attenuation, consistent with pulmonary hypertension.
70 1
Figure 2. Echocardiographic short-axis view of the right ventricle
(RV) and the left ventricle (LV). The right ventricle is massively
enlarged and compressed, and deforms a small left ventricle.
were normal: forced vital capacity (FVC), forced expiratory
volume in 1 second (FEV,), FEVJFVC, and diffusion capacity for carbon monoxide. A ventilation/perfusion scan
demonstrated heterogeneous pulmonary perfusion consistent with a diagnosis of PHT, and interpreted as “low
probability for pulmonary embolus.”
Because of her marked shortness of breath, the
patient was admitted to the intensive care unit. A SwanGanz catheter was placed, revealing a mean right atrial
pressure of 10 mm Hg and a pulmonary artery pressure of
100/62 mm Hg.
A pulmonary angiogram was performed, but the
procedure was complicated by transient weakness of the
patient’s right arm and loss of sensory perception in the right
side of her face. The resulting films were difficult to interpret, and there was a question of pulmonary emboli.
When the patient’s platelet count dropped from 226.0
x IO’fliter to 65.0 X 109/liter while receiving an intravenous
dose of 800 units of heparin per hour, tests for heparininduced aggregation were done. The results of these tests
were positive, suggesting heparin-induced thrombocytopenia (5). Disseminated intravascular coagulation was ruled
out. The patient’s pT/pTT at that time was 15.2/63.0 seconds
(controls 12.4/29.6). Despite apparently adequate anticoagulation, a left temporo-occipital cerebrovascular accident
occurred. Although no clot was visible on sonography of the
inferior vena cava, a bird’s nest filter was placed below the
renal vein to prevent possible recurrent emboli.
Results of Doppler studies for deep venous thrombosis of the lower extremities were negative. Lupus anticoagulant was present (6); the diluted tissue thromboplastin
inhibition assay ratio was 1.9 (control c1.3) (7), and the
dilute Russell viper venom (RVV) time was 40.5 seconds
(control <30) (8). When equal portions of the patient’s blood
were mixed with a control sample, the dilute RVV test was
repeated, with a value of 31 seconds. This is a positive result
(8). Anticardiolipin antibody was present, with an IgG level
right ventricle and right atrium predominantly (heart weight
450 gm). and endocardia1 fibrosis of the right and left atria
(Figure 4A); 2) an organizing thrombus more than 4 weeks
old, with 90% luminal occlusion of the right main pulmonary
artery and hilar stump (Figure 4B); 3) primary plexogenic
arteriopathy involving all pulmonary vessels bilaterally (Figures 4C and D); 4) a probe-patent foramen ovale; and 5 )
atherosclerosis of the pulmonary arteries.
Figure 3. Angiogram of the patient’s right pulmonary artery. There
is no evidence suggestive of either pulmonary emboli or acute
of 24 GPL and an IgM level of 7 GPL (reference ranges < I5
and < 10, respectively). The anti-thrombin 111 level was
normal (71%). Antinuclear antibodies (ANA) were present at
a titer of 1:80, with a speckled pattern. Rheumatoid factor
was absent. Protein C and protein S levels were within
normal limits. Results of tests for human immunodeficitncy
virus antibody were negative.
A second ventilation/perfusion scan of the lungs was
performed and was interpreted by a nuclear radiologist as
indicating a high probability of pulmonary embolism, clue to
new mismatched defects appearing at the right base. A
second pulmonary angiogram was performed (Figure 3).
There were no filling defects or abrupt cut-offs to suggest
either pulmonary emboli or acute thrombosis.
The differential diagnoses at this time were primary
pulmonary hypertension versus chronic thromboembolic
In preparation for possible surgery, a third pulmonary angiogram was performed. There was no evidence of
pulmonary emboli. That same evening, the patient suddenly
became short of breath and cyanotic. Attempts to resuscitate
her were not successful.
Relevant features of the postmortem examination
were as follows: I ) cardiac hypertrophy and dilatation of the
Primary pulmonary hypertension can be “idiopathic,” with no known precipitating factors evident.
An identical clinical picture can be seen with PHT
occurring as a complication of connective tissue diseases, such as systemic lupus erythematosus (SLE)
(9), mixed connective tissue disease (lo), rheumatoid
arthritis (1 1,12), Sjogren’s syndrome (13), polymyositis/
dermatomyositis (14,15), or scleroderma (particularly
the CREST variant [calcinosis, Raynaud’s phenomenon, esophageal dysmotility , sclerodactyly , telangiactasias] [16]), as well as Whipple’s disease (17). Pulmonary fibrosis is commonest in scleroderma, but it can
also occur, although with much lower frequency, in
patients with SLE (18). It is frequently accompanied
by Raynaud’s phenomenon (19). Ingestion of anorexigenic drugs (20) o r the presence of pulmonary schistosomiasis (21) o r of liver disease (with or without
portal hypertension [22] and regardless of ingestion of
oral contraceptives [23,24]) may also result in the
nonthromboembolic type of PHT. This condition can
occur secondary to pretricuspid shunts, anomalous
venous drainage to the right atrium or systemic veins,
or posttricuspid cardiac shunts. There are also a few
reports of familial PHT (25).
Antiphospholipid antibodies have been associated with a variety of venous and arterial occlusions
predominantly affecting the deep veins of the legs and
the vasculature of the cerebrum, which causes transient ischemic attacks and strokes. These occlusions
are usually recurrent. Thrombotic occlusion of the
placental vessels is often the cause of recurrent fetal
loss (26). The combination of arterial and venous
vascular occlusions, often accompanied by thrombocytopenia, has been termed the antiphospholipid syndrome (APS) (27).
Patients with the APS essentially present the
same spectrum of clinical and serologic events,
whether occurring in the setting of lupus or the closely
related “lupus-like” disease (essentially, “moderate”
lupus). Similar clinical manifestations are to be found
in the group of patients with the recently defined
Figure 4. Gross and histologic features of the heart and lungs at postmortem examination. A, There is tremendous hypertrophy of the right
ventricle, and dilatation predominantly of the right ventricle and right atrium (450 gm). The pulmonic valves are thickened, and the branch point
of the right pulmonary artery is occluded (arrow). B, Cross-section of an organizing thrombus (arrow), with 90% luminal occlusion of the right
pulmonary artery, involving the right main pulmonary artery and hilar stump. C , Hematoxylin and eosin-stained section of lung tissue, showing
a typical onion-ring pattern of arteriolar hypertrophy (arrow), bloodless lungs, and intact alveoli. D,Hematoxylin and eosin-stained section of
lung tissue, showing pulmonary plexogenic arteriopathy, consistent with a diagnosis of primary pulmonary hypertension.
“primary” APS (3,4). These patients do not have
antibodies to double-stranded DNA (dsDNA) or to
extractable nuclear antigen; nor do they manifest any
of the major lupus-related signs and symptoms, such
as lupus-type rashes, polyserositis, non-cerebrovascular central nervous system disease, or immune complex renal disease. They may, however, have relatives
with SLE or another closely related connective tissue
disease, and may also demonstrate a low level of C4. It
is possible that there are several subgroups of “prima-
ry” APS, with some patients manifesting more lupuslike features. These patients may also be genetically
distinct from SLE patients, having an increase in DR7
and DRw53 genotypes (28), rather than DR2/3 typically found in SLE patients (29).
However, aPL may also be demonstrated in
patients with primary idiopathic PHT (30) and form
part of the underlying immunologic disturbance in the
condition, as emphasized by some authorities (31-33).
Rich et al (34) analyzed 43 patients with “primary”
PHT. Seventeen (40%) had an ANA titer of 1:80 or
greater, with a speckled pattern of staining in 11,
peripheral in 4, and homogenous in 2. Those itivestigators also compared the sensitivity of the KB cell line
with that of HEp-2 cells and with that of a mouse
kidney substrate. Six of the 11 patients with positive
results on KB cells had a positive titer at 1:80 on
greater dilution of the HEp-2 cell line. This group of
investigators also tested 16 patients with secondary
PHT (congenital heart disease, acquired heart disease,
or lung disease). Only 1 of them had a titer >1:40, and
in that patient, the diagnosis of secondary PHT was
PHT occurring in patients with collagen vascular disease seems to be indistinguishable from “primary” PHT without vasculitis or thromboembolic lesions. The exception to this general rule is that many
patients with rheumatoid arthritis complicated by PHT
seem to have an underlying vasculitis (35,36). Rich and
coworkers (34) emphasized that the predominantly
speckled pattern of ANA staining in both the primary
and secondary (i.e., to collagen diseases) PHT may
indicate that “primary” PHT is itself an example of a
collagen vascular disorder that mainly affects the lung.
The findings in the case reported here seem to
confirm this hypothesis. Our patient clearly had no
clinical history, signs, or serologic features of SLE.
She did not have leukopenia, her platelet count was
normal (apart from the episode of heparin-induced
thrombocytopenia), and antibodies to dsDNA were
absent. The ANA titer of 1:80 and the presence of aPL
are compatible with a diagnosis of a “primary” antiphospholipid syndrome. One of the more unusual
features of this case is that the PHT probably commenced as the primary plexogenic type, as evidenced
by the basic histologic finding of a plexogenic arteriopathy . The condition was, however, complicated by
the development of a large thrombus in the right main
pulmonary artery and the embolic phenomena that
originated from this lesion.
The distinction between primary PHT and
thromboembolic disease with secondary PHT is often
unclear until the postmortem examination. Our patient’s case is believed to be an example of the former.
Although it is well known that low cardiac output, as
was present in our patient, may precipitate thrornboembolic phenomena in patients with primary PHT
(37,38), the large clot in the right main pulmonary
artery in our patient may well have been related to the
aPL. Hers is the first reported case of the development
of a primary occlusion of a major pulmonary vessel in
association with the antiphospholipid coagulopathy.
Special thanks to Dr. Jonathan Tunis, Department of
Pathology, St. Luke’s/Roosevelt Hospital Center, for photographing the pathology specimens.
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idiopathic, antibodies, pulmonaria, complicated, associations, hypertension, thrombosis, primary, antiphospholipid, arterial
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