195
FIBRINOGEN CATABOLISM IN
SYSTEMIC LUPUS ERYTHEMATOSUS
JOHN S. SERGENT, RAYMOND L. SHERMAN, and HAMID AL-MONDHIRY
Because there is mounting evidence that localized
intravascular coagulation may contribute to tissue injury
following a variety of immunologic events, including im-
mune complex diseases, fibrinogen catabolism was studied
in patients with systemic lupus erythematosus to deter-
mine factors correlating with accelerated coagulation.
'%fibrinogen half-life in controls was 90.1 f 11 hours
and the mean SLE half-life was 60.5 f 12. SLE patients
in complete clinical remission had normal half-lives, but
patients with symptomatic clinical disease, including renal
disease, had significantly reduced fibrinogen survival. Ac-
celerated fibrinogen consumption also correlated with pos-
itive tests for anti-DNA antibodies, but not with
From the Department of Medicine, Cornell University
School of Medicine, and the New York Hospital, the Hospital for
Special Surgery, and Memorial Hospital, New Y ork, New York.
Supported in part by a postdoctoral fellowship from The
Arthritis Foundation.
Presented in part at the 39th Annual Meeting of the Ameri-
can Rheumatism Association, June 4-6, 1975, New Orleans, Loui-
siana.
John S. Sergent, M.D.: Assistant Professor of Medicine,
Cornell University Medical College, and Assistant Attending Physi-
cian, the Hospital for Special Surgery (present address: Vanderbilt
University School of Medicine, Nashville, Tennessee); Raymond L.
Sherman, M.D.: Assistant Professor of Medicine, Cornell University
Medical College; Hamid Al-Mondhiry, M.D.: Assistant Professor of
Medicine, Cornell University Medical College, and Assistant Attend-
ing Physician, Memorial Hospital.
Address reprint requests t o John S. Sergent, M.D., Depart-
ment of Medicine, Vanderbilt University School of Medicine, Nash-
ville, Tennessee 37232.
Submitted for publication July 1, 1975; accepted October 3,
1975.
Arthritis and Rheumatism, Vol. 19, No. 2 (March-April 1976)
hypocomplementemia. These observations support the hy-
pothesis that the coagulation system is activated in
patients with immune complex diseases. Further studies
are required to define the role, if any, that coagulation
may play in causing tissue injury.
The finding of intraglomerular fibrin deposition
is prominent in many forms of human and experimental
glomerulonephritis, a n d in c e r t a i n s i t u a t i o n s
anticoagulation is known to exert a major effect on the
severity and progress of the renal lesion (1,2).
Because renal disease is the leading cause of
death in systemic lupus erythematosus (SLE) (3), and
because present information regarding the role of coag-
ulation in patients with SLE nephritis is meager and
confusing, fibrinogen kinetics were studied using lZ5I-
labeled fibrinogen in a variety of patients with SLE.
MATERIALS AND METHODS
Patients. Sixteen adult patients, all fulfilling criteria for
SLE established by the American Rheumatism Association
(4), were studied. Informed consent was obtained in each case,
and unless hospitalized for another reason, the patients were
admitted to the Clinical Research Center of the New York
Hospital. The study group consisted of 13 females and 3 males.
Two patients were studied on two separate occasions; the first
study in each case was during a period of clinically active
systemic and renal disease, and the second during a
corticosteroid-induced remission. Patients with active bleeding
or severe thrombocytopenia were excluded.
Controls included 4 normal volunteers and 1 patient
with a chronic ill-defined dermatitis without systemic disease.
196 SERGENT ET AL

In addition 5 patients with chronic membranoproliferative Normal ranqe

glomerulonephritis, of whom all had proteinuria and 4 had 100
azotemia, were studied.
Corticosteroid Drugs. Because high doses of
corticosteroids may have a mild effect on fibrinogen metabo-
lism (5), when possible patients were studied either on no
therapy or when taking 15 mg or less per day of prednisone.
However two studies were performed on patients taking 25 80

E
mg/day and one on a patient taking 65 mg/day. Two addi-
tional patients were studied before and after steroid-induced 0.. 0..

.
remissions. All other antiinflammatory medications, including
aspirin and indornethacin, were witheld during the period of

ti.:. .
0.
study.
Clinical Assessment. Patients were considered to have
active SLE if they showed any symptoms attributable to the 3.
disease, including fever, arthralgia, easy fatigability, and skin
rash. In addition all patients with proteinuria, a persistently
abnormal urinary sediment, or hematologic abnormalities
were considered active. SLE was designated as being in remis-
sion in asymptomatic patients with no evidence of clinical
- . .
renal or hematologic disease. Patients were considered to have
renal disease if they had proteinuria greater than 300 mg/24
hours or if they had persistent urinary sediment abnormalities.
Serologic Studies. Serum complement was determined
by the method of Kent and Fife (6) with a normal range of
150-250 CH5O U/ml. Anti-DNA antibodies were measured by
the Farr assay of Pincus et u l ( 7 ) with normal being less than
20% DNA binding.
Coagulation Studies. The following screening tests
were performed on all patients: platelet count, clot retraction, n n
prothrombin time, activated partial thromboplastin time, "
thrombin time, fibrinogen level, and a test for fibrinogen S LE SLE S LE
degradation products (FDP) using the staphylococcal clump- (all patients) (active) (remission)
ing test (8).
For studies of fibrinogen catabolism, fibrinogen from a Fig 1
normal donor was purified by differential salting-out tech-
niques and labeled with lZsI by the iodine monochloride tech- a fibrinogen half-life of 60.5 f 12 hours (mean f 1 SD)
nique (9). This material was passed through a 45-p millipore (P < 0.01 by Student's t test). The normal range in
filter and frozen in sterile containers until used. In all studies controls was 90.1 f 11 hours.
the radioactivity was greater than 95% clottable by bovine
thrombin. When the 7 patients with SLE who had clinical
All patients were given Lugol's solution for 24 hours evidence of renal disease were compared with the 1 1
prior to and throughout the period of study. Following in- studies in patients without renal involvement (Figure 2),
jection of approximately 30 pCi in each patient, a period of accelerated fibrinogen consumption was found in those
rapid decay that lasted 12-24 hours took place in the plasma with renal disease (0.02 < P < 0.05). The patients with
radiolabeled fibrinogen. This decay has been previously de-
scribed and attributed to extravascular equilibration (10). membranoproliferative glomerulonephritis had normal
During the week following this period of equilibration, serum fibrinogen catabolism as a group.
and plasma were obtained daily or twice daily, and plasma Hypocomplementemia in the lupus patients was
radiolabeled fibrinogen was determined by subtracting serum not associated with a statistically significant reduction in
radioactivity from that in plasma. Fibrinogen half-life was fibrinogen half-life, but elevated levels of anti-DNA an-
then estimated by plotting remaining plasma radioactivity vs
time as previously described (10). No advantage was found in tibodies were associated with increased fibrinogen
obtaining blood more frequently than once daily. catabolism (0.02 > P > 0.01) (Figure 3).
I n all patients with proteinuria, daily 24-hour
RESULTS urine was collected. An aliquot of this was precipitated
The fibrinogen half-lives in the 18 studies of 16 with T C A a n d another aliquot dialyzed extensively
patients are shown in Figure 1. Although there is a wide against normal saline. In all cases less than 1% of the lzaI
range of values in this group, the patients with clinically in the urine was found to be protein-bound by these
active disease had significantly shortened survival, with techniques.
FIBRINOGEN CATABOLISM IN SLE 197

Normal range Normal range

100

80
v)
L
3
0
L
-
JZ
60
-
Q,
.-
+
0
-
b
I

m
JZ
c
rn
Q, 40
0
.-c
L
.-n
LL

20

S LE SLE M PGN
(renal) (non-renal)
Fig 2
Corticosteroid therapy had no apparent effect on
fibrinogen half-life in these patients, with a mean half-
life in the 8 patients without corticosteroids of 69.7
hours, compared to 67.1 hours in the 10 patients taking
these drugs.
Four patients with clinically active disease were
given intravenous heparin and their fibrinogen catabo-
lism studies were repeated. Two of these patients were
given low doses of heparin, so that their partial
thromboplastin times remained less than twice the con-
trol value. There was little change in their fibrinogen
half-lives: 1 patient showed an increase from 55 to 65
hours and the other a decrease from 53 to 48 hours. One
patient studied while taking enough heparin to maintain
the partial thromboplastin time at greater than twice the
control demonstrated an increase of her fibrinogen half-
life from 69 to 92 hours. A fourth patient was studied on
full doses of heparin, but the study was terminated after
3 days because of heavy menstrual bleeding.
In the 2 patients studied before and after a ste-
0
Normal complement I
Low compIe me nt
Anti-DNA antibodies, negative
Anti-DNA antibodies, positive
Fig 3
roid-induced remission, fibrinogen metabolism returned
to normal, with the half-life increasing from 63 to 92
hours in 1 patient and from 55 to 87 hours in the other.
No patient in this study had significant elevations
of FDP in the serum or reduced plasma fibrinogen lev-
els. There was no correlation between fibrinogen catab-
olism and level of azotemia or amount of proteinuria.
DISCUSSION
Although prominent intraglomerular fibrin de-
position is often seen in SLE, the role of the coagulation
process in causing or potentiating renal damage is not
clear. Kanyerezi et a1 ( 1 1) measured serum and urinary
FDP levels and concluded that SLE patients with ne-
phritis had increased F D P excretion, although serum
levels were similar to those seen in rheumatoid arthritis.
Using similar techniques, Marchesi et a1 (12) found
198
elevated urinary FDP in most patients with SLE ne-
phritis, but the F D P levels fluctuated markedly day by
day and were not considered a useful index of disease
activity.
The study of fibrinogen metabolism using "'I-
labeled fibrinogen is known to be sensitive a n d highly
reproducible (10). It has been applied to many clinical
situations including a variety of renal diseases. Wardle
et a1 (13) and George et a1 (14) have demonstrated
shortened half-lives in patients with acute renal allograft
rejection, and Wardle and Kerr (15) have shown
shortened survival in association with active renal dis-
ease of various types, including 3 patients with SLE. In
addition George et a1 (14) have found accelerated fibrin-
ogen consumption in the hemolytic-uremic syndrome
but not in a variety of pathologically described types of
glomerulonephritis. Their cases were not described in
sufficient detail to determine whether any patients had
SLE.
T h e present studies have demonstrated acceler-
ated fibrinogen catabolism in S L E patients with renal
involvement as well as in other patients with clinically
active SLE. There was also a correlation with the pres-
e n c e of a n t i - D N A a n t i b o d i e s , b u t n o t w i t h
hypocomplementemia. In 2 patients control of the in-
flammatory response with corticosteroids was associ-
ated with prompt normalization of fibrinogen catabo-
lism. These observations are compatible with the
hypothesis that activation of the coagulation system is
prominent in SLE, presumably as a secondary response
to immune complex deposition. Whether this
accelerated coagulation is involved in the mechanism of
tissue damage, as seems true in the lupus-like disease of
the NZB mouse (16), must await further study.
Although anticoagulant therapy is reported t o be
useful in several types of human renal diseases, there are
little data in patients with SLE. Ponticelli et a1 (17)
treated 4 patients with S L E nephritis a n d oliguria with
h e p a r i n , a n d a l t h o u g h 3 i m p r o v e d 1 d i e d of
complications of therapy. Cade et a1 (18) treated a group
of S L E patients with chronic nephritis with depot hepa-
rin therapy, a n d their results indicate better preservation
of renal function in the treated patients than in the
controls.
Although it is not the present authors' practice to
treat SLE nephritis with anticoagulants a t this time,
further study of this mode of therapy is surely indicated.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the help and guid-
ance of Dr. Charles L. Christian and the expert technical
assistance of Mr. Duane Sadula.
SERGENT ET AL
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