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FIBRINOGEN CATABOLISM IN
SYSTEMIC LUPUS ERYTHEMATOSUS
JOHN S. SERGENT, RAYMOND L. SHERMAN, and HAMID AL-MONDHIRY
Because there is mounting evidence that localized hypocomplementemia. These observations support the hy-
intravascular coagulation may contribute to tissue injury pothesis that the coagulation system is activated in
following a variety of immunologic events, including im- patients with immune complex diseases. Further studies
mune complex diseases, fibrinogen catabolism was studied are required to define the role, if any, that coagulation
in patients with systemic lupus erythematosus to deter- may play in causing tissue injury.
mine factors correlating with accelerated coagulation.
'%fibrinogen half-life in controls was 90.1 f 11 hours The finding of intraglomerular fibrin deposition
and the mean SLE half-life was 60.5 f 12. SLE patients is prominent in many forms of human and experimental
in complete clinical remission had normal half-lives, but glomerulonephritis, a n d in c e r t a i n s i t u a t i o n s
patients with symptomatic clinical disease, including renal anticoagulation is known to exert a major effect on the
disease, had significantly reduced fibrinogen survival. Ac- severity and progress of the renal lesion (1,2).
celerated fibrinogen consumption also correlated with pos- Because renal disease is the leading cause of
itive tests for anti-DNA antibodies, but not with death in systemic lupus erythematosus (SLE) (3), and
because present information regarding the role of coag-
From the Department of Medicine, Cornell University ulation in patients with SLE nephritis is meager and
School of Medicine, and the New York Hospital, the Hospital for confusing, fibrinogen kinetics were studied using lZ5I-
Special Surgery, and Memorial Hospital, New Y ork, New York. labeled fibrinogen in a variety of patients with SLE.
Supported in part by a postdoctoral fellowship from The
Arthritis Foundation.
Presented in part at the 39th Annual Meeting of the Ameri- MATERIALS AND METHODS
can Rheumatism Association, June 4-6, 1975, New Orleans, Loui-
siana. Patients. Sixteen adult patients, all fulfilling criteria for
John S. Sergent, M.D.: Assistant Professor of Medicine, SLE established by the American Rheumatism Association
Cornell University Medical College, and Assistant Attending Physi- (4), were studied. Informed consent was obtained in each case,
cian, the Hospital for Special Surgery (present address: Vanderbilt and unless hospitalized for another reason, the patients were
University School of Medicine, Nashville, Tennessee); Raymond L. admitted to the Clinical Research Center of the New York
Sherman, M.D.: Assistant Professor of Medicine, Cornell University Hospital. The study group consisted of 13 females and 3 males.
Medical College; Hamid Al-Mondhiry, M.D.: Assistant Professor of Two patients were studied on two separate occasions; the first
Medicine, Cornell University Medical College, and Assistant Attend- study in each case was during a period of clinically active
ing Physician, Memorial Hospital. systemic and renal disease, and the second during a
Address reprint requests t o John S. Sergent, M.D., Depart-
ment of Medicine, Vanderbilt University School of Medicine, Nash- corticosteroid-induced remission. Patients with active bleeding
ville, Tennessee 37232. or severe thrombocytopenia were excluded.
Submitted for publication July 1, 1975; accepted October 3, Controls included 4 normal volunteers and 1 patient
1975. with a chronic ill-defined dermatitis without systemic disease.
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
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(renal) (non-renal) Normal complement I
Fig 2 Low compIe me nt
Anti-DNA antibodies, negative
Corticosteroid therapy had no apparent effect on Anti-DNA antibodies, positive
fibrinogen half-life in these patients, with a mean half- Fig 3
life in the 8 patients without corticosteroids of 69.7
hours, compared to 67.1 hours in the 10 patients taking roid-induced remission, fibrinogen metabolism returned
these drugs. to normal, with the half-life increasing from 63 to 92
Four patients with clinically active disease were hours in 1 patient and from 55 to 87 hours in the other.
given intravenous heparin and their fibrinogen catabo- No patient in this study had significant elevations
lism studies were repeated. Two of these patients were of FDP in the serum or reduced plasma fibrinogen lev-
given low doses of heparin, so that their partial els. There was no correlation between fibrinogen catab-
thromboplastin times remained less than twice the con- olism and level of azotemia or amount of proteinuria.
trol value. There was little change in their fibrinogen
half-lives: 1 patient showed an increase from 55 to 65 DISCUSSION
hours and the other a decrease from 53 to 48 hours. One Although prominent intraglomerular fibrin de-
patient studied while taking enough heparin to maintain position is often seen in SLE, the role of the coagulation
the partial thromboplastin time at greater than twice the process in causing or potentiating renal damage is not
control demonstrated an increase of her fibrinogen half- clear. Kanyerezi et a1 ( 1 1) measured serum and urinary
life from 69 to 92 hours. A fourth patient was studied on FDP levels and concluded that SLE patients with ne-
full doses of heparin, but the study was terminated after phritis had increased F D P excretion, although serum
3 days because of heavy menstrual bleeding. levels were similar to those seen in rheumatoid arthritis.
In the 2 patients studied before and after a ste- Using similar techniques, Marchesi et a1 (12) found
198 SERGENT ET AL