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Serotonin content of platelets in inflammatory rheumatic diseases.

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532
SEROTONIN CONTENT OF PLATELETS IN
INFLAMMATORY RHEUMATIC DISEASES
Correlation with Clinical Activity
J. ZELLER, E. WEISSBARTH, B. BARUTH, H. MIELKE, and H. DEICHER
Significantly decreased platelet serotonin contents were measured in rheumatoid arthritis, systemic
lupus erythematosus (SLE), progressive systemic sclerosis, and mixed connective tissue disease. An inverse
relationship between platelet serotonin levels and clinical disease activity was observed in both rheumatoid
arthritis and systemic lupus erythematosus. SLE patients with multiple organ involvement showed the lowest platelet serotonin values. No correlation was observed between platelet serotonin contents and
nonsteroidal antiinflammatory drug treatment, presence of circulating platelet reactive IgG, or the amount
of circulating immune complexes. The results are interpreted as indicating platelet release occurring in vivo
during inflammatory episodes of the rheumatic disorders investigated.
In addition to their role in blood coagulation,
platelets have been shown to play an important part as
intravascular inflammatory cells (1). Substances such
as thrombin, collagen, ADP, prostaglandin endoperoxFrom the Zentrum Innere Medizin und Dermatologie, Abteilung Immunologie und Transfusionsmedizin, und Abteilung
Rheumatologie, Medizinische Hochschule Hannover, Hannover,
FRG.
Supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 5 4 4 3 .
J. Zeller, E. Weissbarth, MD, B. Baruth, Professor H.
Deicher, MD: Abteilung Immunologie und Transfusionsmedizin; H.
Mielke, MD: Abteilung Rheumatologie.
Address reprint requests to Prof. H. Deicher, MD. Abteilung Immunologie und Transfusionsmedizin, Zentrum Innere Medii n und Dermatologie, Medizinische Hochschule Hannover, Postfach 61 01 80, D-3000 Hannover 61, FRG.
Submitted for publication June 2, 1982; accepted in revised
form September 23, 1982.
Arthritis and Rheumatism, Vol. 26, No. 4 (April 1983)
ides, certain large immune aggregates, and platelet
antibodies all induce platelet aggregation and the release reaction: stimulation of the platelet membrane
results in the liberation of platelet granule contents
such as serotonin, ADP, permeability and growth
factors, p-thromboglobulin, and lysosomal enzymes
(2-4). Therefore platelets represent an important intravascular potential of proinflammatory mediators,
readily available in active form once the release reaction is taking place.
In recent years, a number of groups have shown
that sera and synovial fluids from patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) can induce the platelet release reaction.
Platelet reactive antibodies (5-7) or certain types of
immune complexes (8-12) have been identified as
causative agents for platelet release and/or aggregation
in vitro. Among the released materials, serotonin and
other platelet permeability factors can cause increased
vascular permeability (13,14), presumably a prerequisite for the deposition of circulating immune complexes in blood vessel walls, e.g., in experimental serum
sickness (1 5,16).
Several lines of evidence indicate that platelets
may also be involved in the pathogenesis of immune
complex vascular disease, particularly in diffuse proliferative SLE nephritis (17,18). An increased platelet
turnover indicating platelet consumption has been
demonstrated in both RA and SLE (19,20). Low levels
of several characteristic platelet constituents have
been found in both disorders (21-24).
In the present study, we have measured serotonin contents of platelets in patients with RA, SLE, and
smaller groups of patients with mixed connective
tissue disease (MCTD) and progressive systemic scle-
PLATELET RELEASE IN RHEUMATIC DISEASES
rosis (PSS). Platelet serotonin levels were correlated
to the actual clinical disease activity. In addition,
circulating immune complexes, release-inducing capacity of the patients' sera, and platelet counts were
obtained. T h e results indicate that significantly decreased platelet serotonin contents are characteristic
of active states of all these diseases.
MATERIALS AND METHODS
Serotonin determination. Preparation of platelets.
Ten milliliters of venous blood was drawn into a polystyrene
vial containing 2 ml ACILA and mixed carefully. After
centrifugation at 136g (1,OOO rpm, Minifuge Heraeus Christ)
at +20°C for 20 minutes, the supernatant platelet-rich plasma
(PRP) was removed with an Eppendorf pipette. After platelet counting, 2 ml of PRP and 2 mlO.4% ice-cold EDTA were
mixed and centrifuged at 1,800g (3,600 rpm, Minifuge) for 20
minutes at +20°C. The supernatant was removed and the
platelet sediment was lysed in 1 rnl ice-cold aqua dest. The
mixture was shaken vigorously, the protein contents were
precipitated by adding 100 p1 ice-cold 200% TCA, and the
tubes incubated for 20 minutes on ice. The tubes were again
centrifuged at 1,800g for 20 minutes and 2 samples of the
protein-free supernatants were frozen at -70°C for later
serotonin determination (14).
OPT-HCl solution. One hundred twenty-five milligrams of ortho-phthaldialdehyd (OPT, for fluorescent analysis) was recrystallized, dissolved in 25 ml ethanol, and mixed
with 250 ml 8N HCl. The OPT-HCI solution was stored at
+4"C in an amber bottle and used for 1 month.
Serotonin standard. Two hundred thirty milligrams
of serotonidcreatinine sulfate was dissolved in 100 ml aqua
dest. This stock solution containing 1 mg/ml serotonin was
frozen in small portions. Vials were thawed for immediate
use and diluted to desired concentration.
Schoeffel spectrofluorometer. A spectrofluorometer
model RRS 1OOO (Schoeffel Instrument Corporation) was
used for serotonin determinations. Optical parameters were
adjusted and checked each time.
OPT reaction. Serotonin contents of patients' samples were determined using the method of Drummond and
Gordon (25). Frozen samples (see above) were thawed and
500 pl was pipetted into a glass vial. Samples, standards, and
blanks (250 pl aqua dest + 50 pl TCA) were mixed with 2 ml
OPT-HCI solution each, incubated for 10 minutes at
+lOO°C (26), and cooled on ice. To remove surplus TCA,
samples were shaken with 2.5 rnl chloroform (chloroform for
spectral analysis) for 5 minutes. The fluorescence of the
aqueous phase was measured at room temperature in the
spectrofluorometer (excitation 360 nm, emission 475 nm).
Two standards of 100 ng and 1,OOO ng serotoninhl were
determined with each measurement: 2 reagent blanks and
the serotonin content of the samples were determined in
duplicate.
Calculation of serotonin contents of platelets. After
the reaction with OPT, serotonin gives a typical fluorescence
533
maximum at 475 nm upon excitation at 360 nm (27), the
fluorescence intensity showing a linear relation to the serotonin content of the measured sample.
Four calibration curves for serotonin concentrations
between 25 and 1,000 ng/ml were obtained; the variation
coefficient was calculated at 4.9%. On the basis of the known
platelet counts, serotonin contents were expressed as ng/109
platelets.
The in vitro serotonin release of platelets was measured according to the method of Weissbarth et al(28) using
freshly obtained patient sera.
Patients and control subjects. Normal controls ( N C ) .
To determine the normal range for serotonin contents/lO'
platelets, blood samples from 60 healthy blood donors were
prepared as described in the following section.
Patients. Fifty-four patients with rheumatoid arthri39 patients with systemic lupus erythematosus
tis (M),
(SLE), 5 patients with progressive systemic sclerosis (PSS),
and 5 patients with mixed connective tissue disease
(MCTD) were investigated.
Blood samples for the preparation of platelets (see
above) and the determination of circulating immune complexes (see following paragraph) were drawn at the same
time. Sera were obtained within 2 hours after clotting at
room temperature, frozen at -70°C, and processed within 2
weeks.
Circulating immune complexes were determined by
the Clq-binding assay (29); results were expressed in pg
aggregated IgG equivalentshnl (pg AGG/ml).
Assessment of clinical activity. To determine the
clinical activity of rheumatoid arthritis, patients were classified using an American Rheumatism Association index comprising both subjective and objective parameters (30). According to this scheme patients can be given from 1 to 30
points representing increasing clinical activity. Clinical activity was classified as low (group I) when this index was
below 9, whereas active disease was diagnosed in patients
reaching indices of 10 or higher.
In SLE, a ranking system based upon grouped symptoms and involvement of organs, as developed in our clinic,
was used. In this system (31), an index of 0 indicates
complete remission; index figures of 1 or 2, low grade
activity; indices of 3 and 4, active diseases; and figures of 5
or greater, active diseases with multiple organ involvement.
One index point each is given for a group of basic symptoms
and reversible organ manifestations (fever, weight loss,
photosensitivity, arthritis, myalgia, erythema, alopecia,
Raynaud symptoms, purpura, icterus, lymphadenopathy).
Two index points are given for serious organ involvement
(hepatomegaly , splenomegaly, pericarditis or myocarditis,
pneumonitis, central nervous system involvement, nephritis). One additional index point is assigned for a number of
laboratory data if values are recorded significantly above the
mean obtained during the last 6 months: erythrocyte sedimentation rate (Westergren method): increase >30 mm (first
hour); circulating immune complexes: increase >80 pg AGG
equivalentshl; serum DNA antibodies: increase >20% (32);
total serum complement activity: decrease > 10 CHSO/ml.
One index point was allowed for physician's judgment
(active = 1; inactive = 0).
Statistical analysis. Platelet serotonin values were
ZELLER ET AL
534
from the normal controls, whereas in the 35 RA
patients with active inflammatory symptoms an average of only 391 ng/109 platelets was measured. The
latter value differed significantly from the normal
controls (2 P = 0.000) as well as from that of group I
patients (2 P = 0.02).
In SLE, similar results were obtained. As depicted in Figure 2, l l patients in complete remission
exhibited normal platelet serotonin contents (mean =
583 ng/109 platelets). With increasing clinical activity,
falling platelet serotonin levels were obtained; patients
with highly active disease showed the lowest levels.
Patients with less active disease with index figures 1
K t s.e. ng Serotonin/10~Platelets
n = 60
54
39
t
T
f
li
PSS
h
Normal
4
Controls
Figure 1. Mean serotonin contents in platelets of normal controls
and rheumatoid arthritis, systemic lupus erythematosus, progressive systemic sclerosis, and mixed connective tissue disease patient
groups.
L
grouped, tested for normal distribution, and subjected to
analysis by use of a 1-test for independent random samples.
RESULTS
Platelet serotonin contents in different inflammatory rheumatic diseases. As shown in Figure 1, the
mean platelet serotonin contents of the normal control
sample (n = 60)amounted to 581 ng/109 platelets (SE
= 2 26 ng/109 platelets). In the RA group (n = 54), a
significantly decreased platelet serotonin level of 438
&lo9 platelets (SE = 2 25 ng/109 platelets) was
obtained (2 P = 0.0o0 versus the control group). The
mean platelet serotonin value for 39 SLE patients was
426 ng/109 platelets (SE = ? 34 ng/109 platelets), again
significantly below the normal range (2 P = 0.000).
The results found in 5 patients with PSS and in 5
MCTD patients were also significantly decreased (2 P
= 0.05 for PSS; 2 P = 0.002 for MCTD).
When platelet serotonin contents in RA patients
were further differentiated according to disease activity, it was shown that significantly decreased platelet
serotonin levels were found exclusively in the group
with active inflammatory states, whereas platelets of
patients in remission exhibited normal serotonin contents (Table 1). Thus, 19 RA patients with low disease
activity showed a mean platelet serotonin content of
5 12 &lo9 platelets, a value not significantly different
K 2 ae. ng Serotonin/~~Q
Platelets
11
12
16
900-
m
m-
200
100
I
T
I
I
.
II
Figure 2. Platelet serotonin contents in systemic lupus erythematosus as related to disease activity. Activity was determined using a
ranking system for group symptoms: group 0 = inactive disease;
group I = ranks 1 and 2; group I1 = ranks 3 and 4. X = normal
controls.
PLATELET RELEASE IN RHEUMATIC DISEASES
535
Table 1. Serotonin contents (ng/109 platelets) in rheumatoid arthritis (RA) as related to disease
activity
f-test (2P1
n
Normal controls
RA total
Group I
Group I1
60
54
19
35
Mean
2
SD
Range
589 2 402
438 2 392
512 ? 312
391 t 408
187-99 1
46-830
and 2 (group I) showed lower values than the control
group, but their mean platelet serotonin level was
found to be significantly higher if compared with group
11. Within group I1 (composed of patients with higher
clinical activity; index figures above 3), 3 patients had
multiple organ involvement, and 1 patient was hospitalized because of an acute phase of the disease. All
differences proved to be statistically significant (Table
Versus
normal
controls
Versus others
0.000
0.975
0.000
Versus group I = 0.02
serotonin release in vitro (7) has been found in 7 of 53
RA sera and in 14 of 38 investigated SLE sera. Tables
4 and 5 give the data on selected patients. Although the
relation between platelet serotonin levels and disease
activity is again apparent, no correlation of platelet
serotonin contents and detectability of this circulating
antibody was observed (correlation coefficient =
0.042). Circulating immune complexes, determined in
simultaneously drawn sera, were found in 39 of 53 RA,
23 of 38 SLE, 2 of 5 MCTD, and 2 of 5 PSS patients. A
relationship to platelet serotonin levels was not apparent from the data (Tables 4 and 5).
2).
Because of the small number of patients in the
PSS and MCTD groups, the results can be regarded as
only preliminary. As groups, however, both diseases
again presented significantly decreased platelet serotonin levels (Figure 1).
Influence of the treatment with nonsteroidal antiinflammatory drugs on platelet serotonin levels. To
ascertain whether drug administration influenced the
results, platelet serotonin contents were measured in
10 RA patients under treatment with different nonsteroidal antiinflammatory agents, and again 20 hours
after withdrawal of the drugs. No patient was taking
acetylsalicylic acid derivatives. As shown in Table 3,
nonsteroidal antiinflammatory medication did not appreciably alter platelet serotonin levels.
Relationship between platelet serotonin contents,
release inducing serum IgG, and circulating immune
complexes. A serum platelet reactive IgG inducing
DISCUSSION
The participation of platelets in chronic inflammatory connective tissue diseases has been documented in several ways. In rheumatoid arthritis, several studies have shown that at least 30% of patients with
active disease display a thrombocytosis accompanied
by an increased platelet turnover, correlating with
disease activity and with extravascular organ manifestations such as vasculitis (21,33-36).
Smith and Castor (22), having found decreased
levels of several platelet constituents including seroto-
Table 2. Serotonin contents (ng/l@ platelets) in systemic lupus erythematosus (SLE) as related to
disease activity
1-test (2P)
n
Normal controls
SLE total
Group 0
Group I
Group I1
60
39
I1
16
12
Mean
?
589 k
426 5
583
356
332 k
*
*
SD
402
431
448
392
364
Range
Versus
normal
controls
Versus others
187-991
0-857
0.000
0.013
0.000
Versus group 1 + I1 = 0.03
Versus group 0 = 0.009
ZELLER ET AL
536
Table 3. Influence of treatment with nonsteroidal antiinflammatory drugs on platelet serotonin
contents in rheumatoid arthritis patients
Serotonin &lo9 platelets
Patient
MUE
REN
DRE
BUS
Medication
Diclofenac
Diclofenac
Diclofenac
Diclofenac
Indomethacin
Indomethacin
Indomethacin
Indomethacin
Indomethacin
Indomethacin
Naproxen
Naproxen
OPA
RE1
LIE
GRO
HAM
szc
mg/day
I50
150
125
150
50
100
I00
150
200
100
Under
treatment
No
treatment
366
640
199
636
30 I
576
206
470
90 I
370
57
826
822
379
955
29
633
58
58
1 .OOo
100
500
nin, acid phosphatase, connective tissue activating
peptide 111, and platelet total protein in RA patients,
discuss whether their results indicate release of these
materials from the platelets, or whether an intrinsic
platelet defect might be the cause of these abnormalities. Such a defect, however, appears unlikely since
our own data clearly demonstrate an inverse relationship between clinical activity and platelet serotonin
contents, with normal values in inactive disease states.
Moreover, an increased platelet turnover cannot be
responsible for the observed changes since it is necessarily accompanied by the appearance in the circulation of an increased number of large dense young
platelets with higher contents of platelet constituents
(35,37).
Therefore the data would be more compatible
with a platelet release reaction taking place in vivo in
active RA, resulting in an increased platelet turnover,
which may then be overcompensated by increased
platelet production leading to thrombocytosis. One
possible cause of such in vivo platelet release is
provided by a platelet reactive IgG found in 24% of RA
patients’ sera (7), although no correlation between
lowered platelet serotonin contents and the presence
of this antibody in the patients’ sera is apparent from
our data (Table 5). This lack of correlation may,
however, be caused by the fact that circulating platelet
antibody is not a representative measure for the actual
in vivo presence of such antibody on the platelet
surface, as has been shown in idiopathic thrombocytopenic purpura (38). Certain immune aggregates
found in RA sera and/or exudates, which have been
shown to induce platelet release in vitro (7,11,12,28) or
platelet aggregation (8,10), may also contribute to the
Table 4. Platelet serotonin contents and related data in selected rheumatoid arthritis patients
Patient
GAS
SUP
DUE
WES
SIU
KOC
BEE
KIE
ROE
PRI
RE1
TAU
Disease
activity
stage
Platelet
serotonin
contents (ng/
lo9 platelet)
serotonin
release*
Immune
complexes
pgAGG/ml t
843
71 I
648
438
131
625
525
162
90
42
20
18
8.2
7.6
7.8
32.4
1.3
14.2
31.1
2.2
0.5
1.2
0.4
2.3
270
345
190
200
I65
760
290
2,900
520
300
240
I60
1
I
I
I
I
I1
I1
11
I1
I1
I1
I1
* Normal range (mean 5 2 SD) =
t Normal range <200 &ml.
1.69 ? 5.36%.
Platelets
% ’H
(X
103/
4
blood)
305
126
120
167
I70
I00
145
140
22 1
435
206
277
PLATELET RELEASE IN RHEUMATIC DISEASES
537
Table 5. Platelet serotonin contents and related data in selected systemic lupus erythematosus
(SLE), mixed connective tissue disease (MCTD), and progressive systemic sclerosis (PSS) patients
Patient
SLE
WER
SUK
ASM
NEY
DEL
EHL
ALT
SCH
LOH
NIE
SCH
HAA
MCTD
SCH
IHS
PSS
Disease
activity
stage
0
0
I
I
I
1
I
I1
I1
I11
111
I11
I1
111
SOM
1
BLU
111
* Normal range (mean 2 2 SD) =
t Normal range <200 pg/ml.
Platelet
serotonin
contents
w109
platelet)
Platelets
% 'H
serotonin
release*
Immune
complexes
pgAGG/mlt
415
30
310
131
97
10.6
36.2
23.3
39.3
67.6
21.6
18.3
38.6
3.0
44.4
43.5
4.3
165
190
680
710
220
365
1,750
I75
I75
490
510
400
106
142
167
172
90
I20
94
I25
220
255
10
168
63 1
215
24.0
12.9
195
255
125
186
294
148
10.3
0.2
I75
I70
I25
I86
830
620
445
336
307
242
180
(X
1031
PI
blood)
1.69 2 5.36%.
release. However, their in vivo reactivity must be
doubted because their reactivity with platelet via Fc
receptors is inhibited by excess IgG (1 1,12).
On the other hand, immune complexes have
been shown to liberate platelet activating factor (PAF)
directly or indirectly from granulocytes and monocytes (38,39), thus providing another possible pathway
leading to platelet release (40). Finally, decreased
levels of platelet constituents may be explained by
platelet activation accompanying activated intravascular coagulation in RA, as documented by elevated
levels of fibrin split products and increased fibrinogen
turnover in active disease states (20,41,42).
In SLE our results confirm and extend observations by other groups (21,43,44) on lowered platelet
serotonin levels. Weiss et a1 (23) have recently described 2 SLE patients with acquired platelet storage
pool deficiency, whose platelets were characterized by
low serotonin, ADP, calcium, p-thromboglobulin, and
acid phosphatase levels and by a markedly decreased
aggregability, caused by platelet antibodies which are
found in a high percentage of patients with SLE
(7,38,45). It has been shown in several laboratories
(19,38, and Weissbarth E, Baruth B: unpublished
observations) that platelet antibodies in SLE patients
decrease in titer or disappear completely upoa appro-
priate treatment. Thus, the observation of the interdependence of platelet serotonin levels and the clinical
activity of SLE reported here as well as by others (21)
may reflect decrease of titer and/or complete disappearance of such antibody in clinical remission.
Other mechanisms of platelet activation via
immune complexes, such as described in RA, may also
apply to SLE. A significant correlation between disease activity and the amount of circulating immune
complexes has been described in both diseases (4649). Thus both platelet antibody dependent and PAF
dependent platelet activatian could be expected to
diminish or disappear with clinical remission in both
diseases.
In experimental immune complex vascular disease, the release of permeability factors and vasoactive mediators from platelets has been shown to promote the deposition of immune complexes in vessel
walls (15,16). A similar process may be operative in
SLE, where local consumption of platelets in SLE
nephritis has been documented (17). Moreover, it has
been shown that in both vasculitis and membranoproliferative glomerulonephritis, a typical selective platelet destruction not accompanied by fibrinogen consumption occurs in active stages (5031). On the other
hand, increased fibrinogen turnover as well as elevat-
ZELLER ET AL
538
ed plasma and serum levels of fibrin split products
have been documented in SLE by other groups
(52,53), indicating an activation of intravascular clotting which may be accompanied by an in vivo release
of platelet contents.
In the few investigated cases of MCTD and
PSS, similar results of low platelet serotonin in the
more active cases have been found. For a more
detailed analysis, however, a larger number of patients
will certainly have to be studied. Increased blood
platelet counts similar to RA have been reported in
PSS (35).
The demonstration that treatment with nonsteroidal antiinflammatory drugs did not alter platelet
serotonin levels agrees with the results of other workers (21). Actually somewhat increased levels of platelet constituents have been reported in individuals
taking acetylsalicylic acid (54). It would therefore
seem unlikely that the process responsible for the
lowered platelet serotonin levels depended on an intact prostaglandin synthesis.
An important difference regarding platelets in
the investigated disease groups, however, is not adequately explained by these considerations. RA and
SLE are accompanied by an increased platelet turnover, but thrombocytosis is observed in RA and PSS
as contrasted to SLE, where thrombocytopenia due to
the reaction of platelet antibodies with their target
cells occurs with considerable frequency. Differences
in amount, specificity, and association constant of
platelet reactive immunoglobulins (6,7), their reaction
with different types of antiglobulins (7,12), differences
in amount, composition, and reactivity of circulating
immune complexes ( 1 1,29,46,47,55) as well as different degrees of intravascular activation of the clotting
system (52,53) may all contribute. The definite role of
single or multiple vectors for the resulting platelet
count and function remains to be determined.
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