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Extravascular fibrin formation and dissolution in synovial tissue of patients with osteoarthritis and rheumatoid arthritis.

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Fibrin deposition is a prominent finding in the
synovium of patients with rheumatoid arthritis (RA).
Macrophages are found in increased numbers in RA
synovium, and these cells are known to produce a
variety of procoagulant and anticoagulant molecules.
Using immunohistologic techniques, the content and
distribution of several important components of the
coagulation system in the synovium of patients with RA,
osteoarthritis (OA), or traumatic joint abnormalities
requiring surgery were investigated. Samples from 3
patients from each category were examined in detail.
RA synovium (compared with that of patients with OA
or joint trauma) had increased numbers of macrophages
and increased expressionlcontent of fibrinogen, tissue
factor, factor XIII, tissue transglutaminase, crosslinked fibrin (fibrin D dimer), urokinase-type plasminogen activator, and cu,-plasmin inhibitor. Macrophage
content in RA synovium was increased in both the lining
cell areas and the interstitial cell areas. Fibrinogen was
distributed throughout the tissue in all samples and was
greater in RA synovium. In trauma and OA synovia,
tissue factor was seen only in association with vessels
(endothelial cells), but in RA synovium, it was markedly
increased throughout the tissues. While fibrin D dimer
From the Veterans Administration and Duke University
Medical Centers, Durham, North Carolina.
Supported in part by the Veterans AfFairs Research Service. the James Swiger Hematology Kesearch Fund, and NIH grants
PO1 AI-23308,1’01 32682. HI,-38245, and P50 AR-39162. Dr. Greenberg is an Established Investigator of the American Heart Association.
J. Brice Weinberg, MD; Anne M. M. Pippen, HS; Charles
S. Greenberg, MD.
Address reprint requests to J. Brice Weinberg, MD, Veterans Affairs and Duke University Medical Centers, 151G, Durham,
NC 27705.
Submitted for publication October 12, 1990: accepted in
revised form February 28, 1991.
Arthritis and Rheumatism, Vol. 34, No. 8 (August 1991)
was seen in small amounts in synovial lining cell areas of
trauma and OA synovia, it was present in increased
amounts in the lining cell and interstitial cell areas of RA
synovium. Factor XI11 and tissue transglutaminase were
present in scant amounts in trauma and OA synovia, but
there were increased amounts of both (especially tissue
transglutaminase) in RA synovium in the vessel, lining
cell, and interstitial cell areas. Urokinase and a2plasmin inhibitor were also markedly increased in RA
synovium. These results suggest that in inflamed synovium, there is ongoing extravascular tissue fibrin formation and dissolution that correlates with the degree of
inflammation and macrophage content. Extravascular
coagulationlfibrinolysis in RA represents a potential
target for therapeutic intervention in this disease.
Mononuclear phagocytes (monocytes and macrophages) are found in normal and inflamed synovial
tissue (1,2). In normal synovium, many of the cells
lining the joint space (the synovial lining cells or the
“type A” cells [I]) are of mononuclear phagocyte
origin. Rheumatoid arthritis (RA) is a systemic inflammatory disease with a synovitis characterized by synovial tissue hyperplasia, with increased numbers of
synovial lymphocytes and mononuclear phagocytes,
accompanied by variable degrees of synovial fibroblast
proliferation (2). Cartilage and bone destruction may
accompany the synovial tissue changes. Synovial macrophages, having migrated there from the blood as
monocytes ( l ) , play important roles in initiating, propagating, and maintaining the inflammation (2). Various
investigators have noted that fibrin is found in the
synovial tissue in RA (3,4). Indeed, in most types of
inflammation (especially immunologically induced inflammation such as delayed-type hypersensitivity re-
Table 1. Results of immunofluorescence studies of synovial tissue from trauma patients, osteoarthritis (OA) patients, and rheumatoid arthritis
(RA) Datients*
RA patients
(sample no.)
OA patients
(sample no.)
Trauma patients
(sample no.)
1 yr.
10 yrs.
2+ LC, 2+ LC,
2 + IC
2+ IC
3+LC, 3+LC,
I + IC
I + IC
4 + EC 4 + EC
3 yrs.
1 + LC
3 yrs.
1 + LC
I + LC
t LC
t LC
I + LC
1 + LC
2+ IC
3+ EC
3+ EC
I + EC
Factor XIII
I+ 1c
I + IC
2+ IC
2+ LC
2+ LC
Tissue plasminogen
Urokinase plasminogen
I + EC
I + EC
1 + EC
I + LC,
1 + IC
Hand (PIP)
5 yrs.
3+ LC,
3+ 1 c
4+ LC,
4+ 1 c
4 + EC,
4 + IC,
4+ LC
3+ LC,
3+ IC
4+ EC,
4+ IC,
4+ LC
2+ LC,
2+ IC
I + EC
>20 yrs.
2+ LC,
2+ IC
4 + LC,
4 + IC
4+ EC,
4 + IC,
4+ LC
4+ LC
I + EC
1+ IC,
3+ EC
2+ IC
1 + LC,
1+ EC
>I0 yrs.
3+ LC,
3+ IC
4 + LC,
3+ IC
4 + EC,
4 + IC,
4+ LC
2+ LC,
2+ IC
4 + EC,
4+ IC,
4+ LC
3 + LC,
3+ IC
I + IC,
f EC
4 + EC,
4 + IC,
4+ LC
3+ LC,
3+ IC
Tissue factor
Hand (PIP)
20 yrs.
I + LC,
I + 1c
I + LC,
I + IC
3+ EC
< 1 mo.
1 + LC,
I + IC
1 + LC,
1 + IC
1 + LC
Fibrin D dimer
t LC
Tissue transglutaminase
Inflammation score
Joint assessed
Disease duration
CD14 (Leu-M3)
cu,-plasmin inhibitor
t IC
I + LC, 4 + LC,
3 + IC
I + 1c
1 + EC 3+ EC,
1 + IC
4 + EC,
4+ IC,
4+ LC
4+ LC,
4 + IC
t EC
* The inflammation scores, based on immunohistologic examination, were derived as described elsewhere (27,28). Other scores were based on
immunofluorescence intensity, using a scale of W + ,where 0 = negative and 4+ = greatest intensity. PIP = proximal interphalangeal; Acet.
= acetaminophen; ASA = acetylsalicylic acid; IAS = intraarticular steroid; NSAID = nonsteroidal antiinflammatory drug; MTX =
methotrexate; Pred. = prednisone; LC = lining cells; 1C = interstitial cells; EC = endothelial cells.
actions), extravascular fibrin formation is prominent
( 3 3 ) . Coagulation is apparently initiated by tissue
factor (TF; thromboplastin) that is expressed on macrophages, endothelial cells, and/or fibroblasts (6,7),
resulting in activation of the extrinsic pathway of
coagulation with eventual formation of fibrin from
fibrinogen. Fibrin can be cross-linked by transglutaminases (factor XI11 or tissue transglutaminase [TTG])
to form a relatively stable, insoluble meshwork of
covalently cross-linked fibrin (8), and the fibrin can be
further modified by attachment of various components
of the biomatrix and/or by degradation by plasmin
(9-11). Products of the coagulation reactions act to
amplify the inflammatory reaction by attracting more
inflammatory cells to the site through the chemotactic
activities of thrombin (12) and fibrin(ogen) degradation
products (13). Also, the extravascular fibrin meshwork
serves as a provisional matrix onto which inflammatory and endothelial cells can adhere and migrate (5).
In addition to other numerous different functions, macrophages are known to elaborate/express
several different enzymedfactors involved in the formation and dissolution of fibrin. Included are TF
(7,14), prothrombinase (15), factor XI11 (16), TTG
(16), and plasminogen activators (urokinase [uPA])
(17). The purpose of this study was to determine (using
immunohistologic techniques) the presence and distribution of several different procoagulant and anticoagulant molecules in tissues from patients who had
trauma necessitating joint surgery, and from patients
with severe osteoarthritis (OA) and RA requiring joint
surgery. The results demonstrate that RA synovium
has increased numbers of macrophages and increased
expression/content of fibrinogen, TF, factor XIII,
TTG, cross-linked fibrin (fibrin D dimer), uPA, and
a,-plasmin inhibitor (a2-PI).
Specimens of sterile human synovial tissue were
obtained from the Duke University Department of Pathology
as “discarded material.” The subjects were those requiring
joint surgery/resection for recent severe trauma or severe
RA or OA. RA and OA were diagnosed by standard criteria
(18). The patients’ records were reviewed to determine
disease duration, medications, and a clinical estimate of
disease activity at the time of the surgery. All OA and RA
patients had advanced disease. Although the “trauma”
samples approximated normal samples most closely, we did
not consider them actually normal because of tissue damage,
hemarthrosis, etc. Synovial samples (-5 X 5 X 5 mm) were
frozen rapidly in liquid nitrogen. Serial, 4 mm-thick, frozen
sections were made and analyzed after staining with hematoxylin and eosin (H & E) and by indirect immunofluorescence techniques after staining as described previously (19).
After H & E staining, synovial tissue samples were scored
(in a blinded manner) for the degree of inflammation as
described elsewhere (20).
For immunofluorescence studies, the following primary antibodies were used: Leu-M3 (mouse monoclonal
anti-CD14, macrophage) (21), rabbit anti-human fibrinogen
(Dakopatts, Copenhagen, Denmark), mouse monoclonal
Al-3 (anti-human brain TF) (22), rabbit anti-human factor
XI11 a chain (Calbiochem, La Jolla, CA) (16), mouse monoclonal anti-guinea pig TTG (23), DD386/22 (mouse monoclonal anti-human fibrin D-dimer) (24), rabbit anti-human uPA
and rabbit anti-human tissue PA (tPA; from Dr. H . Berger,
Jr., Burroughs Wellcome, Research Triangle Park, NC) (25),
and rabbit anti-human a,-PI (American Diagnostica, New
York, NY) (26). Secondary antibodies were fluorescein
isothiocyanate (F1TC)-conjugated goat anti-mouse immunoglobulin and FITC-conjugated goat anti-rabbit immunoglobulin (Tago, Burlingame, CA). Anti-fibrinogen reacts with
both fibrinogen and fibrin. Otherwise, the primary antibodies
are specific for the designated antigens, as determined by
immunoblots and/or immunoprecipitations detailed elsewhere (21-26).
The tissues were examined with the use of a Zeiss
microscope using epifluorescence and phase-contrast optics.
Controls, in which supernatant from mouse myeloma P3
cells or normal rabbit serum was used as primary “antibody” (instead of the primary antibodies designated above),
showed no reactivity with the appropriate secondary
Macrophages, as determined by CD14 expression (21), were present in low numbers scattered in the
interstitium and in the lining cell areas of synovium
from trauma and OA patients (Table 1). As others have
noted from immunohistologic studies (27) and as we
have seen from our studies quantitating macrophages
in enzymatically dissociated synovial tissues (28), RA
synovium had more lining cell and interstitial area
macrophages than did trauma or OA synovium. Fibrinogen was distributed throughout the synovial tissue in all of the samples we examined, being most
prominent in the areas lining the synovial space. There
was more fibrinogen apparent in the tissues from RA
patients, with increased staining in the interstitial
Tissue factor, or tissue thromboplastin, was
seen primarily in association with vessels (especially
with or near endothelial cells) in trauma and OA
synovium. In synovium from RA patients, there was a
marked increase in TF in all areas of the tissue
(vessels, interstitiurn, and lining cell areas) (Figure
1A). When the tissues were examined with antibody
DD386/22, an antibody that recognizes fibrin D dimer
(a product of fibrin that has been cross-linked by a
transglutaminase [TTG or factor XIII], and then partially degraded by plasmin [24]), tissue from trauma
and OA patients had very little positivity. The only
positive cells were in the synovial lining cell areas
(Figure 1B). However, the RA synovial tissues expressed much more fibrin D dimer in the synovial
lining areas, as well as in the interstitium (Figure 1B).
The enzymes capable of cross-linking fibrin are
TTG and factor XI11 (8,16). Factor XI11 is produced by
megakaryocytes (platelets) and mononuclear phagocytes, while TTG is produced by endothelial cells and
mononuclear phagocytes (8,16). TTG was not seen or
was seen only in very low amounts in synovium from
trauma patients (Figure 2A). In OA patient synovium,
TTG was present in very low amounts, being limited
primarily to vessels (mainly endothelial cells), but in
RA synovium, TTG expression was dramatically increased in the tissues (vessels, lining cell areas, and
interstitial areas) (Figure 2A). Factor XIII was noted
in low amounts scattered in the synovial interstitium of
trauma patients (Figure 2B). In OA synovium, there
was slightly more factor XIII, primarily in the synovial
lining cell areas, but in RA synovium, the amount was
markedly increased and present in vessels, lining cell
areas, and in the interstitium (Figure 2B).
Once fibrin is formed, it can be degraded by
plasmin. Plasmin is formed by the action of plasminogen activator on the proenzyme plasminogen (1 1).
Urokinase-type plasminogen activator is found primarily in mononuclear phagocytes (11,17), while tissuetype plasminogen activator is found primarily in endothelial cells (1 1). By immunofluorescence, tPA was not
seen or was seen only in small amounts in the endothelial cell areas of tissue from patients with trauma,
OA, and RA (Table 1). Urokinase-type PA was not
seen in synovium from trauma patients, but it was
present in synovium from OA patients, primarily in the
synovial lining cell areas (macrophage areas) (Figure
3A). In synovium from RA patients, the amount of
uPA was dramatically increased, being seen in vessels,
Figure 1. Expression of A, tissue factor and B, fibrin D-dimer in synovial tissue from trauma (“normal”) patients, osteoarthritis (OA) patients,
and rheumatoid arthritis (RA) patients, by phase-contrast microscopy (top panels) and fluorescence microscopy (bottom panels). In tissue from
trauma and OA patients, tissue factor is seen primarily in the vessels (endothelial cells), but in the synovium from the RA patient, tissue factor
is increased and is seen in essentially all areas. Fibrin D-dimer is seen in small amounts and is limited to the lining cell areas of synovium from
trauma and OA patients, but in synovium from the RA patient, there is increased content of fibrin D-dimer, and it is present in the interstitial
cell area as well as the lining cell area. (Magnification x 400.)
Figure 2. Expression of A, tissue transglutaminase and B, factor XI11 in synovial tissue from trauma (“normal”) patients, osteoarthritis (OA)
patients, and rheumatoid arthritis (RA) patients, by phase-contrast microscopy (top panels) and fluorescence microscopy (bottom panels).
Tissue transglutaminase is present only in scant amounts in tissue from trauma and OA patients, being limited primarily to the vessel areas,
but in RA synovium, there is an increased amount, which is distributed throughout the tissue. Factor XI11 is present in increased amounts and
spread diffusely throughout the RA synovium. (Magnification x 400.)
Figure 3. Expression of plasminogen activator (urokinase) in synovial tissue from trauma (“normal”) patients, osteoarthritis (OA)
patients, and rheumatoid arthritis (RA) patients, by phase-contrast microscopy (top panel) and fluorescence microscopy (bottom
panel). Urokinase is present in small amounts in synovia from trauma and OA patients, being seen primarily in the lining cell areas.
However, in RA synovium, there is an increased amount, which is distributed throughout the tissue. (Magnification x 400.)
as well as in the lining cell and interstitial areas (Figure
3). The primary inhibitor of plasmin is a2-PI (29).
There was no (or very little) a,-PI in trauma or OA
tissue, but it was increased in RA synovium, being
distributed generally throughout the synovium. Table
1 displays the immunofluorescence, histologic, and
inflammation scores, and clinical data.
Thus, in summary, synovial tissues from RA
patients have increased numbers of macrophages,
increased amounts of fibrinogen, TF, fibrin D dimer,
TTG, factor XIII, uPA, and az-PI. This suggests that
in inflamed synovium, there is ongoing extravascular
tissue fibrin formation and dissolution that correlates
with the degree of inflammation and the macrophage
By interacting with B and T lymphocytes and
through their secretion of numerous substances that
affect the function of other cells, mononuclear phagocytes are thought to play very important roles in RA
(2,28,30). Among the important macrophage-derived
mediators are chemotactic factors (e.g., macrophage-
colony-stimulating factor [313 and interleukin-8 [32]),
complement components, growth factors (macrophage
[platelet]-derived growth factor, interleukin- 1, tumor
necrosis factor [TNF], T cell growth factor p), angiogenesis factors, arachidonic acid metabolites, reactive
oxygen species, and various hydrolases and proteinases (including collagenases) (30). In addition to this
array of important mediators, macrophages also produce various factors that can modulate the overall
clotting process (the formation and dissolution of
fibrin). Monocytes and/or macrophages have been
shown to produce TF (14), factor VII (33), factor V
(34), a prothrombinase complex (15), factor XIII (16),
TTG (16), uPA (17), and a,-macroglobulin (35). Also,
other cells in the synovium (fibroblasts and endothelial
cells) can produce TF, TTG, and plasminogen activators. Because of the increased vascular permeability in
the inflamed tissue, there are high tissue levels of
various plasma proteins in synovial tissues.
Increased levels of fibrin and fibrin-like materials are present in synovial fluid and synovial tissue of
RA patients (3,4). The “rice bodies” seen in RA
synovial fluid are composed of fibrin (3). Anderson and
Gormsen noted that the fibrin found in RA synovium
was insoluble in urea, signifying that it had probably
been chemically cross-linked by a transglutaminase
(36). Different investigators have shown that synovial
tissues from arthritis patients have fibrinolytic activities (37), and that synovial macrophages and fibroblasts
display plasminogen activator/plasmin activity (38).
Extravascular coagulation is a prominent feature in immunologically induced inflammation (e.g.,
delayed-type hypersensitivity reactions, Arthus reactions, and experimental glomerulonephritides), in
wound healing, and in tumors (5,39). In these conditions, a variety of factors may be operative in causing
the fibrin formation. In tumors, the neoplastic cells can
supply procoagulant factors (most prominently T F
[39,40]), while in immunologically induced inflammation and in healing wounds, macrophages, fibroblasts,
and/or endothelial cells may supply procoagulants (5).
Products of the coagulation reactions can amplify the
inflammation-thrombin and fibrin(ogen) degradation
products are chemotactic and may modify the function
of inflammatory cells (5,12,13), transglutaminases may
chemically cross-link bioactive molecules (e.g., a,-PI
or fibronectin [9,11]) to biomatrix, and plasmin may
modify the biomatrix and activate proteinases, including collagenase (41). Furthermore, fibrin contributes to
the mass (swelling) of the inflammatory tissue, and
serves as an important part of the provisional matrix
onto which fibroblasts and inflammatory cells attach
and migrate (5,39).
Our work definitively demonstrates that inflammatory synovium from humans with RA has much
fibrin accumulation. This could result from increased
formation and/or decreased dissolution. Tissue factor
in the trauma and OA tissues was seen in small
amounts, being restricted primarily to the endothelial
cell areas, but in RA tissues, it was dramatically
increased, being seen in all areas. Because of the
distribution of T F in the RA synovia, it appears that
T F is increased in macrophages, fibroblasts, and endothelial cells. Others have noted that TF is usually
not expressed in normal endothelial cells (42,43),
except for small amounts in placental vessels (44). We
did see TF in endothelial cells in the synovial samples
from trauma patients, as well as in those from OA and
RA patients. It should be noted, however, that these
trauma patients could not be considered actually normal because of various degrees of tissue damage and
hemarthrosis in these subjects. It has been found that
RA synovial fluid and synovium contain increased
amounts of T N F (45); this may be important in ex-
plaining the increased levels that we demonstrate,
since T N F can increase T F expression in endothelial
cells and in mononuclear phagocytes (46,47).
Previous immunohistologic studies of RA synovium characterizing fibrin have not used antibodies
that could clearly distinguish between fibrinogen and
fibrin (4), but the antibody against fibrin D dimer
demonstrates well that true fibrin is being formed in
the synovial tissue, is being cross-linked, and is being
acted upon (to a limited degree) by plasmin (24). The
RA tissues contained high levels of fibrin D dimer, as
compared with trauma and OA tissues. Remarkably,
the transglutaminases TTG and factor XI11 were also
increased in the RA tissues, providing the ability to
cross-link the fibrin. We have noted before that tissue
macrophages have more transglutaminase activity
than do blood monocytes, and that blood monocytes,
after in vitro “differentiation,” have more transglutaminase activity (16). The finding of increased levels
of TTG and factor XI11 in the RA synovial tissues may
reflect the degree of cellular “differentiation” that has
taken place in the RA synovial tissue.
While tPA levels were not appreciably different
in the synovia of trauma, OA, and RA patients, uPA
was dramatically increased in all areas of the RA
synovial tissue. This finding of increased plasminogen
activator activity in RA tissues correlates with that
noted previously by other investigators (37,38). Cytokines (most notably, interferon- y [48]) have been
shown to increase plasminogen activator levels in
blood monocytes. Interferon-y (protein or messenger
RNA) has been noted to be increased in RA synovial
fluid and synovium (30,49). Other cytokines in the fluid
(e.g., the colony-stimulating factors [SO]) may also
play a role in controlling the expression of plasminogen activator. The significance of the rather selective
increase in uPA compared with levels of TPA is not
The enzymes of the coagulation and fibrinolytic
pathways are regulated by several proteinase inhibitors. Alpha,-macroglobulin, a high molecular weight
proteinase inhibitor of broad specificity, has been
noted in RA synovial fluid and synovial tissue (51,52).
Studies from our laboratory confirm increased levels
in RA synovium (Hoffman M, Weinberg J: unpublished observations). Likewise, we show here that
a,-PI, the most potent plasmin inhibitor (29), is increased in RA synovium. Thus, we have demonstrated
that in the inflamed synovial tissue of RA patients,
there is evidence of increased expression of procoag-
ulant molecules (fibrinogen, TF, TTG, and factor
XIII), increased cross-linked and plasmin-modified
fibrin (fibrin D dimer), and increased anticoagulant
molecules (uPA and q-PI). The remarkable coagulation/anticoagulation, fibrin formatioddegradation activity noted in RA synovium likely contributes to the
local pathology and, through the actions of various
generated enzymes, lymphokines, monokines, and fibrin
degradatory products, perpetuates the inflammation.
This extravascular coagulation/fibrinolysis in
RA represents a target for therapeutic intervention. It
has been noted that anticoagulant therapy can modify
immunologically mediated inflammation in experimental animals and in humans. Warfarin and heparin
anticoagulant treatments have been shown to diminish
delayed-type hypersensitivity reactions ( 3,5) and experimental nephritis in animals (53,54). Defibrination
with the snake venom enzyme ancrod has been noted
to diminish the degree of experimental nephritis in
animals ( 5 3 , systemic lupus erythematosus in animals
(56), and glomerulonephritis in humans (57), disorders
characterized by prominent extravascular fibrin deposition. Belch et a1 noted that the androgen stanolozol
improved the inflammation in RA, and that this reduction of inflammation was accompanied by an increase
in the plasma fibrinolytic activity (58). It is possible
that agents capable of decreasing extravascular fibrin
formation and dissolution might be useful in ameliorating or diminishing the synovitis in RA.
We thank Dr. Frederick Rickles for the anti-tissue
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fibrin, patients, extravascular, formation, arthritis, osteoarthritis, tissue, synovial, dissolution, rheumatoid
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