Gregory M. Vercellotti, MD
Dr. Vercellotti indicated no relevant
conflicts of interest.
Boilard E, Nigrovic PA, Larabee K, et al. Platelets
amplify inflammation in arthritis via collagen-dependent microparticle
production. Science. 2010;327:580-83.
last several years, studies in vascular endothelial biology have highlighted
the intricate linkage between inflammation and thrombosis. Inflammatory stimuli
alter the procoagulant and proinflammatory balance in the endothelium to
support development of a matrix for interactions between blood cells and
adhesion molecules which retard bleeding and recruit inflammatory cells. Platelets
promote the chemo-attraction of leukocytes through a variety of molecules,
including platelet activating factor, IL-1 β, soluble CD40 ligand, macrophage
inflammatory protein 1α, RANTES, PDGF, TGF-β, serotonin, PF-4, P-selectin,
etc.1,2 Platelet microparticles released upon activation can promote
thrombosis3 and attract additional leukocytes. Clinically, atherosclerosis best
reflects this biology as postulated by the late Russell Ross.4 However, other
inflammatory conditions including lung disease, Crohn disease/ulcerative
colitis, and rheumatoid arthritis suggest an incendiary role for platelets.
From the laboratory of David Lee at Brigham and Women’s Hospital, Eric Boilard
et al. show that platelets can make ankles in mice with inflammatory arthritis
“red hot.” This amplified response is due to shed platelet microparticles which
stimulate synoviocytes to dump activating cytokines into the joint space.
In clinical studies, the
investigators showed that synovial fluids from rheumatoid arthritis patients
contained 0.2-1.0 micron diameter CD41 (GPIIb) expressing vesicles, while 19/20
osteoarthritic patients had no such particles. Interestingly, no intact
platelets were detected in the synovial fluids;
|Click image to enlarge
seemed to be carrying microparticles into the joint. In a K/BxN serum transfer
mouse model of inflammatory arthritis, platelet depletion, but not blockade of
the ADP receptor P2YR12 by clopidogrel or absence of thromboxane or GPIIb,
cooled the joint flames. Local rather than systemic platelet activation seemed
to play a role as fibroblast-like synoviocytes and their extracellular
matrix-associated proteins triggered microparticle release. Platelet GPVI and
its associated gamma chain of the Fc receptor proved essential in microparticle
release responding to collagen and collagenrelated peptides. Mechanistically,
platelet microparticles could elicit a range of cytokines including IL-6 and
IL-8 from fibroblast-like synoviocytes. The activation of these cells (so
abundant in the rheumatoid pannus) by platelet microparticles was related to
platelet-associated IL-1 (Figure).
This article suggests
that inhibiting platelet GPV1 may be useful in treating rheumatoid arthritis.
One would think that IL-1 antagonism would be very efficacious, but apparently
platelet microparticle-associated IL-1 is difficult to antagonize. As Zimmerman
points out in an accompanying article,5 we usually don’t think about platelets
playing a significant role in rheumatoid arthritis. Since intact platelets are
not found in the rheumatoid arthritis joint space, how do the microparticles
get there? Could they be hitchhiking on transmigrating white cells? Boilard et
al. propose that platelets release infiltrating microparticles after GPVI
activation when they contact collagen. The microparticles enter the joint space
via fenestrations in permeable subsynovial capillaries (Figure). This
manuscript adds to the evidence for the critical role of platelets in
inflammation and spurs me to speculate whether excessive platelet transfusions
may be providing kindling for inflammatory fires in our thrombocytopenic
- Wagner DD, Burger PC. Platelets
in inflammation and thrombosis. Arterioscler Thromb Vasc Biol. 2003;23:2131-37.
- May AE, Seizer P, Gawaz
inflammatory firebugs of vascular walls. Arterioscler Thromb Vasc Biol.
- Ando M, Iwata A, Ozeki
Y, et al. Circulating
platelet-derived microparticles with procoagulant activity may be a potential
cause of thrombosis in uremic patients. Kidney Int. 2002;62:1757-63.
- Ross R. Atherosclerosis
— an inflammatory disease. N Engl J Med. 1999;340:115-26.
- Zimmerman GA, Weyrich
AS. Arsonists in rheumatoid arthritis. Science. 2010;327:528-29.
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