In addition to their pivotal role in thrombosis and wound repair, platelets participate in inflammatory responses. We investigated the role of platelets in the autoimmune disease rheumatoid arthritis. We identified platelet microparticles—submicrometer vesicles elaborated by activated platelets—in joint fluid from patients with rheumatoid arthritis and other forms of inflammatory arthritis, but not in joint fluid from patients with osteoarthritis. Platelet microparticles were proinflammatory, eliciting cytokine responses from synovial fibroblasts via interleukin-1. Consistent with these findings, depletion of platelets attenuated murine inflammatory arthritis. Using both pharmacologic and genetic approaches, we identified the collagen receptor glycoprotein VI as a key trigger for platelet microparticle generation in arthritis pathophysiology. Thus, these findings demonstrate a previously unappreciated role for platelets and their activation-induced microparticles in inflammatory joint diseases.

The serpins (serine proteinase inhibitors) are a superfamily of proteins (350 -500 amino acids in size) that fold into a conserved structure and employ a unique suicide substrate-like inhibitory mechanism. The serpins were last reviewed in 1994 (1). More recent studies show: 1) an expanded distribution within the kingdoms of metazoa and plantae, as well as certain viruses, 2) a surprising effect on the covalently bound target proteinase, and 3) novel biochemical and biological functions.Most serpins inhibit serine proteinases of the chymotrypsin family. However, cross-class inhibitors have been identified. The viral serpin CrmA and, to a lesser extent, PI9 (SERPINB9) inhibit the cysteine proteinase, caspase 1 (2), and SCCA1

The role of platelets in hemostasis is to produce a plug to arrest bleeding. During thrombocytopenia, spontaneous bleeding is seen in some patients but not in others; the reason for this is unknown. Here, we subjected thrombocytopenic mice to models of dermatitis, stroke, and lung inflammation. The mice showed massive hemorrhage that was limited to the area of inflammation and was not observed in uninflamed thrombocytopenic mice. Endotoxin-induced lung inflammation during thrombocytopenia triggered substantial intraalveolar hemorrhage leading to profound anemia and respiratory distress.By imaging the cutaneous Arthus reaction through a skin window, we observed in real time the loss of vascular integrity and the kinetics of skin hemorrhage in thrombocytopenic mice. Bleeding-observed mostly from venulesoccurred as early as 20 minutes after challenge, pointing to a continuous need for platelets to maintain vascular integrity in inflamed microcirculation. IntroductionInflammation and hemostasis are tightly intertwined. In particular, this is becoming very evident in platelet biology. While the classical role of platelets is to mediate hemostatic plug formation, it has been demonstrated that platelets also play an important role in inflammation. For example, previous studies show that platelets promote inflammatory responses in atherosclerosis, in hepatitis, and after cerebral ischemia. 1-4 Furthermore, early in inflammation prothrombotic functions of platelets are reduced, 5 and activated platelets are capable of up-regulating inflammatory molecules on the endothelium. 6,7 Recently, our group showed that in angiogenesis-which is strongly linked to inflammation 8 -platelets play an important role in preventing hemorrhage of sprouting vessels. 9 That platelets support vascular integrity during injury is well established. Early studies also demonstrated a supportive role for platelets during organ perfusion with buffers 10,11 and growthpromoting effects on endothelial cultures. 12 Whether platelets have a supportive role in inflamed microcirculation still remains experimentally unexplored.In humans, profound thrombocytopenia is found, for example, in patients suffering from idiopathic thrombocytopenic purpura. Interestingly, in the absence of injury, some patients bleed while others do not show spontaneous bleeding despite equally low platelet counts. 13 Thus, thrombocytopenia alone cannot explain this phenomenon and other, yet to be defined contributing factors are required to induce bleeding in thrombocytopenic patients, as suggested in a recent review. 14 As thrombocytopenia may lead to life-threatening bleedings, it is important to further understand the cofactors leading to hemorrhage.In the present study, we investigate the effects of inflammation on vascular integrity during thrombocytopenia. We challenged mice in 4 different inflammatory models and observed the affected blood vessels over time in the presence or absence of platelets. We show that thrombocytopenia rapidly induces massive bleeding in inflamed sk...

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