The guideline group was selected to be representative of UKbased medical experts. MEDLINE and EMBASE were searched systematically for publications in English, using the keywords: thrombotic thrombocytopenia purpura (TTP), AD-AMTS13, plasma exchange (PEX) and relevant key words related to the subsections of this guideline. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the BCSH. The guideline was then reviewed by a sounding board of British haematologists, the BCSH and the British Society for Haematology

Hydrogen sulfide (H₂S) is a gaseous mediator synthesized from cysteine by cystathionine γ lyase (CSE) and other naturally occurring enzymes. Pharmacological experiments using H₂S donors and genetic experiments using CSE knockout mice suggest important roles for this vasodilator gas in the regulation of blood vessel caliber, cardiac response to ischemia/reperfusion injury, and inflammation. That H₂S inhibits cytochrome c oxidase and reduces cell energy production has been known for many decades, but more recently, a number of additional pharmacological targets for this gas have been identified. H₂S activates K(ATP) and transient receptor potential (TRP) channels but usually inhibits big conductance Ca²(+)-sensitive K(+) (BK(Ca)) channels, T-type calcium channels, and M-type calcium channels. H₂S may inhibit or activate NF-κB nuclear translocation while affecting the activity of numerous kinases including p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), and Akt. These disparate effects may be secondary to the well-known reducing activity of H₂S and/or its ability to promote sulfhydration of protein cysteine moieties within the cell.

The role of hydrogen sulfide (H 2 S) in inflammation is controversial, with both pro-and antiinflammatory effects documented. Many studies have used simple sulfide salts as the source of H 2 S, which give a rapid bolus of H 2 S in aqueous solutions and thus do not accurately reflect the enzymatic generation of H 2 S. We therefore compared the effects of sodium hydrosulfide and a novel slow-releasing H 2 S donor (GYY4137) on the release of pro-and antiinflammatory mediators in lipopolysaccharide (LPS)-treated murine RAW264.7 macrophages. For the first time, we show that GYY4137 significantly and concentration-dependently inhibits LPS-induced release of proinflammatory mediators such as IL-1b, IL-6, TNF-a, nitric oxide ( NO), and PGE 2 but increased the synthesis of the antiinflammatory chemokine IL-10 through NF-kB=ATF-2=HSP-27-dependent pathways. In contrast, NaHS elicited a biphasic effect on proinflammatory mediators and, at high concentrations, increased the synthesis of IL-1b, IL-6, NO, PGE 2 and TNF-a. This study clearly shows that the effects of H 2 S on the inflammatory process are complex and dependent not only on H 2 S concentration but also on the rate of H 2 S generation. This study may also explain some of the apparent discrepancies in the literature regarding the pro-versus antiinflammatory role of H 2 S.

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