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From www.bloodjournal.org by guest on June 15, 2017. For personal use only. 4. Ratner L, Lee J, Tang S, et al; AIDS Malignancy Consortium. Chemotherapy for human immunodeficiency virus-associated non-Hodgkin’s lymphoma in combination with highly active antiretroviral therapy. J Clin Oncol. 2001;19(8):2171-2178. 5. Little RF, Pittaluga S, Grant N, et al. Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. Blood. 2003;101(12):4653-4659. 6. Levine AM, Noy A, Lee JY, et al. Pegylated liposomal doxorubicin, rituximab, cyclophosphamide, vincristine, and prednisone in AIDS-related lymphoma: AIDS Malignancy Consortium Study 047. J Clin Oncol. 2013;31(1):58-64. 7. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235-242. 8. Kaplan LD, Lee JY, Ambinder RF, et al. Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies Consortium Trial 010. Blood. 2005; 106(5):1538-1543. 9. Sparano JA, Lee JY, Kaplan LD, et al; AIDS Malignancy Consortium. Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma. Blood. 2010;115(15):3008-3016. 10. Mounier N, Spina M, Gabarre J, et al. AIDS-related non-Hodgkin lymphoma: final analysis of 485 patients treated with risk-adapted intensive chemotherapy. Blood. 2006;107(10):3832-3840. © 2013 by The American Society of Hematology l l l PLATELETS & THROMBOPOIESIS Comment on Kasahara et al, page 3340 Factor XIII: sticking it to platelets ----------------------------------------------------------------------------------------------------Adam D. Munday1 and José A. López1 1 PUGET SOUND BLOOD CENTER RESEARCH INSTITUTE In this issue of Blood, Kasahara et al report that platelet-dependent clot retraction requires factor XIII (FXIII), which covalently associates fibrin polymers with protein located within the platelet plasma membrane at lipid rafts.1 T he formation of hemostatic clots begins with deposition of platelets in the area of vascular injury. The activated platelets adhere to each other, with fibrinogen and von Willebrand factor serving as intermediaries, and provide a surface for the assembly Schematic representation of translocation of fibrin to lipid rafts. On platelet activation, fibrin(ogen) binds to integrin aIIbb3. In the presence of FXIII, the aIIbb3-finbrin(ogen) complex translocates to SM-rich rafts. FXIIIa crosslinks fibrin fibrils to each other and covalently links fibrin to aIIbb3 and possibly other, as yet unidentified, receptors. Concurrently, translocation of cFXIII to the lipid raft–associated actin cytoskeleton would promote crosslinking of receptor cytoplasmic domains to the cytoskeleton. Together, FXIII-dependent crosslinking would cement extracellular fibrin cables to the intracellular platelet cytosolic motors to promote clot retraction. 3246 of coagulation complexes that produce thrombin, which catalyzes the formation of fibrin polymers from fibrinogen. After the clot forms, it retracts to consolidate volume and minimize leakage, a process during which platelets pull on the fibrin polymers. The thrombin generated on the platelet surface also converts plasma FXIII to its active form FXIIIa. FXIII is a member of the transglutaminase family of enzymes, which crosslink proteins by catalyzing the formation of isopeptide bonds between glutamine and lysine residues.2 FXIII has two forms: a plasma form (pFXIII) that is a tetramer of two carrier B-subunits and two catalytic A-subunits3 and an intracellular form (cFXIII) that consists of two catalytic A-subunits. pFXIII circulates as a zymogen that must be activated by thrombin; cFXIII is constitutively active.2 FXIIIa crosslinks not only fibrin, but also crosslinks a2 antiplasmin to fibrin (which inhibits clot lysis) and fibronectin to fibrin. FXIII also has other substrates, which include factor V, Plasminogen activator inhibitor-2, collagen, and the intracellular proteins filamin, actin, and myosin. The importance of FXIII is underscored by the clinical signs and symptoms of its deficiency. Clots formed in the absence of FXIII are unstable and easier to lyse by the fibrinolytic system, the consequence being delayed bleeding after injury or surgery. Affected individuals also experience delayed wound healing, possibly due to the inability of clots to retract properly. In affected women, habitual abortion is common, most likely due to combined abrogation of fibrin/fibronectin crosslinking by FXIII and impairment of firm adhesion of the placenta to the endometrium. Clot retraction requires both platelets and fibrin. Platelets anchor fibrin to their surface and intracellular motors act as a winch to contract the polymerized fibrin fibers. Integrin aIIbb3 on platelets is required to retract clots, because patients with Glanzmann thrombasthenia, who lack the receptor, exhibit defective clot retraction. In mice, FXIII has also been shown to be necessary.4 Using elegant microscopy and biochemical approaches, Kasahara et al show for the first time that fibrin associates with lipid rafts on the platelet surface and that raft integrity is required for clot retraction; raft disruption with methyl-b-cyclodextrin (which removes membrane cholesterol) prevented fibrin BLOOD, 7 NOVEMBER 2013 x VOLUME 122, NUMBER 19 From www.bloodjournal.org by guest on June 15, 2017. For personal use only. association and clot retraction. Using raftspecific affinity labels, they demonstrated that fibrin associates with a subset of lipid rafts that are rich in sphingomyelin (SM) (as opposed to the cholesterol-rich raft population). Platelets from mice lacking either of the enzymes that synthesize sphingomyelin retracted clots poorly. Previous studies have implicated both pFXIII and cFXIII in fibrin association with the platelet surface on thrombin receptor activation.5 Here, Kasahara et al demonstrate that FXIII is required for translocation of fibrin to SM-rich rafts and that this fibrin is a substrate for FXIII. The translocation required the g-chain of fibrin: a recombinant g-chain fusion protein bound to rafts in a FXIII-dependent manner in thrombinactivated platelets. Covalent crosslinking was required for this association because mutating the FXIII crosslinking sites prevented association of the g-chain fusion protein with rafts, as did the transglutaminase inhibitor cystamine. These results point to a novel 2-step mechanism whereby fibrin(ogen) binds to integrin aIIbb3, translocates to SM-rich lipid rafts in a FXIII-dependent manner, and covalently associates with an as yet unidentified receptor. Considered in light of the data indicating that cFXIII translocates to the cytoskeleton of activated platelets6 (which in activated platelets attaches to lipid rafts7), a mechanism emerges whereby, within SM-rich rafts, FXIII crosslinks cytoskeletal and motor elements to promote force transduction from the platelet interior (see figure). The raft-associated fibrin is crosslinked to an unknown receptor (one candidate being avb3), which itself might be crosslinked to the cytoskeleton on the cytoplasmic side to allow the strongest possible linkage between the cytosolic motors and the extracellular cables they tug on to retract the clot. Lack of FXIII would not only be expected to increase fibrin clot lysis, it could also impair that ability of the fibrin to attach to the underlying platelets. These findings also suggest that changes in lipid raft structure or organization could alter clot retraction and impair wound healing. As with many thought-provoking papers, the current paper raises many new questions and opens new areas of research. These include the following. What is the receptor for fibrin within the SM-rich rafts? Is this mechanism specific for thrombin-activated platelets or is it applicable to platelet activation by other agonists? Is there a role for cFXIII-mediated crosslinking of intracellular proteins within lipid rafts? What effect does this crosslinking have on the platelets’ ability to generate contractile forces? Answers to these and other questions will provide further insight into the clinical signs and symptoms of FXIII deficiency. Conflict-of-interest disclosure: The authors declare no competing financial interests. n REFERENCES 1. Kasahara K, Kaneda M, Miki T, et al. Clot retraction is mediated by factor XIII-dependent fibrin-aIIbb3-myosin axis in platelet sphingomyelin-rich membrane rafts. Blood. 2013;122(19):3340-3348. 2. Muszbek L, Yee VC, Hevessy Z. Blood coagulation factor XIII: structure and function. Thromb Res. 1999;94(5):271-305. 3. Lorand L. Factor XIII and the clotting of fibrinogen: from basic research to medicine. J Thromb Haemost. 2005; 3(7):1337-1348. 4. Kasahara K, Souri M, Kaneda M, Miki T, Yamamoto N, Ichinose A. Impaired clot retraction in factor XIII A subunit-deficient mice. Blood. 2010;115(6):1277-1279. 5. Jayo A, Conde I, Lastres P, Jiménez-Yuste V, González-Manchón C. New insights into the expression and role of platelet factor XIII-A. J Thromb Haemost. 2009; 7(7):1184-1191. 6. Serrano K, Devine DV. Intracellular factor XIII crosslinks platelet cytoskeletal elements upon platelet activation. Thromb Haemost. 2002;88(2):315-320. 7. Munday AD, Gaus K, López JA. The platelet glycoprotein Ib-IX-V complex anchors lipid rafts to the membrane skeleton: implications for activation-dependent cytoskeletal translocation of signaling molecules. J Thromb Haemost. 2010;8(1):163-172. © 2013 by The American Society of Hematology l l l PLATELETS & THROMBOPOIESIS Comment on Kahr et al, page 3349 a-Granules at the BEACH ----------------------------------------------------------------------------------------------------Sidney W. Whiteheart1 1 UNIVERSITY OF KENTUCKY COLLEGE OF MEDICINE In this issue of Blood, Kahr et al report the description of a mouse model lacking the Nbeal2 protein and demonstrate its utility in the study of a-granule biogenesis and megakaryocyte development in gray platelet syndrome (GPS).1 G PS (Mendelian Inheritance in Man [MIM] 139090) was first identified by Raccuglia in 1971.2 The first patient, an 11-year-old boy, presented with thrombocytopenia and platelets that had a “peculiar gray color” on Wright-stained blood smears. Analysis showed that these platelets lacked a class of granules that are now known as a-granules. GPS is a rare autosomal recessive disorder associated with macrothrombocytopenia, splenomegaly, myelofibrosis, increased serum B12, and mildto-moderate bleeding tendencies.3 Although fatal in some cases, in other cases, patients have lived into their 7th decade. However, where data are available, it seems that GPS is progressive, because the thrombocytopenia and myelofibrosis worsen with age. Additionally, there is evidence that genetic modifiers affect disease outcomes. Individuals with identical mutations, but from different families, have discordant disease severities.4 The mouse strain reported by Kahr et al1 BLOOD, 7 NOVEMBER 2013 x VOLUME 122, NUMBER 19 and also by Deppermann et al5 represents the first animal model for GPS. The causative gene for GPS was identified on chromosome 3p by 3 groups in 2011.4,6,7 These studies showed that mutations in the coding region of the neurobeachin-like 2 (NBEAL2) gene correlated with GPS in humans. Nbeal2 is a member of a family of proteins known as BEACH–domain-containing proteins (BDCP).8 The BEACH domain gained its name because the charter family member—LYST/CHS1 (lysosomal trafficking regulatory/Chediak-Higashi syndrome 1 protein), defective in the beige mouse and in human Chediak-Higashi syndrome (MIM 214500)—contained this unusual ;300 amino acid domain.9 This domain has a unique peptide-backbone fold, in that its core does not assume regular secondary structures.10 The highly conserved BEACH domain has now been identified in 9 human proteins and in numerous species.8 Most members of this family of generally high molecular weight proteins contain 3247 From www.bloodjournal.org by guest on June 15, 2017. For personal use only. 2013 122: 3246-3247 doi:10.1182/blood-2013-09-526426 Factor XIII: sticking it to platelets Adam D. Munday and José A. López Updated information and services can be found at: http://www.bloodjournal.org/content/122/19/3246.full.html Articles on similar topics can be found in the following Blood collections Free Research Articles (4527 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.