From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
patients in these 2 groups (scenarios 1 and 2) will subsequently experience thrombosis? How can we identify them so as to prevent these thrombotic events? There are still no evidence-based answers for these questions. The general approach for such patients is to eliminate the secondary risk factors for thrombosis, such as obesity and smoking, and recommend antithrombotic prophylaxis in high-risk situations, such as surgery.7 The benefits of low-dose aspirin for primary prevention of thrombosis are still being debated for patients with APS.8 The Euro-Phospholipid Project9 is the biggest prospective study of APS patients, involving 1000 patients with definite APS (as in scenario 3), and has provided important data in terms of the morbidity and mortality of this syndrome. Ninety-three patients (9.3%) died during 10 years of follow-up; the major causes of mortality were thrombosis (36.5% of all deaths), infections (26.9%), and bleeding (10.7%). Survival rates after 5 and 10 years were found to be 94.7% and 90.7%, respectively. In the present study, Gebhart et al prospectively investigated 151 LA-positive patients for a median of 8 years.1 At the beginning of the study, 39 patients had no clinical findings attributed to an autoimmune disease (as in scenario 1), 112 patients were diagnosed with APS, and 29 patients had concomitant systemic lupus erythematosus (as in scenario 3). Thirty patients (20%) experienced thromboembolic events during follow-up; 14 of them were arterial thrombosis. During the study period, 20 patients (13%) died: 10 of thrombosis, 5 of bleeding, and 5 of other causes. The cumulative relative survival rate after 10 years was 79.7%, which is very low compared with both the matched reference normal population and APS cohorts of the Euro-Phospholipid Project. The authors showed that new onset of thrombosis was the strongest predictor of poor prognosis, associated with a sixfold increase in mortality. A poor survival rate was not associated with the presence of aCLs and anti-b2GPI antibodies, prior history of thrombosis or pregnancy complications, or prior diagnosis of an autoimmune rheumatic disease in their cohort.1 Furthermore, a new thrombotic event developed under anticoagulant or antiplatelet therapy in ;75% of the patients. Interestingly, patients receiving anticoagulant and/or antiplatelet therapy showed higher incidences of thrombotic events (23 of 97, 24%) than
3372
patients with no therapy (7 of 54, 13%).1 The Euro-Phospholipid Project also showed similar findings.9 There are several possible explanations for why APS patients who were not receiving antithrombotic therapy had lower thrombosis rates. First, patients who were prescribed antithrombotic therapy may have had additional risk factors for thrombosis and may therefore represent a different high-risk group. Second, the results could indicate that current antithrombotic regimens are not effective or sufficient for preventing thrombosis in APS patients. In both Gebhart’s study and the Euro-Phospholipid Project, some patients experienced thrombosis under therapeutic international normalized ratio [INR] values (INR 2-3). Finally, pathologies other than coagulation activation may also contribute to the development of vascular occlusions in some APS patients, including thrombotic microangiopathy, complement activation, and others. In conclusion, Gebhart et al have clearly shown that the young female patient with LA described above is at increased risk for thrombosis. Our ability to identify higher-risk patients may be improved by better definition of risk factors for thrombosis other than LA and by improved understanding of the unique aspects of the pathophysiology of thrombosis in APS patients. Conflict-of-interest disclosure: The author declares no competing financial interests. n
REFERENCES 1. Gebhart J, Posch F, Koder S, et al. Increased mortality in patients with the lupus anticoagulant: the Vienna Lupus Anticoagulant and Thrombosis Study (LATS). Blood. 2015;125(22):3477-3483. 2. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295-306. 3. Biggioggero M, Meroni PL. The geoepidemiology of the antiphospholipid antibody syndrome. Autoimmun Rev. 2010;9(5):A299-A304. 4. Urbanus RT, Siegerink B, Roest M, Rosendaal FR, de Groot PG, Algra A. Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: a case-control study. Lancet Neurol. 2009;8(11):998-1005. 5. Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood. 2003;101(5):1827-1832. 6. Diz-K¨uçukkaya ¨ R, Hacihanefio˘glu A, Yenerel M, et al. Antiphospholipid antibodies and antiphospholipid syndrome in patients presenting with immune thrombocytopenic purpura: a prospective cohort study. Blood. 2001;98(6):1760-1764. 7. Bertero MT. Primary prevention in antiphospholipid antibody carriers. Lupus. 2012;21(7):751-754. 8. Arnaud L, Mathian A, Ruffatti A, et al. Efficacy of aspirin for the primary prevention of thrombosis in patients with antiphospholipid antibodies: an international and collaborative meta-analysis. Autoimmun Rev. 2014;13(3):281-291. 9. Cervera R, Serrano R, Pons-Estel GJ, et al; on behalf of the Euro-Phospholipid Project Group (European Forum on Antiphospholipid Antibodies). Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients [published online ahead of print January 24, 2014]. Ann Rheum Dis. doi:10.1136/annrheumdis-2013-204838.
© 2015 by The American Society of Hematology
l l l THROMBOSIS AND HEMOSTASIS
Comment on Buchanan et al, page 3484
The first specific antiplatelet antidote ----------------------------------------------------------------------------------------------------David Erlinge
LUND UNIVERSITY
In this issue of Blood, Buchanan and coauthors present the development of a specific antidote for ticagrelor.1 In fact, this is the first specific antidote against any antiplatelet agent.
T
icagrelor is a widely used reversible adenosine 59-diphosphate (ADP) P2Y12 antagonist for treatment of patients with acute coronary syndrome (ACS). In the Platelet Inhibition and Patient Outcomes trial, ticagrelor reduced the combined end point of death from vascular causes, myocardial infarction, or stroke for up to 12 months, and even reduced total mortality.2 However,
patients also experienced increased bleeding events not associated with coronary-artery bypass grafting (CABG). In the recently published Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 trial, patients with a myocardial infarction 1 to 3 years prior to
BLOOD, 28 MAY 2015 x VOLUME 125, NUMBER 22
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
The figure illustrates platelets activated by ADP that aggregate. After treatment with the ADP antagonist ticagrelor, aggregation is limited. If bleeding occurs or the patient needs to undergo urgent surgery, elimination of ticagrelor is currently dependent on liver elimination requiring 3 to 5 days. With the high-affinity Fab ticagrelor antidote, the elimination can be achieved within 30 minutes. After elimination of ticagrelor, the platelets can aggregate in response to ADP again and bleeding can be mitigated. Original magnification 310 400. Professional illustration by Patrick Lane, ScEYEnce Studios.
enrollment were randomized to 2 different doses of ticagrelor vs placebo.3 Even though the study reached its primary end point and demonstrated a significant reduction in ischemic events, this reduction was matched by a similar number of bleeding complications. Furthermore, a patient on ticagrelor cannot undergo urgent CABG or other surgical procedures without increased bleeding risk unless treatment with ticagrelor is interrupted for 3 to 5 days, which increases the risks and causes discomfort for the patient as well as a prolonged hospital stay and higher health care costs. The development of new antithrombotic medications may have reached its end due to an inevitable increase in bleeding complications when new agents are added: the addition of new antithrombotic drugs on top of already established guideline-directed therapies now often results in a neutral balance between ischemic end points and bleeding complications.4,5 Bleeding is associated with increased long-term mortality.6 The explanation for this is complex, with contributing factors including increased anemia, blood transfusions, inflammation,
BLOOD, 28 MAY 2015 x VOLUME 125, NUMBER 22
surgery, and complications due to prolonged hospital care. For bleeding caused by antiplatelet agents, transfusion of platelets may be of some benefit, but specific treatment is not available. The antidote against ticagrelor developed by Buchanan et al is a human antibody antigen-binding fragment (Fab) with a high affinity (20 pM) for both ticagrelor and its active metabolite without binding to ADP or other purines. The design of the Fab was improved by crystallographic determination of the Fab-ticagrelor complex. The markedly higher affinity of the antidote (pM) compared to that of ticagrelor for the P2Y12 receptor (nM) results in elimination of both circulating and P2Y12-receptor–bound ticagrelor. In the study, the antidote reversed the antiplatelet effect of ticagrelor in human platelets in vitro, and rapidly restored ADP-induced aggregation in vivo in mice. Furthermore, the antidote normalized ticagrelor-dependent bleeding in a mouse model of acute surgery. The neutralizing effect had a rapid onset within 30 minutes (see figure). A specific antidote for ticagrelor will be of great value in 2 clinical situations. First, when
a patient suffers a life-threatening bleeding complication, the rapid neutralization of circulating ticagrelor may limit the extent of the bleeding, stabilizing the patient and limiting the long-term risk after a bleeding event. Second, a patient acutely treated with ticagrelor for an ACS who needs urgent CABG could undergo surgery within an hour instead of waiting several days. Similarly, a patient on maintenance therapy may undergo noncardiac emergency surgery with limited bleeding risk. This is the first development of a specific antidote for an antiplatelet agent, fulfilling a long-sought need. For decades, we have used aspirin, clopidogrel, prasugrel, dipyridamol, abciximab, and cilostazol, where the only option for reversal was waiting for systemic elimination of the agent or platelet regeneration, which takes 5 to 10 days. Together with similar developments for newer orally administered anticoagulants such as the antidote idarucizumab for dabigatran,7,8 this represents a new era for antithrombotic drug development. It is possible that regulatory demands will increase for a simultaneous development of antidotes before approving antithrombotic drugs. In fact, a phase III study
3373
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
with available antidote may tip the net balance between anti-ischemic effect and the long-term effects of bleeding complications in a favorable way. It could also be a clinical advantage for newer antiplatelet agents compared to older antiplatelet medications that lack antidotes. The development of a highly specific, rapid, and potent antidote for ticagrelor is an important achievement with great potential to improve patient safety. The findings in human platelets in vitro and in mice models in vivo are promising. However, clinical studies are needed to confirm the effects in humans. Conflict-of-interest disclosure: D.E. has received speaker’s honoraria from AstraZeneca, Eli Lilly, and Boehringer Ingelheim. n REFERENCES 1. Buchanan A, Newton P, Pehrsson S, et al. Structural and functional characterization of a specific antidote for ticagrelor. Blood. 2015;125(22):3484-3490. 2. Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009; 361(11):1045-1057.
3. Bonaca MP, Bhatt DL, Cohen M, et al; PEGASUSTIMI 54 Steering Committee and Investigators. Longterm use of ticagrelor in patients with prior myocardial infarction [published online ahead of print March 14, 2015]. N Engl J Med. doi:10.1056/NEJMoa1500857. 4. Morrow DA, Braunwald E, Bonaca MP, et al; TRA 2P–TIMI 50 Steering Committee and Investigators. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med. 2012;366(15):1404-1413. 5. Mega JL, Braunwald E, Wiviott SD, et al; ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366(1):9-19. 6. Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation. 2006; 114(8):774-782. 7. Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013; 19(4):446-451. 8. Glund S, Moschetti V, Norris S, et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran [published online ahead of print March 19, 2015]. Thromb Haemost. 2015;113(5). doi:10.1160/TH14-12-1080. © 2015 by The American Society of Hematology
l l l TRANSPLANTATION
Comment on Schneidawind et al, page 3491
A party of three: iNKT cells in GVHD prevention ----------------------------------------------------------------------------------------------------Annkristin Heine and Peter Brossart
UNIVERSITY HOSPITAL BONN
In this issue of Blood, Schneidawind et al1 demonstrate that the adoptive transfer of CD41 invariant natural killer T (iNKT) cells from third-party mice protects from lethal graft-versus-host disease (GVHD) through expansion of donor regulatory T cells (Tregs) in a murine model of allogeneic hematopoietic cell transplantation (HCT).
G
VHD is one of the most serious complications after allogeneic HCT.2,3 Although advanced treatment options have been approved and new insight into cellular interactions and immune dysregulation has been gained, GVHD still develops in ;40% to 60% of patients.2 T cells are essential for causing GVHD. These alloreactive donor T cells secrete large amounts of proinflammatory T helper (Th)1-biased cytokines such as interferon g (IFN-g), which results in further T-cell activation and expansion. In contrast, a Th2-directed immune polarization can favor GVDH prevention
3374
(see figure).2 Various attempts have been made to dampen GVHD, such as the use of Tregs that successfully reduce early expansion of alloreactive donor T cells.4 However, Tregs are rare in peripheral blood, and ex vivo expansion is complex and time-consuming. NKT cells are a small subset of lymphocytes that bridge innate immune responses to adaptive immunity. They express several cell surface proteins characteristic for T and NK cells. In general, NKT cells are reactive to lipid antigens presented by CD1d major histocompatibility complex class I–like molecules.5 These CD1d-restricted NKT cells
can be subclassified into at least 2 groups: one using a semi-invariant T-cell receptor (TCR) (iNKT or type I) and one expressing somewhat more diverse TCRs (type II NKT). Activation of iNKT cells stimulates the rapid release of distinct immunoregulatory cytokines that elicit both Th1 (IFN-g) and Th2 (eg, interleukin [IL]-4, IL-10, and IL-13) responses. Of note, CD41 iNKT cells seem to favor the release of Th2-biased cytokines.5 The proportion of immunoregulatory iNKT cells in human blood is highly variable and ranges from ,0.1% to .2% of the entire T-cell pool. Remarkably, this proportion is thought to be genetically regulated.5 Some studies propose a correlation between low numbers of iNKT cells and the occurrence of autoimmune diseases, whereas transfer of NKT cells suppresses different autoimmune and alloimmune reactions in both animal models and humans.6 These observations have paved the way for clinical translation into the field of allogeneic transplantation and GVHD. For instance, higher amounts of CD41 iNKT cells in the stem cell graft have been associated with a significantly lower risk of acute GVHD,7 and low peripheral blood iNKT/T-cell ratios after transplant have been identified as an independent risk factor for developing acute GVHD.8 Lastly, adoptive transfer of both donor and host iNKT cells has been described to suppress GVHD in mice.9,10 This effect mediated by iNKT-cell–secreted IL-4 drives Th2 polarization of conventional donor-derived T cells. Moreover, highly purified NKT-cell infusions protected from GVHD development in mice by limiting T cell–mediated secretion of proinflammatory cytokines such as IFN-g and tumor necrosis factor a.10 Compared to Tregs, markedly lower numbers of CD41 iNKT cells can prevent GVHD through inducing a Th2-biased immune response. In a previous study,9 Schneidawind and colleagues revealed the underlying mechanism of this effect by showing that transfer of donor CD41 iNKT cells provokes a robust expansion of donor CD41CD251FoxP31 Tregs. Of note, a ratio of ,1:20 of CD41 iNKT to conventional T cells was sufficient, whereas a ratio of ;1:1 was needed when purified, expanded Tregs were transferred together with conventional T cells. Staining for Helios revealed that it was not inducible Tregs but naturally occurring Tregs contained within
BLOOD, 28 MAY 2015 x VOLUME 125, NUMBER 22
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2015 125: 3372-3374 doi:10.1182/blood-2015-04-636274
The first specific antiplatelet antidote David Erlinge
Updated information and services can be found at: http://www.bloodjournal.org/content/125/22/3372.full.html Articles on similar topics can be found in the following Blood collections Free Research Articles (4037 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.
patients in these 2 groups (scenarios 1 and 2) will subsequently experience thrombosis? How can we identify them so as to prevent these thrombotic events? There are still no evidence-based answers for these questions. The general approach for such patients is to eliminate the secondary risk factors for thrombosis, such as obesity and smoking, and recommend antithrombotic prophylaxis in high-risk situations, such as surgery.7 The benefits of low-dose aspirin for primary prevention of thrombosis are still being debated for patients with APS.8 The Euro-Phospholipid Project9 is the biggest prospective study of APS patients, involving 1000 patients with definite APS (as in scenario 3), and has provided important data in terms of the morbidity and mortality of this syndrome. Ninety-three patients (9.3%) died during 10 years of follow-up; the major causes of mortality were thrombosis (36.5% of all deaths), infections (26.9%), and bleeding (10.7%). Survival rates after 5 and 10 years were found to be 94.7% and 90.7%, respectively. In the present study, Gebhart et al prospectively investigated 151 LA-positive patients for a median of 8 years.1 At the beginning of the study, 39 patients had no clinical findings attributed to an autoimmune disease (as in scenario 1), 112 patients were diagnosed with APS, and 29 patients had concomitant systemic lupus erythematosus (as in scenario 3). Thirty patients (20%) experienced thromboembolic events during follow-up; 14 of them were arterial thrombosis. During the study period, 20 patients (13%) died: 10 of thrombosis, 5 of bleeding, and 5 of other causes. The cumulative relative survival rate after 10 years was 79.7%, which is very low compared with both the matched reference normal population and APS cohorts of the Euro-Phospholipid Project. The authors showed that new onset of thrombosis was the strongest predictor of poor prognosis, associated with a sixfold increase in mortality. A poor survival rate was not associated with the presence of aCLs and anti-b2GPI antibodies, prior history of thrombosis or pregnancy complications, or prior diagnosis of an autoimmune rheumatic disease in their cohort.1 Furthermore, a new thrombotic event developed under anticoagulant or antiplatelet therapy in ;75% of the patients. Interestingly, patients receiving anticoagulant and/or antiplatelet therapy showed higher incidences of thrombotic events (23 of 97, 24%) than
3372
patients with no therapy (7 of 54, 13%).1 The Euro-Phospholipid Project also showed similar findings.9 There are several possible explanations for why APS patients who were not receiving antithrombotic therapy had lower thrombosis rates. First, patients who were prescribed antithrombotic therapy may have had additional risk factors for thrombosis and may therefore represent a different high-risk group. Second, the results could indicate that current antithrombotic regimens are not effective or sufficient for preventing thrombosis in APS patients. In both Gebhart’s study and the Euro-Phospholipid Project, some patients experienced thrombosis under therapeutic international normalized ratio [INR] values (INR 2-3). Finally, pathologies other than coagulation activation may also contribute to the development of vascular occlusions in some APS patients, including thrombotic microangiopathy, complement activation, and others. In conclusion, Gebhart et al have clearly shown that the young female patient with LA described above is at increased risk for thrombosis. Our ability to identify higher-risk patients may be improved by better definition of risk factors for thrombosis other than LA and by improved understanding of the unique aspects of the pathophysiology of thrombosis in APS patients. Conflict-of-interest disclosure: The author declares no competing financial interests. n
REFERENCES 1. Gebhart J, Posch F, Koder S, et al. Increased mortality in patients with the lupus anticoagulant: the Vienna Lupus Anticoagulant and Thrombosis Study (LATS). Blood. 2015;125(22):3477-3483. 2. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295-306. 3. Biggioggero M, Meroni PL. The geoepidemiology of the antiphospholipid antibody syndrome. Autoimmun Rev. 2010;9(5):A299-A304. 4. Urbanus RT, Siegerink B, Roest M, Rosendaal FR, de Groot PG, Algra A. Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: a case-control study. Lancet Neurol. 2009;8(11):998-1005. 5. Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood. 2003;101(5):1827-1832. 6. Diz-K¨uçukkaya ¨ R, Hacihanefio˘glu A, Yenerel M, et al. Antiphospholipid antibodies and antiphospholipid syndrome in patients presenting with immune thrombocytopenic purpura: a prospective cohort study. Blood. 2001;98(6):1760-1764. 7. Bertero MT. Primary prevention in antiphospholipid antibody carriers. Lupus. 2012;21(7):751-754. 8. Arnaud L, Mathian A, Ruffatti A, et al. Efficacy of aspirin for the primary prevention of thrombosis in patients with antiphospholipid antibodies: an international and collaborative meta-analysis. Autoimmun Rev. 2014;13(3):281-291. 9. Cervera R, Serrano R, Pons-Estel GJ, et al; on behalf of the Euro-Phospholipid Project Group (European Forum on Antiphospholipid Antibodies). Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients [published online ahead of print January 24, 2014]. Ann Rheum Dis. doi:10.1136/annrheumdis-2013-204838.
© 2015 by The American Society of Hematology
l l l THROMBOSIS AND HEMOSTASIS
Comment on Buchanan et al, page 3484
The first specific antiplatelet antidote ----------------------------------------------------------------------------------------------------David Erlinge
LUND UNIVERSITY
In this issue of Blood, Buchanan and coauthors present the development of a specific antidote for ticagrelor.1 In fact, this is the first specific antidote against any antiplatelet agent.
T
icagrelor is a widely used reversible adenosine 59-diphosphate (ADP) P2Y12 antagonist for treatment of patients with acute coronary syndrome (ACS). In the Platelet Inhibition and Patient Outcomes trial, ticagrelor reduced the combined end point of death from vascular causes, myocardial infarction, or stroke for up to 12 months, and even reduced total mortality.2 However,
patients also experienced increased bleeding events not associated with coronary-artery bypass grafting (CABG). In the recently published Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 trial, patients with a myocardial infarction 1 to 3 years prior to
BLOOD, 28 MAY 2015 x VOLUME 125, NUMBER 22
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
The figure illustrates platelets activated by ADP that aggregate. After treatment with the ADP antagonist ticagrelor, aggregation is limited. If bleeding occurs or the patient needs to undergo urgent surgery, elimination of ticagrelor is currently dependent on liver elimination requiring 3 to 5 days. With the high-affinity Fab ticagrelor antidote, the elimination can be achieved within 30 minutes. After elimination of ticagrelor, the platelets can aggregate in response to ADP again and bleeding can be mitigated. Original magnification 310 400. Professional illustration by Patrick Lane, ScEYEnce Studios.
enrollment were randomized to 2 different doses of ticagrelor vs placebo.3 Even though the study reached its primary end point and demonstrated a significant reduction in ischemic events, this reduction was matched by a similar number of bleeding complications. Furthermore, a patient on ticagrelor cannot undergo urgent CABG or other surgical procedures without increased bleeding risk unless treatment with ticagrelor is interrupted for 3 to 5 days, which increases the risks and causes discomfort for the patient as well as a prolonged hospital stay and higher health care costs. The development of new antithrombotic medications may have reached its end due to an inevitable increase in bleeding complications when new agents are added: the addition of new antithrombotic drugs on top of already established guideline-directed therapies now often results in a neutral balance between ischemic end points and bleeding complications.4,5 Bleeding is associated with increased long-term mortality.6 The explanation for this is complex, with contributing factors including increased anemia, blood transfusions, inflammation,
BLOOD, 28 MAY 2015 x VOLUME 125, NUMBER 22
surgery, and complications due to prolonged hospital care. For bleeding caused by antiplatelet agents, transfusion of platelets may be of some benefit, but specific treatment is not available. The antidote against ticagrelor developed by Buchanan et al is a human antibody antigen-binding fragment (Fab) with a high affinity (20 pM) for both ticagrelor and its active metabolite without binding to ADP or other purines. The design of the Fab was improved by crystallographic determination of the Fab-ticagrelor complex. The markedly higher affinity of the antidote (pM) compared to that of ticagrelor for the P2Y12 receptor (nM) results in elimination of both circulating and P2Y12-receptor–bound ticagrelor. In the study, the antidote reversed the antiplatelet effect of ticagrelor in human platelets in vitro, and rapidly restored ADP-induced aggregation in vivo in mice. Furthermore, the antidote normalized ticagrelor-dependent bleeding in a mouse model of acute surgery. The neutralizing effect had a rapid onset within 30 minutes (see figure). A specific antidote for ticagrelor will be of great value in 2 clinical situations. First, when
a patient suffers a life-threatening bleeding complication, the rapid neutralization of circulating ticagrelor may limit the extent of the bleeding, stabilizing the patient and limiting the long-term risk after a bleeding event. Second, a patient acutely treated with ticagrelor for an ACS who needs urgent CABG could undergo surgery within an hour instead of waiting several days. Similarly, a patient on maintenance therapy may undergo noncardiac emergency surgery with limited bleeding risk. This is the first development of a specific antidote for an antiplatelet agent, fulfilling a long-sought need. For decades, we have used aspirin, clopidogrel, prasugrel, dipyridamol, abciximab, and cilostazol, where the only option for reversal was waiting for systemic elimination of the agent or platelet regeneration, which takes 5 to 10 days. Together with similar developments for newer orally administered anticoagulants such as the antidote idarucizumab for dabigatran,7,8 this represents a new era for antithrombotic drug development. It is possible that regulatory demands will increase for a simultaneous development of antidotes before approving antithrombotic drugs. In fact, a phase III study
3373
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
with available antidote may tip the net balance between anti-ischemic effect and the long-term effects of bleeding complications in a favorable way. It could also be a clinical advantage for newer antiplatelet agents compared to older antiplatelet medications that lack antidotes. The development of a highly specific, rapid, and potent antidote for ticagrelor is an important achievement with great potential to improve patient safety. The findings in human platelets in vitro and in mice models in vivo are promising. However, clinical studies are needed to confirm the effects in humans. Conflict-of-interest disclosure: D.E. has received speaker’s honoraria from AstraZeneca, Eli Lilly, and Boehringer Ingelheim. n REFERENCES 1. Buchanan A, Newton P, Pehrsson S, et al. Structural and functional characterization of a specific antidote for ticagrelor. Blood. 2015;125(22):3484-3490. 2. Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009; 361(11):1045-1057.
3. Bonaca MP, Bhatt DL, Cohen M, et al; PEGASUSTIMI 54 Steering Committee and Investigators. Longterm use of ticagrelor in patients with prior myocardial infarction [published online ahead of print March 14, 2015]. N Engl J Med. doi:10.1056/NEJMoa1500857. 4. Morrow DA, Braunwald E, Bonaca MP, et al; TRA 2P–TIMI 50 Steering Committee and Investigators. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med. 2012;366(15):1404-1413. 5. Mega JL, Braunwald E, Wiviott SD, et al; ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366(1):9-19. 6. Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation. 2006; 114(8):774-782. 7. Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013; 19(4):446-451. 8. Glund S, Moschetti V, Norris S, et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran [published online ahead of print March 19, 2015]. Thromb Haemost. 2015;113(5). doi:10.1160/TH14-12-1080. © 2015 by The American Society of Hematology
l l l TRANSPLANTATION
Comment on Schneidawind et al, page 3491
A party of three: iNKT cells in GVHD prevention ----------------------------------------------------------------------------------------------------Annkristin Heine and Peter Brossart
UNIVERSITY HOSPITAL BONN
In this issue of Blood, Schneidawind et al1 demonstrate that the adoptive transfer of CD41 invariant natural killer T (iNKT) cells from third-party mice protects from lethal graft-versus-host disease (GVHD) through expansion of donor regulatory T cells (Tregs) in a murine model of allogeneic hematopoietic cell transplantation (HCT).
G
VHD is one of the most serious complications after allogeneic HCT.2,3 Although advanced treatment options have been approved and new insight into cellular interactions and immune dysregulation has been gained, GVHD still develops in ;40% to 60% of patients.2 T cells are essential for causing GVHD. These alloreactive donor T cells secrete large amounts of proinflammatory T helper (Th)1-biased cytokines such as interferon g (IFN-g), which results in further T-cell activation and expansion. In contrast, a Th2-directed immune polarization can favor GVDH prevention
3374
(see figure).2 Various attempts have been made to dampen GVHD, such as the use of Tregs that successfully reduce early expansion of alloreactive donor T cells.4 However, Tregs are rare in peripheral blood, and ex vivo expansion is complex and time-consuming. NKT cells are a small subset of lymphocytes that bridge innate immune responses to adaptive immunity. They express several cell surface proteins characteristic for T and NK cells. In general, NKT cells are reactive to lipid antigens presented by CD1d major histocompatibility complex class I–like molecules.5 These CD1d-restricted NKT cells
can be subclassified into at least 2 groups: one using a semi-invariant T-cell receptor (TCR) (iNKT or type I) and one expressing somewhat more diverse TCRs (type II NKT). Activation of iNKT cells stimulates the rapid release of distinct immunoregulatory cytokines that elicit both Th1 (IFN-g) and Th2 (eg, interleukin [IL]-4, IL-10, and IL-13) responses. Of note, CD41 iNKT cells seem to favor the release of Th2-biased cytokines.5 The proportion of immunoregulatory iNKT cells in human blood is highly variable and ranges from ,0.1% to .2% of the entire T-cell pool. Remarkably, this proportion is thought to be genetically regulated.5 Some studies propose a correlation between low numbers of iNKT cells and the occurrence of autoimmune diseases, whereas transfer of NKT cells suppresses different autoimmune and alloimmune reactions in both animal models and humans.6 These observations have paved the way for clinical translation into the field of allogeneic transplantation and GVHD. For instance, higher amounts of CD41 iNKT cells in the stem cell graft have been associated with a significantly lower risk of acute GVHD,7 and low peripheral blood iNKT/T-cell ratios after transplant have been identified as an independent risk factor for developing acute GVHD.8 Lastly, adoptive transfer of both donor and host iNKT cells has been described to suppress GVHD in mice.9,10 This effect mediated by iNKT-cell–secreted IL-4 drives Th2 polarization of conventional donor-derived T cells. Moreover, highly purified NKT-cell infusions protected from GVHD development in mice by limiting T cell–mediated secretion of proinflammatory cytokines such as IFN-g and tumor necrosis factor a.10 Compared to Tregs, markedly lower numbers of CD41 iNKT cells can prevent GVHD through inducing a Th2-biased immune response. In a previous study,9 Schneidawind and colleagues revealed the underlying mechanism of this effect by showing that transfer of donor CD41 iNKT cells provokes a robust expansion of donor CD41CD251FoxP31 Tregs. Of note, a ratio of ,1:20 of CD41 iNKT to conventional T cells was sufficient, whereas a ratio of ;1:1 was needed when purified, expanded Tregs were transferred together with conventional T cells. Staining for Helios revealed that it was not inducible Tregs but naturally occurring Tregs contained within
BLOOD, 28 MAY 2015 x VOLUME 125, NUMBER 22
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2015 125: 3372-3374 doi:10.1182/blood-2015-04-636274
The first specific antiplatelet antidote David Erlinge
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