PMID- 26786324
OWN - NLM
STAT- MEDLINE
DCOM- 20180102
LR  - 20230829
IS  - 1538-7836 (Electronic)
IS  - 1538-7836 (Linking)
VI  - 14
IP  - 5
DP  - 2016 May
TI  - Cofactor-independent human antiphospholipid antibodies induce venous thrombosis 
      in mice.
PG  - 1011-20
LID - 10.1111/jth.13263 [doi]
AB  - Essentials Cofactor-independent antiphospholipid antibodies (CI-aPL) are 
      generally considered non-pathogenic. We analyzed the effects of human monoclonal 
      CI-aPL in a mouse model of venous thrombosis. As shown in vitro, CI-aPL induce a 
      procoagulant state in vivo by activation of endosomal NADPH-oxidase. Contrary to 
      common belief, CI-aPL induce venous thrombosis in vivo. SUMMARY: Background There 
      is general consensus that the antiphospholipid syndrome (APS) is caused by 
      antiphospholipid antibodies (aPL) with antibodies against beta2-glycoprotein-I being 
      the most relevant. aPL that bind phospholipids in the absence of protein 
      cofactors are generally considered pathogenetically irrelevant. We showed that 
      cofactor-independent human monoclonal aPL isolated from APS patients induce 
      proinflammatory and procoagulant cellular responses by activating endosomal 
      NADPH-oxidase 2 (NOX2). Similar aPL were detected in all IgG fractions from APS 
      patients analyzed. Objectives We aimed to clarify if cofactor-independent aPL can 
      be thrombogenic in vivo and, if so, whether these effects are mediated via 
      activation of NOX2. Methods Two cofactor-independent human monoclonal aPL, HL5B 
      and RR7F, were tested in a mouse model of venous thrombosis. Genetically modified 
      mice and in vitro assays were used to delineate the mechanisms underlying 
      thrombus induction. Results HL5B and RR7F dramatically accelerate thrombus 
      formation in this mouse model. Thrombus formation depends on tissue factor 
      activation. It cannot be induced in NOX2-deficient mice. Bone marrow chimeras of 
      C57BL/6J mice reconstituted with NOX2-deficient bone marrow showed that leukocyte 
      activation plays a major role in thrombus formation. Neither TLR4 signaling nor 
      platelet activation by our aPL is required for venous thrombus formation. 
      Conclusions Cofactor-independent aPL can induce thrombosis in vivo. This effect 
      is mainly mediated by leukocyte activation, which depends on the previously 
      described signal transduction via endosomal NOX2. Because most APS patients have 
      been shown to harbor aPL with similar activity, our data are of general relevance 
      for the APS.
CI  - (c) 2016 International Society on Thrombosis and Haemostasis.
FAU - Manukyan, D
AU  - Manukyan D
AD  - Institute of Clinical Chemistry and Laboratory Medicine, Mainz, Germany.
AD  - Center for Thrombosis and Haemostasis, University Medical Centre Mainz, Mainz, 
      Germany.
FAU - Muller-Calleja, N
AU  - Muller-Calleja N
AD  - Institute of Clinical Chemistry and Laboratory Medicine, Mainz, Germany.
FAU - Jackel, S
AU  - Jackel S
AD  - Center for Thrombosis and Haemostasis, University Medical Centre Mainz, Mainz, 
      Germany.
FAU - Luchmann, K
AU  - Luchmann K
AD  - Center for Thrombosis and Haemostasis, University Medical Centre Mainz, Mainz, 
      Germany.
FAU - Monnikes, R
AU  - Monnikes R
AD  - Institute of Clinical Chemistry and Laboratory Medicine, Mainz, Germany.
FAU - Kiouptsi, K
AU  - Kiouptsi K
AD  - Center for Thrombosis and Haemostasis, University Medical Centre Mainz, Mainz, 
      Germany.
FAU - Reinhardt, C
AU  - Reinhardt C
AD  - Center for Thrombosis and Haemostasis, University Medical Centre Mainz, Mainz, 
      Germany.
FAU - Jurk, K
AU  - Jurk K
AD  - Center for Thrombosis and Haemostasis, University Medical Centre Mainz, Mainz, 
      Germany.
FAU - Walter, U
AU  - Walter U
AD  - Center for Thrombosis and Haemostasis, University Medical Centre Mainz, Mainz, 
      Germany.
FAU - Lackner, K J
AU  - Lackner KJ
AD  - Institute of Clinical Chemistry and Laboratory Medicine, Mainz, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160316
PL  - England
TA  - J Thromb Haemost
JT  - Journal of thrombosis and haemostasis : JTH
JID - 101170508
RN  - 0 (Antibodies, Antiphospholipid)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Immunoglobulin G)
RN  - 0 (beta 2-Glycoprotein I)
RN  - EC 1.6.3.- (CYBB protein, human)
RN  - EC 1.6.3.- (Cybb protein, mouse)
RN  - EC 1.6.3.- (NADPH Oxidase 2)
SB  - IM
CIN - J Thromb Haemost. 2016 May;14 (5):1008-10. PMID: 26879261
MH  - Adult
MH  - Animals
MH  - Antibodies, Antiphospholipid/*immunology
MH  - Antibodies, Monoclonal/*immunology
MH  - Disease Models, Animal
MH  - Endosomes/metabolism
MH  - Female
MH  - Gene Expression Regulation
MH  - Humans
MH  - Immunoglobulin G/immunology
MH  - Leukocytes/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - NADPH Oxidase 2/genetics/*immunology
MH  - Thrombelastography
MH  - Thrombosis/immunology
MH  - Vena Cava, Inferior/pathology
MH  - Venous Thrombosis/drug therapy/*immunology
MH  - beta 2-Glycoprotein I/*immunology
OTO - NOTNLM
OT  - NADPH-oxidase
OT  - antiphospholipid antibodies
OT  - antiphospholipid syndrome
OT  - tissue factor
OT  - venous thrombosis
EDAT- 2016/01/21 06:00
MHDA- 2018/01/03 06:00
CRDT- 2016/01/21 06:00
PHST- 2015/08/27 00:00 [received]
PHST- 2016/01/05 00:00 [accepted]
PHST- 2016/01/21 06:00 [entrez]
PHST- 2016/01/21 06:00 [pubmed]
PHST- 2018/01/03 06:00 [medline]
AID - S1538-7836(22)03491-2 [pii]
AID - 10.1111/jth.13263 [doi]
PST - ppublish
SO  - J Thromb Haemost. 2016 May;14(5):1011-20. doi: 10.1111/jth.13263. Epub 2016 Mar 
      16.