PMID- 35996342
OWN - NLM
STAT- MEDLINE
DCOM- 20221025
LR  - 20231110
IS  - 1538-7836 (Electronic)
IS  - 1538-7933 (Print)
IS  - 1538-7836 (Linking)
VI  - 20
IP  - 11
DP  - 2022 Nov
TI  - Minimal role for the alternative pathway in complement activation by HIT immune 
      complexes.
PG  - 2656-2665
LID - 10.1111/jth.15856 [doi]
AB  - BACKGROUND: Anti-platelet factor 4 (PF4)/heparin immune complexes that cause 
      heparin-induced thrombocytopenia (HIT) activate complement via the classical 
      pathway. Previous studies have shown that the alternative pathway of complement 
      substantially amplifies the classical pathway of complement activation through 
      the C3b feedback cycle. OBJECTIVES: These studies sought to examine the 
      contributions of the alternative pathway to complement activation by HIT 
      antibodies. METHODS: Using IgG monoclonal (KKO) and/or patient-derived HIT 
      antibodies, we compared the effects of classical pathway (BBK32 and C1-esterase 
      inhibitor [C1-INH]), alternative pathway (anti-factor B [fB] or factor D [fD] 
      inhibitor) or combined classical and alternative pathway inhibition (soluble 
      complement receptor 1 [sCR1]) in whole blood or plasma. RESULTS: Classical 
      pathway inhibitors BBK32 and C1-INH and the combined classical/alternative 
      pathway inhibitor sCR1 prevented KKO/HIT immune complex-induced complement 
      activation, including release of C3 and C5 activation products, binding of immune 
      complexes to B cells, and neutrophil activation. The alternative pathway 
      inhibitors fB and fD, however, did not affect complement activation by KKO/HIT 
      immune complexes. Similarly, alternative pathway inhibition had no effect on 
      complement activation by unrelated immune complexes consisting of 
      anti-dinitrophenyl (DNP) antibody and the multivalent DNP--keyhole limpet 
      hemocyanin antigen. CONCLUSIONS: Collectively, these findings suggest the 
      alternative pathway contributes little in support of complement activation by HIT 
      immune complexes. Additional in vitro and in vivo studies are required to examine 
      if this property is shared by most IgG-containing immune complexes or if 
      predominance of the classic pathway is limited to immune complexes composed of 
      multivalent antigens.
CI  - (c) 2022 International Society on Thrombosis and Haemostasis.
FAU - Barnes, Ayiesha P
AU  - Barnes AP
AUID- ORCID: 0000-0003-3278-675X
AD  - Division of Hematology, Duke University Medical Center, Durham, North Carolina, 
      USA.
FAU - Khandelwal, Sanjay
AU  - Khandelwal S
AUID- ORCID: 0000-0002-5661-3856
AD  - Division of Hematology, Duke University Medical Center, Durham, North Carolina, 
      USA.
FAU - Sartoretto, Simone
AU  - Sartoretto S
AUID- ORCID: 0000-0002-0771-233X
AD  - Division of Hematology, Duke University Medical Center, Durham, North Carolina, 
      USA.
FAU - Myoung, Sooho
AU  - Myoung S
AUID- ORCID: 0000-0002-3462-8491
AD  - Division of Hematology, Duke University Medical Center, Durham, North Carolina, 
      USA.
FAU - Francis, Samuel J
AU  - Francis SJ
AUID- ORCID: 0000-0003-3210-0789
AD  - Division of Hematology, Duke University Medical Center, Durham, North Carolina, 
      USA.
FAU - Lee, Grace M
AU  - Lee GM
AUID- ORCID: 0000-0002-0051-2466
AD  - Division of Hematology, Duke University Medical Center, Durham, North Carolina, 
      USA.
FAU - Rauova, Lubica
AU  - Rauova L
AUID- ORCID: 0000-0003-1990-3077
AD  - Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
FAU - Cines, Douglas B
AU  - Cines DB
AUID- ORCID: 0000-0001-5986-504X
AD  - Department of Pathology and Laboratory Medicine and Medicine, Perelman University 
      of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
FAU - Skare, Jon T
AU  - Skare JT
AUID- ORCID: 0000-0001-8378-7862
AD  - Department of Microbial Pathogenesis & Immunology, Texas A&M University, College 
      Station, Texas, USA.
FAU - Booth, Charles E Jr
AU  - Booth CE Jr
AUID- ORCID: 0000-0001-8737-4627
AD  - Department of Microbiology & Immunology, East Carolina University, Greenville, 
      North Carolina, USA.
FAU - Garcia, Brandon L
AU  - Garcia BL
AUID- ORCID: 0000-0002-6724-8700
AD  - Department of Microbiology & Immunology, East Carolina University, Greenville, 
      North Carolina, USA.
FAU - Arepally, Gowthami M
AU  - Arepally GM
AUID- ORCID: 0000-0003-0496-5064
AD  - Division of Hematology, Duke University Medical Center, Durham, North Carolina, 
      USA.
LA  - eng
GR  - R01 HL151730/HL/NHLBI NIH HHS/United States
GR  - R01 AI146930/AI/NIAID NIH HHS/United States
GR  - R01 HL142122/HL/NHLBI NIH HHS/United States
GR  - R01HL151730/HL/NHLBI NIH HHS/United States
GR  - HL128895/HL/NHLBI NIH HHS/United States
GR  - R01 HL139448/HL/NHLBI NIH HHS/United States
GR  - R01 HL128895/HL/NHLBI NIH HHS/United States
GR  - R35 HL150698/HL/NHLBI NIH HHS/United States
GR  - R01HL142122/HL/NHLBI NIH HHS/United States
GR  - R01AI146930/AI/NIAID NIH HHS/United States
GR  - R01HL139448/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20220901
PL  - England
TA  - J Thromb Haemost
JT  - Journal of thrombosis and haemostasis : JTH
JID - 101170508
RN  - 0 (Antigen-Antibody Complex)
RN  - EC 3.4.21.46 (Complement Factor D)
RN  - 9005-49-6 (Heparin)
RN  - 9007-36-7 (Complement System Proteins)
RN  - 0 (Immunoglobulin G)
RN  - 0 (Receptors, Complement)
RN  - EC 3.1.- (Esterases)
SB  - IM
MH  - Humans
MH  - *Antigen-Antibody Complex
MH  - Complement Factor D
MH  - *Thrombocytopenia
MH  - Heparin/adverse effects
MH  - Complement Activation
MH  - Complement System Proteins
MH  - Immunoglobulin G
MH  - Receptors, Complement
MH  - Esterases/adverse effects
PMC - PMC9938942
MID - NIHMS1868558
OTO - NOTNLM
OT  - antibodies
OT  - antigen-antibody complex
OT  - complement
OT  - heparin
OT  - platelet factor 4
OT  - thrombocytopenia
COIS- Conflict of Interest GMA has an awarded patent for KKO (US Application NO 
      60/143,536); GMA, SK and DBC have pending intellectual property applications. 
      Other remaining authors have no conflicts of interest.
EDAT- 2022/08/24 06:00
MHDA- 2022/10/26 06:00
PMCR- 2023/11/01
CRDT- 2022/08/23 01:23
PHST- 2022/07/23 00:00 [revised]
PHST- 2022/03/31 00:00 [received]
PHST- 2022/08/16 00:00 [accepted]
PHST- 2022/08/24 06:00 [pubmed]
PHST- 2022/10/26 06:00 [medline]
PHST- 2022/08/23 01:23 [entrez]
PHST- 2023/11/01 00:00 [pmc-release]
AID - S1538-7836(22)18483-7 [pii]
AID - 10.1111/jth.15856 [doi]
PST - ppublish
SO  - J Thromb Haemost. 2022 Nov;20(11):2656-2665. doi: 10.1111/jth.15856. Epub 2022 
      Sep 1.