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Evaluation of the Sialidase Inhibitor Oseltamivir in GNE-associated Thrombocytopenia

Fager Ferrari, Marcus LU orcid ; Smolag Klosowska, Karolina LU orcid ; Zetterberg, Eva LU ; Leinoe, Eva ; Blom, A.M. ; Ek, Torben ; Rossing, Maria and Martin, Myriam LU (2021) The XXIX Congress of the International Society on Thrombosis and Haemostasis (ISTH) In Research and practice in thrombosis and haemostasis 5(S2). p.644-645
Abstract
Background: GNE encodes UDP-N-acetyl-glucosamine-2-epimerase/N-acetylmannosamine kinase, the rate limiting enzyme of sialic acid biosynthesis. Biallelic variants in GNE have recently been associated with severe isolated macrothrombocytopenia, attributed to an increased clearance of desialylated platelets. Interestingly, treatment with the sialidase inhibitor oseltamivir has been reported to increase platelet counts in conditions such as immune thrombocytopenia (ITP) and influenza. We present a case of a 17-year-old boy (the proband) with severe congenital macrothrombocytopenia (platelet counts < 10 x 109/L). Whole genome sequencing revealed two previously undescribed compound heterozygous variants in GNE (c.416_426del, p.Ile139Argfs*4... (More)
Background: GNE encodes UDP-N-acetyl-glucosamine-2-epimerase/N-acetylmannosamine kinase, the rate limiting enzyme of sialic acid biosynthesis. Biallelic variants in GNE have recently been associated with severe isolated macrothrombocytopenia, attributed to an increased clearance of desialylated platelets. Interestingly, treatment with the sialidase inhibitor oseltamivir has been reported to increase platelet counts in conditions such as immune thrombocytopenia (ITP) and influenza. We present a case of a 17-year-old boy (the proband) with severe congenital macrothrombocytopenia (platelet counts < 10 x 109/L). Whole genome sequencing revealed two previously undescribed compound heterozygous variants in GNE (c.416_426del, p.Ile139Argfs*4 and c.1352G>A, p.Arg451Gln). The proband was otherwise healthy, with no signs of GNE myopathy. ​​​​

Aims: To investigate the consequences of the identified variants in GNE and evaluate the effect of oseltamivir in GNE-associated thrombocytopenia.

Methods: Sialylation of platelets, granulocytes, lymphocytes and monocytes was determined by flow cytometry in the proband and healthy controls (n = 5), using Sambucus nigra lectin (SNA) and Maackia amurensis lectin II (MAL II). Platelet sialylation was reassessed in the proband following treatment with oseltamivir (75 mg twice daily, off-label use). Informed consent was obtained from all participants. The study was approved by the regional ethical committee.

Results: Sialylation of platelets and leukocytes was markedly decreased in the proband compared with the healthy controls, consistent with a deleterious effect of the compound heterozygous variants in GNE (Figure 1). Platelet sialylation was persistently decreased after 18 days of treatment with oseltamivir, and no clinically significant elevation of the platelet counts could be observed (Figure 1, Figure 2). (Less)
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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Research and practice in thrombosis and haemostasis
volume
5
issue
S2
article number
PB0871
pages
644 - 645
publisher
Wiley
conference name
The XXIX Congress of the International Society on Thrombosis and Haemostasis (ISTH)
conference dates
2021-07-17 - 2021-07-21
ISSN
2475-0379
language
English
LU publication?
yes
id
58968d01-3136-4b53-96ab-a22e4c754226
alternative location
https://abstracts.isth.org/abstract/evaluation-of-the-sialidase-inhibitor-oseltamivir-in-gne-associated-thrombocytopenia
date added to LUP
2021-10-10 12:31:57
date last changed
2021-10-26 07:40:38
@misc{58968d01-3136-4b53-96ab-a22e4c754226,
  abstract     = {{Background: GNE encodes UDP-N-acetyl-glucosamine-2-epimerase/N-acetylmannosamine kinase, the rate limiting enzyme of sialic acid biosynthesis. Biallelic variants in GNE have recently been associated with severe isolated macrothrombocytopenia, attributed to an increased clearance of desialylated platelets. Interestingly, treatment with the sialidase inhibitor oseltamivir has been reported to increase platelet counts in conditions such as immune thrombocytopenia (ITP) and influenza. We present a case of a 17-year-old boy (the proband) with severe congenital macrothrombocytopenia (platelet counts &lt; 10 x 109/L). Whole genome sequencing revealed two previously undescribed compound heterozygous variants in GNE (c.416_426del, p.Ile139Argfs*4 and c.1352G&gt;A, p.Arg451Gln). The proband was otherwise healthy, with no signs of GNE myopathy. ​​​​<br>
<br>
Aims: To investigate the consequences of the identified variants in GNE and evaluate the effect of oseltamivir in GNE-associated thrombocytopenia.<br>
<br>
Methods: Sialylation of platelets, granulocytes, lymphocytes and monocytes was determined by flow cytometry in the proband and healthy controls (n = 5), using Sambucus nigra lectin (SNA) and Maackia amurensis lectin II (MAL II). Platelet sialylation was reassessed in the proband following treatment with oseltamivir (75 mg twice daily, off-label use). Informed consent was obtained from all participants. The study was approved by the regional ethical committee.<br>
<br>
Results: Sialylation of platelets and leukocytes was markedly decreased in the proband compared with the healthy controls, consistent with a deleterious effect of the compound heterozygous variants in GNE (Figure 1). Platelet sialylation was persistently decreased after 18 days of treatment with oseltamivir, and no clinically significant elevation of the platelet counts could be observed (Figure 1, Figure 2).}},
  author       = {{Fager Ferrari, Marcus and Smolag Klosowska, Karolina and Zetterberg, Eva and Leinoe, Eva and Blom, A.M. and Ek, Torben and Rossing, Maria and Martin, Myriam}},
  issn         = {{2475-0379}},
  language     = {{eng}},
  note         = {{Conference Abstract}},
  number       = {{S2}},
  pages        = {{644--645}},
  publisher    = {{Wiley}},
  series       = {{Research and practice in thrombosis and haemostasis}},
  title        = {{Evaluation of the Sialidase Inhibitor Oseltamivir in <i>GNE</i>-associated Thrombocytopenia}},
  url          = {{https://abstracts.isth.org/abstract/evaluation-of-the-sialidase-inhibitor-oseltamivir-in-gne-associated-thrombocytopenia}},
  volume       = {{5}},
  year         = {{2021}},
}