Abstract
Introduction Thrombotic storm (TS) presents as a severe, acute thrombotic phenotype, characterized by multiple clotting events and frequently affecting younger adults. Understanding the extensive hypercoagulation of an extreme phenotype as TS will also provide insight into the pathogenesis of a wider spectrum of thrombotic disorders. Material and methods We completed whole exome sequencing on 26 TS patients, including 1 multiplex family, 13 trios and 12 isolated TS patients. We examined both dominant and recessive inheritance models for known thrombotic factors as well as performed a genome-wide screen. Identified genes of interest in the family and trios were screened in the remaining TS patients. Variants were filtered on frequency (< 5% in 1000 genomes), conservation and function in gene and were annotated for effect on protein and overall functionality. Results We observed an accumulation of variants in genes linked to chondroitin sulfate (CS), but not heparan sulfate metabolism. Sixteen conserved, rare missense and nonsense variants in genes involved in CS metabolism (CHPF, CHPF2, CHST3, CHST12, CHST15, SLC26A2, PAPSS2, STAB2) were identified in over one-third of the TS patients. In contrast, we identified only seven variants in known thrombosis genes (including FV Leiden). Conclusions As CS has multiple functions in the glycocalyx protecting the endothelial cells, reduced availability of CS could diminish the normal control mechanisms for blood coagulation, making these CS metabolism genes strong potential risk factors for TS. Overall, no single gene was identified with strong evidence for TS causality; however, our data suggest TS is mediated by an accumulation of rare pro-thrombotic risk factors.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 43-51 |
| Number of pages | 9 |
| Journal | Thrombosis Research |
| Volume | 161 |
| DOIs | |
| State | Published - Jan 1 2018 |
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Keywords
- Chondroitin sulfates
- Glycocalyx
- Thrombosis
- Whole exome sequencing
ASJC Scopus subject areas
- Hematology
Cite this
Variants in chondroitin sulfate metabolism genes in thrombotic storm. / Nuytemans, Karen; Ortel, Thomas L.; Gomez, Lissette; Hofmann, Natalia; Alves, Natalie; Dueker, Nicole; Beecham, Ashley; Whitehead, Patrice; Hahn Estabrooks, Susan; Kitchens, Craig S.; Erkan, Doruk; Brandão, Leonardo R.; James, Andra H.; Kulkarni, Roshni; Manco-Johnson, Marilyn J.; Pericak-Vance, Margaret A; Vance, Jeffery M.
In: Thrombosis Research, Vol. 161, 01.01.2018, p. 43-51.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Variants in chondroitin sulfate metabolism genes in thrombotic storm
AU - Nuytemans, Karen
AU - Ortel, Thomas L.
AU - Gomez, Lissette
AU - Hofmann, Natalia
AU - Alves, Natalie
AU - Dueker, Nicole
AU - Beecham, Ashley
AU - Whitehead, Patrice
AU - Hahn Estabrooks, Susan
AU - Kitchens, Craig S.
AU - Erkan, Doruk
AU - Brandão, Leonardo R.
AU - James, Andra H.
AU - Kulkarni, Roshni
AU - Manco-Johnson, Marilyn J.
AU - Pericak-Vance, Margaret A
AU - Vance, Jeffery M
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Introduction Thrombotic storm (TS) presents as a severe, acute thrombotic phenotype, characterized by multiple clotting events and frequently affecting younger adults. Understanding the extensive hypercoagulation of an extreme phenotype as TS will also provide insight into the pathogenesis of a wider spectrum of thrombotic disorders. Material and methods We completed whole exome sequencing on 26 TS patients, including 1 multiplex family, 13 trios and 12 isolated TS patients. We examined both dominant and recessive inheritance models for known thrombotic factors as well as performed a genome-wide screen. Identified genes of interest in the family and trios were screened in the remaining TS patients. Variants were filtered on frequency (< 5% in 1000 genomes), conservation and function in gene and were annotated for effect on protein and overall functionality. Results We observed an accumulation of variants in genes linked to chondroitin sulfate (CS), but not heparan sulfate metabolism. Sixteen conserved, rare missense and nonsense variants in genes involved in CS metabolism (CHPF, CHPF2, CHST3, CHST12, CHST15, SLC26A2, PAPSS2, STAB2) were identified in over one-third of the TS patients. In contrast, we identified only seven variants in known thrombosis genes (including FV Leiden). Conclusions As CS has multiple functions in the glycocalyx protecting the endothelial cells, reduced availability of CS could diminish the normal control mechanisms for blood coagulation, making these CS metabolism genes strong potential risk factors for TS. Overall, no single gene was identified with strong evidence for TS causality; however, our data suggest TS is mediated by an accumulation of rare pro-thrombotic risk factors.
AB - Introduction Thrombotic storm (TS) presents as a severe, acute thrombotic phenotype, characterized by multiple clotting events and frequently affecting younger adults. Understanding the extensive hypercoagulation of an extreme phenotype as TS will also provide insight into the pathogenesis of a wider spectrum of thrombotic disorders. Material and methods We completed whole exome sequencing on 26 TS patients, including 1 multiplex family, 13 trios and 12 isolated TS patients. We examined both dominant and recessive inheritance models for known thrombotic factors as well as performed a genome-wide screen. Identified genes of interest in the family and trios were screened in the remaining TS patients. Variants were filtered on frequency (< 5% in 1000 genomes), conservation and function in gene and were annotated for effect on protein and overall functionality. Results We observed an accumulation of variants in genes linked to chondroitin sulfate (CS), but not heparan sulfate metabolism. Sixteen conserved, rare missense and nonsense variants in genes involved in CS metabolism (CHPF, CHPF2, CHST3, CHST12, CHST15, SLC26A2, PAPSS2, STAB2) were identified in over one-third of the TS patients. In contrast, we identified only seven variants in known thrombosis genes (including FV Leiden). Conclusions As CS has multiple functions in the glycocalyx protecting the endothelial cells, reduced availability of CS could diminish the normal control mechanisms for blood coagulation, making these CS metabolism genes strong potential risk factors for TS. Overall, no single gene was identified with strong evidence for TS causality; however, our data suggest TS is mediated by an accumulation of rare pro-thrombotic risk factors.
KW - Chondroitin sulfates
KW - Glycocalyx
KW - Thrombosis
KW - Whole exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85034816438&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85034816438&partnerID=8YFLogxK
U2 - 10.1016/j.thromres.2017.11.016
DO - 10.1016/j.thromres.2017.11.016
M3 - Article
VL - 161
SP - 43
EP - 51
JO - Thrombosis Research
JF - Thrombosis Research
SN - 0049-3848
ER -