In this issue of Blood, Pilli and colleagues1  report that the essential antithrombotic factor protein S is inversely regulated by the transcription factor hypoxia inducible factor 1 (HIF1). This is an important contribution to our understanding of the molecular basis of the augmentation of thrombosis by hypoxia.

An association between increased arterial and venous thrombosis and environmental hypoxia has been well described in the acquired prothrombotic condition polycythemia vera2  and other conditions,2  as well as in familial Chuvash polycythemia, a recessively inherited augmentation of hypoxia sensing.3  Hypoxic cancer tissue may contribute to cancer patients’ propensity to thrombosis.

Hypoxia is sensed and its effect transmitted to an array of physiological processes by HIFs. HIFs are dimers of posttranscriptionally oxygen-regulated HIFα and HIFβ subunits. There are 3 paralogs of HIFα (HIF1α, HIF2α/EPAS, and HIF3α) and 2 paralogs of the HIFβ subunit (ARNT and ARNT2).4  HIFs directly regulate transcription of many known and yet to be discovered genes. HIFs have distinct tissue and gene specificity. For example, the ubiquitously expressed HIF1 upregulates >3% of genes in endothelial cells,5  whereas the more tissue-restricted HIF2 is the principal transcriptional regulator of erythropoietin.6  Levels of HIF dimers are regulated by the posttranslational stability of HIFα subunits.7  In normoxia, these subunits are prolylhydroxylated and bind to VHL protein, targeting them for rapid destruction in the proteasome.8  In contrast, in hypoxia, these HIFα subunits proteins are stabilized, resulting in increased transcription of HIF-regulated genes; similarly, homozygosity for the hypomorphic Chuvash polycythemia mutation VHLR200W also leads to posttranslational stabilization of HIFα subunits at normoxia.9 

The liver is the site of protein S synthesis. Pilli and colleagues report that in a liver cell line HepG2, the level of protein S decreases after hypoxic exposure. In further studies of mice with either a HIF1α gene knockout or a HIF1α gain-of-function mutation, they demonstrate that HIF1 downregulates protein S levels. The decreased protein S levels were associated with increased thrombin, consistent with a prothrombotic effect.

Unexpectedly, they describe that the transcript of HIF1α also increases under these hypoxia-augmenting conditions. The molecular basis of this observation remains to be clarified, as HIFs activate transcription of genes only by direct binding to their promoters; however, HIFs may also repress gene transcription indirectly by the transcriptional activation of microRNAs and repressors.

Hypoxia is common in many disease states, including cancer, wherein it accounts for unique HIF-mediated cancer cell energy generation (ie, the Warburg effect). The hypoxic regulation of other prothrombotic and antithrombotic genes is currently under active investigation, and other hypoxia-controlled thrombotic mechanisms are expected to be uncovered.

Conflict-of-interest disclosure: The author declares no competing financial interests.

REFERENCES

REFERENCES
1.
Pilli
VS
,
Datta
A
,
Afreen
S
,
Catalano
D
,
Szabo
G
,
Majumder
R
.
Hypoxia downregulates protein S expression
.
Blood
.
2018
;
132
(
4
):
452
-
455
.
2.
Zangari
M
,
Fink
L
,
Tolomelli
G
, et al
.
Could hypoxia increase the prevalence of thrombotic complications in polycythemia vera?
Blood Coagul Fibrinolysis
.
2013
;
24
(
3
):
311
-
316
.
3.
Gordeuk
VR
,
Prchal
JT
.
Vascular complications in Chuvash polycythemia
.
Semin Thromb Hemost
.
2006
;
32
(
3
):
289
-
294
.
4.
Graham
AM
,
Presnell
JS
.
Hypoxia inducible factor (HIF) transcription factor family expansion, diversification, divergence and selection in eukaryotes
.
PLoS One
.
2017
;
12
(
6
):
e0179545
.
5.
Manalo
DJ
,
Rowan
A
,
Lavoie
T
, et al
.
Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1
.
Blood
.
2005
;
105
(
2
):
659
-
669
.
6.
Rankin
EB
,
Biju
MP
,
Liu
Q
, et al
.
Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo
.
J Clin Invest
.
2007
;
117
(
4
):
1068
-
1077
.
7.
Wang
GL
,
Jiang
B-H
,
Rue
EA
,
Semenza
GL
.
Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension
.
Proc Natl Acad Sci USA
.
1995
;
92
(
12
):
5510
-
5514
.
8.
Kaelin
WG
Jr
,
Ratcliffe
PJ
.
Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway
.
Mol Cell
.
2008
;
30
(
4
):
393
-
402
.
9.
Ang
SO
,
Chen
H
,
Hirota
K
, et al
.
Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia
.
Nat Genet
.
2002
;
32
(
4
):
614
-
621
.