coagulation activation and cerebral vasculopathy in sickle ...€¦ · coagulation activation and...
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Dr.Raffaella Colombatti Clinic of Pediatric Hematology Oncology
Department of Child and Maternal Health
Azienda Ospedaliera-Univerisità di Padova
Padova, Italy
Coagulation activation and
cerebral vasculopathy
in Sickle Cell Disease
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- SCD, an hypercoagulable state: implications for the
brain
-Role of the coagulation in cerebral vasculopathy:
-Clinical evidence in humans
-In vivo data (animals)/In vitro data
- Implications for therapeutic approaches
Overview
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The ACTIVATED PLATELET
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Is there clinical evidence for a role of
coagulation and platelet activation in the
“sickle brain”?
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FVIII, VWFAg, VWFCB,
ADAMTS13Ag, P-Selectin
ADAMTS13 activity, NO
F1+2, TAT, D-dimer
PAI-1:Ag
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A significant negative correlation was demonstrated between
lesion volume and:
- t-PA:Ag
- ADAMTS13Ag
Increased D-dimer was assciated with a significant
relative risk (RR 6.0, CI 95% 2.45-14.68, p<0.05) to
develop silent infarcts
No correlation with large vessel disease evaluated with
TCD and MRA
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Faulcon BJH 2013; Roberts MB 2012; Novelli Haematologica 2013
TSP1, produced by activated platelets, via its cognate receptor CD47, modulates
vascular responses to hypoxia, regulates vaso-constriction, inhibits angiogenesis and
nitric oxide, and promotes adhesion of sickle RBC to the endothelium, an inciting
event of VOC
Data from the SIT Trial: 65 with SCI, 51 without SCI
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PLT activation was measured through flow cytometry
evaluation of surface P-Selectin
Increased PLTs in children with cerebral large vessel
vasculopathy
Increased P-Selectin in patients with intracranial stenosis
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Hyacinth, PlosOne 2015
Data from the STOP Trial:
Comparison of coagulation parameters at baseline, study exit
and one year post trial between children with:
-SCD and abnormal TCD (transfusion arm and standard care)
-SCD and normal TCD
-AA controls
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At baseline median TAT, D-Dimer, vWF were higher in
STOP subjects compared to AA controls and SCD children
with normal TCD
At study exit TAT, D-Dimer and vWF were significantly lower
in the transfusion arm
Biomarkers of coagulation activation/Thrombin generation
correlated positively with TCD velocity and negatively with
the number of transfusion
“Biomarkers of coagulation activation/thrombin generation
were elevated in children at high risk for stroke. Reduction in
levels of these biomarkers correlated with reduction in
stroke risk (lower TCD velocity), indicating a possible role for
hypercoagulation in SCD associated stroke”
Hyacinth, PlosOne 2015
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Kossorotoff Jped 2014
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- Biomarkers of coagulation activation (TAT and D-
Dimer) are correlated with a history of stroke in adults
- Lower ADAMTS13 levels are associated with lower
CBF in the white matter in children
(Ataga PlosOne, 2012; van der Land BJH, 2015 )
…….moreover
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Clinical trials with “anticoagulant” drugs:
impact for the brain?
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Telen, Blood 2016
ANTICOAGULANTS
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ANTIPLATELET
Telen, Blood 2016
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What do we know about the role of
coagulation and platelet activation in
“brain pathology” in SCD from
experiments in animals?
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Gavins, Blood 2011;
• Thrombus formation is significantly accelerated in both the
arterioles and venules of the cerebral microvasculature in mice that
express HbS
• TF, thrombin activation and an impaired protein C pathway are
implicated in the prothrombotic phenotype of βsmice
• thrombin-mediated platelet aggregation may be an important
feature promoting microvascular thrombosis
• TF immunoneutralization effectively prevented the accelerated
thrombus formation observed in these mutants.
• ATIII was far more effective in preventing arteriolar thrombotic
vessel occlusion, suggesting that ATIII is the most effective thrombin
inhibitor
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Sparkenbaugh Blood 2014; Arumugam Blood 2014; Gavins Blood 2011, Chantrathammachart Blood 2012
Inhibition of TF inhibited activation of coagulation and
attenuated the enhanced thrombosis in cerebral
microvessels in sickle mice
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Conclusions
Some evidence of clinical role of platelet acivation and
“hypercoagulation” in the cerebral vasculopathy of children wih
SCD
More clinical evidence needed (brain “functional” studies?)
Increasing evidence in the mouse model
Studies with antiplatelets and anticoagulants did not include
cerebral vasculopathy (TCD, MRI/MRA, cognition, …) as an
endpoint
Should we include the “BRAIN” as endpoint (secondary,
exploratory,) in cinical trials of drugs targeting coagulation,
adhesion, inflammation?
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Sickle Cell Group
Laura Sainati
Vania Munaretto
Federica Menzato
Maddalena Martella
Coagulation Team
Emiliano De Bon
Maria Teresa Sartori
Alessandra Casonato
Antonella Bertomoro
Agostino Steffan
Graziella Saggiorato Neuroradiology
Renzo Manara
Patrizia Rampazzo
Claudio Baracchini
Giorgio Meneghetti
Federica Viaro
Silvia Favaretto
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THANK YOU for
YOUR ATTENTION