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

- 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

The ACTIVATED PLATELET

Is there clinical evidence for a role of

coagulation and platelet activation in the

“sickle brain”?

FVIII, VWFAg, VWFCB,

ADAMTS13Ag, P-Selectin

ADAMTS13 activity, NO

F1+2, TAT, D-dimer

PAI-1:Ag

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

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

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

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

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

Kossorotoff Jped 2014

- 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

Clinical trials with “anticoagulant” drugs:

impact for the brain?

Telen, Blood 2016

ANTICOAGULANTS

ANTIPLATELET

Telen, Blood 2016

What do we know about the role of

coagulation and platelet activation in

“brain pathology” in SCD from

experiments in animals?

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

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

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?

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

THANK YOU for

YOUR ATTENTION