Coagulation activation and cerebral vasculopathy in Sickle Cell Disease

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1 Coagulation activation and cerebral vasculopathy in Sickle Cell Disease Dr.Raffaella Colombatti Clinic of Pediatric Hematology Oncology Department of Child and Maternal Health Azienda Ospedaliera-Univerisità di Padova Padova, Italy

2 Overview - 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

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6 The ACTIVATED PLATELET

7 Is there clinical evidence for a role of coagulation and platelet activation in the sickle brain?

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9 FVIII, VWFAg, VWFCB, ADAMTS13Ag, P-Selectin ADAMTS13 activity, NO F1+2, TAT, D-dimer PAI-1:Ag

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11 Increased D-dimer was assciated with a significant relative risk (RR 6.0, CI 95% , p<0.05) to develop silent infarcts A significant negative correlation was demonstrated between lesion volume and: - t-pa:ag - ADAMTS13Ag No correlation with large vessel disease evaluated with TCD and MRA

12 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 Faulcon BJH 2013; Roberts MB 2012; Novelli Haematologica 2013

13 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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15 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 Hyacinth, PlosOne 2015

16 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

17 Kossorotoff Jped 2014

18 .moreover - 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 )

19 Clinical trials with anticoagulant drugs: impact for the brain?

20 ANTICOAGULANTS Telen, Blood 2016

21 ANTIPLATELET Telen, Blood 2016

22 What do we know about the role of coagulation and platelet activation in brain pathology in SCD from experiments in animals?

23 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 β s mice 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 Gavins, Blood 2011;

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25 Inhibition of TF inhibited activation of coagulation and attenuated the enhanced thrombosis in cerebral microvessels in sickle mice Sparkenbaugh Blood 2014; Arumugam Blood 2014; Gavins Blood 2011, Chantrathammachart Blood 2012

26 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?

27 Sickle Cell Group Laura Sainati Vania Munaretto Federica Menzato Maddalena Martella Neuroradiology Renzo Manara Patrizia Rampazzo Claudio Baracchini Giorgio Meneghetti Federica Viaro Silvia Favaretto Coagulation Team Emiliano De Bon Maria Teresa Sartori Alessandra Casonato Antonella Bertomoro Agostino Steffan Graziella Saggiorato

28 THANK YOU for YOUR ATTENTION