PB1238 - Effect of constitutive activation of the calcium sensor STIM1 on haemostasis

Tuesday, July 12, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Presenting Author(s)

EG

Eduardo García, MD

Department of Hematology
La Paz University Hospital
Madrid, Madrid, Spain

Co-Author(s)

Elena García Arias-Salgado, PhD

Senior researcher
La Paz University Hospital
Madrid, Madrid, Spain
EM

Elena Monzón Manzano

Research Associate
La Paz University Hospital
Madrid, Madrid, Spain
LD

Lucía Del Pino Molina

Researcher
Center for Biomedical Network Research on Rare diseases (CIBERER U767); Lymphocyte Pathophysiology in Immunodeficiencies Group, IdiPaz
Madrid, Madrid, Spain
YS

Yolanda Soto Serrano

Researcher
Lymphocyte Pathophysiology in Immunodeficiencies Group, IdiPaz
Madrid, Madrid, Spain
PA

Paula Acuña Butta

Bsc
La Paz University Hospital
Madrid, Madrid, Spain
María Teresa Alvarez-Román, MD, PhD

Head of the Thrombosis and Haemostasis Unit
La Paz University Hospital, Madrid, Spain
Madrid, Madrid, Spain
MM

Mónica Martín Salces

Specialist in Hematology
La Paz University Hospital
Madrid, Madrid, Spain
MR

Maria Isabel Rivas Pollmar

Specialist in Hematology
La Paz University Hospital
Madrid, Madrid, Spain
AD

Abel Dos Santos Ortas

Specialist in Hematology
La Paz University Hospital
Madrid, Madrid, Spain
Víctor Jiménez Yuste, MD PhD

Head of Hematology
La Paz University Hospital
Madrid, Madrid, Spain
NB

Nora V V. Butta Coll

Head of Hemostasis laboratory
La Paz University Hospital
Madrid, Madrid, Spain

Background: Quiescent platelets maintain a low cytosolic (cyt) Ca2+ concentration that increases upon platelet activation partially due to depletion of intracellular stores. Stromal interaction molecule 1 (STIM1) is the main Ca2+ sensor on endoplasmic reticulum that regulates Ca2+ entry from the extracellular space.
Stormorken syndrome is a rare autosomaldominantdisease caused by gain-of-function mutations that induce excessive extracellular Ca2+ entry withmild bleeding tendency.

Aims: To study effect of constitutive activation of STIM1 on haemostasis

Methods: A16 years old male patient with Stormorken syndrome (STKP), with asplenia, myopathy, mild muscle weakness, and repeated bleeding, was studied after obtaining his signed consent. Three healthy controls were also recruited.
Platelet activation markers (activity of fibrinogen receptor and surface exposure of P-selectin) were determined in platelet rich plasma (PRP). Platelet annexin V binding to detect phosphatidylserine was assayed in washed platelets. Samples were analyzed by flow cytometry.
Thrombin generation (TG) was determined by calibrated automated thrombogramin PRP adjusted to 290x109platelets/L with 1pM tissue factor (PRP reagent). TG in plasma was triggered with PRP and MP-reagents to detect TG associated, respectively, to phospholipids and tissue factor of microparticles.

Results: Sequencing of STKP showed a previously described mutation in exon 3 of the STIM1 gene, obtaining a variant c.326A>G (p.His109Arg) in heterozygosis.
Platelets from STKP were basally activated and their ability to respond to agonists was diminished, mainly affecting the activation of the fibrinogen receptor. Exposure of phosphatidylserine was higher than in controls (Table 1).
TG dependant on PRP and microparticles were increased (Table 2).

Conclusion(s): Constitutive activation of STIM1 gene induced basal activation of platelets and increased surface-phosphatidylserine which seemed to be functional for anchoring more pro-thrombinase complex to generate thrombin. In accordance to platelet activation, more microparticles seemed to be released increasing TG. Bleeding in STKP seems to be related to an anomalous primary haemostasis and not to coagulation impairment.