Long-term ERT Reduces Bleeding But Not Platelet Function Defects in Gaucher Disease, Study Suggests

Long-term ERT Reduces Bleeding But Not Platelet Function Defects in Gaucher Disease, Study Suggests

Although able to reduce bleeding, long-term enzyme replacement therapy (ERT) did not correct alterations in platelets and other clotting molecules in people with Gaucher disease (GD), a new study shows.

The study, “Platelet function defects in patients with Gaucher disease on long term ERT- implications for evaluation at bleeding challenges,” was published in the journal Blood Cells, Molecules and Diseases.

GD results from mutations in the GBA gene, which cause an enzyme known as beta-glucocerebrosidase to be made incorrectly or not at all and lead to the toxic buildup of the fat molecule glucocerebroside inside cells.

Approximately 40% to 50% of people with GD experience bleeding disorders caused by low levels of platelets (thrombocytopenia) and other clotting factors. 

ERT, which delivers a working version of beta-glucocerebrosidase, has been successfully used in patients with type 1 GD — the most common form of the disease and typically with no manifestations in the brain and spinal cord.

However, the long-term effects of ERT on platelets and other clotting factors have not been assessed. 

To get a clearer picture, researchers in Greece recruited adults with GD who had been treated with ERT long-term. A total of 29 patients were selected, whose median age was 45 years (age range was 22 to 65).  Twenty-seven participants had type 1 and two had type 3 GD.

All had been treated with the ERT Cerezyme (imiglucerase), marketed by Sanofi Genzyme, over one to 22 years (median 13.1 years), with a dose range of 15 to 60 iu/kg every 15 days for type 1 patients, and a fixed 60 iu/kg dose for those with type 3. 

Assessments included a full blood cell count, biochemical and virology tests, and an analysis of platelet function and blood coagulation characteristics.

A blood marker of GD activity — the activity of an enzyme called chitotriosidase — was assessed in addition to ultrasounds to evaluate the size of the spleen and liver. 

Ten participants had their spleen removed (splenectomy), while 23 had a history of bleeding before surgery and/or ERT. Most of these patients (21 of 23) reported reduced bleeding after surgery and ERT. Of note, bleeding history was based on the International Society on Thrombosis and Hemostasis Bleeding Assessment Tool.

Results showed that most patients had abnormal platelet function, specifically a slower blood clot formation, as determined by the Platelet Function Assay (PFA-100). No difference was found between participants who had undergone a splenectomy and those who didn’t. 

Plasma chitotriosidase levels were higher in 79.4% of patients and correlated with a larger spleen size in the 19 patients who had not undergone spleen removal. High chitotriosidase activity was linked to slower clotting and a history of skin bleeding.

Also, higher chitotriosidase levels in 14 patients were associated with low levels of ADAMTS 13 (an enzyme involved in blood clotting) and with abnormally high levels of D-Dimers in 11 patients. D-dimers are small protein fragments present in the blood after a blood clot is degraded (fibrinolysis). 

PAI-1 levels, another test for the fibrinolysis, were reduced in 20 patients (69%).

“Our results … suggest that although patients with Gaucher disease have clinically an ameliorated bleeding diathesis [status], they continue to present abnormal platelet function and increased fibrinolysis,” the researchers wrote.

“In every-day clinical practice PFA-100 testing along with bleeding history and CA [chitotriosidase] levels … could be useful tools for characterizing patients with Gaucher disease with bleeding diathesis when they face a bleeding challenge,” they added.

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José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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