Platelet Activation and Reactivity in a Large Cohort of Patients with Gaucher Disease

Abstract

Patients with Gaucher disease (GD) are at increased risk of bleeding and have varying degrees of thrombocytopenia, making the analysis of platelet function difficult. This study aimed to provide a clinically relevant quantitative assessment of platelet function and determine its relationship with bleeding and GD-related data. Methods: Unstimulated and stimulated platelet function was measured by whole blood flow cytometry of platelet surface activated αIIbβ3 integrin (detected with monoclonal antibody PAC1), P-selectin (CD62P), and lysosomal-associated membrane protein (LAMP3/CD63) in 149 GD patients. Results: GD patients had a higher level of unstimulated CD63 expression than healthy subjects, which was mildly correlated with glucosylsphingosine (lyso-Gb1) levels (r 0.17, p-value 0.042). Splenectomized GD patients had a higher level of unstimulated αIIbβ3 integrin and P-selectin expression. Reduced platelet reactivity (-2 SD of reference range) was found in 79 (53%, 95% CI 44%-61%) patients, of whom 10 (6.7%, 95% CI 3.3%-12%) had more severe platelet dysfunction. In a multivariate model, only lyso-Gb1 levels were associated with the more severe platelet dysfunction. Fifty-four (49%) of 128 adult patients who completed the bleeding tendency questionnaire reported positive bleeding history. In a multivariate logistic model, older age (OR (95% CI), 1.05 (1.01-1.1)) and low P-selectin reactivity (OR (95% CI), 2.03 (1.25-3.35)) were associated with more than one bleeding manifestation. Conclusion: Flow cytometry enables the study of platelet function in thrombocytopenic GD patients. A platelet degranulation defect, but not αIIbβ3 integrin activation defect, is associated with clinical bleeding. In vivo increased CD63 expression may be related to GD-related inflammation.

Platelet Activation is Upregulated in Cirrhotic Patients with Portal Vein Thrombosis

“…Cirrhotic patients with hypersplenism have increased levels of CD62p after splenectomy compared with those presplenectomy [43] . The same result was observed in patients with non-liver diseases such as Gaucher disease who underwent splenectomy [30] . In our study, splenectomy was an independent risk factor for cirrhotic patients with PVT.…”

“…43 The same result was observed in patients with non-liver diseases such as Gaucher disease who underwent splenectomy. 30 In our study, splenectomy was an independent risk factor for cirrhotic patients with PVT. After subgroup analysis, we also found that hyperexpression of activated platelets is common in cirrhotic patients with splenectomy, suggesting that splenectomy may enhance platelet activation and hypercoagulability in vivo.…”

Contribution of Glucosylsphingosine (Lyso-Gb1) to Treatment Decisions in Patients with Gaucher Disease

“…However, not all cases of anemia and thrombocytopenia in patients with GD are related to GD, and isolated cytopenia without other GD-related signs and symptoms should lead to further investigation [ 12 ]. Pseudothrombocytopenia, as seen by one child, can be caused by platelet clumping in vitro and may be induced by antibody-mediated agglutination, e.g., ethylene-diamine-tetra-acetic acid (EDTA)-dependent agglutination, or aggregation secondary to platelet activation, that was found to be more common in GD [ 13 ]. The examination of a peripheral blood smear is recommended in suspected cases.…”

Women with Gaucher Disease

“…These figures are variable, depending on the degree of splenomegaly, involvement of megakaryopoiesis by bone marrow infiltration or coexistence of immune pathologies, such as ITP [ 26 , 27 , 28 ]. In addition, the release of proinflammatory cytokines, such as IL-1, IL-6 or TNF-alpha, together with the accumulation of glucosylceramide and glucosylsphingosine, can produce alterations in platelet functionality and thrombin generation [ 29 , 30 , 31 ]. Coagulopathies of a very heterogeneous nature have been described, with a predominance of deficiencies of factors XI, II, V, VII and X [ 28 , 32 ].…”