Background: SLFN14 is a novel hematopoietic-specific endoribonuclease with an unidentified role . SLFN14 missense mutations have previously been found in five unrelated families with inherited thrombocytopenia and platelet function defects. However, it remains unclear how SLFN14 mutations contribute to platelet function defects in humans.

Aims: To investigate platelet activation and signaling pathways in SLFN14-mutated patients with platelet function defects, macrothrombocytopenia and bleeding.

Methods: Whole blood counting and platelet function assays including platelet aggregation and flow cytometry were used to assess overall platelet function in patients from three families with missense mutations in SLFN14. Signaling downstream of the major platelet receptors GPVI, PAR-1 and ADP receptors was also assessed by western blot.

Results: Patients with mutations in SLFN14 (K219N, V220D and K218E) all presented with macrothrombocytopenia and reduced aggregation responses to collagen, ADP and PAR-1-receptor activating peptide . Transmission electron microscopy of platelets also showed reduced numbers of dense granules compared to controls, correlating with the reduced ATP secretion observed by lumiaggregometry (n=1-5 patients per family). K219N and V220D patients (n=2 patients per mutation) show reduced phosphorylation of Syk-Y525/526, LAT-Y200 and PLCg2-Y1217 in response to collagen and collagen-related peptide.

Conclusion(s): SLFN14-mutated patients have macrothrombocytopenia and significant platelet function defects in response to collagen, ADP and PAR-1-peptide. Reduced GPVI downstream signaling in K219N and V220D patients suggest SLFN14 mutations may mediate ITAM receptor signaling upon activation. These defects in important hemostatic pathways explain the patients’ mild to moderate bleeding. Further investigation is however still required to determine how SLFN14 mediates effects on these pathways.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/elucidation-of-specific-platelet-signaling-pathways-perturbed-in-slfn14-mutated-patients-with-inherited-macrothrombocytopenia-and-bleeding/