Molecular phenotype and bleeding risks of an inherited platelet disorder in a family with a RUNX1 frameshift mutation

Abstract

Inherited platelet dysfunction due to a RUNX1 haploinsufficiency mutation significantly increases bleeding risks.

Electron microscopy examination of platelet whole mount preparations to quantitate platelet dense granule numbers: Implications for diagnosing suspected platelet function disorders due to dense granule deficiency

“…Some of the mild reductions in DG counts that we observed could reflect false positives and also the biology of some PFD. For example, familial PFD due to RUNX1 haploinsufficiency reduces the DG content of platelets; however, only ~50% of the affected family members have DG counts below the RI . Our observations on the test reproducibility and within‐subject CV are important as whole mount EM is the most commonly used method for diagnosing platelet DGD in North America .…”

“…Light transmission aggregometry and DG ATP release findings for many cohort I participants were previously reported but as participants were anonymized with different codes than used for the present study, LTA and DG ATP release data for DGD participants (both cohorts) were retrieved from original medical records. DG counts for samples used for North American Specialized Coagulation Laboratory Association (NASCOLA) EQA exercises on quantitating DG numbers by EM (offered twice annually, between 2003 and 2012) were exclusively used to evaluate within‐subject variability.…”

“…Data collected for cohorts I and II included gender, age (inconsistently recorded for cohort I controls), date of testing, and the DG count for each unique sample. For cohort II, data were also collected on: whether the participant had a bleeding disorder (based on the hematologist's opinion, obtained by chart review, as described); ISTH‐BAT scores; the most recent HRLMP platelet count, mean platelet volume (MPV), DG ATP release findings (determined by lumi‐aggregometry as described, using an agonist panel that included: 1 U/mL thrombin, 5.0 μg/mL Horm collagen, 6 μmol/L epinephrine, 1 μmol/L thromboxane analogue U46619, and 1.6 mmol/L arachidonic acid [AA]) and MA responses (evaluated by LTA, as described, with the agonists: 1.25 and 5.0 μg/mL Horm collagen, 2.5 and 5.0 μmol/L ADP, 6 μmol/L epinephrine, 1 μmol/L thromboxane analogue U46619, 1.6 mmol/L AA, and 0.5, and 1.25 mg/mL ristocetin).…”

“…While the finding of DGD by EM has been associated with a bleeding disorder, we decided to address the typical findings and within‐subject variability for the assay by examining 12 years of prospectively collected data on diagnostic EM tests for DGD. We postulated that this would generate useful evidence, like our studies of LTA and DG ATP release . To explore relationships between confirmed DGD, other laboratory findings, and bleeding, we also evaluated whole mount EM data for an overlapping cohort that had their bleeding history evaluated as part of a study on PFD.…”

Update on diagnostic testing for platelet function disorders: What is practical and useful?

“…Platelet function disorders (PFD) are clinically important bleeding disorders that are particularly challenging for clinical laboratories to diagnose. Many PFD are associated with increased bleeding scores and increased risks for bleeding . Commonly, laboratory tests for PFD are performed to investigate unexplained bruising, heavy menstrual bleeding, prolonged and excessive bleeding from cuts, nosebleeds, and dental and surgical procedures .…”