Please use this identifier to cite or link to this item:
http://hdl.handle.net/11375/25547
Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | Hayward, Catherine | - |
dc.contributor.author | Brunet, Justin | - |
dc.date.accessioned | 2020-07-20T20:39:11Z | - |
dc.date.available | 2020-07-20T20:39:11Z | - |
dc.date.issued | 2019 | - |
dc.identifier.uri | http://hdl.handle.net/11375/25547 | - |
dc.description.abstract | Many rare and severe forms of platelet function disorders (PFD) are now well characterized, however, information is only emerging about the phenotype and causes of many common types of PFD. This thesis aimed to extend the knowledge on uncharacterized PFD that manifest with impaired platelet aggregation function with multiple agonists, and/or platelet dense granule (DG) deficiency (DGD) by addressing some unanswered questions about laboratory findings for these PFD and whether some PFD have defects in platelet procoagulant function in assays using platelet rich plasma. First, we assessed the test characteristics and diagnostic usefulness of testing for DGD by whole mount electron microscopy (EM). We found that this test has acceptable performance characteristics, with a within-subject coefficient of variation (CV) of 12% for samples with normal DG counts. Confirmed DGD by whole mount EM showed significant association with increased bleeding symptoms and the clinical diagnosis of a bleeding disorder (Odds Ratio: 97, 95% CI: 5.7-1700). Light transmission aggregometry, and DG adenosine triphosphate release (estimated by lumi-aggregometry), were not sufficiently sensitive for detecting DGD as their respective sensitivities for detecting platelet function abnormalities due to DGD were only ~52% and 70%. Next, we evaluated for aberrant persistence of platelet non-muscle myosin IIB (MYH10) in a cohort with PFD, including those caused by mutations in transcription factors, such as RUNX1. While some participants with RUNX1 mutations showed the expected abnormal MYH10 findings, one had consistently normal findings. In another family with a PFD of unknown cause that impaired aggregation with multiple agonists, MYH10 findings varied from normal to abnormal among the affecteds. Lastly, we evaluated platelet procoagulant function in PFD using thrombin generation assays, and found that platelet-dependent thrombin generation was normal in many PFD with impaired aggregation responses and/or DGD, with abnormalities detected in the subgroup with RUNX1 mutations. Platelet-dependent thrombin generation was also impaired in Quebec platelet disorder (QPD). Unlike the other PFD subjects studied, QPD participants had platelet Factor V (FV) deficiency. In QPD, but not other participants, platelet FV showed a significant association to endogenous thrombin potential (R2=0.81) and peak thrombin concentration endpoints (R2=0.88) for PRP samples, suggesting platelet FV is important for thrombin generation. The findings from this thesis help clarify the phenotypic abnormalities associated with PFD, with implications for diagnostic testing. The studies also illustrated that the functional defects in some PFD extend to the ability of platelets to support thrombin generation. | en_US |
dc.language.iso | en | en_US |
dc.title | Phenotypic Analysis of Platelets in Patients with Platelet Function Disorders | en_US |
dc.type | Thesis | en_US |
dc.contributor.department | Medical Sciences | en_US |
dc.description.degreetype | Thesis | en_US |
dc.description.degree | Master of Science (MSc) | en_US |
dc.description.layabstract | Platelets are blood cells that are important to limit bleeding as they stick at sites of injury and help blood to clot. The medical term for conditions where platelets don’t function properly is platelet function disorders (PFD). Laboratory tests are important to diagnose PFD. We evaluated our experiences with some tests for diagnosing PFD, including whole mount electron microscopy (EM), a test that looks for a type of PFD called platelet dense granule deficiency. We also evaluated other diagnostic tests, including a test for a platelet protein called MYH10. We also evaluated how platelets support blood clotting - an aspect of platelet function that hasn’t been tested much in PFD. We found that whole mount EM is helpful to diagnose PFD, unlike tests for MYH10. We also found defects in how platelets support blood clotting in some but not all types of PFD. The findings help clarify what tests are useful to assess PFD. | en_US |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
Brunet_Justin_G_FinalSubmission2018Dec_Masters.pdf | 4.84 MB | Adobe PDF | View/Open |
Items in MacSphere are protected by copyright, with all rights reserved, unless otherwise indicated.