Congenital platelet defects.

Abstract

Congenital platelet defects (CPDs) are rare disorders of primary hemostasis. Clinical characteristics and burden of disease are poorly described. Next to that, the current diagnostic tools lack sensitivity and specificity for CPDs. We are in need of improved platelet function diagnostics. This thesis aimed to gain insight into the bleeding phenotype and health-status related quality of life (HR-QoL) of patients with CPDs and to evaluate the diagnostic yield of advanced diagnostic tests. Chapter 2 reviewed the currently available diagnostic tests for platelet function and their pitfalls. The laboratory diagnostics entail many techniques and these are often insufficient to diagnose mild CPDs. We described flow cytometry and whole-exome sequencing (WES) as promising additional tests for diagnosing CPDs. In Chapter 3, we evaluated the bleeding phenotype and diagnostic characteristics of CPD patients. The most common diagnostic subgroups were ADP and thromboxane A2 pathway defects and isolated thrombocytopenia. The most common bleeding symptoms were heavy menstrual bleeding (HMB) and bleeds after a hemostatic challenge. Glanzmann thrombasthenia and female sex were associated with a more severe bleeding phenotype. In Chapter 4-6 we evaluated improved and advanced diagnostic tests. Chapter 4 showed that the self-administered ISTH bleeding assessment tool (self-BAT) was sufficiently reliable and feasible to detect a bleeding tendency in patients with (suspected) CPDs. This supports the use of the self-BAT as a screening tool. A self-BAT completed at home would save valuable time during an outpatient clinic visit and enhance screening before referral to the hemoaphilia treatment center for a suspected CPD. The diagnostic accuracy of mepacrine fluorescence measured on the flow cytometer for storage pool disease was evaluated in Chapter 5. This test showed good discriminative ability and, although the sensitivity and specificity were moderate, we showed that this test can be used to exclude storage pool disease in patients suspected for a CPD. A DNA-based approach has been proposed to increase the diagnostic rate of CPDs. Genetic analysis can provide accurate diagnoses and is proposed to be performed as a first-line investigation. However, Chapter 6 showed a limited diagnostic yield of genetic testing with a selected gene panel in patients suspected for a CPD. We recommended to not perform genetic analysis as a first-line investigation, but only in patients in whom a CPD is confirmed. Chapter 7 reported the HR-QoL of patients with suspected or confirmed CPDs. We showed that HR-QoL is significantly impaired in suspected or confirmed CPD patients as compared to the general Dutch population and that this patient group is one to care for. Taken together, this thesis contributed to our understanding of CPDs. We gained insight into the clinical characteristics and burden of disease of patients with CPDs and showed the advantages and limitations of advanced diagnostic tests. In the near future, we should continue to put these patients in the spotlight in order to create awareness among health professionals and society and we should continue to gain insight into platelet pathophysiology and molecular mechanisms in order to improve the diagnostic work-up for CPDs.