Mapping the Diagnostic Maze of Platelet Function Disorders

Platelet function disorders are characterized by (spontaneous) bruising, prolonged bleeding time and menorrhagia. Severe platelet function disorders can give rise to life threatening bleeding episodes, but unrecognized mild platelet function disorders can be equally dangerous. Therefore, the diagnosis of platelet function disorders is important. In almost half of the patients with platelet function disorders, the exact cause remains unclear, so there is an unmet need for improved diagnostic tests to identify a platelet function disorder in patients with a bleeding tendency. The aim of this thesis is to improve the diagnostic approach for platelet function disorders and to identify the pathophysiological mechanism in patients with bleeding symptoms of unknown cause. A potential test for the diagnosis of platelet function disorders, recommended by the International Society for Thrombosis and Haemostasis, is to measure agonist induced platelet reactivity on the flow cytometer. However, this test is barely used as a diagnostic tool because it lacks validation and standardization. In chapter 2 the challenges among validating and implementing new diagnostic tests for platelet function disorders are discussed. The main obstacle is the lack of a gold standard to compare a new assay, but it is feasible in a clearly defined patient population, in which many other causes for a bleeding disorder are excluded. Chapter 3 describes the validation of this flow cytometric platelet function test and showed that it has added value in diagnosing a platelet function disorder compared to light transmission aggregometry (LTA), the most commonly used platelet function test. However, it is not yet able to replace this assay and should be performed in addition to this test. Another application of this flow cytometric test is the use of mepacrine fluorescence for diagnosis dense granule deficiency. It has been shown in chapter 4 that mepacrine fluorescence is well suited as a screening tool for dense granule deficiency. Although genetic testing was suggested to be promising in diagnosing platelet function disorders, the diagnostic value of genetic analysis in patients with suspected platelet function disorders was limited, as described in chapter 5. Therefore, we are still in a better understanding of the role of genetics in platelet function disorders. In Chapter 6 we have identified and described a new mechanism of severe macrothrombocytopenia in two young sisters with a GNE mutation. This genetic variant results in hyposialylated platelets, which are rapidly removed from the circulation in the liver. Finally, chapter 7 shows how bleeding symptoms can occur as a consequence of monoclonal gammopathy and that those bleeding symptoms can be successfully managed by threating the monoclonal antibody. The work presented in this thesis contributes to the better understanding of platelet function disorders and its diagnosis. However, the diagnostic maze of platelet function disorders is not solved yet and deserves further research to help those patients to find their diagnosis