Abstract
Platelet function plays a critical role in hemostasis, and dysfunction in this mechanism is implicated in a range of bleeding disorders. The most rare inherited platelet function disorders (IPFDs) are relatively easy to diagnose. However, the more prevalent IPFDs often show a high diagnostic difficulty, leading to underdiagnosis. In terms
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of treatment of IPFD patients, no prophylactic treatment is available, causing high patient burden and relatively low quality of life for patients suffering from a severe IPFD. This thesis describes novel diagnostic and therapeutic approaches for this group of disorders. Advanced diagnostics … In Chapter 2, we described the characterization of a tetrameric nanobody-based glycoprotein VI (GPVI) platelet agonist and compared it to current agonists used in platelet diagnostics, that are hard to standardize and difficult to produce. We showed that our nanobody is able to discriminate between healthy controls and GPVI-related platelet disorders to a similar extent as collagen or cross-linked collagen-related peptide (CRP-XL). In this way, we provide a more stable, easier to produce alternative to current GPVI agonists, which is beneficial for standardization of platelet diagnostics. In Chapter 3, we have validated a novel whole blood-based rapid test for delta storage pool disease (δ-SPD), based on platelet ATP secretion. The current standard for diagnosis of δ-SPD is laborious, has a long turn-around time and requires large volumes of blood. We aimed to introduce a microarray that decreases the labor intensiveness, turn-around time and required volume of blood. With its high sensitivity, this test is able to exclude δ-SPD, decreasing the need to send all patients for more advanced diagnostic techniques. In Chapter 4, we have compared the platelet proteome of healthy controls and people with Glanzmann thrombasthenia (GT). We have shown that platelets from GT patients show downregulation of several platelet specific α-granule proteins. … and novel therapeutics for inherited platelet function disorders In Chapter 5, we introduced a potential novel prophylactic treatment for inherited bleeding disorders. HMB-001 is a bispecific antibody that recognizes (activated) coagulation factor VII (FVII(a)) and TREM-like transcript-1 (TLT-1) on the activated platelet surface, thereby targeting FVIIa to the platelet surface and boosting fibrin formation to compensate for defects in primary hemostasis. Our preclinical data has shown that HMB-001 is effective in enhancing fibrin formation ex vivo, prolonging endogenous FVIIa half-life in nonhuman primates and potentiating FVIIa hemostatic activity in mouse bleeding studies. HMB-001 has therefore potential to offer subcutaneous prophylactic treatment to prevent bleeds in people with GT and other inherited bleeding disorders, with a low-frequency dosing regimen.
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