Blood coagulation is a highly specialized process that is required to prevent blood loss following vascular damage. Central to the formation of a blood clot are the blood coagulation proteins... Show moreBlood coagulation is a highly specialized process that is required to prevent blood loss following vascular damage. Central to the formation of a blood clot are the blood coagulation proteins factor V and factor X. Aside from preventing blood loss, the coagulation system can also be exploited to gain selective advantages. The procoagulant venom of the Australian Elapid snakes comprises a powerful prothrombin-activating enzyme complex consisting of FV- and FX-like proteins that are specifically expressed in the venom gland. These coagulation proteins have evolved into potent toxins due to some remarkable gain-of-function adaptations that enable this prothrombinase-like complex to initiate coagulation in an uncontrolled manner. In this thesis, we focus on the unique evolutionary adaptations of the P. textilis venom derived proteins v-ptFV and v-ptFX. By using biochemical approaches, we assess the structure-function relationships of several uniquely modified structural elements Show less
Factor Xa‐targeting DOACs were recently found to reduce recurrentVTE efficiently in cancer patients when compared to the standard treatment withlow‐molecular‐weight heparins (LMWHs). While the... Show moreFactor Xa‐targeting DOACs were recently found to reduce recurrentVTE efficiently in cancer patients when compared to the standard treatment withlow‐molecular‐weight heparins (LMWHs). While the anticancer effects of LMWHshave been extensively studied in preclinical cancer models, the effects of FXa‐targetingDOACs on cancer progression remain to be studied.We investigated whether the FXa‐targeting DOAC rivaroxaban and thethrombin‐targeting DOAC dabigatran etexilate (DE) affected human breast cancergrowth and metastasis in orthotopic xenograft models.Mice that were put on a custom‐made chow diet supplementedwith rivaroxaban (0.4 or 1.0 mg/g diet) or dabigatran etexilate (DE) (10 mg/g diet)showed prolonged ex vivo coagulation times (prothrombin time [PT] and activatedpartial thromboplastin time [aPTT] assay, respectively). However, rivaroxabanand DE did not inhibit MDA‐MB‐231 tumor growth and metastasis formationin lungs or livers of 7‐week‐old fully immunodeficient NOD/SCID/ƴC−/− (NSG) mice.Comparable data were obtained for rivaroxaban‐treated mice when using NOD‐SCIDmice. Rivaroxaban and DE treatment also did not significantly inhibit tumor growthand metastasis formation when using another human triple negative breast cancer(TNBC) cell line (HCC1806) in NOD‐SCID mice. The FXa and thrombin‐induced geneexpression of the downstream target CXCL8 in both cell lines, but FXa and thrombin,did not significantly stimulate migration, proliferation, or stemness in vitro.Although effectively inhibiting coagulation, the DOACs rivaroxaban andDE did not inhibit orthotopic growth and metastasis of human TNBC. It remains to beinvestigated whether DOACs exert antitumorigenic effects in other types of cancer. Show less
