An active pool of __Tissue Factor__ (TF) is required to initiate blood coagulation, but the mechanism that regulates the activation of TF is highly debated. The reduced coagulant activities of both... Show moreAn active pool of __Tissue Factor__ (TF) is required to initiate blood coagulation, but the mechanism that regulates the activation of TF is highly debated. The reduced coagulant activities of both human and mouse disulfide-mutated TF indicates that the formation of a Cys186-Cys209 or Cys190-Cys213 disulfide bond in the extracellular domain of TF controls its procoagulant function. Also the strong evolutionary conservation of this allosteric disulfide bond supports previous assumption. Procoagulant active TF is also found intravascularly on small vesicles (microparticles), and high levels of microparticle-associated TF is thought to increase the risk for thrombosis in cancer patients. Despite the fact that chemotherapy is an independent risk factor for thrombosis, chemotherapy-induced tumor destruction was not associated with an increase in microparticle-associated TF in testis cancer patients. The soluble isoform of TF, alternatively spliced TF (asTF), induces angiogenesis through interaction with integrins and independent of intracellular protease-activated receptor (PAR)-mediated signaling. PAR-2 but not PAR-1 plays a role in arteriogenesis in vivo. Furthermore, PAR-2 is involved in the anti-inflammatory response that may promote arteriogenesis. Show less
Myocardial infarction and ischaemic stroke are both forms of arterial thrombosis. It is unclear to what extent hypercoagulability is a causal factor of these diseases and whether this effect might... Show moreMyocardial infarction and ischaemic stroke are both forms of arterial thrombosis. It is unclear to what extent hypercoagulability is a causal factor of these diseases and whether this effect might be different for myocardial infarction and ischaemic stroke. Several measures of hypercoagulability were investigated in the RATIO study, a nationwide population based case-control study which includes 248 women with myocardial infarction, 203 women with ischaemic stroke and 925 control women, all under 50 years of age. Chapter 2 describes the relationship of a positive family history of arterial thrombosis and the risk of either myocardial infarction or ischaemic stroke. Chapters 3-6 focus on the intrinsic coagulation proteins. Chapters 7-9 describe a genetic approach that focuses on the role of fibrinogen and coagulation factor XIII. Chapter 10 discusses the role of the fibrinolytic capacity, chapter 11 discusses VWF and ADAMTS13, and chapter 12 discusses the risk of myocardial infarction and ischaemic stroke associated with the presence of markers of the antiphospholipid syndrome. Chapter 13 provides a summary and discussion of these results. These results suggest that hypercoagulability is a cause of ischaemic stroke, whereas it does not have a major effect on the risk of myocardial infarction in young women. Show less
