The work described in this thesis had two objectives, specifically focusing on people aged 70 years and older: first, we aimed to investigate the associations between several thrombosis-related... Show moreThe work described in this thesis had two objectives, specifically focusing on people aged 70 years and older: first, we aimed to investigate the associations between several thrombosis-related risk factors described in young and middle-aged populations and the risk of venous thrombosis (VT) in the elderly; second, we aimed to provide insight into several long-term consequences (i.e., health-related quality of life (HRQoL) and long-term risk of mortality) after a first VT at old age. Show less
Background: There is room for improvement of prevention of venous thromboembolism (VTE) after lower-leg cast application or knee arthroscopy. Information about the mechanism of clot formation in... Show moreBackground: There is room for improvement of prevention of venous thromboembolism (VTE) after lower-leg cast application or knee arthroscopy. Information about the mechanism of clot formation in these patients may be useful to identify new prophylaxis targets. We aimed to study the effect of 1) lower-leg injury and 2) knee arthroscopy on thrombin generation. Methods: A cross-sectional study was conducted using plasma samples of POT-(K)CAST trials to measure ex vivo thrombin generation (Calibrated Automated Thrombography [CAT]) and plasma levels of prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin (TAT), fibrinopeptide A (FPA). Plasma was obtained shortly after lower-leg trauma or before and after (< 4 h) knee arthroscopy. Participants were randomly selected from those who did not develop VTE. For aim 1, samples of 88 patients with lower-leg injury were compared with 89 control samples (i.e., preoperative samples of arthroscopy patients). Linear regression was used to obtain mean differences (or ratios if ln-retransformed because of skewedness) adjusted for age, sex, body mass index, comorbidities. For aim 2, pre- and postoperative samples of 85 arthroscopy patients were compared, for which mean changes were obtained. Results: In patients with lower-leg injury (aim 1), endogenous thrombin potential, thrombin peak, velocity index, FPA and TAT were increased as compared with controls. In arthroscopy patients (aim 2), pre- and postoperative levels were similar for all parameters. Conclusion: Lower-leg trauma increases thrombin generation both ex vivo and in vivo, in contrast to knee arthroscopy. This may imply that the pathogenesis of VTE is different in both situations. Show less
The venom of the Australian snake Pseudonaja textilis contains coagulation factors V (five) and X (ten) which have been adapted to derail the blood clotting system of its prey. Snake venom factor V... Show moreThe venom of the Australian snake Pseudonaja textilis contains coagulation factors V (five) and X (ten) which have been adapted to derail the blood clotting system of its prey. Snake venom factor V is unique in that is constitutively active, unlike its human counterpart. The snake liver transcriptome was found to contain alternatively spliced factor V mRNA that encoded for either the activated protein or its quiescent form. A potential pre-mRNA splicing mechanism was uncovered that may yield the active protein. Snake venom factor V is also particularly stable due to several modifications to its molecular structure. These modifications have been investigated in detail by engineering chimeras of human and snake venom factor V. The snake venom factor X molecule was also investigated in more detail. It was discovered that this enzyme is insensitive to the action of certain anticoagulant drugs (Factor Xa inhibitors) due to a unique molecular modification. A Human factor X can be modified in similar fashion, so that it is no longer sensitive to the action of Factor Xa inhibitors. This finding could make an important contribution to acute care for patients who experience life-threatening bleeding after the use of FXa inhibitors. Show less
The aim of this thesis is to identify emerging risk factors for VTE. To achieve this goal, we describe the supposedly causal role of statin and glucocorticoid use (i.e. two drugs that can influence... Show moreThe aim of this thesis is to identify emerging risk factors for VTE. To achieve this goal, we describe the supposedly causal role of statin and glucocorticoid use (i.e. two drugs that can influence inflammation) with changes in hemostasis and VTE risk. Systemic glucocorticoid use increases the relative risk of first VTE by more than three-fold and confers an 5% absolute risk of recurrent VTE per year. On the other hand, rosuvastatin use may reduce the risk of first VTE by 40%. Although the mechanisms behind this association are not fully elucidated, this thesis shows that rosuvastatin is capable of decreasing the thrombin generation potential by 10% in patients with a prior VTE. This thesis has shown that both statins and systemic glucocorticoids can affect the risk of VTE, improving the knowledge on the influence of these two commonly prescribed drugs on VTE pathophysiology. These findings have the potential to further refine the assessment of VTE risk since they highlight that the use of these drugs should be considered when evaluating the risk of VTE. Finally, this thesis provides insight into new therapeutic approaches since the results underscore that treatment strategies on VTE prevention in patients already taken statins, which may be sufficient for VTE prevention, are lacking. Treatment strategies to prevent glucocorticoid-associated VTE are also needed. Show less
