Cover Page
The handle
http://hdl.handle.net/1887/123180
holds various files of this Leiden
University dissertation.
Author:
Rietveld, I.M.
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ENGLISH SUMMARY
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ENGLISH SUMMARY
Blood coagulation is a complex system that involves components from the vessel wall, circulating platelet and blood cells, and plasma proteins for effective blood clot formation, of which an overview is provided in Chapter 1. In short, following damage to the vessel wall, a series of enzymatic steps hallmarking coagulation is triggered due to subendothelial tissue factor exposure to circulating coagulant proteins. This leads via various enzymatic steps including positive feedback reactions in which thrombin plays a key role in the formation of a fibrin network that stabilizes the primary blood clot to prevent bleeding. The quick formation of the fibrin clot is kept in balance by anticoagulant reactions and negative feedback reactions. When the levels of pro- and anticoagulant factors in blood differ from normal, these enzymatic reactions might be out of balance. This may either result in too little fibrin formed or unstable fibrin networks leading to bleeding, or in an excess of fibrin clot formation, leading to VTE. The effect of altered levels of various coagulation factors in these disease states is described in the following chapters.
Bleeding in FXI deficiency
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active FV variant had limited effect on enhancing thrombin generation in FXI deficiency, the APC-resistant FV variant could increase thrombin generation and restore clot stability. Therefore, when the substitution of FXI in FXI deficiency as therapeutic treatment is not possible, future alternative therapies might focus on targeting the protein C pathway to restore hemostasis in FXI deficiency.
Increased coagulation factor levels in VTE
Altered coagulation factor levels are not only associated with bleeding, but also with VTE, in which case (obstructive) blood clots are formed in the veins. Elevated levels of many coagulation factors are associated with an increased risk for VTE, but the precise contribution of these factors is incompletely understood. In Chapter 3, the levels of eight procoagulant factors (fibrinogen, prothrombin, FVII, FVIII, FIX, FX, FXI, and VWF) were measured in 2377 patients who experienced a first VTE event and in 2940 healthy control subjects of the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study. The dependence on concurrent increased coagulation factor levels and risk for developing VTE was determined. For all coagulation factors we found that the VTE risk increased with increasing factor levels, with odds ratios (ORs; >99th
percentile compared with the reference group (<25th percentile)) between 1.8 and 4.0,
except for FVIII and VWF for which higher risks were found (OR 23.0 and 24.0, respectively). To study the relation between the concurrent coagulation factor levels, each factor was adjusted for all other coagulation factors. This resulted in an attenuation of all ORs, with the highest remaining risk for FVIII and VWF (OR 16.0 and 17.6, respectively). Consistent with this observation, adjustment of the individual coagulation factor levels (other than those of FVIII and VWF) for the FVIII and VWF levels resulted in similar ORs. This indicates that the observed relation between high coagulation factors and VTE is largely explained by FVIII and VWF. Therefore, FVIII and VWF appear to be the most important link between elevated coagulation factors and VTE.
Altered levels of FV in VTE
In addition to the earlier mentioned procoagulant coagulation factors that are associated with VTE, several studies report an association between increased or decreased levels of FV and VTE. In Chapter 4, we used the MEGA study to determine the relation between both high and low levels of FV and VTE. High levels of FV (> 95th percentile) were associated
with VTE (OR 1.86; reference group 25th–50th percentile). We observed that this association
was largely dependent on concurrent high levels of FVIII. Therefore, VTE seems not directly caused by high levels of FV, but the relation appears to be mediated by FVIIII. Low levels of FV (< 1st percentile) were also associated with VTE (OR 1.46). Here the association was
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can also act as an anticoagulant by, amongst others, functioning as a cofactor for the APC-dependent inactivation of activated FVIII. Furthermore, as a variant of FV (FV-short) is known to interact with the anticoagulant protein TFPI, a reduction in FV-short levels may result in lowered anticoagulant TFPI levels, thereby potentially increasing the risk for VTE. Future research will be needed to evaluate this hypothesis.
