While haemophilia

A and B are characterized by haemorrhages into joints and muscle, it is notable that bleeding occurs frequently into skeletal, but rarely cardiac muscle. This observation suggests that the clotting system does not function in an identical fashion in all vascular beds, even within organs with seemingly analogous physiological functions. Mice expressing low levels of TF (≈1% http://www.selleckchem.com/products/BIBW2992.html of normal; sufficient to avoid the intra-uterine lethality associated with complete deficiency [8]) have contributed to our understanding of the role of vessel wall TF in haemophilic patterns of bleeding. Specifically, in the perivascular space of normal mice and humans, TF is abundant in the heart, lung, brain, testis, uterus and placenta, MI-503 price but not in joints or skeletal muscle. However, these ‘low TF’ mice – as well as those

lacking factor VII expression – develop age-dependent bleeding into the heart, lungs, brain, testis, uterus and placenta [9]. Collectively, these observations suggest that haemostasis in joints and skeletal muscles is critically dependent on factors VIII (FVIII) and IX (FIX), whereas the ‘extrinsic pathway’ comprising TF and FVIIa is more pertinent in the maintenance of haemostasis in other organs, such as the heart [10]. Factor VIII is normally produced by specialised endothelium such as sinusoidal endothelial cells in the liver [11]. Utilizing gene transfer or cellular therapy, successful targeting of FVIII expression to this specialized form of endothelium has been achieved in mouse models of haemophilia A [12,13], although equally satisfactory haemostatic outcomes can be obtained by non-selective endothelial expression of FVIII [14,15]. On the other hand, mice engineered to express mutant FIX that fails to bind to collagen

type IV (while retaining normal procoagulant activity in standard clotting assays) exhibit a mild haemorrhagic phenotype [16]. This observation is likely explained by the fact that the full haemostatic effect of FIX is partially dependent on its binding to sub-endothelial collagen IV, but it remains unclear whether haemostasis is equally impaired in all vascular beds. Finally, the vessel wall contribution to selleck compound haemostasis offers some special opportunities and challenges in the development of bypassing therapies for haemophilic patients with inhibitors. High-dose recombinant factor FVIIa probably works primarily through TF-independent activation of factor X. However, abnormal endothelial expression of TF in the patient with atherosclerotic disease (or possibly sepsis) may pose a risk of thrombosis. It remains to be seen whether other emerging bypassing therapies, such as those that inhibit TF pathway inhibitor [17], exhibit a favourable risk–benefit profile in haemophilia, particularly in the presence of abnormal vessel wall TF expression.