Full Review Haemostasis in chronic kidney disease

The coagulation system has gained much interest again as new anticoagulatory substances have been introduced into clinical practice. Especially patients with renal failure are likely candidates for such a therapy as they often experience significant comorbidity including cardiovascular diseases that require anticoagulation. Patients with renal failure on new anticoagulants have experienced excessive bleeding which can be related to a changed pharmacokinetic profile of the compounds. However, the coagulation system itself, even without any interference with coagulation modifying drugs, is already profoundly changed during renal failure. Coagulation disorders with either episodes of severe bleeding or thrombosis represent an important cause for the morbidity and mortality of such patients. The underlying reasons for these coagulation disorders involve the changed interaction of different components of the coagulation system such as the coagulation cascade, the platelets and the vessel wall in the metabolic conditions of renal failure. Recent work provides evidence that new factors such as microparticles (MPs) can influence the coagulation system in patients with renal insufficiency through their potent procoagulatory effects. Interestingly, MPs may also contain microRNAs thus inhibiting the function of platelets, resulting in bleeding episodes. This review comprises the findings on the complex pathophysiology of coagulation disorders including new factors such as MPs and microRNAs in patients with renal insufficiency. INTRODUCTION The introduction of new anticoagulants into clinical practice has again shed light on the problem of coagulation disorders in patients with chronic renal failure as these patients can experience severe bleeding disorders during a therapy with such new compounds. A major problem is the prolonged halflife of some new substances due to pharmacokinetic changes namely accumulation of the compounds during renal failure. Moreover, even without coagulation-modifying compounds, the function of the coagulation system itself is already profoundly changed in patients with renal failure, as they are prone to episodes of prolonged bleeding. On the other hand, they may also develop excessive formation of thrombi [1]. Bleeding disorders are the result of insufficient function of platelets, the coagulation cascade and/or activation of the fibrinolytic system, while hypercoagulability is rather the result of disorders of the coagulation regulatory factors as well as platelet hyperreactivity [1, 2]. Little is known so far about the reasons why one patient develops bleeding problems, while another tends to head towards excessive thrombus formation. However, both problems are of significant clinical relevance as some patients can be endangered by fatal bleeding episodes such as prolonged bleeding from the dialysis fistula, gastrointestinal bleeding or cerebral haemorrhage, while other patients experience a prothrombotic status associated with an increased number of cardiovascular events or © The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. 29 recurrent thrombosis of the dialysis access with insufficient dialysis quality [2]. The reasons for these disorders are complex and involve the coagulation cascade, the fibrinolytic system, the platelets, the endothelium, or, the vessel wall with its extracellular matrix. The relationship between these components is influenced by uraemic toxins and metabolic compounds accumulating during renal insufficiency [3]. Furthermore, patients with renal insufficiency suffer from a varying degree of inflammation, which also influences haemostasis [4]. Structural changes in the vessel wall related to arteriosclerosis may also influence coagulation [5]. Thus, patients with renal failure have a complex disturbance of their coagulation system, which makes them prone to severe bleeding episodes or thromboembolic events. If this already heavily disturbed system is further deranged by anticoagulants, potentially fatal sequalae can result particularly if one considers that anticoagulants may accumulate in patients with renal insufficiency due to their reduced renal elimination [6]. Altogether, patients with renal insufficiency are prone to coagulation disorders due to the complex interactions of uraemic toxins, morphologically changed vessel walls including the endothelium with the coagulation cascade and platelets, which is further complicated by anticoagulants that have the potential to accumulate in these patients. INCREASED RISK OF BLEEDING Bleeding has been reported in 40–50% of patients with chronic renal failure or on haemodialysis (HD) [7, 8]. Another study reported bleeding events in 24% of patients on HD [9]. A hospital-based study showed that the risk of bleeding episodes is increased ∼2-fold in patients with renal failure [10]. Clinically, an increased bleeding tendency in patients with renal failure may present as gastrointestinal bleeding, bleeding from cannulation sites, retinal haemorrhage, subdural haematoma, epistaxis, haematuria, ecchymosis, purpura, bleeding from the gums, gingival bleeding, genital bleeding, haemoptysis, telangiectasia, haemarthrosis and petechiae (Table 1) [7, 8]. What could be the pathophysiological basis for the increased risk of bleeding in patients with renal failure?