Keywords

Introduction

Bleeding episodes substantially contribute to morbidity and mortality in patients with end-stage renal disease. Here, uremia with the accumulation of uremic toxins plays an important pathogenic role [1]. In particular, an impaired function of platelets, the disturbed interaction between the vessel wall with its endothelium and its extracellular matrix with the platelets, and anemia are all involved in the complex problem of the increased bleeding tendency in uremic patients [1, 2]. Bleeding episodes occur in 24–50% of patients on hemodialysis (HD) [3,4,5]. A hospital-based analysis reported an approximately twofold increased risk of bleeding in patients with renal failure [6]. Furthermore, bleeding events and access site bleeding requiring transfusion were significantly associated with degrees of renal insufficiency in patients undergoing percutaneous coronary intervention [4]. Clinically, an increased bleeding tendency in patients with renal failure may present as gastrointestinal bleeding, bleeding from cannulation sites, retinal hemorrhage, subdural hematoma, epistaxis, hematuria, ecchymosis, purpura, bleeding from the gums, gingival bleeding, genital bleeding, hemoptysis, telangiectasia, or hemarthrosis [4, 5].

Anticoagulants, particularly direct oral anticoagulants (DOACs) with their potential to accumulate in patients with renal failure, may further interfere with this system, thus promoting bleeding episodes in such patients [7]. While DOACs were associated with a non-statistically significant decreased risk for major bleeding compared to vitamin K antagonist in patients with eCrCL (estimated creatinine clearance) <50 mL/min, they differ from each in their relative risk, with only apixaban and edoxaban being associated with a decreased risk while rivaroxaban and dabigatran are not [8].

Pathophysiology of Bleeding in Patients with Uremia

Clot Formation and Platelets

Patients with advanced chronic kidney disease seem to have an increased clot strength [9,10,11]. Furthermore, the clot formation is delayed and lysis is decreased in these patients, which is associated with increased fibrinogen levels. A delayed clot formation may predispose to bleeding complications in patients with advanced chronic kidney disease, while the increased clot strength and decreased breakdown may be related to thrombosis [6, 12]. This increased clot strength seems to be associated with increased levels of fibrinogen in patients with advanced chronic kidney disease [13]. This could be a compensatory mechanism to regulate the deranged hemostasis in these patients [10, 14]. Thus, increased levels of fibrinogen and increased clot strength could be also responsible for the thrombotic events in chronic kidney disease patients. Patients on hemodialysis on the other hand have a decreased clot strength and increased lysis as compared to chronic kidney disease patients not on dialysis. This could be related to the decreased levels of fibrinogen and von Willebrand factor (VWF) or increased tissue plasminogen activator levels after dialysis [15, 16].

However, platelet function itself is also heavily disturbed in uremia [1, 8]. This is emphasized by the observation that platelet function returns to normal after successful kidney transplantation [17]. The pathogenesis of bleeding complication is believed to be multifactorial, including an acquired platelet function disorder characterized by reduced integrin activation and aggregation in response to agonist stimulation [18]. On the other hand, a study in patients with chronic kidney disease undergoing percutaneous coronary intervention showed that the prevalence of high residual platelet reactivity for ADP was higher among patients with more severe chronic kidney disease (CKD G 3–5) [19]. High residual platelet reactivity was not associated with major cardiocirculatory events in a 2-year follow-up of these patients. Interestingly bleeding risks were significantly lower in patients with high residual platelet reactivity for ADP.

Uremic toxins such as phenol, phenolic acid (impairment of primary aggregation to ADP), and guanidinosuccinic acid (inhibition of the second wave of ADP-induced platelet aggregation) influence platelet function [20,21,22] although a correlation between the bleeding time and the concentration of the dialyzable uremic metabolites was not detected so far [23]. However, dialysis improves platelet function and reduces the bleeding risk [24,25,26,27,28]. Urea itself does not seem to interfere with platelet function [29]. Platelet components such as α-granules [25, 30] have an increased ATP/ADP ratio and a reduced content of serotonin in uremia. Furthermore, the thrombin-triggered release of ATP together with an increased calcium content and a disturbed intracellular calcium flux could contribute to the impaired platelet function in uremia [25]. The disturbed arachidonic acid and prostaglandin metabolism with an impaired synthesis and/or release of thromboxane A2 leads to a reduced adhesion and aggregation of platelets contributing to bleeding episodes [25, 31], which can be reversed by dialysis [32]. In addition, ultrafiltrates collected from uremic patients inhibited platelet-activating factor synthesis that could account for the decreased platelet activity [33]. Furthermore, circulating fibrinogen fragments have been demonstrated that can also interfere with hemostasis as they competitively bind to the glycoprotein (GP) IIb/IIIa receptor on platelets resulting in a decreased adhesion and aggregation potential of platelets [34]. Oxidative stress and inflammation also have a profound effect on platelet function [35].

Platelet–Vessel Wall Interactions

A decreased amount of GPIb on platelets [4] together with the insufficient binding of VWF and fibrinogen to activated platelets from uremic patients can reduce the function of the GPIIb/IIIa complex that is important for the binding of platelets to the vessel wall in order to stop bleeding. In addition, a functional defect in VWF–platelet interaction can be related to an increased bleeding tendency in uremic patients [36, 37].

Moreover, vasoactive substances such as nitric oxide (NO), inhibiting platelet aggregation through the formation of cGMP, or prostacyclins, which modulate vascular tone, can also play a role in defective hemostasis in uremia. Plasma levels of prostacyclin, NO generation of platelets, and the concentration of NO metabolites, which is also related to the lower hemoglobin levels (see below), are increased in the plasma of uremic patients, thus contributing to dysfunctional hemostasis with an increased bleeding risk [38, 39].

Anemia

Anemia can promote bleeding episodes in uremic patients as it directly influences the bleeding time [40,41,42]. In anemia platelets flow in the middle of the bloodstream due to the lower number of erythrocytes. This impairs the interaction between platelets and the vessel wall resulting in a prolonged bleeding time. And erythrocytes significantly improve platelet adhesion and aggregation in in vitro flow chamber systems, and negative correlations have been found between hematocrit and bleeding time. Furthermore, the low number of erythrocytes with a reduced hemoglobin amount leads to a reduced scavenging of NO [43], thus decreasing ADP and thromboxane A2 release via an enhanced activation of guanylyl cyclase [44] with increased cGMP levels. This inhibits platelet aggregation and inactivation of prostacyclin [45]. Consistently, erythropoietin treatment has a beneficial effect on the bleeding time, but not platelet activation, in renal failure patients [18].

Drugs

Drug–platelet interactions have fundamental effects on platelet function and thus on bleeding disorders, which is also the case in patients with uremia. Antibiotics such as third-generation cephalosporins and β-lactam antibiotics play a role under these circumstances [46, 47]. β-Lactam antibiotics interact with platelets through an interference with ADP receptors. These effects are related to dose and duration of the therapy. Acetylsalicylic acid has been shown to significantly prolong the bleeding time in patients with renal failure [48]. Furthermore, other nonsteroidal anti-inflammatory drugs also alter platelet function through the inhibition of cyclooxygenase, although this is reversible after discontinuation of the drug.

As many anticoagulants are eliminated by the kidney, they can accumulate if their dose is not adapted to the patient’s renal function [7]. Anticoagulants that can accumulate in patients with renal impairment include low-molecular-weight heparins (LMWHs), direct factor Xa inhibitors like danaparoid and fondaparinux, and the DOACs such as rivaroxaban, edoxaban, or apixaban as well as the direct thrombin inhibitors refludan and dabigatran. Interestingly, the effect of vitamin K antagonists such as phenprocoumon or warfarin could be aggravated in patients with end-stage renal disease as these patients can develop a vitamin K deficiency [49]. Discussions on the use of the different anticoagulants at different stages of chronic kidney disease are presented in a comprehensive recent review [50].

Management of Bleeding in Patients with Uremia

Management of bleeding in patients with uremia encompasses substances, blood compounds, and procedures that can be used alone or partly in combination (see Table 19.1). However, it must be emphasized that while treating bleeding episodes in uremic patients with potential comorbidities, clot formation is promoted that could lead to other clinical problems in terms of thrombus formation or embolism at other sites (i.e., myocardial ischemia, fistula occlusion).

Table 19.1 Management of bleeding in uremic patients
Full size table

Dialysis

Uremic toxins contribute to the bleeding tendency in patients with end-stage renal disease. The removal of uremic toxins by dialysis improves platelet function with a reduced risk of bleeding [24,25,26,27,28]. On the other hand, hemodialysis itself can enhance the bleeding tendency, due to the intradialytically administered anticoagulants (i.e., heparin) but also due to continuous platelet activation at the dialyzer membrane resulting in a decreased platelet activity [28, 51, 52]. Furthermore, an activation defect of the platelet GPIIb/IIIa complex could be involved in the bleeding tendency of some patients related to hemodialysis [24] as the expression of the GPIIb/IIIa receptor on thrombocytes is higher in peritoneal dialysis [53], which has been shown to maintain in vitro platelet aggregation better as compared to hemodialysis [54]. Moreover, peritoneal dialysis was associated with better platelet aggregation as compared to hemodialysis [55]. The reasons include apart from anticoagulant administration during hemodialysis also the removal of pro-coagulation factors, platelet loss related to the dialyzer, disruption of platelet cytoskeleton, a decrease of RNA-rich platelets, and a reduction of reticulated platelets [56]. Furthermore, a better elimination of middle molecules could be responsible for the advantages of peritoneal dialysis with respect to hemodialysis [54]. However, it is not known how actual dialysis procedures such as hemodiafiltration (HDF) compare to peritoneal dialysis as also HDF effectively eliminates middle molecules. Of note, hemodialysis and peritoneal dialysis could also promote coagulation [57, 58].

Future studies should analyze the effect of modern dialysis techniques (i.e., HDF) or an increase in dialysis time on the bleeding tendency of uremic patients.

Erythropoietin

Chronic kidney disease, particularly in advanced stages, is associated with anemia due to the lack of erythropoietin (EPO). As anemia is associated with an increased bleeding tendency in uremia, the administration of erythrocytes [59] or EPO [60, 61] reduces the bleeding time as well as bleeding episodes. Administration of recombinant erythropoietin leads to an increased number of erythrocytes, thus shifting platelets more to the vessel wall where they can interact with injured sites and stop bleeding [61,62,63]. Furthermore, the number of reticulated platelets with an increased metabolic activity is higher after the administration of EPO [64, 65], the platelet aggregation and the platelet interaction with the sub-endothelium is higher [61,62,63], and erythropoietin improves platelet signaling through tyrosine phosphorylation [66]. Additionally, the scavenging capacity of NO is improved with higher hemoglobin levels after EPO therapy resulting in a lower stimulation of guanylyl cyclase with reduced production of cGMP leading to an improved platelet aggregation (see above) [43].

EPO at a dose of 40–150 U/kg intravenously three times a week has been studied in uremic bleeding [61, 63, 64]. A hematocrit greater than 30% is associated with a normalization of the bleeding time [61,62,63]. The effect occurs rather slowly after 7 days. However, EPO can be beneficial also in an acute setting as it can improve platelet function by increasing the number of GPIIb/IIIa receptors on platelets as well as increasing thrombin-induced phosphorylation of platelet proteins [62, 63, 66]. Thus, it can be used in acute bleeding episodes but also as a prophylaxis.

However, problems exist with the target parameter: the 2012 KDIGO (Kidney Disease Improving Global Outcomes) guidelines for the management of anemia in patients with renal failure refer to the hemoglobin level as the target parameter for the guidance of the EPO therapy which should be ≤11.5 g/dL as higher hemoglobin levels were associated with an increased incidence of myocardial infarction and a higher mortality [67]. The hematocrit is more variable and should be used with caution as a target parameter. Furthermore, a potential deficit of iron should also be treated before the administration of EPO can be effective. Thus, EPO should be used with caution in patients with bleeding episodes only if anemia is present with a hemoglobin below 10.5 g/dL and normal iron stores.

Vasopressin Analogues

Bleeding disorders can be treated with desmopressin (1-deamino-8-d-arginine vasopressin, DDAVP) in patients with end-stage renal disease [37]. Most studies analyzed the bleeding time that cannot properly predict the bleeding tendency in uremic patients [56]. However, also with the in vitro closure time test, the beneficial effects of desmopressin on primary hemostasis could be demonstrated [68]. A prospective non-controlled study in uremic patients on antiplatelet drugs demonstrated that a single dose of desmopressin before invasive procedures could improve platelet function measured by collagen/epinephrine closure time of PFA-100™ and was also well tolerated [69]. Furthermore, it can be also used as a prevention of bleeding episodes in such patients (i.e., renal biopsies, endoscopy, and surgery). It is administered at a dose of 0.3–0.4 μg/kg as a single dose subcutaneously or over 30 min intravenously. Both administration routes can effectively restore primary hemostasis in uremic patients [70]. So far no data exist on orally administered desmopressin although it should also be theoretically effective. Due to its rapid onset, it is recommended as the first-line treatment in uremic patients with active bleeding [56]. However, its effect reaches its maximum after 4–6 h and has nearly vanished after 8–24 h [37]. Even after one dose, tachyphylaxis might occur; thus its duration of activity is rather short [56] and treatment should not be repeated after one dose [56]. In patients with antiplatelet drugs [69] as well as heparin, desmopressin can also reduce the prolonged bleeding time [71]. Its mechanism of action is an increase of VWF, factor VIII, and tissue plasminogen activator (tPA) from storage sites mediated via the activation of vasopressin V2R receptors on endothelial cells. Plasminogen activator inhibitor 1 (PAI-1) level is diminished due to tPA release and tPA and PAI-1 complex formation. Furthermore, functional protein C level is also decreased in patients with uremia after administration of desmopressin [5, 72, 73]. Furthermore, it increases the expression of GPIb on platelets [72]. This minimizes the effects of dysfunctional VWF and leads to larger VWF multimers that reduce bleeding time [74, 75].

Conjugated Estrogens

Bleeding episodes can be also treated with conjugated estrogens in patients with uremia [76,77,78,79,80]. A double-blind randomized crossover study revealed that the administration of estrogens (0.6 mg/kg/day i.v. for 5 days) leads to a reduced bleeding time as well as an increased platelet activity in patients on hemodialysis [81]. The therapeutic effect was achieved for 7–14 days after treatment where the effect starts already 6 h after administration of the substance. An oral dose of 50 mg/kg/day leads to a measurable reduction of the bleeding time 2 days after administration and lasts for approximately 4–5 days [72, 82]. Furthermore, a transdermal estradiol patch with a dose of 50–100 μg/day can be applied twice a week [83]. This approach is also suitable for longer treatment periods as it was used for 2 months during this study. Even transdermal doses ≤50 μg daily might be effective [84]. Successful treatment of nasal bleeding has also been achieved with topical intranasal estrogens in patients with von Willebrand disease and hemophilia [85].

An increase of platelet reactivity could be mediated through the increase of β-thromboglobulin and thromboxane B2 as well as an increased synthesis of VWF and factor VIII together with a reduction of protein S levels [5]. Furthermore, uremia is associated with an increased generation of endothelium-derived NO [86], which can be prevented by estrogens [87]. Estrogens need more time until the therapeutic effect begins, while its duration is substantially longer in comparison to desmopressin [76].

Fresh Frozen Plasma, Cryoprecipitate, and Factor VIIa

Cryoprecipitate contains substantial amounts of VWF, factor VIII, fibrinogen, factor XIII, and fibronectin and thus can immediately correct defects in primary hemostasis. However, this effect will last for only 4–12 h [5, 36, 45]. It should be used only in emergency situations where a rapid correction of hemostatic defects is needed, particularly if hypofibrinogenemia with fibrinogen levels <1 g/L is present [72]. However, the effect in patients with end-stage renal disease is difficult to predict [36, 37, 88]. Infections, anaphylactic reactions, and volume overload could be adverse reactions in patients with renal failure [5, 72]. In contrast to cryoprecipitate, fresh frozen plasma contains all coagulation factors and should be used in patients with severe bleeding due to warfarin or phenprocoumon therapy where cryoprecipitate is not effective due to its low content in vitamin K-dependent coagulation factors [89].

Moreover, some case reports describe the use of recombinant activated factor VII (rFVIIa) for treatment of bleeding in uremic patients [90,91,92,93]. This approach seems attractive, as it should act only locally at the site of bleeding [94]. Thus, it has been successfully used also in a patient with bleeding after a kidney biopsy [94]. However, due to the lack of studies, only little experience exists with the use of rFVIIa in uremic patients.

Platelet Transfusion

Platelet transfusions are immediately effective in reducing the bleeding risk for approximately 4–5 h [5]. This approach should be used in emergency situations if immediate correction is warranted or if the pharmacologic approach is not effective. In transplant candidates a risk of alloimmunization, although low, exists [5].

Tranexamic Acid

Tranexamic acid inhibits fibrinolysis by forming a reversible complex with plasminogen and preventing its conversion to plasmin [5]. It can be administered orally or intravenously [72, 95]. Tranexamic acid effectively stops cerebral, gastrointestinal, or angiodysplasia-associated bleedings of the colon in patients on hemodialysis [96,97,98]. However, as it is eliminated via the kidneys, the dose should be limited to 20 mg/kg every 48 h i.v. or 10 mg/kg every 48 h p.o. [72]. Thus, tranexamic acid should not be administered over longer time periods. Single doses of tranexamic acid can be combined with other compounds in uremic patients in order to control bleeding.

Summary

Uremia develops in patients with end-stage renal disease without an adequate renal replacement therapy. Bleeding episodes are a significant clinical problem in such patients. They could be of mild character but could also result in fatal outcomes. The increased bleeding tendency in uremia results from an impaired function of platelets and a disturbed platelet–vessel wall interaction. Furthermore, anemia and anticoagulants/antiplatelet drugs contribute to the increased risk of bleeding in these patients. Management of bleeding episodes in uremic patients includes an adequate dialysis for the removal of uremic toxins that could interfere with the function of platelets and the correction of anemia with EPO in order to increase the number of red blood cells that shift platelets more to the vessel wall where they can interact with sites of injury as well as a better capacity to scavenge NO through increased amounts of hemoglobin. Furthermore, estrogens can be administered that alter VWF, factor VIII, compounds of the arachidonic acid metabolism, and the production of NO. Desmopressin improves platelet function through the release of VWF and factor VIII. In severe cases, also fresh frozen plasma or rFVIIa can be administered. Moreover, tranexamic acid that inhibits the conversion of plasminogen to plasmin can be given. In severe bleeding episodes, also combinations of the above therapeutic approaches can be considered (Table 19.1).