Correspondence *Texas Tech University Health Sciences Center School of Pharmacy, Dallas Fort Worth Regional Campus, 4500 S Lancaster Road, Building #7, Dallas, TX 75216, USA

Email anthony.busti@ttuhsc.edu

Introduction

Uremic bleeding is a well-recognized complication in patients with renal failure.¹ It was described by Reisman almost 100 years ago in two patients with renal failure from Bright's Disease (a term no longer used but described as acute or chronic nephritis) who experienced severe and generalized bleeding.² The clinical importance of bleeding associated with chronic renal failure itself is, however, difficult to assess, especially as various dialysis techniques, comorbidities and medications are known to affect platelet aggregation and/or the coagulation cascade. When abnormal ecchymosis or bleeding occurs in patients with chronic renal failure, it is, therefore, likely to be multifactorial in nature. This Review describes normal hemostatic and homeostatic processes that prevent unnecessary bleeding, before explaining the pathophysiology of uremic platelet dysfunction and blood loss. Published studies on treatments for uremic bleeding syndrome are discussed, and evidence-based recommendations for the management of bleeding or the risk of bleeding in uremic patients are offered.

Normal hemostatic mechanisms

Under normal circumstances, platelets circulate throughout the body in an inactivated or nonadhesive state. A number of agonists can activate platelets. One of the most common is disruption of the vascular endothelium, which evokes a series of biochemical reactions to maintain normal hemostasis. The first set of reactions occurs when a platelet comes into contact with the damaged vascular endothelial surface. Exposure of the damaged endothelial lining permits introduction of collagen (particularly types I, III and VI), fibronectin, thrombospondin, von Willebrand factor (vWF), laminins, and microfibrils, which leads to a change in platelet morphology and provides support for platelet adhesion.^{3, 4, 5, 6} These changes are also facilitated when activated platelets secrete large quantities of ADP from dense granules. Activated platelets can then also contribute to adhesion through the release of various adhesive proteins (e.g. vWF, fibrinogen, fibronectin, vitronectin, and thrombospondin) from -granules.⁷ These changes effect growth of the platelet, facilitating adhesion such that collagen fibers and other platelets can be bound to ultimately form an occlusive plug. Activated platelets also secrete thromboxane A₂ (TxA₂), a well-known and potent platelet aggregator that works to stabilize the friable hemostatic plug.⁸

A second set of reactions involves activation of the coagulation cascade that eventually leads to formation of thrombin.^{9, 10} Production of thrombin is crucial to the formation and stabilization of a developing thrombus. Thrombin converts fibrinogen to fibrin monomers.^{11, 12} It also facilitates the conversion of factor XIII to factor XIIIa, which is required for clot stabilization.^{13, 14, 15} In addition, thrombin binds to protease-activated receptors on platelets, ultimately resulting in upregulation of glycoprotein Ib/IX (GPIb/IX) and glycoprotein IIb/IIIa (GPIIb/IIIa; also known as _IIb3) receptors.^{16, 17, 18, 19} GPIb/IX is a particularly important receptor for binding vWF, causing adhesion of platelets to the endothelium.²⁰ Inadequate interaction of GPIb/IX and vWF is thought to contribute to platelet dysfunction seen in uremia.

In addition to these hemostatic mechanisms, there are several homeostatic mechanisms that maintain the balance between clot formation and bleeding. Tissue plasminogen activator, urokinase plasminogen activator, prostacyclin (PGI₂), nitric oxide (NO) and ectoapyrases are released by normal, functioning endothelial cells to maintain a local antithrombotic intravascular surface and degrade ADP.^{21, 22}

Another homeostatic mechanism influencing hemostasis is laminar blood flow. This is partially influenced by hematocrit and local endogenous vasodilators, which modulate blood viscosity and vasomotor tone, respectively. A normal hematocrit facilitates the flow of red blood cells midstream, which displaces platelets such that they are closer to the endothelium; consequently, platelets can react quickly to damage to the vasculature.^{23, 24, 25} The second aspect of laminar blood flow that influences hemostasis is vessel radius, which is regulated by a number of neurological and chemical mediators including, but not limited to, PGI₂ and NO. Each of the above areas of normal hemostatic regulation is commonly altered in patients with uremia secondary to acute or chronic kidney failure.

Pathophysiology

It has been known for many decades that uremic bleeding and platelet dysfunction put patients at increased risk of general bleeding. The exact mechanism by which the risk is increased remains largely unknown, but seems to be multifactorial. Understanding of the various dysfunctional components helps to explain the pathophysiology of uremic bleeding and serves as the basis for current approaches to prevention and treatment.

Assessment

Patients with uremic bleeding typically present with ecchymoses, purpura, epistaxis and bleeding from venipuncture sites. These patients can also present with gastrointestinal or intracranial bleeding.⁴⁶ While diagnosis of uremic bleeding is still based on clinical symptoms of bleeding, evaluation of bleeding time is the most useful test to assess clinical bleeding in uremic patients.⁴⁷ Bleeding time is measured by making a small incision on the ear lobe, finger, upper arm or thigh and recording the time from the first drop of blood to the last. Normal bleeding time can range from 1–7 minutes. Azotemic indices such as blood urea nitrogen and creatinine do not correlate as well with clinical bleeding as does bleeding time. Mild thrombocytopenia might also be observed in patients with uremic bleeding; however, platelet levels rarely fall below 80 10³ cells/mm³ and cannot alone account for the severity of bleeding in these patients. Other measures of hemostasis such as prothrombin time and activated partial thromboplastin time typically remain normal.

Prevention by dialysis

As with any medical condition, prevention should always be considered for uremic bleeding. Despite preventive efforts, abnormal bruising or bleeding can still occur, reflecting the multifarious nature of uremic bleeding. Fortunately, dialysis has beneficial effects on common complications other than bleeding in patients with chronic kidney disease.

Dialysis is a necessary component of the management of patients with significantly impaired renal function. One important role of dialysis is the removal of metabolic by-products and uremic retention solutes. Uremic retention solutes have varied physicochemical properties that influence their susceptibility to removal by dialysis. These solutes can be divided into the following three categories: small water-soluble compounds, larger 'middle-sized' compounds, and protein-bound compounds. High-flux dialysis membranes (e.g. those with a large pore size) are required to remove large retention solutes; these compounds are not efficiently removed via traditional dialysis methods.⁴⁸ Proteomic analysis indicates that high-flux membranes remove substantially more polypeptides with a molecular weight greater than 5 kDa than do low-flux membranes.⁴⁹

Until recently, intradialytic kinetics of small water-soluble guanidine compounds, including guanidine, creatinine, creatine, methylguanidine, GSA and guanidinoacetic acid, were assumed to be similar to those of urea. Eloot et al., however, determined that the volume of distribution of these compounds (except GSA) was markedly higher than that of urea, a characteristic that reduces the efficiency of their removal by dialysis.⁵⁰ It has been suggested that removal of these compounds requires longer or more-frequent dialysis sessions. Binding of these compounds to protein might also influence the effectiveness of dialysis as a treatment and/or preventive measure for uremic bleeding.

In all studies of dialysis for prevention or treatment of uremic bleeding, dialysis has had an uncertain effect on platelets and coagulation. Platelet function has been shown to both worsen and improve after dialysis, making it difficult to interpret the efficacy of other treatment options for uremic bleeding.^{51, 52, 53, 54} Dialysis, particularly 48 h of weekly peritoneal dialysis, has been shown to maintain normal in vitro platelet aggregation as measured by light transmission platelet aggregometry.³⁶ More equivocally, hemodialysis has been shown in some studies to improve platelet numbers, platelet factor 3 availability and activity, prothrombin consumption index and clot retraction, and to reduce clinical bleeding.^{37, 55, 56} A study by Nenci et al., however, indicated that hemodialysis was inferior to peritoneal dialysis;⁵⁷in vitro aggregation of platelets from patients undergoing peritoneal dialysis was superior to that of patients receiving hemodialysis. Hemodialysis patients showed no improvement in platelet aggregation compared with uremic patients not receiving dialysis. The mechanisms underlying the inferiority of hemodialysis in improving platelet function have not been fully elucidated, but possibly include the requirement for heparin during hemodialysis (thereby increasing the risk of bleeding), the removal of compounds necessary for coagulation, platelet loss if cuprophan dialysis is used (not seen with polyacrylonitrile dialysis), disruption of platelet cytoskeleton organization by repeated platelet stress, a decrease in the percentage of RNA-rich platelets, and a reduction in the percentage of available reticulated platelets.^{37, 58, 59, 60}

The limitations of most of the studies on dialysis for prevention or management of uremic bleeding (listed in Table 1) are lack of clinically useful end points, inadequate sample sizes, or poor randomization techniques.^{36, 37, 55, 56, 57} For example, the study performed by Stewart and Castaldi assessed actual clinical bleeding episodes (which completely resolved with dialysis) and bleeding time, while others assessed only laboratory measures of platelet function.^{36, 37, 55, 56, 57} In the Stewart and Castaldi study, bleeding time was measured using the Ivy method (which was not used in other studies of uremic bleeding) and was defined as having normalized when less than 9 min. The investigators found that bleeding time normalized during 30% of dialysis sessions. Other methods that have been used to assess platelet function primarily evaluate platelet aggregation by light transmission aggregometry; some trials showed improvement in this parameter in patients receiving dialysis. The studies listed in Table 1 are, however, all at least 25 years old, which makes it difficult to extrapolate and apply the results to current dialysis technology. In addition, light transmission aggregometry is primarily a research technique that is not presently useful in clinical practice. Frequent dialysis remains the standard of care for many complications associated with chronic kidney disease but its impacts on the prevention and treatment of uremic bleeding are still largely unknown.

Table 1 Dialysis for prevention and treatment of uremic platelet dysfunction

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Treatment

Treatments for uremic bleeding target the various factors that seem to have a role in platelet dysfunction. Interventions can exert acute (within 6 h) or delayed (within several weeks) effects, and this should be taken into consideration when they are used for a given clinical scenario. Of the interventions presented in this section, EPO could be considered for prevention as well as for treatment.

Erythropoietin

Patients with chronic kidney disease often suffer from anemia caused by decreased production of EPO by the kidneys. Recombinant human EPO, commonly used to correct anemia, might also help to stem uremic bleeding by several different mechanisms. First, recombinant human EPO stimulates division and differentiation of erythroid progenitor cells, thereby inducing erythropoiesis. This increase in the number of circulating red blood cells displaces platelets closer to the vascular endothelium, decreasing response time to vascular damage. The net result is a reduction in bleeding time.^{61, 62, 63} Second, recombinant human EPO increases the number of reticulated platelets, which seem to be more metabolically active.^{64, 65} Third, recombinant human EPO enhances platelet aggregation as well as interaction between platelets and the subendothelium.^{61, 62, 63} Fourth, recombinant human EPO might also improve platelet signaling through tyrosine phosphorylation, which enhances the response of platelets to activating stimuli.⁶⁶ Finally, hemoglobin acts as a scavenger of NO;⁴⁵ therefore, if hemoglobin levels were to be increased using recombinant human EPO, it is proposed that NO levels would drop, resulting in less effective stimulation of guanylyl cyclase and reduced production of cGMP. Although some of these mechanisms are not well defined, they could be of benefit in the prevention and treatment of uremic bleeding (as seen in several trials; see Table 2).^{61, 62, 63, 64, 67} Adequate dialysis might minimize the required dose of recombinant human EPO, which would reduce costs.^{68, 69} This effect might not occur beyond a Kt/V (index of urea clearance) of 1.33.

Table 2 Recombinant human erythropoietin for uremic platelet dysfunction

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Recombinant human EPO regimens of 40–150 U/kg intravenously three times a week have been studied for prevention or treatment of uremic bleeding.^{61, 62, 64} The goal of treatment with recombinant human EPO, regardless of the dose used, is a hematocrit greater than 30% to decrease bleeding time to a normal or near-normal value.^{61, 62, 63} Assuming normal iron stores and baseline hematocrit, achieving a hematocrit greater than 30% can take up to 9 weeks in uremic patients.⁶³ It is important, however, to understand that beneficial effects on platelets can occur as soon as 7 days after initiation of treatment, as a result of an increase in the number of reticulated platelets.⁶⁵ Recombinant human EPO can be beneficial in the acute setting by improving both platelet adhesion and aggregation.^{62, 63}

In conclusion, recombinant human EPO can be used as prophylaxis for uremic bleeding, and also (in combination with other treatment options) during acute bleeding episodes.

Cryoprecipitate

Cryoprecipitate is a blood product rich in factor VIII, vWF and fibrinogen that is commonly used in various bleeding diatheses. The mechanism of action of cryoprecipitate has not been fully elucidated, but it is postulated that this precipitant might increase the proportion of functional clotting factors in a patient's plasma (Table 3).^{70, 71} Cryoprecipitate is a reasonable therapeutic option in uremic patients at high risk of bleeding or with active bleeding. Cryoprecipitate should have a beneficial effect on bleeding time within the first 4–12 h in most patients. Dosing is 10 bags of American-Red-Cross-prepared cryoprecipitate given intravenously over 30 min. Each bag contains variable amounts of factor VIII and fibrinogen. One advantage of using cryoprecipitate is the fast onset of action (approximately 1 h).⁷⁰ Disadvantages include risk of post-transfusion hepatitis, HIV, fever, and allergic reaction. Rare but severe reactions include anaphylaxis, pulmonary edema and intravascular hemolysis. The response in uremic patients can be unpredictable.^{70, 71}

Table 3 Cryoprecipitate for uremic platelet dysfunction

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Desmopressin

The most common agent used in uremic patients with active bleeding is desmopressin (1-deamino-8-D-arginine vasopressin [DDAVP]). It is predominately used to treat diabetes insipidus, mild type I von Willebrand's disease, and bleeding associated with hemophilia A. The mechanism of action of DDAVP has not been fully elucidated, but it is believed to exert part of its hemostatic effect by releasing factor VIII from storage sites, potentially increasing the concentration of factor VIII and minimizing the effects of dysfunctional vWF.⁷² Mannucci et al. reported that larger vWF–factor-VIII multimers are present in the plasma after infusion of DDAVP, which might reduce bleeding time.^{19, 73} Although the clinical effect of larger vWF–factor-VIII multimers is not well known, there is a strong association between their presence and shortening of bleeding time (Table 4).^{19, 73, 74}

Table 4 Desmopressin for uremic platelet dysfunction

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Desmopressin doses for uremic bleeding are approximately 10-fold higher than doses used for diabetes insipidus, and range from 0.3 g/kg to 0.4 g/kg intravenously or subcutaneously as a single injection.^{19, 73} One important advantage of DDAVP is its rapid onset of action in the setting of acute bleeding caused by uremic platelet dysfunction. The short duration of DDAVP activity could be an advantage; however, bleeding time tended to return towards baseline within 24 h, indicating patients are once again at risk of bleeding. This clinical effect is consistent with currently available literature and should be anticipated. Studies have shown that DDAVP increases vWF–factor-VIII levels and decreases bleeding time within approximately 1 h after infusion or injection.⁷³ This advantage is important for patients needing biopsies or major surgery who might not otherwise have been considered for these procedures because of their prolonged bleeding time.¹⁹ Another advantage of DDAVP over cryoprecipitate is the avoidance of risk of exposure to various blood-borne pathogens. Disadvantages of DDAVP include reported tachyphylaxis after one dose, headache, facial flushing, and rare thrombotic events.^{19, 73} The tachyphylaxis that develops is thought to be caused by depletion of vWF from endothelial stores.²¹ In addition to its short duration of activity, the potential for tachyphylaxis makes consideration of treatments other than DDAVP imperative, especially in patients with active bleeding.

Estrogens

Estrogens are commonly used for hormone replacement therapy, but also have a unique place in the treatment of uremic bleeding. While it is still uncertain how estrogens work to treat patients with prolonged bleeding time secondary to uremia, it has been postulated that the hormones decrease production of L-arginine, which is a precursor of NO.⁷⁵ By decreasing NO concentrations, which seem to be higher in uremia, there is less guanylyl cyclase stimulation and less production of cGMP. This potentially leads to increased production of TxA₂ and ADP, which are crucial contributors to formation of platelet plugs. Although none of the studies in uremic bleeding has assessed the impact of estrogens on coagulation, it is plausible that the capacity of these hormones to decrease antithrombin III and protein S levels, and increase factor VII concentrations, might contribute to the therapeutic effect in this clinical situation.⁷⁶

Currently available data show that conjugated estrogens can safely and effectively improve bleeding time and clinical bleeding in both males and females (Table 5)^{77, 78, 79, 80, 81, 82, 83, 84} The dose of conjugated estrogens needed to produce these effects is 0.6 mg/kg intravenously over 30–40 min once daily for 5 consecutive days.^{78, 79, 80} The time to onset of action for conjugated estrogens is about 6 h; maximum effect is evident at 5–7 days with a duration of approximately 14–21 days.^{78, 79, 80} More data exist to support use of intravenous estrogen, but oral and transdermal therapy have also been shown to be beneficial. The long-lasting effect of conjugated estrogens is important in patients who are scheduled to undergo surgery in the near future, who might not have been surgical candidates because of prolonged bleeding time. Estrogens have also been successfully used in patients with gastrointestinal bleeding, a common complication associated with uremic platelet dysfunction.^{82, 83, 84}

Table 5 Conjugated estrogens for uremic platelet dysfunction

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Evidence-Based Recommendations

It is clear from the available literature that much of the evidence supporting treatment recommendations for uremic bleeding comes from studies performed 25–30 years ago. At that time, medical care was different from today; studies were poorly designed, with small sample sizes and inconsistent methods of assessing platelet function that are not currently used in standard clinical practice. Nonetheless, many clinicians today have patients with either active bleeding or a high risk of bleeding because of chronic renal failure. As a result of the complexity of uremic platelet dysfunction and the varying degrees of efficacy of potential treatments, we have proposed an evidence-based management algorithm that can help guide clinicians through most clinical scenarios of uremic bleeding (Figure 1). We have also answered common questions relating to management of uremic bleeding. The responses to and rationale underlying these basic questions are consistent with and supportive of the proposed treatment algorithm. It is important to keep in mind that these recommendations are not a substitute for a clinician's judgment and must be used alongside consideration of extraneous variables that might be contributing to the bleeding.

Figure 1 Algorithm for the management of uremic platelet dysfunction

If at any stage in the algorithm the patient with uremic platelet dysfunction should start to actively bleed, the clinician should return to the top of the algorithm. This algorithm is not intended to replace sound clinical judgment or prevent additional consideration of patient factors that could influence management decisions. Abbreviations: DDAVP, desmopression (1-deamino-8-D-arginine vasopressin; single doses of 0.3–0.4 g/kg body weight intravenous); EPO, erythropoietin.

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Conclusions

Uremic bleeding in patients with chronic renal failure is extremely complex. One factor contributing to this complexity is the incomplete elucidation of the pathophysiology of the condition. As we do not fully understand the mechanisms underlying uremic bleeding, prevention and treatment for many different clinical scenarios are not clearly defined. Treatment options tend to focus on one, perhaps two, aspects of the pathophysiology; their relative effects are summarized in Table 6. EPO works to increase the number of red blood cells, allowing platelets to travel in closer proximity to the endothelium. Cryoprecipitate and desmopressin work to increase the proportion of normal or functional factors that might be dysfunctional in patients with uremic bleeding. Estrogens are thought to work by decreasing NO levels, thereby increasing concentrations of TxA₂ and ADP. Multiple interventions that simultaneously affect different aspects of the pathophysiology of uremic bleeding might most effectively prevent bleeding in high-risk patients and limit active bleeding in those for who cessation of blood loss is more pressing. The benefit of early evaluation to identify patients at high risk of bleeding cannot be underestimated. By determining which patients are most at risk, clinicians can utilize dialysis and EPO in the early stages of uremic bleeding, and employ desmopressin, cryoprecipitate and/or estrogens prior to a surgical procedure, thereby possibly preventing bleeding secondary to uremic platelet dysfunction. If a patient presents with uremia, clinicians should remain vigilent for early signs and symptoms of bleeding so that the efficacy of intervention can be maximized.

Table 6 Summary of relative effects of different treatment options in uremic bleeding

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Subject areas under which this article appears: Progression of renal disease