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.
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]
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]
Desmopressin doses for uremic bleeding are approximately 10-fold higher than doses used for diabetes insipidus, and range from 0.3 μg/kg to 0.4 μg/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]
