Evidence-Based Treatment Recommendations for Uremic Bleeding - Page 7 (2024)

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.

Should a Hemodynamically Stable, Actively Bleeding Uremic Patient be Given Recombinant Human EPO?

Yes, if the baseline hematocrit is less than 30% and iron stores are normal (strength of recommendation/evidence, IIa/B [see Figure 2 for strength of recommendation/evidence scales]).

As a result of the delayed onset of the beneficial effects of recombinant human EPO, patients who are actively bleeding and hemodynamically unstable are unlikely to benefit from administration of this agent in the acute setting. The use of recombinant human EPO, however, has been shown to have a positive impact on uremic bleeding as soon as 7 days after initiation of therapy and early use in hemodynamically stable patients is probably beneficial when baseline hematocrit is less than 30% and iron stores are normal. The dosing would be the same as recommended in the product insert (target hematocrit ≥30%), as this is the level at which the greatest benefit in reducing bleeding time is apparent. A hematocrit at this level will also facilitate the distribution of platelets towards the endothelium, where adhesion and aggregation are more likely to be initiated. Patients with uremia secondary to chronic kidney disease will generally require EPO replacement therapy for treatment or prevention of anemia; recombinant human EPO is, therefore, already a standard of care for these patients.

Does Recombinant Human EPO Prevent Bleeding Caused by Uremic Platelet Dysfunction?

Yes, if the hematocrit is increased to more than 30% (strength of recommendation/evidence, IIa/B [see Figure 2 for strength of recommendation/evidence scales]).

Studies have shown that when the hematocrit is greater than 30%, bleeding time is reduced in most patients because of displacement of platelets such that they are closer to the vascular endothelium. This displacement decreases the time required for adhesion and aggregation in response to damage. The decrease in bleeding time would theoretically help prevent uremic bleeding. It is important to remember the complex nature of, and the multiple factors contributing to, uremic platelet dysfunction. Use of recombinant human EPO should, therefore, be only one part of a clinician's strategy for preventing uremic bleeding. As stated above, patients with chronic kidney disease might require recombinant human EPO to treat or prevent anemia, and this agent is therefore already a standard of care in this population.

Will Dialysis Offer any Acute Benefit to a Uremic Patient With Active Bleeding?

Yes (strength of recommendation/evidence, IIa/B [see Figure 2 for strength of recommendation/evidence scales]).

There are limited data on the efficacy of dialysis in actively bleeding uremic patients. Results, however, are promising. A small study showed complete resolution of clinical bleeding in all patients who were actively bleeding prior to dialysis.^[37] Frequent dialysis might also improve indices of platelet aggregation and bleeding time in some patients, theoretically contributing to cessation of bleeding. Dialysis is the standard of care for patients with renal failure; it will facilitate removal of uremic retention solutes in plasma, but should be used in combination with other treatments (Figure 1).

Does Dialysis Prevent Uremic Platelet Dysfunction?

Possibly (strength of recommendation/evidence, IIa/B [see Figure 2 for strength of recommendation/evidence scales]).

Studies^{[36,37,55,56,57]} support the conclusion that dialysis—in particular, peritoneal dialysis—improves platelet function, as it can result in measures of platelet aggregation returning to normal values (comparable to those of healthy controls). Patients had pre-existing uremic platelet dysfunction, and the goal of the studies was to determine if platelet function could be normalized by dialysis. Studies support a target serum creatinine concentration of less than 6 mg/100 ml to maintain normal platelet function. Data indicate that peritoneal dialysis can normalize platelet function, but it is not known if hemodialysis or peritoneal dialysis can prevent the first occurrence of uremic platelet dysfunction.

Can Estrogen be Administered to Male Uremic Patients With Active Bleeding?

Yes (strength of recommendation/evidence, IIb/B [see Figure 2 for strength of recommendation/evidence scales]).

All of the studies of estrogen discussed in this Review included male patients. No adverse effects of the hormone were reported, other than hot flashes. Most of the studies that evaluated estrogens limited duration of administration to five consecutive days. Adverse effects of long-term administration of conjugated estrogens in males, therefore, remain unknown and administration of this hormone for more than 5 days cannot be recommended.

Should Estrogen be Administered Orally, Transdermally or Intravenously?

Intravenously (strength of recommendation/evidence, IIa/B [see Figure 2 for strength of recommendation/evidence scales]).

Oral, transdermal and intravenous routes of administering conjugated estrogens to manage uremic platelet disorder have all been evaluated. Each of these routes has been associated with decreased bleeding time. Nevertheless, intravenous administration has been studied most frequently and seems to be the preferred route. Studies of intravenous conjugated estrogens at doses of 0.6 mg/kg/day reported decreased bleeding time. We therefore recommend intravenous administration over oral and transdermal routes.

What Dose of Estrogen Most Effectively Prevents or Treats Bleeding in Uremic Patients?

The most effective dose of estrogen depends on the route of administration (strength of recommendation/evidence, IIa/A/B [see Figure 2 for strength of recommendation/evidence scales]).

Three studies evaluating patients with uremic bleeding using a dose of 0.6 mg/kg/day conjugated estrogens intravenously all detected a decrease in bleeding time.^[78,79,80] Lower doses have also been evaluated and shown to be ineffective.^[79] When treating a patient with oral conjugated estrogens, doses of 50 mg/day, for an average of 7 days, have been shown to be effective. Transdermal estrogen has been effective when administered at doses of 50–100 μg/day. As stated above, all tested routes of administration and doses decreased bleeding time; however, 0.6 mg/kg/day intravenously has been the most frequently studied protocol with reproducible results.

Are Conjugated Estrogens Preferable to Estrogen–Progesterone Combination Products?

Yes, however combination products have been shown to be effective (strength of recommendation/evidence, IIa/B [see Figure 2 for strength of recommendation/evidence scales])

Conjugated estrogens have been much more extensively studied than estrogen–progesterone combination products, which have been evaluated in one study. Bronner et al. evaluated combination products and showed cessation of bleeding and decreased requirement for blood transfusions.^[82] No other studies have been performed to determine if these results are reproducible. After reviewing trials that tested estrogens for treatment of uremic bleeding, we recommend the use of conjugated estrogens 0.6 mg/kg/day intravenously rather than combination products.

Should DDAVP be First-line Therapy in a Uremic Patient With Bleeding?

Yes (strength of recommendation/evidence, I/A [see Figure 2 for strength of recommendation/evidence scales]).

DDAVP has repeatedly been shown to improve bleeding time in patients who are actively bleeding or who are being prepared for surgery. DDAVP improves dysfunctional platelet activity by stimulating release of factor VIII from endothelial stores and by increasing vWF activity. As a result of its rapid onset of action, DDAVP is commonly used as the first-line agent in patients with active bleeding or those who are about to undergo surgery.

Should DDAVP Treatment be Repeated if Bleeding is not Controlled by the Initial Dose?

No (strength of recommendation/evidence, I/C [see Figure 2 for strength of recommendation/evidence scales])

DDAVP administration should not be repeated because of the risk of tachyphylaxis. It is postulated that tachyphylaxis occurs as a result of depletion of factor VIII and vWF endothelial stores. If bleeding has not been controlled after one dose of DDAVP, then consideration should be given to other treatment options such as cryoprecipitate or conjugated estrogens.

Should DDAVP be Administered Orally or Intravenously?

Intravenously (strength of recommendation/evidence, I/B [see Figure 2 for strength of recommendation/evidence scales]).

To our knowledge no trial has evaluated oral DDAVP in uremic bleeding. Oral administration of DDAVP might be as beneficial as intravenous therapy, but there are currently no data to support this. At this time, we can recommend only the use of intravenous DDAVP. Trials of oral administration of DDAVP for uremic bleeding should be performed before any recommendation can be made for or against its use.

When Should Cryoprecipitate be Administered to a Uremic Patient With Bleeding?

If the patient is hemodynamically stable but in need of urgent surgery or control of bleeding; also for patients who are hemodynamically unstable and who cannot tolerate extra fluid (see treatment algorithm Figure 1; strength of recommendation/evidence, IIb/B [see Figure 2 for strength of recommendation/evidence scales]).

Cryoprecipitate, rich in factor VIII, vWF and fibrinogen, should be reserved for patients who are either actively bleeding or in need of urgent surgery. It is also an important treatment option for patients who have received one dose of DDAVP but have not achieved hemostasis. Before administration of cryoprecipitate, patients should be evaluated to determine if they are able to tolerate the associated increase in intravascular volume. Care should also be given when administering blood products because of the potential for transmission of infectious disease such as hepatitis and HIV.

Is the Combination of Cryoprecipitate and DDAVP Beneficial in Uremic Bleeding?

Theoretically, yes (strength of recommendation/evidence, IIb/D [see Figure 2 for strength of recommendation/evidence scales]).

No study has evaluated the combination of cryoprecipitate and DDAVP. As these two agents have different mechanisms of action, it is proposed that they could be given in combination with additive benefits.

Do Omega-3 Fatty Acids Increase the Risk of Bleeding in Patients With Uremia?

Not known, but theoretically possible (level of evidence, D [see Figure 2 for strength of recommendation/evidence scales]).

There has been growing interest in this question in conditions (other than uremic bleeding) in which the risks of bleeding or blood loss are increased. This interest exists because many patients now use fish oil supplements to treat lipid abnormalities and various inflammatory conditions. When omega-3 fatty acids—whether as supplements or in food—are incorporated into the diet, they can partially replace omega-6 fatty acids in the cell membranes of many cells (erythrocytes, platelets, endothelial cells, lymphocytes, monocytes, granulocytes and fibroblasts, to name but a few). This partial replacement results in competition between omega-3 and omega-6 fatty acids during production of endoperoxides (e.g. TxA₂ and prostaglandin). Specifically, eicosapentaenoic acid, an omega-3 fatty acid, competes with arachidonic acid at the level of cyclooxygenase and lipoxygenase during production of prostaglandin and leukotriene. As a result of this competition, eicosapentaenoic acid and docosahexaenoic acid, another omega-3 fatty acid, cause a decrease in TxA₂ and an increase in PGI₃ production. Although there is no evidence to support or disprove the risk of this biochemical competition, these effects could theoretically increase a patient's chance of bleeding in the setting of uremic platelet dysfunction.