INTRODUCTION — The association between kidney dysfunction and bleeding was first recognized in the mid-1700s [1,2]. However, the mechanisms underlying this association remain incompletely understood. Impaired platelet function is one of the main determinants of abnormal bleeding in patients with a low glomerular filtration rate (GFR).
Although often referred to as "uremic bleeding," bleeding in this setting generally occurs in patients who do not have clinical symptoms or signs of uremia. As such, the term "uremic" in many studies discussed herein is a misnomer when used to describe patients undergoing regular maintenance dialysis or patients with advanced chronic kidney disease (CKD) who do not yet require dialysis.
This topic reviews treatment and prevention of bleeding in patients with severely decreased GFR. Separate topics discuss:
●Thrombosis risk with impaired kidney function.
•Venous thromboembolism (see "Overview of the causes of venous thrombosis", section on 'Renal diseases')
•Arterial thrombosis (see "Chronic kidney disease and coronary heart disease")
●Other causes of platelet dysfunction.
•Liver disease (see "Hemostatic abnormalities in patients with liver disease")
•Von Willebrand disease (see "Clinical presentation and diagnosis of von Willebrand disease")
•Hereditary platelet disorders (see "Inherited platelet function disorders (IPFDs)")
•Cause unknown (see "Approach to the adult with a suspected bleeding disorder")
PATHOGENESIS — Bleeding associated with kidney disease can have many causes.
●Platelet dysfunction – Platelet dysfunction is thought to be the main determinant of abnormal bleeding in patients with reduced glomerular filtration rate (GFR).
The cause of impaired platelet function in patients with low GFR is incompletely understood. Reduced activation of integrin alpha IIb/beta3 (previously called glycoprotein IIb/IIIa), which serves as a receptor for fibrinogen, has been implicated in several in vitro studies [3-5]. Platelet granule dysfunction (storage pool disorder) has also been observed [6,7]. In contrast, von Willebrand factor levels and function, including interactions with platelets, appear to be normal . (See "Platelet biology and mechanism of anti-platelet drugs".)
A role for increased nitric oxide (NO) in platelet dysfunction also has been suggested. The mechanism by which estrogens may reduce bleeding in some patients with severely decreased GFR is not well understood but may involve lowering L-arginine, which is a precursor for NO . (See 'Chronic refractory GI bleeding: Estrogens' below.)
Studies in which normal platelets were mixed with "uremic" plasma and vice versa suggest that a humoral (circulating) factor is responsible for the platelet dysfunction . However, the specific factor(s) responsible have not been identified. Contributions of several molecules have been proposed, including urea, creatinine, phenol, phenolic acid, and guanidinosuccinic acid .
●Anemia – Anemia is common in chronic kidney disease (CKD). Anemia by any mechanism may reduce platelet interactions with endothelial cells; conversely, a hematocrit >30 percent is thought to improve platelet binding to vessel walls by a rheologic mechanism. When red blood cells (RBCs) occupy a greater portion of the vessel lumen, platelets are pushed towards the vessel wall in a skimming layer at the endothelial surface. This close proximity allows the platelets to adhere to the endothelium more efficiently at sites of injury.
Small studies have demonstrated that individuals with CKD treated with erythropoietin to increase their hematocrit had shortening of bleeding times and improved platelet binding to endothelial cells [10,11].
●Medications – Many patients with CKD have comorbidities treated with anticoagulant or antiplatelet medications. These agents, and/or heparin administered during routine hemodialysis, may contribute to increased bleeding risk.
Patients with severely reduced GFR may display increased bleeding sensitivity to aspirin; a transient, cyclooxygenase-independent prolongation of the bleeding time following use of aspirin was greater in individuals with CKD than in individuals without CKD .
●Dialysis – Although dialysis may improve hemostasis by removing toxins that inhibit platelet function, hemodialysis may contribute to bleeding risk due to heparin use . Studies evaluating dialysis as a means of reducing bleeding in patients with severely decreased GFR have been limited by small sample size and lack of assessment of clinically important outcomes .
In contrast to platelet dysfunction, levels of prohemostatic clotting factors are generally normal or increased in CKD. Reduced levels of the natural anticoagulants protein S and protein C that occur in nephrotic syndrome increase the risk of thrombosis rather than bleeding .
The main interventions to reduce bleeding risk in patients with low GFR include optimizing dialysis, treating anemia, and monitoring medications that affect hemostasis. (See 'Prevention of bleeding' below.)
ASSESSMENT OF BLEEDING RISK — Bleeding associated with reduced glomerular filtration rate (GFR) can occur in patients with chronic kidney disease (CKD) on dialysis, patients with CKD not undergoing dialysis, and patients with acute kidney injury. Over time, with advances in the management of CKD and the treatment of anemia, concerns about bleeding due to kidney function impairment have decreased. Nevertheless, impaired kidney function remains a risk factor for bleeding, as indicated by most bleeding risk scores. (See "Risks and prevention of bleeding with oral anticoagulants", section on 'Bleeding risk scores'.)
There is no readily available and reliable assay to determine the magnitude of platelet dysfunction or the risk of bleeding in individuals with reduced GFR. The bleeding time, used in many early studies, is a poor surrogate for clinical bleeding and is rarely performed due to labor intensity and operator-dependence (see "Platelet function testing", section on 'Tests not commonly used'). Studies using the bleeding time as a surrogate for bleeding risk have found little correlation between the degree of kidney function impairment and the magnitude of platelet dysfunction .
There is no specific cutoff for blood urea nitrogen (BUN) or serum creatinine that separates higher from lower bleeding risk. We consider patients who meet any of the following criteria to be at high risk for uremic platelet dysfunction:
●Estimated GFR (eGFR) <15 mL/min/1.73 m2
●Oligoanuric acute kidney injury
However, individuals with eGFR <30 mL/min/1.73 m2 and even <60 mL/min/1.73 m2 may be at greater risk than individuals without kidney function impairment, and patients with reduced GFR often have comorbidities and/or take medications that increase bleeding risk (table 1).
Observational studies report that bleeding risk is correlated with reduced eGFR [16,17]. For example, in a study including over 500,000 adults, the adjusted relative risk (aRR) of bleeding increased with lower eGFR as follows :
●eGFR 60 to 90 – aRR 1.0 (95% CI 0.9 to 1.1)
●eGFR 45 to 60 – aRR 1.4 (95% CI 1.2 to 1.6)
●eGFR 30 to 45 – aRR 1.7 (95% CI 1.5 to 2.0)
●eGFR 15 to 30 – aRR 1.9 (95% CI 1.5 to 2.4)
●eGFR <15 – aRR 3.0 (95% CI 1.3 to 6.6)
The aRRs above applied to individuals with urinary albumin-to-creatinine ratio <30 mg/g; similar correlations and greater risks were seen for higher levels of albuminuria .
An earlier study involving >11,000 older adults (>65 years) reported an incidence of major hemorrhage within the first three years of starting dialysis of 14 percent (approximately 1 in 7) .
Typical sites of bleeding — Platelet dysfunction in patients with severely decreased glomerular filtration rate (GFR) may manifest as abnormal bleeding involving the skin, resulting in easy bruising; the oral and nasal mucosa; gastrointestinal (GI) and urinary tracts; central nervous system; and respiratory system. Excessive bleeding may also occur in response to injury or invasive procedures [19-21].
In a 2022 case-control study including nearly 6000 participants, individuals with stage 1 through 5 chronic kidney disease (CKD) were almost twice as likely to have an intracerebral hemorrhage as individuals without CKD (odds ratio 1.95, 95% CI 1.35-2.89) .
In a series of >11,000 older adults starting dialysis, sites of bleeding included :
●Lower GI tract – 9 percent
●Upper GI tract – 6 percent
●Intracerebral – 1 percent
●Subarachnoid – 0.1 percent
Laboratory findings — There is no readily available assay that indicates bleeding is due to reduced GFR rather than another cause.
Platelet count, prothrombin time (PT), and activated partial thromboplastin time (aPTT) are generally unaffected by CKD. If a patient with reduced GFR has thrombocytopenia or prolonged PT and/or aPTT, the cause of the abnormality should be evaluated and addressed. (See "Diagnostic approach to thrombocytopenia in adults" and "Clinical use of coagulation tests", section on 'Evaluation of abnormal results'.)
Some tests of platelet function are abnormal in individuals with reduced GFR, but these typically are not part of the evaluation, and their clinical relevance is unclear:
●Platelet aggregometry – Aggregometry is the gold standard test for platelet dysfunction, but it is generally used by hematologists to determine the cause of platelet dysfunction when standard evaluations have been unrevealing. Platelet aggregometry and related assays have shown a mixture of abnormalities in individuals with reduced GFR (reduced or increased platelet aggregation, depending on the agonist) [23-28]. Indications for platelet aggregometry are discussed separately. (See "Platelet function testing", section on 'Uses of aggregometry'.)
●Bleeding time – Bleeding time is mostly of historical interest. It was commonly used in the past as a surrogate for bleeding risk, and many of the studies evaluating the pathogenesis of uremic platelet dysfunction observed prolonged bleeding times in many patients with reduced GFR . (See 'Pathogenesis' above.)
However, there are no data that unequivocally demonstrate associations between prolonged bleeding time and an increased risk of either spontaneous or postprocedure bleeding among patients with CKD. The bleeding time is rarely performed due to poor standardization, accuracy, and reproducibility. (See "Platelet function testing", section on 'Tests not commonly used'.)
TREATMENT OF BLEEDING
Identify and treat bleeding source and comorbidities — As with any patient who has an active bleed, the primary goal is to identify and treat the source of blood loss.
Comorbidities and medication-induced changes that may be contributing to bleeding should be evaluated and treated, such as:
●Disseminated intravascular coagulation (DIC) (see "Evaluation and management of disseminated intravascular coagulation (DIC) in adults")
●For gastrointestinal (GI) bleeding, lesions such as ulcers, gastritis, angiodysplasia, or polyps (see "Approach to acute upper gastrointestinal bleeding in adults" and "Approach to acute lower gastrointestinal bleeding in adults")
●For postoperative bleeding, an anatomic or pathologic cause of bleeding
●Anticoagulation (see "Reversal of anticoagulation in intracranial hemorrhage" and "Management of warfarin-associated bleeding or supratherapeutic INR" and "Management of bleeding in patients receiving direct oral anticoagulants" and "Heparin and LMW heparin: Dosing and adverse effects", section on 'Bleeding')
Acute life-threatening bleeding — We do not routinely treat uremic platelet dysfunction in patients who are bleeding. However, in patients with severely reduced glomerular filtration rate (GFR) who are experiencing acute life-threatening bleeding, potential hemostatic therapies include desmopressin (DDAVP), platelet transfusions, and Cryoprecipitate. There is no high-quality evidence demonstrating that these therapies have clinical benefit, but they have a theoretical rationale and may be the only interventions available after causes of bleeding other than kidney function impairment are addressed. (See 'Identify and treat bleeding source and comorbidities' above.)
●DDAVP – We generally do not use DDAVP to treat bleeding in patients with uremic platelet dysfunction. However, other UpToDate contributors administer DDAVP to patients with reduced GFR who have major bleeding, particularly in the surgical setting. (See 'Details of DDAVP administration' below and "Anesthesia for dialysis patients", section on 'Management of bleeding'.)
●Platelet transfusion – We do not routinely use platelet transfusion to treat bleeding in patients with reduced GFR, since it is likely that transfused platelets rapidly acquire the same uremic defect as native ones. However, some experts administer platelet transfusions in addition to DDAVP to a patient on maintenance dialysis who has uncontrolled bleeding. (See "Anesthesia for dialysis patients", section on 'Management of bleeding' and "Platelet transfusion: Indications, ordering, and associated risks", section on 'Ordering platelets'.)
●Cryoprecipitate – Cryoprecipitate is rarely used to treat bleeding in patients with uremic platelet dysfunction although it is still included in some transfusion protocols. If used, Cryoprecipitate would generally be reserved for patients with severe bleeding for which another cause cannot be identified, especially if they have low or borderline fibrinogen levels. The dose is 10 units, given every 12 to 24 hours (more frequently for hypofibrinogenemia, in which case dosing is titrated to plasma fibrinogen level). (See "Cryoprecipitate and fibrinogen concentrate", section on 'Uremic bleeding'.)
Evidence for Cryoprecipitate is limited. In a study of six patients with reduced GFR, it was thought to help control a major bleeding episode in four and shortened the bleeding time in all six . Subsequent small studies have not shown consistent reductions in bleeding time or clinical bleeding .
Chronic refractory GI bleeding: Estrogens — Rarely, estrogen has been used for patients on maintenance hemodialysis who have chronic gastrointestinal (GI) tract bleeding due to angiodysplasia not amenable to other treatment. However, clinical experience is limited, and randomized trials are lacking. (See "Unique aspects of gastrointestinal disease in dialysis patients".)
If used, reasonable doses of conjugated estrogens include:
●Intravenous – 0.6 mg/kg daily for five days
●Oral – 25 to 50 mg orally per day
●Transdermal – 50 to 100 mcg of transdermal estradiol twice weekly
The intravenous route is preferred due to greater study, but oral and transdermal routes may be more practical [13,31-33].
Most studies of estrogen therapy to treat GI bleeding in patients with reduced GFR have been of limited duration (five to seven days). Longer-term use may be limited by estrogen-related side effects. However, it is possible that compounds with weaker estrogenic activity and fewer side effects may be used successfully for longer periods of time . Onset of action is within one day, with peak control reached over five to seven days and continued activity one week or more after therapy has been discontinued [31-33].
Estrogens have been reported to control GI bleeding in case series of patients with severely reduced GFR, most of whom were undergoing maintenance hemodialysis [31-36].
Other interventions for GI angiodysplasia are discussed separately. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions", section on 'Gastrointestinal lesions'.)
PREVENTION OF BLEEDING
Spontaneous bleeding — To reduce the risk of spontaneous bleeding in patients at high risk for uremic platelet dysfunction, we optimize routine chronic kidney disease (CKD) care. (See 'Assessment of bleeding risk' above.)
●Optimize dialysis regimen and treat anemia – The principal ways of reducing spontaneous bleeding risk in a patient with severely reduced glomerular filtration rate (GFR) are to optimize the dialysis regimen (if the patient is on dialysis) and to treat anemia. (See "Prescribing and assessing adequate hemodialysis" and "Prescribing peritoneal dialysis".)
If anemia is present in a patient with reduced GFR, we evaluate for underlying cause(s) and treat as appropriate. Individuals with CKD can have more than one cause of anemia, and anemia should not be attributed solely to CKD without reviewing other possible contributing factors. (See "Diagnostic approach to anemia in adults" and "Anemia of chronic disease/anemia of inflammation".)
If the hemoglobin is <10 g/dL due to CKD, we use an erythropoiesis-stimulating agent (ESA) to raise the hemoglobin to ≥10 g/dL (hematocrit ≥30 percent). Iron also may be indicated. Details are presented separately. (See "Treatment of anemia in nondialysis chronic kidney disease", section on 'Treatment' and "Treatment of anemia in patients on dialysis".)
●Judicious use of anticoagulation and antiplatelet agents – Anticoagulation or antiplatelet therapy should be used if needed, but anticoagulant dose reduction may be appropriate in some individuals with reduced GFR; details are presented separately. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Chronic kidney disease'.)
We generally advise patients to avoid antiplatelet agents (aspirin and nonsteroidal antiinflammatory drugs) for fever or routine aches and pains, especially when alternative such as acetaminophen are available.
However, patients taking antiplatelet agents for prevention of cardiovascular disease or other indications may reasonably continue them after reviewing the risk-benefit balance. (See "Overview of primary prevention of cardiovascular disease" and "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)
Invasive procedures — Options that may reduce bleeding risk in patients with severely decreased GFR who are undergoing a high-risk invasive procedure (table 2) include identification of other bleeding risks, therapy for anemia, desmopressin (DDAVP), and dialysis.
Identify other bleeding risks — The patient history and laboratory testing for other hemostatic abnormalities may identify the need for specific therapies, such as a reversal agent for anticoagulation or treatment of a clotting factor deficiency. (See "Perioperative blood management: Strategies to minimize transfusions", section on 'Systemic hemostatic agents'.)
Treatment of anemia — To help prevent bleeding in patients with severely decreased GFR who are undergoing a high-risk invasive procedure, therapy for anemia (if present) should be attempted as feasible. No high-quality data have shown that risk of bleeding is ameliorated with treatment of anemia, but raising the hemoglobin to approximately 10 g/dL may reduce the bleeding time, occasionally to a normal level, in some patients [11,37].
Our approach to anemia depends on whether the procedure is elective or urgent, on the degree of anemia, and whether the patient may be eligible for future kidney transplant:
●Elective procedures – For patients who are planning to undergo nonurgent, elective, high-risk invasive procedures, the hemoglobin is raised to approximately 10 g/dL with a recombinant ESA and/or iron if needed [11,13]. (See "Treatment of anemia in nondialysis chronic kidney disease", section on 'Treatment' and "Treatment of anemia in patients on dialysis".)
●Urgent procedures – Use of an ESA and/or iron is not an option for patients undergoing urgent procedures because these therapies take weeks to be effective. For patients at high risk for uremic platelet dysfunction (see 'Assessment of bleeding risk' above) who are undergoing an urgent high-risk invasive procedure, are not planning to pursue kidney transplant, and have hemoglobin <9 g/dL, we suggest red blood cell (RBC) transfusion targeted to raise the hemoglobin level to approximately 10 g/dL.
We avoid RBC transfusions to prevent uremic bleeding in patients with CKD who are potential kidney transplant candidates because of the risk of allosensitization. We do not avoid RBC transfusion in potential kidney transplant candidates who have severe anemia or rapidly falling hemoglobin; indications for RBC transfusion in such patients are the same as those for the general population. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Symptomatic patient'.)
Raising the hemoglobin to approximately 10 g/dL may reduce the bleeding time in some patients, but improvements in clinically important outcomes have not been demonstrated .
●DDAVP – The use of DDAVP to prevent uremic bleeding before, during, or after an invasive procedure is controversial. Some experts use DDAVP preoperatively or prior to an invasive procedure in patients on chronic dialysis who have a history of excessive bleeding or who are not optimally dialyzed before surgery [38-40]. (See 'Details of DDAVP administration' below and "Medical management of the dialysis patient undergoing surgery", section on 'Uremic bleeding'.)
●Dialysis – We generally do not initiate dialysis before an invasive procedure solely to reduce bleeding risk, nor do we augment or intensify an existing dialysis prescription. However, if feasible, dialysis may be initiated in patients with severely reduced GFR who are planning to start dialysis, or dialysis may be intensified in patients who are inadequately dialyzed, prior to an elective procedure.
Hemodialysis or peritoneal dialysis can partially correct the bleeding time and other in vitro tests of platelet function in patients with severely reduced GFR [41-43]; however, it is unknown whether either dialysis modality actually decreases the risk of major bleeding.
If hemodialysis is performed immediately before or on the day of a high-risk invasive procedure, systemic anticoagulation should be avoided . (See "Anticoagulation for the hemodialysis procedure".)
DETAILS OF DDAVP ADMINISTRATION
●Potential indications – The benefits of desmopressin (DDAVP) to treat bleeding or to reduce the risk of bleeding in patients with reduced glomerular filtration rate (GFR) are uncertain. DDAVP may be used to treat or prevent bleeding on a case-by-case basis after weighing the potential risks of therapy.
•Some experts use DDAVP prior to surgery or invasive procedures in patients on chronic dialysis who have a history of excessive bleeding or who are not optimally dialyzed before surgery. DDAVP has also been used in individuals with chronic kidney disease (CKD) who are taking antiplatelet agents and require a procedure . (See 'Other measures' above.)
•Some experts use DDAVP in patients with acute bleeding. (See 'Acute life-threatening bleeding' above.)
●Dosing and monitoring – DDAVP dosing is the same whether used for prevention or treatment of bleeding. The dose is 0.3 mcg/kg intravenously or subcutaneously (intravenous [IV] administration is preferred for treatment of bleeding). For IV administration, DDAVP is given in 50 mL of saline over 15 to 30 minutes. If administered preoperatively, it should be given 30 to 60 minutes prior to the procedure. Dosing can be repeated after 12 hours or once daily, but tachyphylaxis occurs after the first two or three doses, and therapy is generally not extended beyond one to two days.
Efficacy is monitored clinically; there is no laboratory test that can be used to determine benefit. The putative effect is expected to occur within one hour of administration and last for four to eight hours.
●Risks – Risks of DDAVP include increased blood pressure, thrombosis, and hyponatremia, especially if free water intake is increased [45-48].
●Supporting evidence – No convincing data have demonstrated that DDAVP reduces the risk of clinically important bleeding associated with invasive procedures in patients with severely reduced GFR. Most supporting data for DDAVP are limited to observational studies, including small studies demonstrating reduced bleeding times in patients with uremic platelet dysfunction [38,49]. Bleeding time is a surrogate for bleeding risk that has not been validated in trials of clinically important bleeding. DDAVP is commonly used in von Willebrand disease for minor bleeding and minor procedures. (See "von Willebrand disease (VWD): Treatment of minor bleeding, use of DDAVP, and routine preventive care", section on 'DDAVP'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults".)
SUMMARY AND RECOMMENDATIONS
●General principles – Bleeding associated with kidney disease can have many causes. Platelet dysfunction is thought to be the main determinant of abnormal bleeding in patients with severely reduced glomerular filtration rate (GFR). (See 'Introduction' above and 'Pathogenesis' above.)
●Clinical features – Common bleeding sites include skin, mucosal (especially gastrointestinal [GI] tract), and intracerebral. There is no readily available assay that indicates bleeding is due to kidney function impairment. Platelet count, prothrombin time (PT), and activated partial thromboplastin time (aPTT) are unaffected by lower GFR. Platelet aggregation studies and bleeding time may be abnormal but are rarely performed. (See 'Typical sites of bleeding' above and 'Laboratory findings' above.)
●Risk assessment – There is no specific cutoff for blood urea nitrogen (BUN) or serum creatinine that separates higher from lower bleeding risk. We consider patients who meet any of the following criteria to be at high risk for uremic platelet dysfunction (see 'Assessment of bleeding risk' above):
•Estimated GFR <15 mL/min/1.73 m2
•Oligoanuric acute kidney injury
●Treatment of bleeding – The primary goal is to identify and address the bleeding source. Despite the lack of high-quality evidence demonstrating benefit in this setting, desmopressin (DDAVP), platelet transfusion, Cryoprecipitate, and estrogen are sometimes used in certain clinical scenarios. (See 'Acute life-threatening bleeding' above and 'Chronic refractory GI bleeding: Estrogens' above and 'Details of DDAVP administration' above.)
●Prevention of bleeding – In patients with severely reduced GFR who are undergoing a high-risk invasive procedure (table 2), options that may reduce bleeding risk include therapy for anemia, DDAVP, and dialysis.
•Anemia – For patients at high risk for uremic platelet dysfunction (see 'Assessment of bleeding risk' above) who are undergoing an urgent high-risk invasive procedure, are not planning to pursue kidney transplant, and have hemoglobin <9 g/dL, we suggest red blood cell (RBC) transfusion targeted to raise the hemoglobin level to approximately 10 g/dL (Grade 2C).
For patients who are planning to undergo elective, high-risk invasive procedures, the hemoglobin is raised to approximately 10 g/dL with a recombinant erythropoiesis-stimulating agent (ESA) and/or iron (See 'Treatment of anemia' above.)
•DDAVP – The benefit of periprocedural DDAVP to prevent uremic bleeding is uncertain. Some experts use DDAVP preoperatively or prior to an invasive procedure in patients on chronic dialysis who have a history of excessive bleeding or who are not optimally dialyzed before surgery. (See 'Other measures' above and 'Details of DDAVP administration' above.)
•Dialysis – It is unknown whether dialysis decreases the risk of uremic bleeding. In general, the use of dialysis solely to reduce the risk of bleeding is limited to patients who are inadequately dialyzed or to patients with severely reduced GFR who are planning to initiate dialysis. (See 'Other measures' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Steven Coutre, MD, who contributed to earlier versions of this topic review.
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