Hemostatic Abnormalities in Renal Disease

Miriam Galbusera

Giuseppe Remuzzi

Patrizia Ondei

Patients with renal disease suffer from complex hemostatic abnormalities leading to two opposite complications: bleeding tendency and thrombotic risk. Bleeding may be a serious complication of acute and chronic renal failure.¹ The clinical manifestations vary from ecchymoses, epistaxis, bleeding from gums, venipuncture sites, and sites of fistula access to overt gastrointestinal bleeding. Although the frequency of severe hemorrhage has been reduced by the advent of dialysis and the use of erythropoietin to correct anemia, a bleeding diathesis still represents a problem for uremic patients, particularly during surgery or invasive procedures such as biopsies.

Nonetheless, abnormalities of blood coagulation and fibrinolysis in chronic renal failure render uremic patients highly susceptible to the development of cardiovascular and thrombotic complications. In addition, contemporary patient populations are older and have a high prevalence of hypertension and atherosclerotic vascular disease.² The presence of these comorbidities renders uremic patients more likely to receive drugs such as antiplatelet agents and anticoagulants that may increase the risk of bleeding.

PATHOGENESIS OF UREMIC BLEEDING

In patients with kidney diseases, platelet defects and platelet-vessel wall abnormalities are the main determinants of hemorrhagic tendency, but other contributing factors including the abnormal production of nitric oxide (NO), uremic toxins, and anemia account for a multifactorial pathogenesis of bleeding (Table 127.1).

Platelet Abnormalities

Severe thrombocytopenia is very rare and is limited to renal failure associated with disseminated intravascular coagulation, hemolytic uremic syndrome (HUS)/thrombotic thrombocytopenic purpura (TTP), eclampsia, and renal allograft rejection. Thrombocytopenia may also be caused during hemodialysis by the anticoagulant heparin.³

The majority of studies on uremic platelet were reported during the 1980s and 1990s and identified numerous biochemical abnormalities (reviewed in ref.⁴, ⁵) including a decreased capacity to synthesize thromboxane A₂ by the prostaglandin-forming enzyme cyclooxygenase,⁶, ⁷ a reduction in platelet granule ADP and serotonin content,⁸ an increase in cyclic AMP (cAMP),⁹ dysregulation of adenylate cyclase,¹⁰ and impairment of Ca²⁺dependent platelet function.¹¹, ¹² A storage pool defect is supported by finding subnormal dense granule content,⁸, ¹³ impaired release of α-granule proteins and β-thromboglobulin,¹⁴ and reduced release of platelet ATP in response to thrombin.¹³ Moreover, platelet cytoskeletal dysfunction due to either a reduction in cytoskeletal proteins or a decrease in actin incorporation after thrombin stimulation has been reported.¹⁵ All the above abnormalities and the defective platelet aggregation in response to various stimuli contribute to impaired platelet adhesion and aggregation in injured vessels.

Platelet adherence to foreign surfaces is significantly impaired in patients with end-stage renal disease.¹⁶, ¹⁷, ¹⁸ Defective function of the platelet glycoprotein (GP)IIb-IIIa complex receptor may account for the decreased binding of von Willebrand factor (vWF) and fibrinogen to stimulated uremic platelets¹⁹ and the reduced vWF-dependent adhesion and thrombus formation.¹⁶, ¹⁷, ¹⁸ Dialysis improved the binding capacity of GPIIb-IIIa complex, suggesting a role of uremic toxins or receptor occupancy by fibrinogen fragments present in uremic blood.¹⁹, ²⁰

Although quantitative and qualitative vWF abnormalities have not been consistently reported in uremic patients,¹⁷, ²¹, ²² a functional defect in the vWF-platelet interaction cannot be excluded based on evidence that cryoprecipitate (a plasma derivative rich in vWF) and desmopressin (a synthetic derivative of antidiuretic hormone that releases autologous vWF from storage sites) significantly shorten the bleeding time in these patients.²³, ²⁴ Increased levels of the platelet inhibitors prostacyclin (PGI₂) and NO have also been reported in uremia.²⁵, ²⁶ The beneficial effect of conjugated estrogens on the bleeding times of uremic patients might be mediated by changes in the NO synthesis pathway since the NO precursor l-arginine reversed the effect of estrogens on bleeding.²⁷ Dialysis partially correct platelet dysfunction, suggesting that uremic toxins such as the guanidinosuccinic acid involved in NO generation²⁶ may play a role in platelet abnormalities.

Role of Anemia

Anemia is a constant feature of acute and chronic renal failure and is the main determinant of the prolonged bleeding time in uremic patients. There is evidence that the bleeding time is inversely related to the hematocrit in uremia²⁸, ²⁹ as well as in other types of anemia. The cloning of the human erythropoietin gene and the production of recombinant human erythropoietin (rhEPO) has provided clinicians with a powerful tool to correct the anemia associated with renal failure, thereby eliminating dependency upon transfusion.

Dialysis

Dialysis improves platelet functional abnormalities and reduces, but does not eliminate, the risk of hemorrhage. Hemodial ysis, because of the interaction between blood and artificial surfaces, may induce chronic platelet activation that
can lead to platelet exhaustion and dysfunction. It has been found that plasma levels of the potent NO inducers TNF-α and IL-lβ increase during dialysis.³⁰, ³¹ These cytokines are generated in vivo by monocytes during hemodialysis with complement-activating membranes. Thus, while dialysis removes uremic toxins, it also affects platelet activation and NO synthesis. Heparin, used to prevent filter clotting, can occasionally induce platelet activation and thrombocytopenia.³

Table 127.1 Factors involved in uremic bleeding

– Abnormal Platelet Function

– Decreased capacity to form thromboxane A₂; reduction in serotonin and ADP content; increased intracellular cAMP; impaired Ca²⁺-dependent functions; reduction in dense granule content; impaired release of the platelet α-granule protein and

β-thromboglobulin; abnormalities in ex vivo platelet aggregation; impaired platelet adhesion and aggregation to injured vessel

– Enhanced Production of NO

– Uremic Toxins

– Anemia

– Altered blood rheology; defective platelet diffusivity; decreased release of ADP by erythrocytes; erythropoietin deficiency

– Medication Effects

– Anticoagulants; antiplatelet agents; NSAIDs; β-lactam antibiotics; third-generation cephalosporins

Role of Medications

Antiplatelet agents such as aspirin, as well as anticoagulants, increase the frequency of major bleeding in individuals with chronic renal insufficiency. Aspirin, at a dose of 100 mg/day, has been shown to significantly prolong the bleeding time in uremic patients when compared to controls³² and anticoagulant therapy increases rates of bleeding in patients with end-stage renal disease as compared to the general population.³³, ³⁴, ³⁵ A recent study³⁶ showed that the risk for major bleeding episodes per year of exposure was 0.8%, 3.1%, 4.4%, and 6.3% in patients undergoing hemodialysis while taking neither warfarin nor aspirin, taking warfarin alone, taking aspirin alone, or taking the combination of warfarin and aspirin, respectively.

Given this bleeding risk, randomized, controlled trials are necessary to evaluate the efficacy and the safety of these agents in the secondary prevention of cardiovascular events in this high-risk population. Other medications that may increase the risk of bleeding in uremia include β-lactam antibiotics that accumulate in uremic patients³⁷ and act by perturbing platelet membrane function and interfering with ADP receptors.³⁸ The prolonged bleeding time and the abnormal platelet aggregation are related to the dose and duration of treatment and are promptly reversible after drug discontinuation. Third-generation cephalosporins may also inhibit platelet function and lead to marked disturbance of blood coagulation.³⁹ Nonsteroidal antiinflammatory drugs (NSAIDs) such as indomethacin, ibuprofen, naproxen, phenylbutazone, and sulfinpyrazone also inhibit platelet cyclooxygenase and disturb platelet function, but, in contrast to aspirin, the inhibitory effect of these compounds is readily reversed as the blood concentration of the drugs falls upon cessation of administration.⁴⁰

Clinical Manifestation

The clinical presentation of uremic bleeding ranges from mild and clinically unimportant bleeding (petechiae, purpura, and epistaxis) to severe hemorrhage (gastrointestinal bleeding, intracranial bleeding, and hemorrhagic pericarditis). Gastrointestinal bleeding occurs with the greatest frequency and has been observed in up to one-third of uremic patients. Low-grade gastrointestinal bleeding may be even common. Upper gastrointestinal bleeding accounts for 3% to 7% of all deaths in patients with end-stage renal disease.⁴¹ A prospective study⁴² found that acute gastrointestinal hemorrhage in patients with impaired renal function was associated with an increase in mortality and a 37% increase in length of hospital stay as compared to nonrenal patients.⁴² The causes of bleeding are usually peptic ulcers, hemorrhagic esophagitis, gastritis, duodenitis, gastric telangiectasias, and diverticular disease.⁴³, ⁴⁴ Other bleeding complications reported in chronic uremia are subdural hematoma, spontaneous retroperitoneal bleeding, spontaneous subcapsular hematoma of the liver, intraocular hemorrhage, and although now rare, hemorrhagic pericarditis with cardiac tamponade.¹

LABORATORY ASSESSMENT

To identify patients at risk for hemorrhagic complications several tests have been used to establish which abnormal laboratory findings in uremia correlate best with an increased likelihood of clinically significant bleeding. Coagulation screening tests such as activated partial thromboplastin time, prothrombin time, and thrombin time are generally normal in uremia,⁴⁵ and there is no good correlation between blood urea nitrogen or creatinine and clinical bleeding.⁴⁵ Diagnosis of uremic bleeding still relies on clinical symptoms, and the cutaneous bleeding time (normal values: 1 to 7 minutes)⁴⁵ remains the most useful test for bleeding caused by uremia.⁴⁶, ⁴⁷ The bleeding time is an index of the primary phase of hemostasis, that is, the interaction of the platelet with the blood vessel wall, and the formation of the platelet plug.

THERAPEUTIC STRATEGIES FOR UREMIC BLEEDING

The approach to uremic bleeding must be considered in two contexts: the treatment of patients with active bleeding and the prevention of bleeding in patients at high risk because of
invasive procedures or surgery. The strategy depends on the urgency of the situation, the severity of uremia, and the previous therapy employed (Table 127.2).

Dialysis

Bleeding in uremia has been easier to control since the introduction of dialysis.²⁸, ⁴⁸ Studies indicate that dialysis ameliorates clinical bleeding,⁴⁹ improves platelet aggregation⁴⁹, ⁵⁰ and prothrombin consumption index.⁴⁹ Dialysis removes uremic toxins, including urea, creatinine, phenol, phenolic acids, or guanidinosuccinic acid, and improves platelet functional abnormalities.⁵¹, ⁵², ⁵³ However, platelet activation induced by interaction of blood with the artificial surface and the use of systemic anticoagulation may contribute to bleeding tendency. The risk of bleeding may be minimized by using peritoneal dialysis or alternatives to routine heparinization to prevent clotting in the extracorporeal circulation during hemodialysis.

Peritoneal dialysis is more effective in correcting platelet abnormalities than hemodialysis.⁵⁴ The reasons for the superiority of peritoneal dialysis in ameliorating platelet function abnormalities are not completely understood, but are likely due in part to the avoidance of heparin and better clearance of the middle molecular weight molecules.

To minimize the risk of bleeding in hemodialysis and continuous renal replacement therapies several strategies (reviewed in ref.⁵⁵) such as low-dose heparin, heparin-free dialysis, and regional anticoagulation with citrate can be used.

In patients with moderate risk of bleeding, the use of minimum dose of heparin reduces bleeding complications when compared with other methods such regional heparinization. The protocol usually involves a bolus of 500 U of heparin every 30 minutes or a continuous infusion of heparin to keep the activated clotting time >150 but <200 seconds. This technique has the advantage that no additional equipment is needed in the dialysis circuit, but some minimal degree of anticoagulation still occurs.⁵⁵

Heparin-free dialysis is the method of choice in patients with active bleeding or at high risk of bleeding. To avoid clotting of dialyzer, extracorporeal blood flow is rapidly increased to 250 to 350 mL/min and maintained throughout the treatment and 250 to 300 mL saline flushes are administered every 15 to 30 minutes into the arterial limb (predialyzer) to reduce hemoconcentration and to wash fibrin strands. The volume of saline is removed during the dialysis session. Because of its simplicity and safety, heparin-free dialysis can be used in approximately 90% of intensive care patients.⁵⁵

Table 127.2 Guidelines for the prevention and treatment of bleeding in patients with uremia

In all patients with hemorrhagic complications or who are undergoing major surgery, the adequacy of dialysis should be reviewed
–	The dialysis schedule—using alternatives to routine heparinization—should be changed for 1 or 2 months in patients who have experienced severe hemorrhage or who have undergone recent cardiovascular surgery
Patients with acute bleeding episodes may be treated with desmopressin at a dose of 0.3 µg/kg, administered intravenously (added to 50 mL of saline over 30 min) or subcutaneously
–	Intranasal administration of this drug at a dose of 3 µg/kg is also effective and well tolerated
–	The effect of desmopressin lasts only a few hours, and it tends to lose efficacy when repeatedly administered
In patients with persistent chronic bleeding, the treatment of choice should lead to a long-lasting hemostatic competence
–	Bleeding in patients with renal failure and hematocrit <30% must be treated with erythropoietin
–	Blood or red blood cell transfusions to improve hematocrit values should be administered to severely anemic patients. Hemostatic effect of red blood cell transfusion is achieved when the hematocrit rises above 30%
–	Conjugated estrogens given by intravenous infusion in a cumulative dose of 3 mg/kg as daily divided doses (i.e., 0.6 mg/kg for 5 consecutive days) is the most appropriate treatment