Hemostasis in renal disease: Pathophysiology and management

1

1 REVIEW

Hemostasis in Renal Disease: Pathophysiology and Management MARY E. EBERST, M.D.,

LEE

R. BERKOWITZ,

M.D., Chapel MI/, forth

The hemostatic abnormalities commonly encountered in patients with renal disease can significantly threaten the well-being of the patient and pose difficult management issues for the clinician. In this review, we explore the pathophysiology underlying the bleeding diathesis and hypercoagulability that can occur. Current therapeutic interventions are also discussed.

Carolina

R

enal disease can result in significant disorders of hemostasis. Both a bleeding diathesis and a hypercoagulable state may be caused by renal abnormalities. The bleeding diathesis generally results in mucosal bleeding and increased blood loss with surgical procedures [1,21. The hypercoagulability leads to thrombotic events, such as pulmonary emboli and renal vein thrombosis [3-51. In this review, we discuss the pathophysiology and management of these acquired coagulopathies of renal disease. Each results from multiple defects in hemostasis and each may be managed in different ways. Because of this complexity, we have separated our discussion into two distinct coagulopathies. This separation does not mirror the clinical situation in which both coagulopathies may occur in the same patient.

PATHOPHYSIOLOGY DIATHESIS

From the Department of Emergency Medicine (MEE) and Medicine (LRB), University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina. Requests for reprints should be addressed to Mary E. Eberst, M.D., Department of Emergency Medicine, CB# 7594, Chapel Hill, North Carolina 27599-7594. Manuscript submitted April 1, 1992, and accepted in revised form March 8, 1993.

168

February

1994

The American

Journal

of Medicine

Volume

OF THE BLEEDING

The bleeding tendency seen in association with renal disease tends to be related to the degree and duration of uremia [6]. In general, the more severe the uremia and the longer its duration, the greater the risk of bleeding, although the threshold varies widely for any given degree of azotemia [71. The bleeding diathesis usually disappears after renal transplantation, supporting the concept that these hemostatic abnormalities are acquired [Bl. The bleeding time is the clinical test that is most often prolonged in uremia. Reflective of primary hemostatic function, the bleeding time measures the interaction between platelets and the vessel wall. Fibrinogen, as well as several activated clotting factors, is also involved in this interaction. Prolongation of the bleeding time is not directly related to the severity of renal failure, however, there is some correlation, and it is more likely to be significantly prolonged in patients with severe renal failure (creatinine greater than 6.7 mg/dL) [7,9-121. Recent reviews .of the literature on bleeding times have raised questions regarding whether the test is a good predictor of hemorrhage. In a report of a thousand consecutive renal biopsies, 2% of patients developed perirenal hematoma. The positive predictive value of the bleeding time for this complication was 4% [ 131. Another analysis of data 96

HEMOSTASIS

IN RENAL

DISEASE

/ EBERST

AND

BERKOWITZ

VESSEL WALL

HEMATOCRIT * 30% Figure 1. The effect of anemia on hemostasis, In flowing blood with a relatively normal hematocrit (>30%), the red blood cells (RBC) mainly occupy the center of the vessel while the platelets are in a skimming-layer at the endothelial surface. This is optimal for plateletendothelial cell interaction and the formation of a platelet plug. In the setting of anemia, such as that which occurs in renal disease, the RBCs and platelets are dispersed during flow through the vessel, a less than ideal situation for primary hemostasis.

FLOW

OF BLOOD

\ ENDOTHELIAL CELLS

HEMATOCRIT < 25%

-

from five studies of bleeding in uremia showed that the predictive value of the bleeding time was not superior to the predictive values of the platelet count or hematocrit [lo]. These studies suggest that the bleeding time should be used as a marker of hemostatic dysfunction in uremia, but should not be used to predict clinical outcome. A number of factors have been reported as contributing to the bleeding diathesis in uremia. Included are uremic retention products, anemia, platelet dysfunction, deficiency of coagulation factors, and thrombocytopenia. Uremic Retention Products It has long been held that dialyzable factors contribute to the abnormal bleeding in patients with renal failure 1141. Small molecular weight substances (up to 500 daltons) including guanidinosuccinic acid, phenol, phenolic acid, and urea have been shown to impair platelet aggregation and the release of platelet factor 3 [l&171. Middle molecular weight molecules (500-3,000 d) have also been shown to impair platelet function by inhibiting platelet aggregation, inhibiting release of arachidonic acid from the platelet membrane, stimulating prostacyclin synthesis by the endothelium, and inhibiting the release of serotonin from platelets [15,18]. Despite these findings, there is no correlation between the levels of these dialyzable substances and the bleeding time in uremic patients [161. Furthermore, dialysis improves platelet function but rarely normalizes the bleeding time [16,191. These observations have led to the notion that uremic retention products contribute to bleeding in patients with renal failure, but other nondialyzable factors must be involved. Recently, an endothelial-derived relaxing factor, now identified February

as nitric oxide (NO) has been implicated as a mediator of uremic bleeding [20] because NO has the ability to impair the interaction between platelets and the vessel wall. Chronic Anemia The anemia associated with chronic renal failure is multifactorial [5,21-231. The primary factor is believed to be the deficient production of erythropoietin, because administration of erythropoietin can completely reverse the anemia in nearly all patients treated [241. Also possibly contributing to this anemia are: (1) shortened red blood cell survival time; (2) “uremic inhibitors” of erythropoiesis [24,25]; and (3) iron deficiency due to blood loss during dialysis and from the gastrointestinal tract. The severity of the anemia generally correlates with the degree of renal failure [121. Of the multiple factors that influence primary hemostasis and the bleeding time in uremic patients, the prolongation of the bleeding time best correlates with the hematocrit; they are inversely related C261. The influence of the hematocrit on platelet function is shown in Figure 1. With a normal hematocrit, the red blood cells mainly occupy the center and the platelets are in a skimming-layer along the endothelial surface as blood courses through a vessel. With endothelial damage, the platelets are in close proximity to adhere and begin formation of a platelet plug. However, when the hematocrit is decreased, as in uremia, platelets will be dispersed, impairing plateletendothelial cell adherence needed to initiate hemostasis. Platelet function can be optimized by increasing the red blood cell concentration, which results in a greater proportion of platelets at the vessel wall and increased platelet adhesion to the subendothelium [27-291. In addition to this effect on 1994

The American

Journal

of Medicine

Volume

96

169

HEMOSTASIS

IN RENAL

DISEASE

/ EBERST

AND

BERKOWITZ

Arachidonic Acid Cyclooxygenase L Endoperoxides PLATELET MEMBRANE.

ENDOTHELIAL CELLS 1

Thromboxane A2 (TxA2) Thromboxane B2 (TxB2)

platelets, red blood cells are also important for providing adenosine diphosphate (ADP) to platelets, which enhances their reactivity [ 171. Multiple studies of human blood have demonstrated the beneficial effect of increased hematocrit on improvement in the bleeding time [26,28-301. Optimal rheology is attained when the hematocrit is maintained between 26% and 30% [26,28-301. Levels higher than this are no more effective in correcting the bleeding time 15,311. Higher hematocrits (greater than 40%) may even be detrimental due to an increase in whole blood viscosity, which may contribute to an increased risk of thrombotic complications [31,32]. Uremia-Induced

Platelet Dysfunction ADHESION: Platelet adhesion is the interaction between platelets and the vascular subendothelium. Normal adhesion is dependent on von Willebrand factor (vWF), platelet membrane receptor glycoprotein Ib (GPIb), fibronectin, and red blood cell factors, including concentration, size, and rigidity of the cells 128,331. Platelets from uremic patients have been shown to have impaired platelet adhesion in viuo that is demonstrated as abnormal glass bead retention in. vitro [28]. The abnormality in platelet adhesion is thought to result from an abnormal interaction between vWF and GPIb 1341. Because no abnormalities in GPIb have been identified in uremic patients [6,15,35], the focus of investigation has been on IMPAIRED

PLATELET

VWF.

The endothelial cells of uremic patients have been shown to synthesize a normal vWF molecule [36]. Multiple studies have also documented normal or increased levels of vWF and factor VIII in patients with uremia [19,34,37-401. The elevated levels may result from long-term, low-grade endothelial damage and recurrent platelet activation by hemodialysis 1341. It has been suggested that vWF is functioning abnormally in the uremic environment resulting in 170

February

1994

The American

Journal

of Medicine

Volume

Figure 2. Arachidonic acid metabolism and prostaglandin synthesis in the platelet membrane and vascular endothelium. In a uremic environment, the balance is shifted with decreased production of platelet thromboxanes and increased production of vascular prostacyclin.

an abnormal interaction with GPIb 1341. Functional evaluation of vWF, as measured by the ristocetin cofactor activity, has occasionally been found to be reduced in patients with renal failure [ 11. In plasma, vWF circulates in multimeric form, with the high-molecular-weight multimers being essential for the interaction with platelets [41,421. One study 1431 found an abnormal vWF multimerit pattern in patients with uremia, with reduced or absent amounts of the highest molecular weight forms. Other studies, however, have not confirmed these findings [19,37,39,40,44]. Although specific structural or functional defects in vWF are not consistently found, transfusion of cryoprecipitate or the use of desmopressin (DDAVP), which cause an increase in vWF, does correct the prolonged bleeding time in patients with uremia 135,391. ABNORMAL PROSTAGLANDIN SYNTHESIS BY PLATELETS AND ENDOTHELIAL CELLS: Unbalanced prosta-

glandin synthesis in the platelets and vascular endothelial cells of uremic patients are believed to contribute to the defect in primary hemostasis (Figure 2). In platelets, it has been shown that there is abnormal mobilization and metabolism of arachidonic acid that results in decreased generation of thromboxanes (TxA1 and TxB2), potent stimulators of platelet aggregation [19,45-481. A functional defect in the enzyme cyclooxygenase has been proposed [17,19,45,46,491, but no direct evidence for this has been found 1121. Others have suggested inhibition of arachidonic acid metabolism by some unidentified substance present in uremic plasma 145,461. Abnormal prostaglandin metabolism also occurs in the vascular endothelial cells of patients with renal failure. In contrast to platelets in which there is decreased thromboxane formation, there are elevated levels of prostacyclin activity in the endothelial cells of renal failure patients compared to normal controls [1,49]. Proposed explanations for this include the presence of an unknown substance 96

HEMOSTASIS

in uremic plasma that stimulates prostacyclin production 150,511 or increased prostacyclin synthesis as a response of endothelial cells to chronic endothelial damage [34]. It has also been suggested that the activity of adenylate cyclase may be enhanced by unknown uremic substances [521. Although prostacyclin is a potent inhibitor of platelet function, a direct relationship between elevated prostacyclin levels and prolongation of the bleeding time has not been established 1531. Prostacyclin generation also does not appear to be significantly effected by hemodialysis. Similar levels are found in uremic patients who are aggressively dialyzed and those who are managed conservatively 1191. PLATELET MEMBRANE DEFECTS: It is well documented that platelet membrane phospholipids are modified by the uremic environment 1371. One of the first defects of uremic platelets to be characterized was reduced activity of Platelet Factor 3 112,541. This factor has procoagulant activity by promoting the interaction between platelets and phospholipids. Diminished activity results in abnormal prothrombin consumption. This defect is not reflected in the bleeding time. ACQUIREDPLATELETSTORAGEPOOLDEFECTS:Pl&!-

lets from some uremic patients have been shown to have an acquired platelet storage pool defect. Identified abnormalities include: reduced content of serotonin and ADP in the dense granules, increased adenosine triphosphate (ATP) /ADP ratio, and diminished release of ATP at the time of platelet activation [19,55,56]. The basis for these abnormalities is uncertain, but factors in uremic plasma are thought to inhibit ATP release and serotonin uptake into platelets 1561. These storage pool defects can contribute to abnormal platelet aggregation 1551. ABNORMAL CALCIUM HOMEOSTASIS: Abnormalities in calcium homeostasis are believed to contribute to the platelet dysfunction seen in uremia by increasing the platelet calcium content. This is thought to be due to increased prostacyclin and adenylate cyclase activity, which in turn induces a qualitative change in GPIb that results in reduced binding of vWF and impaired platelet adhesion [1,57,581. These calcium abnormalities cannot be attributed to elevated levels of parathyroid hormone (PTH) that can be present in patients with renal failure [16,19,591. Although PTH has been shown to inhibit platelet aggregation and serotonin secretion in vitro [1,16], there is no correlation between PTH levels and impaired platelet aggregation 116,601. Furthermore, patients with primary hyperparathyroidism and elevated PTH levels have normal platelet function [ 151. February

IN RENAL

DISEASE

/ EBERST

AND

BERKOWITZ

EFFECTOFDRUGS ONPLATELETFUNCTIONINUREMIC PATIENTS: The platelet dysfunction of uremia

may be exacerbated by antibiotics and other commonly prescribed drugs such as aspirin, diazepam, chlordiazepoxide, and diphenhydramine. The combination of uremia and drug interactions has a more profound effect on platelet function than either factor alone [71. The best example of this is the use of aspirin [61,62]. Antibiotics that exacerbate platelet dysfunction in renal failure patients include penicillin, penicillin derivatives, and some cephalosporins 163,641. Deficiency of Coagulation Factors In renal failure patients, particularly those with the nephrotic syndrome, acquired deficiencies of clotting factors can be present. The decreases in factor levels result from loss in the urine, sequestration in the kidney, and abnormal distribution due to changes in intravascular volume [38]. Most commonly, coagulation factors from the intrinsic pathway are reduced 1651. Acquired factor IX deficiency has been described in nephrotic patients. Usually this only occurs when urine protein excretion exceeds 15 grams per 24 hours [66]. The factor IX level usually remains above 10% so that there is not spontaneous bleeding, but the activated partial thromboplastin time may be prolonged. Low levels of factor VII have also been found in patients with the nephrotic syndrome independent of antibiotic exposure [38]. Patients with renal failure appear to be especially susceptible to the reduction of vitamin Kdependent coagulation factors that can result from exposure to antibiotics, particularly the thirdgeneration cephalosporins which contain the Nmethyl-thiotetrazole side chain (ie, moxalactam, cefamandole, cefotaxime, and cefoperazone) [17,671. Factor XIII has also been found to be reduced in some patients with renal failure; an acquired inhibitor to factor XIII has been described in this setting [51. Thrombocytopenia Patients with uremia frequently have a platelet count that is lower than normal, however, uremia alone rarely results in a count less than lOO,OOO/ mm3, and this should not account for prolongation of the bleeding time and abnormal bleeding [6,16,681. Kinetic studies have shown that platelet survival is normal in dialysis patients [69]. Although the count may transiently decrease during dialysis, it returns to baseline shortly after the completion of dialysis [65]. Explanations for this mild thrombocytopenia include a possible inhibitory effect of the uremic environment on mega1994

The American

Journal

of Medicine

Volume

96

171

HEMOSTASIS

IN RENAL

DISEASE

/ EBERST

AND

BERKOWITZ

TABLE I Available Therapies for Managementof the Bleeding Diathesis Associated With Renal Disease Dialysis: hemodialysis or peritoneal dialysis Correction of anemia: recombinant human erythropoietin packed red blood cells

or transfusion of

DDAVP (desmopressin) Conjugated estrogen Cryoprecipitate Platelet transfusion

karyocytopoiesis and the contribution of hypersplenism that may be present secondary to chronic antigenic stimulation [51. Platelet counts below 100,000/mm3 should raise concern for other etiologies of thrombocytopenia including infection and medications. Despite repeated exposure to heparin during hemodialysis, immune related heparinassociated thrombocytopenia rarely occurs in chronic renal failure patients [6].

MANAGEMENT OF THE BLEEDING DIATHESIS (TABLE I) Dialysis A number of studies have documented that dialysis improves platelet function, as measured by the bleeding time, in uremic patients [7,16,55,701. This improvement is transient, lasting 1 to 2 days after each dialysis treatment and is only partial in that the bleeding time rarely corrects completely [16,191. Although early studies proposed that hemodialysis (HD) and peritoneal dialysis (PD) were equally effective in improving the bleeding diathesis associated with uremia 181, it appears that PD may actually be superior. Reported advantages of PD include more effective removal of uremic toxins [11,531, fewer abnormalities in arachidonic acid metabolism 1711, and fewer adverse effects on platelet aggregation because there is no contact with the dialysis membrane [6,71]. Hemostatic disadvantages associated with HD include activation of the coagulation cascade, repeated exposure to heparin, increased incidence of acquired platelet storage pool defects, and modifications of the fibrinolytic system and the natural inhibitors of coagulation. One example is a decrease in antithrombin III during HD [71,72]. Correction of Anemia With Recombinant Human Erythropoietin or Transfusion of Packed Red Cells Because platelet function improves when the hematocrit is increased (see above), correction of 172

February

1994

The American

Journal

of Medicine

Volume

the anemia associated with renal failure may improve hemostasis [Figure 11. Two commonly used methods to correct the anemia are transfusion of packed red cells and administration of recombinant human erythropoietin (rhEP0). The minimum target hematocrit for either modality should be approximately 26% [26,28-301. Transfusing packed red cells has the advantage of immediate correction of the hematocrit. Disadvantages include iron overloading and viral transmission. In general, these disadvantages take precedence, although transfusions may be given in an acute situation. This efficacy-toxicity profile for transfusing packed red cells is reversed for rhEP0. rhEP0 is slower in its action, but is not associated with iron overload or viral toxicities. There now exist several years of experience using rhEP0 for treatment of the anemia associated with renal failure. rhEP0 is biologically and immunologically identical to the native hormone with its primary target being committed erythroid progenitor cells [30,73,741. In addition to the increased red cell mass that results from rhEP0 stimulation, there may be a qualitative improvement in the red cells, as well as an effect on the megakaryocytes [75,761. There is no evidence that rhEP0 has a direct effect on platelet function or directly activates intravascular hemostasis [77,781. Greater than 95% of reported patients, either predialysis or dialysis-dependent, appear to respond to rhEP0 [21,22,25,30,31,75,77-861. After therapy with rhEP0 is initiated, a reticulocytosis and increase in the red cell mass are evident within 10 to 14 days. Early trials used relatively high doses of rhEP0 administered intravenously (150 units per kilogram, three times per week) resulting in a dose-related rapid rise in the red cell concentration [87]. Although the incidence of adverse reactions (see below) does not appear to be directly dose-related, it appears that a more gradual increase in the red cell concentration is preferable [21,22,82,84]. Lower doses, such as 35 to 50 units per kilogram, three times per week are now commonly used to attain a goal hematocrit around 35% [21,221. Subcutaneous administration of rhEP0 has also proven effective and permits easier treatment and lower dosing due to the prolonged halflife [25,88,891. Some patients may show a relative resistance to rhEP0 and require higher doses or a longer time to respond, but rarely are patients totally unresponsive [go]. Iron deficiency is said to be the most common cause of relative resistance; iron deficiency should be corrected before treatment with rhEP0 begins and many patients will require long-term iron replacement therapy due to the 96

HEMOSTASIS

increased utilization by accelerated erythropoiesis [22,30,83,91,921. Other causes of resistance to rhEP0 include: acute or chronic blood loss, infections and other inflammation, severe hyperparathyroidism, acute or chronic hemolysis, osteitis fibrosis, aluminum intoxication, and vitamin deficiencies [21,30,74,80,931. Early studies showed a 15% incidence of adverse reactions to rhEP0 therapy [77]. The most common complications are accelerated hypertension in up to 30% of patients, seizures in up to 5% of patients, thrombotic occlusion of hemodialysis vascular accesses, increased clot formation within the dialyzer, and elevated predialysis levels of blood urea nitrogen, creatinine, and potassium [21,22,30,77,78,90,941. The hypertension and thrombosis may be related to increased vascular resistance and increased blood viscosity that occurs with the rise in hematocrit [95-971. Seizures may occur secondary to hypertension. There is no evidence that any of these complications are directly due to the drug itself [77,981. There is controversy surrounding the effect of raising the hematocrit on the rate of progression of renal failure [25]. Some patients appear to have increased progression 1991, while other studies have not verified this finding [86,100,1011. Antibody formation to the rhEP0 product or anaphylactic reactions have not been reported 130,821. DDAVP (Desmopressin) Desmopressin (l-deamino-S-D-arginine vasopressin) a synthetic analog of vasopressin, has been shown to be beneficial in controlling bleeding associated with uremia. At least 50% to 75% of uremic patients with prolonged bleeding times have transient shortening or normalization of the bleeding time after treatment with DDAVP [35,39,102,1031. The mechanism by which DDAVP leads to a shortening of the bleeding time is complex. DDAVP promotes the release of vWF from storage sites in endothelial cells into plasma, resulting in a quantitative increase in vWF, including large multimeric forms not usually present in plasma [37,102,1041061. DDAVP may also cause release of factor VIII from hepatocytes 11021. A third procoagulant effect is on the platelet membrane. Platelet upta.ke of serotonin and release of ATP by activated platelets are increased in the presence of DDAVP [39]. Which of these is the crucial effect of DDAVP in uremia is not clear [19,37,39,40,44,102,107,108]. The usual intravenous or subcutaneous DDAVP dose is 0.3 micrograms per kilogram of body weight. This results in maximum shortening of the bleeding time within 1 to 2 hours and the effect persists February

IN RENAL

DISEASE

/ EBERST

AND

BERKOWITZ

for about 4 hours 1371. Intranasal DDAVP may also be effective [log]. Typically administered every 12 hours, successive infusions of DDAVP can lead to tachyphylaxis within 24 to 48 hours, presumably because of depletion of the vWF stores within the endothelium [ llO,lll]. However, tachyphylaxis is not a constant phenomenon and the typical response usually returns in 3 to 4 days [102,1121. When used in combination with elevation of the hematocrit (by rhEP0 or packed red cell transfusion), DDAVP may have an additive effect in improving the bleeding time [ 751131. Side effects associated with DDAVP are generally mild including headache, flushing, minor hypotension, tachycardia, nausea, abdominal cramps, and local site reaction [ 1021. Potentially severe consequences including hyponatremia and thrombosis rarely occur [1051. There is one report of myocardial infarction occurring in a hemophiliac patient treated with DDAVP 1.1141. Conjugated Estrogen Based upon the observation that the abnormal bleeding tendency in women with vonwillebrand disease improves during pregnancy, Liu et al 11151 studied the effect of conjugated estrogen on patients with bleeding associated with uremia. They found an improvement in the bleeding time in greater than 80% of subjects. Since then, other investigators have found similar improvement [103,115-1181. The mechanism of action of conjugated estrogens is unknown. Proposed mechanisms include inhibition of vascular prostacyclin 11161 and the release of high molecular weight vWF multimers, which has been observed in pregnancy 1110, 115,116l but has not been documented in renal failure patients. The usual intravenous dose of conjugated estrogen is 0.6 mgikg daily for 5 consecutive days [ 116,117]. The initial effect upon the bleeding time can be seen in 6 hours, peak response occurs in 5 to 7 days, and the effect may persist for up to 14 days [116,117]. Oral conjugated estrogens have also been shown to be effective [ 1191. At a dose of 50 mg daily, a median of 7 days of treatment is required to improve or normalize the bleeding time. Compared to intravenous administration, the beneficial effect of oral conjugated estrogens is shorter. The bleeding time can become prolonged within 4 days after treatment with oral conjugated estrogens. The majority of patients treated with conjugated estrogens have no side effects 11151. When side effects occur, they are generally mild. Minor complications include hot flashes, nausea, vomiting, fluid retention, hypertension, gynecomastia, and loss of 1994

The American

Journal

of Medicine

Volume

96

173

HEMOSTASIS

IN RENAL

DISEASE

/ EBERST

AND

BERKOWITZ

TABLE II Management

of Bleeding in Patients With Renal Disease

Long-term objectives

(1) Adequate dialysis (2) Maintain hematocrit >25%, use of recombinant human erythropoietin as needed

Acute bleeding episodes

(1) Verify that patient is adequately dialyzed (2) If hematocrit is <25%, transfuse packed red blood cells to reach this level (3) Administer DDAVP, 0.3 kg/kg IVor subcutaneously; onset of action in 1 to 2 hours (4) Administration of conjugated estrogens, 0.6 mg/kg IV; onset of action is 6 hours to several days

Life-threatening bleeding

(1) Infusion of cryoprecipitate, 10 bags IV; beneficial effect seen in 1 hour (2) Platelet transfusions

IAVP = desmopressin; IV = intravenously.

libido. Potentially serious complications include an increased risk of thromboembolic disease and malignancy [115,1161. Compared to other available therapies used to manage uremic bleeding, advantages of conjugated estrogen are that it provides longer-term management than DDAVP, there is no development of tachyphylaxis as can occur with the use of DDAVP, and there is no risk of viral transmission that can occur with cryoprecipitate. Cryoprecipitate The use of cryoprecipitate to control bleeding associated with uremia was first demonstrated in 1980 1441. Cryoprecipitate contains fibrinogen, factor VIII, vWF, fibronectin, and factor XIII. In patients with uremia and a prolonged bleeding time, the usual infusion of cryoprecipitate consists of 10 bags. This typically shortens the bleeding time within 1 hour and the effect may persist for up to 18 hours. The specific mechanism of action of cryoprecipitate in shortening the bleeding time is not known. Infusion results in only minor increases in the levels of fibrinogen, factor VIII, and vWF, and in vitro platelet aggregation studies are unchanged by cryoprecipitate despite correction of the bleeding time 1441. The major risk of administration of cryoprecipitate is viral transmission. Because of this risk, the role of cryoprecipitate has largely been replaced by DDAVP. Cryoprecipitate may be used when a patient is refractory to DDAVP or in the situation of life-threatening bleeding. There is no additive or synergistic effect when cryoprecipitate is used in combination with DDAVP [41]. 174

February

1994

The American

Journal

of Medicine

Volume

Platelet Transfusion Routine platelet transfusion is not advantageous in the management of bleeding associated with uremia because frequently platelets become dysfunctional shortly after entering the uremic environment [41,44]. Platelet transfusion is only advocated in emergency situations with uncontrolled hemorrhage. In this setting, platelets should be used in combination with DDAVP, cryoprecipitate, and packed red blood cells [4 11. Table II illustrates a treatment plan for the management of bleeding in patients with renal disease. Adequate dialysis and maintenance of the hematocrit at 25% or greater should be ongoing goals for all renal failure patients. Recombinant human erythropoietin can be used chronically if needed for hematocrit support. Therapy for acute bleeding episodes begin similarly with optimization of dialysis and transfusions of packed red blood cells to raise the hematocrit to about 25%. Simultaneously, DDAVP is used and can have an effect in 1 to 2 hours. If bleeding continues, conjugated estrogens can be added, although their effect may not be realized for several days. When life-threatening hemorrhage occurs, cryoprecipitate infusions may be rapidly beneficial. Platelet transfusions should be given, although they are of questionable utility. HYPERCOAGULABILITY ASSOCIATED WITH RENAL DISEASE There are a variety of coagulation abnormalities that result in a hypercoagulable state in patients with renal disease (Figure 3). The highest incidence of thromboembolic events has been observed in patients with nephrotic syndrome in which the incidence approaches 30% 1351. Thrombosis also occurs in patients with other types of renal pathology, particularly in patients with membranous nephropathy, lupus nephritis, and mesangiocapillary glomerulonephritis [4,51. Potential mechanisms of hypercoagulability in patients with renal failure, both nephrotic and non-nephrotic, will be disussed by review of the specific contributory factors. Abnormalities involving antithrombin III, protein S, and fibrinolysis are of greatest importance. Acquired Antithrombin III Deficiency Antithrombin III (AT III) is a naturally occurring inhibitor of coagulation that inhibits the serine protease coagulation factors (factors XII, XI, X, IX, VII, and thrombin) except factor VII. Low levels of AT III can be found in 7% to 60% of patients with renal disease as a result of protein loss in the urine [ 120,12 11. The plasma AT III level correlates positively with the serum albumin level 96

HEMOSTASIS

IN RENAL

DISEASE

/ EBERST

AND

BERKOWITZ

1 Decreases in: 1

1Antithrornbin III \ /I

/I

\L Figure 3. Pathogenic mechanisms contributing to hypercoagulability in renal disease. Alterations in the levels of these proteins, as well as changes in platelet aggregation and fibrinolysis are implicated in the predisposition to thrombosis that occurs in patients with renal disease.

v/

1i

HYPERCOAGULABILITY

Increases in: Platelet Aggregation

and negatively with the degree of proteinuria [122,1231. Low AT III concentrations are most commonly found in patients with a urine protein excretion greater than 10 g per 24 hours or a serum albumin concentration of less than 2 g/dL [1231251. In addition to low AT III levels, some uremic patients have reduced activity of AT III, the functional abnormality apparently induced by the uremic environment [1261. Dialysis does not appear to alter the AT III level on a long-term basis, although it may decrease slightly during dialysis because of exposure to heparin [126,1271. Related to AT III, heparin cofactor II is a naturally occurring inhibitor of thrombin [ 1281. Its deficiency has been associated with thromboembolic phenomena. Some chronically dialyzed patients have normal levels of AT III, but significantly reduced levels of heparin cofactor II [ 1271. Abnormalities of Protein S Protein S is another naturally occurring anticoagulant; its presence is required for the activity of protein C. Some patients with nephrotic syndrome have reduced protein S activity [3,122,1261. Although the total concentration of protein S antigen may be elevated in these patients, the “free” active protein S level is decreased. The low level of free protein S is thought to result from elevated levels of its binding protein, C4b, and selective urinary loss of the uncomplexed protein 131. Protein S concentrations are not altered by hemodialysis 11261. Abnormal Fibrinolysis A reduction in fibrinolytic activity can be identified in up to 60% of patients with nephrotic syndrome [5,72,122,129,1301. Reduced fibrinolytic activity results from the accumulation of inhibitors such as alpha-2-antiplasmin and plasminogen activator-inhibitor, and the urinary loss of fibrinoFebruary

lytic activators, particularly plasminogen [4,5, 122,129l. Triglyceride levels are often elevated and are inversely related to fibrinolytic activity [130]. In addition, therapy with corticosteroids may also contribute to decreased fibrinolysis 11251. Enhanced Platelet Aggregation A number of observations suggest that platelets may become hyperaggregable, predisposing to thrombosis in patients with renal disease. Elevated levels of plasma lipids and decreased plasma albumin are thought to alter platelet membranes in a way that increases their aggregability. The degree of hyperaggregability correlates with hypoalbuminemia [4]. In patients with nephrotic syndrome, there are also changes in arachidonic acid metabolism that lead to preferential formation of thromboxanes that enhance platelet aggregation [4,122]. A third observation is that recurrent platelet stimulation by extracorporeal circulation during hemodialysis or hemofiltration can increase aggregability

ml. Abnormalities of Protein C Protein C is a naturally occurring anticoagulant protein that inhibits the activity of factors V and VIII. In patients with renal disease, protein C levels are variable dependent upon the type and severity of the disease that is present. Chronic renal failure patients without nephrotic syndrome often have decreased levels of protein C 11311. These low levels may result from an inhibitory substance in the uremic environment that depresses protein C activity [1311. Supportive of this, is a correlation between decreasing protein C activity and increasing serum creatinine, as well as increases in protein C activity after dialysis [126,1311. Nephrotic patients may have normal, elevated, or low levels of protein C [122,1311. In general, 1994

The American

Journal

of Medicine

Volume

96

175

HEMOSTASIS

IN RENAL

DISEASE

/ EBERST

AND

BERKOWITZ

nephrotic patients have elevated levels because protein C is highly negatively charged, which impedes its urinary excretion despite a molecular weight similar to albumin 11321. The level of protein C appears to be inversely related to the concentrations of serum albumin and AT III [132,1331. It is postulated that the elevated levels of protein C may partially compensate for the low AT III level and other abnormalities that predispose nephrotic patients to thrombosis [132,1341. Abnormalities of Contact Factors Changes in the contact activation pathway involving factor XII, high molecular-weight kininogen and prekallikrein have been identified in patients with renal disease. Decreased factor concentrations and dysfunctional molecules occur [1351371. There is no definite evidence that these factors predispose to thromboembolic disease, although theoretically, the changes described could lead to thrombosis because these factors are important in initiating fibrinolysis. Elevated Levels of Clotting Factors and Thrombocytosis Nephrotic patients may have increased levels of coagulation proteins including fibrinogen, factors V and VIII, and the vitamin K-dependent proteins [38,133,138]. The elevated levels result from increased hepatic synthesis that may be a response to proteinuria 11381. Decreased serum albumin concentration and decreased intravascular oncotic pressure most likely contribute to the increased levels [4,381. Elevation of the fibrinogen level has also been observed [122]. Its hepatic synthesis is increased proportionally to the quantity of proteinuria. There are no changes in fibrinogen catabolism. Fibrinogen, as well as factors V and VIII, may also be elevated because they are acute-phase reactants [134]. Steroid therapy has been reported to increase the level of factor VIII 11251. Thrombocytosis occurs in up to one half of nephrotic patients [5,122]. The cause of this is not known.

DIAGNOSIS AND TREATMENT HYPERCOAGULABLE STATE

OF THE ACKNOWLEDGMENT

Because thromboemboli secondary to hypercoagulability account for significant morbidity and mortality in patients with renal disease, it is imperative that the clinician recognize and treat patients with this complication. There are two ways to diagnose hypercoagulability. A clinical diagnosis can be made when the patient has two thrombotic events that are independent of each 176

February

1994

The American

other anatomically and temporally. A good example would be two episodes of deep vein thrombosis occurring months apart. In contrast, the patient who develops a deep vein thrombosis and then experiences a pulmonary embolus several days later, would not be considered hypercoagulable. There are also a variety of laboratory tests that may lead to a diagnosis of hypercoagulability. Assays for AT III, protein S, protein C, as well as the fibrinolytic system, can be performed. Reductions greater than 50% of one of these proteins would indicate a risk for thrombi. These tests must be interpreted with caution, however, since not all patients with reductions in these assays have recurrent thrombi and some patients with recurrent thrombi have no abnormalities of these tests [139,140]. Because of these potential problems with laboratory testing, a clinical diagnosis of hypercoagulability is more reliable and probably safer for the patient. Treatment options for the hypercoagulable patient are limited and there is no way to completely reverse such a predisposition in an individual patient. Adequate dialysis, whether HD or PD, can temporarily improve the thrombogenic setting by removal of inhibitors of the natural anticoagulants 11261 and potentially altering the levels of these anticoagulants, although these changes are probably not hemostatically significant [126,1271. Compared to PD patients, HD patients may have improved fibrinolytic activity because the extracorporeal circulation can directly activate fibrinolysis via factor XII [80,1291. Once a diagnosis of thromboembolic disease is established, systemic anticoagulation should be initiated with heparin, followed by oral therapy with warfarin. Systemic or local use of thrombolytic agents, such as streptokinase or urokinase, is a consideration as in any other patient with significant thrombosis. The optimal duration of anticoagulation is not clearly established in these patients, however, indefinite therapy is reasonable unless there is a resolution of the underlying disease state [4]. Long-term prophylactic anticoagulation in high-risk patients without documented thromboembolic disease is not of proven benefit.

Journal

of Medicine

Volume

We wish to express our gratitude preparation of the manuscript.

to Marietta

Gray for her expert assistance

in

REFERENCES 1. Remuzzi G. Bleeding in renal failure. Lancet 1988; 1: 1205-8. 2. Zuckerman GR, Cornette GL, Clause RE, Hatter HR. Upper gastrointestinal bleeding in patients with chronic renal failure. Ann Intern Med 1985; 102: 588-92.

96

HEMOSTASIS 3. Vigano-D’Angelo S, D’Angelo A, Kaufman CE, Sholer C, Esmon CT, Comp PC. Protein S deficiency occurs in the nephrotic syndrome. Ann Intern Med 1987; 107: 42-7. 4. Llach F. Hypercoagulability, renal vein thrombosis, and other thrombotrc complications of nephrotic syndrome. Kidney Int 1985; 28: 429-39. 5. Hocking WG. Hematologic abnormalities in patients with renal diseases. Hematol Oncol Clin North Am 1987; 1: 229-60. 6. Saito H. Hemostatic disorders associated with renal disease. In: Ratnoff OD, Forbes CD, editors. Disorders of Hemostasis. Phrladelphia: WB Saunders, 1990: 480-92. 7. Steiner RW, Coggins C, Carvalho ACA. Bleeding time in uremia: a useful test to assess clinical bleeding. Am J Hematol 1979; 7: 107-17. 8. Nencr GG, Berrettini M, Agnelli G, Parise P, Buoncristiani U, Ballatori E. Effect of peritoneal dialyses, hemodialysis and kidney transplantation on blood plateletfunction. Nephron 1979; 23: 287-92. 9. George JN, Shattil SJ. The clinical importance of acquired abnormalities of plateletfunction. N Engl J Med 1991; 324: 27-39. 10. Rogers RPC, Levin J. A critical reappraisal of the bleeding time. Semin Thromb Hemost 1990; 16: l-20. 11. Lind SE. The bleeding time does not predict surgical bleeding. Blood 1991; 77: 2547-52. 12. Gordge MP, Faint RW, Rylance PB, Neild GH. Platelet function and the bleeding time in progressive renal failure. Thromb Haemost 1988; 60: 83-87. 13. Diaz-Buxo JA, Donadio JV. Complications of percutaneous renal biopsy: an analysisof 1,000 consecutive biopsies. Clin Nephrol 1975; 4: 223. 14. Bazilinski N, Shaykh M, Dunea G, et a/. Inhibition of platelet function by uremic middle molecules. Nephron 1985; 40: 423-8. 15. Castaldi PA, Gorman DJ. Disordered platelet function in renal disease. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, editors. Hemostasis and Thrombosis, Basic Principles and Clinical Practice. Philadelphia: Lippincott, 1987: 960-4. 16. Remuzzi G, Pusineri F. Coagulatron defects in uremia. Kidney Int 1988; 33 (Suppl24): S13-S17. 17. Andrassy K, Ritz E. Uremia as a cause of bleeding. Am J Nephrol 1985; 5: 313-9. 18. Pales JL, Lopez A, Asenio A, et a/. Inhibitory effect of peak 2-4 uremic middle molecules on platelet aggregation. Eur J Haematol 1987; 39: 197-202. 19. Livio M, Benigni A, Remuzzi G. Coagulation abnormalities in uremia. Sem Nephrol 1985; 5: 82-90. 20. Remuzzi G, Perico N, Zoja C, Corna D, Macconi D, Vigano G. Role of endothelium-derived nitricoxide in the bleedrng tendency of uremia. J Clin Invest 1990; 86: 1768-71. 21. Aronoff GR, Duff DR, Sloan RS, et al. The treatment of anemia with low-dose recombinant human erythropoietin. Am J Nephrol 1990; 10 (Suppl 2): 40-3. 22. Eschbach JW, Adamson JW. Recombinant human erythropoietin: implicationsfor nephrology. Am J Kidney Dis 1988; 11: 203-9. 23. Eschbach JW. The anemia of chronic renal failure: pathophysiology and the effects of recombinant erythropoietin. Kidney lnt 1989; 35: 134-48. 24. Eschbach JW, Adamson JW. Anemia of end-stage renal disease (ESRD). Kidney Int 1985; 28: l-5. 25. Watson AJ, Gimenez LF, Cotton S, Walser M, Spivak JL. Treatment of the anemia of chronic renal failure with subcutaneous recombinant human erythropoietin. Am J Med 1990; 89: 432-5. 26. Fernandez F, Goudable C, Sie P, et al. Low hematocrit and prolonged bleeding time in uraemic patients: effect of red cell transfusions. Br J Haematol 1985; 59: 139-48. 27. Turitto VT, Weiss HG. Red blood cells: their dual role in thrombus formation. Science 1980; 207: 541-3. 28. Castillo R, Lozano T, Escolar G, Reyert L, Lopez J, Ordinas A. Defective platelet adhesion on vessel subendothelium in uremic patients. Blood 1986; 68: 337-42. 29. Livio M, Marchasi D, Remuzzi G, Gotti E, Mecca G, DeGaetano G. Uraemic bleeding: role of anemia and beneficial effect of red cell transfusions. Lancet 1982; 2: 1013-5. 30. Eschbach JW, Haley NR, Adamson JW. The anemia of chronic renal failure: pathophysiology and effects of recombinant erythropoietin. In: Klinkmann H, Smeby LC, editors. Contrib Nephrol, Terminal Renal Failure:

February

IN RENAL

DISEASE

/ EBERST

AND

BERKOWITZ

Theraputic Problems, Possibilities, and Potentials, Basel: Karger 1990: 432-5. 31. Moia M, Vizzotto L, Cattaneo M, Mannucci PM, Casati S, Ponticelli C. Improvement in the hemostatic defect of uraemia after treatment with recombinant human erythropoietin. Lancet 1987; 2: 1227-9. 32. Carvalho AC. Acquired platelet dysfunction in patients with uremia. Hematol Oncol Clin North Am 1990; 4: 129-43. 33. Aarts PAMM, Bolhuis PA, Sakariassen KS, Heethaar RM, Sixma JJ. Red blood cell size is important for adherence of blood platelets to artery endothelium. Blood 1983; 62: 214-7. 34. Turney JH, Woods HF, Fewell MR, Weston MJ. Factor VIII complex in uraemia and effectsof haemodialysis. BMJ 1981; 282: 1653-6. 35. Shattil S, Bennett JS. Acquired qualitative platelet disorders. In: Williams WJ, Beutler E, Erslev AJ, Lichtman M, editors. Hematology. New York: McGraw-Hill, 1990: 1420-2. 36. Winter M, Seghatchian MJ, Cameron JS. An abnormal factor VIII molecule in uraemia [letter] Lancet 1983; 1: 1112. 37. Mannucci PM, Remuzzi G, Pusineri F, et al. Deamino-8-D-arginine vasopressin shortens the bleeding time in uremia. N Engl J Med 1983; 308: 8-12. 38. Vaziri ND, Branson HE, Ness R. Changes of coagulation factors IX, VIII, VII, Xand V in nephroticsyndrome. Am J Med Sci 1980; 280: 167-71. 39. Watson AJS, Keogh JAB. Effect of l-deamino-8.D-arginine vasopressin on the prolonged bleeding time in chronic renal failure. Nephron 1982; 32: 49-52. 40. Soslau G, Schwartz AB, Putatunda B, et a/. Desmo-pressin-induced improvement in bleeding times in chronic renal failure patients correlates with platelet serotonin uptake and ATP release. Am J Med Sci 1990; 300: 372-9. 41. Bridges KR. Hemorrhagic complications associated with renal failure. J Crit illness 1989; 4: 17-33. 42. Deykin D. Uremic bleeding. Kidney Int 1983; 24: 698-705. 43. Gralnick HR, McKeown LP, Williams SB, Shafer BC, Pierce L. Plasma and platelet vonwillebrand factor defects in uremia. Am J Med 1988; 85: 806-10. 44. Janson PA, Jubelirer SJ, Weinstein MJ, Deykin D. Treatment of the bleeding tendency in uremia with cryoprecipitate. N Engl J Med 1980; 303: 1318-21. 45. Remuzzi G, Benigni A, Dodesini P, et al. Reduced platelet thromboxane formation in uremia: evidence for a functional cyclooxygenase defect. J Clin Invest 1983; 71: 762-8. 46. Remuzzi G, Marchesi D, Livio M, et a/. Altered platelet and vascular prostaglandin generation in patients with renal failure and prolonged bleeding times. Thromb Res 1978; 13: 1007-15. 47. Bloom A, Greaves M, Preston FE, Brown CB. Evidence against a platelet cyclooxygenase defect in uraemic subjects on chronic haemodialysis. Br J Haematol 1986; 62: 143-9. 48. Smith MC, Dunn MJ. Impaired platelet thromboxane production in renal failure. Nephron 1981; 29: 133-7. 49. Remuzzi G, Cavenaghi AE, Mecca G, Donati MB, DeGaetano G. Prostacyclin-like activity and bleeding in renal failure. Lancet 1977; 2: 1195-7. 50. Defreyn G, Vergara Dauden M, Machin SJ, Vermylen J. A plasma factor in uraemia which stimulates prostacyclin release from cultured endothelial cells. Thromb Res 1980; 19: 695-9. 51. Deckmyn H, Zoja C, Arnout J, et al. Partial isolation and function of the prostacyclin regulating plasma factor. Clin Sci 1985; 69: 383-93. 52. Vlachoyannis J, Schoeppe W. Adenylase cyclase activity and CAMP content of human platelets in uraemia. EurJ Clin Invest 1982; 12: 379-81. 53. Remuzzi G. Bleeding disorders in uremia: pathophysiology and treatment. Adv Nephrol 1989; 18: 171-86. 54. Hutton RA, O’Shea MJ. Haemostatic mechanism in uraemia. J Clin Pathol 1968; 21: 406-11. 55. DiMinno G, Martinez J, McKean ML, DeLaRosa J, Burke JF, Murphy S. Platelet dysfunction in uremia. Multifaceted defect partially corrected by dialysis. Am J Med 1985; 79: 552-9. 56. Soslau G, Brodsky I, Putatunda B, Parker J, Schwartz AB. Selective reduction of serotonin storage and ATP release in chronic renal failure patient platelets. Am J Hematol 1990; 35: 171-8. 57. Ware JA, Clark BA, Smith M, Salzman EW. Abnormalities of cytoplasmic calcium in platelets from patients with uremia. Blood 1989; 73: 172-6. 58. Fox JEB, Reynolds CC, Phillips DR. Calcium dependent proteolysis occurs during platelet aggregation. J Biol Chem 1983; 258: 9973-81.

1994

The American

Journal

of Medicine

Volume

96

177

HEMOSTASIS

IN RENAL

DISEASE

/ EBERST

AND

BERKOWITZ

59. Gura V, Creter D, Levi J. Elevated thrombocyte calcium content in uremia and its correction by l-alpha (OH) vitamin D treatment. Nephron 1982; 30: 237-9. 60. Docci D, Turci F, Delvecchio C, Gollini C, Baldrati L, Pistocchi E. Lack of evidence for the role of secondary hyperparathyroidism in the pathogenesis of uremic thrombocytopathy. Nephron 1986; 43: 28-32. 61. Livio M, Vigano G, Benigni A, Mecca G, Remuzzi G. Moderate doses of aspirin and risk of bleeding in renal failure. Lancet 1986; 2: 414-6. 62. Gaspari F, Vigano G, Orisio S, Bonati M, Livio M, Remuzzi G. Aspirin prolongs bleeding time in uremra by a mechanism distinct from platelet cyclooxygenase inhibition. J Clin Invest 1987; 79: 1788-97. 63. Sattler FR, Weitekamp MR, Ballard JO. Potential for bleedingwith the new beta-lactam antibiotics. Ann Intern Med 1986; 105: 924-31. 64. Fass RJ, Copelan EA, Brandt JT, Moeschberger ML, Ashton JJ. Plateletmediated bleeding caused by broad-spectrum penicillins. J Infect Dis 1987; 155: 1242-8. 65. Levin RD, Kwaan HC, lvanovich P. Changes in platelet function during hemodialysis. J Lab Clin Med 1978; 92: 779-86. 66. Natelson EA, Lynch EC, Hettig RA, Alfrey Jr CP. Acquired factor IX deficiency in the nephroticsyndrome. Ann Intern Med 1970; 73: 373-8. 67. Lipsky JJ. Antibiotic-associated hypoprothrombinemia. J Antimicrob Chemother 1988; 21: 281-300. 68. Gafter U, Bessler H, Malachi T, Zevin D, Djaldetti M, Levi J. Platelet count and thrombopoietic activity in patients with chronic renal failure. Nephron 1987; 45: 207-10. 69. George CRP, Slichter SJ, Quadracci LJ, Striker GE, Harker LA. A kinetic evaluation of hemostasis in renal disease. N Engl J Med 1974; 291: 1111-5. 70. Remuzzi G, Livio M, Marchiaro G, Mecca G, DeGaetano G. Bleeding in renal failure: altered platelet function in chronic uraemia only partially corrected by haemodialysis. Nephron 1978; 22: 347-53. 71. Komarnicki M, Pietrzak I. Mechanisms of platelet aggregatron disturbances and their relation to treatment in patients with chronic uremia. Int J Artif Organs 1988; 11: 91-4. 72. Sultan Y, London GM, Goldfarb B, Toulon P, Marchais SJ. Activation of platelets, coagulation and fibrinolysis in patients on long-term haemodialysis: influence of Cuprophan and Polyacrylonitrile membranes. Nephrol Dial Transplant 1990; 5: 362-8. 73. Davis JM, Arakawa T, Strickland TW, Yphantis DA. Characterization of recombinant human erythropoietin produced in Chinese hamster ovary cells. Biochemistry 1987; 26: 2633-8. 74. Kawano Y, Takaue Y, Minakuchi J, et al. Impaired production of burst promoting activity by blood mononuclear cells from chronic uremic patients. Am J Hematol 1991; 36: 9-13. 75. Jacquot C, Masselot JP, Berthelot JM, Peterlongo F, Castaigne JP. Addition of desmopressin to recombinant human erythropoietin in treatment of haemostatic defect of uraemia [letter]. Lancet 1988; 1: 420. 76. lshibashi T, Koziol JA, Burstein SA. Human recombinant erythropoietin promotes differentiation of murine megakaryocytes in vitro. J Clin Invest 1987; 79: 286-9. 77. Johnson WJ, McCarthy JT, Yanagihara T, et al. Effects of recombinant human erythropoietin on cerebral and cutaneous blood flow and on blood coagulability. Kidney Int 1990; 38: 919-24. 78. Gordge MP, Leaker B, Pate1 A, Oviasu E, Cameron JS, Neild GH. Recombinant human erythropoietin shortens the uraemic bleeding time without causing intravascular haemostatic activation. Thromb Res 1990; 57: 171-82. 79. vanGeet C, Hauglustaine D, Verresen L, Vanrusselt M, Vermylen J. Haemostatic effects of recombinant human erythropoietin in chronic haemodialysis patients, Thromb Haemostasis 1989; 61: 117-21. 80. Drueke TB. Resistance to recombinant human erythropoietin in hemodialysis patients. Am J Nephrol 1990; 10 (Suppl 2): 34-9. 81. Winearls GC, Oliver DO, Pippard MJ, Reid C, Downing MR, Cotes PM. Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet 1986; 2: 1175-8. 82. Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin: results of a combined phase I and phase II clinical trial. N Engl J Med 1987; 316: 73-8. 83. Akizawa T, Koshikawa S, Takaku F, et a/. Clinical effect of recombinant human erythropoietin on anemia associated with chronic renal failure. A multi-institutional study in Japan. Int J Artif Organs 1988; 11: 343-50.

178

February

1994

The American

Journal

of Medicine

Volume

84. Casati S, Passerini P, Campise MR, et a/. Benefits and risks of protracted treatment with human recombinant erythropoietin in patients having haemodialysis. BMJ 1987; 295: 1017-20. 85. Adamson JW, Eschbach JW. Treatment of the anemia of chronic renal failure with recombinant human erythropoietin. Annual Rev Med 1990; 41: 349-60. 86. Eschbach JW, Kelly MR, Haley NR, Abels RI, Adamson JW. Treatment of the anemia of progressive renal failure with recombinant human erythropoietin. N Engl J Med 1989; 321: 158-63. 87. Ad Hoc Committee for the National clinical use of recombinant erythropoietin Am J Kidney Dis 1989; 14: 163-9.

Kidney Foundation. Statement on the in anemia of end-stage renal disease.

88. Kindler J, Eckardt KU, Ehmer B, et al. Single-dose pharmacokinetics of recombinant human erythropoietin in patients with various degrees of renal failure. Nephrol Dial Transplant 1989; 4: 345-9. 89. McMahon FG, Vargas R, Ryan M, et a/. Pharmacokinetics and effects of recombinant human erythropoietin after intravenous and subcutaneous injections in healthy volunteers. Blood 1990; 76: 1718-22. 90. Eschbach JW, Abdulhadi MH, Browne JK, et al. Recombinant human erythropoietin in anemic patients with end-stage renal disease: results of a phase Ill multicenter clinical trial. Ann Intern Med 1989; 111: 992-1000. 91. vanWyck DB, Stivelman JC, Ruiz J, Kirlin LF, Katz MA, Ogden DA. Iron status in patients receiving erythropoietin for dialysis-associated anemia. Kidney Int 1989; 35: 712-6. 92. Macdougall IC, Lewis NP, Saunders MJ, et al. Long-term cardiorespiratory effects of amelioration of renal anaemia by erythropoietin. Lancet 1990; 335: 489-93. 93. Muirhead N, Hodsman AB. Occult infection and resistance of anaemia to rHuEpo therapy in renal failure. Nephrol Dial Transplant 1990; 5: 232. 94. Besarab A, Medina F, Musial E, et a/. Recombinant human erythropoietin does not increase clotting in vascular accesses. ASAIO Trans 1990; 36: M749. 95. Nonast-Daniel B, Deschodt G, Brunkhorst R, et al. Long-term effects of treatment with recombinant human erythropoietin on haemodynamics and tissue oxygenation in patients with renal anemia. Nephrol Dial Transplant 1990; 5: 444. 96. Abraham PA, Opsahl JA, Keshaviah PR, eta/. Bodyfluid spaces and blood pressure in hemodialysis patients during amelioration of anemia with erythropoietin. Am J Kidney Dis 1990; 16: 438-46. 97. Haley NR, Davidson RC, Eschbach JW, Adamson Patterns of development of hypertension with recombinant

JW, Easterling T. human erythropoi-

etin (rHuEpo) therapy: a prospective study [abstract]. Am J Hypertens 1989; 2 (SuppI): 56A. 98. Erslev AJ. Erythropoietin. N Engl J Med 1991; 324: 1339-54. 99. Garcia DL, Anderson S, Rennke HG, Brenner BM. Anemia lessens and its prevention with recombinant human erythropoietin worsens glomerular injury and hypertension in rats with reduced renal mass. Proc Natl Acad Sci USA 1988; 85: 6142-6. 100. Canadian Erythropoietin Study Group. Association between erythropoietin and quality of life and exercise capacity of patients receiving hemodialysis. BMJ 1990; 300: 573-8. 101. Lim VS, Fangman J, Flanaghan MJ, DeGowin RL, Abels RT. Effect of recombinant human erythropoietin on renal function in humans. Kidney Int 1990; 37: 131-6. 102. Mannucci PM. Desmopressin: a nontransfusional form of treatment for congenital and acquired bleeding disorders. Blood 1988; 72: 1449-55. 103. Mannucci PM, Altieri D, Faioni E. Vasopressin analogues, their role in disordersof hemostasis. Ann NY Acad Sci 1987; 509: 71-81. 104. Ruggeri ZM, Mannucci PM, Lombardi R, Federici AB, Zimmerman TS.’ Multimeric composition of factor Vlll/vonWillebrand factor following administration of DDAVP: implications for pathophysiology and therapy of vonWillebrand disease subtypes, Blood 1982; 59: 1272-8. 105. Byrnes JJ, Larcada A, Moake JL. Thrombosisfollowingdesmopressin for uremic bleeding. Am J Hematol 1988; 28: 63-5. 106. Kohler M, Harris A. Pharmacokinetics and haematological effects of desmopressin. EurJ Clin Pharmacol 1988; 35: 281-5. 107. Carvalho ACA. Bleeding in uremra-A clinical challenge. N Engl J Med 1983; 308: 38-40. 108. DiMichele DM, Hathaway WE. Use of DDAVP in inherited and acquired platelet dysfunction. Am J Hematol 1990; 33: 39-45.

96

HEMOSTASIS 109. Shapiro MD, Kelleher SP. lntranasal Deamino-8-D-Arginine Vasopressin shortens the bleedingtime in uremia. Am J Nephrol 1984; 4: 260-l. 110. Canavese C, Salomone M, Pacittr A, Mangiarotti G, Calitri V. Reduced response of uremic bleeding time to repeated doses of desmopressin [letter]. Lancet 1985; 1: 867-8. 111. Mannucci PM. Desmopressin (DDAVP) for treatment of drsorders of hemostasis. Prog Hemost Thromb 1986; 8: 19-45. 112. Mannucci PM, Ruggeri ZM, Pareti FI, Capitanio AM. DDAVP in hemophilia [letter]. Lancet 1977; 2: 1171-Z. 113. Gotti E, Mecca G, Valentino C, Cortinovis E, Bertani T, Remuzzi G. Renal biopsy in patients with acute renal failure and prolonged bleeding time [letter]. Lancet 1984; 2: 978-9. 114. Bond L, Bevan D. Myocardial infarction in a patient with hemophilia treated with DDAVP [letter]. N Engl J Med 1988; 318: 121. 115. Liu YK, Kosfeld RE, Marcum SG. Treatment of uremic bleeding with conjugated estrogen. Lancet 1984; 2: 887-90. 116. Livio M, Mannucci PM, Vigano G, et al. Conjugated estrogens for the management of bleeding associated with renal failure. N Engl J Med 1986; 315: 731-5. 117. Vigano G, Gaspari F, Locatelli M, Pusineri F, Bonati M, Remuzzi G. Dose-effect and pharmacokinetics of estrogens given to correct bleeding time in uremia. Kidney Int 1988; 34: 853-8. 118. Seth S, Geier TM. Use of conjugated estrogens to control gastrointestinal bleeding in two patients with chronic renal failure. Clin Pharm 1988; 7: 906-9. 119. Shemin D, Elnour M, Amarantes B, Abuelo JG, Chazan JA. Oral estrogens decrease bleeding time and improve clinical bleeding in patients with renal failure. Am J Med 1990; 89: 436-40. 120. Wagoner RD, Stanson AW, Holley KE, Winter CS. Renal vein thrombosis in idiopathic membraneous glomerulopathy and nephrotic syndrome: incidence and significance. Kidney Int 1983; 23: 368-74. 121. Boneu B, Bouissou F, Abbal M, Sie P, Caranobe C, Barthe P. Comparison of progressive antithrombin activity and the concentration of three inhibitors in nephrotic syndrome. Thromb Haemostasis 1981; 46: 623-5. 122. Kanfer A. Coagulation factors in nephrotic syndrome. Am J Nephrol 1990; 10 (Suppl 1): 63-8. 123. Kauffmann RH, Veltkamp JJ, VanTilburg NH, VanEs LA. Acquired antithrombin Ill deficiency and thrombosis in the nephrotic syndrome. Am J Med 1978; 65: 607-13. 124. Eknoyan G. Detecting thromboemboli in the nephrotic syndrome. J Crit Illness 1990; 5: 1137-40.

February

IN RENAL

DISEASE

/ EBERST

125. Sullivan MJ, Hough DR, Agodoa LCY. Peripheral

AND

BERKOWITZ

arterial thrombosis

due

to the nephrotic syndrome: the clinical spectrum. South Med J 1983; 76: 1011-6. 126. Lai K-N, Yin JA, Yuen PMP, Li PKT. Effect of hemodialysis on protein C, protein S, and anbthrombin III levels. Am J Kidney Dis 1991; 17: 38-42. 127. Toulon P, Jacquot C, Capron L, Frydman MO, Vignon D, Aiach M. Antithrombin III and heparin co-factor II in patients with chronic renal failure undergoing hemodialysis. Thromb Haemostasis 1987; 57: 263-8. 128. Parker KA, Tollefsen DM. The protease specificity of heparin cofactor II. Inhibition of thrombin generated during coagulation. J BIOI Chem 1985; 260: 3501-5. 129. Canavese C, Stratta P, Pacitti A, et al. Impaired fibrinolysis in uremia: parbal and variable correction by four different dialysis regimes. Clin Nephrol 1982; 17: 82-9. 130. Mittra KK, Vajpeyi GN. Plasma lipids and fibrinolybc activity in patients with chronic renal failure. J Indian Med Assoc 1987; 85: 357-8. 131. Sorensen PJ, Knudsen F, Nielsen AH, Dyerberg J. Protein C activity in renal disease. Thromb Res 1985; 38: 243-9. 132. Rabinger-Faschrng I, Lechner K, Niessner H, Schmidt P, Balzer E, Mannhalter C. High levels of plasma protein C in nephrotic syndrome. Thromb Haemostasis 1985; 53: 5-7. 133. Cosio FG, Harker C, Batard MA, Brandt JT, Griffen JH. Plasma concentrations of the natural anticoagulants protein C and protein S in patients with proteinuria. J Lab Clin Med 1985; 106: 218-22. 134. Mannucci PM, Valsecchi C, Bottasso B, D’Angelo A, Casati S, Ponticelli C. High plasma levels of protein C activity and antigen in the nephrotic syndrome. Thromb Haemostasrs 1986; 55: 31-3. 135. Thompson AR. Factor XII and other hemostatic protein abnormalities in nephrotic syndrome patients. Thromb Haemostasis 1982; 48: 27-32. 136. Ragni MV, Lewis JH, Hasiba U, Spero JA. Prekallikrein (Fletcher factor) deficiency in clinical diseasestates. Thromb Res 1980; 18: 45-54. 137. Vicente V, Alegre A, Alberta I, Lopez Borrasca A, Gomez JR, Macias JF. Changesof contact phase proteins during haemodialysis. Haematologia 1988; 21: 159-62. 138. Kendall AG, Lohmann RC, Dossetor JB. Nephrotic syndrome: a hypercoagulable state. Arch Int Med 1971; 127: 1021-7. 139. Miletich J, Sherman L, Braze G Jr. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987; 317: 991-6. 140. Heijboer H, Brandjes DPM, Buller HR, Sturk A, Wouter ten Cates J. Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients withdeep-vein thrombosis. N Engl J Med 1990; 323: 1512-6.

1994

The American

Journal

of Medicine

Volume

96

179