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1 1 REVIEW

Hemostasis in Renal Disease: Pathophysiology

and Management

MARY E. EBERST, M.D. , LEE R. BERKOWITZ, M.D., Chapel MI/ , forth Car ol ina

The hemostatic abnormalities commonly

encountered in patients with renal disease

can signif icantly threaten the well-being of

the patient and pose diff icult management

issues for the clinician. In this review, we

explore the pathophysiology underlying the

bleeding diathesis and hypercoagulabil ity

that can occur. Current therapeutic inter-

ventions are also discussed.

From the Department of Emergency Medicine (MEE) and Medicine

(LRB), University of North Ca rol ina at Chape l H i l l School of Medicine,

Chapel Hi l l , North Carol ina.

Requests for reprints should be addressed to Mary E. Eberst , M.D.,

Department of Emergency Medicine, CB# 759 4, C hapel Hi l l , North

Carol ina 27599-7594.

Manuscript submit ted Apri l 1, 1992, and accepted in revised form

March 8, 1993.

R

nal disease can result in significant disorders

of hemostas is. Both a bleeding diathesis and a

hypercoagulable state may be caused by renal

abnormalities. The bleeding diathesis genera lly

results in mucosal bleeding and increased blood

loss with surgical procedures [1,21. The hypercoagu-

labil ity leads to thrombotic events, such as pulmo-

nary 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 differ-

ent ways. Because of this complexity, we have

separated our discussion into two distinc t coagu-

lopathies. This separation does not mirror the

clinical situation in which both coagulopathies

may occur in the same patient.

PATHOPHYSIOLOGY OF THE BLEEDING

DIATHESIS

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

wide ly 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 clot-

ting factors, is also involved in this interaction.

Prolongation of the bleeding time is not direc tly

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 consecu tive renal biopsies , 2 of

patients developed perirenal hematoma. The posi-

tive predic tive value of the bleeding time for this

complication was 4 [ 131. Another analysis of data

168

February 1994

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HEMOSTASIS IN RENAL DISE ASE / EBERST AND BERKOWITZ

Figure 1. The effect of anemia on hemo-

stasis, 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 endothe-

lial surface. This is optima l for platelet-

endoth elial cell interaction and the for-

mation 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.

HEMATOCRIT < 25

-

from five studies of bleeding in uremia showed that

the predict ive value of the bleeding time was not

superior to the predic tive 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 clin ica l outcome.

as nitric oxide (NO) has been implicated as a

mediator of uremic bleeding [20] because NO has

the ability to impair the interaction between plate-

lets and the vessel wall.

Chronic Anemia

A number of factors have been reported as

contributing to the bleeding diathes is in uremia.

Included are uremic retention products, anemia,

platelet dysfunction, deficiency of coagulation fac-

tors, and thrombocytopenia.

Uremic Retention Products

It has long been held that dialyzable factors

contribute to the abnormal bleeding in patients

with renal failure 1141. Sma ll molecular weight

substances (up to 500 daltons) including guanidino-

succinic acid, phenol, phenolic acid, and urea have

been shown to impair platelet aggregation and the

release of platelet factor 3 [l&171. Middle molecu-

lar weight molecules (500-3,000 d) have also been

shown to impair platelet function by inhibiting

platelet aggregation, inhibiting release of arachi-

donic acid from the platelet membrane, stimulat-

ing pros tacyclin synthesis by the endothelium, and

inhibiting the release of serotonin from platelets

[15,18].

The anemia associated with chronic renal failure

is multifactorial [5,21-231. The primary factor is

believed to be the deficient production of erythro-

poietin, because administration of erythropoietin

can complete ly reverse the anemia in nearly all

patients treated [241. Also poss ibly contributing to

this anemia are: (1) shortened red blood cell sur-

vival time; (2) “uremic inhibitors” of erythropoi-

esis [24,25]; and (3) iron deficiency due to blood

loss during dialysis and from the gastrointestinal

tract. The severity of the anemia generally corre-

lates with the degree of renal failure [121.

Despite these findings, there is no correlation

between the leve ls of these dialyzable substances

and the bleeding time in uremic patients [161.

Furthermore, dialysis improves platelet function

but rare ly 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 non-

dialyzable factors must be involved. Recently, an

endothelial-derived relaxing factor, now identified

Of the multiple factors that influence primary

hemostasis and the bleeding time in uremic pa-

tients, 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 skim-

ming-layer along the endothelial surface as blood

courses through a vesse l. With endothelial dam-

age, the platelets are in close proxim ity to adhere

and begin formation of a platelet plug. However,

when the hematocrit is decreased, as in uremia,

platelets wil l be dispersed, impairing platelet-

endothelial cell adherence needed to initiate hemo-

stasis. Platelet function can be optimized by increas-

ing the red blood cel l concentration, which results

in a greater proportion of platelets at the vessel

wall and increased platelet adhesion to the suben-

dothelium [27-291. In addition to this effect on

VESSEL WALL

HEMATOCRIT * 30

FLOW OF BLOOD

\

ENDOTHELIAL CELLS

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HEMOSTASIS IN RENAL DISEA SE / EBERST AND BERKOWITZ

Arachidonic Acid

L

Cyclooxygenase

Endoperoxides

PLATELET MEMBRANE.

Thromboxane A2 (TxA2)

ENDOTHELIAL CELLS 1

Thromboxane B2 (TxB2 )

platelets, red blood cells are also important for

providing adenosine diphosphate (AD P) to plate-

lets, which enhances their reac tivity [ 171.

Multiple studies of human blood have demon-

strated 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 h igher than this are no more effective in

correct ing the bleeding time 15,311. Higher hemato-

crits (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

IMPAIRED PLATELET ADHESION:

Platelet adhesion

is the interaction between platelets and the vascu-

lar subendothelium. Normal adhesion is depen-

dent on von Willebrand factor (vWF), platelet

membrane receptor glycoprotein Ib (GPIb), fibro-

nectin, and red blood cell factors, including concen-

tration, size, and rigid ity of the cel ls 128,331.

Platele ts 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 abnormali-

ties in GPIb have been identified in uremic patients

[6,15,35], the focus of investigation has been on

VWF.

The endothelial cel ls of uremic patients have

been shown to synthesize a normal vWF molecule

[36]. Multiple studies have also documented nor-

mal or increased levels of vWF and factor VIII in

patients with uremia [19,34,37-401. The elevated

leve ls may result from long-term, low-grade endo-

thelial 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 199 4 The American Journal of Medicine Volum e 96

Figure 2. Arachidonic acid metabolism

and prostaglandin synthesis in the plate-

let membrane and vascular endothe-

lium. In a uremic environment, the

balance is shifted with decreased pro-

duction of platelet thromboxanes and

increased production of vascular prost-

acyclin.

an abnormal interaction with GPIb 1341. Func-

tional 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

essent ial for the interaction with platelets [41,421.

One study 1431 found an abnormal vWF multi-

merit pattern in patients with uremia, with re-

duced 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 de-

fects in vWF are not consistently found, transfu-

sion of cryoprecipitate or the use of desmopressin

(DDAV P), which cause an increase in vWF, does

correct the prolonged bleeding time in patients

with uremia 135,391.

ABNORMAL PROSTAG LANDIN SYNTHESIS BY PLATE-

LETS AND ENDOTHELIAL CELLS: Unbalanced prosta-

glandin synthesis in the platelets and vascular

endothelial cel ls 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 genera-

tion 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 metabo-

lism by some unidentified substance present in

uremic plasma 145,461.

Abnormal prostaglandin metabolism also occurs

in the vascu lar endothelial cel ls 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 endo-

thelial cell s of renal failure patients compared to

normal controls [1,49]. Proposed explanations for

this include the presence of an unknown substance

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in uremic plasma that stimulates prostacyclin pro-

duction 150,511 or increased prostacyclin synthesis

as a response of endothelial cell s to chron ic endothe-

lial damage [34]. It has also been suggested that

the activ ity of adenylate cyclase may be enhanced

by unknown uremic substances [521. Although

pros tacyclin is a potent inhibitor of platelet func-

tion, a direct relat ionship between elevated prosta-

cyc lin leve ls and prolongation of the bleeding time

has not been established 1531. Prostacyclin genera-

tion a lso does not appear to be significantly effected

by hemodialysis. Similar levels are found in uremic

patients who are aggressive ly dialyzed and those

who are managed conservatively 1191.

PLATELET MEMBRANE DEFECTS: It is well docu-

mented that platelet membrane phospholipids are

modified by the uremic environment 1371. One of

the first defects of uremic platelets to be character-

ized was reduced activity of Platelet Factor 3

112,541. This factor has procoagulant activ ity by

promoting the interaction between platelets and

phospholipids. Diminished activity results in abnor-

mal 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. Iden-

tified abnormalities include: reduced content of

serotonin and ADP in the dense granules, in-

creased 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 HOMEOSTA SIS: 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 pros tacyclin 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 hor-

mone (PTH) that can be present in patients with

renal failure [16,19,591. Although PTH has been

shown to inhibit platelet aggregation and seroto-

nin secretion in vitro [1,16], there is no correlation

between PTH leve ls and impaired platelet aggrega-

tion 116,601. Furthermore, patients with primary

hyperparathyroidism and elevated PTH levels have

normal platelet function [ 151.

EFFECTOFDRUGS ONPLATELETFUNCTI ONI NURE-

MIC PATIENTS: The platelet dysfunction of uremia

may be exacerbated by antibiot ics and other com-

monly prescribed drugs such as aspirin, diazepam,

chlordiazepoxide, and diphenhydramine. The com-

bination 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]. Antibio tics that exacer-

bate 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, sequestra-

tion in the kidney, and abnormal distribution due

to changes in intravascular volume [38].

Most commonly, coagulation factors from the

intrin sic pathway are reduced 1651. Acquired factor

IX deficiency has been described in nephrotic pa-

tients. 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 acti-

vated partial thromboplastin time may be pro-

longed. 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 espe-

cially susceptible to the reduction of vitamin K-

dependent coagulation factors that can result from

exposure to antibiotics, particularly the third-

generation cephalosporins which contain the N-

methyl-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 inhib i-

tor 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]. Al-

though 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 inhibi-

tory effect of the uremic environment on mega-

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TABLE I

Available Therapies for M anagemen tof the Bleeding Diathesis

Associated With R enal Disease

Dialysis: hemodialysis or peritonea l dialysis

Correction of anemia: recombinant human erythropoietin or transfusion of

packed red blood cells

DDAVP (desmopressin)

Conjugated estrogen

Cryoprecipitate

Platelet transfusion

karyocytopoiesis and the contribution of hyper-

splenism that may be present secondary to chron ic

antigenic stimulation [51. Platelet counts below

100,000/mm3 should raise concern for other etiolo-

gies of thrombocytopenia including infection and

medications. Despite repeated exposure to heparin

during hemodialysis, immune related heparin-

associated thrombocytopenia rarely occurs in

chron ic 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 correc ts completely

[16,191. Although early studies proposed that hemo-

dialysis (HD) and peritoneal dialysis (PD) were

equally e ffective in improving the bleeding diathe-

sis associated with uremia 181, it appears that PD

may actua lly 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 dia lysis membrane [6,71]. Hemostatic

disadvantages associated with HD include activa-

tion of the coagulation cascade, repeated exposure

to heparin, increased incidence of acquired platelet

storage pool defects, and modifications of the fibri -

nolyt ic system and the natural inhibitors of coagu-

lation. 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

HEMOSTASIS IN RENAL DISEAS E / EBERST AND BERKOWITZ

the anemia associated with renal failure may im-

prove hemostas is [Figure 11. Two commonly used

methods to correc t the anemia are transfusion of

packed red cell s and administration of recombi-

nant human erythropoietin (rhEP0). The mini-

mum target hematocrit for either modality should

be approximately 26 [26,28-301. Transfusing

packed red cell s has the advantage of immediate

correction of the hematocrit. Disadvantages in-

clude iron overloading and viral transmission. In

general, these disadvantages take precedence, a l-

though transfusions may be given in an acute

situation. This efficacy-toxicity profile for transfus-

ing 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 associ-

ated with renal failure. rhEP0 is biologically and

immunologically identica l to the native hormone

with its primary target being committed erythroid

progenitor cel ls [30,73,741. In addition to the in-

creased red cell mass that results from rhEP0

stimulation, there may be a qualitative improve-

ment in the red cell s, as well as an effect on the

megakaryocytes [75,761. There is no evidence that

rhEP0 has a direct e ffect on platelet function or

directly activates intravascular hemostasis [77,781.

Greater than 95 of reported patients, either

predialysis or dialysis-dependent, appear to re-

spond to rhEP0 [21,22,25,30,31,75,77-861.

After therapy with rhEP0 is initiated, a reticulo-

cytosis 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 ad-

verse 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 com-

monly used to attain a goal hematocrit around 35

[21,221. Subcutaneous administration of rhEP0

has also proven effective and permits easier treat-

ment and lower dosing due to the prolonged half-

life [25,88,891.

Some patients may show a relative resistance to

rhEP0 and require higher doses or a longer time to

respond, but rare ly are patients totally unrespon-

sive [go]. Iron deficiency is said to be the most

common cause of relative resistance; iron defi-

ciency should be corrected before treatment with

rhEP0 begins and many patients will require

long-term iron replacement therapy due to the

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increased utilization by accelerated erythropoiesis

[22,30,83,91,921. Other causes of resistance to

rhEP0 include: acute or chronic blood loss, infec-

tions and other inflammation, severe hyperparathy-

roidism, acute or chronic hemolysis, osteitis fibro-

sis, 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 com-

mon complications are accelerated hypertension in

up to 30 of patients, seizures in up to 5 of

patients, thrombotic occlusion of hemodialysis vas-

cular 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 oc-

curs with the rise in hematocrit [95-971. Seizures

may occur secondary to hypertension. There is no

evidence that any of these complications are di-

rect ly 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 in-

creased 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 vasopres-

sin) a synthet ic analog of vasopressin, has been

shown to be beneficia l 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 DDAV P leads to a

shortening of the bleeding time is complex. DDAV P

promotes the release of vWF from storage sites in

endothelial cel ls into plasma, resu lting in a quanti-

tative increase in vWF, including large multimeric

forms not usually present in plasma [37,102,104-

1061. 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 c lear [19,37,39,40,44,102,107,108].

The usual intravenous or subcutaneous DDAV P

dose is 0.3 micrograms per kilogram of body weight.

This results in maximum shortening of the bleed-

ing time within 1 to 2 hours and the effect pe rsists

for about 4 hours 1371. Intranasal DDAVP may

also be effective [log]. Typically administered ev-

ery 12 hours, successive infusions of DDAVP can

lead to tachyphylax is within 24 to 48 hours, pre-

sumably because of depletion of the vWF stores

within the endothelium [ llO, lll]. However, tachy-

phylaxis is not a constant phenomenon and the

typical response usually returns in 3 to 4 days

[102,1121. When used in combination with eleva-

tion 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 DDAV P are gener-

ally mild including headache, flushing, minor hypo-

tension, tachycardia, nausea, abdominal cramps,

and local site reaction [ 1021. Potentially severe

consequences including hyponatremia and throm-

bosis 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 pa-

tients 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 simi lar improvement

[103,115-1181.

The mechanism of action of conjugated estro-

gens 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 estro-

gen is 0.6 mgikg daily for 5 consecutive days

[ 116,117]. The initia l 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]. Ora l 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 bleed-

ing 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 compli-

cations include hot flashes, nausea, vomiting, fluid

retention, hypertension, gynecomastia, and loss of

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TABLE II

Management of Bleeding in Patients With Renal Disease

Long-term

objectives

(1) Adequate dialysis

(2) Maintain hematocrit >25%, use of

recombinant hu man erythropoietin as

needed

Acute bleeding

episodes

(1) Verify that patient is adequately dia-

lyzed

(2) If hematocrit is

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HEMOSTASIS IN RENAL DISEA SE / EBERST AND BERKOWITZ

Figure 3. Pathoge nic mechanisms con-

tributing to hypercoagulability in renal

disease. Alterations in the levels of

these proteins, as well as changes in

platele t aggregation and fibrinolysis are

implicated in the predisposition to

thrombosis that occurs in patients with

renal disease.

1 Decreases in:

1 1Antithrornbin III \ /I /I v/

\L 1i

HYPERCOAGULABILITY

Increases in:

Platelet Aggregation

and negative ly 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 [123-

1251. In addition to low AT III leve ls, some uremic

patients have reduced activ ity of AT III, the func-

tional abnormality apparently induced by the ure-

mic environment [1261. Dia lysis does not appear to

alter the AT III level on a long-term basis, al-

though it may decrease slightly during dialysis

because of exposure to heparin [126,1271.

Related to AT III, heparin cofactor II is a

natura lly occurr ing inhibitor of thrombin [ 1281.

Its deficiency has been associated with thromboem-

bolic phenomena. Some chronically dialyzed pa-

tients have normal leve ls of AT III, but sign ifi-

cantly reduced leve ls of heparin cofactor II [ 1271.

Abnormalities of Protein S

Protein S is another naturally occurring antico-

agulant; its presence is required for the activ ity of

protein C. Some patients with nephrotic syndrome

have reduced protein S activ ity [3,122,1261. Al-

though 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 leve ls

of its binding protein, C4b, and selec tive 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 identi-

fied in up to 60 of patients with nephrotic

syndrome [5,72,122,129,1301. Reduced fibrinolytic

activity results from the accumulation of inhibi-

tors such as alpha-2-antiplasmin and plasminogen

activator-inhibitor, and the urinary loss of fibrino-

lytic activators, particularly plasminogen [4,5,

122,129l. Triglyceride leve ls are often elevated and

are inversely related to fibrinolytic activity [130].

In addition, therapy with corticosteroids may also

contribute to decreased fibr inolysis 11251.

Enhanced Platelet Aggregation

A number of observations suggest that pla telets

may become hyperaggregable, predisposing to

thrombos is in patients with renal disease. Elevated

levels of plasma lipids and decreased plasma albu-

min are thought to alter platelet membranes in a

way that increases their aggregability. The degree

of hyperaggregability correla tes with hypoalbumin-

emia [4]. In patients with nephrotic syndrome,

there are also changes in arachidonic acid metabo-

lism that lead to preferential formation of throm-

boxanes that enhance platelet aggregation [4,122].

A third observation is that recurrent platelet stimu-

lation by extracorporeal circulation during hemodi-

alysis or hemofiltration can increase aggregability

ml.

Abnormalities of Protein C

Protein C is a naturally occurring anticoagulant

protein that inhibits the activ ity 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 leve ls of protein C

11311. These low leve ls may result from an inhib i-

tory substance in the uremic environment that

depresses protein C activ ity [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 dia lysis

[126,1311.

Nephrotic patients may have normal, elevated,

or low levels of protein C [122,1311. In general,

February 19 94 The American Journal of Medicine Volum e 96 175

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nephrotic patients have elevated levels because

protein C is highly negatively charged, which im-

pedes its urinary excretion despite a molecular

weight simi lar 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 part ially compensate for the low

AT III leve l and other abnormalities that pred is-

pose nephrotic patients to thrombos is [132,1341.

Abnormalities of Contact Factors

Changes in the contact activation pathway invo lv-

ing factor XII, high molecular-weight kininogen

and prekallikre in have been identified in patients

with renal disease. Decreased factor concentra-

tions and dysfunctional molecules occur [135-

1371. There is no definite evidence that these

factors predispose to thromboembolic disease, al-

though theoretically, the changes described could

lead to thrombosis because these factors are impor-

tant 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 in-

creased hepatic synthesis that may be a response to

proteinuria 11381. Decreased serum albumin con-

centration and decreased intravascular oncotic pres-

sure most likely contribute to the increased levels

[4,381.

Elevat ion of the fibrinogen leve l has also been

observed [122]. Its hepatic synthesis is increased

proportionally to the quantity of proteinuria. There

are no changes in fibrinogen catabolism. Fibrino -

gen, as well as factors V and VIII, may also be

elevated because they are acute-phase reactants

[134]. Steroid therapy has been reported to in-

crease 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 OF THE

HYPERCOAGULABLE STATE

Because thromboemboli secondary to hyperco-

agulability account for significant morbid ity and

mortality in patients with renal disease, it is

imperative that the clinic ian recognize and treat

patients with this complication. There are two

ways to diagnose hypercoagulability. A clinical

diagnos is can be made when the patient has two

thrombotic events that are independent of each

other anatomically and temporally. A good ex-

ample would be two episodes of deep vein thrombo-

sis occurring months apart. In contrast, the pa-

tient who develops a deep vein thrombosis and

then experiences a pulmonary embolus severa l

days later, would not be considered hypercoagu-

lable. There are also a variety of laboratory tests

that may lead to a diagnos is of hypercoagulab ility.

Assays for AT III, protein S, protein C, as well as

the fibrinolytic system, can be performed. Reduc-

tions 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 recur-

rent 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 hypercoagulab le pa-

tient are limited and there is no way to complete ly

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 leve ls of these

anticoagulants, although these changes are prob-

ably not hemostatically significant [126,1271. Com-

pared to PD patients, HD patients may have

improved fibrinolytic activity because the extracor-

poreal 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 thrombo-

lytic agents, such as streptokinase or urokinase, is

a consideration as in any other patient with signi fi-

cant thrombos is. The optimal duration of antico-

agulation is not clea rly estab lished in these pa-

tients, however, indefinite therapy is reasonable

unless there is a resolution of the underlying

disease state [4]. Long-term prophylactic anticoagu-

lation in high- risk patients without documented

thromboembolic disease is not of proven benefit.

ACKNOWLEDGMENT

We wish to express our gratitud e to Marie tta Gray for her expert assistance in

preparat ion of the manuscript .

REFERENCES

1. Remuzzi G. Bleed ing in renal fai lure. Lancet 1988; 1: 1205-8.

2. Zuckerman GR, Cornette GL, Clause RE , Hatter HR. Upper gastrointest inal

bleeding in pat ients wi th chronic renal fai lure. An n Intern Med 1985; 102:

588-92.

HEMOSTASIS IN RENAL DISEA SE / EBERST AND BERKOWITZ

176 February 1994 The American Journal of Medicine

Volume 96

8/18/2019 1-s2.0-0002934394901384-main

10/12

3. V igano-D ’Angelo S , D ’Angelo A , Kaufman CE, Sholer C , Esmon CT, Comp

PC. Protein S def iciency occurs in the nephrot ic syndrome. Ann Intern M ed

1987; 107: 42-7.

4. Llach F. Hypercoagulabi l i ty, renal vein thrombosis, and other thrombotrc

compl icat ions of nephrot ic syndrome. Kidney Int 1985; 28: 429-39.

5. Hocking W G. Hematologic abnorma l i t ies in pat ients w i th renal diseases.

Hema tol Oncol Cl in North Am 1987; 1: 229-60.

6. Sai to H. Hemostat ic disorders associated with rena l disease. In: Ratnoff

OD, Forbes CD, edi tors. Disorders of Hemostasis. Phrlade lphia: WB Saunders,

1990: 480-92.

7. Steiner RW, Co ggins C, Carvalho ACA. Bleed ing t ime in uremia: a useful test

to assess cl inical bleeding . Am J Hema tol 1979; 7: 107-17.

8. Nencr GG, Berret t ini M, Agn el l i G, Parise P, Buoncrist iani U, Bal latori E.

Effect of peri toneal dialyses, hemodialysis and kidney t ransplantat ion on blood

platelet funct ion. Nephron 1979; 23: 287-92.

9. George JN, Shatt i l SJ. The cl inical importance of acquired abnormal i t ies of

platelet funct ion. N Engl J Med 1991; 324: 27-39.

10. Rogers RPC, Levin J. A cri t ical reappraisal of the bleeding t ime. S emin

Thromb Hemost 1990; 16: l -20.

11. Lind SE. The bleeding t ime does not predict surgical bleeding. Blood

1991; 77: 2547-52.

12. Gordge M P, Faint RW, Rylance PB, Nei ld GH. Platele t funct ion and the

bleeding t ime in progressive renal fai lure. Thromb Haemost 1988; 60:

83-87.

13. Diaz-Buxo JA, Donadio JV. Compl icat ions of percutaneous renal biopsy:

an analysisof 1,000 consecut ive biopsies. Cl in Nephrol 1975; 4: 223.

14. Bazi l inski N, Shaykh M, Dunea G, et

a/.

Inhibi t ion of platelet funct ion by

uremic middle molecules. Nephron 1985; 40: 423-8.

15. Castaldi PA, Gorman DJ. Disordered platelet funct ion in renal disease. In:

Colman RW, Hirsh J, Marder VJ, Salzman EW, edi tors. Hemostasis and

Thrombosis, Basic Principles and Cl inical Pract ice. Phi lade lphia: Lippincott ,

1987: 960-4.

16. Remuzzi G, Pusineri F. Coagulatron defects in uremia. Kidney Int 1988;

33 (Suppl24): S13-S17 .

17. Andrassy K, Ri tz E. Uremia as a cause of bleeding . Am J Nephrol 1985; 5:

313-9.

18. Pales JL, Lopez A, Asenio A, et a/ . Inhibi tory ef fect of peak 2-4 uremic

middle molecules on platelet aggregat ion. Eur J Haem atol 1987; 39:

197-202.

19. Livio M, Ben igni A, Remuzzi G. Coagula t ion abnormal i t ies in uremia. Sem

Nephrol 1985; 5: 82-90.

20. Remuzzi G, Perico N, Zoja C, Corna D, Macconi D, Vigan o G. Role of

endothel ium-derived ni t ricoxide in the bleedrng tendency of uremia. J Cl in

Invest 1990; 86: 1768-71.

21. Aronoff GR, Duff DR, Sloan RS , et al . The t reatment of anem ia with

low-dose rec ombinant human erythropoiet in. Am J Nephrol 1990; 10 (Suppl

2): 40-3.

22. Eschbach JW, Adamso n JW. Recombinan t human erythropoiet in: impl ica-

t ionsfor nephrology. Am J Kidney Dis 1988; 11: 203-9.

23. Eschbach JW. The anem ia of chronic rena l fai lure: pathophysiology and

the ef fects of recombinant erythropoiet in. Kidney lnt 1989; 35: 134-48.

24. Eschbach JW, Adamson JW. Anem ia 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

anem ia of chronic renal fai lure with subcutaneous recombinant human

erythropoiet in. Am J Med 1990; 89: 432-5.

26. Fernandez F, Goudab le C, Sie P, et al . Low hematocri t and prolonged

bleeding t ime in uraemic pat ients: ef fect of red cel l t ransfusions. Br J Haema tol

1985; 59: 139-48.

27. Turi t to VT, Weiss HG. Red blood cel ls: their dua l role in thrombus

format ion. Science 1980; 207: 541-3.

28. Cast i l lo R, Lozano T, Escolar G, Reyert L, Lopez J, Ordinas A. Defect ive

platelet adhesion o n vessel subendo thel ium in uremic pat ients. Blood 1986;

68: 337-42.

29. Livio M, Marchasi D, Remuzzi G, Gott i E, Mecca G, DeGaetano G. Uraemic

bleeding: role of anem ia and benef icial ef fect of red cel l t ransfusions. Lancet

1982; 2: 1013-5.

30. Eschbach JW, Haley NR, Adamson JW. The anem ia of chronic renal

fai lure: pathophysiology and ef fects of recombinant erythropoiet in. In: Kl ink-

mann H , Smeby LC , edi tors. Contrib Nephrol , Terminal Renal Fai lure:

Theraput ic Problems, P ossibi l i t ies, and Potent ials, Basel : Karger 1990:

432-5.

31. Moia M, Vizzot to L, Cattaneo M, Mannucci PM, Casat i S, Pont icel l i C.

Improvement in the hemostat ic defect of uraemia af ter t reatment wi th

recombinant human erythropoiet in. Lancet 1987; 2: 1227-9.

32. Carvalho AC. Acquired platelet dysfunct ion in pat ients wi th uremia.

Hematol Oncol Cl in North Am 1990; 4: 129-43.

33. Aarts PA MM, Bolhuis PA, Sakariassen KS, Heethaar RM, Sixma JJ. Red

blood cel l size is important for adherence of blood platelets to artery

endothe l i um. B lood 1983; 62: 214-7.

34. Turney JH, Woods HF, Fewel l MR, Weston MJ. Factor VI I I complex in

uraemia and ef fectsof haemodialysis. BMJ 1981; 282: 165 3-6.

35. Shatt i l S, Bennett JS. Acquired qual i tat ive platelet disorders. In: Wi l l iams

WJ, Beut ler E, Erslev AJ, Lichtman M, edi tors. Hematology. New York:

McGraw-Hi l l , 1 990: 1420-2.

36. Winter M, Seghatchian MJ, Cameron JS. An abnorma l factor VI I I molecule

in uraemia [ let ter] L ancet 1 983; 1: 1112.

37. Mannucci PM, Remuzzi G, Pusineri F, et al . Deamino-8-D-arg inine

vasopressin shortens the bleeding t ime in uremia. N Eng l J Med 1 983; 308:

8-12.

38. Vaziri N D, Branson HE, Ness R. Changes of coagulat ion factors IX, VI I I ,

VI I , Xand V in nephrot icsyndrome. Am J Med Sci 1980; 280: 167-71.

39. Watson AJS, Keog h JAB. Effect of l -deamino-8.D-arginine vasopressin on

the prolonged bleeding t ime in chronic renal fai lure. Nephron 1982; 32:

49-52.

40. Soslau G, Schwartz AB, Putatunda B, et a/ . Desmo-pressin-induced

improvement in bleeding t imes in chronic re nal fai lure pat ients correlates with

platelet serotonin uptake and ATP release. Am J Med Sci 1990; 300: 372-9.

41. Bridges KR. Hemorrhagic compl icat ions associated with renal fai lure. J

Cri t i l lness 1989; 4: 17-33.

42. Deykin D. Uremic bleeding . Kidn ey Int 1983; 24: 698-705.

43. Gralnick HR, McKeown LP, Wi l l iams SB, Shafer BC , Pierce L. Plasma and

platelet vonwi l lebrand factor defects in uremia. A m J Med 1988; 85:

806-10.

44. Janson PA, Jubel i rer SJ, Weinstein MJ, Deykin D. Treatment of the

bleeding tendency in uremia w ith cryoprecipi tate. N Eng l J Med 1980; 303:

1318-21.

45. Remuzzi G, Benig ni A, Dodesini P, et

al.

Reduced platelet thromboxane

format ion in uremia: evidence for a funct ional cyclooxygenase defect . J Cl in

Invest 1983; 71: 762-8.

46. Remuzzi G, Marchesi D, Livio M, et a/ . Al tered platelet and vascular

prostaglandin generat ion in pat ients wi th renal fai lure and prolonged bleeding

t imes. Thromb Res 1978; 13: 1007-15.

47. Bloom A, Greaves M, Preston FE, Brown CB. Evidence ag ainst a platelet

cyclooxygenase defect in uraemic subjects on chronic haemodialysis. Br J

Haem atol 1986; 62: 143-9.

48. Smith MC , Dunn MJ. Impaired platelet thromboxane product ion in renal

fai lure. Nephron 1981; 29 : 133-7.

49. Remuzzi G, Cavenagh i AE, Mecca G, Donat i MB, DeGaetano G. Prostacy-

cl in-l ike act ivi ty and bleeding in renal fai lure. Lan cet 1 977; 2: 1195-7.

50. Defreyn G, Vergara Dauden M, Machin SJ, Vermylen J. A plasma factor in

uraemia which st imulates prostacycl in release f rom cul tured end othel ial cel ls.

Thromb Res 1980; 19: 695-9.

51. Deckmyn H, Zoja C, Arnout J, et

al.

Part ial isolat ion and funct ion of the

prostacyclin regulat ing plasma factor. Cl in Sci 1985; 69: 383-93.

52. Vlachoyannis J, Schoeppe W. Adenylase cyclase act ivity and CAM P

content of human platelets in uraemia. EurJ Cl in Invest 1982; 12: 379-81.

53. Remuzzi G. Bleed ing disorders in uremia: pathophysiology and treatment.

Adv Nephrol 1989; 18: 171-86.

54. Hutton RA, O’Shea MJ. Haemostat ic mechanism in uraemia. J Cl in Patho l

1968; 21: 406-11.

55. DiMinno G, Mart inez J, McKean ML, DeLaRosa J, Burke JF, Murphy S.

Platelet dysfunction in uremia. Mult i faceted defect part ial ly corrected by

dialysis. Am J Med 1985; 79: 552-9.

56. Soslau G, Brodsky I , Putatunda B, Parker J, Schwartz AB. Select ive

reduct ion of serotonin storage an d ATP release in chronic renal fai lure pat ient

platelets. Am J Hematol 1990; 35: 171-8.

57. Ware JA, Clark BA , Smith M, Salzman EW. Abnormal i t ies of cytoplasmic

calcium in platelets f rom pat ients wi th uremia. Blood 1989; 73: 172-6.

58. Fox JEB, Reynolds CC, Phi l l ips DR. Calcium depende nt proteolysis occurs

during platelet aggregat ion. J Biol Chem 198 3; 258: 9 973-81.

HEMOSTASIS IN RENAL DISE ASE / EBERST AND BERKOWITZ

February

1994

The American Journal of Medicine Volume 96

177

8/18/2019 1-s2.0-0002934394901384-main

11/12

59. Gura V, Creter D, Levi J. Elevated thrombocyte calcium content in uremia 84. Casat i S, Passerini P, Campise MR, et a/ . Benef i ts and risks of protracted

and i ts correct ion by l -alpha (OH) vi tamin D treatment. Nephron 1982; 30: t reatment w i th human recombinant erythropoiet in in pat ients having haemod i-

237-9.

alysis. BMJ 1987; 295: 1017-20.

60. Docci D , Turci F, Delvecchio C, Gol l ini C, Baldrat i 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, Vigan o G, Benig ni A, Mecca G, Remuzzi G. Moderate doses of

aspirin and risk of bleeding in renal fai lure. Lancet 1986; 2: 414-6.

62. Gaspari F, Vigano G, Orisio S, Bonat i M, Livio M, Remuzzi G. Aspirin

prolongs bleeding t ime in uremra by a mechanism dist inct f rom platelet

cyclooxygenase inhibi t ion. J Cl in Invest 1987; 79: 1788-97.

63. Satt ler FR, Weitekamp MR, Bal lard JO. Potent ial for bleedingw ith the new

beta-lactam ant ibiot ics. Ann Intern Med 1986; 105: 924-31.

64. Fass RJ, Copelan EA, Brandt JT, Moeschberger ML, Ashton JJ. Platelet-

mediated bleeding caused by broad-spectrum penici l l ins. J Infect Dis 1987;

155: 1242-8.

85. Adamson JW, Eschbach JW. Treatment of the anem ia of chronic renal

fai lure with recombinant human erythropoiet in. Annu al Rev Med 1990; 4 1:

349-60.

86. Eschbach JW, Kel ly MR, Haley NR, Abels RI, Adamson JW. Treatment of

the anem ia of progressive renal fai lure with recombinant human erythropoi-

et in. N Engl J Med 19 89; 321: 158-63.

87. Ad Hoc Comm it tee for the Nat ional Kidney Foundat ion. Statement on the

cl inical use of recombinant erythropoiet in in anem ia of end-stage renal disease.

Am J Kidney Dis 1989; 14: 163-9.

65. Levin RD, Kwaan HC, lvanovich P. Changes in platelet funct ion during

hemodialysis. J Lab Cl in Med 1978; 92: 779-86.

66. Natelson EA, Lynch EC, Hett ig RA, Al f rey Jr CP. Acquired factor IX

def iciency in the nephrot icsyndrome. Ann Intern Med 1970; 73: 373-8.

67. Lipsky JJ. Ant ibiot ic-associated hypoprothrombinem ia. J Ant imicrob C he-

mother 19 88; 21: 281-300.

68. Gafter U, Bessler H, Malachi T, Zevin D, Djaldet t i M, Levi J. Platelet count

and thrombopoiet ic act ivi ty in pat ients wi th chronic renal fai lure. Nephron

1987; 45: 207-10.

69. George CRP, Sl ichter SJ, Quadracci LJ, Striker GE, Harker LA. A kinet ic

evaluat ion of hemostasis in renal disease. N Eng l J Med 1974; 291: 1111-5.

70. Remuzzi G, Livio M, Marchiaro G, Mecca G, DeGaetano G. Bleed ing in

renal fai lure: al tered platelet funct ion in chronic uraemia only part ial ly

corrected by haemodialysis. Nephron 1978 ; 2 2: 347-53.

71. Komarnicki M, Pietrzak I . Mechanisms of platelet aggregatron distur-

bances and their relat ion to t reatment in pat ients wi th chronic uremia. Int J

Art i f Organs 1 988; 11: 91-4.

72. Sul tan Y, London GM, Goldfarb B, Toulon P, Marchais SJ. Act ivat ion of

platelets, coagulat ion and f ibrinolysis in pat ients on long-term haemodialysis:

inf luence of Cuprophan and Polyacryloni t ri le membranes. Nephrol D ial Trans-

plant 1990; 5: 362-8.

73. Davis JM, Arakawa T, Strickland TW, Yphant is DA. Characterizat ion of

recombinant human erythropoiet in produced in Chinese hamster ovary cel ls.

Biochemistry 1987; 26: 2633-8.

74. Kawano Y, Takaue Y, Minakuchi J, et al . Impaired product ion of burst

promot ing act ivity by blood mononuclear cel ls f rom chronic uremic pat ients.

Am J Hematol 1991; 36: 9-13.

88. Kindler J, Eckardt KU, Ehmer B, et al . Single-dose pharmacokinet ics of

recombinant human e rythropoiet in in pat ients wi th various degrees of renal

fai lure. Nephrol Dial Transplant 1989; 4: 345-9.

89. McMahon FG, Vargas R, Ryan M, et a/ . Pharmacokinet ics and effects of

recombinant human erythropoiet in af ter intravenous and subcutaneous injec-

t ions in heal thy volunteers. Blood 199 0; 76: 1718-22.

90. Eschbach JW, Abdulhadi MH, Browne JK, et al . Recombinan t human

erythropoiet in in anemic pa t ients w i th end-stage renal disease: resul ts of a

phase I l l mult icenter cl inical t rial . Ann Intern Med 1989; 111: 992-1000.

91. vanWyck DB, St ivelman JC, Ruiz J, Kirl in LF, Katz MA, Ogden DA. I ron

status in pat ients receiving erythropoiet in for dialysis-associated anem ia.

Kidney Int 1989; 35: 712-6.

92. M acdoug al l IC, Lewis N P, Saunders MJ, et al . Long-term cardiorespiratory

ef fects of amel iorat ion of renal anaem ia by erythropoiet in. Lancet 1990 ; 335:

489-93.

93. Muirhead N, Hodsman AB. Occul t infect ion and resistance of anaem ia to

rHuEpo therapy in renal fai lure. Nephrol Dial Transplant 1990; 5: 232.

94. Besarab A, Medin a F, Musial E, et a/ . Recombinan t huma n erythropoiet in

does not increase c lot t ing in vascular accesses. ASAIO Trans 1990; 36:

M749.

95. Nonast-Daniel B, Deschodt G, Brunkhorst R, et al . Long-term ef fects of

t reatment wi th recombinant human erythropoiet in on haemodynamics and

t issue oxygenat ion in pat ients wi th renal anemia. Nephrol Dial Transplant

1990; 5: 444.

75. Jacquot C, Masselot JP, Berthelot JM, Peterlongo F, Castaigne JP.

Addit ion of desmopressin to recombinant human erythropoiet in in t reatment of

haemostat ic defect of uraemia [ let ter]. Lancet 1988; 1: 420.

76. lshibashi T, Koziol JA, Burstein SA. Human recombinant erythropoiet in

promotes di f ferent iat ion of murine megakaryocytes in vi t ro. J Cl in Invest

1987; 79: 286-9.

77. Johnson WJ, McCarthy JT, Yanagiha ra T, et al . Ef fects of recombinant

human erythropoiet in on cerebral and cutaneous blood f low and on blood

coagulabi l i ty. Kidney Int 1990; 38: 919-24.

78. Gordge MP, Leaker B, Pate1 A, Oviasu E, Cameron JS, Nei ld G H.

Recombinan t human erythropoiet in shortens the uraemic bleeding t ime

without causing intravascular haemostat ic act ivat ion. Thromb Res 1990; 57:

171-82.

96. Abraham PA, Opsahl JA, Keshaviah PR, eta/ . Bod yf luid spaces and blood

pressure in hemodialysis pat ients during am el iorat ion of anem ia with erythro-

poiet in. A m J Kidney Dis 1990; 16: 438-46.

97. Haley NR, Davidson RC, Eschbach JW, Adamso n JW, Easterl ing T.

Patterns of developme nt of hypertension with recombinant human erythropoi-

et in (rHuEpo) therapy: a prospect ive study [abstract] . Am J Hypertens 1989;

2 (SuppI): 56A.

98. Erslev AJ. Erythropoiet in. N Engl J Med 1991; 324: 1339-54.

99. Garcia DL, Anderson S, Rennke HG, Brenner BM. Anem ia lessens and i ts

prevent ion with recombinant human erythropoiet in worsens glomerular injury

and hypertension in rats wi th reduced renal mass. Proc Nat l Acad Sci USA

1988; 85: 6142-6.

100. Canadian Erythropoiet in Study Group. Associat ion between erythropoi-

et in and qual i ty of l i fe and exercise capaci ty of pat ients receiving hemodialysis.

BMJ 1990; 3 00: 573-8.

79. vanGeet C, Hauglustaine D, Verresen L, Vanrussel t M, Vermylen J.

Haemostat ic ef fects of recombinant human erythropoiet in in chronic hae modi-

alysis pat ients, Thromb Haemostasis 1989; 61: 117-21.

80. Drueke TB. Resistance to recombinant human erythropoietin in hemodialy-

sis pat ients. Am J Nephrol 1990; 10 (Suppl 2): 34-9.

81. Winearls GC, Ol iver DO, Pippard MJ, Reid C, Downing MR, Cotes PM.

Effect of human erythropoiet in derived f rom recombinant DNA on the anaem ia

of pat ients m aintained by chronic haemodialysis. Lancet 1986; 2: 1175-8.

82. Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW.

Correct ion of the anem ia of end-stage renal disease with recombinant human

erythropoiet in: resul ts of a combined phase I and ph ase I I cl inical t rial . N Eng l J

Med 1987; 316: 73-8.

83. Akizawa T, Koshikawa S, Takaku F, et a/ . Cl inical ef fect of recombinant

human erythropoiet in on anem ia associated with chronic renal fai lure. A

mult i -inst i tut ional study in Japan. Int J Art i f Organs 1988; 11: 343-50.

101. Lim VS, Fangma n J, Flanaghan MJ, DeGowin RL, Abels RT. Ef fect of

recombinant human erythropoiet in on renal funct ion in humans. Kidney Int

1990; 37: 131-6.

102. Mannucci PM. Desmopressin: a nontransfusional form of t reatment for

congenital and acquired b leeding disorders. Blood 1988; 72: 1449-55.

103. Mannucci PM, Al t ieri D, Faioni E. Vasopressin analogues, their role in

disordersof hemostasis. Ann NY Acad Sci 1987; 509: 71-81.

104. Ruggeri ZM, Mannucci PM, Lombard i R, Federici AB, Zimmerma n TS. ’

Mult imeric composi t ion of factor Vl l l /vonWil lebrand factor fol lowing adminis-

t rat ion of DDAV P: impl icat ions for pathophysiology and therapy of vonWil l -

ebrand disease subtypes, Blood 1982; 59: 1272-8.

105. Byrnes JJ, Larcada A, Moake JL. Thrombosisfol lowingdesmopressin for

uremic blee ding. Am J Hema tol 1988; 28: 63-5.

106. Kohler M, Harris A. Pharmacokinet ics and haema tological ef fects of

desmopressin. EurJ Cl in Pharmaco l 1988; 35: 281-5.

107. Carvalho ACA. Bleedin g in uremra-A cl inical cha l lenge. N Engl J Med

1983; 308: 38-40.

108. DiMichele DM, Hathaway WE. Use of DDA VP in inheri ted and acquired

platelet dysfunct ion. Am J Hema tol 1990; 33: 39-45.

HEMOSTASIS IN RENAL DISEAS E / EBERST AND BERKOWITZ

178 February 199 4 The American Journal of Medicine Volu me 96

8/18/2019 1-s2.0-0002934394901384-main

12/12

HEMOSTASIS IN RENAL DISE ASE / EBERST AND BERKOWITZ

109. Shapiro MD, Kel leher SP. lntranasal Deamino-8-D-A rginine Vasopressin

shortens the bleeding t ime in uremia. Am J Nephrol 1984; 4: 260-l .

110. Canavese C, Salom one M, Paci t t r A, Mangiarot t i G, Cal i t ri V. Reduced

response of uremic bleeding t ime to repeated doses of desmopressin [ let ter] .

Lancet 1985 ; 1: 867-8.

111. Mannucci PM. Desmopressin (DDAVP) for t reatment of drsorders of

hemostasis. Prog Hemost Thromb 1986; 8 : 19-45.

112. Mannucci PM, Ruggeri ZM, Paret i FI , Capitanio AM. DDAV P in hemo-

phi l ia [let ter]. Lancet 1977; 2: 1171-Z.

113. Gott i E, Mecca G, Valent ino C, Cort inovis E, Bertani T, Remuzzi G. Renal

biopsy in pat ients wi th acute ren al fai lure and prolonged bleeding t ime [ let ter] .

Lancet 198 4; 2: 978-9.

114. Bond L, Bevan D. Myocardial infarct ion in a pat ient w i th hemoph i l ia

treated w ith DDAV P [ let ter] . N Engl J Med 1988; 318: 121.

115. Liu YK, Kosfeld R E, 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

manag ement of bleeding associated with renal fai lure. N Engl J Med 1986;

315: 731-5.

117. Vigan o G, Gaspari F, Locatel l i M, Pusineri F, Bonat i M, Remuzzi G.

Dose-ef fect and pharmacokinet ics of estrogens given to correct bleeding t ime

in uremia. Kidney Int 1988; 34: 853-8.

118. Seth S, Geier TM. Use of conjugated estrogens to control gastrointest inal

bleeding in two pat ients wi th chronic renal fai lure. Cl in Pharm 1988; 7:

906-9.

119. Shem in D, Elnour M, Amarantes B, Abue lo JG, Chazan JA. Oral

estrogens decrease bleeding t ime and improve cl inical blee ding in pat ients wi th

renal fai lure. Am J Med 1990 ; 89: 436 -40.

120. Wagoner RD, Stanson AW, Hol ley KE, Winter CS. Renal vein thrombosis

in idiopathic membrane ous glomerulopathy and nephrot ic syndrome: inci-

dence and signi f icance. Kidney Int 1983; 23: 368-74.

121. Boneu B, Bouissou F, Abba l M, Sie P, Caranobe C, Barthe P. Compari-

son of progressive ant i thrombin act ivity and the concentrat ion of three

inhibi tors in nephrot ic syndrome. Thromb Haemostasis 1981; 46: 623-5.

122. Kanfer A. Coagu lat ion factors in nephrot ic syndrome. Am J Nephrol

1990; 10 (Suppl 1): 63-8.

123. Kauffmann RH, Vel tkamp JJ, VanTi lburg NH, VanEs LA. Acquired

ant i thrombin I l l def iciency and thrombosis in the nephrot ic syndrome. Am J

Med 1978; 65: 607-13.

124. Eknoyan G. Detect ing throm boembo l i in the nephrot ic syndrome. J Cri t

I l lness 1990; 5: 1137-40.

125. Su l l ivan MJ, Hough DR, Agodo a LCY. Peripheral arterial thrombosis due

to the nephrot ic syndrome: the cl inical spectrum. South Med J 1983; 76:

1011-6.

126. Lai K-N, Yin JA, Yuen P MP, L i PKT. Ef fect of hemodialysis on protein C,

protein S , and anbthrombin I I I levels. Am J Kidney Dis 1991; 17: 38-42.

127. Toulon P, Jacquot C, Capron L, Frydman MO, Vignon D, Aiach M .

Ant i thrombin I I I and heparin co-factor I I in pat ients wi th chronic renal fai lure

undergoing hem odialysis. Thromb Haemostasis 1987; 57: 263-8.

128. Parker KA, Tol lefsen DM. The protease speci f ici ty of heparin cofactor I I .

Inhibi t ion of thrombin generated during coagulat ion. J BIOI Chem 1985; 260:

3501-5.

129. Canavese C, Strat ta P, Paci t t i A , et al . Impaired f ibrinolysis in uremia:

parbal and variable correct ion by four di f ferent dialysis regimes. Cl in Nephrol

1982; 17: 82-9.

130. Mit t ra KK , Vajpeyi GN. Plasma l ipids and f ibrinolybc act ivity in pat ients

with chronic renal fai lure. J Indian Med Assoc 1987; 85: 357-8.

131. So rensen PJ, Knudsen F, Nielsen A H, Dyerberg J. Protein C act ivity 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 nephrot ic syndrome. Thromb

Haemostasis 1985; 53: 5-7.

133. Cosio FG, Harker C, Batard MA, Brandt JT, Gri f fen JH. Plasma

concentrat ions of the natural ant icoagulants protein C and protein S in pat ients

with proteinuria. J Lab Cl in Med 1985; 106: 218-22.

134. Mannucci PM, Valsecchi C, Bottasso B, D’Ang elo A, Casat i S, Pont icel l i

C. High plasma levels of protein C act ivity and ant igen in the nephrot ic

syndrome. Th romb Haemostasrs 1986; 55: 31-3.

135. Thompson AR. Factor XI I and other hemostat ic protein abnormal i t ies in

nephrot ic syndrome pat ients. Thromb Haemostasis 1982; 48: 27-32.

136. Ragni MV, Lewis JH, Hasiba U, Spero JA. Prekal l ikrein (Fletcher factor)

def iciency in cl inical 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. Haema tologia 1988;

21: 159-62.

138. Kend al l AG, Lohma nn RC, Dossetor JB. Nephrot ic syndrome: a hyperco-

agulab le state. Arch Int Med 1971; 127: 1021-7.

139. Mi let ich J, Sherman L, Braze G Jr. Absence of thrombosis in subjects

with heterozygous protein C def iciency. N Engl J Med 1987; 317: 991-6.

140. Hei jboer H, Brandjes DPM, Bul ler HR, Sturk A, Wouter ten Cates J.

Def iciencies of coagulat ion-inh ibi t ing and f ibrinolytic proteins in outpat ients

withdeep-vein thrombosis. N Eng l J Med 1990; 323: 1512-6.

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