The session on anticoagulation
started with an overview of the
coagulation cascade and coagulation
problems in patients with end-stage
renal failure. These patients,
whether treated by peritoneal or hemodialysis
have evidence of increased intravascular
coagulation, as shown by increased
coagulation cascade activity. This upregulation
of the coagulation system leads to
thrombin deposition on indwelling venous
dialysis catheters and increased platelet
activation and adhesion to native and artificial
arteriovenous fistulas and grafts. The
release of platelet-derived growth factors
leads to vascular smooth muscle hypertrophy
and eventual stenosis and thrombosis
of fistulas and grafts.
Apart from standard unfractionated
heparin, there is now a plethora of possible
extracorporeal anticoagulants. Some of
these were reviewed by Andrew Davenport,
MD, University of London, UK. Low molecular
weight heparins (LMWHs) tend to have
a greater effect on factor X activation and
less effect on thrombin compared to standard
heparin, although the relative activity
varies from one LMWH to another LMWH.
The half-life of LMWH is prolonged compared
to heparin, so in cases of over anticoagulation,
protamine may not be as
effective, depending upon the ratio of factor
Xa to IIa activity. Most studies have
reported less dialyzer membrane fouling
and clot deposition with LMWHs than with
standard heparin.
Of the other newer anticoagulants,
hirudin is most effective in preventing
thrombin activity. Although its half-life is
increased in renal failure, hirudin can be
cleared from the circuit when high-flux
membranes are used, and to some extent
by hemophan. Hirudin can be used for
patients with heparin-associated thrombocytopenia
due to the presence of antibodies
directed against platelet factor 4, who
require systemic anticoagulation. Whereas
there is a possibility of cross reactivity with
the synthetic heparinoids (approximately
< 10%), it is much higher with the LMWHs
(estimated from 85% to 90%). Prostacyclin
and the serine protease inhibitors (aprotinin
and nafamostat) are expensive and
should be reserved for special cases, such
as patients with pulmonary hypertension,
and liver failure, and possibly postneurosurgery
when both clot stability and an
extracorporeal anticoagulant are required.
John C. Van Stone, MD, University of
Missouri, Columbia, Missouri, reviewed his
experience with citrate, a potent regional
anticoagulant that not only blocks both
coagulation cascades, but also prevents
platelet activation. This makes citrate a very
effective anticoagulant, but because most
patients degrade it very rapidly, it does not
have a systemic anticoagulant effect, and
can, therefore, be used in patients at risk of
hemorrhage. Citrate may bind both calcium
and magnesium, and therefore should
be used with a specially designed zero calcium
dialysate, with calcium infused into
the venous return line to maintain a normal
serum calcium. When citrate was first
used as concentrated trisodium citrate,
there were reports of hypernatremia and
alkalosis, but the incidence of complications
has been reduced by the use of
lower concentrations of citrate and/or acid
citrate dextrose.
The withdrawal of urokinase has led to
a switch to recombinant tissue plasminogen
activator (rTPA) for thrombolysis of
arteriovenous (AV) fistulas and grafts, and
venous catheters. David Green, MD, PhD,
Northwestern University, Chicago, Illinois,
reviewed the currently available antithrom-bolytics:
streptokinase, anistreplase [anisoylated
plasminogen streptokinase activator
complex (APSAC)], urokinase, and rTPA.
New, investigational thrombolytic agents
are being studied; these include staphyloki-nase
and single chain urokinase (scu-PA).
Major disadvantages of streptokinase
are its low specificity for fibrin, rapid inactivation
of streptokinase–plasminogen com-plex
in plasma, and induction of antibodies
to streptococcal proteins. Anisoylation protects
the active site of the complex from
inactivation. APSAC has been used in the
treatment of acute myocardial infarction,
but has not been tried in venous thrombosis.
Compared to urokinase, rTPA has a
much higher specificity for fibrin, and is,
therefore, more likely to penetrate and bind
fibrin within a preformed clot. rTPA also
has a shorter half-life. Most centers currently
utilize 2 mg of rTPA instilled into the
catheter lumen to effectively lyse venous
dialysis catheter thrombus. For AV fistula or
graft thrombosis larger doses are required,
usually between 5 and 10 mg, although in
some cases repeated boluses or an infusion
have been required for successful
fibrinolysis, with up to 50 mg of rTPA
being given. Generally, rTPA has been
well tolerated, with local bleeding the
main problem, and initial success
reported in 74% of cases (range 58% –
100%). Obviously, rTPA should not be used
in patients with a history of recent surgery,
biopsy (within 2 weeks), or stroke (within 3
months), or in those with active peptic
ulcer disease, uncontrolled hypertension or
untreated retinopathy, and pregnancy. A
major disadvantage of rTPA is its high cost.
Following thrombolysis the question arises
as to whether patients should be prophylactically
anticoagulated with antiplatelet
agents such as aspirin, ticlopidine, or clopidogrel
for AV fistulas and grafts, or warfarin
for hemodialysis catheters.
Zbylut J. Twardowski, MD, PhD,
University of Missouri, Columbia, Missouri,
reviewed the published literature on warfarin.
Whereas there is extensive information
about the efficacy of warfarin and
target INR (International Normalized Ratio)
for patients with artificial heart valves, atrial
fibrillation, pulmonary emboli, deep
venous thrombosis, and lupus anticoagulant,
there is a dearth of randomized controlled
data for hemodialysis patients.
Many centers have tried low dose warfarin
(1 mg per day), based on a study in cancer
patients, and found this to be ineffective in
preventing catheter thrombosis in many
patients. Although most support the use of
warfarin following catheter problems, individual
units have their own guidelines, with
doses ranging from normal INR using 1 – 2
mg per day to formal systemic anticoagulation
with INR from 1.5 – 3.0. A stepwise
dosing of warfarin is emerging as useful in
preventing catheter-associated thrombosis.
With this method, patients are placed on
low dose warfarin after the first clotting
episode. With each subsequent episode, the
dose is increased to raise INR by 0.5 until
clotting episodes do not recur. In selected
patients, warfarin doses similar to those in
patients with artificial heart valves (target
INR 3.0 – 4.0) have been used to prevent
clotting. More than 200 drugs and food
ingredients can potentially interfere with
warfarin, as can other comorbid conditions,
such as hypothyroidism. Thus, although
warfarin has been around for many years
and is inexpensive, it requires careful monitoring,
which increases cost of therapy.
This last point was emphasized in the
discussion that followed. Dr. Davenport,
presiding over the discussion, pointed
out that there are advanced studies of
oral LMWHs that may eventually replace
warfarin.
