Low-grade chronic hemolysis is common in uremia, as red blood cell life span is clearly
decreased with reduced renal function. Using isotope red cell tagging, it has been
shown that red cell life span averages about 1/2 to 1/3 of normal in uremia. In addition,
uremic erythrocytes have been found to be less deformable and osmotically more fragile
when compared to their normal counterparts. Transfusion of uremic erythrocytes into
an individual with normal renal function will restore the life span of those cells
to normal. On the other hand, normal erythrocytes transfused into a uremic individual
will have shortened survival. In the past, chronic hemolysis in maintenance dialysis
patients may have manifested as increased blood transfusion require-ments. However,
these days such hemolysis probably more often presents itself as erythropoietin resistance
(larger erythropoietin doses being required for a given therapeutic response). A variety
of abnormalities (such as impairment of red cell enzymatic activities and reduced
synthesis of Na+ - K+ pump units by uremic reticulocytes) have been suggested to be
the causes for the heightened predisposition of uremic erythrocytes to hemolysis.
Uncommonly, patients on dialysis can have severe (at times life-threatening) hemolysis.
These patients fit into either of two categories, depending on whether hemolysis involves
all or the majority of the patients being dialyzed under similar circum-stances in
a given dialysis center or whether the hemolysis is patient specific. Hemolysis in
the former is often the result of water-borne toxins, centralized dialysis equipment
failure, or blood tubing defects—whereas in the latter it results from medication
or possibly inadequate dialytic therapy. Use of constricted blood tubing systems and
of hypo-osmolal or abnormally warm dialysate results in intravascular hemolysis, whereas
drug-induced hemolysis is usually extravascular.
Signs and Symptoms of Hemolysis
The signs and symptoms of hemolysis are largely nonspecific, but certain findings
are suggestive. Blood undergoing intravas-cular hemolysis can show color changes from
cherry red to port wine. A sudden deepening of skin pigmentation during or shortly
after dialysis can also be a consequence of severe intravascular hemolysis. It is
highly likely that these blood and skin color changes are all related to the release
of hemoglobin and methe-moglobin from erythrocytes, as well as the generation of methemalbumin
and a complex containing hemopexin and heme. In slowly developing hemolysis, the patient
may not notice any symptoms at all.
In severe acute or subacute hemolysis, the most common presenting symptoms are anorexia,
nausea, vomiting, abdominal pain, diarrhea, and back pain. Patients with hemolysis
can also present with headache, lethargy, malaise, chills, diaphoresis, hypotension,
hypertension, dyspnea, chest pain, palpitation, leg cramps, cyanosis, dark urine (and
death can be associated). Pancreatitis can also occur. Laboratory findings include
a low hemoglobin concentration, an elevated serum bilirubin level, reticulocytosis,
the presence of Heinz bodies, the presence of methemalbumin in the serum, and an elevated
serum lactic dehydrogenase value.
Other laboratory evidences of hemolysis comprise low hapto-globin levels, a reduced
Cr15 erythrocyte survival with splenic sequestration, and an abnormal Coomb's test.
The onset of clinical manifestations varies, depending on the cause of hemolysis.
Occurrence of symptoms within 2 hours of starting dialysis (e.g., hemolysis due to
defective blood tubing) and 8 to 24 hours after the onset of dialysis (e.g., copper-induced
hemolysis) has been reported.
Causes of Hemolysis
Refer to Table 30.1
in regard to this section.
Causes of Hemolysis
A Water supply or other toxins
Nitrites and nitrates
Combination of acetic acid, peracetic acid, and hydrogen peroxide
B Hydrogen peroxide
C Hypo-osmolal dialysate and hemodilution
D Dialysate temperature >42°C
Dialysis equipment or other dialysis problems
Faulty blood tubing (e.g., abnormal narrowing)
Kinking of blood tubing
Small-bored cannula or needle
Very high blood flows
Abutting of “arterial” needle against wall of vascular access
Malocclusion of blood pump
Thrombosis of vascular catheter
Dialyzer blood port clots
Traumatic arteriovenous fistula
E Patient-specific factors
Uremia (e.g., insufficient dialysis)
Lack of erythropoietin
Underlying systemic illness (e.g., SLE)
Water Supply or Dialysate Problem
Chlorine is the most commonly used antiseptic agent for water supplies in the United
States. Unfortunately, chlorine can react with other compounds in water to form undesirable
byproducts (such as trihalomethanes). A growing practice is to combine chlorine and
ammonia to form chloramine (a compound containing NCl groups and produced by the attachment
of chlorine to nitrogen) and to use this chemical as an alternative bactericidal compound.
Despite being much less reactive than chlorine, chloramine has been found to cause
hemolysis outbreaks among dialysis patients in various parts of the world. Most recently,
in a dialysis unit in Brazil 16 patients who developed hemolysis after having been
exposed to high concentrations of chlorine and chloramine in product water were described.
Deionization tanks can only remove undesirable ions in exchange for hydrogen or hydroxyl
ones but cannot remove nonionic substances such as chloramine. Similarly, reverse
osmosis removes 99% of ionic contaminants, 100% of colloidal material, and 100% of
microorganisms—but cannot remove chloramine. Chloramine is ordinarily removed by passage
through carbon filters. Often such passage is adequate to prevent chloramine-induced
hemolysis. However, if the chloramine-contaminated water is pumped through a carbon
filter too forcefully the elevated water pressure generated can create artificial
channels within the device—thus allowing the passage of chloramine-contaminated water
into the dialysate. In addition, traditional carbon filters may not have enough capacity
to prevent hemolysis when tap water chloramine concentrations are inordinately high—as
in the case of drought. An alternative method of removing chloramine from dialysate
is to enrich the latter with ascorbic acid. However, serum ascorbic acid levels should
be monitored to prevent hypervitaminosis C and secondary hyper-oxalosis. This ascorbic
acid approach has not been widely adopted.
Chloramine concentrations are determined indirectly by subtracting free chlorine levels
from total chloramine values. The Association for the Advancement of Medical Instrumen-tation
(AAMI) has set a level of 0.1 mg/L as the maximum concentration of chloramine allowed
in a dialysate. Chloramine levels as low as 0.25 mg/L have been reported to bring
about shortened erythrocyte life span, manifested by an increased erythropoietin requirement.
Chloramine-induced hemolysis can present as methemoglobinemia, Heinz body anemia,
or acute intravascular hemolysis (if chloramine levels are markedly elevated).
In the early days of hemodialysis, an often-reported cause of hemolysis was copper
poisoning. The leakage of copper from copper-containing dialysis equipments leads
to hemolysis, especially in the face of exhausted deionizers whose effective ion-binding
sites are too depleted to be able to remove the metal adequately. More recently, the
use of copper in dialysis equipment has dramatically lessened. Less frequently, zinc-contaminated
dialysate has been reported to induce hemolysis in dialysis patients.
Nitrates and Nitrites
These compounds have engendered hemolysis in home hemodialysis patients who used nitrate-
and nitrite-rich well water as their water supply to generate a dialysate.
Formaldehyde is used as a sterilant for reprocessing used dialyzers and for the disinfection
of the dialysate circuit of certain dialysis machines. The chemical has also been
found in the filters used in a water filtration system. If faulty rinsing procedures
are employed or formaldehyde-tainted water filtration filters are used, formaldehyde
can inadvertently be introduced into the blood. Formaldehyde in the blood may lead
to the development of auto-antibodies against erythrocytes in the form of anti-N-like
antibodies that can result in hemolysis. These anti-N-like antibodies are cold agglutinins
and show a preference for agglutinating erythrocytes with the NN blood type.
In addition to its other myriad detrimental effects on the body, formaldehyde is a
reducing agent and capable of converting NAD to NADH—thus bringing about an inhibition
of glycolysis at the level of glyceraldehyde 3-phosphate dehydrogenase and a resultant
decline in ATP stores. This reduction in ATP availability (as well as the sterilant's
other harmful effects) can foster hemolysis. Other sterilizing agents that have been
implicated in inducing hemolysis are glutaraldehyde, sodium hypochlorite, and a mixture
of acetic acid, peracetic acid, and hydrogen peroxide. A recent report describes an
outbreak of hemolysis in 19 children in a pediatric dialysis unit as a result of disinfecting
the water treatment system with a concentrated solution of hydrogen peroxide. There
was a mean reduction in hemoglobin levels of 12%.
A reduction of serum osmolality to 260 mmoles/kg does not seem to affect erythrocyte
mechanical fragility. However, if osmolality is lowered further a significant degree
of hemolysis may occur. Hemodilution can be caused by misadventures such as adminis-tering
hypo-osmolal plasma expanders. It can also result from dialyzing against hypo-osmolal
dialysates, as a result of using a faulty conductivity-measuring device. For instance,
in 1994 (in a dialysis center) human error caused a central dialysate delivery machine
to be switched to the “rinse and water” mode instead of being directed to the “dialysate”
mode. As a consequence, several patients were inadvertently dialyzed with a hypo-osmolal
dialysate. The afflicted patients developed symptoms within only 3 minutes of initiating
dialysis. One of these patients died as a result.
A dialysate temperature in excess of 42°C has been associated with hemolysis that
may last for days or even weeks.
Problems with Dialysis Equipment or Procedure
When blood is forced to flow through a narrow orifice or channel, the formed elements
are subjected to substantial turbulence and immense shearing strain. As a result,
red blood cells can become damaged and fragmented—a phenomenon known as the red cell
fragmentation syndrome. Such damaged cells, often shaped like triangles or helmets
(for example), are very susceptible to lysis. In 1998, an outbreak of hemolysis took
place in three different states—affecting a total of 30 patients. The hemolysis was
attributed to the use of defective blood tubing sets containing abnormally narrow
Of the 25 patients affected in Nebraska and Maryland alone, more than 90% required
hospitalization. Of the admitted patients, 32% required intensive unit care—and 36%
had to be given blood transfusions. Other causes of obstruction in the vascular circuit
that can foster hemolysis include partial occlusion of a vascular catheter (e.g.,
at its tip, by a thrombus, development of a thrombus at a dialyzer blood port, wide
disproportion between the caliber of a dialysis needle or of a cannula (both being
too small) and the blood flow rate (being too high), malocclusion of a roller pump
with its consequent constricting effect on the blood path within the pump segment
of an “arterial” blood tubing, impingement of the bevel of an “arterial” needle against
the wall of a vascular access, and kinking of a blood tubing.
The abutting of an “arterial” needle against the wall of a vascular access can obstruct
the needle's bevel and reduce the caliber of the blood path. If the blood pump now
keeps on pumping at the original speed, a vacuum can be created that can lead to “arterial”
tubing collapse as well as a highly turbulent and often to-and-fro movement of the
blood within that tubing. This scenario most often occurs when the delivery of blood
through the “arterial” needle is inadequate, as in the case of access stenosis. Kinking
can be the result of the improper manner in which blood tubing is routed over a hard
and narrow support, especially if easily collapsible tubing is used. Hemolysis asso-ciated
with blood path problems is mainly intravascular in nature. However, milder stimuli
may lead to less significant damage to red blood cells—causing them to be removed
subsequently by the reticuloendothelial system (extravascular hemolysis).
It has been found that the smaller the diameter of a hemodialysis blood cannula the
higher the hemolytic effect. Moreover, the position of the apical and lateral holes
of a cannula determines the magnitude of blood damage. Even with catheters that are
available commercially today, if the blood flow is 500 mL/min or higher there is a
higher risk of erythrocyte damage. Thus, when high blood flows are required larger-size
cannulas should be used. Single-needle dialysis is also a risk factor for hemolysis.
Whether a high ultrafiltraion rate can foster hemolysis is controversial. Dialysis
with a negative arterial chamber pressure greater than −350 mmHg, has been found to
cause a mild hemolysis. The latter is not severe enough to lead to an increased requirement
for erythropoietin dosage. However, one study found that during ultrafiltration even
at negative pressures as high as −710 mmHg on the blood side of the ultrafiltering
membrane no measurable hemolysis was discerned. A recent report describes a patient
with mechanical hemolysis secondary to a traumatic carotid-jugular arteriovenous fistula
that manifested as hypore-sponsiveness to erythropoietin therapy. The hemolysis resolved
after surgical correction of the fistula. Most commonly, low-grade hemolysis is seen
with prosthetic or calcified cardiac valves.
Uremia and Hemolysis
Patients on hemodialysis are more prone to develop hemolysis than patients with normal
renal function when exposed to the same offending agents. In one study, the combination
of uremia and bacteremia led to significantly more hemolysis than either uremia or
bacteremia alone. It has been suggested that there may be an increased susceptibility
of uremic erythrocytes to lysis as a result of the presence of noxious agents or of
oxidative stress. Lipid peroxidation of the red blood cell membrane (caused by increased
free radical formation that occurs in uremia alone and by exposure of polymorphonuclear
leucocytes to artificial mate-rials in the extracorporeal circuit during hemodialysis),
along with the consequent lack of cell deformability and the presence of splenic sequestration,
may be an underlying mechanism.
Whether antioxidants that reduce free radical production can prevent red blood cell
damage in uremic patients is at present unknown. Many trials have evaluated the effectiveness
of vitamin E-coating of the dialyzer membrane and glutathione and vitamin C infusion
on both oxidative damage to red blood cells and hemolysis. Although most studies have
found a benefit, the findings were not yet extensive enough to warrant universal implementation.
Recently, the use of electrolyzed-reduced water that contains active hydrogen and
possesses a lower redox potential (to prepare dialysates for hemodialysis) has been
suggested to reduce hemodialysis-enhanced production of reactive oxygen species and
proinflammatory cytokines, peroxidation of erythrocytes, and hemolysis.
The beneficial effects on erythrocytes (including that of the reduction of erythropoietin
dosage because of the amelioration of hemolysis) are believed to be related to the
scavenging of reactive oxygen species by the electrolyzed-reduced water used to prepare
the dialysate. Electrolyzed-reduced water is generated by passing compressed water
into a compartment of electrolysis through a solenoid valve. Treatment with erythropoietin
may not only augment red cell generation but reduce hemolysis in patients with uremia.
Withdrawal of erythropoietin has been found to lead to neocytolysis (selective hemolysis
of the youngest red cells).
Insufficient dialysis may also lead to hemolysis, as revealed by the U.S. National
Cooperative Dialysis Study. In this study, the hematocrit value in the group with
a mid-week blood urea nitrogen (BUN) level of 105 to 115 mg/dL was significantly lower
than the value in the group with a corresponding BUN value of 76 mg/dL. Although this
difference in hematocrit may partly be due to reduced red cell production or more
occult bleeding, some investigators have observed an inverse relationship between
BUN concentrations and red cell life span. Others have shown that the osmotic resistance
of the red cells to hemolysis is impaired with uremia and is improved after dialysis.
Other causes of hemolysis include medications, co-existing illnesses, and electrolyte
abnormalities. Medications are a well-known cause of hemolysis in dialysis patients,
especially in those with glucose-6-dehydrogenase deficiency. Some common offending
agents include aspirin, penicillins, cephalosporins (especially cefotetan), sulfonamides,
sulfones, nitrofurantoin, phenacetin, primaquine, quinidine, hydralazine and some
vitamin K derivatives. One case report describes massive hemolysis after intramuscular
injection of diclofenac. Another report reviewed a patient with severe acute respiratory
syndrome on long-term dialysis who developed hemolysis after being treated with ribavirin.
Systemic disease states such as systemic lupus erythematosus, scleroderma, periarteritis
nodosa, thrombotic thrombocytopenic purpura, the hemolytic uremic syndrome, malignant
hyper-tension, and certain malignant tumors all predispose to the occurrence of microangiopathic
hemolytic anemia. Hyperslenism due to causes such as chronic hepatitis, transfusion
hemo-siderosis, marrow fibrosis, and silicone deposition is well documented to cause
hemolytic anemia. A low serum phosphorus concentration from any cause may lead to
a predisposition to hemolysis.
Consequences and Treatment of Hemolysis
With severe hemolysis, a profound anemia may occur that may require blood transfusions.
However, the more immediate danger in end-stage renal disease patients is that of
hyperkalemia. This problem is exacerbated if hemolysis occurs after blood has passed
through the dialyzer.
After the diagnosis of hemolysis is confirmed, one needs to find and then remove the
cause. Obviously, discontinuation of dialysis is important if intradialytic acute
hemolysis is suspected. The blood present in the dialyzer and in the blood tubing
should not be returned to the patient, as this blood may contain excessive amounts
of potassium. In addition, it is imperative to monitor the electrocardiogram frequently
in these patients so that hyperkalemia can be detected promptly. Further management
should follow available guidelines intended for the treatment of hyperkalemia (if
present) and for that of severe anemia.