HEMATOLOGIC COMPLICATIONSOF CANCER 0889-8588/96 $0.00 + .

20

HEMOLYTIC DISORDERS
ASSOCIATED WITH CANCER
Michael Rytting, MD, Laura Worth, MD, PhD,
and Norman Jaffe, MD, DSc

Hemofysis is a term used to designate destruction of red blood cells

by lysis. It may manifest itself by a variety of clinical signs and symp-
toms. The phenomenon is caused by intrinsic abnormalities of the red
blood cells or by the external environment. A working outline of the
causes that may be encountered in clinical practice is presented in Table
1. The condition can often be readily recognized by examination of
the peripheral blood smear (Fig. 1). This inexpensive investigation will
generally draw attention to the condition; once the abnormality is recog-
nized, sequential investigations may be initiated. These are depicted in
Table 2.
Three principal environmental causes of hemolytic anemia in malig-
nancy have been identified: (1) hemolysis mediated by autoantibodies
to red cells; (2) hemolysis due to microangiopathic disorders; and (3)
chemotherapy-induced red cell destruction. These three environmental
stressors occur rarely in cancer patients, and they form the subject of
this review.

AUTOIMMUNE HEMOLYTIC ANEMIA

Autoimmune hemolytic anemia (AHA) is an unusual complication

of malignancy. The true incidence is difficult to gauge, because sub-
threshold quantities of immunoglobulin may be present on red cells and
remain undetected without special techniques.%,58 In addition, isoim-

From the Department of Pediatrics, University of Texas M.D. Anderson Cancer Center,
Houston, Texas

HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA

-
VOLUME 10 * NUMBER 2 APRIL 1996 365
366 RY'ITINGetal

Table 1. HEMOLYTIC ANEMIAS

Antibody mediated: idiopathic, lymphoproliferative diseases, rheumatic diseases, drugs,
infection, isoimmunization,transfusion reactions
Mechanical trauma: prosthetic valves, grafts, vasculitis (microangiopathichemolysis),
arteriovenous malformations
Defects in hemoglobin synthesis and structure
Red blood cell enzymatic defects
Red blood cell membrane deficits
Miscellaneous: march hemoglobinuria, parasitic infections, venoms, thermal injury

munization following transfusion at times may cloud the diagnosis.50

The phenomenon is characterized by the following features: moderate to
severe anemia, spherocytosis, shortened red blood cell survival, positive
direct antiglobulin test (DAT), erythroid hyperplasia of the bone mar-
row, polychromasia, and reticul~cytosis.~~* 87 Hemolysis may be discov-
ered after, or simultaneously with, the diagnosis of ~ancer.4~ Lympho-
cytic malignancies, especially neoplasms of B-cell origin, are said to
account for about one half of all cases of secondary AHA.59,76 In addition,
a varied group of solid tumors has been associated with this complica-
tion.
AHA in conjunction with malignancy may be mediated by warm-
reacting antibodies or by cold-reacting antibodies. Rarely, both cold-
and warm-reacting antibodies are present on the affected red blood

Figure 1. Peripheral blood smear in a patient with hemolytic anemia. The red blood cells
are characterized by a variety of morphologic abnormalities. These include burr cells, red
cell fragments, tear drops, and microspherocytes.
 HEMOLYTIC DISORDERS ASSOCIATED WITH CANCER 367

Table 2. HEMOLYSIS INVESTIGATION: DECISION-MAKING PROCESS

Anemia with suspected hernolysis
1
Normal mean corpuscular volume
1
Evaluate for red cell destruction or increased red cell production
(1) Peripheral smear
(2) Reticulocyte count
(3) Haptoglobin, indirect bilirubin
(4) Consider plasma hemoglobin, urine hemosiderin, urine hemoglobin
1
Laboratory examination positive for increased RBC destruction or
increased RBC production
1
Coombs test
(+) (-)
J 1
Immune-mediated Nonimmune hernolysis,
hemolytic anemia bleeding

cells.z7,73 As with AHA that is independent of malignancy, red blood

cells may be coated with IgG, IgM, complement, or rarely IgA.
Autoimmune hemolysis and warm-reacting antibodies are particu-
larly evident in patients with lymphoreticular disorders.25,59, 87 In the
majority, the antibodies are of the IgG class, but occasionally IgA or IgM
antibodies are detected.21,27, 29, 51* 59 The warm-reacting IgG antibodies
react primarily with red cell antigens of the Rh system, but other antigen
systems are not e~empt.2~8 89 In Hodgkin’s disease one may encounter
antibodies to I(t), an unusual antigen that may represent a transition
between i, an antigen strongly expressed on cord blood cells, and I, an
adult red cell antigen.27, 29
Chronic lymphocytic leukemia (CLL) and lymphomas are the neo-
plasms most commonly accompanied by warm AHA. Up to 25% of CLL
patients demonstrate AHA.21* 59 With specialized methods for subthresh-
old antibody concentrations, the association may be encountered even
more frequently. In non-Hodgkin’s lymphoma, warm AHA appears at
an incidence of 2% to 3%.43The incidence in Hodgkin’s disease is
~ i m i l a r Recently,
.~ hairy cell leukemia and AHA have been linked.22
Patients with cutaneous T-cell lymphoma and warm AHA have also
been described.24,
Warm antibody AHA is a rare accompaniment to various solid
tumors, especially carcinomas and ovarian tumors. About 30 patients
with ovarian germ cell tumors and AHA have been reported. In addi-
tion, solid tumors of breast, lung, colon, pancreas, testis, kidney, thymus,
and uterus have occasionally been accompanied by Coomb’s positive
anemia.’, 12, 17, 20, 50, 53, 62, 70, 86
Cold-reacting antibodies that cause AHA, like their warm-reacting
counterparts, are a rare complication of cancer. The antibodies are
mostly of the IgM species, although IgG and IgA cold agglutinins are
368 RYTTING et a1

also described.‘jO,
75 The antibodies display monoclonal characteristics and
thermal amplitude; as the temperature approaches zero degrees Celsius,
agglutination of red cells increases. Generally, cold-reacting antibodies
occur in elderly persons with known lymphoproliferative disorders such
as lymphoma, CLL, myeloma, and Waldenstrom’s macroglobulinemia.*s,
74 The anemia is usually chronic, and Raynaud’s phenomenon may be

present.I8 Bence-Jones proteinuria is common in these patients.18,*l IgM

with anti-I specificity is the dominant antibody species. Anti-I’ and anti-
A1 antibodies also occasionally appear.ls, @,67, 74, 82 In a review by Crisp
et al,’8 cold agglutinins of IgM kappa clonality were mostly anti-I,
whereas the majority of IgM lambda cold agglutinins were anti-i. Also,
the authors found that no cold agglutinins were part of the IgM my-
eloma proteins of cancer. These results were confirmed by Isbister et
al.41Interestingly, trisomy 3 has been found in B-lineage neoplasms that
produced cold aggl~tinins.~~, 74
Cold agglutinin-mediated hemolysis and solid tumors are unusual
companions.21,85 Some assert that their association may be coincidental;
case reports of resolution of hemolysis upon removal of solid tumors
appear to contradict this 85
Red blood cell destruction in cold agglutinin-mediated hemolytic
anemia differs from the destruction observed in warm antibody-
mediated hemolytic anemia. In cold agglutinin disease, red blood cells
are removed by the liver and some may return to the circulation.26In
addition, the removal of IgM-coated cells is dependent upon comple-
ment. This perhaps accounts for the poor response to splenectomy
seen in cold agglutinin disease. The spleen destroys IgG-coated cells
particularly well, and splenectomy can have a limited but helpful role
in patients with warm AHA and cancer.7,16, 26
The mechanism by which patients with cancer develop AHA is
speculative. There are currently three hypotheses, any of which may be
favored by different investigators: (1) the tumor produces an antigen
that alters the red cell surface; (2) the tumor incites host antibody
production and these antibodies cross-react with red blood cell antigens;
and (3) the tumor itself produces antibodies that coat red cells and cause
hemolysis.17,21* 29* 36, At least in CLL, investigators have shown that
malignant lymphocytes produce monoclonal antibodies that react with
blood cell antigens, supporting the concept that this particular neoplasm
produces antibodies responsible for h e m o l y s i ~Immunocompetent
.~~ cells
have also been found within solid tumors.12Whether these cells infiltrate
from the circulation or are derived from the neoplasm is difficult to
determine. All three hypotheses are compatible with the plentiful reports
of resolution of hemolysis upon removal of neoplasms. The resumption
of hemolysis with return of malignancy also agrees with the preceding
possible mechanisms of AHA in malignancy.
The most effective management of AHA in the setting of cancer is
to treat the underlying malignancy. Extirpation of solid tumors and
chemotherapy or irradiation of lymphoid cancers often result in resolu-
tion of the hemo1ysis.l.20, 70, 85 In many instances, resumption of autoim-
 HEMOLYTIC DISORDERS ASSOCIATED WITH CANCER 369

mune hemolysis indicates that relapse has occurred. In cases in which

tumor removal is not possible, splenectomy, steroids, and intravenous
immunoglobulin have each achieved sporadic success.6,16, 21, 41, 50, 66

MICROANGIOPATHIC HEMOLYTIC ANEMIA

Microangiopathic hemolytic anemia (MAHA) is an uncommon he-

molytic disorder seen in a variety of clinical situations, including in
instances of underlying malignancy. Brain et a19 reviewed and further
analyzed MAHA. The condition is a severe and frequently fatal hemo-
lytic anemia. It is characterized by helmet cells, schistocytes, and burr
cells in the peripheral blood smear. Of the 25 patients described by Brain
et al, five had disseminated carcinomas: stomach (three), prostate (one),
and lung (one). At autopsy, tumor emboli or fibrin thrombi were docu-
mented, and Brain et a1 speculated that the hemolysis resulted from the
passage of red blood cells through abnormal blood vessels, resulting in
fragmentation of the cells.
Further evidence to support the fragmentation theory was published
in subsequent studies and in vitro animal experiments. Rubenberg et
aP9produced diffuse intravascular coagulation (DIC) in rabbits by infus-
ing pit viper venom. The rapid defibrination resulted in an increase in
fibrin formation and in its deposition in small blood vessels. Red blood
cells were trapped in the fibrin network or irreversibly damaged as they
passed through the network, resulting in hemolysis and in abnormally
shaped cells in the peripheral blood smear. The intravenous injection of
Walker carcinoma-256 cells into rats produces a clinical picture similar
to microangiopathic hemolysis in patients with carcinoma. Intravascular
fibrin deposition around the tumor emboli is thought to be an important
mechanism in the initiation of the h e m o l y ~ i s . ~ ~
Brain et als further evaluated the mechanism by which disseminated
carcinoma could initiate fibrin deposition and cause MAHA. Specifically,
release of procoagulant substances was considered to be a possible
etiology for MAHA. Mucin produced by adenocarcinomas was consid-
ered possibly responsible for initiating DIC, which could result in
MAHA. The injection of purified mucin was subsequently shown to
produce DIC and, thus, microangiopathic hemolysis, via factor X activa-
tion6-?
Review of the literature suggests that disseminated carcinoma of
the stomach, lung, and breast account for approximately 75% of the
cancer-associated MAHA.”, 57 Non-mucin producing tumors have occa-
sionally been implicated. Some of the non-mucin producing tumors
include pulmonary small cell carcinoma, malignant pheochromocytoma,
malignant hemangioendothelioma, splenic lymphoma, and nonmeta-
static thymoma.*,19, 23, 65 It is not uncommon for a patient with meta-
static disease to initially present with MAHA. A single report also
describes a woman treated for MAHA, with a search for cancer yielding
no evidence of disease.I5 Six months later, however, an isolated breast
370 RYTTING et a1

carcinoma was detected on a screening mammogram. It is not possible

to evaluate whether these two events were related; however, this and
other cases of nonmetastatic cancer associated with MAHA suggest a
more-than-chance relationship.
Because not all cancer patients with MAHA have evidence of DIC
or fibrin deposition at autopsy, other factors must be considered when
the condition is detected in such patients. A prospective study evaluated
four patients with malignancy and MAHA.4 All patients were found to
have severe intimal proliferation of the pulmonary arterioles. In three of
the four, tumor emboli were found in lung tissue. Only one patient,
however, had fibrin thrombi, suggesting that other factors, in addition
to the thrombi, were possibly responsible for development of MAHA. It
was proposed that the narrowing of the pulmonary arteriole would have
been sufficient for hemolysis. This is further supported by the finding
of MAHA in a patient with severe primary pulmonary hypertension
who had narrowing of the pulmonary arteriolar diameter.4
Because the exact cause of MAHA is unknown, removal or treat-
ment of the underlying malignancy should be con~idered.3~. 39, 46, 81 Other
coexisting conditions that may cause MAHA, such as DIC, diabetes
mellitus, and vascular disorders, should also be investigated. In addition
to treatment of the malignancy, the prevailing management for DIC and
other related coagulation disorders should be implemented.

CHEMOTHERAPY

Hemolysis in cancer has been observed in association with dissem-

inated malignancies treated with a variety of chemotherapeutic agents.
The diseases include adenocarcinoma of the stomach, adenocarcinoma
of the breast, squamous cell carcinoma, embryonal cell carcinoma of
the testis, teratocarcinoma of the testis, Sertoli-Leydig cell tumor, and
myelomonocytic le~kemia.~, 11, 44, 52, 79 The possibility that chemotherapy
alone in these circumstances could have been responsible for the hemo-
lysis cannot be excluded.
One of the less commonly documented forms of hemolysis in cancer
is the hemolytic uremic syndrome (HUS). This term was coined by
Gasser30to describe the association of acute hemolytic anemia, thrombo-
cytopenia, and renal failure in infants and children. It represents a group
of pathologically similar disorders. The hallmark is variable degrees of
renal failure, thrombocytopenia, and microangiopathic hemolytic
anemia.30,32 The etiology is unknown, but several putative factors have
been implicated in the pathogenesis. Many cases have been associated
with a prodromal diarrhea or a respiratory illness,1° and the clustering
of cases within a family appears to implicate an infectious agent.*o,77 In
some countries, viral and bacterial infections have been linked to epi-
demics of the syndrome, the most frequent of which is infection with
Escherichia coli and Shigell~.'~,
37* 45
Chemotherapeutic agents have also been listed as causative factors
 HEMOLYTIC DISORDERS ASSOCIATED WITH CANCER 371

in the development of HUS (see Table 1).These include mitomycin C,

5-fluorouracil, cis-diamminedichloroplatinum I1 (CDDP), Adriamycin,
vinblastine, bleomycin, cytarabine, prednisone, neocarsinostatin, mitox-
antrone, etoposide, dactinomycin, cyclophosphamide, and dacarbazine.
The anthracyclines appear to have been associated with HUS only when
administered in combination with mitomycin C and 5-fluorouracil. HUS,
following treatment with mitomycin C for disseminated malignancy and
accompanied by immunologic abnormalities and vascular insufficiency,
is a well-established entity. Mitomycin C is also known to be nephro-
toxic; it appears to cause a vasculitis with glomerular and arteriolar
necrosis, onion skinning, and fibrin deposition in the kidney walls?* The
apparent risk of developing HUS after the administration of mitomycin
C is between 4% and 15%.61r68
The development of HUS following treatment with CDDP is of
interest. The mechanism by which it may cause the problem has not
been elucidated; however, several hypotheses have been advanced. One
is an alteration in the character and amount of the von Willebrand factor
(vWF), which has been seen in post-chemotherapy arterial thrombotic
syndromes.54vWF is a large multimeric protein involved in platelet
adhesion, linking platelets to the vessel wall via platelet glycoprotein
lb. Some investigators have also demonstrated increased levels of vWF
antigen in post-chemotherapy arterial thrombotic syndromes after treat-
ment with CDDP-based regimens.& These multimers are synthesized
by vascular endothelial cells after endothelial cell perturbation with
chemotherapy. CDDP may also bond to erythrocyte membrane
complex.3*,55 This mechanism appears to be similar to that of penicillin-
induced hemolysis.
Among the reports of CDDP-associated HUS is the occurrence of a
syndrome in combination with bleomycin and vinblastine.80CDDP in
this instance was considered to potentiate the vascular effects of the
latter two agents. Because CDDP is nephrotoxic, it appears reasonable
to assume that the agent may compound the renal vascular injury and
fibrin deposition associated with mitomycin C. These events may be the
initiation mechanism of CDDP nephrotoxicity. The phenomenon may be
followed by partial obstruction of the renal vascular lumen and destruc-
tion of erythrocytes and platelets by mechanical damage during pas-
sage.42
Review of the literature indicates that the time interval for the
development of HUS after the administration of chemotherapy is ex-
tremely variable (Table 3). The disease has manifested itself between 1
day and 7 months following initiation of chemotherapy, and it has
occurred up to 14 months post chemotherapy.
The possibility that chemotherapeutic agents may initiate HUS,
particularly CDDP and mitomycin C, indicates the importance of careful
monitoring of kidney function and of the hemogram in patients under-
going therapy with these agents. Although vigorous hydration with
intravenous fluids and mannitol is generally recommended for patients
undergoing treatment with CDDP, consider that these substances may
Table 3. CHEMOTHERAPEUTIC AGENTS AND TIME INTERVALS TO DEVELOPMENT OF HEMOLYTIC UREMIC SYNDROME
Time Interval
Patient From From
Characteristics Agent Initiation of Administration
Reference Age (yrs) Sex Type of Cancer Chemotherapy Implicated Chemotherapy of Last Course
Canpolat et all3 16 M Osteosarcoma CDP CDP 10 mos 7 mos
Jackson et a142 66 F Squamous cell carcinoma of the pharynx CDP, B, VC CDP -56 days 3 days
61 F Squamous cell carcinoma of larynx CDP, 8, VC CDP -54 days 1 day
24 M Embryonal and teratocarcinoma of the testis CDP, 8, VC CDP -8 mos 4 mos
60 M Squamous cell carcinoma of tongue CDP, B, VC CDP -2% mos 2 rnos
29 M Embryonal cell carcinoma of testis CDP, B, VC CDP -6 mos 2 mos
Van der Meer et also 23 F Sertoli-Leydig cell tumor CDP, Vb, B CDP -4 mos NS
Kambhu et a144 NS NS ACUP M, A, Vn M 6-8 mos NS
Van der Gaast et a179 NS NS ACUP 5-F, A, M M 10 mos NS
Mergenthaler et aI5* 54 M Adenocarcinoma of Vater’s papilla 5-F, A, M M 8 mos NS
Okumura et alss 47 F AMMoL MT, E A, C, P, N NS 6 mos 1 mos
Weinblatt et aP2 14.5 F Undifferentiated sarcoma Vc, D, Cy A, B CDP 14 mos 6 wks
54 days- 1 day-7 mos
14 mos

CDP = cisplatin; B = bleomycin; VC = vincristine;- = estimated; Vb = vinblastine; ACUP = adenocarcinoma of the unknown primary; M = mitomycin C; A =
Adriamycin; Vn = vindesine; 5-F = 5-fluorouracil; AMMoL = acute rnyelomonocytic leukemia; C = cytarabine; P = prednisone; N = neocarsinostatin; MT = mitoxantrone;
E = etoposide; D = dactinomycin; CY = cyclophosphamide; Da = dacarbazine; NS = not stated.
 HEMOLYTIC DISORDERS ASSOCIATED WITH CANCER 373

be harmful if renal function is compromised by a “sudden” ongoing

intravascular thrombotic process. Treatment of HUS involves manage-
ment of renal impairment and supportive care for the hemolytic anemia.

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Address reprint requests to

Norman Jaffe, MD, DSc
Department of Pediatrics
University of Texas
M.D. Anderson Cancer Center
1515 Holcombe Boulevard
Houston, TX 77030