Clinical Review

Microangiopathic Hemolytic
Anemia and Thrombocytopenia in
Patients With Cancer
Jordan M. Morton, MD, and James N. George, MD

University of Oklahoma Health Sciences

Center, Oklahoma City, OK
Abstract
The unexpected occurrence of thrombotic microangiopathy (TMA), characterized by
microangiopathic hemolytic anemia and thrombocytopenia, in a patient with cancer
requires urgent diagnosis and appropriate management. TMA is a term used to describe
multiple syndromes caused by microvascular thrombosis, including thrombotic
thrombocytopenic purpura (TTP), Shiga toxin–mediated hemolytic uremic syndrome,
and complement-mediated TMA. In patients with cancer, systemic microvascular
metastases and bone marrow involvement can cause microangiopathic hemolytic
anemia and thrombocytopenia. This occurs most often in patients with known
metastatic cancer, but microangiopathic hemolytic anemia and thrombocytopenia may
occur unexpectedly in patients without known metastatic disease or be the presenting
features of undiagnosed cancer. TMA may also be caused by commonly used
chemotherapy agents, either through dose-dependent toxicity or an acute immune-
mediated reaction. These causes of TMA must be distinguished from TTP, which
results from a severe deficiency of ADAMTS13 and is the most common cause of TMA
among adults without cancer. The importance of this distinction is to avoid
inappropriate use of plasma exchange, which is associated with major complications.
Plasma exchange is the essential treatment for TTP, but it has no known benefit for
patients with cancer-induced or drug-induced TMA. We will describe cancer-induced
and drug-induced TMA using the experience of the Oklahoma TTP–Hemolytic
Uremic Syndrome Registry and data from a systematic review of all published reports
of drug-induced TMA. We will illustrate the principles of evaluation and management
of these disorders with patients’ stories.

INTRODUCTION antiglobulin (Coombs) test. The evaluation

ASSOCIATED CONTENT
See accompanying commentaries
on pages 531 and 533
DOI: 10.1200/JOP.2016.012096
The occurrence of microangiopathic he-
molytic anemia and thrombocytopenia in
a patient with cancer may be unexpected
and alarming. These abnormalities are the
characteristic clinical features of throm-
botic microangiopathy (TMA) syndromes,
which are disorders of systemic micro-
vascular thrombosis.1 Microangiopathic
hemolytic anemia is defined by evidence
of hemolysis (increased serum indirect
bilirubin and decreased haptoglobin),
fragmented RBCs, and a negative direct
of unexpected microangiopathic hemolytic
anemia and thrombocytopenia in patients
with cancer focuses on two principal eti-
ologies: cancer-induced TMA, commonly
caused by systemic microvascular metas-
tases, and chemotherapy-induced TMA
(Fig 1). They must be distinguished from
other causes of TMA, such as thrombotic
thrombocytopenic purpura (TTP), caused
by severe ADAMTS13 deficiency; Shiga
toxin–induced hemolytic uremic syndrome
(HUS), caused by enteric infection with a

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Morton and George
Microangiopathic hemolytic
anemia and thrombocytopenia
in a patient with cancer
Cancer-induced Chemotherapy-
TMA induced TMA
Systemic microvascular Dose-dependent
metastases toxicity
Bone marrow Drug-dependent
metastases or necrosis antibody reaction
FIG 1. Evaluation of patients with cancer who have microangiopathic he-
molytic anemia and thrombocytopenia. There are two principal causes of
microangiopathic hemolytic anemia and thrombocytopenia occurring to-
gether in patients with cancer. Cancer itself can cause microangiopathic
hemolytic anemia and thrombocytopenia by systemic microvascular me-
tastases or bone marrow involvement of cancer. Many common chemo-
therapy agents have been associated with microangiopathic hemolytic
anemia, thrombocytopenia, and pathologic features of thrombotic micro-
angiopathy (TMA) in kidneys. These drugs can cause TMA by dose-
dependent toxicity or development of drug-dependent antibodies that can
result in acute immune-mediated kidney injury with TMA.
Shiga toxin–secreting organism, such as Escherichia coli O157:
H7; and complement-mediated TMA (also described as
atypical hemolytic uremic syndrome). Although TTP may be
the most common cause of TMA among adults without cancer,
it is not common. The incidence is only three cases per 1 million
people per year.2 The importance of the diagnosis of TTP
is the requirement for its specific treatment: plasma exchange.
Shiga toxin–induced HUS is primarily a disease of young
children manifested by a prodrome of abdominal pain and
bloody diarrhea; it has no specific treatment.3 The frequency
of complement-mediated TMA is not known, but consider-
ation of its diagnosis is increasing with the availability and
advocacy of a drug to inhibit uncontrolled complement
activation (eculizumab).4
The diagnosis of cancer-induced TMA or chemotherapy-
induced TMA is important to initiate appropriate treatment
of metastatic cancer or avoid a potentially toxic drug. The
distinction of cancer-induced TMA and chemotherapy-
induced TMA from TTP and complement-mediated TMA
is also important to avoid unnecessary plasma exchange,
which has risk for major complications, or inappropriate use
of eculizumab, which is extremely expensive. The goal of
this review is to describe the mechanisms and clinical fea-
tures of cancer-induced TMA and chemotherapy-induced
TMA.
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MECHANISMS OF TMA IN PATIENTS WITH CANCER
Cancer-Induced TMA
Patient 1
A 52-year-old woman had progressive dyspnea and weakness
for 2 weeks, then suddenly developed acute abdominal pain
and syncope.5,6 Three years previously, she had had breast
cancer with axillary node involvement treated with mastec-
tomy and chemotherapy. Physical examination was normal
(hemoglobin, 7.5 gm/dL; platelet count, 17,000/mL; lactate
dehydrogenase [LDH], 1,431 U/L; fibrinogen, 424 mg/dL;
blood smear, many schistocytes; computed tomography [CT]
of chest and abdomen, normal). TTP was diagnosed, and
plasma exchange was begun. ADAMTS13 was not measured.
She developed respiratory distress with hypoxia on day 4.
CT suggested pulmonary emboli. She died on day 6. Gross
autopsy was normal; no pulmonary emboli were identified.
Microscopic autopsy demonstrated microvascular clusters of
breast cancer cells throughout her lungs and in all other
organs, including the bone marrow.
Comment
With her breast cancer history, a bone marrow biopsy would
have been appropriate and would have diagnosed her meta-
static cancer. The pulmonary involvement with respiratory
distress, which occurred after plasma exchange was begun,
was strong evidence against the diagnosis of TTP. Plasma
exchange was appropriate for the sudden onset of symp-
toms, but a bone marrow biopsy could have made the di-
agnosis of metastatic cancer. Her rapid death was probably
not preventable.
Systemic metastatic cancer can cause severe micro-
angiopathic hemolytic anemia and thrombocytopenia that
may be indistinguishable from TTP. Microvascular obstruc-
tion by tumor cells causes red cell fragmentation and platelet
consumption in the tumor emboli. Among all 509 patients
enrolled in the Oklahoma TTP-HUS Registry from 1989
through 2015, on the basis of a request for plasma exchange for
clinically suspected TTP, 11 had a final diagnosis of metastatic
cancer. Of these 11 patients, 10 were enrolled in from 1989
through 2005, and their cases have been previously described6;
only one patient had a final diagnosis of metastatic cancer after
2005. We think that the decreased frequency of metastatic
cancer misdiagnosed as TTP in our community is a result of
physicians more often performing bone marrow biopsies in
patients with suspected TTP who have atypical features or a
Copyright © 2016 by American Society of Clinical Oncology

history of cancer. Nine different malignancies were represented
in these 11 patients: breast cancer (n 5 2), non–small-cell lung
cancer (n 5 2), and pancreatic, renal, and prostate cancer and
Kaposi sarcoma, non-Hodgkin lymphoma, acute lymphocytic
leukemia, and refractory anemia with excess blasts (n 5 1 each).
Patient 2
A 48-year-old white man had intermittent back pain, cough,
and fever for 3 months.7 Physical examination was normal
(hemoglobin, 13.5 gm/dL; platelet count, 25,000/mL; WBC,
3,700/mL with a normal differential; creatinine, 1.7 mg/dL;
LDH, 1,737 U/L; fibrinogen, 858 mg/dL; blood smear, many
schistocytes; CT of chest and abdomen, normal). TTP was
diagnosed, and plasma exchange and corticosteroids were
begun. After 5 days, his back pain resolved, but his platelet
count was unchanged. A marrow biopsy demonstrated ne-
crosis with no viable cells. We had never encountered necrosis
of the bone marrow in a patient with TTP, but we considered
that it may be possible because of the ischemia caused by
microvascular thrombosis. Over the next 5 weeks, refractory
TTP continued to be the diagnosis, because no alternative
etiology was apparent. Repeat CT scans of his chest, abdomen,
and pelvis were normal except for mild splenomegaly. Rit-
uximab was added. Two additional bone marrow biopsies also
demonstrated necrosis with no viable cells. Then, a fourth
bone marrow biopsy, 5 weeks after admission, documented
acute lymphocytic leukemia (ALL).
Comment
In this patient, bone marrow biopsies were not initially di-
agnostic, but because the presenting symptoms were not
typical for TTP and because treatment with plasma exchange,
corticosteroids, and rituximab did not improve thrombocy-
topenia (but probably did cause a partial response of his
ALL), a persistent search for an alternative etiology eventually
resulted in the correct diagnosis.
After this experience, we systematically searched for all
published reports of bone marrow necrosis; 186 articles de-
scribed 384 patients.7 Although many different etiologies were
reported, hematologic malignancies were the most common
cause (n 5 206 [54%]). ALL was the most common hema-
tologic malignancy (66 patients). Other malignant disorders
accounted for 74 patients (19%). The most common diagnosis
among patients with nonmalignant disorders was sickle
cell hemoglobinopathies (n 5 20). There were six reports of
seven patients with bone marrow necrosis who had an initial
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TMA in Patients With Cancer
diagnosis of TTP or HUS. However, the final diagnoses in
these patients were metastatic carcinoma (n 5 5) and he-
moglobin S/b thalassemia (n 5 2). Therefore, there have been
no published reports of TTP causing bone marrow necrosis.
In a retrospective review of bone marrow biopsy specimens
that demonstrated necrosis, malignancy was identified in 90%
of patients.8 The most common primary solid tumor iden-
tified was prostate adenocarcinoma. The story of our patient7
illustrates that malignant diseases can mimic the laboratory
features of TTP and that a persistent search for an etiology
other than TTP may be required.
Disseminated intravascular coagulation (DIC) is an ad-
ditional mechanism for microangiopathic hemolytic anemia
and thrombocytopenia in patients with cancer. DIC occurs in
most patients with acute promyelocytic leukemia, caused by
release of procoagulants by abnormal promyelocytes.9 In a
review of 1,117 patients with various solid tumors, DIC was
diagnosed in 6.8%.10 Mucinous tumors, such as pancreatic,
gastric, and ovarian tumors, can secrete enzymes capable of
activating coagulation factor X. A low plasma fibrinogen level
(, 150 mg/dL) is consistent with DIC. DIC is rare in patients
with TTP. Therefore, the occurrence of DIC without an ap-
parent etiology, such as sepsis, is an indication to search for
occult cancer.
Drug-Induced TMA
Patient 3
A 52-year-old man was treated for metastatic chol-
angiocarcinoma with the GEMOX (gemcitabine plus oxali-
platin) regimen (gemcitabine on day 1 and oxaliplatin
day 2) for 6 months, followed by gemcitabine maintenance.11
GEMOX was resumed after 4 months for progressive disease.
During cycle six, he developed hematuria immediately after
receiving oxaliplatin. Laboratory data were unchanged. At
cycle seven, 30 minutes after oxaliplatin administration,
he developed fever, chills, lumbar pain, and hematuria. His
hemoglobin was 9.4 gm/dL (compared with 11.6 gm/dL on the
previous day), and his platelet count was 54,000/mL (com-
pared with 161,000/mL on the previous day). His LDH was
1,370 U/L, and his creatinine was increased. TMA was di-
agnosed and attributed to gemcitabine.
Comment
This case report describes the characteristic features of
immune-mediated, drug-induced TMA caused by the for-
mation of a drug-dependent antibody.12 There was previous
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Morton and George
intermittent exposure that could have caused development
of drug-dependent antibodies. Then, the immune-mediated
reaction occurred suddenly, within minutes after a sub-
sequent exposure. The initial reaction was mild, but the
subsequent reaction was severe, with systemic symptoms and
acute kidney injury. Although the authors of this report at-
tributed the reaction to gemcitabine, presumably because
gemcitabine has been one of the most commonly reported
causes of drug-induced TMA,13 the repeated sudden occur-
rences of clinical features of TMA promptly after oxaliplatin
administration, on the day after the gemcitabine infusions,
provide definite evidence for oxaliplatin-induced TMA.
Patient 4
A woman was initially treated for rectal adenocarcinoma with
the FOLFOX (infusional fluorouracil, leucovorin, and oxali-
platin) regimen, which was resumed after a 2-year interval
because of disease progression.14 On day 1 of cycle two,
oxaliplatin was infused first. Severe symptoms occurred
suddenly during the infusion. She had chest pain, confusion,
anemia (with schistocytes on the peripheral blood smear),
thrombocytopenia, and acute kidney injury. She was treated
with plasma exchange, corticosteroids, and dialysis. Because
of low plasma ADAMTS13 activity (18% [normal, 60% to
130%]), she was diagnosed with oxaliplatin-induced TTP. Her
anemia and thrombocytopenia recovered, and her kidney
function improved so that dialysis could be stopped 3 weeks
later.
Comment
This patient had evidence for an immune-mediated reaction to
oxaliplatin. Her case does not fulfill criteria for definite evi-
dence, because she did not receive oxaliplatin again (appro-
priate, of course), and oxaliplatin-dependent antiplatelet
antibodies were not documented. However, her data provide
probable evidence, which is sufficient to recognize the risk of
immune-mediated, drug-induced TMA caused by oxaliplatin.
TTP is not an appropriate diagnosis, because the criterion for
TTP is a severe deficiency of ADAMTS13 activity, defined as
less than 10%. Less severe deficiencies of ADAMTS13 activity
are common in patients with any major illness. Acute kidney
injury is rare in patients with TTP. The role of plasma exchange
and corticosteroids in her recovery cannot be known. It may
be assumed that her recovery would have been the same if
she had not received these treatments. There are also multi-
ple reports of oxaliplatin-induced thrombocytopenia with
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documentation of oxaliplatin-dependent antiplatelet anti-
bodies.15 These reports provide additional precedent for
immune-mediated, oxaliplatin-induced TMA.
Drug-induced TMA can be caused by dose-dependent
toxicity or an immune-mediated reaction after development
of drug-dependent antibodies. Many common chemothera-
peutic drugs have been reported to cause TMA, often de-
scribed as HUS or TTP. In most reports, the mechanism has
been dose-dependent toxicity. In our systematic review,13
there were many reports of TMA attributed to gemcitabine,
mitomycin, interferon alfa, and cisplatin; however, most did
not provide evidence for a definite or probable causal as-
sociation (Table 1). The frequency of these case reports has
created the assumption that these drugs are common causes of
drug-induced TMA. However, the documentation of a drug as
the cause of TMA must be based on clinical evidence, not the
frequency of previous reports.
In contrast to the sudden onset of systemic symptoms and
kidney injury caused by immune-mediated TMA, the onset of
toxicity-mediated TMA is typically gradual, with renal failure
developing over weeks to months. One example is mitomycin,
the package insert for which has a black box warning for “HUS”
associated with cumulative doses of more than 50 mg/m2. In
the six reports with definite or probable evidence for dose-
dependent, mitomycin-induced TMA,13 the cumulative doses at
the onset of TMA were from 30 to 80 mg/m2. The time to onset
after initiation of mitomycin was from 2 to 12 months. In our
review of the nine reports with definite or probable evidence for
dose-dependent, gemcitabine-induced TMA, the cumulative
doses at the onset of TMA were from 9,000 to 56,000 mg/m2.
The time of onset after initiation of gemcitabine was from
2 to 8 months.13 The mechanism of dose-dependent, toxicity-
mediated TMA has been well described for bevacizumab.16
Dose-dependent, toxicity-mediated TMA can also be acute
if an excessive dose of a drug is administered. This is appar-
ent in the reports of pentostatin-induced TMA.17,18 Acute
toxicity-mediated TMA is more commonly associated with
intravenous narcotics.19
EVALUATION OF TMA IN PATIENTS WITH CANCER
The initial evaluation of patients with unexpected microan-
giopathic hemolytic anemia and thrombocytopenia involves
two principal questions. First, is the patient being treated with a
drug that has evidence for causing drug-induced TMA? These
data are available on our Web site.15 If the symptoms are
sudden and recurrent with repeated administration of a drug,
Copyright © 2016 by American Society of Clinical Oncology
 TMA in Patients With Cancer

Table 1. Published Reports of Drug-Induced TMA almost always causes severe kidney injury, which is rare in
Associated With Cancer Drugs patients with TTP.
Immune-Mediated If the drug exposures do not suggest drug-induced TMA,
Dose-Dependent Toxicity Reactions (no. of then an important evaluation is to distinguish the clinical
(no. of published reports) published reports) features of cancer-induced TMA from those of TTP.20 Table 2
Reports With All Reports With All lists the demographic, clinical, and laboratory features of
Agent Evidence* Reports Evidence* Reports cancer-induced TMA and TTP. Acquired TTP is an auto-
Bevacizumab 4 8 NA NA immune disorder with many similarities to systemic lupus
Cisplatin 0 14 NA NA
erythematosus, including its common occurrence in young
black women.21 Weakness, weight loss, pulmonary symp-
Docetaxel 1 1 NA NA
toms, and pain are common symptoms in patients with
Everolimus 1 1 NA NA cancer-induced TMA. Back or bone pain is common in pa-
Gemcitabine 9 85 1 1 tients with cancer-induced TMA, because marrow in-
volvement is a common cause of TMA. Weakness and dyspnea
Imatinib NA NA 1 1
resulting from severe anemia are common presenting symp-
Interferon 6 31 NA NA toms in patients with TTP, but weight loss, pulmonary symp-
alfa
toms other than dyspnea,22 and pain almost never occur in
Mitomycin 6 60 NA NA patients with TTP.
Oxaliplatin 0 3 2 3 Both cancer-induced TMA and TTP may cause severe
microangiopathic hemolytic anemia and thrombocytopenia.
Pentostatin 3 4 NA NA
Marrow involvement by cancer can cause a leukoerythroblastic
Sunitinib 2 4 NA NA reaction, characterized by nucleated red cells and immature
Vincristine 1 1 NA NA granulocytes (promyelocytes and myeloblasts) on the blood
smear. The LDH value may be high in patients with systemic
NOTE. Data are from a systematic review of all reports describing drug-
induced thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, cancer, even higher than expected with TTP. Coagulation
or TMA.13 The data for all reports are accessible online.15 abnormalities and abnormal liver function both suggest
Abbreviations: NA, not applicable (no published reports); TMA, thrombotic cancer-associated TMA rather than TTP. Measurement of
microangiopathy.
*Reports with evidence presented data supporting a probable or definite
ADAMTS13 activity is appropriate for all patients pre-
causal association of the drug with TMA. To achieve probable evidence, the senting with microangiopathic hemolytic anemia and
suspected drug had to be the only drug administered or the other drugs had to thrombocytopenia. ADAMTS13 is a plasma enzyme required
be continued or restarted. For drugs causing TMA by dose-dependent for proteolysis of von Willebrand factor. A severe deficiency
toxicity, the additional criterion required to achieve definite evidence was that
the signs of TMA had to improve when the drug was discontinued (except
(activity , 10%) defines TTP (with approximately 90% ac-
kidney injury, which may persist). Most reports of TMA associated with curacy).21 The deficient activity is caused by an autoantibody
gemcitabine, interferon alfa, or mitomycin did not achieve probable evidence, to ADAMTS13 that allows the presence of ultralarge von
because multiple other drugs were administered concurrently and were not
Willebrand factor molecules, which can cause intravascu-
continued or resumed. For drugs causing TMA by immune-mediated re-
actions, the additional criterion required to achieve definite evidence was lar platelet thrombi. Although the result of testing for
that repeated signs of TMA occurred with repeated drug exposures or that ADAMTS13 activity may not be available for several days
drug-dependent antibodies to platelets, neutrophils, or other cells were and therefore does not contribute to the initial evaluation,
documented.
this test is important for subsequent confirmation or ex-
clusion of the diagnosis of TTP.
then acute immune-mediated, drug-induced TMA caused Whenever cancer-induced TMA is considered, a bone
by a drug-dependent antibody should be suspected. If the marrow biopsy is appropriate. Documentation of malignant
patient has had slowly progressive kidney failure accompa- cells in the marrow provides the diagnosis. Malignant disease
nying the microangiopathic hemolytic anemia and throm- may also be suspected, or confirmed, by the results of imag-
bocytopenia, then dose-dependent, toxicity-mediated, drug- ing studies. Lung involvement suggests malignant disease,
induced TMA should be suspected. Drug-induced TMA because it is rare in TTP.22

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Morton and George

Table 2. Distinguishing Initial Clinical Features of Patients With Cancer-Induced TMA and TTP
Clinical Feature Cancer-Induced TMA TTP

Demographics Often older age; no sex or race disparities; not obese Predominately young (median age, 40 years); 77% female;
seven-fold increased incidence among blacks2; often
obese

Presenting symptoms
Duration Typically gradual (weeks to months) Typically acute (several days)
General Weakness, fatigue, weight loss Weakness, fatigue common; no weight loss
Bleeding Uncommon Common (purpura, hematuria)
GI Uncommon Nausea, vomiting, diarrhea common
Respiratory Common Rare (except dyspnea related to anemia)
Neurologic May have CNS metastases, with focal signs Confusion common; 30% have transient focal signs
(numbness, weakness, aphasia)
Pain Common (back pain, localized bone pain) Abdominal pain common

Laboratory data
Anemia May be severe Typically severe (hemoglobin, 6-8 g/dL)
Thrombocytopenia May be severe Typically severe (platelet count, 10,000-20,000/mL)
WBCs May be increased May be increased
Peripheral blood smear Schistocytes common; may also have many nucleated Schistocytes common; nucleated RBCs uncommon;
RBCs, immature granulocytes immature granulocytes do not occur
LDH May be higher than in TTP Increased
Liver function tests May be abnormal (transaminases, alkaline phosphatase, Normal (indirect bilirubin may be increased as a result of
direct bilirubin) hemolysis)
Creatinine May be increased Uncommonly increased
Coagulation tests Abnormalities consistent with DIC may occur (prolonged Normal
aPTT, low fibrinogen)
ADAMTS13 activity Normal or mildly decreased (. 20%) Severely decreased (, 10%)

Bone marrow biopsy Infiltrating carcinoma or necrosis Normal

Imaging (CT, PET/CT) Diffuse metastatic disease common Normal

Abbreviations: aPTT, activated partial thromboplastin time; CT, computed tomography; DIC, disseminated intravascular coagulation; PET, positron emission
tomography; LDH, lactate dehydrogenase; TMA, thrombotic microangiopathy; TTP, thrombotic thrombocytopenic purpura.

A current diagnostic dilemma is the consideration of
complement-mediated TMA (also described as atypical
HUS). Complement-mediated TMA is now commonly con-
sidered in patients with microangiopathic hemolytic anemia
and thrombocytopenia, because the marketing of its specific
treatment, eculizumab (approved in 2011), is frequently
encountered by oncologists. The diagnostic features of
complement-mediated TMA used for initial clinical trials were
not specific and included: microangiopathic hemolytic ane-
mia, thrombocytopenia, increased serum creatinine, nega-
tive testing for Shiga toxin, and ADAMTS13 activity of
5% or greater.4 These clinical features do not distinguish
complement-mediated TMA from either cancer-induced
TMA or drug-induced TMA. Complement-mediated TMA
can only be diagnosed when all other etiologies of TMA,
including cancer and drugs, are excluded. The consideration
of eculizumab is limited by its extreme expense (wholesale cost
for 1 year, $614,3761) and the assumption that it should be
continued forever.
MANAGEMENT OF TMA IN PATIENTS WITH CANCER
The distinction between cancer-induced TMA and TTP is es-
sential for the initial management decision: either to begin plasma
exchange for possible TTP or to defer plasma exchange while
searching for an alternative etiology of microangiopathic he-
molytic anemia and thrombocytopenia. If the clinical features
are not consistent with the typical presentation of TTP, deferral
of plasma exchange for additional diagnostic evaluation is
appropriate, because plasma exchange is associated with major
complications. We have documented the complications of
plasma exchange in all Oklahoma Registry patients since
1996.23,24 In 342 patients, there have been seven deaths (2%),

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four caused by complications of central venous catheter insertion
and three caused by sepsis related to the central venous catheter.
Nonfatal complications have included 31 patients with bacter-
emia, seven with catheter-related venous thrombosis requiring
systemic anticoagulation, and one with pericardial tamponade
caused by the catheter guide wire perforating the right ventricle.
When a diagnosis of cancer-induced TMA is established,
the urgent decision is whether to treat with appropriate
chemotherapy or plan for palliative care. These patients have
an extremely poor prognosis. In our experience, the median
survival was only 3 days.6
Whether any treatment, other than withdrawal of the drug,
affects the outcome of patients with drug-induced TMA is not
known. For patients with severe kidney failure, the urge to in-
tervene with some treatment is strong. Plasma exchange is often
considered; however, a review of 44 patients with TMA attributed
to gemcitabine reported that patients treated with plasma ex-
change had no better outcomes than those not treated with plasma
exchange.25 Overall, 45% of patients recovered kidney function.
Our opinion is that plasma exchange has no benefit for patients
with drug-induced TMA. Multiple other treatments have been
tried, and when the patients have recovered, case reports have
been published. Because there are no clinical features that dis-
tinguish complement-mediated TMA from drug-induced TMA,
the use of eculizumab has been reported. One report described the
use of eculizumab in four patients with gemcitabine-induced
TMA, with subsequent resolution of microangiopathic hemolytic
anemia and thrombocytopenia but incomplete recovery of kidney
function.26 Rituximab has also been described as successful
treatment of gemcitabine27 and mitomycin-induced28 TMA
in reports of single patients. Our opinion is that there is no
evidence to support the use of eculizumab or rituximab for
patients with drug-induced TMA. Supportive care may be
the best management
In conclusion, when a patient with cancer presents with
unexpected microangiopathic hemolytic anemia and throm-
bocytopenia, it is prudent to pursue the diagnostic evaluation
for cancer-induced TMA with imaging and/or bone marrow
biopsy. The potential for drug-induced TMA should also be
assessed by review of the patient’s treatment to identify drugs
that have been documented to cause TMA. It is appropriate to
defer plasma exchange for possible TTP while these evalua-
tions are performed. Early institution of appropriate che-
motherapy for systemic malignancy and avoidance of drugs
associated with TMA are the most important management
principles.
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TMA in Patients With Cancer
Acknowledgement
Supported by the Hematology-Oncology Section, University of Oklahoma Health
Sciences Center (Oklahoma City, OK).
Authors’ Disclosures of Potential Conflicts of Interest
Disclosures provided by the authors are available with this article at
jop.ascopubs.org.
Author Contributions
Conception and design: All authors
Collection and assembly of data: All authors
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
Corresponding author: James N. George, MD, Room CHB 237, Department of
Biostatistics and Epidemiology, College of Public Health, The University of
Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, OK
73126-0901; e-mail: james-george@ouhsc.edu.
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 TMA in Patients With Cancer

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Microangiopathic Hemolytic Anemia and Thrombocytopenia in Patients With Cancer

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For
more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jop.ascopubs.org/site/misc/ifc.xhtml.

Jordan M. Morton James N. George

No relationship to disclose No relationship to disclose

Copyright © 2016 by American Society of Clinical Oncology Volume 12 / Issue 6 / June 2016 n jop.ascopubs.org
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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.