Thrombosis Research 133 S2 (2014) S63–S69

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Thrombosis Research
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t h o m r e s

Thrombocytopenia in cancer patients

Howard A. Liebman*
Jane Ann Nohl Division of Hematology and Center for the Study of Blood Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, CA

ARTICLE INFO ABSTRACT

Keywords: Thrombocytopenia is a frequent complication of cancer and its treatment. The causes of
Thrombocytopenia thrombocytopenia in cancer patients can be diverse and multifactorial. Systemic chemotherapy is the
Cancer most frequent cause of thrombocytopenia. The degree and duration thrombocytopenia depends upon
Chemotherapy
whether the chemotherapeutic treatment is myeloablative, as used in stem cell transplants, or non-
Platelet transfusions
myeloablative, as typically used in solid non-hematologic malignancies. Additional causes of significant
thrombocytopenia include tumor involvement of bone marrow and spleen; microangiopathic
disorders such as disseminated intravascular coagulation, thrombotic thrombocytopenic purpura or
hemolytic uremia syndrome. Lymphoproliferative malignancies can also be associated with secondary
immune thrombocytopenia. Due to the broad differential diagnosis associated with cancer related
thrombocytopenia, a careful diagnostic evaluation is indicated. The goal of treatment should be to
maintain a safe platelet count to allow effective treatment of the underlying malignancy, prevent
bleeding complications and to minimize the use of platelet product transfusion.
© 2014 Elsevier Ltd. All rights reserved.

Thrombocytopenia is a frequent complication of cancer and
its treatment. The incidence and degree of thrombocytopenia
is dependent upon the type of malignancy, stage and approach
to treatment. The frequency of platelet counts less than 100 x
109/L can vary widely ranging from nearly 100% of patients with
acute leukemia to less than 5% in patients treated for head and
malignancies. In some malignant disorders the development of
thrombocytopenia may be multifactorial. In lymphoproliferative
malignancies, thrombocytopenia can result from splenic seques-
tration of platelets in patients with splenomegaly, decreased
production due to bone marrow replacement and/or systemic
chemotherapy, and immune-mediated platelet destruction
[1]. The malignancies, treatments and other cancer-related
disorders that are associated with significant thrombocytopenia
are listed in table 1, The focus of this review is the diagnosis
and management of the frequently encountered causes of
thrombocytopenia in cancer patients.
Chemotherapy-related thrombocytopenia (CRT)
Chemotherapeutic approaches to cancer treatment can be
generally divided into myeloablative and non-myeloablative
chemotherapy. Bone marrow ablative therapies as used in
the treatment of acute leukemia, autologous and allogeneic
stem cell transplant are associated with a prolonged course
of thrombocytopenia requiring platelet transfusion support.
* Corresponding author at: Jane Anne Nohl Division of Hematology and Center
for the Study of Blood Diseases, University of Southern California-Keck School
of Medicine, Norris Cancer Hospital, RM 3466, 1441 Eastlake Ave, Los Angeles,
CA 90033, USA. Tel.: 323-865-3950; fax: 323-865-0060.
E-mail address: liebman@usc.edu (H.A. Liebman).
The therapeutic goal of non-myeloablative chemotherapy
is to maximize tumor response with minimal bone marrow
suppression. In this regards, the frequency and degree of
chemotherapy induced thrombocytopenia is dependent upon the
chemotherapeutic regimen, individual drug doses and number
of treatment cycles given. Also the timing of the platelet nadir
and kinetic of platelet recover may differ significantly depending
upon the specific chemotherapeutic regimen. Regimens utilizing
drugs such as carboplatin or nitrosoureas can have delayed
platelet nadirs while regimens incorporating alkylating agents
such as cyclophosphamide or ifosfamide are associated with
earlier platelet nadirs.
Non-Myeloablative Chemotherapy
The contemporary chemotherapeutic management of most
non-hematologic malignancies is to give sufficient doses of
the chemotherapeutic drug(s) without inducing transfusion
dependent cytopenias. However, chemotherapeutic regimens
that result in NCI platelet toxicity grade 3 (platelet 25 to 49.9 X
109/L) and grade 4 (platelets <25 X 109/L) often require delays in
further treatment pending platelet recover which can result in a
poorer therapeutic outcome. In a retrospective study of 609 solid
tumor and lymphoma patients treatment delays occurred in 22%
of treatment cycles due to bleeding and in 30% of cycles due to
thrombocytopenia [2]. Most of the preferred chemotherapeutic
regimens utilized for the treatment of the more common non-
hematologic malignancies such as colon, lung, breast and prostate
have a low incidence of NCI grade 3 and 4 thrombocytopenia.
For example, the two most frequently used chemotherapeutic
regimens for advanced colon cancer, FOLFOX (5-fluorouracil,
leucovorin, oxaliplatin) and FOLFIRI (5-flurouracil, leucovorin,

0049-3848/$ – see front matter © 2014 Elsevier Ltd. All rights reserved.
S64 H.A. Liebman / Thrombosis Research 133 S2 (2014) S63–S69
Table 1
Causes of Thrombocytopenia in Cancer Patients
Direct Cancer Effect
Solid tumors and hematologic malignancies with bone marrow
involvement
Splenomegaly due to tumor involvement, portal or splenic vein
thrombosis
Treatment Induced:
Systemic chemotherapy: Myeloablative and Non-myeloablative
Radiation
Microangiopathic Disorders:
DIC
TTP/HUS
Vasculitis
Immune Disorders:
ITP
LGL
Drugs
DIC: disseminated intravascular coagulation; TTP/HUD: Thrombotic
Thrombocytopenic Purpura/Hemolytic Uremic Syndrome; ITP: Immune
Thrombocytopenia; LGL: Large Granular Lymphocytic Proliferation.
irinotecan), have a combined grade 3/4 thrombocytopenia
reported in 1.7% and <2% of treated patients respectively [3,4].
However, the commonly used carboplatin and Paclitaxel
combination for the treatment of advanced adenocarcinoma
of the lung report grade 3/4 platelet adverse events in 4.9 % of
patients [5].
First line treatment of ovarian cancer with cisplatin contain-
ing regimens is associated with a >70% over all response, but
most patients relapse due to platinum resistance [6]. Platinum
resistance can be overcome in many of these patients by the
use of dose dense (AUC>2) carboplatin [7]. However, subse-
quent dose dense therapy is limited by high grade (NCI 3/4)
thrombocytopenia [7,8]. However, a surprising observation is
that the addition of weekly paclitaxel allows for the use higher
doses of carboplatin to be delivered with a platelet sparing effect
[9,10]. While the mechanism of this platelet sparing effect has
not been fully characterized, one report has found increased
CFU meg P-glycoprotein expression and increased blood levels
of bone marrow stromal cell-derived thrombopoietin in the
subjects receiving paclitaxel [11].
Thrombocytopenia is also seen with newer targeted
therapies [12]. Multi-kinase drugs used in the treatment of
non-hematopoietic malignancies can also inhibit important
cellular kinases necessary for the growth and differentiation
of hematopoietic progenitor cells. Sunitinib, is a multi-
targeted tyrosine kinase FDA approved for the treatment of
renal cell carcinoma, pancreatic neuroendocrine tumors and
gastrointestinal stromal tumors [13-15]. The drug has inhibitory
activity against platelet derived growth factor receptor, c-kit and
FLIT-3, kinases important in hematopoietic maintenance [16]. A
systematic review found high-grade (NCI 3/4) thrombocytopenia
in 117 of 1547 (7.6%) patients treated with sunitunib [17]. As
might be predicted targeted therapies used for the treatment
of hematologic malignancies are most often associated with a
significant incidence of high grade thrombocytopenia, although
the mechanisms responsible for thrombocytopenia can vary
[12], HDAC inhibitors cause thrombocytopenia by delaying
megakaryocyte maturation, proplatelet formation and budding
[18,19].
Management of chemotherapy-induced thrombocytopenia
typically involves delay or dose reduction of the chemotherapeutic
drugs. Unlike myeloablative therapy, chemotherapy for non-
hematologic malignancies rarely requires platelet transfusion
support and major thrombocytopenic bleeding is a relatively rare
complication. However, strategies that reduce the frequency and
degree of thrombocytopenia could potentially improve patient
outcomes by allowing more dose intensive treatment with fewer
treatment delays.
Beginning in the late 1990s a number of clinical trials were
undertaken to assess whether thrombopoietic cytokines (Il-3,
Il-6, Il-11) could reduce the frequency and severity of CRT. Only
interleukin 11 (Il-11) was approved by the US Food and Drug
administration for management of CRT based on a phase II
randomized, placebo controlled clinical trial in which patients
were transfused for platelet counts less that 20 X 109/L [20]. The
clinical endpoint was reduction in platelet transfusions. Daily
injections of 50g/kg of Il-11 resulted in a statistically significant
reduction in platelet transfusions when compared to placebo.
However, toxicities for this agent were significant including atrial
arrhythmias, fluid retention, dyspnea and fatigue. [20] A clinical
trial in adolescent and young adults treated for a variety of non-
hematologic tumors and relapsed lymphoma with ifosfamide,
carboplatin and etopside (ICE) evaluated the safety and toxicity
subcutaneous Il-11 in a dose escalation protocol. The maximum
tolerated dose was 50g/kg with a similar adverse event profile
as previously reported, but additional toxicities of papilledema
(16%) and periosteal bone formation (11%) were also observed
[21]. While both of these trial demonstrated a reduction in
platelet transfusions, neither were designed to show a reduction
in treatment delay, improved therapeutic outcome and the
toxicity profile of Il-11 limited it clinical use in the US.
With the isolation, characterization and synthesis of
thrombopoietin (TPO) in 1994 [22-24], recombinant human
thrombopoietin (rhTPO) and a structurally related pegylated
recombinant human megakaryocyte growth and development
factor (PEG-rHuMGDF) were evaluated in a number of clinical
trials [25-27]. However, although several trials of PEG-rHuMGDF
in patients treated with carboplatin combination therapies
showed a higher platelet nadir and shorter time to platelet
recovery, with repeated cycles thrombocytopenia became the
dose limiting toxicity and the use of PEG-rHuMGDF did not allow
for more extended treatment [27]. Because of the development
of cross-reactive antibodies against endogenous TPO, clinical
assessment of PEG-rHuMGDF was halted. Several small trials of
recombinant TPO in patients receiving dose intense chemotherapy
also demonstrated a higher platelet nadir and a faster recovery
of the platelet counts in the treated patients [28-32]. However,
its value in maintaining a safe platelet count, reducing the need
for platelet transfusions and preventing treatment delays due to
thrombocytopenia with multiple cycles of chemotherapy was
not demonstrated. In contrast to the use of these thrombopoietic
cytokines in patients receiving dose intense, non-myeloablative
chemotherapy, neither rhTPO or PEG-rHuMGDF showed efficacy
in shortening the duration of thrombocytopenia for patients
receiving myeloablative treatment for acute leukemia and stem
cell transplantation [33-37].
A new generation thrombopoietic agents structurally un-
related to TPO, but capable of stimulating the TPO receptor
with an excellent safety profile have been developed and
subsequently two drugs, romiplostim and eltrombopag, have
been approved for the treatment of immune thrombocytopenia
(ITP) and thrombocytopenia associated with hepatitis C-related
thrombocytopenia [38-40]. Because of their excellent safety as
documented in over 8 years of use in patients with ITP, several
exploratory studies have been undertaken to evaluate their use
in CRT. Preliminary reports of small phase I/II studies document
their safety with some efficacy in CRT [41-44].
Myeloablative Chemotherapy
The primary goal of thrombocytopenic management following
myeloablative chemotherapy is the prevention of major bleeding
 H.A. Liebman / Thrombosis Research 133 S2 (2014) S63–S69
with the minimal use of platelet transfusions. Reduction in
the number of platelet transfusion would reduce the overall
demand on the limited platelet supply and possibly reduce the
risk of platelet allo-immunization in patients who will require
future myeloablative treatment. Current guidelines recommend
a platelet transfusion threshold of less than 10X109/L for
patients undergoing treatment for acute leukemia and stem cell
transplantation [45,46]. However, even with platelet transfusion
prophylaxis, approximately 70% of patients undergoing stem
cell transplantation or chemotherapy for hematologic cancer
may have WHO grade 2 or greater bleeding episodes [47]. Such
bleeding episodes occur even with larger transfused doses of
platelets [47]. The results of a randomized, open label, non-
inferiority comparing a non-prophylaxis platelet transfusion
strategy compared to a standard prophylaxis regimen in
patients with hematologic malignancies were recently reported
[48]. The trial results continued to support the use of routine
platelet prophylaxis in this patient population. The authors also
noted that despite platelet prophylaxis a significant number of
patients (43%) had WHO grade 2 to4 bleeding events [48]. Since
platelet transfusions alone cannot guarantee that patients with
hematologic malignancies will not bleed, adjunctive therapies
have been studied in small trials. Anti-fibrinolytic drugs such
as Epsilon Aminocaproic acid and Tranexamic acid, have been
shown to reduce bleeding in several small clinical trials in
thrombocytopenic patients with hematologic malignancies
[49-52]. A Cochrane review of this literature concluded that it
is difficult to make firm recommendation in view of the small
number of studies performed and a lack of uniform endpoints
[53]. However, the authors conclude that the available literature
is suggestive that in combination with platelet transfusion, anti-
fibrinolytic drugs may have value in reducing thrombocytopenic
bleeding in patients with hematologic cancers and should be
studied in a larger placebo controlled trial [53].
Disseminated intravascular coagulation (DIC)
Cancer can be associated with acute or chronic DIC,
depending primarily on the type of cancer. There is a spectrum
of thrombohemorrhagic diagnostic entities associated with
solid tumors, including low-grade DIC, venous thromboembolic
disease, primary fibrinogenolysis, microangiopathic hemolytic
anemia, and nonthrombotic valvular endocarditis [54].
Malignancy-related chronic DIC, as observed with solid tumors,
is less often associated with severe thrombocytopenia and
bleeding. In contrast, DIC associated with leukemia is often
acute in presentation and associated with significant bleeding
manifestations. DIC has been described in patients with both
acute myelocytic and lymphocytic leukemia, and to a lesser
extent with other hematologic malignancies [55-60]. Among
these diagnostic entities, acute promyelocytic leukemia (APL)
is most commonly associated with life-threatening hemorrhage
secondary to DIC and other hemostatic abnormalities.
The pathogenesis of DIC associated with APL has remained
controversial; consequently, the optimal therapeutic approach
associated with this condition remains unclear. Leukemic cells
from patients with APL have been found to express issue factor
and a factor X-activating protease [60-63]. Markedly elevated
plasma levels of prothrombin fragment 1-2 and thrombin-
antithrombin III complexes document the excessive generation
of thrombin in this leukemia [64].
Investigators have also provided evidence for primary fibrino-
genolysis as a contributing factor associated with serious bleeding
seen in patients with acute promyelocytic leukemia [49,65-67]. It
is likely that the combination of coagulation factor consumption,
primary fibrinogenolysis and thrombocytopenia resulting from
S65
bone marrow suppression and platelet consumption contribute
account for the high risk of bleeding in the patient with APL.
The incidence of coagulopathy and hemorrhage-related
mortality associated with acute promyelocytic leukemia
has significantly decreased since the introduction of the
differentiating agent all-trans-retinoic acid into induction
regimens, with bleeding frequently abating within 48 hours
[68,69]. However, fatal intracranial bleeding events continue
to be observed, especially when there is a delay in initiating
therapy. Unlike patients thrombocytopenic from myeloablative
chemotherapy, a higher platelet transfusion threshold
(>50 X109/L) is recommended in the early phase of APL treatment
[70].
Malignancy and chemotherapy associated TTP/HUS
The microangiopathic hemolytic anemia syndromes, throm-
botic thrombocytopenic purpura (TTP)/hemolytic uremic syn-
drome (HUS) have with increasing frequency been reported
in cancer patients and with various chemotherapeutic agents
[71-78]. Since the first reports in the early 1980s of HUS/
TTP/ in cancer patients, the characteristics of this syndrome
suggest a different mechanism from classical HUS and TTP.
Chemotherapeutic drugs most frequently reported to be
associated with the development of HUS/TTP include mitomycin
C, gemcitabine and oxaloplatin [72-76]. The few recent reports
of ADAMTS13 activity find nearly all cases with levels above
10% [76,77]. Also, there is little information regarding the role
of complement proteins in this disorder. However, endothelial
activation and injury appears to be common to those cases
associated with chemotherapeutic agents. The response to
plasma exchange appears variable with some reported responses
and many cases refractory to exchange [78,79]. This disorder
will be more fully discussed in the accompanying review of
complement related disorders by Dr. Ilene Weitz.
Immune thrombocytopenia (ITP) with lymphoproliferative
malignancy
Thrombocytopenia is a well-recognized complication of
lymphoproliferative disorders [80]. The pathogenesis of
thrombocytopenia in these disorders is multifactorial. Immune
platelet destruction is estimated to occur in about 1% to 5% of
patients [81-86]. While cases of immune thrombocytopenia
(ITP) have been reported with nearly all lymphoproliferative
disorders, the majority of cases are reported in patients with
chronic lymphocytic leukemia (CLL) [87]. Hodgkin’s disease (HD)
[88], and large granular T-lymphocyte clonal proliferations (LGL)
[89].
Thrombocytopenia with CLL
Single-institution retrospective studies reported ITP in 1% to
2% of patients with CLL, an incidence estimated to be one tenth
of that reported for CLL-associated autoimmune hemolytic
anemia [83,87,90]. The Italian adult GIMEMA group reported
that 35 of 3150 (1%) CLL patients included in a multicenter
study of autoimmune phenomena in B-cell CLL developed ITP
[91]. Advanced CLL stage, Older age and systemic treatment
were found to be independent risk factors for the development
of autoimmune hemolytic anemia, but it is uncertain whether
this also holds true for the cases of ITP [91]. Active CLL does not
correlate with the onset or severity of ITP, which is distinctly
different from the patients with autoimmune hemolytic anemia
[91,92]. ITP can precede a diagnosis of CLL, and studies using
flow cytometry performed on the bone marrow specimens of
S66 H.A. Liebman / Thrombosis Research 133 S2 (2014) S63–S69
older patients with ITP may reveal small clones of monoclonal
CLL phenotypic CD19/CD5-positive lymphocytes [83,93,94]. A
retrospective cohort study found ITP in 69 of 1,270 (5%) patients
with CLL [92]. ITP occurred at any time in the course of the
disease, with a median time to diagnosis of 13 months (range,
0 to 81 months). Laboratory characteristics of the CLL patients
with ITP included a higher frequency of unmutated IgVH genes
(54% v 18%), more frequent involvement of the VH1 family (43% v
21%; P = .01), and a lower frequency of the VH4 family (4% v 22%;
P = .02) [92]. The predominance of unmutated CLL B lymphocytes
and the unique VH gene distribution observed may reflect a CLL
subset with a greater propensity to autoimmune phenomena.
As might be predicted by the greater frequency of patients with
unmutated CLL, the patients with ITP had a lower 5-year survival
(64% v 82%; P= .001) [92]. CLL-ITP patients were also less likely to
respond to intravenous immunoglobulin (IVIg) and prednisone
treatment alone (19 of 35; 51%) when compared to the platelet
responses observed when therapy was directed against the CLL
using cytotoxic chemotherapy (27 of 41; 66%) [92].
Patients with ITP associated with CLL will usually respond
to the classic first-line ITP agents, including corticosteroids,
IVIg, and splenectomy [81,82,86]. Rituximab has been used
successfully in refractory patient, both as a single agent and in
combination with other cytotoxic agents [95,96]. Combination
protocols including high-dose rituximab, dexamethasone,
and cyclophosphamide have been utilized in the treatment of
refractory autoimmune hemolytic anemia and may be effective
in the treatment of refractory cases [97]. These more aggressive
combination rituximab-containing regimens may be superior
to standard ITP treatment due to their efficacy in treating the
underlying CLL [92]. Alemtuzumab, an approved treatment of
CLL, was used in one report to successfully to treat a patient with
refractory ITP associated with CLL [98,99]. However, a recent
report on the use of alemtuzumab for the treatment of multiple
sclerosis (MS) found acute ITP as an unexpected complication
of MS treatment [100]. Recent reports have also shown that
thrombopoietin receptor agonists are effective in increasing
platelet counts in refractory cases of CLL associated ITP [101-
104].
Thrombocytopenia in Hodgkin’s Disease (HD)
The prevalence of ITP associated with HD has been estimated
at 0.2% to 1% [88,94,105,106]. In a review of the 4,090 patients
with HD in the British National Lymphoma Investigation
Registry, only eight cases of ITP were found [102]. The majority
of reported HD-ITP cases occurred after the diagnosis of HD
[88,94,105-107]. The median time to the development of ITP
after the diagnosis of HD in the Registry was 23 months (range,
3 to 57 months), with six of the eight cases developing ITP
while in remission [106]. However, a large population-based
case-controlled epidemiologic study in Scandinavia found a
statistically significant increased risk of HD in patients with a
history of ITP, suggesting that ITP may precede a diagnosis of HD
[108].
Patients in complete remission after treatment for HD with
no evidence of recurrent disease can be treated successfully
with standard ITP protocols including corticosteroids [109,110],
splenectomy [111], and/or azathioprine [110]. ITP developing in
patients with active disease can usually remit with treatment of
the HD.
Large Granular T-Lymphocyte Proliferation
Large granular T-lymphocyte proliferation (LGL) is a clonal
proliferation of mature T lymphocytes, which predominately
express the CD8 phenotype [112]. LGL clonal proliferations are
often found in patients with rheumatologic disorders, such as
rheumatoid arthritis, but can occur independently. Neutropenia
and anemia are frequently reported in association with LGL
[89,113]. Thrombocytopenia can occur in up to 20% of patients,
but severe thrombocytopenia is observed in only 1% of patients
[89]. The development of severe thrombocytopenia is most often
due to suppression of megakaryopoiesis by the LGL cytotoxic
lymphocytes [113-115]. Amegakaryocytic thrombocytopenia
frequently develops in conjunction with other cytopenias
[113-115]. Treatment should be directed against the LGL clone
employing cytotoxic therapy (cyclophosphamide) or cyclosporine
[89,112-115]. Alemtuzumab has been successfully used to treat
a patient with LGL-associated pure red blood cell aplasia and
therefore could offer a noncytotoxic treatment alternative [116].
Immune-mediated platelet destruction is not uncommon in
lymphoproliferative disorders, particularly in those disorders
often associated with other autoimmune phenomena. ITP has
been identified in most lymphoproliferative disorders, but is
most common in patients with CLL, HD, and LGL. As with other
forms of secondary ITP, although the standard first-line agents
for ITP, corticosteroids and/or IVIg, can be used in an attempt
to elevate platelet levels acutely if needed, treatment of the
underlying condition must be the principal focus of therapeutic
strategies.
Conflict of interest statement
Dr. Liebman has received research support from Amgen,
Celgene and Immunomedics. He has received consulting fees
from Cangene and Bristol Myers Squibb.
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