Gregor Tratar1
Cancer-associated Venous Thromboembolism
and Thrombocytopenia
ABSTRACT
KEY WORDS: cancer-associated thromboembolism, thrombocytopenia, venous thromboembolism,
anticoagulation therapy
Venous thromboembolism often occurs in patients with cancer. The risk of venous thrombo-
embolism is increased because of the prothrombotic state (platelet activation, increased
tissue factor expression) as well as cancer treatment (surgery, central venous lines,
chemotherapy). On the other hand, thrombocytopenia also frequently develops in cancer
patients due to cancer itself (e.g., in haematological malignancies) or due to anti-cancer
therapy. The management of cancer-associated thromboembolism in patients with thrombo-
cytopenia is therefore challenging due to increased risk of recurrent venous thrombo-
embolism on one hand and increased risk of bleeding on the other. Generally, the use of
full-dose anticoagulation is considered safe in patients with a platelet count above 50×109/L.
However, in patients with more pronounced thrombocytopenia, a careful assessment of
venous thromboembolism recurrence risk and risk of bleeding must be made. In this paper,
we review the current recommendations regarding thrombocytopenia and cancer-asso-
ciated thromboembolism management in these patients.
1 Doc. dr. Gregor Tratar, dr. med., Klinični oddelek za žilne bolezni, Univerzitetni klinični center Ljubljana, Zaloška cesta 7,
1000 Ljubljana; Katedra za inteno medicino, Medicinska fakulteta, Univerza v Ljubljani,, Zaloška cesta 7, 1000 Ljubljana;
gregor.tratar@kclj.si
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CANCER AND VENOUS
THROMBOEMBOLISM
Venous thromboembolism (VTE), encom-
passing deep vein thrombosis (DVT) and
pulmonary embolism (PE), is a common
complication in cancer patients. It is esti-
mated that approximately 15% of cancer
patients will develop VTE during the course
of their disease and that active cancer is
responsible for up to 20% of otherwise
unexplained VTE (1, 2). According to recent
data, the risk of VTE in cancer patients is
15-times higher than in patients without
cancer (3). Patients with cancer who devel-
op VTE have a worse prognosis than those
without VTE. The mechanisms of cancer-
-associated thromboembolism (CAT) include
all the components of the Virchow triad
(vessel wall damage, stasis, hypercoagula-
bility). Many of them are cancer specific:
thrombocytosis with platelet activation,
leucocytosis and neutrophil extracellular
traps, the expression of tissue factor and ele-
vated levels of plasminogen activator
inhibitor-1 (PAI-1). Other factors also influ-
ence the risk of CAT, i.e. cancer surgery, the
insertion of central venous catheters, and
chemotherapy. Because CAT recurrence rate
is high and associated with poor prognosis,
CAT management is challenging (4, 5).
The Low-Molecular-Weight Heparin
versus a Coumarin for the Prevention of
Recurrent Venous Thromboembolism in
Patients with Cancer (CLOT) trial in 2003
clearly showed that treatment with low-
-molecular-weight heparins (LMWH) in
the first six months after CAT was more
effective than warfarin and this approach
has long represented the mainstay of anti-
coagulation in CAT (6). However, in recent
years, several trials proved the effectiveness
of direct oral anticoagulants (DOACs) for the
treatment of CAT, and DOACs (rivaroxaban,
apixaban, edoxaban) are now recommend-
ed as the first line anticoagulant treatment
option in CAT as well (7, 8). An increased risk
of bleeding in gastrointestinal tumours
and possible interactions with cancer treat-
ment must be taken into account.
CANCER AND
THROMBOCYTOPENIA
Thrombocytopenia often occurs in cancer
patients. It can be a result of the under-
lying disease (e.g., in haematological malig-
nancies), but most often it is a consequence
of oncological treatment. Severe thrombo-
cytopenia occurs in about 30% of patients
with solid tumours and in about 50% of
patients with haematological malignan-
cies (8). Without anticoagulant treatment,
the risk of bleeding increases at a platelet
count < 25 × 109/L and the risk of sponta-
neous major bleeding increases at a platelet
count < 10 × 109/L. Chemotherapy-induced
thrombocytopenia (CIT) is usually managed
with platelet transfusions although the
duration of platelet count improvement is
short-lived and transfusions are not prac-
tical for the long-term maintenance of
platelet count throughout chemotherapy.
Therefore, platelet transfusions are usual-
ly only used in severe thrombocytopenia
(platelet count < 10 × 109/L) and/or in case
of bleeding complications (8). Thrombopoietin
receptor agonists (TPO-RAs) are a promis-
ing therapeutic option in patients with
solid tumours but are currently only
approved for the treatment of specific types
of thrombocytopenia (e.g. immune thrombo-
cytopenia) and have not been tested in
CIT. Due to a lack of phase 3 clinical trials,
the current guidelines of the Scientific and
Standardization Committee (SSC) of the
International Society on Thrombosis and
Haemostasis (ISTH), suggest the use of
TPO-RAs only in the setting of clinical tri-
als or the use of romiplostim when con-
sidering TPO-RA use outside of clinical trial
settings (8).
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THE MANAGEMENT OF
CANCER-ASSOCIATED
THROMBOEMBOLISM
IN PATIENTS WITH
THROMBOCYTOPENIA
CAT is associated with an increased risk of
recurrence but the use of full-dose anti-
coagulation in thrombocytopenic patients
is considered risky due to an increased risk
of bleeding. Generally, the use of full-dose
anticoagulation is considered safe in patients
with a platelet count > 50 × 109/L (9). The
management of anticoagulation in patients
with more pronounced thrombocytopenia
is uncertain. Usually, LMWHs are used
due to the lack of data on the use of
DOACs in this setting. For patients with
severe thrombocytopenia and acute CAT
(up to one month), the guidelines suggest
either a full-dose of LMWH and platelets
transfusions to maintain a platelet count of
40–50 × 109/L in patients with a high risk
of thrombosis progression or a 50% reduc-
tion of the LMWH dose in patients with low
risk of thrombosis progression. For suba-
cute CAT (more than one month), the guide-
lines suggest a 50% reduction of the
LMWH dose or the use of a prophylactic
LMWH dose. In patients with a platelet
count < 25 × 109/L, temporary discontinua-
tion of anticoagulation is suggested (9).
Some recommendations use a somewhat
higher cut-off value for the discontinuation
of anticoagulation at 30 × 109/L (10).
CONCLUSION
CAT management is especially challenging
in cancer patients with thrombocytope-
nia. The cause and the degree of thrombo-
cytopenia, risk of bleeding, risk of recurrent
VTE and other patient characteristics must
be taken into account when selecting
optimal anticoagulant treatment for such
patients.
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