10.4081/btvb.2023.60
With ageing of the population, both the risks of cardiovascular disease (CVD) and cancer are increasing worldwide, and the risk factors (e.g. obesity, diabetes) are often shared between the two conditions. Thus, more subjects will also develop the two illnesses concurrently [...].
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Bleeding, Thrombosis and Vascular Biology
Antiplatelet therapy
How to manage antithrombotic treatments in thrombocytopenic patients with cancer. Comments on the European Haematology Association guidelines
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Commentaries
2023-01-27
2022-11-11
2023-01-27
2023-04-04
Bleed Thromb Vascul Biol
Bianca Rocca
2023/01/27
10.4081/btvb.2023.60
Department of Safety and Bioethics, Section of Pharmacology, Catholic University School of Medicine, Rome
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Antiplatelet therapy
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Falanga A, Leader A, Ambaglio C, et al. EHA guidelines on management of antithrombotic treatments in thrombocytopenic patients with cancer. HemaSphere 2022;6:e750.
How to manage antithrombotic treatments in thrombocytopenic patients with cancer. Comments on the European Haematology Association guidelines
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                                                                                                                   COMMENTARY

How to manage antithrombotic treatments in thrombocytopenic patients
with cancer. Comments on the European Haematology Association guidelines
Anna Falanga,1,2 Hugo ten Cate,3,4 Bianca Rocca5
1
  Department of Transfusional Medicine and Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy; 2University of Milano
Bicocca, School of Medicine, Monza, Italy; 3Maastricht University Medical Center and CARIM School for Cardiovascular Disease,
Maastricht, the Netherlands; 4Center for Thrombosis and Hemostasis, Gutenberg University Medical Center, Mainz, Germany;
5
  Department of Safety and Bioethics, Section of Pharmacology, Catholic University School of Medicine, Rome, Italy




                                                                                                ly
    Correspondence: Hugo ten Cate, Maastricht University Medical




                                                                                        on
                                                                               BACKGROUND
    Center, P Debeyelaan 25, 6229 HX Maastricht, the Netherlands.
    Tel: +43 3884262.                                                               With ageing of the population, both the risks of car-
    E-mail: h.tencate@maastrichtuniversity.nl or
                                                                               diovascular disease (CVD) and cancer are increasing




                                                                                   e
    h.ten.cate@mumc.nl
                                                                               worldwide, and the risk factors (e.g. obesity, diabetes) are
    Key words: thrombosis; bleeding; cancer; thrombocytopenia; an-
    ticoagulation; antiplatelet therapy.
                                                                              us
                                                                               often shared between the two conditions. Thus, more sub-
                                                                               jects will also develop the two illnesses concurrently.1
                                                                              al
    Contributions: the authors contributed equally.                                 The continuous improvement and refinement of anti-
                                                                               cancer therapy, outcomes and survival of cancer leaves
                                                           ci

    Conflict of interest: the authors declare no potential conflict of in-     more persons exposed to CV risk factors (e.g. hypertension)
    terest.
                                                         er


                                                                               and diseases (e.g. atrial fibrillation). Subjects with cancer
    Funding: HtC’s research is supported by grants from the Nether-            may also develop acute thrombosis while on chemotherapy,
                                                        m



    lands Heart Foundation, Thrombosis Foundation, ZON-MW and                  since some drugs increase the thrombotic risk. Moreover,
    support for research projects was obtained from Bayer. AF’s re-
                                                                               it is well established that cancer patients are also at in-
                                            om




    search is supported from Foundation ARTET Onlus, Bergamo.
    BR’s research is supported by grants from the Cancer Research              creased risk of venous and arterial thrombosis and of car-
    UK (Catalyst Award–Aspirin for Cancer Prevention Collaboration             dioembolic complications, independently of other factors.2-4
    C569/A24 and support for research projects was obtained from
                                                                               Hence, patients with cancer are increasingly likely to be on
                                      -c




    Bayer.
                                                                               antithrombotic medication for prophylaxis, acute treatment
                             on




    Ethical approval and consent to participate: not applicable.               or secondary prevention of thromboembolism.
                                                                                    Subjects with cancer requiring antithrombotic med-
    Informed consent: the manuscript does not contain any individual
                                                                               ications often develop intercurrent episodes of thrombo-
                       N




    person’s data in any form.
                                                                               cytopenia (TP) associated with cancer or, more often, with
    Availability of data and material: data and materials are available        chemotherapy. TP can significantly and independently in-
    by the authors.
                                                                               crease the risk of major bleeding, on the other hand can-
    Received: 11 November 2022.                                                cer- or chemotherapy-related transient TP does not protect
    Accepted: 7 December 2022.                                                 against thrombosis. Thus, when TP occurs, physicians
    Publisher’s note: all claims expressed in this article are solely those    need to decide on the complex management of antithrom-
    of the authors and do not necessarily represent those of their affili-     botic medications, including the transient drug interrup-
    ated organizations, or those of the publisher, the editors and the re-     tion or de-escalation strategies. These decisions are not
    viewers. Any product that may be evaluated in this article or claim
    that may be made by its manufacturer is not guaranteed or endorsed
                                                                               only based on the degree of TP, since cancer is independ-
    by the publisher.                                                          ently associated with thrombotic risk as well. Thus, a care-
                                                                               ful and complex decision making with regard to
    ©
     Copyright: the Author(s), 2023                                            antithrombotic medication(s) is needed, taking into ac-
    Licensee PAGEPress, Italy
    Bleeding, Thrombosis and Vascular Biology 2023; 2:60                       count multiple factors, from the thrombosis, cancer and
    doi:10.4081/btvb.2023.60                                                   chemotherapy perspectives.
                                                                                    Since trials on antithrombotic drugs typically exclude
    This work is licensed under a Creative Commons Attribution-
    NonCommercial 4.0 International License (CC BY-NC 4.0).                    patients with cancer as well as patients at highest risk for
                                                                               bleeding, including those with TP, there is hardly any

                                                Bleeding, Thrombosis and Vascular Biology 2023; 2:60
12                                                     A. Falanga et al.




high-quality evidence to guide the management of pa-               tion, a number of general pharmacological strategies to
tients with cancer and TP with an indication of antithrom-         prevent bleeding (i.e. gastroprotection, avoidance of non-
botic medication(s), thus there is a relevant, albeit              steroidal anti-inflammatory drugs as analgesics) is recom-
growing, unmet therapeutic need.                                   mended, summarized in the paragraph below.
    It is for this growing population that the Scientific
Working Group on Bleeding and Thrombosis of the Eu-                General recommendations for all antithrombotic
ropean Haematology Association (EHA) has developed                 regimens in cancer patients with thrombocytopenia
Guidelines to provide practice guidance to help clinicians         (Falanga et al.)5
in the management of patients with cancer and TP in need
                                                                   •   In all patients on single or combined antithrombotic
of antithrombotic medication.5 A task force was assem-
                                                                       drugs, we advise against the use of traditional NSAIDs
bled based on the selection of representatives from the
                                                                       and high doses of aspirin (≥300 mg) as analgesic or
EHA in collaboration with the European Society of Car-
                                                                       antipyretic drugs. Level 1, grade A
diology, to obtain a broad and relevant representation for
                                                                   • In all patients on single or combined antithrombotic
the hematology, oncology, cardiology and clinical phar-
                                                                       drugs, we recommend using proton pump inhibitors
macology fields.
                                                                       to prevent gastrointestinal bleeding. Level 1, grade A
    This task force undertook a comprehensive review
                                                                   • Among patients receiving clopidogrel, omeprazole




                                                                                            ly
of the relevant available literature for antiplatelet and
                                                                       and esomeprazole are not recommended, and panto-




                                                                                    on
anticoagulant agents, or their combination, different
                                                                       prazole must be considered instead. Level 1, grade A
reperfusion techniques, including assessment of the risk-
                                                                   • Clinically relevant drug-drug interactions should be
benefit ratio in the conditions of TP and cancer. The level
                                                                       always considered, especially for clopidogrel, tica-




                                                                               e
of evidence and the strength of the recommendation of
                                                                       grelor, warfarin, and dabigatran. Level 1, grade D
particular management options were weighed and
graded according to the Oxford Centre for Evidence-
Based Medicine (available at: https://www.cebm.ox.
                                                                           us
                                                                   • In all patients at high/very-high CV risk, we advise to
                                                                       always optimize the treatment of modifiable CV or
                                                                       cardioembolic risk factors including hypertension and
                                                                  al
ac.uk/resources/levels-of-evidence). Each recommenda-
                                                                       hypercholesterolemia. Level 5, grade D
tion underwent a Delphi consensus among the Experts.
                                                     ci

                                                                   • Platelet function monitoring is not recommended to
The outcome of this process was recently published as a
                                                   er


                                                                       guide single or dual antiplatelet therapy (APT). Level
consensus based open access guideline.5 Here, we high-
                                                                       1, grade A
light several points and refer to the original document
                                                  m



                                                                       In patients in whom antithrombotic therapy is con-
for all details.5
                                                                   tinued, TP should be regularly verified, depending on
                                         om




                                                                   stage of chemotherapy and platelet count, see table 2
                                                                   of the original document.5 Coxibs can be a valuable op-
GENERAL CONSIDERATIONS
                                                                   tion for analgesia given their gastrointestinal and hemo-
                                    -c




    Thrombocytopenia is a broad term and first the Task            static safety.
                             on




Force defined a clinically relevant range of platelet counts           In general, the task force recommended against
based on the National Cancer Institute Common Termi-               platelet transfusion to correct the platelet count except for
nology Criteria for Adverse Events with an upper limit of          critical situations characterized by a very high thrombotic
                        N




100×109/L further segregated in four strata, with a lower          risk or acute thrombosis and severe, grade 4 TP. In such
platelet count <25×109/L as the stratum with the highest           exceptional cases thrombopoietin administration may also
risk of major bleeding in cancer patients, in absence of           be considered on an individual basis taking into account
antithrombotic medication.                                         the likely duration of the TP and the delayed effect of the
    As for the general management of patients with an ab-          thrombopoietic agents.
solute indication for antithrombotic therapy and TP, both
the risks of thrombosis and bleeding should be carefully
weighed (see tables 3 and 4 of Falanga et al.).5 This              ANTITHROMBOTIC MANAGEMENT AND
should also include reassessment of the indication for an-         THROMBOCYTOPENIA
tithrombotic therapy in addition to traditional bleeding
                                                                   Anticoagulation
and thrombosis risk factors. The duration of TP should be
estimated, and a clear antithrombotic therapy plan should              The use of anticoagulant therapy for the main indi-
be formulated on an individual patient basis, and this             cations of atrial fibrillation (AF), venous thromboem-
should be frequently re-assessed. Once the TP has raised           bolism and mechanical heart valve is indicated in Figure
above a certain threshold, specific for each condition, re-        1 in the source document5 depicting continued use of
suming antithrombotic therapy in case it had been                  therapeutic doses of anticoagulation in patients with TP
stopped, should be put in place without delays. In addi-           grades 1-2 and reduced or arrested doses in grades 3-4.

                                     Bleeding, Thrombosis and Vascular Biology 2023; 2:60
              EHA guidelines on management of antithrombotic treatments in thrombocytopenic patients with cancer                 13



In case of cessation of anticoagulation, alternative op-             should be avoided based on their higher bleeding risk as
tions with devices like inferior vena caval filters or in-           compared with clopidogrel, as shown in Figure 2. For
termittent pneumatic compression (prophylaxis), and                  acute coronary interventions in acute coronary syndrome
central venous catheter removal and, in case of AF, left             (ACS) the risks and benefits should be carefully weighed
atrial appendage occlusion, may be considered on an in-              in the individual patient (table 7 in Falanga et al.).5 Dual
dividual basis.                                                      APT with aspirin and clopidogrel can be used for transient
                                                                     ischemic attack or acute ischemic stroke for 21 days in
Antiplatelet therapy                                                 grade 1 and 2 TP, provided there are no additional bleed-
    Single antiplatelet therapy (APT, mostly low-dose                ing risk factors; for grades 3-4 either low-dose aspirin
aspirin) for secondary prevention can usually be contin-             monotherapy or no APT is recommended, until recovery
ued in those with grade 1, and grade 2 TP, in absence of             of platelet count, as shown in Figure 2. For acute symp-
major bleeding risk factors, while it should be halted in            tomatic intracranial artery stenosis, the same restrictions
grade 3, unless there are major thrombotic risk factors,             apply but the duration of dual APT, if applicable, differs
and stopped in grade 4 TP, as shown in Figure 1. The ad-             from above.
vice is similar for aspirin and clopidogrel, although for                Combinations of anticoagulants and APT should
clopidogrel drug-drug-interactions should be considered              preferably be avoided unless the risk of arterial thrombo-




                                                                                       ly
since clopidogrel safety/efficacy profile is modified by             sis is very high, as in the ACS, and TP is within the grade




                                                                               on
several CYP450-interacting drugs and may, in turn, af-               1-2 range.
fect also some chemotherapeutic agents based on the                      The use of thrombolytic therapy for acute ischemic
same mechanism (supplementary table in Falanga et                    stroke should be avoided given the high bleeding risk and




                                                                          e
al.).5 Primary prevention with low-dose aspirin, can only            alternative options including mechanical thrombectomy
be continued in grade 1 TP, but is not recommended for
>1 grades TP.
    Dual APT should be tailored, depending on the sever-
                                                                   usare preferred. For acute and life- threatening pulmonary
                                                                     embolism, the use of thrombolysis or surgical clot re-
                                                                     moval should be considered only in experienced centers
                                                            al
ity of TP, but in general should preferably comprise of as-          and on a case-by-case basis, after having measured the
pirin and clopidogrel, while prasugrel and ticagrelor                degree of TP.
                                               ci
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                                            m
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                      on
                 N




Figure 1. Management of SAPT for secondary prevention in cancer patients with TP. The flow chart depicts the recommendations for
patients with a clear indication of single antiplatelet drug in the setting of secondary prevention of serious vascular events. CV =
cardiovascular; DDI = drug-drug interaction; NSAID = nonsteroidal anti-inflammatory drugs; SAPT = single antiplatelet therapy; TP
= thrombocytopenia. Reproduced from reference 5, with permission.


                                      Bleeding, Thrombosis and Vascular Biology 2023; 2:60
14                                                      A. Falanga et al.




                                                                                             ly
                                                                                      on
                                                                                e
                                                                            us
Figure 2. Management of APT in patients with ACS and POST-PCI. The flow chart depicts the recommendations for patients with a
clear indication for dual antiplatelet drug in the setting of acute coronary syndromes (ACS) or after percutaneous coronary
                                                                   al
revascularization (PCI). CV = cardiovascular; DDI = drug-drug interaction; DAPT = dual antiplatelet therapy; NSAID = nonsteroidal
anti-inflammatory drugs; SAPT = single antiplatelet therapy; TP = thrombocytopenia. Reproduced from reference 5, with permission.
                                                      ci
                                                    er
                                                   m




CONCLUSIONS                                                         REFERENCES
                                          om




   How to treat thrombocytopenic cancer patients with                1. Willems RAL, Winckers K, Biesmans C, et al. Evolving data
acute or chronic thromboembolic diseases remains an                     on cardiovascular complications in cancer. Thromb Res
                                                                        2022;213:S87-S94.
                                    -c




unmet clinical need and a challenge for the future. Well-
designed randomized clinical studies are needed. How-                2. Donnellan E, Khorana AA. Cancer and venous thromboem-
                             on




                                                                        bolic disease: a review. Oncologist 2017;22:199-2.
ever, for the time being, this guideline based on current
                                                                     3. Navi BB, Reiner AS, Kamel H, et al. Risk of arterial throm-
available evidence, can be an aid for clinicians for com-               boembolism in patients with cancer. J Am Coll Cardiol
                         N




plex decision making at the patient side.                               2017;70:926-38.
                                                                     4. Navi BB, Reiner AS, Kamel H, et al. Arterial thromboem-
                                                                        bolic events preceding the diagnosis of cancer in older per-
                                                                        sons. Blood 2019;133:781-9.
                                                                     5. Falanga A, Leader A, Ambaglio C, et al. EHA guidelines
                                                                        on management of antithrombotic treatments in thrombo-
                                                                        cytopenic patients with cancer. HemaSphere 2022;6:e750.




                                     Bleeding, Thrombosis and Vascular Biology 2023; 2:60
