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Pène et al. Annals of Intensive Care (2025) 15:25 Annals of Intensive Care
https://doi.org/10.1186/s13613-025-01447-x

REVIEW Open Access

Thrombocytopenia in the intensive care unit:

diagnosis and management
Frédéric Pène1,2* , Lene Russell3,4 and Cécile Aubron5

Abstract
Background This narrative review aims to describe the epidemiology and aetiologies of thrombocytopenia in criti-
cally ill patients, the bleeding risk assessment in thrombocytopenic patients, and provide an update on platelet
transfusion indications.
Results Thrombocytopenia is a common disorder in critically ill patients. The classic definition relies on an absolute
platelet count below 150 × ­109/L. Alternatively, the definition has extended to a relative decrease in platelet count
(typically within a range of >30–>50% decrease) from baseline, yet remaining above 150 × ­109/L. Thrombocytopenia
may result from multiple mechanisms depending upon the underlying conditions and the current clinical setting.
Regardless of the causes, thrombocytopenia accounts as an independent determinant of poor outcomes in critically
ill patients, albeit often of unclear interpretation. Nevertheless, it is well established that thrombocytopenia is associ-
ated with an increased incidence of bleeding complications. However, alternative factors also contribute to the risk
of bleeding, making it difficult to establish definite links between nadir platelet counts at the expense of potential
adverse events. Platelet transfusion represents the primary supportive treatment of thrombocytopenia to prevent
or treat bleeding. As randomised controlled trials comparing different platelet count thresholds for prophylactic plate-
let transfusion in the ICU are lacking, the prophylactic transfusion strategy is largely derived from studies performed
in stable haematology patients. Similarly, the platelet count transfusion threshold to secure invasive procedures
remains based on a low level of evidence. Indications of platelet transfusions for the treatment of severe bleeding
in thrombocytopenic patients remain largely empirical, with platelet count thresholds ranging from 50 to 100 × ­109/L.
In addition, early and aggressive platelet transfusion is part of massive transfusion protocols in the setting of severe
trauma-related haemorrhage.
Conclusion Thrombocytopenia in critically ill patients is very frequent with various etiologies, and is associated
with worsened prognosis, with or without bleeding complications. Interventional trials focused on critically ill patients
are eagerly needed to better delineate the benefits and harms of platelet transfusions.

*Correspondence:
Frédéric Pène
[email protected]
1
Service de Médecine Intensive – Réanimation, Hôpital Cochin,
Assistance Publique‑Hôpitaux de Paris. Centre, Université Paris Cité, 27 rue
du Faubourg Saint‑Jacques, 75014 Paris, France
2
Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Cité,
Paris, France
3
Department of Intensive Care, Copenhagen University Hospital
Gentofte, Hellerup, Denmark
4
Department of Clinical Medicine, University of Copenhagen,
Copenhagen, Denmark
5
Service de Médecine Intensive – Réanimation, CHU de Brest, Université
de Bretagne Occidentale, Brest, France

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Introduction over the first days to reach a nadir around days 4–5 fol-
Platelets are non-nucleated cells derived from megakar- lowing ICU admission [5, 6]. Therefore, the definition of
yocytes, the giant precursor cells within the bone mar- ICU-related thrombocytopenia has been broadened to
row. They have a lifespan of 7–10 days, and their count also include a relative decrease in platelet count (typi-
is maintained at a steady state balanced by bone marrow cally within a range of >30–>50% decrease, yet remaining
production. It is noteworthy that platelets undergo cir- above 150 × ­109/L) [7]. The prevalence in reported studies
cadian quantitative and functional variations in healthy ranges from 12 to 77%, and the overall incidence from 8
subjects. During the day, platelet counts increase by to 56 per 100 ICU admissions [7]. This variation in pre-
5%, and activation patterns are more pronounced in the vious studies is largely explained by most being small,
morning [1]. retrospective and single-centre, and because definitions
Platelets are mainly recognised for their haemostatic of thrombocytopenia varied considerably. Recently, the
role, which relies on the number of circulating platelets large prospective international PLOT-ICU cohort study
and their functional integrity. They patrol the vessel walls has provided a global view of thrombocytopenia in the
and become adherent to altered surfaces when activated ICU [8]. The study included 1168 patients from 52 ICUs
by von Willebrand factor (vWF) and collagen. Once acti- in 10 countries, mainly medical patients with a relatively
vated, platelets release their granules’ contents, includ- high number of haemato-oncological diseases (14.4%),
ing adenosine diphosphate (ADP), to recruit additional and excluded patients admitted to the ICU for post-oper-
circulating platelets and amplify platelet activation and ative monitoring after elective surgery. The frequency of
aggregation, thereby contributing to the haemostatic any thrombocytopenia was 43.2% (95% CI 40.4–46.1),
clot. Furthermore, platelets are immunomodulatory cells, distributed into baseline and ICU-acquired thrombo-
owing to their critical roles in the rolling and diapedesis cytopenia in 23.4% (20.0–26.0) and 19.8% (17.6–22.2),
of neutrophils towards inflammatory sites and by deploy- respectively [8].
ing neutrophil extracellular traps to contain local infec- Observational studies have reported high variability
tious processes. Additionally, platelet activation is part of in the risk factors for developing thrombocytopenia in
various pathogenic thrombotic mechanisms, including the ICU; however, comparing risk factors across studies
the immunothrombosis seen in the context of a dysregu- is challenging as case mix, definitions of thrombocyto-
lated immune response [2, 3]. penia and analytic methods differ. Nevertheless, higher
Thrombocytopenia is common in critically ill patients, disease severity scores at ICU admission have consist-
though its significance is complex and depends on prior ently been associated with the development of thrombo-
comorbid conditions and ongoing pathogenic pro- cytopenia [8–12]. Other baseline conditions which have
cesses. It is also associated with worse outcomes, includ- been associated with an increased risk of thrombocyto-
ing an increased risk of bleeding. In addition to treating penia include onco-haematological neoplasms and liver
the underlying disorder, managing thrombocytopenia disease. The most common acute condition in patients
often involves supportive measures, primarily platelet developing thrombocytopenia in the ICU is sepsis [8,
transfusion. 11–13]. In the PLOT-ICU study, septic shock increased
This narrative review aims to describe the epidemiol- the risk of severe thrombocytopenia with an odds ratio of
ogy and aetiologies of thrombocytopenia in critically ill 6.90 (2.82–16.89) in adjusted analyses [8].
patients, discuss the risk of bleeding in thrombocyto-
penic patients, and provide an update on indications for
platelet transfusion. Diagnosis of thrombocytopenia
The mechanisms responsible for thrombocytopenia in
critically ill patients largely depend on the underlying
Epidemiology of thrombocytopenia in critically ill conditions and the current clinical setting (Table 1). ICU-
patients acquired thrombocytopenia is mainly ascribed to vari-
Over 70 studies have been published over the past ous peripheral mechanisms, including dilution, splenic
40 years reporting on the frequency of thrombocy- sequestration, destruction, and consumption. Bone mar-
topenia in the ICU. In most studies, the diagnosis of row failure, due to both malignant and non-malignant
thrombocytopenia typically relies on an absolute plate- disorders and recent cytotoxic chemotherapy, implies
let count below 150 × ­109/L, which corresponds to the hypoproliferative thrombocytopenia. Furthermore, rela-
classification in the SOFA score system as mild, moder- tive deficiencies in haematologic growth factors such as
ate, severe and very severe when below 150, 100, 50 and thrombopoietin, the primary regulator of platelet pro-
20 × ­109/L, respectively [4]. Platelet count is a dynamic duction, may limit the thrombopoietic response in criti-
variable in critically ill patients and typically decreases cally ill patients [14].
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Table 1 Diagnostic work-up of thrombocytopenia in the critically ill patient

Clinical conditions Alleged mechanisms of thrombocytopenia Main relevant investigations

Medical background
Onco-hematological neoplasms Bone marrow suppression Most often obvious from the medical history
Cytotoxic chemotherapy Bone marrow explorations
Liver cirrhosis Hypersplenism Dosage of vitamins B9 and B12
Hypoproliferative (alcohol toxicity, vitamin deficien-
cies)
Pregnancy and peri-partum Thrombotic microangiopathy Liver blood tests
HELLP syndrome Haemolysis markers with schistocytes
TTP Proteinuria
HUS Ratio sFlt-1/PlGFa
ADAMTS13 activity
Exploration of complement inhibition pathways
Post-partum haemorrhage Dilution, consumption Haemostasis tests with quantification of D-dimers
Disseminated intravascular coagulation
Hemorrhagic shock, hemorrhagic surgery Dilution, consumption Haemostasis tests
Travel from endemic areas Malaria Thin and thick blood smears, malaria antigen
Dengue fever Serology, PCR, ELISA test
Sepsis Disseminated intravascular coagulation Haemostasis tests with quantification of D-dimers
Haemophagocytosis
Immune-mediated destruction
Acute coronary syndrome Anti GPIIb/IIIa treatment
Extracorporeal circulations Membrane clotting
Sickle cell disease Bone marrow necrosis Bone marrow explorations
Associated organ dysfunctions
Neurological manifestations Thrombotic microangiopathy Cerebral CT-scanb
TTP, malignant hypertension ADAMTS13 activity
Acute kidney injury Thrombotic microangiopathy ADAMTS13 activity
HUS, malignant hypertension, TTP, scleroderma Exploration of complement inhibition pathways
renal crisis
Venous and/or arterial thrombosis Heparin-induced thrombocytopenia Anti-PF4 ­antibodiesc
Catastrophic anti-phospholid syndrome APTT coagulation test
Anti-phospholipid and anti-β2 GPI antibodies
Intravascular disseminated coagulation Haemostasis tests with quantification of D-dimers
Biological features
Severe isolated thrombocytopenia Spurious thrombocytopenia Blood smears
Platelet count on citrated samples
Auto-immune or drug-induced thrombocytopenia Viral serologies
HIV test
Associated anemia and/or leuconeutropenia Bone marrow malignant infiltration Bone marrow explorations
Pancytopenia Haemophagocytic lymphohistiocytosis
Abnormal circulating leukocytes Aplastic anemia
Major macrocytosis Vitamin B9/B12 deficiencies Dosage of vitamins B9 and B12
Hypersegmented neutrophils
Mononucleosis syndrome Viral infections, toxoplasmosis, HIV infection Serologies
HIV test
Haemolysis Thrombotic microangiopathy ADAMTS13 activity
TTP, HUS, malignant hypertension, renal sclero- Exploration of complement inhibition pathways
derma crisis Direct antiglobulin test
Evans syndrome
Bone marrow haemophagocytosis Haemophagocytic lymphohistiocytosis Biological components of the H-score
ADAMTS13 a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13, APTT activated partial thromboplastin time, HELLP haemolysis,
liver enzymes, low platelets, HUS haemolytic uremic syndrome, PF4 platelet factor 4, PlGF placental growth factor, sFlt-1 fms-like tyrosine kinase 1, TTP thrombotic
thrombocytopenic purpura
a
A low sFlt-1/PlGF ratio (typically < 38) allows ruling out pre-eclampsia
b
To rule out intracranial haemorrhage
c
Performs with high negative predictive value. Positivity of anti-PF4 antibodies imposes further confirmatory platelet aggregation tests
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Spurious thrombocytopenia Indications for bone marrow explorations

Some technical artefacts may impair the measurement Bone marrow aspirates, obtained by bone puncture of
of platelet counts owing to ex vivo platelet aggregation. sternum or iliac crest, provide unique quantitative and
When detected in an automated haemocytometer, severe qualitative analyses of medullary precursors. A rich bone
thrombocytopenia must be controlled with blood smears marrow with an abundance of megakaryocytes points
to identify platelet aggregates [15]. Spurious thrombocy- towards peripheral mechanisms. Conversely, the absence
topenia is often ascribed to insufficient anticoagulation of megakaryocyte lineage, dystrophic megakaryocytes,
within sampling tubes. An alternative phenomenon of and malignant infiltration suggest hypoproliferative
pseudo-thrombocytopenia is related to ethylenediamine mechanisms. Haemophagocytosis is a common cytologi-
tetraacetic acid (EDTA)-induced aggregation of platelets cal pattern in the bone marrow of critically ill patients
as a consequence of antiplatelet antibodies, which rec- and is often associated with sepsis and transfusions [20].
ognise platelet antigens on the platelet membrane when Features of haemophagocytosis raise the question of
modified by EDTA [16]. Platelet count enumeration the diagnosis of haemophagocytic lymphohistiocytosis,
in citrated samples usually resolves the clumping, but which relies not only on cytopenia but also on alternative
platelet counts may be significantly underestimated by clinical and biological manifestations [21].
10–20% compared to EDTA samples [17]. The diagnostic yield of bone marrow explorations in
the ICU has been assessed through a prospective diag-
Diagnostic workup nostic study of critically ill patients with thrombocy-
Thrombocytopenia in critically ill patients is usually mul- topenia (here defined as platelet count < 100 × ­109/L or
tifactorial. The medical background, including comor- relative decrease by 30%). Bone marrow aspirates were
bidities and ongoing acute conditions, most often allows performed in 208 patients. Megakaryocytes were present
an accurate assessment of the causes and mechanisms of in 93% of bone marrow smears. However, the diagnostic
thrombocytopenia without further extensive investiga- and therapeutic yields of such a systematic approach were
tions (Table 1). In patients with haemorrhagic surgery relatively poor and resulted in new information in 22% of
or trauma, thrombocytopenia relies on consumption cases, with further implications in management in 9%
coagulopathy and dilution resulting from aggressive fluid only [18]. Bone marrow explorations should, therefore,
resuscitation. be restricted to absolute thrombocytopenia associated
In non-surgical patients, thrombocytopenia present at with non-regenerative anaemia and/or leukoneutrope-
the time of ICU admission can result from underlying nia and/or the presence of abnormal circulating cells and,
comorbid conditions, including haematological malig- more generally, when the mechanisms of thrombocyto-
nancies, cytotoxic chemotherapy, auto-immune diseases, penia remain very unclear. In case of inadequate or failed
chronic alcoholism and vitamin deficiencies. As for the aspiration, a bone marrow trephine biopsy taken from
latter, when assessed in a systematic diagnostic work- the hip bone may occasionally be required for the definite
up, the prevalence of folate deficiency was 33% in ICU diagnosis of aplastic anaemia and myelofibrosis and for
patients with absolute or relative thrombocytopenia, the staging of lymphoma.
whereas B12 deficiency was very uncommon [18]. ICU-
acquired or ICU-aggravated thrombocytopenia can gen- Sepsis
erally be ascribed to the ongoing acute process (sepsis, Sepsis is a prominent determinant of ICU-acquired
haemorrhage) and/or treatments and procedures (drug- thrombocytopenia mostly ascribed to endothelial dam-
induced thrombocytopenia, renal replacement therapy, age and sepsis-associated coagulopathy [22]. Alternative
extracorporeal membrane oxygenation). Also, throm- mechanisms have been suggested, including impaired
bocytopenia may indicate the presence of disseminated thrombopoiesis owing to dampened production of
intravascular coagulation (DIC), manifested by systemic thrombopoietin, haemophagocytosis and immune-
activation of coagulation with consumption of coagula- mediated destruction of platelets [14, 23, 24]. In addi-
tion factors and platelets and generation of fibrin, along tion, sepsis has been shown to cause platelet dysfunction,
with variable fibrinolytic activity. The biological and including reduced aggregation capacities [25].
clinical presentations of DIC are rather dependent on
the underlying disease. Sepsis-associated DIC exhibits a Thrombotic microangiopathy
thrombotic phenotype where fibrinolysis is typically sup- Thrombotic microangiopathies encompass various
pressed and likely contributes to organ dysfunctions. DIC diseases where thrombocytopenia results from exten-
associated with haematological malignancies exhibits a sive thrombotic mechanisms within the microcircu-
fibrinolytic phenotype and exposes patients to bleeding lation. Thrombotic microangiopathies include the
complications [19]. classical thrombotic thrombocytopenic purpura (TTP)
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and haemolytic uremic syndrome (HUS), as well as alter- Bleeding risk assessment
native disorders such as malignant hypertension, cata- Different scales for bleeding severity assessment have
strophic antiphospholipid syndrome, scleroderma renal been developed depending on clinical settings. The
crisis and cancer- and transplantation-associated throm- most used assessment tool for grading bleeding severity
botic microangiopathy. Although the syndrome refers to is derived from the World Health Organization (WHO)
histological patterns, the diagnosis of thrombotic micro- scale, which ranges from 1 to 4 [(1) minor bleeding; (2)
angiopathy primarily relies on haematological features mild bleeding; (3) severe bleeding; (4) debilitating bleed-
such as the association of peripheral thrombocytopenia ing] [8]. A sound relationship between platelet count
and schistocytic haemolytic anaemia. Associated organ and bleeding has long been established in non-critically
failures may overlap but typically include neurological ill onco-haematological patients with hypoprolifera-
and cardiac manifestations in TTP and renal dysfunction tive thrombocytopenia [32, 33]. A dramatic increase in
in HUS. TTP and HUS are caused by different patho- the incidence of severe to debilitating bleeding is indeed
physiological mechanisms: through inherited or acquired observed when platelet count drops below 10 × ­109/L.
deficiency in the vWF-cleaving protease ADAMTS13 (a Notably, the risk of bleeding in this setting is also driven
disintegrin and metalloprotease with thrombospondin by additional mechanisms, owing to altered haemostatic
type 1 repeats, member 13) in TTP, endothelial injury functions of platelets as well as damage to endothelial
related to Shigatoxin-producing Enterobacteriaceae in cells or associated coagulopathy [33, 34].
typical post-diarrhoea HUS and unleashed complement Most studies have reported higher rates of bleeding
activation in atypical HUS. Owing to the hazard of fast in critically ill patients with thrombocytopenia. In the
deterioration and sudden death, TTP represents a major PLOT-ICU cohort study, 27.6% of thrombocytopenic
diagnostic and therapeutic challenge for intensivists [26]. patients bled in the ICU, of whom 57.6% had severe or
The peripartum period encompasses various conditions, debilitating bleeding (WHO grade 3 or 4) [8]. In contrast,
often associated, including post-partum haemorrhage, only 7.3% of patients without thrombocytopenia bled in
disseminated intravascular coagulation and HELLP (Hae- the ICU, most of whom (81.2%) had minor or mild bleed-
molysis, Elevated Liver enzymes and Low Platelet count) ing (WHO grade 1 or 2). In a French cohort of patients
syndrome as thrombotic microangiopathy complicating with septic shock, the incidence of ICU-acquired severe-
pre-eclampsia. However, the endothelial injury inherent to-debilitating bleeding was 14.4%, 15.3% and 20.3% in
to pregnancy and peri-partum may also precipitate TTP patients with mild, moderate and severe thrombocyto-
and HUS [27]. penia, respectively, vs. 3.6% in non-thrombocytopenic
patients [12].
It is noteworthy that thrombocytopenia is not consist-
Prognostic value of thrombocytopenia ently retained in multivariate prediction models for ICU-
Most studies consistently show that thrombocytopenia is acquired bleeding [12, 30, 35, 36] and that the common
associated with worse outcomes in a dose–response man- correlation of platelet count with severe haemorrhage, as
ner. Although it has been established that ICU patients observed in non-critically ill patients with onco-haema-
with thrombocytopenia have higher rates of bleeding, the tological malignancies, appears less consistent in criti-
association between thrombocytopenia and higher mor- cally ill patients [8, 18, 35]. These data suggest that the
tality or fewer days alive without the use of life-support risk of bleeding is not solely dependent on platelet count
is also found in non-bleeding patients [7, 28, 29]. This is but may depend on both the mechanism of thrombocy-
especially true in patients with severe thrombocytopenia topenia and alternative mechanisms involved in critical
(<50 × ­109/L), who have significantly higher mortality and illness. Hypoproliferative thrombocytopenia generally
are more likely to experience severe or debilitating bleed- harbours a higher risk of bleeding than peripheral throm-
ing complications compared with patients with no or less bocytopenia, which is characterised by sustained platelet
severe thrombocytopenia [8]. However, the association production and preserved haemostatic functions. In criti-
with mortality does not necessarily represent a causal cally ill patients with haematological malignancies, hence
relationship, and thrombocytopenia should most often with a high frequency of hypoproliferative thrombocyto-
be considered as a marker of severity (e.g. bone marrow penia, the risk of bleeding was approximately three times
failure due to malignancy) rather than the direct cause of higher compared to their non-critically ill counterparts
the increased mortality. Although the increased risk of [37]. Accordingly, the overall and major bleeding rates
bleeding seen in patients with severe thrombocytopenia among 116 critically ill patients with acute leukaemia or
may contribute to mortality, this is also likely to be influ- myelodysplastic syndromes were considerably high, 57%
enced by underlying conditions, such as haematological and 33%, respectively [30]. Several additional factors con-
malignancy or trauma [30, 31]. cur with the increased risk of bleeding in ICU settings,
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Pène et al. Annals of Intensive Care (2025) 15:25 Page 6 of 12

including alternative coagulation disorders, anticoagu- rotational thromboelastometry (ROTEM), available as

lant and antiplatelet agents, co-existing liver disease, and point-of-care assays provide a comprehensive view of
the extent of organ failures (Fig. 1). Interestingly, kidney clot formation and lysis with regard to early platelet
dysfunction, as assessed by chronic or acute renal fail- aggregation, but also to the coagulation/anticoagula-
ure or by the requirement of renal replacement therapy, tion and fibrinogenesis/fibrinolysis balances. The over-
has been consistently linked to ICU-acquired bleeding, all stability of the clot is represented by the ‘maximum
possibly owing to defective platelet aggregation related amplitude’ value in TEG, corresponding to the ‘maxi-
to hyperuremia [35, 36, 38]. Although DIC is primarily mum clot firmness’ in ROTEM, both dependent on
ascribed to underlying hypercoagulable processes, oozing platelets and fibrin. Although the use of viscoelastic
at wounds, around central lines, and catheters are more tests has been found to save time in the management
common clinical manifestations associated with platelet of trauma-associated bleeding [40], their application to
deficiencies and coagulation factors [39]. A recent bleed- other conditions remains controversial. For instance,
ing episode should be considered a warning event asso- most patients with sepsis typically present with a maxi-
ciated with further recurrence or new-onset bleeding mum amplitude within or above the reference range
events [36]. despite many being thrombocytopenic [41]. The ability
Besides standard laboratory haemostasis tests, vis- of TEG to identify patients at high risk of bleeding is
coelastic tests such as thromboelastography (TEG) and very low, both in patients with sepsis and in critically ill
patients with haematological malignancies [42].

Fig. 1 Risk factors of bleeding in thrombocytopenic critically ill patients

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Platelet transfusions haemostatic capacities. In a recent phase 2 multicentre

Platelet transfusion is given to prevent or treat bleed- randomised controlled trial, the early administration of
ing in four main settings: (1) Prevention of bleeding in cold-stored platelets in severely injured patients was safe
patients with severe thrombocytopenia, (2) Prior to inva- and did not result in significantly different 24-h mortal-
sive procedures in thrombocytopenic patients, (3) Treat- ity compared to standard care [46]. Frozen platelets could
ment of WHO grade 2–4 bleeding in thrombocytopenic increase availability, especially in remote areas, as they
patients, and (4) Management of massive bleeding with can be stored for several years. Lyophilised platelets are
haemorrhagic shock regardless of platelet count (Table 2) under development. Here, platelets are treated either
[43]. with paraformaldehyde or trehalose to stabilise the plate-
let membrane, allowing storage at room temperature for
Platelet products several years before being reconstituted with sterile water
There is high variability in platelet processing methods [45]. Such alternative platelet products are only consid-
across countries with differences in the type of additive ered for therapeutic transfusion and are currently only
solution, the pathogen inactivation method, the storage available in very few settings, such as the treatment of
duration (usually between 5 and 7 days), and platelet dose armed services personnel.
and volume of platelet concentrates. Platelets are stored
at room temperature (20–24 °C) under slow and constant Side effects of platelet transfusions
agitation. The short shelf-life of platelet concentrates puts In a post-hoc analysis of a large randomised trial on
them at risk of shortage and waste [44]. Platelet concen- platelet dosing strategies in haematology patients, up
trates can be prepared from a single donor by apheresis to 10% of platelet transfusions were associated with
or be pooled from whole blood from several donors to adverse events, that were mainly fever for 66% of them
amount to an adult therapeutic platelet dose [44]. The [47]. Although room temperature preserves some plate-
efficacy of single-donor apheresis platelets and whole let function and maximises platelet recirculation, it also
blood-derived platelets are similar, and the choice of facilitates bacterial growth and causes morphological and
products mainly depends on their availability unless spe- biochemical changes to the platelets, so-called “storage
cific indications are present, such as documented anti- lesions”. Improvements in platelet manufacturing include
HLA immunisation. systematic pathogen reduction and plasma replacement
Alternative platelet products include cold-stored, fro- by platelet additive solution. In France, the pathogen
zen and lyophilised platelets [45]. Cold-stored plate- inactivation method includes the synthetic psoralene
lets are stored at 1–6 °C for up to 14 days. Although compound amotosalen in combination with ultraviolet
cold-stored platelet concentrates result in lower post- A (UVA) light treatment since November 2017, which
transfusion platelet increments, they exhibit increased resulted in a steep reduction in transfusion-transmitted

Table 2 Suggested platelet transfusion thresholds in critically ill patients

Indications Platelet count threshold (x ­109/L) Clinical setting

Prophylactic platelet transfusion 10 Hypoproliferative and peripheral thrombocytopenia

20 If judged to have additional risk factors for ­bleedinga
50 Therapeutic-dose anticoagulation treatment
Pre-procedural platelet transfusion 10–20 Ultrasound-guided CVC placement (in compressible sites)
40–50 Lumbar puncture, non-neuroaxial surgery
80 Epidural analgesia
100 Neuroaxial surgery
Therapeutic platelet transfusion 30 Mild bleeding
50 Severe to debilitating bleeding
100 Intracranial haemorrhage
No platelet transfusion Thrombotic microangiopathies (TTP+++, HUS, HELLP
syndrome, DIC, HIT, CAPS)b
Immune thrombocytopenic ­purpurab
Reversal of antiplatelet agents in intracranial haemorrhage
The proposed thresholds should be adapted to the individual patient’s condition and the associated risk factors for bleeding. Adapted from (59–61, 69, 70, 75, 78)
CAPS catastrophic antiphospholipid syndrome, CVC central venous catheter, DIC disseminated intravascular coagulation, HELLP haemolysis, liver enzymes, low
platelets, HIT heparin-induced thrombocytopenia, HUS haemolytic uremic syndrome, TTP thrombotic thrombocytopenic purpura
a
Such as fever ≥ 38.5 °C, infection, severe mucositis, lesion at risk of bleeding, fast decrease in platelet count
b
No indication for prophylactic transfusion. Therapeutic transfusion if severe or debilitating bleeding
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blood infections [48]. Importantly, as systematic patho- ongoing infection, high blood pressure, severe mucosi-
gen reduction technology does not prevent the transmis- tis, and a sharp drop in platelet count within the last 72 h
sion of non-enveloped viruses, the risk of hepatitis E and [60].
A virus transmission persists [48]. Plasma replacement Critically ill patients have different risk factors for
contributed to the drop in transfusion-related acute lung thrombocytopenia, and they also have additional risk fac-
injury secondary to platelet transfusion in France [49]. tors for bleeding, likely hampering the generalisation of
Other complications include circulatory overload, aller- platelet transfusion practices in haematology patients to
gic reaction, anti-human leukocyte antigen (HLA) and ICU patients. The clinical practice guidelines from the
anti-human platelet antigen (HPA) allo-immunisation. European Society of Intensive Care Medicine (ESICM)
Platelet concentrates may also harbour immunomodula- suggest not using prophylactic platelet transfusion unless
tory properties, as suggested by the consistent associa- the platelet count falls below 10 × ­109/L in non-bleeding
tion of platelet transfusions with the further development critically ill adults, though based on very low certainty of
of hospital-acquired infections [50–52]. The safety of evidence [61]. Prophylactic platelet transfusion is usually
prophylactic platelet transfusions was challenged in the contra-indicated in patients with thrombotic microangi-
randomised trial PLANET2, which assessed two platelet opathies, especially in TTP, where platelet transfusions
count thresholds (25 × ­109/L vs. 50 × ­109/L) in pre-term have occasionally been associated with thrombotic
neonates [53]. Unexpectedly, a higher risk of bleeding events and dramatic clinical deterioration [62, 63]. This
and a trend towards increased mortality was observed restriction may extend to alternative thrombocytopenic
in the higher threshold arm. Though this may not apply thrombotic disorders [63].
to adult critically ill patients, such paradoxical findings
in neonates suggest that bioreactive components from Post‑transfusion platelet response
platelet concentrates may have promoted inflammation The yield of platelet transfusion is typically assessed at
and tissue injury. the bedside by the absolute increment in platelet count.
However, more accurate measurements exist. The cor-
Indications for prophylactic platelet transfusion rected count increment (CCI = (post-transfusion platelet
In the absence of a completed randomised controlled count − pre-transfusion platelet count) x body surface/
trial comparing different platelet count thresholds for number of platelets within concentrate) and the plate-
prophylactic platelet transfusion in the ICU, the trans- let transfusion recovery (PTR = (post-transfusion
fusion strategy in critically ill patients remains largely platelet count − pre-transfusion platelet count) x body-
derived from the studies performed in stable haematol- weight × 0.075/number of platelets within concentrate)
ogy patients. Two randomised controlled trials assessed adjust for both the administered platelet dose and the
prophylactic (triggered by a platelet count below estimated blood volume [64]. A poor platelet response,
10 × ­109/L) vs. therapeutic-only platelet transfusion strat- as assessed by a CCI < 7 on the day after transfusion, has
egies in patients with haematological malignancies who been observed in 50–75% of transfusion episodes in criti-
received intensive chemotherapy for acute leukaemia or cally ill patients [65, 66]. Factors independently associ-
autologous hematopoietic stem cell transplantation. A ated with poor platelet increment in critically ill patients
decrease in grade 2–4 bleeding was observed in patients included higher patient severity scores, sepsis at admis-
receiving prophylactic platelet transfusion as compared sion, underlying haematological malignancy, storage
to the therapeutic-only arm [54, 55]. Most importantly, duration of platelet concentrates, fever and antibiotic
intracranial haemorrhage was more frequent in the sub- therapy at the time of the transfusion [65, 66]. Refrac-
group of patients with acute leukaemia allocated to the toriness is characterised by a poor transfusion yield
therapeutic-only strategy. This suggests that not only (either CCI < 7 or PTR less than 20%, obtained within
the nadir platelet count but also the duration of throm- 1 h of transfusion completion) following two consecu-
bocytopenia is a determinant of severe bleeding. Platelet tive transfusion episodes with ABO-compatible plate-
count transfusion thresholds of 10 × ­109/L vs. 20 × ­109/L let concentrates featuring short storage time (less than
have been assessed in patients with haematological 3 days). Refractoriness to platelet transfusion, more
malignancies, where the restrictive arms demonstrated broadly assessed by the closest post-transfusion platelet
significant decreases in platelet transfusions without count, has been found to occur in 23.3–54.8% of criti-
increasing the risk of bleeding [56–59]. Most guidelines cally ill patients and has been associated with increased
currently recommend platelet count transfusion thresh- risk of bleeding [65, 67]. Both immune and non-immune
olds of 10–20 × ­109/L, taking into account the presence factors may result in transfusion refractoriness. Immune
of factors known to shorten the platelet lifespan or to mechanisms are documented in 20% of refractoriness in
increase the risk of bleeding, including fever > 38.5 °C, patients with iterative platelet transfusions and include
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allo-immunisation to human leukocyte antigen (HLA) early administration of platelet transfusion might be ben-
or human platelet antigen (HPA), ABO incompatibility, eficial. In the PROPPR trial that compared 1:1:1 vs. 1:1:2
anti-platelet autoantibodies and drug-related antibodies. ratios of platelet: plasma: red blood cells, death due to
Non-immune reasons rely on shortened platelet lifespan, exsanguination was less frequent in patients randomised
including spleen enlargement, pregnancy, disseminated in the 1:1:1 ratio group (i.e. receiving higher amounts of
intravascular coagulation, graft-versus-host disease, and platelets and plasma), yet without difference in 24-h mor-
sinusoidal obstruction syndrome [64, 65, 67, 68]. The tality [72]. Accordingly, a secondary analysis of this trial
transfusion strategy in patients with immune-mediated found that early platelet transfusion was associated with
refractoriness relies on HLA- or HPA-matched, or cross- reduced 24-h and 30-day mortality rates (5.8% vs. 16.9%;
match-compatible platelet concentrates [68]. A therapeu- p = 0.05, and 9.5% vs. 20.2%; p = 0.05, respectively) [73].
tic-only transfusion strategy, i.e. to administer platelet In this study, early platelet transfusion also led to better
transfusion only in case of overt significant bleeding of achievement of haemostasis (94.9% vs. 73.4%; p = 0.01)
grade 2 or higher, may also be considered in this setting. and was less often associated with death due to exsan-
guination (1.5% vs. 12.9%; p < 0.01) [73]. Hamada et al.
Indications for pre‑procedural platelet transfusion reported in a retrospective multicentre observational
The platelet count transfusion threshold to secure inva- study that included 19,596 trauma patients a significant
sive procedures remains based on a low level of evi- decrease in 24-h all-cause mortality in patients receiv-
dence. The ESICM guidelines recommend no transfusion ing early (<6 h) platelet transfusion (OR 0.52, 95% CI
before invasive procedure when the platelet count is 0.34–0.79; p < 0.05) as compared to patients with no
above 100 × ­109/L and before central venous catheter or late platelet transfusion [31]. The management of
(CVC) insertion and percutaneous tracheotomy when non-trauma critically ill patients with severe bleeding
the platelet count is between 50 × ­109/L and 100 × ­109/L is derived mainly from the transfusion strategy set in
[61]. The French guidelines advocate a minimal platelet trauma patients.
count of 50 × ­109/L for lumbar puncture, liver biopsy, In addition, platelet transfusions have been previously
bronchoscopy, osteomedullary biopsy, and a platelet considered to offset the effect of antiplatelet agents in
count increased to at least 80 × ­109/L for epidural anal- treating severe bleeding. In a trial where adults suffer-
gesia insertion or ablation [60]. However, the supporting ing from intracranial haemorrhage with a Glasgow Coma
evidence was of low certainty and based on observa- Scale score between 8 and 15 and under antiplatelet
tional studies and small randomised trials at high risk agents were randomised to receive one platelet transfu-
of biases. A recent trial randomised thrombocytopenic sion or none, transfused patients unexpectedly exhibited
patients with platelet counts between 10 and 50 × ­109/L, worse outcomes of death or dependence at 3 months
hospitalised either in the ICU or in the haematology [74], strongly arguing against this strategy [75].
ward, to receive one platelet transfusion vs. none prior to
ultrasound-guided placing of a CVC [69]. Patients ran- Thrombopoiesis‑stimulating agents
domised to the no-transfusion group had more catheter- Regardless of underlying aetiologies, thrombocytope-
related bleeding than those who received a prophylactic nia is often associated with inadequate thrombopoietic
platelet transfusion (OR 2.45, 90% CI 1.27–4.70). How- response. Folic acid supplementation is indicated for
ever, this difference was not found in the subgroup of treating absolute folate deficiency and can be consid-
only ICU patients. Therefore, these results suggest that ered to prevent any relative deficiency resulting from
ultrasound-guided insertion of CVC in compressible enhanced hematopoietic response towards sustained
sites can be performed safely in the ICU without pre-pro- haemolysis and platelet consumption. Thrombopoiesis-
cedural platelet transfusion. stimulating agents stimulate megakaryocyte differen-
tiation and proliferation to promote platelet production.
Indications for therapeutic platelet transfusion Thrombopoiesis-stimulating agents have emerged as
High-quality evidence to guide clinical practice regard- promising treatments for various causes of thrombo-
ing therapeutic platelet transfusion for active bleeding cytopenia, including myelodysplastic syndromes, cyto-
is lacking. The British Society of Haematology specifies toxic chemotherapy, immune thrombocytopenia and
a platelet count threshold of 30 × ­109/L in case of minor cirrhosis. Experience in critically ill patients is limited,
bleeding [70]. The guidelines for the management of although a meta-analysis provided encouraging results in
major bleeding and coagulopathy following trauma rec- sepsis patients where recombinant human thrombopoi-
ommend maintaining a platelet count above 50 × ­109/L etin increased platelet count after 7 days and decreased
and above 100 × ­109/L in case of major bleeding and/or the need for platelet transfusion [76]. Nonetheless,
brain injury [71]. In case of massive bleeding in trauma, the potential for thrombosis is of concern, and the use
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Pène et al. Annals of Intensive Care (2025) 15:25 Page 10 of 12

of thrombopoiesis-stimulating agents in critically ill 3. de Stoppelaar SF, van’t Veer C, Claushuis TAM, Albersen BJA, Roelofs JJTH,
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