Intensive Care Med
https://doi.org/10.1007/s00134-024-07478-5
UNDERSTANDING THE DISEASE
Ten tips on sepsis‑induced
thrombocytopenia
Marc Leone1* , Nathan D. Nielsen2,3 and Lene Russell4,5
© 2024 Springer-Verlag GmbH Germany, part of Springer Nature
Thrombocytopenia is a commonly observed phenome- develops in ~ 30% of thrombocytopenic septic patients
non in sepsis and a frequent cause of anxiety for the clini- [5].
cian at the bedside, raising a host of questions, including Thrombocytopenia in sepsis is associated with worse
the concerns about a low platelet count, the interaction outcomes [3] and, if early (< 24 h) or sustained, has
between sepsis and platelets, the other causes of throm- prognostic utility [3, 4, 6]. However, it remains unclear
bocytopenia, or the indications of platelet transfusion. whether thrombocytopenia in sepsis is an indicator (an
Though much of the effect of sepsis on platelet physiol- affected “innocent bystander”) or cause (an “active par-
ogy and function is yet unknown, in this article we have ticipant” in organ injury) of sepsis severity [7]. The risk of
undertaken to address many of these common questions. coagulation-related complications increases at < 100,000/
µL, and fear of bleeding complications may prevent clini-
How do we measure platelets? cians from performing needed procedures or surgery.
A platelet count is the number of platelets per volume,
typically analysed by automated instruments. In cases Immune mechanisms connect sepsis
of abnormal counts, counts are repeated manually. to thrombocytopenia
Reported platelet counts are strictly quantitative and Platelets are key players in haemostasis but also have cru-
qualitative platelet dysfunction can occur in patients cial roles in inflammation. Immune-mediated platelet
with low, normal or elevated platelet counts [1]. Platelet activation is an integral infection response, as platelets
function can be affected by drugs, intrinsic platelet dys- interact with immune and complement systems, releas-
function, or renal or liver disease, and unfriendly envi- ing agents that promote neutrophil activation and leuko-
ronments. Specialised assays to measure platelet function cyte recruitment, express pattern recognition receptors,
exist and viscoelastic testing can provide some qualitative and stimulate neutrophil extracellular trap formation [8].
insights but their clinical relevance is controversial. Severe thrombocytopenia is associated with dysregu-
lated host immunity in septic patients with altered gene
Thrombocytopenia is common in sepsis and is expression, including reduced leukocyte adhesion and
associated with outcomes increased complement signalling [7].
Thrombocytopenia (a platelet count < 150,000/μL) is
common in intensive care unit (ICU) patients [2] and Vascular integrity—a link between
seen in > 55% of sepsis cases and at higher rates in septic thrombocytopenia and organ injury
shock [3, 4]. Severe thrombocytopenia (≤ 50,000/μL) [2] Platelets safeguard vascular integrity by optimising the
barrier function of microvessels and reducing extrava-
sation of both water and plasma proteins, especially in
inflammatory states. Platelets directly block gaps in the
*Correspondence:
[email protected]1
Department of Anaesthesiology and Intensive Care Unit, North Hospital, vascular lining, thereby maintaining endothelial struc-
Assistance Publique Hôpitaux, Service d’Anesthésie Et de Réanimation, ture, and release soluble factors that enhance endothe-
Hôpital Nord, Chemin Des Bourrely, Universitaires de Marseille, Aix lial barrier function. The loss of endothelium-supporting
Marseille University, 13015 Marseille, France
Full author information is available at the end of the article functions contributes to organ oedema and tissue haem-
orrhage in sepsis-induced thrombocytopenia [9].
Differential diagnoses—sepsis‑induced vs. other caused by ethylenediamine tetraacetic acid (EDTA) that
causes? can be resolved by the use of citrated sample tubes),
Sepsis-induced thrombocytopenia is a multifactorial extracorporeal devices, and underlying hepatosplenic
phenomenon, as platelets are irreversibly expended in disease, malignancy or myeloproliferative disorders [10].
the immune response. Other aetiologies include entities A review of the peripheral blood film (“smear”) can be
such as disseminated intravascular coagulation (DIC) useful in establishing the aetiology of thrombocytopenia,
and sepsis-associated reactive hemophagocytosis [6]. as can bone marrow aspiration in selected circumstances.
However, while sepsis is a more common cause of throm-
bocytopenia, potentially lethal prothrombotic conditions Antimicrobials can cause thrombocytopenia
should always be ruled out. These conditions include Drug-induced thrombocytopenia, including that caused
heparin-induced thrombocytopenia (HIT), immune- by antimicrobials (e.g.: vancomycin, antifungals, lin-
mediated thrombotic thrombocytopenic purpura (iTTP) ezolid, beta-lactams, ciprofloxacin [11]) is responsible
and haemolytic uremic syndrome (HUS) (Fig. 1). Addi- for 10–20% of ICU thrombocytopenia cases, and should
tional causes include drug-induced thrombocytope- be considered in severe thrombocytopenia (< 20,000/μL)
nia, immune thrombocytopenia (ITP), haemodilution, complicated by bleeding, occurring 5–10 days after drug
pseudo-thrombocytopenia (an in vitro phenomenon exposure. Stopping the drug (if feasible) is recommended,
THROMBOCYTOPENIA
IN SEPSIS
(Platelet < 150 x 109/L)
Treat the underlying
condion.Administer
Exclude life-threatening
thrombosis-prophylaxis
Exclude possible pro-thrombotic conditions
unless severe
thrombocytopenia Pseudo-thrombocytopenia
DIC Severe thrombocytopenia
INR / PT ↑ & Fibrinogen ↓ +
Extracorporeal circuits? Exposure to heparin? →
Drug-induced? HIT?
Other? Haemolysis, purpura, bleeding,
↑ Ferrin, ↑ tri-glycerides schistocytes
→ HLH? on blood smear and normal
Avoid platelet
transfusions unless the
patient is bleeding
or platelet count If likely, or in doubt,
< 10-20 x 109/L seek expert advice
Fig. 1 How to manage thrombocytopenia in my patient with sepsis? DIC, disseminated intravascular coagulation; HIT, heparin-induced thrombo-
cytopenia; HLH, hemophagocytic lymphohistiocytosis; HUS, hemolytic uremic syndrome; INR, international normalised ratio; PT, prothrombin time;
TTP, thrombotic thrombocytopenic purpura
and, in cases of severe bleeding, administering platelets, mortality rates in sepsis patients receiving platelet trans-
intravenous immunoglobulin (IVIG) ± corticosteroids fusions is reported, though causality is unclear [15].
[12]. Conversely, a trial of prophylactic platelet transfusion
for central venous catheter (CVC) placement found dif-
Sepsis‑associated coagulation activation and DIC ferences in catheter-related bleeding, suggesting some
are not the same benefit to transfusion [16]. Current guidelines suggest
In sepsis, immune and coagulation systems are activated transfusion to achieve platelet counts > 20,000/µL prior
[7]. The coagulation response in sepsis is a continuum, to CVC placement and other low-risk procedures, and
and DIC represents one extreme, where the coagula- counts > 50,000/µL prior to lumbar puncture and higher-
tion response is overwhelming and injurious. Despite risk procedures.
wide-spread coagulation, bleeding, typically oozing from
injection sites and wounds, is often seen in DIC. There Take‑home message
is no specific treatment for DIC beyond effectively treat- Thrombocytopenia in sepsis is common, but many
ing the precipitating cause, monitoring coagulation sta- uncertainties remain. Associations between thrombocy-
tus, administering thromboprophylaxis (at a minimum) topenia and bleeding, transfusion, and mortality follow a
when possible and managing bleeding or thrombotic “dose–response” pattern with worse outcomes accompa-
complications. nying more severe thrombocytopenia, but causality is not
Thrombocytopenia in sepsis does not necessarily equal established.
DIC. If in doubt, the International Society on Thrombo- Advances are required to better understand, and
sis and Haemostasis (ISTH) DIC score may be helpful provide optimal support for, septic patients with
(Fig. 1). thrombocytopenia.
Risk of bleeding depends on more than just Author details
1
platelet count Department of Anaesthesiology and Intensive Care Unit, North Hospital,
Assistance Publique Hôpitaux, Service d’Anesthésie Et de Réanimation, Hôpital
Several studies have found higher rates of bleeding, often Nord, Chemin Des Bourrely, Universitaires de Marseille, Aix Marseille University,
severe, in patients with thrombocytopenia [3, 4]. While 13015 Marseille, France. 2 Division of Pulmonary, Critical Care and Sleep
severe thrombocytopenia is associated with bleeding, Medicine, Department of Internal Medicine, University of New Mexico School
of Medicine, Albuquerque, NM, USA. 3 Section of Transfusion Medicine
the correlation with platelet nadir is not always linear, and Therapeutic Pathology, Department of Pathology, University of New
suggesting that bleeding risk is not solely dependent on Mexico School of Medicine, Albuquerque, NM, USA. 4 Department of Intensive
platelet count but rather due to alternative mechanisms Care, Copenhagen University Hospital Gentofte, Hellerup, Denmark. 5 Depart-
ment of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
such as endothelial dysfunction [4], e.g.: septic haema-
tological ICU patients reported a higher incidence and Declarations
severity of bleeding than non-ICU haematology patients
Conflicts of interest
with similar thrombocytopenia [13]. ML served as speaker for Shionogi and consultant for AOP Pharma and Viatris.
NDN serves on advisory boards for Inotrem and Adrenomed. LR has no con-
flict of interest to disclose.
Thrombocytopenia does not exclude thrombosis
Sepsis is a risk factor for thrombosis even in thrombocy- Publisher’s Note
topenic patients—in one study, 4.5% of patients without Springer Nature remains neutral with regard to jurisdictional claims in pub-
thrombocytopenia developed new thrombi versus 7.5% lished maps and institutional affiliations.
of patients with thrombocytopenia [3]. Another study Received: 14 February 2024 Accepted: 3 May 2024
of haematological malignancy patients found that while
thrombocytopenia ≤ 50,000/µL was generally associated
with lower thrombosis incidence, the risk was increased
in ICU patients [14]. It remains uncertain whether References
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