Trends in Anaesthesia and Critical Care xxx (2011) 1e4

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Trends in Anaesthesia and Critical Care

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REVIEW

Thrombocytopenia in critically ill patients: A review of the literature

Anis Chaari*, Fatma Medhioub, Mohamed Samet, Kamilia Chtara, Rania Allala, Hssan Dammak,
Hatem Kallel, Mabrouk Bahloul, Mounir Bouaziz
Department of Intensive Care, Habib Bourguiba University, Service de Réanimation médicale, Hôpital Habib Bourguiba, Route el Ain Km 1, 3029 Sfax, Tunisia

s u m m a r y
Keywords: Thrombocytopenia is a common hematologic problem encountered in critically ill patients. Several
Thrombocytopenia conditions are particularly associated with this disorder (DIC, trauma, sepsis.). Its onset usually arise
Critical care
debates concerning its exact cause, evaluation of risk of bleeding, transfusion requirement and prog-
Epidemiology
Prognosis
nostic impact. Epidemiologic and prognostic data available in the literature about thrombocytopenia in
critically ill patients are different according to studied population and thresholds adopted to define this
hematologic disorder.
The aim of this review is to describe the epidemiology of thrombocytopenia in critically ill patients, to
report the main causes of thrombocytopenia in ICU and to establish its prognostic impact.
Ó 2011 Elsevier Ltd. All rights reserved.

1. Introduction
Thrombocytopenia is a common hematologic problem
encountered in critically ill patients.1,2 In these patients, several
conditions such as acute bleeding, sepsis, acute respiratory distress
syndrome (ARDS), Drug induced thrombocytopenia disseminated
intravascular coagulation (DIC). are particularly associated with
thrombocytopenia.3e5 However, making the etiologic diagnosis of
this disorder can be difficult as this particular group of patients can
amass numerous potential causes of thrombocytopenia. Moreover,
its onset can arise several questions: Should we prescribe platelets
transfusion? Should we stop some medications? Is there an
important risk of bleeding? . Studies conducted in intensive care
units gave different epidemiologic and prognostic results.1e5 These
differences can be explained by the heterogeneity of studied pop-
ulations (medical, surgical or trauma) and by the different thresh-
olds adopted to define thrombocytopenia even though most
studies adopted 150
109/ml to define this disorder.1e5
The aim of this review is to describe the epidemiology of
thrombocytopenia in critically ill patients, to report the main causes
of thrombocytopenia in ICU and to establish its prognostic impact.
2. Epidemiology of thrombocytopenia in ICU
Epidemiologic data are widely variable according to adopted
thresholds to define thrombocytopenia and according to studied
population. The prevalence of thrombocytopenia on admission to
the ICU ranges from 8.3 to 67.6% whereas 13e44.1% of critically ill
patients experience a thrombocytopenia during their ICU stays.5 In
medical patients, the incidence of a platelets count under
150
109/L ranges from 35 to 44% whereas 20e25% of patients
experience a platelets count under 100
109/L.2,4,6,7 In surgical and
trauma patients, the incidence is higher with 35e41% of patients
having less than 100
109/L.4,8,9
3. Pathophysiology of thrombocytopenia
3.1. Platelets function
Platelets are important factors orchestrating primary hemostasis.
In normal conditions,1012 platelets continuously flow along 1000 m2
of vascular bed in the human body.10 When the integrity of the vessel
wall is disrupted, platelets interact with subendothelial collagen via
“the circulating Von Willebrand factor” and their glycoprotein Ib
receptors in order to stop acute bleeding. Secondly, activated
platelets aggregation is assured by glycoprotein IIbIIIa using circu-
lating fibrinogen as ligand.4,10 Moreover, activated platelets release
various proteins from their storage granules (serotonin, adenosine
diphosphate, coagulation factors, heparin binding proteins.) as
well as eicosanoids (prostaglandins and thromboxane A2) from
series of enzymatic reactions involving cyclooxygenase enzyme.4,10
Finally, phospholipid membrane of activated platelets provide an
excellent surface for thrombin generation and fibrin formation.11
3.2. Mechanisms of thrombocytopenia

* Corresponding author. Tel.: þ216 26349334; fax: þ216 74243427. In critically ill patients, thrombocytopenia is often multifactorial
E-mail address: anischaari2004@yahoo.fr (A. Chaari). involving four different mechanisms: decrease of platelets

2210-8440/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tacc.2011.05.003

Please cite this article in press as: Chaari A, et al., Thrombocytopenia in critically ill patients: A review of the literature, Trends in Anaesthesia
and Critical Care (2011),
Descargado doi:10.1016/j.tacc.2011.05.003
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2 A. Chaari et al. / Trends in Anaesthesia and Critical Care xxx (2011) 1e4
production, increase of platelets consumption, dilution or spurious
thrombocytopenia.3
Platelets production depends on megakaripoiesis in the bone
marrow and is mainly regulated by thrombopoïetin produced by
the liver.3,11 In ICU, impaired platelets production is usually caused
either by toxic effect of medications or active phagocytosis of
megakaryocytes and other hematopoietic cells by monocytes and
macrophages particularly in septic patients.12 On the other hand,
excess of platelets consumption or destruction is frequent in criti-
cally ill patients, mainly because of disseminated intravascular
coagulation.3,4,10 Spurious thrombocytopenia is due to platelets
clumping in vitro because of insufficient anticoagulation of the
blood sample or EDTA dependant agglutinins.3
4. Causes of thrombocytopenia in critically ill patients
4.1. Trauma
Trauma remains the first cause of mortality among young
people aged less than 45 years in developed countries.13 Victims
usually suffered injuries of the vascular wall, particularly endo-
thelial cells and subendothelium. Endothelial cells continuously
produce nitric oxide (NO) in order to prevent platelet activation and
tissue Plasminogène Activator (t-PA) in order to break down fibrin.
These cells express heparin sulfates acting as cofactors for anti-
thrombin III and thrombomodulin which interact with thrombin in
order to activate “C” protein.14,15 On the other hand, subdenthelial
matrix exposure to plasma and blood cells induces platelets
adhesion, activation and aggregation.3,4,14,15 If the bleeding is not
promptly stopped, disseminated intravascular coagulation (DIC)
took place and induces a vicious circle worsening bleeding and
platelets/clot factors consumption. Hence, two principle causes can
explain thrombocytopenia onset in trauma patients: DIC and
dilutional effect of resucitation fluid and blood products trans-
fusion.3,14,15 Moreover, platelet activation and function are deeply
influenced by trauma: In a prospective study, Jacoby et al16 studied
platelet activation and function in 100 trauma patients: Platelet
function was assessed by the PFA-100 analyser whereas platelet
activation was assessed by 3 parameters using flow cytometry:
Platelet microparticles, expression of P-selectin (CD62P) and
expression of glycoprotein GPIIbIIIa. Analyses were performed at
H0, H24, H48 and H72 after trauma. Platelet function was increased
till H24 and then normalized till H72 whereas activation markers
were enhanced till H72. When survivors and dead were compared,
decrease of platelet function was significantly correlated to poor
outcome.
Besides acute bleeding, other circumstances can be at the origin
of DIC: Isolated head trauma can be associated with deep throm-
bocytopenia and excessive clot factor consumption. In fact, brain
injuries release thromboplastin into the circulation. This phenom-
enon induces the activation of extrinsic activation pathway leading
to a consumptive coagulopathy.14 Similarly, bone fracture with
marrow fat embolization cans have the same consequences.14
4.2. Sepsis and septic shock
Sepsis is a clear risk factor for thrombocytopenia in critically ill
patients and the severity of sepsis correlates with the decrease of
platelet count.4,10 In septic patients, thrombocytopenia can be
induced by impaired platelet production, increased consumption or
destruction, or sequestration of platelets in the spleen.4,10 Impaired
platelet production by the bone marrow despite high circulation
levels of thrombopoïétine and pro-inflammatory cytokines (Tumor
Necrosis Factor a, Interleukin-6) can be explained by hemophago-
cytosis consisting of active phagocytosis of megakaryocytes and
Please cite this article in press as: Chaari A, et al., Thrombocytopenia in critically ill patients: A review of the literature, Trends in Anaesthesia
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other hemopoietic cells by monocytes abd macrophages.4,10 This
phenomenon is dependent of high levels of Macrophage Colony
Stimulating Factor in sepsis.12 In 2004, the “Histiocyte Society”
established precise criteria for the diagnosis of hemophagocytic
lymphohistiocytosis (HLH)17 and bicytopenia was considered
among these criteria. HLH is a life threatening disorder in which
deregulation of natural killer cells and cytotoxic T cells can lead to
multiple organ failure.18 Its incidence in septic patients ranges from
0.8 to 4%.18,19 Few studies aimed to evaluate the prognostic impact
of this syndrome in critically ill patients: In a retrospective study
conducted in an ICU unit, Buyse et al20 included 56 patients who
suffered HLH during their ICU stay. Septic causes were incriminated
in 13 patients (23.2%) and thrombocytopenia was identified as an
independent factor predicting poor outcome (OR ¼ 4.75; CI
[1.20e18.81]).
Septic induced DIC is an important cause of thrombocytopenia
in critically ill patients.3,4 In fact, sepsis is associated to a massive
release of pro-inflammatory cytokines activating coagulation
cascade.21 Hence, DIC onset can be explained by several factors:
- Exposure of vascular subendothelium secondary to endothelial
injury due to an immune reaction against invasive path-
ogen.22,23 This phenomenon is amplified by the expression of
a tissue factor by the endothelial cells and monocytes.22
- Depletion of Tissue Factor Pathway Inhibitor (TFPI): This factor
is produced by endothelial cells in order to inhibit coagulation
induced by tissue factor.22,24
- Thrombomodulin and protein C dysfunction: In septic shock,
activated protein C is deeply decreased and facilitates regional
hypoperfusion. For these reasons, activated protein C was
proposed as a therapeutic option for severe septic shock
(APACHE (II)  25 or organ failure count  2).25
- Depression of plasminogen pathway but this phenomenon was
not exploited for the establishment of another therapeutic
option.22
4.3. Drug-induced thrombocytopenia
The incidence of drug-induced thrombocytopenia is not well
known in critically ill patient because of the multiplicity of drugs
prescribed for these patients and the difficulty to establish the
direct link between this disorder and one treatment or another.3,4
Thrombocytopenia may be caused by drug-induced myelosup-
pression or by immune mediated mechanisms.4 The diagnosis is
often based upon the timing of initiation of the suspected
medication.4 Heparin induced thrombocytopenia (HIT) is
a particular model as bleeding events are exceptional whereas
thrombotic events are particularly frequent.26 Early HIT takes
place within the first 5 days following heparin introduction and is
usually mild. However, late (HIT) is a life threatening condition
related to an immune mechanism.27 This complication involves
IgG (IgG1 or IgG3) immunoglobulin; heparin and “platelet factor
4” (PF4) and can induce thrombotic sequelae in 30e80% of
patients.3,27 Its onset is less frequent with Low Molecular Weight
Heparin.28
Biologic diagnosis of (HIT) is usually difficult and includes the
serotonin release assay, the heparin induced platelet aggregation
assay and the Enzyme-Linked ImmunoSorbent Assay (ELISA).3
When the diagnosis of late HIT is considered, heparin administra-
tion should be stopped and three therapeutic options can be
proposed: lepirudin (direct thrombin inhibitor), argatroban and
danaparoid (heparanoid).3,4,29 Warfarin anticoagulation should not
be introduced before platelet count rise as it can initially exacerbate
prothrombotic state via a protein C deficiency.3,29
 A. Chaari et al. / Trends in Anaesthesia and Critical Care xxx (2011) 1e4
4.4. Thrombotic microangiopathy
Thrombotic microangiopathy (TM) is a syndrome involving
thrombotic thrombocytopenic purpura (TTP), Hemolytic-Uremic
Syndrome (HUS), malignant hypertension, HELLP syndrome and
chemotherapy induced microangiopathy.4,30 This micro vascular
occlusive disorder is characterized by a systemic or renal platelets
aggregation, thrombocytopenia and mechanical hemolysis.30
Despite these commune characteristics, each disease has its
proper pathophysiology. In fact, TTP is due to a decreased plasmatic
level of a von Willebrand cleaving metalloprotease (ADAMTS-13)
till to 0e5% of normal rates.30,31 As a result, endothelial cells
express large multimers of von Willebrand factors and enhance
platelets aggregation with no fibrinogen or fibrin.30,32 Clinical
manifestations are dominated by neurologic impairment.3,30 HUS is
often due to endothelial cells injuries induced by a toxin liberated
by a particular serotype of E. coli O157:H7.30,32 This association
explains the fact that HUS is usually preceded by a gastroenteritis
episode and occurs as a single episode.30,33 Clinical manifestations
are dominated by renal impairment.3,30e32 Although these two
disorders are linked to different pathophysiologic mechanisms,
they are both managed similarly.3 Plasma exchange is an effective
therapy yielding superior remission and survival rates compared to
plasma infusion alone.34
5. Bleeding complications
Bleeding events associated to thrombocytopenia are life
threatening complications and hemorrhagic diathesis may put ICU
patients at additional risk of bleeding.2 On the other hand, in
surgical and trauma ICU, bleeding and transfusions contribute
significantly to the development of thrombocytopenia.8,9 In
medical ICU patients, bleeding events occur usually after throm-
bocytopenia onset, thus, they constitute a potential complication
rather than cause of thrombocytopenia.2 Moreover, the risk of
bleeding increases with thrombocytopenia severity. In fact,
patients with platelet count <50
109/ml had 4e5 folds higher risk
of hemorrhage compared to other critically ill patients.2,6,7 In
a prospective observational study, Strauss et al2 reported in
a medical ICU that thrombocytopenic patients had higher incidence
of bleeding events (33% Vs 9%; p < 0.001). In multivariate analysis,
only nadir platelet count remained significantly associated with
higher risk of hemorrhage (OR ¼ 4.1; p [ 0.004). The prognosis
impact of this complication depends on two parameters: The
hemodynamic impact (shock) and bleeding site. The incidence of
intracranial bleeding is limited, ranging from 0.3 to 0.5%. However,
88% of patients presenting intracranial bleeding suffer thrombo-
cytopenia with a platelet count less than 100
109/ml.35
6. Platelets count kinetic in critically ill patients
In critically ill patients, an acute and transient decrease of
platelet count can be seen within the first days of ICU stay.36e38
Different mechanisms can explain this initial thrombocytopenia:
Impairment of platelet production due to a depression of the bone
marrow (infection, toxic substances), increase platelets destruction
(such as hemophagocytosis), excessive platelets consumption (DIC,
sepsis, trauma.) and hemodilution (transfusion or fluid loading).
This biphasic evolution of platelet count has been previously re-
ported. Akca et al36 reported in a prospective multicenter observa-
tional study conducted in 16 ICU and including 257 patients who
stayed in the ICU for more than 2 weeks, that platelet count reach its
nadir within the first 4 days of ICU stay. Secondly, they reported that
platelet count increased till normalization within the first week of
ICU stay. Patients with favorable outcome significantly increase
Please cite this article in press as: Chaari A, et al., Thrombocytopenia in critically ill patients: A review of the literature, Trends in Anaesthesia
and Critical Care (2011),
Descargado doi:10.1016/j.tacc.2011.05.003
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3
their platelets within the 9th day of ICU whereas patients with poor
outcome remained with the same level of platelets. Nijsten et al38
reported that a blunted rise in platelet count in critically ill
patients was associated with worse outcome. In fact, there was no
difference between survivors and non survivors in admission
platelet count. However, non survivors had a significantly lower rise
in platelet count between days 2 and 10 than survivors. Hence,
a particular attention should be given to platelet count kinetic as it
can have a prognostic value in critically ill patients.
7. Platelet transfusions
Platelet transfusion is usually debated in thrombocytopenic
critically ill patients. In fact, this group of patient is at high risk of
bleeding and need frequently invasive interventions (surgery,
catheters.). On the other hand, transfusions carry multiple risks
(infectious or immune complications). For these reasons, each
transfusion decision should take into account several factor: Eval-
uation of risk of bleeding, depth of thrombocytopenia, cause of
thrombocytopenia and comorbidities. A threshold of 5 to 10
109/
ml can be used in patients with no bleeding risk whereas a threshold
of 15e20
109/ml is recommended in patients with concomitant
fever of infection.3 In patients having acute bleeding or needing
invasive procedures, a threshold of 50
109/ml should be adopted.3
In injured patients, early transfusion can help to prevent the
coagulopathy of trauma and a minimal platelet count of 100
109/
ml should be kept.13 Besides platelets, plasma and red blood cells
transfusion, particular efforts should be made in order to stop
bleeding and to keep the patient warm and well resuscitated.14
Finally, there is an increasing evidence for the use of systemic
fibrinolysis inhibitor and procoagulant molecule such as recombi-
nant factor VIIa.14
8. Prognosis value of thrombocytopenia
Several studies tried to establish the prognostic value of throm-
bocytopenia in critically ill patients and conclusions were different
according to studied populations and adopted thresholds defini-
tion.2,6 Clinical severity at admission, assessed ether by SOFA score
or APACHE II score was reported to be an independent predictive
factor of acquired thrombocytopenia.2,8 As a result, thrombocyto-
penia could be considered as a marker of clinical severity rather than
a direct cause responsible of higher mortality.7 In a prospective
cohort including 261 patients admitted in a medical-surgical ICU,
Crowther et al39 reported that patients who experienced thrombo-
cytopenia <150
109/ml (46%) had higher ICU mortality (39% Vs
23.6%; p ¼ 0.03), required longer mechanical ventilation and were
more likely to receive platelet, fresh frozen plasma or red blood cell
transfusions. Vanderschueren et al6 also reported higher ICU and
hospital mortality in thrombocytopenic critically ill patients with
poorer outcome for patients who had presented during their ICU
stay a drop of platelet count to < 50% of admission.
Moreover, the leading cause for thrombocytopenia may have
a prognosis value in critically ill patients. Strauss all2 reported that
septic shock was an independent risk factor correlated with higher
ICU mortality (OR ¼ 3.65; CI95% [1.40e9.52]). In fact, the patho-
physiology of septic shock is characterized by the development of
a procoagulant state induced by inflammatory cytokines which
activate coagulation cascade and inhibit fibrinolysis.40,41 As a result,
DIC is considered as the most feared complication of sepsis,
resulting of dysregulation of coagulation.20 This fear is due to the
risk of multi-organ failure induced by local circulations hypo-
perfusion which can considerably worsen patient’s prognosis.40e42
4 A. Chaari et al. / Trends in Anaesthesia and Critical Care xxx (2011) 1e4
9. Conclusion
Thrombocytopenia is a common hematologic problem
encountered in critically ill patients. Several conditions are partic-
ularly associated with this disorder (DIC, trauma, sepsis.). Prog-
nosis depends on the leading cause of thrombocytopenia, bleeding
events and platelet count kinetic. Transfusion decision should take
into account the evaluation bleeding risk, depth of thrombocyto-
penia, cause of thrombocytopenia and comorbidities.
Conflict of interest
None.
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