review
How do we approach thrombocytopenia in critically ill
patients?
Jecko Thachil1 and Theodore E. Warkentin2
1
Department of Haematology, Manchester Royal Infirmary, Manchester, UK and 2Department of Pathology and Molecular Medicine,
McMaster University, Hamilton Regional Laboratory Medicine Program, Hamilton General Hospital, Hamilton Health Sciences,
Hamilton, Ontario, Canada
Summary
A low platelet count is a frequently encountered haematolog-
ical abnormality in patients treated in intensive treatment
units (ITUs). Although severe thrombocytopenia (platelet
count <20 9 109/l) can be associated with bleeding, even
moderate-degree thrombocytopenia is associated with organ
failure and adverse prognosis. The aetiology for thrombocy-
topenia in ITU is often multifactorial and correcting one
aetiology may not normalise the low platelet count. The clas-
sical view for thrombocytopenia in this setting is consump-
tion associated with thrombin-mediated platelet activation,
but other concepts, including platelet adhesion to endothelial
cells and leucocytes, platelet aggregation by increased von
Willebrand factor release, red cell damage and histone
release, and platelet destruction by the complement system,
have recently been described. The management of severe
thrombocytopenia is platelet transfusion in the presence of
active bleeding or invasive procedure, but the risk-benefit of
prophylactic platelet transfusions in this setting is uncertain.
In this review, the incidence and mechanisms of thrombocy-
topenia in patients with ITU, its prognostic significance and
the impact on organ function is discussed. A practical
approach based on the authors’ experience is described to
guide management of a critically ill patient who develops
thrombocytopenia.
Keywords: anticoagulation, critical care, platelet, thrombocy-
topenia, thrombosis.
Platelets are versatile cells with a wide range of functions.
They were initially recognised as ‘blood dust’ in the late 19th
century, but were soon recognized as the principal cells
involved in haemostasis and thrombosis (Stasi & Newland,
2011). More recently, their capabilities have been extended to
Correspondence: Dr Jecko Thachil, Department of Haematology,
Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL,
UK.
E-mail: jecko.thachil@cmft.nhs.uk
ª 2016 John Wiley & Sons Ltd
British Journal of Haematology, 2017, 177, 27–38
include participation in inflammation, wound healing,
endothelial barrier function, angiogenesis, tissue regeneration,
foetal vascular remodelling and bone formation (Nurden,
2011). As such, they play a role in several diseases affecting
different organs and organ systems (Thachil, 2015). This
multi-functionality may explain the common finding of
thrombocytopenia in patients with various co-morbidities
admitted to the intensive therapy unit (ITU).
The incidence of critical illness
thrombocytopenia
The incidence of thrombocytopenia in ITU can vary depend-
ing on the type of care provided (medical, surgical or mixed)
and the threshold used for defining thrombocytopenia (150
or 100 9 109/l). It may also vary depending on the clinical
presentations predominantly dealt with in each ITU, which
can vary in different centres (e.g. cardiac surgery versus liver
transplant units) (Stephan et al, 1999; Hui et al, 2011).
Thrombocytopenia can develop prior to arrival or during the
ITU stay. A practical pointer in this regard is that the throm-
bocytopenia that develops after arrival in the ITU is likely to
be caused by an intervention (e.g. surgery, resuscitation flu-
ids causing haemodilution or drugs like vancomycin) or
development of a complication (e.g. sepsis or liver impair-
ment) in the ITU. As such, the timing of thrombocytopenia
onset may help in suggesting a possible diagnosis (discussed
later).
Mechanisms for thrombocytopenia in ITU
patients
The mechanisms for thrombocytopenia in the ITU are usu-
ally multifactorial (see Table I). The classic view is that “con-
sumption” via thrombin-mediated platelet activation is the
most common explanation. In some patients this is associ-
ated with clear laboratory evidence of parallel consumption
of coagulation factors [“overt” disseminated intravascular
coagulation (DIC)], whereas in other patients, non-overt
DIC is implicated (Neame et al, 1980). It has been suggested
that if there is a decrease in platelet count in the setting of
First published online 16 December 2016
doi: 10.1111/bjh.14482
Review
Table I. Mechanisms of thrombocytopenia in the critically ill.
• Increased platelet consumption – with or without overt
disseminated intravascular coagulation
• Increased platelet consumption with clinically-overt thrombosis
(e.g., pulmonary embolism, heparin-induced thrombocytopenia)
• Platelet aggregation due to high von Willebrand factor multimers
in sepsis or inflammatory disorders
• Increased destruction – by autoantibodies in immune
thrombocytopenia (ITP) or drug-dependent antibodies (D-ITP) or
alloantibodies in post-transfusion purpura
• Platelet adherence to other cells including vascular endothelial
cells or leucocytes in sepsis or inflammatory disorders
• Complement mediated platelet destruction in sepsis or
inflammatory disorders
• Haemolysis induced platelet aggregation in haemolytic disorders
• Histone induced thrombocytopenia in any condition which causes
extensive cell damage
• Artificial membrane capture of platelets in medical devices (e.g.
haemofiltration, extracorporeal membrane oxygenation and
cardiac assist devices)
• Haemodilution from administration of large amount of fluids or
blood products
• Splenic sequestration – portal hypertension, hypersplenism or
splenomegaly of any cause
• Decreased production of platelets – chemotherapy or
radiotherapy, bone marrow disorders, drug or virus-induced
marrow failure, haemophagocytosis, haematinic deficiency
(B12 or folate)
• Pseudothrombocytopenia (laboratory artefacts)
In many cases, more than one mechanism is causing or contributing
to the thrombocytopenia
conditions which can cause DIC, such as sepsis, non-overt
DIC should be considered by serially monitoring routine
coagulation measures, such as prothrombin time (PT), acti-
vated partial thromboplastin time (APTT), fibrinogen and
D-dimers (Thachil, 2016a). If there is worsening of these
additional laboratory values, DIC can be implicated as the
cause for the thrombocytopenia (Thachil, 2016a). In addition
to increased consumption, other mechanisms for thrombocy-
topenia in ITU include destruction of platelets in the circula-
tion, haemodilution, splenic sequestration and decreased
production from the bone marrow. These were reviewed by
Greinacher and Selleng (2010) and hold true in most cases,
but some other often overlooked reasons specific for ITU are
discussed below.
Taking the example of the sepsis syndrome, platelet aggre-
gation/adhesion to leucocytes and endothelial cells may be a
common mechanism for ITU thrombocytopenia. Extensive
endothelial activation characteristic of sepsis is associated
with the release of large amounts of von Willebrand factor
multimers and reciprocally decreased amounts of the multi-
mer-cleaving protease, ADAMTS13, which may not be a cau-
sal link but due to the underlying illness (Kremer Hovinga
et al, 2007). The exaggerated endothelial activation allows
large numbers of platelets to be attached to the vascular
28
endothelial cells, leading to thrombocytopenia. There is also
increasing evidence for platelet interaction with white cells
through the formation of platelet-neutrophil aggregates and
platelet-monocyte complexes in sepsis and other inflamma-
tory conditions. For example, Johansson et al (2011) demon-
strated that bacteria isolated from patients with Gram-
positive bacteraemia could induce platelet-neutrophil com-
plex formation via platelet P-selectin and neutrophil Mac-1
complex. Similarly, a study of 113 septic adults in ITU with
severe-sepsis/septic-shock showed elevated platelet-monocyte
aggregates (Rondina et al, 2015). They were associated with
increased risk of mortality in older patients. In these cases,
although marked thrombocytopenia was not described,
attachment of platelets to each other and endothelial/leuco-
cytes may lead to thrombocytopenia.
The complement system forms part of the host defence by
complementing the immune system. Platelets can also func-
tion as antimicrobial cells. These two are connected in vari-
ous ways. For example, platelets contain complement factors
and express receptors for the complement pathway on their
surfaces (Peerschke & Ghebrehiwet, 1998). Stimulated plate-
lets can activate the complement system, while several com-
ponents of the complement system can activate platelets
(Polley & Nachman, 1983; Peerschke & Ghebrehiwet, 1998).
This beneficial interaction can become over-exaggerated
when excessive complement activation accompanies disorders
like sepsis/inflammation. Complement destruction of plate-
lets in this setting can contribute to thrombocytopenia (Peer-
schke et al, 2010). Atypical haemolytic uraemic syndrome
(aHUS) is the classical disease where an inability to control
complement activation can result in thrombocytopenia and
micro-angiopathic haemolytic anaemia (Scully & Goodship,
2014).
Haemolysis can occur in ITU patients from the use of
drugs, rare disorders like thrombotic microangiopathy
(TMA) and in some DIC cases. In TMA, thrombocytopenia
arises due to increased platelet aggregation from ADAMTS13
deficiency and due to the release of red cell adenosine
diphosphate, which is a potent platelet aggregatory agent
(Claus et al, 2009). Data from paroxysmal nocturnal
haemoglobinuria patients also suggest that free-haemoglobin
released by the haemolytic process can scavenge the most
potent platelet anti-aggregatory agent, nitric oxide (Riddell &
Owen, 1999; Rother et al, 2005).
A newly identified reason for thrombocytopenia in criti-
cal illness is the effect of extracellular histones (Fig 1 and
reviewed in Alhamdi et al, 2016). Animal studies from the
Wagner laboratory noted histone infusions to cause rapid
and profound thrombocytopenia (Fuchs et al, 2011),
through platelet aggregation. This aggregatory effect is
mediated by the activation of integrins and crosslinking of
platelets and fibrinogen. Alhamdi et al (2016) recently
showed that high histone levels during ITU stay strongly
predicted the development of moderate to severe thrombo-
cytopenia.
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British Journal of Haematology, 2017, 177, 27–38

Fig 1. Mechanisms for thrombocytopenia
induced by histones. Histones are proteins
associated with the nucleus that are released by
active process from activated immune cells like
neutrophils (as part of neutrophil extracellular
traps) and passively by release from any dam-
aged cell, where they may be associated with
deoxyribonucleic acid (DNA). Recent studies
summarised by Alhamdi and Toh (2016) have
shown that they can be involved in processes
which can cause host damage through causing
thrombocytopenia, endothelial damage and
organ injury.
In summary, the mechanisms for thrombocytopenia in
critically ill patients vary, with more than one mechanism
often responsible. For example, a septic patient treated with
antibiotics may have sepsis-induced platelet aggregation and
histone- and complement-mediated thrombocytopenia as ini-
tial contemporaneous explanations which subsequently wors-
ens/recurs because of antibiotic-induced platelet-reactive
antibodies. Considering the different pathophysiological
mechanisms is important in tailoring platelet-specific treat-
ment. Also, managing one cause may not be enough to cor-
rect the thrombocytopenia fully.
Practice pointers to identify a cause of
thrombocytopenia in critically ill (Fig 2)
Rapidity of development of thrombocytopenia
An acute drop in platelet count can indicate an immune
cause. Drug-induced thrombocytopenia (D-ITP) is a classic
example explained by formation of drug-dependent platelet-
reactive antibodies (Von Drygalski et al, 2007; Arnold et al,
2013). A less common explanation for precipitous thrombo-
cytopenia is post-transfusion purpura (PTP), from the for-
mation of transiently-autoreactive platelet alloantibodies
approximately 1 week following blood-product transfusion.
Passive alloimmune thrombocytopenia refers to acute throm-
bocytopenia that begins within hours of transfusion, and
explained by platelet-reactive alloantibodies within the blood
product (Warkentin & Smith, 1997). Although autoimmune
thrombocytopenia (ITP) rarely develops in the ITU, life-
threatening haemorrhage in ITP patients could lead to ITU
admission.
D-ITP typically results in severe thrombocytopenia, with
median nadir platelet counts described as 20 9 109/l, often
ª 2016 John Wiley & Sons Ltd
British Journal of Haematology, 2017, 177, 27–38
Review
associated with mucocutaneous bleeding and also systemic
symptoms including fever/chills (Warkentin, 2007; Priziola
et al, 2010). The median time from drug initiation to the
development of low platelet count is 14 days, although with
previous exposure, it can develop within 3 days (Aster et al,
2009). One of the difficulties in diagnosing D-ITP in ITU is
that the patient may have been treated with multiple drugs,
many of which can cause the thrombocytopenia. Consulting
the well-established and updated database listing all drugs
reported to cause thrombocytopenia at http://www.ouhsc.ed
u/platelets/ditp.html is advisable (George et al, 1998). Other
published lists of drugs causing D-ITP are also available
(Aster et al, 2009; Reese et al, 2010; Arnold et al, 2013).
These provide the level of clinical evidence to implicate the
drug and also whether drug-dependent antibodies have been
previously identified. Another dilemma is that, in some cases,
it is probably essential that the drug be continued and thus
discontinuation may not be an easy decision. The authors
consider the diagnosis of D-ITP if the timing of severe
thrombocytopenia onset fits a known drug trigger of D-ITP
(per databases) and no other obvious explanation is evident,
and discontinue or switch one/two likely drugs at a time to
assess the response.
Although precipitous platelet count falls in the setting of
acute infection have been reported (Warkentin, 2015a,b),
more gradual development of thrombocytopenia is usually
noted in septic and inflammatory disorders.
Timing of onset of thrombocytopenia
Thrombocytopenia that develops in the first 2–3 days of ITU
admission (range, 1–4 days) is a response to the reason for
admission, such as postoperative state or trauma. It is prefer-
able to keep a watchful wait in these patients, with regular
blood checks and no intervention to ‘correct’
29
Review

Fig 2. Clues for the diagnosis of thrombocy-

topenia in critically-ill patients. ITP, immune
thrombocytopenia; HIT, heparin-induced
thrombocytopenia, PTP, post-transfusion pur-
pura; PT, prothrombin time; APTT, activated
partial thromboplastin time; DIC, disseminated
intravascular coagulation.

thrombocytopenia unless the platelet count is very low Thrombocytopenia in combination with thrombosis
(<10 9 109/l) or the patient is bleeding. In postoperative
When thrombocytopenia develops in conjunction with large-
patients, the drop in platelet count is the result of combina-
vein or artery thrombosis, the differential diagnosis narrows.
tion of platelet consumption from tissue injury/wound heal-
HIT is the classic disorder characterized by the combination
ing and blood losses, as well as haemodilution. These are
of thrombocytopenia and large-vessel venous or arterial
expected to be compensated by the bone marrow in the fol-
thrombosis. A recent review by Warkentin (2015c) gives an
lowing days. In a prospective study of nearly 600 patients
overview of HIT presentation in critically-ill patients, includ-
who underwent cardiac surgery, platelet counts fell below
ing DIC-associated venous limb gangrene. Cancer-associated
normal in 56
3% of patients and below 50 9 109/l in 2
9%
DIC can also present with this combination, sometimes even
of patients within 10 days after surgery (Selleng et al, 2010).
mimicking HIT (Warkentin, 2015a; Warkentin et al, 2015a).
The lowest level was recorded typically between days 1–4
Antiphospholipid syndrome can present with macrovascular
after surgery with the count increasing to the pre-surgery
thrombosis and thrombocytopenia. An unusual and over-
level soon after. Similar mechanisms in an exaggerated man-
looked cause of thrombocytopenia is the massive-clot throm-
ner may explain the thrombocytopenia in trauma patients
bocytopenia, where patients with pulmonary embolism (~3%
although haemodilution from generous blood-product
of cases) have large numbers of platelets incorporated into
replacement can be an additional factor. The 2–3 day delay
the extensive thrombi (Kitchens, 2004).
in thrombopoietic response mirrors platelet production
Thrombocytopenia with combined macro- and microvas-
kinetics where megakaryocytes take up to 3 days to release
cular thrombosis points to disorders such as severe HIT
large number of platelets from the bone marrow (Kaushan-
with HIT-associated DIC, as well as the catastrophic variety
sky, 2009), with the platelet count expected to rise to levels
of antiphospholipid syndrome (CAPS). Definite CAPS is
approximately 2–3-times baseline by day 14.
defined as thromboses in three or more organs developing
It is well-known to the journal readers that the onset of
in less than a week, microthrombosis in at least one organ
heparin-induced thrombocytopenia (HIT) is at least 5 days
and persistent antiphospholipid screen positivity (Cervera
after beginning an immunizing heparin exposure, although
et al, 2013). Many patients with CAPS have moderate or
recent heparin exposure (within the previous 100 days) may
severe thrombocytopenia (even though thrombocytopenia is
cause rapid-onset HIT upon heparin re-exposure, if the
not one of the criteria of CAPS). Patients with overt DIC
recent exposure had resulted in immune-sensitization. The
of numerous aetiologies can develop microthrombosis;
explanation for the association between recent heparin expo-
indeed, DIC and resulting microthrombosis is the key
sure and rapid-onset HIT is the characteristic transience of
pathophysiological process that explains acral-limb ischae-
platelet-activating HIT antibodies, which are usually no
mic necrosis (“symmetrical peripheral gangrene”) in ITU
longer detectable >100 days following an episode of HIT
patients.
(Warkentin & Kelton, 2001).

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British Journal of Haematology, 2017, 177, 27–38

Recently, “shock liver” (also known as acute ischaemic
hepatitis or acute hepatic necrosis) has been identified as a
risk factor for development of symmetrical peripheral gan-
grene in ITU patients with acute DIC (Siegal et al, 2012;
Warkentin, 2015a,b,c). Shock liver is a “coumarin equiva-
lent” (protein C depletion with DIC/severe liver dysfunction
contributes to natural anticoagulant failure) thus predispos-
ing to microthrombosis. Such patients also have compro-
mised peripheral blood flow due to hypotension/shock and
vasopressor therapy. This syndrome resembles coumarin-
induced venous limb gangrene and DIC secondary to HIT or
metastatic cancer (Warkentin & Pai, 2016). In the author’s
(TEW) experience, 85–90% of ITU patients with symmetric
peripheral gangrene have preceding shock-liver (the remain-
ing have severe thrombocytopenia or chronic liver disease as
distinguishing features) (Warkentin, 2015a,b,c). Our practice
is thus to measure serial liver enzymes in addition to platelet
counts and coagulation assays in shocked ITU patients, and
to consider certain therapies (heparin administration with
anti-factor Xa monitoring; antithrombin concentrates;
plasma infusion) in patients with incipient limb-ischaemia
with the clinical picture of DIC and recent/concurrent shock
liver (Warkentin & Pai, 2016).
The value of an absolute platelet count
In the critically-ill, severity of thrombocytopenia can be use-
ful in the differential diagnosis. An acute drop in the count
to <20 9 109/l is uncommonly due to sepsis or DIC. In con-
trast, D-ITP usually causes platelet counts <20 9 109/l, but
this is seen in only 5 10% of HIT patients (and then in
combination with overt DIC). Platelet counts <20 9 109/l is
classical for TTP but unusual for aHUS, where the median
count is 50 9 109/l OR a >25% decrease from baseline.
Approximately one-fifth of severe aHUS patients have plate-
let counts >150 9 109/l; because their baselines are
250 9 109/l or higher (De Serres & Isenring, 2009).
Thrombocytopenia in patients confirmed to have sepsis
In patients requiring medical ITU admission, sepsis or SIRS is
probably the commonest cause of thrombocytopenia with the
severity and incidence being greater in those with septic shock
(Venkata et al, 2013). The explanation is multifactorial with
platelet binding to the endothelium, leucocyte-platelet aggre-
gate formation, immune-mediated mechanisms, haemophago-
cytosis, bone marrow suppression, complement activation and
in patients with the greatest degree of thrombocytopenia,
overt DIC (Larkin et al, 2016). If the platelet counts worsen
despite appropriate antibiotics along with other laboratory
markers, this would suggest the development of DIC and the
need for additional interventions including blood product
transfusions and administration of agents like thrombomod-
ulin or antithrombin (Thachil, 2016a). On the other hand, if
the platelet counts are stable or improving, it may be a
ª 2016 John Wiley & Sons Ltd
British Journal of Haematology, 2017, 177, 27–38
Review
surrogate marker for improvement from sepsis. Since multiple
factors contribute to the sepsis-associated thrombocytopenia,
correcting the platelet count to normal by one intervention
may not always be easy. Supportive treatment with focus on
fully treating the septic episode is the key.
Thrombocytopenia with abnormal coagulation profile
Abnormal clotting screen in the presence of thrombocytope-
nia usually denotes extensive thrombin generation as would
be seen in septic DIC (Thachil, 2016b). It should however be
borne in mind that the clotting screen (normal in up to
50%) and a low fibrinogen (lower than 1 g/l in less than
30% of cases) may not always be present in DIC (Levi &
Meijers, 2011). Indeed, as fibrinogen is an acute phase reac-
tant, DIC can even feature supranormal fibrinogen levels as
shown in a recently reported case of DIC and symmetrical
peripheral gangrene complicating Klebsiella pneumosepsis
(Warkentin, 2015b). In all cases of DIC, D-dimer is however
markedly raised, and we recommend serial measurements of
quantitative D-dimer levels in laboratory assessment of possi-
ble DIC. Another clinical condition which can cause abnor-
mal clotting screen-thrombocytopenia picture is liver
impairment due to the lack of synthesis of coagulation fac-
tors and thrombopoeitin respectively (Afdhal et al, 2008).
Splenomegaly in liver disease can also cause chronic throm-
bocytopenia. Liver enzymes may be normal despite extensive
liver impairment creating a diagnostic dilemma.
Thrombocytopenia in patients with artificial devices
Thrombocytopenia is reported to occur in three-fourths of
patients receiving continuous renal-replacement therapy (Fer-
reira & Johnson, 2015). Immune destruction, co-morbid
conditions and secondary to drugs (including heparin) used
in these patients are mechanisms described but the dialysis-
specific issues are related to the adherence of platelets to the
dialysis-filtration membrane (Ferreira & Johnson, 2015). Dia-
lyzer membrane-induced thrombocytopenia was first noted
three decades ago by Vicks et al (1983) prior to routine
blood counts when patients developed haemorrhage related
to thrombocytopenia. The relevance of haemofilter mem-
brane type was confirmed by Liu et al (2010) by comparing
platelet loss using polysulfone and cellulose-triacetate filters
with or without anticoagulation with the latter associated
with significantly lower occurrence of thrombocytopenia.
Another mechanism related to the haemofilter is the reten-
tion of platelets; which can be attenuated by higher blood
flow rates (Mulder et al, 2003). Similar membrane retention
of platelets may be a factor in the thrombocytopenia related
to artificial machines likes cardiac-assist devices and extracor-
poreal membrane-oxygenator. These have been reviewed
recently by Eckman and John (2012) and Murphy et al
(2015). In all these devices, since heparin is usually adminis-
tered to maintain circuit patency, the possibility of HIT
31
Review

should always be considered, especially if (a) thrombocytope-
nia begins approximately 1–2 weeks after initiating heparin
exposure, (b) thrombosis occurs (either in the device or else-
where), or (c) anaphylactoid reactions occur during initiation
of haemodialysis with bolus heparin administration (Perbet
et al, 2015).
Heparin-induced thrombocytopenia
It is likely that HIT is both over and under-diagnosed in the
ITU. Many studies show that the incidence of “true” HIT is
<1% in the ITU population despite the fact that majority of
the patients get exposed to heparin. It is important that the
4Ts score is calculated in all patients and reliable laboratory
assays are performed to confirm or exclude HIT (see Fig 3).
Thrombosis that begins 5 or more days after receiving heparin
should always prompt consideration of HIT (Warkentin,
2006); indeed, in approximately one-half of HIT patients,
thrombosis is the presenting feature of HIT (Warkentin & Kel-
ton, 1996), with thrombocytopenia becoming apparent only
over the ensuing days (Greinacher et al, 2005). Hypotension
in an ITU patient with possible HIT should prompt considera-
tion of acute adrenal failure (adrenal vein thrombosis causing
bilateral adrenal haemorrhagic necrosis); initiation of corticos-
teroid therapy can be life-saving in this situation (Warkentin
et al, 2015b). Detailed discussion of HIT has recently been
published in the journal by Scully et al (2016).
Bone marrow disorders
Haematological malignancies can be a cause of thrombocy-
topenia and may present acutely with associated severe infec-
tions or anaemia which may require circulatory support.
Myelodysplastic syndromes can present with isolated throm-
bocytopenia but with heightened susceptibility to infections
as the presenting symptom needing intensive care admission.
Bone marrow examination is required in these cases espe-
cially if the blood film shows abnormalities in the erythrocyte
and leucocyte lineages. It may also be helpful in distinguish-
ing from TMA.
Thrombocytopenia as a marker of organ
impairment in critically ill
It is widely recognised that platelets are the key cellular com-
ponent of the haemostatic mechanism. But increasingly, it is

Fig 3. Algorithm for laboratory assessment for heparin induced thrombocytopenia. *Denotes practice in places where serotonin release assay
(SRA) is not available (JT approach). **Preferred approach especially if SRA is available (TEW approach). ***“HIT likely” status based upon
ELISA positivity may only indicate ~50–75% probability of true HIT, so if an SRA is available, this test should be considered (especially if the
4Ts is only intermediate). ELISA, enzyme linked immunosorbent assay; HIT, heparin-induced thrombocytopenia; OD, optical density.

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British Journal of Haematology, 2017, 177, 27–38

also recognised that they play a very active role in several
other physiological functions (Nurden, 2011). It thus
becomes no surprise that thrombocytopenia is associated
with organ impairment including in the case of renal failure,
acute lung injury(ALI)/respiratory distress syndrome and vas-
cular leakage syndromes (Thachil, 2015). Some examples for
these correlations are given below.
Despite the underlying cause for renal impairment, a
declining platelet count may be considered an easily-available
laboratory-marker for the diagnosing impending renal failure
(ARF). Ono et al (2006) found the incidence of ARF and
serum creatinine levels in patients with sepsis and
ADAMTS13 activity <20% to be significantly higher than
those with levels >20% (41
2% vs. 15
4%). This was due to
unusually-large VWF multimers from ADAMTS13 deficiency
possibly caused by septic protease cleavage and decreased
liver synthesis in the liver. In a smaller study, platelet count
<120 9 109/l, the ratio of von Willebrand factor propeptide
to ADAMTS13 was increased many-fold in patients with sev-
ere-sepsis/septic-shock on day-one and remained markedly
elevated for a week (Fukushima et al, 2013). In another
study, Claus et al (2009) showed that plasma VWF levels
increased while ADAMTS13 activity decreased with increas-
ing severity of systemic inflammation including sepsis,
emphasizing the role of platelet aggregation in the develop-
ment of organ failure especially kidney impairment.
Acute lung injury (ALI) is a life-threatening pulmonary
syndrome often noted in ITU patients and is a common
cause for prolonged stay, serious morbidity and high mortal-
ity. Platelets play a major role in the development of this
syndrome (Yadav & Kor, 2015). Animal data show that dur-
ing mechanical ventilation, platelets release chemotactic pro-
teins which promote leucocyte recruitment and
proinflammatory characteristics of ALI (Zarbock & Ley,
2009). Bronchoalveolar lavages from ALI patients have
increased levels of platelet granules associated with greater
severity of the syndrome (Idell et al, 1989). Weyrich and
Zimmerman (2013) have summarized several experimental
and clinical observations where platelets are integral to the
barrier function of the alveolar capillary endothelium.
Thrombocytopenia which develops in critically-ill patients
can lead to disruption of this barrier integrity and lead to
pulmonary oedema, characteristic of ALI.
The crucial role of platelets in maintaining the endothelial
vascular integrity can be a critical factor for preventing vas-
cular oedema commonly observed in the critically-ill. Plate-
lets maintain the stability of the vasculature by various
mechanisms, including release of cytokines and growth fac-
tors which helps in closing the small intercellular gaps at the
vascular endothelial level (Nachman & Rafii, 2008). In this
context, it is useful to remember the fact that thrombocy-
topenia by itself is not a cause of bleeding in most patients
(as patients with ITP) but can lead to disruption of endothe-
lial barrier integrity which leads to vascular leakage of red
cells (petechiae/bruising) and extravascular fluid
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British Journal of Haematology, 2017, 177, 27–38
Review
accumulation (leading to oedema/effusions). This property
could explain the difference between the bleeding seen in
patients who are receiving antiplatelet agents where petechiae
are rarely seen compared to gastrointestinal and intracranial
bleeding, which may have developed in regions with pre-
existing, quiescent lesions (Nachman & Rafii, 2008).
A very recent paper assessed the association of admission
thrombocytopenia with the host response in 931 patients
with sepsis (Claushuis et al, 2016). The investigators mea-
sured 17 plasma biomarkers which are known to indicate
dysregulation of pathways implicated in sepsis. They identi-
fied that platelet counts <50 9 109/l were associated with
increased cytokines and endothelial-cell activation but also
impaired vascular integrity. Interestingly, blood microarray
analysis demonstrated impaired leucocyte-adhesion and
increased complement-signalling suggesting impaired host-
response.
In summary, thrombocytopenia is a risk factor for the
development of organ failure and vascular leakage, both
common complications in the critically-ill. Although detailed,
prospective studies have not been performed, a gradual but
definite decline in platelet count may be considered an early
marker of these complications. Also, the “prognostic value”
of thrombocytopenia has not yet been studied in patients
who develop it from conditions other than sepsis.
Thrombocytopenia as a marker of poor
prognosis
Even in the absence of bleeding, thrombocytopenia has been
demonstrated to be a key prognostic factor in critically-ill
patients. Counts <100 9 109/l was associated with increased
ITU and hospital stay and higher mortality in the Baughman
et al (1993). Similarly, Crowther et al (2005) showed these
patients had higher ITU/hospital mortality, required longer
mechanical ventilation, and were more likely to receive
blood-products. However, admission platelet counts do not
discriminate between survivors and non-survivors in ITU.
The platelet indices which correlated strongly with an
increased mortality were prolonged and severe thrombocy-
topenia and the lack of increase in platelet count.
Severity of thrombocytopenia being an indicator of poor
prognosis was evident in the study where mortality increased
from 9% in those with count >150 9 109/l to 73% if
<20 9 109/l (Vanderschueren et al, 2000). Strauss et al
(2002) also showed higher mortality with a nadir platelet
count <100 9 109/l with mortality varying by severity (12%
for mild, 47% for moderate, 56% for severe, and 67% for
very severe thrombocytopenia). Severe thrombocytopenia
may be suggestive of severe underlying illness but platelet
count by itself inversely correlated with mortality indepen-
dent of illness severity and organ dysfunction (Vander-
schueren et al, 2000). This is of practical importance because
platelet count can be a simple marker which can be useful
during the course of ITU stay in place of the well-known
33
Review
scoring systems like APACHE II, which is relevant at admis-
sion and the first 24 h.
The duration of thrombocytopenia is also crucial for prog-
nostication. Among the patients who had thrombocytopenia
on day 4, the mortality rate was 33%, while the 20% who
continued to be thrombocytopenic on day 14, the mortality
rate was 66% (Akca et al, 2002). Duration of thrombocy-
topenia was also significantly longer in non-survivors
(Strauss et al, 2002).
Changes in the platelet count over time are also relevant.
The ESICM data showed a biphasic pattern in the ITU plate-
let counts with an initial sudden decrease followed by an
increase (Akca et al, 2002). This may be a physiological
response to stress as it has been observed in post-surgical
patients and after platelet-apheresis (Lasky et al, 1981). Of
the 204 thrombocytopenic patients, 67 had no relative
increase in platelet count on day 14 and their mortality rate
was significantly greater (30% vs. 11%; Akca et al, 2002).
Similar association of a blunted rise in the counts being asso-
ciated with increased mortality was noted in over 1400
admissions by Nijsten et al (2000), who suggested platelet
count to be as good as APACHE II score for prognostication
of critically-ill patients.
Management of the critically ill
thrombocytopenic patient (Fig 4)
Since thrombocytopenia is usually a consequence of the
underlying illness, specific management of the causative con-
dition should result in improvement of the platelet counts.
As such, more importance should be given to understanding
and appropriately treating the condition which could have
led to the thrombocytopenia. The fact that severe
34
thrombocytopenia can lead to bleeding is well-known and
platelet transfusions may be indicated. However, the authors
would also consider signs of microvascular impairment as
being a “complication” of thrombocytopenia. In other words,
if the patient develops acral limb ischaemia, renal impair-
ment, cerebrovascular signs or ALI in the days following a
marked drop in the platelet count, it may be relevant to con-
sider antithrombotic therapy.
Bleeding in the thrombocytopenic patient
Bleeding is the biggest fear in relation to thrombocytope-
nia although it is unusual for a patient to bleed unless the
platelet count is <20 9 109/l. Even a threshold of
20 9 109/l is based on studies on patients with hypoprolif-
erative bone marrow who may not have the capacity to
compensate by increasing thrombopoeisis (Tosetto et al,
2009). Although hypoproliferative conditions can exist in
the ITU patients, the commonest causes of thrombocytope-
nia in these patients are usually increased platelet con-
sumption. In such cases, platelet transfusion is not likely
to be beneficial and may even be harmful. On a different
note, despite moderate thrombocytopenia, platelet dysfunc-
tion may be an accompaniment of conditions (e.g. sepsis,
trauma etc.) needing ITU admission and can cause bleed-
ing even if the platelet count is over 50 9 109/l (Yaguchi
et al, 2004). Despite severe thrombocytopenia, patients may
not bleed in many cases since endothelial activation, an
integral part of the underlying disease processes, would
cause the release of large amounts of VWF which can
compensate for the low platelet count and function as has
been demonstrated in patients with liver disease (Hugen-
holtz et al, 2009). In the postoperative patient, a surgical
Fig 4. Algorithm for the management of
thrombocytopenia in the critically-ill.
ª 2016 John Wiley & Sons Ltd
British Journal of Haematology, 2017, 177, 27–38

cause may contribute to bleeding despite the patient being
thrombocytopenic.
Platelet count thresholds for transfusions
Platelet transfusions are often used to treat thrombocytopenia
despite any evidence for its benefit. Stanworth et al (2013)
showed that up to 30% of critically ill patients receive a trans-
fusion, the majority of which are for prophylaxis rather than
treatment of bleeding. Different guidelines recommend platelet
transfusion thresholds largely based on expert opinion (Lieber-
man et al, 2014 and Kumar et al, 2015).
The most commonly accepted platelet count threshold for
transfusions are a level of 10 9 109/l for those without and
20–30 9 109/l for those with additional risk factors for bleed-
ing, such as concomitant coagulopathy (DIC) or severe hepatic
or renal dysfunction (Squizzato et al, 2016). If platelet dys-
function is a possibility, a higher threshold of 50 9 109/l
should be considered. If neurological complications like
intracranial bleed may have occurred, a threshold of
100 9 109/l has been suggested. In those patients who are not
bleeding, platelet transfusions may be required if there is a
need for surgical or radiological intervention. Thresholds for
platelet counts have been set for many procedures which are
often undertaken in the ITU with very poor evidence-base. A
retrospective analysis of 604 central venous catheter (CVC)
insertions in 193 patients with acute leukaemia receiving
chemotherapy or stem-cell transplantation had half of the
patients with thrombocytopenia (Zeidler et al, 2011). In mul-
tivariate analysis, only patients with counts <20 9 109/l were
at higher risk for bleeding even without prophylactic transfu-
sions suggesting this threshold may be acceptable for at least
CVC insertion. We tend to use the following general principles
to guide us about the need for prophylactic transfusions.
• Is the interventional procedure necessary or can an alter-
nate method be used to make the diagnosis, eg; in the case
of need for biopsy?
• Is the thrombocytopenia likely to be due to hypoprolifera-
tive bone marrow or increased consumption or destruction
of platelets? If it is the former, the risk of bleeding is
higher and a higher threshold like 50 9 109/l may be used
depending on the bleeding risk of the procedure while in
the case of latter, lower thresholds of 20 9 109/l may be
considered (not evidence-based).
• The procedures, if at all possible, are done by a senior
physician/surgeon. Assistance from radiology like ultra-
sound may help minimise bleeding for biopsy procedures.
Further studies are warranted to accurately assess the
bleeding risk from low platelet count using methods like
thrombin generation tests and possibly platelet-related
thromboelastography methods.
One of the commonest conundrums in this context is the
safety of platelet transfusions in TMA or HIT. Goel et al
(2015) utilized the Nationwide Inpatient Sample to evaluate
ª 2016 John Wiley & Sons Ltd
British Journal of Haematology, 2017, 177, 27–38
Review
platelet transfusion practices and their association with out-
comes over 5 years. Although the authors found higher odds
of arterial thrombosis and mortality among transfused
patients, unavailability of platelet count data suggest this con-
clusion may be confounded (as thrombocytopenia severity
predisposes both to thrombosis and platelet transfusion trig-
ger). We would avoid transfusions unless there is perceived
risk of life-threatening haemorrhage in these situations.
Thrombocytopenia as a risk for organ impairment
As discussed before, platelet aggregation and adhesion to the
endothelium, circulating platelet-leucocyte aggregates, as well
as DIC-associated fibrin deposition, can lead to microvascu-
lar ischaemia, which can manifest as organ failure. We would
consider the development of organ failure in those who had
a marked decrease in platelet count as the surrogate marker
of microvascular ischaemia. The suspicion will be made
stronger if multiple organs are affected simultaneously and
also if there are features of excess thrombin generation like
abnormal PT and APTT. In these cases, we would consider
antithrombotic therapy especially if the risk of bleeding is
not high (not considering the low platelet count by itself as a
risk factor for bleeding). The choice of agent is a prophylac-
tic dose of anticoagulant drug like low molecular weight hep-
arin. We do not consider abnormal clotting screen
accompanying the lower platelet count as a contraindication
for commencing the anticoagulant drug. However, close
supervision will be maintained to detect any bleeding early in
such cases. We do however avoid giving anticoagulation if
the platelet count is <25 9 109/l unless there is evidence of a
macrovascular thrombus (e.g., deep-vein thrombosis) or con-
cern for microvascular thrombosis (e.g., symmetrical periph-
eral gangrene).
Antiplatelet therapy for sepsis?
Since platelet activation is an accompaniment of many con-
ditions in ITU admission, there has been interest in using
antiplatelet therapy to improve patient outcome. There are
several observational studies which show the use of aspirin
may have a beneficial effect (L€ osche et al, 2012; Chen et al,
2015; Tsai et al, 2015). For example, patients with commu-
nity acquired pneumonia who were receiving anti-platelet
therapy were less likely to need ITU admission and had
shorter hospital stay (Boyle et al, 2015). ITU patients who
were on antiplatelet therapy have better survival and interest-
ingly lesser risk of developing ALI and multi-organ failure
and lesser risk of mortality (Winning et al, 2010; Harr et al,
2013; Valerio-Rojas et al, 2013; Boyle et al, 2015). Despite all
these studies, there is still a lack of randomised controlled
trials in this setting. The authors would not routinely use
aspirin or antiplatelet therapy in these cases unless on a trial
basis. However, we would continue the antiplatelet agent if
the patients were already receiving it and has not acquired a
35
Review

heightened bleeding risk in the ITU up to a platelet count
threshold of 25 9 109/l.
Thrombosis in the thrombocytopenic patient
Managing acute venous thrombosis in a patient with throm-
bocytopenia is a difficult dilemma. Firstly, it is important to
rule out the conditions which can present with this combina-
tion (e.g. HIT, APS, DIC). If these are excluded, the authors
would consider it safe to therapeutically anticoagulate the
patient if the platelet count is above 50 9 109/l. But if it is
between 30–50 9 109/l, unfractionated heparin may be cho-
sen as the anticoagulant of choice because of its easy
reversibility and renal safety. If the count is less than
30 9 109/l, anticoagulation is not administered or given at a
reduced dose but mechanical thromboprophylaxis is ensured,
and any thrombotic risk factors (e.g. removal of central lines)
are addressed. In all these cases, detailed discussions are
made with the family about the high-risk situation and plate-
let counts are monitored closely to safely initiate or stop
anticoagulation.
Summary
In summary, thrombocytopenia is a common haematological
abnormality encountered in ITU. The severity and signifi-
cance of this complication is varied. Several different
aetiologies need to be kept in mind when trying to identify
the cause. The different pathophysiological mechanisms
described in this article can be helpful in this respect. Certain
clinical variables including timing and severity also are
potentially useful. A drop in platelet count from normal to
between 50–150 9 109/l can be relevant in that it may repre-
sent an easy marker for underlying microvascular ischaemia
and thus organ impairment. Although a bleeding patient
with associated thrombocytopenia will definitely benefit from
platelet transfusions, there is still uncertainty on how to
select the patients who may require prophylactic platelet
transfusions. More trials are required in this regard.
Acknowledgements
JT conceived the idea, performed the literature search and
wrote the paper. TEW performed the literature search and
wrote the paper. Both the authors approved the final version.
Conflicts of interests
T.E. Warkentin has received royalties from Taylor & Francis
(Informa), consulting fees and/or research funding from
Aspen Global, Instrumentation Laboratory, Medtronic Dia-
betes, and W.L. Gore, and has provided expert witness testi-
mony relating to HIT and non-HIT thrombocytopenia and
coagulopathies. J.T. no conflicts.

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