Analtyic Review

Thrombocytopenia in the Intensive Care Unit

Helena L. Wang, MD1, Claudine Aguilera, MD1, Kevin B. Knopf, MD2,Tze-Ming Benson Chen, MD1, David M. Maslove, MD3, andWare G. Kuschner, MD3,4

AbstractThrombocytopenia is a common laboratory finding in critically ill patients admitted to the intensive care unit. Potential etiologiesof thrombocytopenia are myriad, ranging from acute disease processes and concomitant conditions to exposures and drugs.The mechanism of decreased platelet counts can also be varied: laboratory measurement may be spurious, plateletproduction may be decreased, or platelet destruction or sequestration may be increased. In addition to evaluation for thecause of thrombocytopenia, the clinician must also guard against spontaneous bleeding due to thrombocytopenia, prophylaxagainst bleeding resulting from an invasive procedure performed in the setting of thrombocytopenia, and treat active bleedingrelated to thrombocytopenia.

Keywordsthrombocytopenia, platelet destruction, platelet consumption, platelet sequestration, platelet transfusion, critical care

Received October 12, 2010, Received Revised July 7, 2011. Submitted July 8, 2011.

Introduction

Thrombocytopenia is defined as a platelet count of <150 000/

mL or a decrement of >50% from a previous measurement.

Thrombocytopenia may occur in up to 20% of medical inten-

sive care unit (ICU) admissions,1 35% of surgical ICU

admissions,2 and 45% of trauma ICU admissions.3 However,

clinical bleeding does not occur until the platelet count is

much lower than the defined parameters of thrombocytope-

nia; that is, typically under 50 000/mL for surgical bleeding

and even lower for spontaneous bleeding. Recent data sup-

port that the risk of spontaneous hemorrhage is extremely

low for patients with a platelet count >10 000/mL.4

In this article, we review the major mechanisms of thrombo-

cytopenia—decreased production, sequestration, and increased

destruction—and review diseases (eg, sepsis and thrombotic

thrombocytopenic purpura [TTP]), conditions (eg, dissemi-

nated intravascular coagulation [DIC]), and exposures (eg,

drugs and cardiopulmonary bypass) that result in thrombocyto-

penia (Table 1). We review specific management strategies that

clinicians can follow in evaluating and treating thrombocytope-

nia in the critically ill patient.

While heparin-induced thrombocytopenic thrombotic syn-

drome has justifiably received significant attention as an

important cause of thrombocytopenia in the ICU, there are

many other causes of thrombocytopenia that should be con-

sidered in the critically ill patient. In addition to reviewing the

etiology and pathophysiology of thrombocytopenia, we review

the spectrum of clinical effects associated with low platelet

counts and the range of management strategies that may be

appropriate. We give special attention to newer drugs and treat-

ments employed in the ICU that affect platelet counts and func-

tion (Figures 1 and 2).

Platelet Production

Platelets arise from megakaryocytes in the human bone mar-

row. The numbers and size of megakaryocytes increase in

response to demand for more platelets. The exact mechanism

by which platelets are formed has not been clearly demon-

strated. The possibility has been raised of proplatelets being

transformed into platelets in the lung following release from

the bone marrow.5 If platelet production is indeed dependent

on final transformation in the lung, then the high incidence

of thrombocytopenia associated with respiratory failure should

be unsurprising.

1 Division of Pulmonary and Critical Care Medicine, California Pacific Medical

Center, San Francisco, CA, USA2 Division of Hematology/Oncology, California Pacific Medical Center, San

Francisco, CA, USA3 Division of Pulmonary and Critical Care Medicine, Stanford University School

of Medicine, Stanford, CA, USA4 Medical Service, Pulmonary Section, U.S. Department of Veterans Affairs Palo

Alto Health Care System, Palo Alto, CA, USA

Corresponding Author:

Ware G. Kuschner, VA Palo Alto Health Care System, 3801 Miranda Avenue,

Pulmonary Section, Mail Code: 111P, Palo Alto, CA 94304, USA.

Email: kuschner@stanford.edu

Journal of Intensive Care Medicine28(5) 268-280ª The Author(s) 2012Reprints and permission:sagepub.com/journalsPermissions.navDOI: 10.1177/0885066611431551jic.sagepub.com

Regulation of platelet production is also not fully under-

stood. Platelet counts vary among normal persons but remain

relatively constant within each individual throughout life in the

absence of physiologic or pathologic perturbations.6 Beyond

maintaining a relatively constant platelet count, the body also

maintains a constant total platelet mass.7 Thus, an alteration

in platelet count is offset by a proportional change in platelet

size such that the total body mass of platelets remains

unchanged.

Platelet production is regulated by thrombopoietin (TPO), a

hormone produced in the liver and kidney that causes the mega-

karyocytes to increase in number and differentiate to platelets.

Thrombopoietin receptor is present on hematopoeitic stem

cells in the bone marrow. Plasma concentrations of TPO vary

inversely with the platelet count in patients, and mature plate-

lets are capable of removing TPO from the circulation. Trans-

fusion of exogenous platelets similarly leads to clearance of

TPO from the circulation. Circulating TPO becomes bound

to the c-Mpl receptor on the surface of transfused platelets and

is degraded following internalization.8

Normal Platelet Function

Platelets survive in the circulation for 8 to 10 days, with

approximately one third of the total platelet mass located in the

spleen. Younger platelets may be more hemostatically active as

suggested by studies in dogs in which platelets became less

responsive to thrombin and collagen when tested on subsequent

days.9,10 It has also been noted that patients with idiopathic

thrombocytopenic purpura generally do not have serious bleed-

ing despite having a very small number of young platelets. This

is in contrast to patients with platelets that are similarly low in

number, but of mixed age, as seen in marrow failure following

chemotherapy.

Exposure of circulating platelets to collagen fibrils when the

integrity of the endovascular lining is compromised leads to an

activation cascade which culminates in local clot formation.

This series of events begins with signaling molecules released

by platelet alpha granules (including von Willebrand factor,

fibrinogen, and platelet-derived growth factor) and platelet

dense granules (adenosine diphosphate and serotonin), leading

to conformational change of platelets, specifically of the glyco-

protein IIb/IIIa receptor on the surface. Activated platelets

secrete thromboxane A2 and adenosine diphosphate, which in

turn attract and activate additional platelets. Activated platelets

also bind circulating fibrinogen via the glycoprotein IIb/IIIa

receptor. Each fibrinogen molecule can bind to glycoprotein

IIb/IIIa receptors, of which each platelet has approximately

50 000 copies on its surface. These connections facilitate

Figure 1. Confirmation of low platelet count.

Table 1. Differential Diagnosis of Thrombocytopenia.

Decreased Production Massive Consumption Destruction

Transient infectionsMumps Clot formation Idiopathic thrombocytopenic purpuraRubellaVaricella

Chronic infectionsHepatitis C Disseminated intravascular coagulation DrugsHuman immunodeficiency virus

Alcohol abuse Thrombotic thrombocytopenic purpuraDecreased thrombopoietin HELLP syndrome

HELLP: hemolysis, elevated liver enzymes, low platelets.

Wang et al 269

formation and stabilization of very large local platelet

aggregates.11

Platelets can also be activated by thrombin, which is gener-

ated by an interaction between tissue factor and factor VIIa.

Thrombin-induced platelet activation and fibrin deposition

contribute further to the growth and strength of local hemo-

static plugs.

Laboratory Measurement

Platelets can be counted either manually or using an automated

cell counter. The manual method involves use of a hemocyt-

ometer. Even distribution of the platelets and absence of

clumping of the platelets are essential to accurate counting

by the technician.

Automated cell counters come in several varieties including

optical and flow cytometric counters. Counting accuracy has

been improved by optical counters which identify platelets

by their light-scattering properties,12 while flow cytometers

quantify platelets by measuring the intensity of fluorescence

from labeled antibodies directed against platelet surface

antigens.13

Clumping of platelets can lead to an inaccurate platelet count,

tending toward thrombocytopenia. Appropriate blood collection

involves addition of EDTA as an anticoagulant. Once collected

outside the body, platelets tend to change shape, which can

affect the results of electronic counts. As such, blood samples

should be analyzed within 3 hours of collection to minimize

counting errors related to ex vivo platelet shape alteration. Spur-

ious thrombocytopenia due to clumping can be minimized by

ascertaining that an adequate volume of EDTA is added to the

sample. If EDTA-dependent agglutinins are present, clumping

is unavoidable, but this is rare, occurring in <1% of normal indi-

viduals. These autoantibodies are directed against a platelet sur-

face epitope on glycoprotein IIb/IIIa that is revealed upon

EDTA exposure.14 Such situations can be elucidated, and an

accurate platelet count obtained, by repeating blood collection

and platelet counting using heparin or citrate as an anticoagulant

in lieu of EDTA (Figure 3).15

Platelet Dysfunction With Normal Counts

In addition to the quantitative measurement of platelets, plate-

let function can be assessed indirectly, but is difficult to do ex

Figure 2. Clinical evaluation of thrombocytopenia.

270 Journal of Intensive Care Medicine 28(5)

vivo. Measurement of in vivo bleeding time is impractical and

subject to methodological difficulties, particularly in patients

in the ICU.16 Platelet aggregometry methods were developed

whereby platelet counts are performed before and after stimu-

lation of the sample with platelet agonists, such as epinephrine

or collagen, to induce clumping.17 More recently, platelet func-

tion assays have become commercially available wherein pla-

telet function is indirectly assessed by agglutination of fibrin-

coated beads.18 Another method to assess platelet function is

to measure the drop in flow through a capillary tube as platelets

form a hemostatic plug along the internal surface coated with a

platelet agonist.19

Prolongation of the bleeding time has long been associated

with azotemia, although a correlation between degree of blood

urea nitrogen elevation and clinical bleeding has not been

demonstrated.20 It has been proposed that circulating toxins

adversely affect platelet function21 as normal platelet function

is restored upon mixing platelets from a uremic patient with

normal serum. Other factors cited include abnormal or

decreased expression of platelet glycoproteins, altered release

of signaling molecules such as arachadonic acid and

prostaglandin, and abnormal platelet cytoskeleton. Thus, clini-

cians might seek to assess the degree of coagulopathy in the

setting of uremia by measuring platelet functionality via meth-

ods as described above. In practice, platelet functionality is dif-

ficult to ascertain and difficult to interpret in all but the most

specialized laboratories and therefore coagulopathy due to ure-

mia mostly remains a clinical observation.

Although rare, some individuals also have inherited defects

in their platelet function. Such defects include the giant platelet

disorders of glycoprotein abnormalities and alpha granule defi-

ciency,22 small platelets as seen in Wiskott-Aldrich syn-

drome,23 and the absent platelet clumping of Glanzmann

thrombasthenia.24

Two hematologic disorders—myelodysplastic syndrome

and myeloproliferative disorders (MPDs)—can have a drama-

tically increased risk of bleeding with normal platelet counts

due to platelet dysfunction. In the case of MPD, there is an

increased risk of bleeding with elevated platelet counts, partic-

ularly in patients whose platelet count is >800 000/mL. The

increased incidence of hemorrhage in patients with thrombocy-

tosis is due to reduced levels of von Willebrand factor in the

Figure 3. Laboratory evaluation of thrombocytopenia.

Wang et al 271

plasma.25 The bleeding can be quite severe in some patients;

judicious use of platelets and replacement of factors (eg, fresh

frozen plasma) are appropriate management strategies.

Clinicians may opt to correct platelet dysfunction in the

setting of clinical bleeding or in anticipation of a surgical

procedure. Correction of anemia to a hematocrit above 30%allows platelets to occupy the space closest to the endothelial

surface, while red blood cells occupy the center of the vessel

such that the platelets are more aptly positioned to adhere to

the endothelium and form a plug in the event of endothelial

injury.26 Administration of 1-desamino-8-D-arginine vasopres-

sin increases the release of preformed factor VIII/von Willeb-

rand factor multimers,27 improving bleeding time within an

hour and lasting up to 24 hours.28 Similarly, infusion of cryo-

precipitate enhances platelet aggregation through substances

such as factor VIII/von Willebrand multimers.29 Administra-

tion of conjugated estrogens can be employed for prolonged

control of bleeding30 as peak effects on the bleeding time are

seen after 5 to 7 days of therapy.31 The effect of estrogen on

hemostasis in a uremic milieu is thought to be mediated by

estrogen receptors as it is neutralized by blockade with agents

such as tamoxifen.32

Mechanisms of Thrombocytopenia

Massive Consumption

Thrombocytopenia may occur due to massive consumption of

circulating platelets in the setting of exuberant clot formation

in response to massive hemorrhage. Patients in such settings

usually also receive massive transfusions of blood products,

which can then dilute the platelet count. This latter effect is

variable such that one cannot predict the degree of thrombocy-

topenia based on number of units, nor type of blood product,

transfused.33 A general rule of thumb is to transfuse one pher-

esis pack (6 units) of platelets for every 6 units of packed red

blood cells in anticipation of a platelet count of less than

75 000/mL.

Platelets can also be consumed in the setting of DIC. The

mechanisms that normally tightly regulate thrombin formation

become overwhelmed, such that thrombin circulates freely,

causing widespread activation of platelets. Platelets are thus

consumed in response to the bleeding associated with DIC.34

Platelet transfusions can be administered as part of the suppor-

tive care (with a goal platelet count of 75 000/mL if the patient

is actively bleeding or 10 000/mL to prophylax against sponta-

neous bleeding) while definitive treatment is directed at the

underlying process driving the DIC.35

Thrombocytopenia resulting from platelet consumption is

also seen in TTP. In contrast to DIC, in which there is massive

activation of the coagulation cascade, TTP is characterized by

areas of endothelial injury and local platelet activation, most

commonly in the renal and cerebral circulations, while sparing

the pulmonary and hepatic vasculature.36 Unique to TTP are

unusually large von Willebrand factor (ULVWf) multimers

that are contained within the thrombi characteristic of TTP, and

promote further platelet aggregation.37 It is thought that defi-

ciency of ADAMTS13 (A Disintegrin-like And Metallopro-

tease with ThromboSpondin type 1 repeats) allows ULVWf

multimers to go uncleaved and accumulate,38 thus driving the

thrombosis in TTP. Plasma exchange in treatment of TTP is

more effective than plasma infusion alone, as the former serves

to remove ULVWf multimers as well as replace

ADAMTS13.39 Platelet transfusions are typically avoided in

TTP in the absence of bleeding due to concern about ‘‘fueling

the fire’’ of consumption.

The ‘‘HELLP’’ (hemolysis, elevated liver enzymes, low pla-

telets) syndrome in pregnant women is also characterized by

thrombocytopenia resulting from consumption in the formation

of local hemostatic plugs. It is thought that endothelial damage

occurs in areas of placental ischemia, leading to platelet activa-

tion and aggregation.40 Platelets can be transfused to a count of

greater than 75 000/mL in the treatment of active bleeding.

Platelet Destruction

Increased platelet destruction usually occurs as an immune-

mediated phenomenon, with less evidence of physical destruc-

tion in situations such as cardiopulmonary bypass or within

giant hemangiomata. Patients with ITP can demonstrate plate-

let autoantibodies which can arise spontaneously or following

an infection,41 although the absence of platelet autoantibodies

does not rule out ITP, nor is their presence sufficient to make

a diagnosis. Postinfectious ITP may represent cross-reactivity

of virus-specific antibodies with normal platelet antigens.42

There is also evidence of immune-mediated decreased platelet

production in some patients with ITP.43 Idiopathic thrombocy-

topenic purpura remains a diagnosis of exclusion.

Thrombocytopenia induced by heparin and its analogs is an

entity distinct from other forms of drug-induced thrombocyto-

penia. Up to 2% of patients receiving heparin will develop

heparin-induced thrombocytopenia (HIT) with 30% of such

patients developing syndromic thrombocytopenia and throm-

bosis (HITTS). Both HIT and HITTS occur 5 to 10 times more

frequently in patients receiving unfractionated heparin than in

those receiving low-molecular-weight heparin. Only a few

studies have assessed the incidence of HIT in patients in the

ICU. Two Canadian studies suggest that HIT is rarely the cause

of thrombocytopenia in the ICU. In these studies, only 1 of 65

medical–surgical ICU patients who were clinically suspected

of having HIT actually had serologic evidence of HIT.1,44 The

diagnosis of HIT/HITTS should be considered in any patient

receiving heparin with an otherwise unexplained drop in their

platelet count of at least 50% and/or a new thrombotic event

5 to 10 days after initiation of heparin therapy.45 Even heparin

flushes have been known to cause HIT on occasion. The onset

of HIT/HITTS has occasionally been seen as early as 10 hours,

especially if the patient has received heparin in the previous 3

months, or as late as 3 weeks post-heparin therapy induction.46

The most common symptoms of HIT are extension or enlarge-

ment of a previously diagnosed clot or development of a new

clot at another location in the body while on heparin therapy.

272 Journal of Intensive Care Medicine 28(5)

Heparin-induced thrombocytopenia/HITTS can cause both

venous and arterial thromboses which can lead to deep venous

thrombosis and pulmonary embolus, or myocardial infarction,

stroke, and acute leg ischemia, respectively. Skin lesions at

heparin injection sites and acute systemic reactions after an

intravenous (IV) bolus of heparin are relatively specific signs

for HIT. An acute systemic reaction is often displayed within

5 to 120 minutes of infusion and may consist of fever, chills,

hypertension, tachycardia, shortness of breath, and chest pain.

This acute systemic reaction can occur in up to 25% of

patients.47 The skin lesions at the site of injection can occur

in 10% to 20% of patients with HIT, and both necrotizing and

non-necrotizing lesions (erythematous plaques) may be seen.

Adrenal hemorrhagic necrosis can occur in 3% to 5% of

patients with HIT and is characterized by flank pain or abdom-

inal pain. If adrenal necrosis is bilateral, then death from adre-

nal crisis as a result of adrenal vein thrombosis with secondary

hemorrhagic infarction may occur.48-50

Most patients with HIT/HITTS have circulating antibodies

to complexes containing platelet factor 4 (PF4) and heparin.

Heparin-PF4 complexes form preferentially when the molar

ratios of these 2 components are roughly equal. These

heparin-PF4 complexes are the most antigenic. Immune com-

plexes made up of heparin-PF4 complexes and antibodies

against these complexes are usually of the IgG type. The tail

of the antibody then binds to the FcgIIa receptor, a protein

on the surface of the platelet, which results in platelet activation

and the formation of platelet microparticles, leading to clot for-

mation and consequently thrombocytopenia.51

The first screening test in someone suspected of having HIT

is an enzyme-linked linked immunosorbent assay (ELISA)

aimed at detecting antibodies against heparin-PF4 complexes.

Since the ELISA test detects all circulating antibodies that bind

heparin-PF4 complexes, there are false positives when using

this method. It is thus highly sensitive but not specific. There-

fore, those with positive ELISA results are verified with a func-

tional assay. This test uses platelets and serum from the patient;

the platelets are washed and mixed with serum and heparin.

The sample is then tested for the release of serotonin, a marker

of platelet activation. If this serotonin release assay shows high

serotonin release, the diagnosis of HIT is confirmed.50,51 This

is considered the ‘‘gold standard’’ for diagnosis with a positive

predictive value approaching 100%, although the negative pre-

dictive value is only 30% and therefore a negative test does not

necessarily exclude the diagnosis.52 Because it takes an aver-

age of 4 days for the result of this test to return, treatment must

be initiated for HIT based upon clinical and other laboratory

suspicion prior to this test result becoming available.

For patients with suspected and verified HIT/HITTS, treat-

ment is aimed at minimizing further thrombosis in addition to

stabilizing the platelet count. These patients are especially

prone to warfarin necrosis and should therefore not receive

warfarin as initial treatment.53 Warkentin discussed the ‘‘six

treatment principles of heparin-induced thrombocytopenia’’

in 2006.50 Heparin should be immediately discontinued and

an alternative nonheparinoid anticoagulant should be instituted

at therapeutic doses. It is useful at this point to list heparin as an

allergy in the patient’s chart so that further heparin is not admi-

nistered, including during hemodialysis. Warfarin administra-

tion should be avoided until substantial platelet recovery has

occurred (if warfarin has already been administered, then treat

with vitamin K), and platelet transfusions should be avoided as

well. Testing for HIT antibodies should be undertaken, as well

as possible evaluation for lower-limb deep venous thrombosis.

Three main nonheparinoid treatment options exist: lepirudin,

argatroban, and danaparoid—although the latter is not avail-

able in the United States and argatroban is not available in the

United Kingdom. Patients treated with lepirudin, which is

cleared by the kidneys and thus should be avoided in the setting

of renal failure, showed a relative risk reduction of death of

0.52 and a relative risk reduction of amputation of 0.42 when

compared to historical controls.54,55 Patients treated with arga-

troban, which is metabolized by the liver and thus should be

avoided in the setting of hepatic impairment, showed a relative

risk reduction of 0.2 and 0.18 for death and amputation, respec-

tively, when compared to historical controls.56,57 Bivalirudin is

another commercially available direct thrombin inhibitor in the

United States. Its efficacy in achieving anticoagulation in the

setting of HIT has been demonstrated to be equivalent to that

of argatroban.58 After there has been at least partial recovery

of the platelet count, then warfarin should be started and con-

tinued for at least 4 weeks if no thrombosis occurred, or 3

months if thrombosis did occur, although this area requires fur-

ther study.59

The clinical significance of heparin-dependent antibodies

in the absence of thrombocytopenia or thrombosis, which is

particularly common in patients who have undergone car-

diac surgery, is unknown.60 In patients diagnosed with HIT,

the incidence of subsequent thrombosis is approximately

53%, in a venous:arterial ratio of 4:1. Thus, anticoagulation

with this diagnosis, or high suspicion of this diagnosis,

remains the standard of care.61,62 Special cases in which the

patient is at concomitant risk of bleeding from another dis-

ease, such as liver failure, require individual determination

of the relative risks and benefits of pharmacologic

anticoagulation.

The immune response to heparin appears to be transient and

the PF4-heparin antibodies disappear from the circulation

within a median of 85 days.45 Although rigorous data are lack-

ing, patients should receive alternative anticoagulation for most

indications. For certain procedures, such as cardiac bypass sur-

gery, the use of direct thrombin inhibitors poses a considerable

bleeding risk, and it is recommended that patients with a

remote history of HIT who have negative tests for PF4-

heparin antibodies receive anticoagulant therapy with heparin

during the procedure, with an alternative anticoagulant agent

used postoperatively, if needed.63

Decreased Production

Disorders and toxic therapies, for example, chemotherapy,

that suppress or damage the bone marrow can cause

Wang et al 273

thrombocytopenia, usually in conjunction with anemia and

leukopenia. This can be seen in transient viral infections, such

as mumps, rubella, and varicella, as well as in chronic infec-

tions such as chronic hepatitis C infection and infection with

the human immunodeficiency virus (HIV). Acute infections

such as parvovirus and cytomegalovirus can also cause throm-

bocytopenia, although more often than not, this manifests as

pancytopenia.

Human immunodeficiency virus affects megakaryocytes,

causing abnormalities in the ultrastructure, resulting in

decreased platelet production.64 There is also evidence of

increased apoptosis of megakaryocytes in the setting of HIV

infection.65 Patients infected with HIV also have a higher inci-

dence of HIT,66 ITP, and possibly hemolytic uremic syn-

drome–thrombotic thrombocytopenic purpura, particularly if

the viral load is not well controlled.

Alcohol abuse can result in thrombocytopenia through sev-

eral mechanisms. Alcohol has a direct toxic effect on megakar-

yocytes, affecting platelet production. Decreased production in

the setting of alcohol abuse can be exacerbated by the accom-

panying dietary deficiency of folate and/or vitamin B12, which

often manifests as macrocytosis. Should alcoholic cirrhosis

develop, concomitant splenomegaly can result in sequestration

of circulating platelets.67

Platelet Sequestration

Platelet sequestration in the spleen can increase from 33% up to

90% of the total platelet mass in the setting of splenomegaly.

This can be seen in clinical settings such as cirrhosis, portal

hypertension, and polycythemia vera. Other diagnoses com-

monly seen in ICU patients include infection and congestive

heart failure, which account for 16% to 36% and 4% to 10%of cases of splenomegaly, respectively.68 In these instances,

clinical bleeding is not common despite measured thrombocy-

topenia, as the total platelet mass and platelet survival are nor-

mal.69 The platelets sequestered in the spleen can enter the

general circulation in response to usual coagulation pathway

signaling.

Common Conditions and Etiologies forThrombocytopenia in the ICU

Drug Effects

Drugs can adversely affect platelet function, production, and

recruitment. Aspirin inhibits COX-1, blocking thromboxane

A2 production and thus disrupting platelet aggregation. Non-

steroidal anti-inflammatory drugs inhibit COX-1 to a lesser

degree than aspirin such that the bleeding risk is somewhat

less.70 Clopidogrel use has become increasingly common as

it now carries indications for acute treatment of myocardial

infarction as well as long-term, use following drug-eluting cor-

onary artery stent placement. Activation of the glycoprotein

IIb/IIIa receptor is irreversibly blocked by the active metabolite

of clopidogrel.71 Clopidogrel has also been identified as cause

of TTP. Other antiplatelet agents in clinical use include dipyr-

idamole and ticlopidine, both of which disrupt platelet aggrega-

tion by preventing activation of the glycoprotein IIb/IIIa

receptor complex.72

Conjunctive use of platelet glycoprotein IIb/IIIa receptor

antagonists, such as abciximab and eptifibatide, in the setting

of percutaneous coronary revascularization has become the

standard of care in the past decade. In addition to preventing

platelet aggregate formation, abciximab, a human-murine

monoclonal antibody, also displaces fibrinogen from activated

glycoprotein IIb/IIIa receptors, facilitating dispersal of newly

formed platelet aggregates.73 Adjunctive use of glycoprotein

IIb/IIIa inhibitors has significantly improved the reduction in

risk afforded by percutaneous coronary revascularization.

However, use of this adjunctive medical therapy is associated

with risks including bleeding requiring red cell transfusion and

thrombocytopenia requiring platelet transfusion.74

Although not common, acute profound thrombocytopenia,

defined as a platelet count <20 000/mL occurring within 24

hours of initial treatment, can occur following glycoprotein

IIb/IIIa inhibitor administration. There is evidence to suggest

that affected individuals have preexisting serum antibodies to

epitopes in the glycoprotein IIb/IIIa complex that are induced

by administration of certain members of this class of com-

pounds. Alternatively, the drug–receptor complex may induce

an immune response.75 Thrombocytopenia associated with gly-

coprotein IIb/IIIa inhibitor administration generally responds

to platelet transfusion, is not associated with major clinical

sequellae,76 and platelet counts return to baseline within 2

weeks.77 Re-administration of glycoprotein IIb/IIIa inhibitors

should be done with extreme caution as re-challenge may be

associated with an increased risk of thrombocytopenia in cer-

tain individuals.78

Many other drugs, which were not designed or intended to

target platelets, have been implicated as potential causes of

thrombocytopenia (Table 3). It is difficult to determine whether

a specific drug is the cause of thrombocytopenia in particular

instances as the patient may be taking multiple potentially cul-

prit medications, and the patient’s underlying illness may also

contribute to decreased platelet counts. Typically, 5 to 7 days of

exposure are necessary to develop drug-induced thrombocyto-

penia, and a platelet count of <20 000/mL increases the likeli-

hood that a patient has drug-induced thrombocytopenia.

Reese et al79 recently developed a database of drugs associ-

ated with thrombocytopenia and classified those drugs with

the greatest evidence of association with thrombocytopenia.

Evidence included published case reports of suspected

Table 2. Drugs Affecting Platelet Function.

AspirinNonsteroidal anti-inflammatory drugsClopidogrelDipyridamoleTiclodipine

274 Journal of Intensive Care Medicine 28(5)

drug-induced thrombocytopenia; isolation of drug-dependent,

platelet-reactive antibodies from the serum of patients with sus-

pected drug-induced thrombocytopenia; and reports within the

Food and Drug Administration’s (FDA) Adverse Event Report-

ing System of drugs associated with thrombocytopenia. Of the

1468 suspected drugs, 23 drugs had evidence of association

with thrombocytopenia by all 3 methods.79 Here we discuss

several such drugs that are commonly employed in the care

of ICU patients.

Trimethoprim/sulfamethoxazole (TMP/SMX) has long been

employed as prophylaxis against Pneumocystis jiroveci pneu-

monia, in the empiric treatment of urinary tract infections, and

more recently in treatment of community-acquired methicillin-

resistant Staphylococcus aureus. Reports of adverse drug

reactions suggest an incidence of TMP/SMX-induced thrombo-

cytopenia of 1 in 25 000 patients.80

Piperacillin is commonly used in its combination form with

tazobactam in empiric treatment of suspected gram-negative

infections, particularly in the abdomen, as well as in treatment

of suspected or proven infections due to Pseudomonas aerugi-

nosa. Thrombocytopenia has been associated with piperacillin

more frequently than with other b-lactam drugs.81 Retrospec-

tive data suggest current use of b-lactam antibiotics is associ-

ated with an increased risk of thrombocytopenia (odds ratio

7.4, 95% confidence interval 1.8-29.6).82

Vancomycin has been the mainstay of treatment for

methicillin-resistant Staphylococcus aureus infections. It is

also commonly employed in empiric treatment of suspected

or proven gram-positive infections, particularly in the blood

and skin or other soft tissues. The incidence of vancomycin-

associated thrombocytopenia ranges from 0.5% in a retrospec-

tive study comparing safety with teicoplanin83 to 21% in a

prospective long-term use study comparing safety with

linezolid.84 It has also been suggested that administration of van-

comycin has a negative effect on the posttransfusion platelet

increment.85

Use of linezolid has increased significantly in the recent

years as it has similar clinical indications to those of vancomy-

cin and is also available in an oral formulation. The incidence

of linezolid-associated thrombocytopenia was reported as <3%in clinical trials86 but has since been reported to be as high as

35% in studies of long-term use84 during which patients were

usually transitioned from an IV to oral formulation after 7 days.

Potential risk factors for developing linezolid-associated

thrombocytopenia include renal insufficiency87 and end-stage

renal disease.88

Ranitidine is commonly administered to intubated and

mechanically ventilated ICU patients as prophylaxis against

stress-induced gastric ulcers. Use of histamine-receptor antago-

nist medications, as a class, is commonly cited as a potential

cause for thrombocytopenia. There are limited published data

supporting an association between ranitidine administration

and thrombocytopenia.89

Phenytoin is a commonly employed anticonvulsant medica-

tion and is frequently administered in loading doses to ICU

patients. There are limited case reports of phenytoin-

associated thrombocytopenia, predominantly in the neurosurgi-

cal literature. However, a correlation between phenytoin

administration and thrombocytopenia was demonstrated in a

surgical ICU population.90

Sepsis

Thrombocytopenia occurs in over 50% of patients with septic

shock.91 It is not clear whether this is a result of decreased pro-

duction or massive consumption. Hemophagocytosis, specifi-

cally of megakaryocytes, has been observed in bone marrow

aspirates from patients with sepsis,92 lending support to the

possibility of decreased production. Massive consumption is

supported by the observation that within the first 24 hours of

the onset of sepsis, there is evidence of platelet activation as

measured by b-thromboglobulin and PF4 levels.93

It has long been observed that the degree of coagulation acti-

vation correlates with a patient’s shock status.94 Unlike the

poor predictive value of scores such as MODS (Multiple Organ

Dysfunction Score), SAPS (Simplified Acute Physiology

Score), and APACHE (Acute Physiology And Chronic Health

Evaluation), minimal platelet counts of <150 000/mL in ICU

patients correlate with higher ICU mortality, as does a drop

in platelet count to �50% from admission.95

Hypothermia

Mild systemic hypothermia has been increasingly employed in

the last decade in an effort to increase the rate of neurologic

recovery after resuscitation from cardiac arrest.96 Selective

brain cooling has been used experimentally, as well as in the

pediatric population for perinatal hypoxic encephalopathy.97

Table 3. Drugs Associated With a Decrease in Platelet Count.79

AbciximabAcetaminophenAmpicillinCarbamazepineEptifibatideEthambutolHaloperidolIbuprofenIrinotecanLinezolidNaproxenOxaliplatinPhenytoinPiperacillinQuinidineQuinineRifampinSimvastatinSulfisoxazoleTirofibanTrimethoprim-sulfamethoxazoleValproic AcidVancomycin

Wang et al 275

More recently, systemic hypothermia has been evaluated in

patients with acute stroke98 and acute severe traumatic brain

injury99 in an effort to improve neurologic outcomes, and

in acute liver failure as a bridge to liver transplantation.100

Protocols to induce therapeutic hypothermia vary among insti-

tutions but generally involve use of an external cooling device

to cool patients over 24 hours to target temperatures of 32�C to

34�C, followed by passive rewarming over a period of 8 hours.

Some institutions employ ‘‘long-term’’ hypothermia (>72

hours) in treatment of severe brain edema following neurologic

insults such as subarachnoid hemorrhage.101

Decreased platelet counts and bleeding are recognized com-

plications associated with therapeutic hypothermia. This was

identified in canine models in the 1950s, at which time heparin

was evauated to minimize the associated bleeding tendency.102

Later descriptions arose from cases in neonatal cold injury103

and open heart surgery with extracorporeal circulation.104 In

addition to the cold-associated platelet aggregation, a second

stage of irreversible platelet aggregation has been described

to occur during rewarming.105 This 2-hit hypothesis may pro-

vide an explanation for the massive pulmonary hemorrhage and

other bleeding catastrophes seen in infants who die while being

rewarmed, and for delayed traumatic intracerebral hemorrhage.

The mechanism of thrombocytopenia induced by hypother-

mia is not completely understood. In vitro studies demonstrate

that platelets are hyperreactive to fluid shear stress at lower

temperatures106 (24�C, 32�C, and 35�C) as compared with that

at 37�C. Resultant enhanced mechanical cross-linking is sus-

pected to be responsible for enhanced platelet aggregation and

resultant thrombocytopenia from consumption.

Pneumonia and sepsis, which are each independent risk fac-

tors for thrombocytopenia, are also recognized complications

associated with therapeutic hypothermia.

Transfusion Strategies

Following collection from donors, red cells are separated from

plasma by centrifugation, and platelets are concentrated by

repeat centrifugation. Platelet concentrates can be stored for

up to 8 days107 under constant agitation at room temperature,

although the incidence of bacterial contamination increases,108

and efficacy of transfusion decreases,109 beyond 5 days of stor-

age. Individual units are usually transfused as parts of 5 to 10

unit pools when given as prophylactic therapy in adults or in

treatment of bleeding. Alternatively, a volume of platelet con-

centrate equivalent to 6 to 10 units can be collected from a sin-

gle donor using platelet pheresis. This donation method is

advantageous in reducing the number of donors to which a reci-

pient is exposed, thus decreasing infection risk as well as anti-

genic exposure.

Following transfusion of platelets, the platelet count peaks

approximately 1-hour posttransfusion and returns to baseline

in approximately 72 hours. Platelet count and platelet survival

are not as robust clinically as would be mathematically pre-

dicted such that transfusion of 6 units of platelets generally

raises the platelet count by 25 000/mL. Factors that negatively

influence the platelet count increment include increased

duration of storage prior to transfusion, presence of splenome-

galy, fever, or infection in the recipient.110 Refractoriness,

defined as a platelet count increment of <5000/mL 1-hour post-

transfusion, is seen in situations such as ITP wherein antibodies

destroy platelets at an accelerated rate.111

The American Society of Clinical Oncology in 2001 pub-

lished practice guidelines for platelet transfusion in patients

with cancer. These guidelines indicate 10 000/mL as a threshold

for transfusion to prophylax against spontaneous bleeding. A

platelet count above 40 000 to 50 000/mL is recommended as

sufficient to perform invasive procedures (such as placement

of central venous catheters and transbronchial or endoscopic

biopsies) safely, in the absence of other coagulopathies. Bone

marrow biopsies can be performed safely at platelet counts

<20 000/mL. It is recommended that a posttransfusion platelet

count is obtained to demonstrate that the desired platelet count

has been reached, and that additional platelets be available for

transfusion on short notice in the event of unexpected

bleeding.111

Recommendations published by the Italian Society of

Transfusion Medicine and Immunohaematology in 2009

includes lumbar puncture and liver biopsy on its list of invasive

procedures that can be safely performed with a platelet count

above 50 000/mL. In the setting of active bleeding and massive

red cell concentrate transfusion, targeting a platelet count of

75 000/mL is suggested as the platelet count can become

diluted.112

The American Society of Hematology published similar rec-

ommendations in 2007. The committee also recommended

transfusion of platelets to achieve a count >100 000/mL in

patients with intracerebral bleeding and during or following

neurosurgical procedures. Recommended measures to prevent

platelet alloimmunization include use of ABO-compatible pla-

telets, which also achieve superior posttransfusion platelet

count increments. However, the data to support leukoreduction

in the general population are inconclusive.113

Platelet refractoriness should raise one’s suspicion for alloim-

munization. Management options of alloimmunized patients

include selection of human leukocyte antigen (HLA)-compatible

donors from a registry, identification of HLA-antibody

Table 4. Platelet Transfusion Goals.

Platelet Transfusion Goal,1000/mL

Prophylaxis against spontaneousbleeding

10

Active bleeding 75Bone marrow biopsy 20Central venous catheter placement 50Transbronchial biopsy 50Lumbar puncture 50Liver biopsy 50Intracerebral bleeding 100Peri-neurosurgical procedure 100

276 Journal of Intensive Care Medicine 28(5)

specificities and finding compatible donors, or performing plate-

let cross-match tests. Failure of these measures to improve post-

transfusion platelet increments may be due to failure to detect

relevant antibodies, or a nonimmune cause. Nonimmune platelet

refractoriness can be seen in patients who have developed lym-

phocytotoxic antibodies, patients with splenomegaly, and female

patients who have had �2 pregnancies. Only splenectomy and

giving ABO-compatible platelets have been shown to improve

the platelet count response to transfusion in such patients.114 Stra-

tegies which do not affect the platelet count, but of may be benefit

in controlling bleeding include giving small-dose, frequent trans-

fusions of platelets; administration of IV IgG, fibrinolytic inhibi-

tors, or recombinant factor VIIa.115

Summary

Thrombocytopenia is a common finding in patients in the ICU,

although clinically significant bleeding generally does not

occur in the absence of severely decreased platelet counts. The

potential etiologies of thrombocytopenia in ICU patients are

myriad and often overlap. Treatment of the underlying disease

process often results in improvement of the platelet count in

conjunction with avoidance of potentially marrow- or

platelet-toxic therapies. Supportive care in the form of platelet

transfusions can be administered in the interim.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to

the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, author-

ship, and/or publication of this article.

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