REVIEW

CURRENT
OPINION Heparin-induced thrombocytopenia
Theodore E. Warkentin a,b

Purpose of review
Thrombocytopenia and heparin exposure are common in critically ill patients, yet immune heparin-induced
thrombocytopenia (HIT), a prothrombotic adverse effect of heparin, rarely accounts for thrombocytopenia in
this patient population. The review discusses the clinical and laboratory features that distinguish HIT from
non-HIT thrombocytopenia.
Recent findings
The frequency of HIT in heparin-exposed critically ill patients is approximately 0.3–0.5% versus at least a
30–50% background frequency of non-HIT thrombocytopenia. Most patients who form anti-PF4/heparin
antibodies do not develop HIT, contributing to HIT overdiagnosis. Disseminated intravascular coagulation
(DIC), particularly in the setting of cardiogenic or septic shock associated with ‘shock liver’, can cause
ischemic limb gangrene with pulses, mimicking a clinical picture of HIT. However, whereas non-HIT-related
DIC with microthrombosis can be treated with heparin, HIT usually requires nonheparin anticoagulation.
HIT-associated DIC can result in an elevated INR, which could reflect factor VII depletion because of
extrinsic (tissue factor) pathway-mediated activation of coagulation.
Summary
Greater understanding of the various clinical and laboratory features that distinguish HIT from non-HIT
thrombocytopenia could help improve outcomes in patients who develop thrombocytopenia and
coagulopathies in the ICU.
Keywords
disseminated intravascular coagulation, heparin-induced thrombocytopenia, ischemic limb gangrene with
pulses, shock liver

INTRODUCTION &&
(e.g., chondroitin sulfate) [12 ]. In-vivo thrombin
Heparin-induced thrombocytopenia (HIT) is an generation results from formation of procoagulant,
adverse drug reaction with counter-intuitive fea- platelet-derived microparticles [13] and monocyte
tures, such as its strong association with thrombosis, activation with tissue factor expression [14].
despite being caused by an anticoagulant. At least The review highlights the clinical and serolog-
50% of patients with serologically-proven HIT ical features of HIT, emphasizing timing of onset of
develop thrombosis [1–3], a rate 12-fold higher than thrombocytopenia in pointing to a potential diag-
controls [4]. Thrombi usually involve large veins nosis of HIT, and the role of platelet activation
and/or arteries (‘macrothrombosis’) [1–3], although assays to judge pathogenicity of heparin-dependent
some patients with concomitant disseminated intra- antibodies. The explanations for limb ischemia in
vascular coagulation (DIC) evince microthrombosis the critically ill patient will also be discussed.
&&
[5,6 ].
HIT is caused by platelet-activating IgG anti-
a
bodies [7] that recognize multimolecular complexes Department of Pathology and Molecular Medicine and bDepartment of
Medicine, Michael G. DeGroote School of Medicine, McMaster Univer-
comprised of (cationic) platelet factor 4 (PF4) and
sity, Hamilton, Ontario, Canada
the (polyanionic) sulfated polysaccharide, heparin
Correspondence to Professor Theodore E. Warkentin, Hamilton
[8,9]. Despite its key immunizing role, heparin is not Regional Laboratory Medicine Program, Room 1–270B, Hamilton Health
necessarily required for antibody pathogenicity; this Sciences, Hamilton General Site, 237 Barton St. East, Hamilton, ON L8L
is because certain ‘strong’ HIT antibodies activate 2X2, Canada. Tel: +1 905 527 0271 x46139; fax: +1 905 577 1421;
&&
platelets even in the absence of heparin [5,10,11 ], e-mail: [email protected]
probably because PF4 forms antigenic complexes Curr Opin Crit Care 2015, 21:576–585
with endogenous platelet-associated polyanions DOI:10.1097/MCC.0000000000000259

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 Heparin-induced thrombocytopenia Warkentin

&&
artery thrombosis [6 ,15,22,23]. Rarely, severe
KEY POINTS HIT-associated DIC leads to microthrombosis and

HIT accounts for only a small minority (at most, 1%) of critical limb ischemia even in the absence of war-
&&

patients who have thrombocytopenia in the ICU (overall farin therapy [6 ].

frequency of HIT of 0.3–0.5% among a background HIT is uncommon in the ICU; for at most one in
frequency of thrombocytopenia of 30–50%). 100 thrombocytopenic ICU patients is HIT the
explanation [24]. The clinician must distinguish

Whereas virtually all patients with HIT have anti-PF4/
heparin antibodies, only a minority of critically ill the (relatively) uncommon patient with HIT among
patients with detectable anti-PF4/heparin antibodies the many without. Although scoring systems for
develop HIT (thus risking HIT ’overdiagnosis’ if a HIT are available, such as the 4Ts [25–27] and the
positive anti-PF4/heparin immunoassay is automatically HIT Expert Probability [28,29] systems, generally
considered indicative of HIT). speaking, almost all ICU patients score ‘low prob-

The diagnosis of HIT is made most reliably if the patient ability’ for HIT. Indeed, for HIT to be realistically
develops unexpected thrombocytopenia bearing a entertained in an ICU patient, thrombosis and/or a
plausible temporal relationship with a proximate clear new-onset thrombocytopenia bearing
heparin exposure, and if high levels of anti-PF4/ temporal relationship to a preceding heparin
heparin antibodies with platelet-activating properties exposure would be necessary (vide infra).
are detected.

Non-HIT acute disseminated intravascular coagulation
with severe depletion of natural anticoagulants (e.g., SEROLOGICAL PICTURE
antithrombin, protein C), particularly in the setting of HIT is a ‘clinical–pathological’ syndrome [30,31],
hypotension and ’shock liver’, is associated with that is, the patient should exhibit both a clinical
symmetrical peripheral gangrene, thus potentially picture consistent with HIT, for example, thrombo-
mimicking the clinical picture of HIT (differential
cytopenia and/or thrombosis bearing a temporal
diagnosis of thrombocytopenia, coagulopathy, and
ischemic limb necrosis). relationship with a preceding immunizing exposure
to heparin (‘clinical’), and the serological profile of
HIT, namely detectability within patient serum (or
plasma) of the pathognomonic, heparin-dependent,
CLINICAL PICTURE platelet-activating antibodies (‘pathological’). A
Unexpected thrombocytopenia arising from a recent consensus conference statement recom-
platelet count fall that begins about 1 week after mended the following diagnostic framework [32]:
an exposure to heparin is the hallmark of HIT intermediate or high-probability clinical picture
&&
[15,16 ]. With new thrombosis, the likelihood of (scoring at least 4 points in the 8-point 4Ts scoring
HIT becomes even greater. Lower-limb deep-vein system [25–28]) and heparin-dependent, platelet-
thrombosis (DVT) with or without pulmonary activating antibodies, as shown either by a positive
embolism is the most common complication serotonin-release assay (SRA) [33,34] or heparin-
(50% of patients) [1–4]; upper-limb DVT occurs induced platelet activation test [35] along with a
less often, and is invariably associated with concur- corroborating positive PF4-dependent immuno-
rent or recent intravascular catheter use [17]. Less assay, such as an enzyme-immunoassay (EIA) [36].
common venous thromboses include cerebral (dural The approach reduces risk of HIT overdiagnosis
sinus) and splanchnic (mesenteric, adrenal) veins &
[37 ].
[15,18]. Adrenal vein thrombosis occurs in approxi-
mately 2% of patients, and manifests as adrenal
hemorrhagic infarction; when adrenal necrosis is HEPARIN-INDUCED THROMBOCYTOPENIA
bilateral, acute adrenal failure can result, and adre- VIEWED THROUGH THE 4TS
&
nal replacement therapy lifesaving [15,19 ]. Arterial The clinical picture of HIT is reviewed through the
thrombosis in HIT typically involves (in descending 4Ts scoring system (Table 1) [25–28].
order) lower limb, cerebral, coronary, mesenteric,
and brachial arteries; the appearance of the platelet-
rich arterial thrombi popularized ‘white clot syn- Thrombocytopenia
drome’ as a synonym for HIT [20]. The first ‘T’, ‘T’hrombocytopenia, evaluates decline
Approximately 5% of patients develop ischemic in the platelet count. In HIT, there usually is a large-
limb necrosis [21], most often because of warfarin- magnitude platelet count decline (usually, >50%)
induced protein C depletion leading to microthrom- that does not attain very low platelet count values.
bosis in a limb affected by DVT (‘warfarin-induced Indeed, 0 points are assigned if the platelet count
venous limb gangrene’) or because of acute limb falls to <10  109/l, and only 1 point given for a

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Hematological emergencies

Table 1. 4Ts scoring system

Points (0, 1, or 2 for each of four categories: maximum possible score ¼ 8)

2 1 0

Thrombocytopenia >50% platelet fall to nadir 20 30–50% platelet count fall <30% platelet fall; or nadir <10
(or >50% directly resulting
from surgery); or nadir 10–19
Timinga of platelet count fall, thro- Day 5–10 onseta (typical/delay- Consistent with day 5–10 fall, Platelet count fall 4 days (unless
mbosis, or other sequelae (first ed-onset HIT); or 1 day [with but not clear (e.g., missing picture of rapid-onset HIT – see
day of putative immunizing exp- recent heparin exposure within platelet counts); or, 1 day two left boxes)
osure to heparin ¼ day 0) past 30 days (rapid-onset HIT)] (heparin exposure within past
31–100 days) (rapid-onset
HIT); or, platelet fall after
day 10
Thrombosis or other sequelae Proven new thrombosis; or skin Progressive or recurrent thrombo- None
(e.g., skin lesions, anaphy- necrosis (at injection site); or sis; or erythematous skin lesions
lactoid reactions) postintravenous heparin bolus (at injection site); or suspected
anaphylactoid reaction thrombosis (not proven); hemo-
filter thrombosis
oTher cause for thrombocytopenia No explanation for platelet count Possible other cause is evident Definite other cause is present
fall is evident

Pretest probability score: 6–8 ¼ high; 4–5 ¼ intermediate; 0–3 ¼ low. The scoring system shown above includes minor modifications compared with previously
published versions.
a
First day of immunizing heparin exposure considered day 0; the day the platelet count begins to fall is considered the day of onset of thrombocytopenia (it
generally takes 1 to 3 more days until an arbitrary threshold that defines thrombocytopenia is passed). Usually, heparin administered at or near surgery is the
most immunizing situation (i.e., day 0).

platelet count between 10 to 19  109/l, whereas a Indeed, a study [41] of 12 postorthopedic surgi-
>50% platelet count fall with nadir 20  109/l cal HIT patients with serial blood sample availability
scores the maximum 2 points. (Only 10% of HIT showed the following clinical and serological profile
patients develop a platelet count nadir <20  109/l of HIT:
[38].) Many ICU patients develop platelet count falls
similar to that seen in HIT, and thus this criterion is (1) Day 0: first day of heparin administration
usually not very helpful for distinguishing between (usually, postoperative day 1);
HIT and non-HIT thrombocytopenia. (2) Day 2: expected postsurgery platelet count
nadir;
(3) Day 4: rising platelet count; first day anti-PF4/
Timing heparin antibodies detected (EIA);
In contrast, the second ‘T’, ‘T’iming of onset of (4) Day 6: first day of (HIT-related) platelet count
thrombocytopenia (or thrombosis) in relation to a fall;
preceding heparin exposure, is more diagnostically (5) Day 8: first day that the platelet count fall
helpful. This is because most critically ill patients exceeds 50%;
develop a single phase of thrombocytopenia that (6) Day 10: first day of thrombosis.
occurs early, either when admitted to ICU immedi-
ately postsurgery or with acute illness directly from Of course, biological variability was seen around
the community. Indeed, even uncomplicated elec- these (median) day values, but the overall pattern is
tive surgery is characterized by an early postopera- clear. Further, this tight timeline indicates HIT is a
tive platelet count fall, with the platelet count nadir point immunization event, antibody formation is
usually occurring on postoperative day 2 (range, triggered soon after surgery, when heparin admin-
days 1–4) [39]. istration coincides with PF4 released from activated
However, in patients with HIT there is a second platelets [31].
decline in the platelet count that typically begins Sometimes, a patient already has circulating HIT
5–10 days after an immunizing heparin exposure antibodies because of recent heparin exposure
(usually, heparin given intraoperatively or in the (within the previous 100 days); when heparin is
early postoperative period). It is this unexpected restarted, there is an abrupt platelet count drop
second episode of platelet count decline beginning (‘rapid-onset’ HIT) [40]. Some patients have associ-
about 1 week after heparin administration that ated acute inflammatory or cardiorespiratory
characterizes ‘typical-onset’ HIT [40]. symptoms and signs (HIT-associated ‘acute

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 Heparin-induced thrombocytopenia Warkentin

anaphylactoid reaction’) [42–44]. Because HIT anti- ill patients have plausible non-HIT explanations for
bodies are transient, rapid-onset HIT only occurs in thrombocytopenia. Accordingly, one might score 0
patients who have been immunized within the or 1 points (virtually never 2 points) when applying
previous weeks or a few months. Importantly, any this criterion to an ICU patient.
time HIT antibodies are actively formed – whether
for the first time, or on a second occasion in a
patient with previous HIT whose antibody levels HEPARIN-INDUCED THROMBOCYTOPENIA
have waned – there is at least a five-day interval -ASSOCIATED DISSEMINATED
between the immunizing (or reimmunizing) hepa- INTRAVASCULAR COAGULATION
rin exposure and the beginning of the HIT-associ- HIT has been classically viewed as a pure platelet
&&
ated platelet count fall [45 ]. activation syndrome. However, in recent years, the
‘Delayed-onset’ HIT was first used to indicate marked hypercoagulability of HIT has been appreci-
&&
HIT that begins [10] after stopping heparin. More ated, including its association with DIC [4,5,6 ,15].
recently the term has been used to also indicate Although 10–20% of patients with HIT have overt
those patients in whom HIT worsens (progressive DIC, probably DIC exists in most patients, as even
or persisting decline in the platelet count) even after normal fibrinogen levels are relatively low for the
&&
stopping heparin [5,6 ]. These patients often have patient’s usual postoperative state. Also, HIT-associ-
unusually severe thrombocytopenia with overt ated elevations in INR and activated partial throm-
(decompensated) DIC. Patients’ sera induce strong boplastin time (APTT) are less common than in
platelet activation in vitro (and presumably in vivo) other DIC conditions. Nonetheless, HIT-associated
&&
even in the absence of heparin [10,11 ]. DIC is associated with poor patient outcomes, such
as microvascular cerebral ischemia [51] and acral
&&
limb ischemic necrosis [6 ,15], and often occurs
Thrombosis in delayed-onset HIT [5].
The third ‘T’, ‘T’hrombosis, reflects HIT’s strong Figure 1 illustrates a patient who developed an
association with thrombosis. Indeed, one study elevated INR (from 1.2 to 1.5) and a falling fibrino-
showed a HIT-associated venous thromboembolism gen (from 6.2 to 4.2 g/l) at the time that HIT devel-
frequency of 50% versus a control rate of 4% [4]. oped. Coagulation factor levels were measured, and
HIT-associated thrombosis begins as early as day 5 mildly reduced factors, particularly factor VII [nadir,
(sometimes even before the HIT-related platelet 0.37 U/l (normal, 0.50 to 1.50)], explained the elev-
count fall is evident) [46,47], or as late as several ated INR, perhaps indicating extrinsic (tissue factor)
weeks post-HIT diagnosis. pathway activation in HIT (as could be explained by
Venous predominates over arterial thrombosis tissue factor expression by activated monocytes
(ratio, 4 : 1). Ischemic limb gangrene despite [14]). Interestingly, this patient’s extrinsic factor
palpable pulses usually occurs in a limb with DVT, level profile (VII < X < II) has also been observed
and usually represents a consequence of warfarin in warfarin-associated hypercoagulability compli-
therapy [22,23]. The hallmark of so-called warfarin- cating both HIT [22] and cancer-associated DIC
&
induced ‘venous limb gangrene’ is a supratherapeu- [52 ]. Another interesting aspect illustrated by this
tic international normalized ratio (INR; usual- patient’s clinical course was the abrupt increase in
ly > 4.0), which represents a surrogate marker for fibrin D-dimer level after intravenous therapeutic-
severe protein C depletion via parallel severe dose UFH was discontinued (because of HIT diag-
depletion in factor VII. When limb ischemia arises nosis) and despite subsequent (subtherapeutic) fon-
because of large-artery thrombosis, urgent throm- daparinux dosing, supporting the (counterintuitive)
boembolectomy may be limb-saving [48]. notion that stopping heparin could paradoxically
Miscellaneous features of HIT include necrotiz- ‘worsen’ HIT-associated hypercoagulability, if there
ing skin lesions at heparin injection sites [49] (and is inadequate dosing of nonheparin anticoagulation.
&
rarely at noninjection sites [50 ]) and anaphylactoid
reactions [42] beginning within 30 min postintrave-
nous unfractionated heparin (UFH) bolus [43] or NONHEPARIN-INDUCED
within 2 h following low-molecular weight heparin THROMBOCYTOPENIA ACRAL LIMB
(LMWH) injection [44]. ISCHEMIC SYNDROMES
There are explanations besides HIT for ischemic
limb gangrene syndromes encountered in ICU
OTher patients, such as symmetrical peripheral gangrene
&&
The fourth ‘T’, o‘T’her cause(s) of thrombocytope- (SPG) and purpura fulminans (PF) [6 ]. ‘Shock liver’
nia, is also relatively unhelpful, since most critically (acute ischemic hepatitis) coinciding with (non-

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Hematological emergencies

1.8 100
71-year-old male (144 kg)
INR rise to 1.5
1.5 75

APTT, sec
INR

1.2 50
Intubated and ventilated (multiple cardiac arrests)
0.9 25

D-dimer rise to
20 000 8 >20,000 1.00
Acute NSTEMI
VF (recurrent) 15 000 7 0.75

D-dimer, mg/l
400

anti-Xa, U/ml
Fibrinogen, g/l
10 000 6 0.50
Heart catheterization
Fibrinogen
PCI 5000 5 0.25
fall
IABP (cardiogenic shock)
0 4 0

300
Relative factor levels: VII < X < V < II (mean)
VII: 0.57 0.37 0.40 0.39 0.43
Platelet count (x10 /l)

X: 0.67 0.57 0.68 0.67 0.65

-9

200 Echocardiogram: large V: 0.98 0.77 0.73 0.77 0.81

left ventricular thrombus
II: 0.91 0.91 0.86 1.01 0.92
Onset of HIT

100 UFH 5000 U

q12h SC x3 Platelet count nadir = 65 Death
Fondaparinux (day 12)
UFH adjusted by APTT (maximum, 3000 U/h days 3 to 4) 7.5mg qD SC

0
0 2 4 6 8 10 12
Days after heparin

FIGURE 1. HIT-associated DIC. Following onset of HIT, the patient developed an elevated INR (from 1.2 to 1.5), a falling
fibrinogen (from 6.2 to 4.2 g/l), and a rising fibrin D-dimer level (from 3140 to >20 000 mg/l fibrinogen equivalent units).
Interestingly, the D-dimer increase occurred after stopping heparin, indicating that cessation of heparin can worsen HIT-
associated hypercoagulability. Dosing of fondaparinux was probably inadequate for this 144-kg patient. Factor studies
revealed that the elevated INR was likely explained mostly by decreased levels of factor VII. APTT, activated partial
thromboplastin time; DIC, disseminated intravascular coagulation; HIT, heparin-induced thrombocytopenia; IABP, intra-aortic
balloon pump; INR, international normalized ratio; NSTEMI, non-ST elevation myocardial infarction; PCI, percutaneous
coronary intervention; q12 h, every 12 h; qD, every day (once-daily); SC, subcutaneous; U, units; UFH, unfractionated
heparin; VF, ventricular fibrillation.

HIT) DIC, called ‘acute DIC/hepatic necrosis-limb mimicking HIT (thrombocytopenia, coagulopathy,
necrosis syndrome’, has been linked to acral limb acute limb ischemia with pulses), the anticoagulant
&&
ischemic necrosis in patients with septic shock or of choice is heparin [6 ].
&& && &&
cardiogenic shock [6 ,53,54,55 ,56 ]; in essence,
shock liver is a ‘warfarin equivalent’ predisposing
to severe depletion in protein C (as well as anti- EARLY-ONSET AND PERSISTING
thrombin). Patients have profoundly disturbed pro- THROMBOCYTOPENIA
coagulant–anticoagulant balance, that is, marked Many ICU patients develop thrombocytopenia soon
thrombin generation coincides with protein C after admission. When heparin is given and early-
&&
depletion [6 ,54]. Just as DVT localizes micro- onset thrombocytopenia persists beyond 5 days, the
thrombosis to areas distal to the DVT in HIT, in issue of HIT may be raised. However, Selleng et al.
SPG and PF, hypotension and vasopressors lead to [57] showed that ‘early-onset and persisting throm-
sluggish acral blood flow, predisposing to acral bocytopenia’ was unlikely to indicate HIT, even if
microthrombosis. Despite the clinical picture the patient formed anti-PF4/heparin antibodies;

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 Heparin-induced thrombocytopenia Warkentin

rather, the thrombocytopenia reflects the natural TREATMENT OF HEPARIN-INDUCED

history of critical illness-associated thrombocytope- THROMBOCYTOPENIA
nia plus the high frequency of forming clinically- The treatment principles of strongly-suspected (or
&&
irrelevant antibodies. However, if a superimposed confirmed) HIT include [56 ]:
platelet count fall and/or thrombosis occurs within
the day 5–10 ‘window’ of HIT, and platelet-activat- (1) Three do’s
ing antibodies are demonstrated, then the patient (a) do stop/avoid heparin (including ‘flushing’
plausibly has concomitant HIT [57–59]. intravascular catheters);
(b) do commence alternative nonheparin anti-
coagulant (usually in therapeutic doses);
AVOIDING HEPARIN-INDUCED (c) do indicate potential diagnosis of HIT in the
THROMBOCYTOPENIA OVERDIAGNOSIS medical record;
By insisting on both a positive EIA and washed (2) Three don’ts
platelet activation assay (SRA or heparin-induced (a) don’t give warfarin (treat with vitamin K if
platelet activation), the risk of a wrong diagnosis warfarin already given [21,76,77]);
of HIT is reduced. For example, certain platelet (b) don’t order prophylactic platelet transfu-
aggregation tests commonly give false-positive sions [21,77];
results when testing blood from patients, com- (c) don’t insert an inferior vena cava filter;
&
pared with the (washed platelet) SRA [60,61,62 ]. (3) Three diagnostics:
Thus, if the EIA is negative (or weakly positive), a (a) test for HIT antibodies (immunoassay and
false-positive platelet activation test should be platelet activation assay);
&
considered [37 ]. A more common issue is a (b) test for DIC;
false-positive EIA; indeed, for approximately (c) image for lower-limb DVT (presence of
three-quarters of ICU patients, a positive EIA is DVT influences duration of anticoagulant
not accompanied by a positive SRA, and the therapy).
patient is unlikely to have HIT [63,64]. The risk
of HIT ‘overdiagnosis’ [65] is minimized by con- Some of these recommendations may not be
sidering the ‘strength’ of the EIA result, for helpful. For example, stopping heparin could para-
example, a strong-positive EIA (>2.00 units of doxically increase HIT-associated hypercoagulabil-
optical density) points to a 90% probability of a ity. Indeed, as shown in Figure 1, the patient’s fibrin
positive SRA [66]. D-dimer levels rose dramatically after stopping IV
therapeutic-dose UFH. Further, progression to
venous limb gangrene in severe HIT typically occurs
PREVENTION OF HEPARIN-INDUCED after stopping heparin [22].
THROMBOCYTOPENIA The suggestion (i.e., ‘weak’ recommendation)
LMWH (vs. UFH) use is associated with an approxi- [21,77] to avoid prophylactic platelet transfusions
mate ten-fold reduced risk of HIT [2,67,68], attri- reflects observational studies indicating that platelet
butable to a three-fold lower immunization risk transfusions did not seem deleterious [78,79] and
and (among those forming clinically-relevant the reality that in the ICU a non-HIT diagnosis is
antibodies) three-fold lower ‘breakthrough’ of overwhelmingly more likely than HIT, and so the
thrombocytopenia [2,3]. The greater capacity of risk-benefit analysis in a severely thrombocytopenic
UFH (vs. LMWH) to form highly immunogenic ultra patient would likely favor platelet transfusions even
large complexes with PF4, and for the larger PF4/ if HIT is a possibility.
heparin/IgG complexes to activate platelets, likely A recent administrative database study
explains differences in HIT risk [9]. The reduced risk suggested that platelet transfusions were associated
of HIT with LMWH is best established for enoxa- with arterial thrombosis and mortality in patients
&
parin [2,3], but seems likely also with certoparin [69] with HIT [80 ]. However, implications regarding
&&
and dalteparin [56 ,67,70]. Indeed, the Prophylaxis platelet transfusions for HIT cannot be drawn. The
for Thromboembolism in Critical Care Trial (PRO- authors did not have access to laboratory results,
TECT) trial [71] suggested that dalteparin (vs. UFH) and so HIT diagnosis could not be ascertained. More
prophylaxis reduces risk of HIT in critically ill importantly, the authors had no access to platelet
patients by 75% [70], a risk reduction also sup- count values, or even whether the platelet trans-
ported by observational studies from France [72,73]. fusions were given before or after thrombotic events.
Dalteparin can be given in prophylactic doses in ICU The lack of platelet count data is a fatal methodo-
patients, since bioaccumulation is negligible even in logical flaw, as severity of thrombocytopenia is both
renally-compromised or dialysis patients [74,75]. a transfusion trigger as well as a known risk factor for

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Hematological emergencies

Table 2. Diagnostic and therapeutic approach to HIT: highlighting use of fondaparinux

A. Baseline (pretreatment) diagnostic evaluation:
Complete blood count/differential with blood film, including assessment of nucleated red blood cells (normoblasts), reticulocyte count, and red cell
fragmentsa
Coagulation tests:b PT (INR),c PTT,d fibrinogen,e fibrin D-dimer (quantitativef), and/or other fibrin-specific marker(s) (e.g., fibrin monomer), ATg
Chemistry tests: creatinine, LDHh (compared with simultaneously-measured AST, ALT, and CK), bilirubin
Lower-limb ultrasound for DVT (routine)i
Upper-limb ultrasound for DVT (if upper-limb swellingj)
B. Serial laboratory assessment (at least once-daily):
Complete blood count (follow normoblast count, if elevated)
Coagulation tests:b PT (INR),c PTT,d fibrinogen,e fibrin D-dimer (quantitativef), and/or other fibrin-specific marker(s),  ATg
Antifactor Xa level calibrated for fondaparinux (drawn at 0600 h each morning), especially if there is renal dysfunction (e.g., estimated creatinine
clearance <60 ml/min/1.73 m2);
 creatinine (if there is renal dysfunction);
 LDH (if initially elevated and hemolysis is suspected);
 AST, ALT, and bilirubin (if hepatic dysfunction is suspected);
 CK (if ischemic limb injury is suspected)
C. Therapeutic-dose fondaparinux regimen for treatment of (strongly-suspected or confirmed) acute HIT, including HIT-associated thrombosis:
First dose (afternoon/eveningk): 7.5 mg (or 10 mgl) by subcutaneous injectionm for patient weighing 50–100 kgn
Second and subsequent doses (morning at 0800 ho): 7.5 mg by subcutaneous injection
Dosing adjustments for renal failure:
Do not reduce the first dose or two; subsequently, reduce daily dose to 5 or 2.5 mg, depending on the extent of renal dysfunction, and results of
antifactor Xa levels (if available)
Target (trough) anti-Xa level (fondaparinux) is 0.60–1.00 anti-Xa U/mlp
AT concentrates: give 1000 U every 12 h (if AT depletion is documented and fondaparinux is being used for anticoagulation)g
D. Prophylactic-dose regimen for fondaparinuxq
2.5 mg by subcutaneous injectionr
E. Freeze residual plasma samples
Facilitate retrospective analysis of cases

ALT, alanine aminotransferase; AST, aspartate aminotransferase; AT, antithrombin; CK, creatine kinase; DIC, disseminated intravascular coagulation; DVT, deep-
vein thrombosis; FEU, fibrinogen equivalent units; LDH, lactate dehydrogenase; PT (INR), prothrombin time (international normalized ratio); PTT, (activated) partial
&&
thromboplastin time. Reprinted with permission from [56 ].
a
Normoblastemia, reticulocytosis, and, less often, red cell fragments can be seen in severe HIT-associated DIC.
b
The author follows serial coagulation markers, especially in patients with severe HIT-associated DIC, where effective anticoagulation should result in decrease in
INR, increase in fibrinogen, and decrease in fibrin D-dimer levels.
c
An otherwise unexplained elevated INR in a patient with HIT suggests possibility of HIT-associated DIC.
d
An elevated (A) PTT increases risk of ‘(A) PTT confounding’ with use of (A) PTT-adjusted anticoagulant, for example, argatroban or bivalirudin.
e
As HIT usually occurs in postoperative patients, an elevated fibrinogen level is expected; thus, a fibrinogen level that is low [<1.5 g/l (<100 mg/dl)] or low-
normal [1.5–2.5 g/l (150–250 mg/dl)] can be seen in severe HIT-associated DIC.
f
In our laboratory, fibrin D-dimer is routinely reported up to 4000 FEU mg/ml (higher values are reported as >4000 FEU mg/ml), but on request can be further
quantitated up to 20 000 FEU mg/ml; serial D-dimers are useful in assessing response to therapy.
g
AT is measured at baseline, and followed serially if there is HIT-associated DIC (fondaparinux is an AT-dependent factor Xa inhibitor).
h
Lactate dehydrogenase (LD or LDH) is a marker of hemolysis, and elevated levels are sometimes seen in severe HIT-associated DIC. Initial assessment of LDH
should be compared with liver enzymes (ALT, AST) and muscle enzymes (AST, CK), as an isolated increase in LDH is most specific for hemolysis.
i
Approximately 50% of patients with HIT are found to have lower-limb DVT.
j
Upper-limb DVT occurs in 10% of patients with HIT and is invariably associated with concurrent/recent use of an intravascular catheter.
k
As HIT is often recognized by reduced platelet counts, and as routine CBCs are generally drawn in the morning in hospitalized patients, treatment for HIT is thus
frequently started in the afternoon or evening.
l
10 mg, rather than 7.5 mg, may be appropriate even for a 50–100 kg patient if HIT is judged very severe (e.g., with overt DIC), or if initial dose is given in the
morning and therefore a 20–24 h interval before next (morning) dose is anticipated.
m
Intravenous (i.v.) injection can be considered if immediate anticoagulation is desired. If given i.v., flush the line afterwards, or administer the fondaparinux in 25
to 50 ml normal saline over 3–5 min.
n
Dosing decreased to 5 mg if body weight <50 kg and increased to 10 mg if body weight >100 kg.
o
The rationale for administering second and subsequent doses in the morning – even if the first dose was given in the preceding afternoon or evening – is that it
will help to achieve early therapeutic levels of anticoagulation (since there will usually be <20 h interval between the first two doses); in addition, it will facilitate
determining trough plasma anticoagulant levels (if desired) by drawing antifactor Xa levels at the morning blood draw.
p
A target trough drug level of 0.6–1.0 anti-Xa U/ml is currently being used by the author; although the anti-Xa level (drawn at approximately 0600 h) will not be
available at the time that the fondaparinux injection is given (approximately 0800 h), the goal of serial anti-Xa levels is to assess whether drug accumulation that
warrants subsequent dose reduction is occurring.
q
Low-dose (prophylactic-dose) fondaparinux regimen may be appropriate if: patient has low (or intermediate) probability for acute HIT and no thrombosis is
evident; or for various other settings of prophylactic-dose anticoagulation, for example, patient with history of previous HIT who requires postoperative
thromboprophylaxis.
r
Assumes normal renal function.

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 Heparin-induced thrombocytopenia Warkentin

HIT-associated thrombosis [15,38,81], thus con- [5,36]. Neither pose risk of APTT confounding, as
founding any putative association. drug levels are measured directly (as antifactor Xa
Inferior vena cava filters are not recommended levels). However, reduced dosing (after a full loading
for use in patients with HIT given risk of DVT dose) is appropriate in renally-compromised
&&
progression to critical limb ischemia [82]. patients [56 ]. Prophylactic dosing is probably
appropriate for ICU patients, unless there is throm-
Choice of anticoagulant bosis or strong suspicion (or confirmation) of HIT.
UFH is the preferred anticoagulant for critically ill Fondaparinux is increasingly being used to treat HIT
&&
patients; it is the only agent approved by the US despite its off-label status for this indication [90 ].
Food and Drug Administration for the ‘treatment of Table 2 summarizes my diagnostic and therapeutic
acute and chronic consumption coagulopathies approach to managing HIT from the viewpoint of
(disseminated intravascular coagulation)’ [83]. Its treatment with fondaparinux.
advantages include nonrenal/nonhepatic clearance,
short half-life, availability of antidote (protamine CONCLUSION
sulfate), accurate lab monitoring (antifactor Xa There are numerous diagnostic and treatment chal-
level), and low cost. Given that the efficacy and lenges in the critically ill patient with thrombocy-
safety of nonheparin anticoagulants are unknown topenia, including the difficulty in distinguishing
in coagulopathic ICU patients, and given that non- HIT from non-HIT thrombocytopenia, and the
HIT thrombocytopenia exceeds HIT 100-fold, there quintessential dilemma of choosing the right anti-
are relatively few thrombocytopenic ICU patients coagulant when heparin is contraindicated for HIT
where HIT is strongly considered. Finally, the but the ideal anticoagulant for non-HIT thrombo-
approved drug for HIT (argatroban) is ineffective cytopenia with DIC.
in many coagulopathic patients because of ‘APTT
confounding’. Acknowledgements
The author would like to thank Jo-Ann I. Sheppard for
Activated partial thromboplastin time help in preparing the figure.
confounding
Incorrect anticoagulant dosing because of mislead- Financial support and sponsorship
ing APTT values during lab monitoring is ‘APTT
&& && None.
confounding’ [6 ,55 ]. For example, if the baseline
(preargatroban) APTT is elevated, perhaps because of
Conflicts of interest
liver dysfunction or HIT-associated DIC, then
nomogram-adjusted argatroban dosing can lead to T.E.W. reports receiving fees for serving on an advisory
systematic underdosing [51,55 ,84 ].
&& & board from Instrumentation Laboratory, consulting fees
from W.L. Gore, lecture fees from Instrumentation
Argatroban Laboratory and Pfizer Canada, fees for providing expert
Only argatroban, a direct thrombin inhibitor, is testimony in cases regarding thrombocytopenia, coagul-
currently approved to treat HIT in the USA (lepir- opathy, or ischemic limb losses, and royalties from
udin has been discontinued). However, no con- Taylor & Francis Group (Informa) for editing a book
trolled studies are available to show that on heparin-induced thrombocytopenia. He also reports
argatroban is effective to treat HIT. The approval that his institution has received fees from W.L. Gore to
trials [85,86] did not require positive laboratory provide laboratory testing for a randomized controlled
testing for HIT, and so most enrolled patients likely trial of heparin-coated versus nonheparin-coated hemo-
did not have HIT, in contrast to the (historical) dialysis grafts. No other potential conflicts of interest
controls who were antibody-positive. Further, the relevant to this article were reported.
high limb amputation rate in the argatroban-treated Off-label treatments: The article discusses fondaparinux
study patients (13.7%) [21] raises concerns about and danaparoid as off-label options for the treatment of
argatroban-warfarin overlap, a situation with risk for HIT.
venous limb gangrene [87,88] (both agents prolong
the INR [89]). Argatroban is also a costly medication. REFERENCES AND RECOMMENDED
READING
Indirect factor Xa inhibitors Papers of particular interest, published within the annual period of review, have
been highlighted as:
Indirect (antithrombin-dependent) factor Xa inhibi- & of special interest
tors, such as danaparoid (not available in the USA) && of outstanding interest

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 Heparin-induced thrombocytopenia Warkentin

55. Warkentin TE. Anticoagulant failure in coagulopathic patients: PTT confound- 74. Douketis J, Cook DJ, Meade M, et al. Prophylaxis against deep vein throm-
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