HeparinInduced Thrombocytopenia

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 67, NO.
21, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2016.02.073
THE PRESENT AND FUTURE
STATE-OF-THE-ART REVIEW
Heparin-Induced Thrombocytopenia
A Comprehensive Clinical Review
Benjamin S. Salter, DO,a Menachem M. Weiner, MD,a Muoi A. Trinh, MD,a Joshua Heller, MD,a Adam S. Evans, MD,a
David H. Adams, MD,b Gregory W. Fischer, MDa
ABSTRACT
Heparin-induced thrombocytopenia is a profoundly dangerous, potentially lethal, immunologically mediated adverse

drug reaction to unfractionated heparin or, less commonly, to low–molecular weight heparin. In this comprehensive
review, the authors highlight heparin-induced thrombocytopenia’s risk factors, clinical presentation, pathophysiology,
diagnostic principles, and treatment. The authors place special emphasis on the management of patients requiring
procedures using cardiopulmonary bypass or interventions in the catheterization laboratory. Clinical vigilance of this
disease process is important to ensure its recognition, diagnosis, and treatment. Misdiagnosis of the syndrome, as
well as misunderstanding of the disease process, continues to contribute to its morbidity and mortality.
(J Am Coll Cardiol 2016;67:2519–32) © 2016 by the American College of Cardiology Foundation.
U nfractionated heparin (UFH) and other

heparin derivatives, such as low–molecular
weight heparin (LMWH), are among the
most frequently prescribed medications worldwide
even with continued heparin therapy, and is not
associated with increased thrombotic risk (10–12).
Type II refers to the antibody-mediated, potentially
fatal disorder, now referred to as HIT, in which heparin
(1). They are routinely used for therapeutic and therapy needs to be discontinued as soon as the diag-
prophylactic anticoagulation in a multitude of medi- nosis is suspected (10,13,14). It also requires the
cal and surgical conditions (2). Although hemorrhag- implementation of an alternative anticoagulation
ic events are the most common complication of strategy to prevent the development of HIT with
heparin therapy, thrombotic complications are thrombosis (HITT) (15).
also possible in patients who develop heparin- In this comprehensive review, we highlight HIT’s
induced thrombocytopenia (HIT) (3). Mortality asso- risk factors, clinical presentation, pathophysiology,
ciated with HIT is reported at between 20% and diagnostic principles, and treatment. We place special
30% (4,5). emphasis on the management of patients requiring
HIT is a dangerous, potentially lethal, immunolog- procedures using cardiopulmonary bypass (CPB) or
ically mediated adverse drug reaction to UFH or, less interventions in the catheterization laboratory.
commonly, to LMWH (6,7). An older nomenclature Increased awareness of this condition among clini-
defined 2 types of HIT: type I and type II (8). Type I, cians is important to ensure its early recognition and
seen in 10% to 30% of patients given heparin, was treatment, to avoid serious complications (1). Misdi-
characterized by a benign, mild thrombocytopenia agnosis of the syndrome, as well as misunderstanding
occurring in the first 2 days after heparin administra- of the disease process, continues to contribute to its
Listen to this manuscript’s
tion (9). Platelet count spontaneously normalizes, morbidity and mortality (11).
audio summary by
JACC Editor-in-Chief
Dr. Valentin Fuster.
From the aDepartment of Anesthesiology, Mount Sinai Medical Center, New York, New York; and the bDepartment of Cardiac
Surgery, Mount Sinai Medical Center, New York, New York. The authors have reported that they have no relationships relevant to
the contents of this paper to disclose. John A. Bittl, MD, served as Guest Editor for this paper.
Manuscript received December 22, 2015; revised manuscript received February 3, 2016, accepted February 8, 2016.
Descargado para jefferson candela rada (jcandela1@fucsalud.edu.co) en Fundacion Universitaria de Ciencias de la Salud de ClinicalKey.es por Elsevier en enero 21, 2019.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2019. Elsevier Inc. Todos los derechos reservados.
2520 Salter et al. JACC VOL. 67, NO. 21, 2016
Heparin-Induced Thrombocytopenia MAY 31, 2016:2519–32
ABBREVIATIONS INCIDENCE, EPIDEMIOLOGY, AND decline immediately post-exposure (4,35). Such a

AND ACRONYMS RISK FACTORS robust response can be the result of previous expo-
sure to heparin in the past 100 days and residual
ACCP = American College of
Chest Physicians
Studies indicate that the prevalence of HIT antibody presence from heparin sensitization (35).
ranges from 0.1% to 5.0% in patients Last, the remaining patients exhibit delayed-onset
ACT = activated clotting time
receiving heparin (3,8,16,17), with about 25% HIT, occurring an average of 9.2 days after initiating
aPTT = activated partial
thromboplastin time to 50% of these patients developing HITT therapy; however, signs and symptoms can appear up
CPB = cardiopulmonary bypass
(9,18). The risk for developing HIT varies to 3 weeks post-exposure (35).
considerably according to several patient- Frequently, post-surgical patients exhibit a unique
DTI = direct thrombin inhibitor
and drug-related factors (3,8,16). The pa- bimodal pattern of platelet decline. Initially, they
ECT = ecarin clotting time
rameters most strongly associated with an may develop thrombocytopenia on post-operative
ELISA = enzyme-linked
immunosorbent assay
increased risk for the development of HIT day 1, but this usually rebounds in 5 to 6 days (36–38).
are: 1) the duration of heparin therapy; A second decline in platelet count is more likely to be
FDA = U.S. Food and Drug
Administration 2) the type and dose of heparin administered; associated with HIT and should warrant further
HIT = heparin-induced 3) the indication for treatment; and 4) the investigation (23,37–40). Importantly, clinicians
thrombocytopenia patient’s sex. should use the new, post-operative platelet count as a
HITT = heparin-induced Prolonged exposure to heparin therapy baseline.
thrombocytopenia with (>5 days) has been shown to be a frequent Although HIT is characterized by thrombocyto-
thrombosis
risk factor for developing thrombocytopenia penia, the disease process results in a paradoxical,
IgG = immunoglobulin G
and the further development of HIT (19–21). prothrombotic disorder, with an incidence of throm-
INR = international normalized
UFH conveys a risk 10 times greater than bosis ranging from 50% to 89% in untreated patients
ratio
that of LMWH (22–26), whereas the penta- (1,4,6,23,41). It can lead to devastating arterial and
LMWH = low–molecular weight
heparin
saccharide fondaparinux is rarely associated venous thromboembolic complications, including
with HIT, having been described in only a pulmonary embolism, mesenteric ischemia, ischemic
PCI = percutaneous coronary
intervention few case reports (27,28). Also, the origin of limb necrosis, acute myocardial infarction, and stroke
PF4 = platelet factor 4 heparin affects the risk, with bovine UFH (5,6,8,42). Venous thromboses predominate over
UFH = unfractionated heparin
associated with a higher risk than porcine arterial thromboses in medical patients with HIT or
UFH (19,29). Therapeutic anticoagulation following orthopedic surgery (40), whereas arterial
doses frequently result in greater platelet reductions; and venous thromboses occur with similar frequency
in HIT, however, even exposure to very small following vascular and cardiac surgery in patients
amounts of heparin (heparin flushes) can lead to the with HIT (7). Additionally, 10% to 20% of patients
formation of HIT antibodies (21,30). have localized skin necrosis at heparin injection sites
With regard to the indication for heparinization, (4,5), and up to 20% of patients can develop dissem-
surgical (particularly cardiac and orthopedic) or inated intravascular coagulation (43).
trauma patients (1% to 5%) have a far greater risk than However, when the clinical picture includes
medical or intensive care unit patients (<1%) for the thrombocytopenia, it is important to review the
development of HIT (31,32). multiple scenarios that should be included in the
And finally, female patients have approxi- differential diagnosis. These disease processes
mately twice the risk for developing HIT, often include acute pulmonary embolism, end-stage renal
attributed to their increased immune responses disease, sepsis, and patients with recent CPB,
(19,20,22,23,26,33,34). indwelling arterial devices (e.g. intra-aortic balloon
pump, ventricular assist device, extracorporeal
CLINICAL PRESENTATION
membrane oxygenation), and medications (4,44).
The main clinical presentation of HIT is thrombocy- CLINICAL SCORING SYSTEMS

topenia. After heparin exposure, platelet numbers
decline rapidly, sometimes by 50% or more from The diagnosis of HIT involves both clinical and labo-
baseline. Platelet counts fall below 150 109 /l in 90% ratory components; thus, there are several proposed
of patients, with a median nadir of about 55 10 9/l scoring systems to predict the likelihood of HIT by
(35). There are 3 patterns of onset for HIT: rapid, clinical characteristics. They include the HIT Expert
typical, and delayed. Sixty percent of patients with Probability Score by Cuker et al. (36), a post-CPB
HIT exhibit the typical pattern, resulting in a platelet scoring system by Lillo-Le Louët et al. (39), and the
decline 5 to 10 days after exposure. In 30% of cases, commonly used 4 T’s scoring system by Warkentin
the onset pattern is rapid, where platelet numbers et al. (45,46).
JACC VOL. 67, NO. 21, 2016 Salter et al. 2521
MAY 31, 2016:2519–32 Heparin-Induced Thrombocytopenia
of thrombosis or other HIT sequelae; and 4) the

T A B L E 1 Post-CPB Scoring System
probability of other causes of thrombocytopenia
Variable Clinical Scenario Points (45,46). Each category receives a score of 0 to 2, and
Platelet count Pattern A (platelet count begins to 2 the resulting total score places patients at low, in-
recover after CPB but then begins
to fall again >4 days after CPB) termediate, or high pre-test risk for having HIT. The 4
Pattern B (thrombocytopenia occurs 1 T’s system has a high negative predictive value and is
immediately after CPB and persists
our preferred method of excluding HIT (41), as the
for >4 days without recovery)
Time from CPB $5 days 2 probability of a true diagnosis in patients with low
to index date <5 days 0 scores is low (47). However, the positive predictive
CPB duration #118 min 1 value (10% to 20% for an intermediate score of 4 to 5
>118 min 0 points, 40% to 80% for a high score of 6 to 8 points) is
less reliable and more contingent on the clinician
Total score: $2 points ¼ high probability of HIT, <2 points ¼ low probability of
HIT. Reprinted with permission from Lillo-Le Louët et al. (39). evaluating the patient. Thus, an intermediate or high
CPB ¼ cardiopulmonary bypass; HIT ¼ heparin-induced thrombocytopenia. score should prompt laboratory testing, further
investigation, and possible alternate anticoagulation
(45,47,48).
The first scoring system is the HIT Expert Proba- PATHOPHYSIOLOGY OF HIT
bility Score (36), which uses 26 experts’ opinions of
the importance of various diagnostic characteristics The pathophysiology of HIT involves the formation of
associated with HIT. Although the HIT Expert Proba- a heparin/platelet factor (PF)-4 complex and the
bility Score is promising (100% sensitivity, 60% subsequent binding of immunoglobulin G (IgG) anti-
specificity), the information needed to complete the bodies over 4 to 14 days (49). Although several other
score may not always be readily available, and the antibodies, including immunoglobulin M and immu-
proposed results warrant validation in larger pro- noglobulin A, have been associated with HIT, their
spective studies. The second clinical scoring system, clinical relevance is minor or uncertain (50,51). IgG
by Lillo-Le Louët et al. (39) (Table 1), is specific for the antibodies recognize neoepitopes on PF4 (within the
post-CPB population and assesses the timing of polyanion/PF4 complex) and activate monocytes and
platelet decline and CPB duration. Reports suggest a platelets via their cellular Fc g RIIa receptors (48,52).
negative predictive value of 97%; however, this Consequently, this activation results in the genera-
probability model was developed retrospectively, has tion of thrombin, tissue factor, platelet-fibrin
not been validated in prospective trials, and cannot thrombi, procoagulant microparticles, and the
be applied to nonsurgical patients. further release of PF4 (8,16,44,49).
The widely used 4 T’s clinical scoring system The duration of this process is due to the required
evaluates the following 4 criteria (Table 2): 1) the maturation of precursor B cells becoming plasma
degree of thrombocytopenia; 2) the timing of platelet cells, which, in turn, excrete large amounts of
decline after heparin administration; 3) the presence monoclonal antibodies. The target antigen implicated
T A B L E 2 The 4 T’s Clinical Scoring System
Category 2 Points 1 Point 0 Points
Thrombocytopenia Platelet count falls >50% and platelet Platelet count falls 30%–50% and Platelet count falls <30% and platelet
nadir $20 109/l platelet nadir 10–19 109/l nadir <10 109/l
Timing Clear onset between 5 and 10 days or Consistent with days 5–10 fall, but Platelet count fall <4 days without
platelet fall #1 day (prior heparin not clear (e.g., missing platelet recent heparin exposure
exposure within 30 day) counts), or onset after day 10, or
fall #1 day (prior heparin
exposure 30–100 days ago)
Thrombosis New thrombosis (confirmed), or skin Progressive or recurrent thrombosis, None
necrosis at heparin injection sites, or non-necrotizing (erythematous)
or acute systemic reaction after skin lesions, or suspected
intravenous heparin bolus thrombosis (not proven)
Other causes of Nonapparent Possible Definite
thrombocytopenia
Probability of HIT: high, 6 to 8 points (21.4% to 100%); intermediate, 4 or 5 points (7.9% to 28.6%); low, 0 to 3 points (0% to 1.6%). Reprinted with permission
from Lo et al. (45).
HIT ¼ heparin-induced thrombocytopenia.
in the HIT process is a complex of heparin and PF4, a a functional (platelet activation) assay (48). These
positively charged protein synthesized by megakar- tests measure platelet activation from the heparin-
yocytes and stored in platelet alpha granules (44,53). PF4-antibody complex by mixing donor platelet-rich
Normally, plasma contains only trace levels of PF4, plasma with patient plasma and heparin. The overall
but the concentration can be increased 15- to 30-fold specificity increases by exposing samples to both
in the presence of a heparin infusion (40,44). In therapeutic and supratherapeutic levels of heparin
addition, elevated PF4 levels are seen in several (2-point testing) and by using washed platelets
different patient populations, including those with (as opposed to platelet-rich plasma) (40,72,73). The
infection, diabetes, or renal disease, or in response to 2 most common functional assays are the heparin-
trauma or CPB (54). induced platelet activation assay and the serotonin
release assay.
LABORATORY STUDIES
The heparin-induced platelet activation assay will
exhibit platelet aggregation and an increase in
It is important to remember that laboratory studies
turbidity at therapeutic concentrations of heparin,
are necessary if a clinician (i.e., clinical scoring sys-
but not at supratherapeutic concentrations (74,75).
tem) is suspicious for a diagnosis of HIT. Currently,
The serotonin release assay, generally considered the
the 2 classes of tests used to assist in the diagnosis of
gold standard because of its high sensitivity (>95%)
HIT are immunologic (antigenic) and functional
and specificity (>95%) (73), measures the sample’s
(platelet activation) assays. Overall, these tests
radioactivity and the percentage release of serotonin
identify different steps along the pathogenesis of
from platelets (74).
HIT: the antigen assay detects the initial immune
Because the functional assays are time consuming,
response, whereas the functional assay detects the
are expensive, and can require outside laboratory
activation of platelets, leading to thrombosis.
assistance, ELISA is usually the initial test in the
Immunologic assays, such as the enzyme-linked
diagnosis of HIT (6). Recently however, Mullier et al.
immunosorbent assay (ELISA), have a high degree of
(76) developed the platelet microparticle generation
sensitivity (99%) (55) and thus have high negative
assay to minimize the radioactivity and difficulty of
predictive value, making them excellent tests to rule
performing the serotonin release assay. Although
out a diagnosis of HIT. However, by detecting less
early studies are very promising, it seems that more
pathological immunoglobulins (immunoglobulin A
investigation needs to be undertaken (72,76).
and immunoglobulin M), false positives result in
Overall, the clinical suspicion and HIT probability
lower specificity (40,55). This is important for car-
(as determined by a clinical scoring system) will
diovascular surgery patients, who occasionally test
direct the approach to diagnosing HIT. Usually, pa-
positive on ELISA but are rarely diagnosed with HIT
tients with low probability scores are safe to continue
(33,40,56). Additionally, there may be non-IgG-
receiving heparin therapy. Intermediate or greater
mediated proteins (such as neutrophil-activating
probability scores merit further testing by immuno-
peptide-2 or interleukin-8) involved in HIT that will
logic assay and even consideration for alternate
not be detected by ELISA (51,57).
anticoagulation if suspicion is high. A negative
There are several recommended ways to increase
immunologic assay in intermediate-risk patients
the specificity and positive predictive value of
effectively eliminates the diagnosis of HIT. It is very
immunologic assays. First, patients with high clinical
rare for a patient with high clinical suspicion to have a
suspicion of HIT should be explicitly tested for IgG, as
negative antibody test result, especially when using
it is the most clinically significant antibody (58–61).
methods to increase specificity. These cases, along
Second, the degree of reactivity on immunoassay,
with any patient with a positive immunologic test
designated by optical density, should guide diagnosis
result, warrant further confirmation using a func-
and treatment (62–64). Studies have shown that
tional platelet assay.
higher overall optical density scores are more often
associated with a positive serotonin release assay (63) MANAGEMENT AND TREATMENT
and with higher risk for thrombosis (65–68).
Furthermore, repeating the ELISA using 2-point CESSATION OF THERAPY. It is of paramount impor-
testing (discussed later) increases the specificity of tance when a clinician has at least a moderate suspi-
HIT testing (69,70) but can decrease the negative cion of HIT that heparin administration from any
predictive value and sensitivity (71). source be terminated. This includes exposure to
The diagnostic approach to HIT is further enhanced LMWH, heparin-coated catheters, and heparin flushes
by combining the results of immunologic testing with (6,30). If warfarin therapy has been started when HIT
is diagnosed, reversal with vitamin K should occur clotting time (ACT); thus, baseline laboratory values
because of its depletion of proteins C and S and the should be obtained to avoid confounding and subse-
increased risk for venous limb gangrene (6,77). quent treatment failure (91).
Warfarin also increases the activated partial throm- The alternative agents must be immediate acting
boplastin time (aPTT) and can lead to underdosing of and capable of interrupting the activated coagulation
the selected direct thrombin inhibitor (DTI) for cascade at the level of thrombin or factor Xa (92).
treatment (78). Therapy for HIT needs to be individualized and based
Although rare and controversial, fondaparinux has on several important aspects, most notably the type
also been reported to create a similar clinical condi- of patient (cardiovascular, orthopedic, and so on),
tion to that of HIT; conversely, it has also been organ function, the likelihood of additional pro-
studied as a treatment alternative (79–82). cedures, and bleeding risk (93,94). The 2012 ACCP
Cessation alone is not enough to prevent throm- clinical guidelines recommend treating HIT and HITT
botic events. The 30-day risk for subsequent throm- with the nonheparin anticoagulant agents lepirudin,
bosis following the cessation of heparin therapy is argatroban, and danaparoid (6). Of those 3, only the
estimated to be at least 19% and possibly as high as DTI argatroban is approved by the U.S. Food and Drug
52% (83–85). This emphasizes the importance of Administration (FDA). The antifactor Xa danaparoid
beginning rapid-acting, alternate anticoagulation to is not used for treatment in the United States, and
reduce the heightened thrombin production and lepirudin is no longer manufactured. Bivalirudin is
lessen the risk for thromboembolism. not currently approved for treatment of HIT, but
PLATELET TRANSFUSION. Although it may seem several studies have investigated its potential
intuitive to transfuse platelets to patients with HIT to (95–97). Finally, although novel oral anticoagulant
control bleeding or for prophylaxis secondary to agents (rivaroxaban, dabigatran, and apixaban) are
thrombocytopenia, treatment guidelines prior to 2010 being investigated, there are no current guidelines for
warned against platelet transfusion. From 1970 to their use in the treatment of HIT or HITT.
2010, several different case series provided varying Alternative anticoagulation in patients with HIT
results. Whereas earlier studies demonstrate a lack of should not include either LMWH or warfarin, as both
sustained platelet count and an increased risk for can worsen the thrombin generation and risk for
thrombosis, the latter case series concluded the thrombosis (6,77). Moreover, LMWH’s cross-reactivity
opposite to be true (86–89). with HIT antibodies is quite significant and can
Because of the limited evidence available, the 2012 approach 90% (98,99).
American College of Chest Physicians (ACCP) guide- ARGATROBAN. B a s i c c h a r a c t e r i s t i c s . Argatroban
lines do not recommend routine platelet transfusion is a synthetic DTI that reversibly binds to thrombin
in patients with HIT. However, they do support and does not require AT3 for its activity. Currently, it
transfusions to severely thrombocytopenic patients is approved for prophylaxis or treatment of throm-
with HIT who are bleeding or necessitate transfusion bosis in patients with HIT or as an anticoagulant
during the performance of an invasive procedure with agent during percutaneous coronary intervention
a high risk for bleeding (6). More recently, Goel et al. (PCI) when heparin is contraindicated (92,100–103).
(90) further stratified the risk for platelet transfusion Initiating an argatroban infusion produces imme-
by using the Nationwide Inpatient Sample registry, diate anticoagulant effects as increasing plasma con-
producing results from the largest available inpatient centrations are obtained. Steady-state levels usually
database. Among those diagnosed with HIT, 7.1% occur within 1 to 3 h and are maintained until the
received platelet transfusions; 20.6% of these pa- infusion is discontinued or the dose is adjusted.
tients experienced thrombotic complications, Argatroban exerts its anticoagulant effects by inhib-
revealing a significant association between platelet iting thrombin-catalyzed or induced reactions,
transfusions and arterial thrombotic events in HIT. including fibrin formation, activation of coagulation
ALTERNATIVE ANTICOAGULATION. Recommenda- factors V, VIII, and XIII, activation of protein C, and
tions for alternative anticoagulation are for patients platelet aggregation. In addition, argatroban is
whose diagnoses have been confirmed by laboratory capable of inhibiting the action of both free and clot-
results (in addition to the appropriate clinical bound thrombin (92,100,102–104).
context) or have a high suspicion for HIT on the basis P h a r m a c o k i n e t i c s . Unlike several other DTIs, the
of clinical evaluation alone. It is important to clearance of argatroban primarily consists of hepatic
remember that HIT can cause an increase in aPTT, metabolism with biliary excretion and does not
international normalized ratio (INR), and activated require dose adjustment in renal failure. The half-life
of argatroban in patients without hepatic impairment reliant on antithrombin (AT3) concentration, bivalir-
is 40 to 50 min (4,101,102,104). udin does not need a cofactor to function. In addition,
DOSING. For prophylaxis or treatment of thrombosis bivalirudin inhibits platelet activation and adhesion
in HIT, the prescribing information for argatroban by decreasing circulating von Willebrand factor and
recommends an initial infusion of 2 mg/kg/min, and it by directly attenuating thrombin’s receptor-mediated
is advised to obtain a baseline aPTT before beginning activation of platelets (106).
therapy. An initial dose of 0.5 m g/kg/min is recom- Specifically, bivalirudin is FDA approved for use
mended for patients with moderate to severe hepatic during PCI and percutaneous transluminal coronary
impairment and HIT, but obtaining an acceptable angioplasty in patients with acute or previous HIT and
aPTT may take longer and require more dose adjust- in patients with HITT. Although not approved for the
ments (100,103). A reduced dose should be consid- treatment of HIT, several retrospective studies have
ered in patients with heart failure, multiple-organ evaluated its therapeutic role in this patient popula-
system failure, severe anasarca, or who are tion and support it as a possible alternative (95–97).
post-cardiac surgery. It is suggested to begin the However, when comparing bivalirudin and arga-
initial infusion rate between 0.5 and 1.2 m g/kg/min, troban, Skrupky et al. (95) found the incidence of new
with subsequent adjustments every 2 h using the thromboembolic events to be 2-fold higher in their
aPTT (Table 3) (6,104). patients receiving bivalirudin (8% vs. 4%); bleeding
Although argatroban showed promising results as events occurred at similar rates for both groups.
an anticoagulant agent in patients with HIT or HITT Recent small, single-center, retrospective analyses
requiring PCI (105), it is not commonly used by by Vo et al. (107) and Bain and Meyer (108) suggest
practitioners, and dosing instructions will thus not be that bivalirudin appears to be able to reach thera-
reviewed here. peutic aPTT values quicker, maintain its therapeutic
M o n i t o r i n g . Argatroban prolongs prothrombin time, levels more consistently, and achieve similar out-
aPTT, and ACT; both aPTT and ACT are useful point- comes compared with argatroban in patients with
of-care tools for monitoring the impact of arga- HIT. Furthermore, in the largest retrospective series
troban anticoagulation (6,40,100,101). For use in HIT, to date, Joseph et al. (109) reiterated the positive re-
a target range of 1.5 to 3 times the initial aPTT (not to sults from previous studies, thus supporting the need
exceed 100 s) is required, and steady-state levels are for further research into bivalirudin’s safety and ef-
typically obtained within 1 to 3 h (Table 3). ficacy for the treatment of HIT.
P h a r m a c o k i n e t i c s . Bivalirudin exhibits linear phar-
BIVALIRUDIN. B a s i c c h a r a c t e r i s t i c s . Bivalirudin is
macokinetics and, as mentioned previously, does not
a DTI that is effective on both free and clot-bound
bind to plasma proteins other than thrombin. The
thrombin and does not bind to other plasma pro-
binding of thrombin to bivalirudin is temporary,
teins. Structurally, it is a synthetic hirudin analogue,
because of the proteolytic action of thrombin itself on
but with less immunogenicity and reliance on renal
the shared bond; this is the major component of
clearance than hirudin. Unlike heparin, which is
bivalirudin’s clearance. A lesser component of renal
excretion exists, which accounts for approximately
T A B L E 3 Dosage and Monitoring of Argatroban for Patients 20% of the drug’s clearance (110,111).
With HIT or HITT (103,142) Drug elimination is relative to glomerular filtration
Infusion Rate
rate (and independent of dose and sex); thus, the
(m g/kg/min)* Monitoring 25- to 30-min half-life in a healthy patient is extended
Normal organ function 2 Until steady-state aPTT is to 1 h in severe renal disease and to 3.5 h in end-stage
1.5–3 times baseline‡§
renal disease requiring hemodialysis (110,112). In
Hepatic impairment 0.5†
(total serum bilirubin addition, approximately 25% can be cleared by he-
>1.5 mg/dl) modialysis (111).
Heart failure 0.5–1.2
M o n i t o r i n g . The response to a dose of bivalirudin
Multiple organ system
failure is reflected with linear increases in prothrombin
Anasarca time, aPTT, ACT, and thrombin time (113,114). ACT
Post-cardiac surgery tends to be less precise at high concentrations of
bivalirudin (such as may be used for anticoagulation
*Not to exceed 10 mg/kg/min. †Steady-state aPTT may take longer and require
more dose adjustments. ‡aPTT drawn 2 h after initial bolus dose and after any dose
for CPB). The less commonly available ecarin clotting
adjustments. §Not to exceed 100 s. time (ECT) point-of-care test is recommended for
aPTT ¼ activated partial thromboplastin time; HIT ¼ heparin-induced
thrombocytopenia; HITT ¼ heparin-induced thrombocytopenia with thrombosis.
intraoperative monitoring during CPB with bivalir-
udin (110). The ECT test uses ecarin to produce
meizothrombin when mixed with prothrombin and evidence (6). As previously mentioned, fondapar-
can be used to quantify the effect of DTIs (115). inux has been implicated as a causative agent of HIT.
D o s i n g . The recommended dose of bivalirudin in However, additional studies have shown effective
patients with HIT or HITT undergoing PCI begins with results and minimal cross-reactivity with HIT serum,
a bolus of 0.75 mg/kg, followed by a continuous making it an unlikely precipitating agent (27,120–122).
infusion at 1.75 mg/kg/h for the entire length of the In a recent retrospective, propensity-matched study
procedure. If ongoing treatment is needed post- by Kang et al. (123), fondaparinux had similar effec-
procedure, the infusion may be continued for up to tiveness and safety as argatroban and danaparoid in
4 h and then decreased to 0.2 mg/kg/h for up to 20 h. patients with suspected HIT. To date, this is the
Patients with renal impairment will need dosage ad- largest study providing evidence for the use of fon-
justments on the basis of their creatinine clearance, daparinux. Although there are several possible limi-
as the half-life increases with worsening function. See tations to this study, it certainly supports the need for
Table 4 for dosing recommended by the manufac- further investigation into fondaparinux’s role in HIT
turer; note that there is no reduction in the bolus dose treatment.
for any degree of renal impairment (111).
PLASMAPHERESIS. Research into the use of plasma-
Proposed bivalirudin dosing for the medical treat-
pheresis in patients with HIT or HITT began in the
ment of HIT and HITT is different from the estab-
late 1980s, when reports showed favorable outcomes
lished PCI dosing guidelines discussed previously.
for both pretreatment before CPB and treatment for
Infusion rates range from 0.05 to 0.2 mg/kg/h in pa-
thrombosis (124–126). Since then, several other in-
tients with normal renal function. Patients with renal
vestigators have published similar results for both
dysfunction or hepatic dysfunction and those in an
respective clinical scenarios: adjunctive treatment to
intensive care setting require lower doses to achieve
remove IgG antibodies before CPB (127–131) and those
appropriate aPTT values (1.5 to 2.5 times baseline).
with HITT (132–136). Interestingly, in a randomized
Bivalirudin has been started at 0.14 mg/kg/h in pa-
controlled study performed in 1999, Robinson et al.
tients with hepatic dysfunction, 0.03 to 0.05 mg/kg/h
(137) showed decreased mortality in HIT patients
in those with renal or combined hepatic and renal
when treated within 4 days of the onset of
dysfunction, and 0.03 to 0.04 mg/kg/h in patients
thrombocytopenia.
receiving continuous renal replacement therapy
Nonetheless, in the most recent guidelines by the
(10,95,96,109,116,117).
American Society of Apheresis, therapeutic plasma
FONDAPARINUX. Fondaparinux increases the ability exchange is a grade 2c recommendation for treatment
of antithrombin to inactivate factor Xa. It does not of patients with HIT (pre-CPB and HITT) (138).
bind to or interact with other plasma proteins, is Furthermore, the updated ACCP guidelines do not
eliminated mostly unchanged in the urine (up to discuss the use of plasmapheresis for treatment of
80%), and has a half-life of 15 to 17 h (up to 21 h in patients with HIT, regardless of the clinical scenario
older patients). In addition, steady-state plasma (6). Despite this, interest in the use of plasmapheresis
levels are achieved after the third or fourth once-daily continues; most recently, it was shown to alleviate
dose (118,119). Monitoring is usually unnecessary clinical symptoms and reduce thrombotic risk in an
during therapy, thus offering a major advantage over HIT patient with intracerebral hemorrhage (139).
other anticoagulant agents and avoiding the issue of
confounding discussed earlier (43). CONVERSION TO ORAL ANTICOAGULANT THERAPY.
In the most recent ACCP guidelines, HIT and According to the ACCP guidelines, a transition to
HITT therapy with fondaparinux was not recom- warfarin therapy is required for 3 months in patients
mended, because of a lack of non-case-report-based with HITT and 4 weeks in those with isolated HIT.
The guidelines also recommend delaying the initia-
tion of therapy until the platelet count has recovered
T A B L E 4 Bivalirudin for PCI in HIT and HITT (111) to at least 150 109 /l, because concurrent thrombo-
cytopenia may reflect the ongoing prothrombotic
CrCl (ml/min) Bolus Dose (mg/kg) Infusion Dose (mg/kg/h)
state of HIT (6). However, as there is no direct evi-
$90 0.75 1.75
30–59 0.75 1.75 dence to support a particular platelet threshold to
<30 0.75 1 begin therapy, some clinicians advocate beginning
Hemodialysis 0.75 0.25 treatment as soon as the platelet count begins to
rise (140).
CrCl ¼ creatinine clearance; PCI ¼ percutaneous coronary intervention; other
abbreviations as in Table 3.
Further evidence suggests an association between
warfarin therapy in patients with HIT and venous
2526
Heparin-Induced Thrombocytopenia
Salter et al.
T A B L E 5 Trials Evaluating the Use of Bivalirudin in Cardiac Surgery
Results With
Bivalirudin Q-Wave Myocardial
First Author (Study) (Ref. #) Design Surgery Population Comparator Outcomes Studied (vs. Heparin) Bleeding Rates* Mortality Infarction
Merry et al. (154) Multicenter, OPCAB 100 patients Bivalirudin vs. UFH Blood loss, graft No significant UFH: 805 ml (IQR: UFH: 30-day: 0 of 50 UFH: 7 of 50
randomized without HIT with protamine flow at 3 months increase in blood 517–1,117 ml) Bivalirudin: 30-day: Bivalirudin: 8 of 50
unblinded, reversal loss, superior Bivalirudin: 793 ml (IQR 1 of 50
prospective graft flow 320–4,909 ml)
p ¼ 0.165
Dyke et al. Multicenter, 2:1 CPB for 150 patients Bivalirudin (n ¼ 98) Mortality, bleeding, No significant UFH: 668 ml UFH: UFH:
(EVOLUTION-ON) randomized, primary or without HIT vs. UFH with myocardial differences in Bivalirudin: 793 ml 30-day: 1 of 52 7-day: 1 of 52
(156) unblinded, reoperation protamine infarction, stroke, composite p ¼ 0.0009 12-week: 2 of 52 30-day: 1 of 52
prospective CABG or reversal (n ¼ 52) need for repeat outcome seen at Bivalirudin: 12-week: 1 of 52
valve revascularization 7 days (95% vs. 30-day: 3 of 52 Bivalirudin:
96%), 30 d (95% 12-week: 3 of 52 7-day: 1 of 98
vs. 94%), 12 week 30-day: 1 of 98
(95% vs. 92%) 12-week:
1 of 98
Smedira et al. Multicenter, 2:1 OPCAB 157 patients Bivalirudin (101 Mortality, bleeding, No significant UFH: 783 ml (IQR: UFH: UFH:
(EVOLUTION-OFF) randomized, without HIT patients) vs. UFH myocardial differences in 528–1,032 ml) 7-day: 1 of 56 7-day: 0 of 56
(157) unblinded, with protamine infarction, need composite Bivalirudin: 717 ml 30-day: 1 of 56 30-day: 0 of 56
prospective reversal (n ¼ 56) for repeat outcome seen at (IQR: 475–1,190 ml) 12-week:1 of 56 12-week: 0 of 56
revascularization 7 days (96% vs. Bivalirudin: Bivalirudin:
95%), 30 days 7-day: 1 of 101 7-day: 2 of 101
(93% vs. 93%), 30-day: 2 of 101 30-day: 2 of 101
12 weeks (93% 12-week: 2 of 101 12-week: 2 of 101
vs. 93%)
Koster et al. Multicenter, CPB for 49 patients with None Mortality, myocardial Composite outcome Bivalirudin: 998 7-day: 1 of 49 7-day: 0 of 49
(CHOOSE-ON) prospective primary or confirmed infarction, stroke, seen at 7 days 598 ml 30-day: 3 of 49 30-day: 0 of 49
(42) reoperation HIT need for repeat (94%), 30 days 12-week: 3 of 49 12-week: 0 of 49
CABG or revascularization (86%), 12 weeks
valve (82%)
Dyke et al. Multicenter, OPCAB 51 patients with None Mortality, myocardial Composite outcome Bivalirudin: 926 7-day: 0 of 51 7-day: 3 of 51
(CHOOSE-OFF) prospective confirmed infarction, stroke, seen at 7 days 525 ml 30-day: 0 of 51 30-day: 5 of 51
(155) HIT need for repeat (92%), 30 days 12-week: 0 of 51 12-week: 5 of 51
revascularization (88%), 12 weeks
(88%)
*All bleeding rates are for 24-h period, except for Merry et al. (12-h bleeding rates).
JACC VOL. 67, NO. 21, 2016

CABG ¼ coronary artery bypass graft; OPCAB ¼ off-pump coronary bypass procedure; IQR ¼ interquartile range; UFH ¼ unfractionated heparin; other abbreviations as in Table 1.
MAY 31, 2016:2519–32

limb gangrene; these patients commonly present with

T A B L E 6 Bivalirudin Protocol
supratherapeutic INRs from the severe protein C
General Guidelines
depletion (6,141). Thus, premature cessation of a
Advance communication and planning with perfusion and surgery are critical.
nonheparin anticoagulant agent before the thera-
Anesthesia staff should calculate in advance the likely amount of bivalirudin that will be
peutic effect of warfarin occurs can increase the risk required for the case and obtain it from the pharmacy.
for a new thrombotic event. It is critical to overlap the All flush solutions, lines, and cell saver must be prepared with bivalirudin (0.1 mg/ml; 1 ml
for every 5 ml cell saver processed) instead of heparin.
nonheparin anticoagulant agent with warfarin for at
The bivalirudin is supplied as 250 mg/vial and is typically prepared as 250 mg in 50 ml
least 5 days to safely reduce the prothrombin levels (although 500 mg in 100 ml is probably more convenient).
and to begin treatment at low doses (#5 mg) to avoid Dosing
complications (6). Initial bivalirudin load
Finally, clinicians must specifically recognize the 1.25 mg/kg load over 5 min
50 mg in pump prime
cumulative effect of argatroban and warfarin on INR
Maintenance
when transitioning to oral anticoagulation and should
2.5 mg/kg/h infusion (42 mg/kg/min)
consult their institutions for using INR as an indicator Use a dedicated line through a separate pump.
of effect. Recommendations for overlapping therapy, Monitoring
depending on the dose of argatroban, include stop- Keep kaolin ACT >500 s (or at least 2.5 times baseline).
ping argatroban when the INR is >4, waiting 4 to 6 h, ◦ If <500 s, bolus 0.25 mg/kg and increase infusion by 0.25 mg/kg/h.
and continuing therapy with warfarin alone if the INR Avoid circulatory stasis. Use recirculation limbs and keep cardioplegia circulating if
containing blood. Avoid hemofiltration during CPB to avoid removal of bivalirudin.
is within the desired therapeutic range (103,142).
Management at the end of CPB
Some experts also suggest the alternative option of Careful consideration of the likely success of separation from CPB is necessary, and the
transitioning from argatroban to fondaparinux, which anesthesia, perfusion, and surgical teams should agree upon the strategy for termination
of the bivalirudin infusion.
has a minimal effect on INR (6).
Stop infusion 10–15 min before weaning from CPB and then either:
REEXPOSURE TO HEPARIN. Typically, the heparin- ◦ Empty pump into the cell saver system to remove bivalirudin and replace with crystalloid.
dependent antibodies fall to undetectable levels af- ◦ Add 50 mg bivalirudin to the pump circuit, keep the blood recirculating (may require a
cross limb bridge between the venous and arterial lines), and initiate 50 mg/h infusion
ter 50 to 85 days (35). Thus, once antibodies are no
into the bypass circuit, which should be continued until such time as it is clear that the
longer present, the AACP guidelines recommend the patient will not require urgent return to CPB.
(short-term) use of heparin for cardiac surgery pa- Ultrafiltration by the perfusionist can remove approximately 70% of the bivalirudin from the
patient.
tients with histories of HIT. However, for patients
If separation from CPB does not occur within 20 min of stopping infusion, redose patient with
with histories of HIT undergoing PCI, the recom- 0.5 mg/kg and restart infusion at 2.5 mg/kg/h.
mendation is to use a nonheparin anticoagulant
ACT ¼ activated clotting time; CPB ¼ cardiopulmonary bypass.
agent (6).
HIT AND CPB
A patient with HIT who requires cardiac surgery is a However, in patients with subacute (detectable
particular challenge, requiring a team approach to antibody and normal platelet counts) or acute HIT
provide optimal care (4,143). UFH is the gold standard (antibody plus thrombocytopenia), re-exposure to
anticoagulant for CPB, but patients with HIT may heparin must be avoided, and an alternative strategy
need to be administered alternative drugs (14). for anticoagulation is needed. The safety profiles of
Patients requiring cardiac surgery with histories of these alternatives are not well studied, and there are
HIT >100 days prior should have serologic testing, as no known reversal agents (148), so all attempts to
HIT antibodies are transient and generally become delay the surgery should be made (4,6,41).
nondetectable within 50 to 85 days (35). If antibody is For patients requiring cardiac surgery, past
undetectable and platelet count has recovered, the options have included an alternative anticoagulant
ACCP recommendation is that patients can be safely agent (bivalirudin or argatroban), combining
re-exposed to heparin during cardiac surgery UFH with a platelet antagonist (epoprostenol,
(4,41,144–146). Although studies indicate that there is iloprost, or tirofiban), or the use of plasmapheresis
no amnestic immune response (35,147), these pa- (4,128,143,149–152). Although it is still not FDA
tients should be closely monitored for thrombocyto- approved for use in CPB (6,14), the ACCP recommen-
penia in the post-operative period, with a low dation is to use the DTI bivalirudin for the procedure
threshold for prophylactic use of alternative anti- and postoperative period, because of the evidence
coagulation (11). Furthermore, heparin use should be demonstrating its usefulness and safety compared
limited to the procedure, with alternative anticoagu- with other DTIs (4,6,11,153). Bivalirudin has been
lant agents used perioperatively (4,6,16). shown in 5 randomized trials for both on-pump and
CENTRAL I LLUSTRATION Heparin-Induced Thrombocytopenia: From Exposure to Treatment
EXPOSURE PATHOPHYSIOLOGY SYMPTOMS DIAGNOSIS TREATMENT
Antigen-antibody Thrombocytopenia Heparin cessation

Heparin Clinical scoring
complex
Arterial/venous Alternate
LMWH Assay testing
Platelet activation thrombosis anticoagulation
Salter, B.S. et al. J Am Coll Cardiol. 2016;67(21):2519–32.
LMWH ¼ low–molecular weight heparin.
off-pump cardiac surgery to be a feasible alternative recommendation was based on pooled data from
to heparin, without significantly increased mortality multiple randomized trials (>19,000 patients without
or morbidity, including bleeding (Table 5) (42,154–157). HIT) that demonstrated the efficacy and safety of
Although ECT is recommended for intraoperative bivalirudin anticoagulation during PCI, with a similar
monitoring, because it is not widely available, ACT incidence of ischemic complications and a reduction
can be used as a safe alternative, with bivalirudin in bleeding compared with UFH (6,162–167). Although
producing a linear dose-response anticoagulant effect more recent clinical trials (168–170) have also shown a
(15,42). A target plasma drug level of 10 to 15 m g/ml similar or lower bleeding risk with bivalirudin
should be achieved at the start of CPB, which corre- (compared with UFH plus a glycoprotein IIb/IIIa re-
sponds to an ECT of 400 to 500 s or an ACT >500 s ceptor inhibitor or UFH alone), they demonstrated a
(14,158). Approximately 4 to 5 half-lives are needed significantly increased risk for stent thrombosis. In
for the effects of bivalirudin to be eliminated, unless light of these new data that call into question the
their elimination is accelerated by hemodialysis or clinical utility and cost-effectiveness of bivalirudin in
extracorporeal hemofiltration (148,159,160). A treat- PCI, its use in patients without HIT has been ques-
ment protocol for bivalirudin anticoagulation during tioned (168). However, in patients with HIT, bivalir-
CPB is in Table 6. udin remains the best option (6).
Other areas of importance in regard to HIT and CPB
CONCLUSIONS
include blood stasis and temperature management. It
is critical to avoid blood stasis during CPB (4),
HIT is a rare complication seen in patients receiving
because this allows bivalirudin metabolism to
anticoagulation therapy with heparin. Because of
continue, increasing the risk for thrombus formation
the high morbidity and mortality of this condition,
because of decreasing local bivalirudin levels, despite
it is paramount that all physicians managing these
the presence of adequate systemic levels (148,161).
patients be aware that thrombocytopenia can
In addition, hypothermia reduces the proteolysis
represent an early warning sign mandating further
of bivalirudin; therefore, the patient’s core tempera-
workup to exclude HIT as a possible etiology
ture should be maintained close to 37 C following
(Central Illustration). With vigilance and an elevated
separation from CPB, and care should be taken to
degree of suspicion, the diagnosis can be confirmed
maintain body temperature during the early post-
while still in the early phase of the condition,
operative period (4).
and appropriate alternative anticoagulation thera-
HIT AND THE CATHETERIZATION pies started, resulting in reduction of morbidly and
LABORATORY mortality.
Argatroban, lepirudin, and bivalirudin have all been REPRINT REQUESTS AND CORRESPONDENCE: Dr.
FDA approved as antithrombotic agents for patients Benjamin Salter, DO KCC 8th Floor, One Gustave L.
with HIT requiring PCI, but the ACCP recommends Levy Place, Box 428, New York, New York 10029.
the use of bivalirudin or argatroban (6,11). This E-mail: benjamin.salter@mountsinai.org.
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Bivalirudin versus heparin and protamine in Study Investigators. A randomized comparison of cardiopulmonary bypass, platelets

HeparinInduced Thrombocytopenia

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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 67, NO.

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2016.02.073

THE PRESENT AND FUTURE

Heparin-induced thrombocytopenia is a profoundly dangerous, potentially lethal, immunologically mediated adverse

U nfractionated heparin (UFH) and other

Heparin-Induced Thrombocytopenia MAY 31, 2016:2519–32

ABBREVIATIONS INCIDENCE, EPIDEMIOLOGY, AND decline immediately post-exposure (4,35). Such a

The main clinical presentation of HIT is thrombocy- CLINICAL SCORING SYSTEMS

of thrombosis or other HIT sequelae; and 4) the

T A B L E 2 The 4 T’s Clinical Scoring System

Category 2 Points 1 Point 0 Points

Heparin-Induced Thrombocytopenia MAY 31, 2016:2519–32

Heparin-Induced Thrombocytopenia MAY 31, 2016:2519–32

T A B L E 5 Trials Evaluating the Use of Bivalirudin in Cardiac Surgery

JACC VOL. 67, NO. 21, 2016

MAY 31, 2016:2519–32

limb gangrene; these patients commonly present with

HIT AND CPB

Heparin-Induced Thrombocytopenia MAY 31, 2016:2519–32

CENTRAL I LLUSTRATION Heparin-Induced Thrombocytopenia: From Exposure to Treatment

EXPOSURE PATHOPHYSIOLOGY SYMPTOMS DIAGNOSIS TREATMENT

Antigen-antibody Thrombocytopenia Heparin cessation

Salter, B.S. et al. J Am Coll Cardiol. 2016;67(21):2519–32.

LMWH ¼ low–molecular weight heparin.

Heparin-Induced Thrombocytopenia MAY 31, 2016:2519–32

Heparin-Induced Thrombocytopenia MAY 31, 2016:2519–32

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