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Anti-thrombotic Therapy in Heart Failure and Cardiomyopathy
risk is especially increased only when higher doses (>1,000 mg) are used. As expected, across all ran-
domized studies there were more bleeding episodes for warfarin compared to aspirin.
CLINICAL PERSPECTIVES
The role of anti-thrombotic therapy in patients with heart failure and cardiomyopathy remains
contentious. Despite data suggesting a benefit with warfarin compared to aspirin therapy, important
limitations preclude widespread implementation in this patient population. It will be of interest to see
if newer anticoagulants such as anti-factor Xa or anti-factor IIa agents can provide similar efficacy as
warfarin without the monitoring hassles in the setting of heart failure.
Nevertheless, it is important to point out that the risk of thromboembolic events in patients with
heart failure in sinus rhythm is low (1–3% per year), thus, prophylactic use of warfarin is controversial
and has not been widely accepted. The ongoing Warfarin vs. Aspirin in Reduced Cardiac Ejection
Fraction (WARCEF) trial is a National Institutes of Health funded, randomized, double-blind, pla-
cebo-controlled trial designed to test the hypothesis that there is no difference between warfarin (INR
2.5–3.0) and aspirin (325 mg daily) in three- to five-year event-free survival for the composite end-
point of death or stroke (ischemic or hemorrhagic) among patients with cardiac ejection fraction £
35% who do not have atrial fibrillation or mechanical valves (44). However, at present, warfarin
should be considered in patients with heart failure with persistent or paroxysmal atrial fibrillation,
evidence of left ventricular thrombi (especially mobile) or left ventricular aneurysms, known hyper-
coagulable states, history of thromboembolism, and patent foramen ovale. Aspirin is primarily indi-
cated in patients with ischemic heart diseases as secondary prevention, and although there is a lack of
evidence to indicate an adverse interaction with ACE inhibitors, routine use of aspirin in patients with
non-ischemic cardiomyopathy has yet to be supported.
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Dotsenko O, Kakkar VV (2007) Antithrombotic therapy in patients with chronic heart failure: rationale, clinical evidence
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433
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23 Heparin-Induced Thrombocytopenia
John R. Bartholomew
Co n t e n t s
Introduction
Incidence
Pathogenesis
Clinical Features
Temporal Patterns Of Hit
Laboratory Testing For Hit
Direct Thrombin Inhibitors
Lepirudin
Argatroban
Bivalirudin
Hit And Cardiac Surgery
Platelet Factor 4 Heparin Antibodies In Patients Without Hit
Conclusion
References
Ab s t r A c t Heparin-induced thrombocytopenia (HIT) is a transient, prothrombotic, immune-mediated
complication of unfractionated heparin (UFH) or any of the low molecular weight heparin (LMWH) prepa-
rations that can result in venous or arterial thrombosis, amputation or death. It classically develops within
5–14 days of administration of either agent, although it may occur more rapidly if there has been recent
exposure; or delayed days to weeks after either preparation has been discontinued. Thrombocytopenia,
once considered necessary for the diagnosis is no longer essential, whereas a 50% reduction from the
patients baseline count is considered a more specific finding. Immediate cessation of UFH or LMWH is
recommended once the diagnosis is suspected, and therapy initiated with a non-heparin anticoagulant to
prevent and/or treat the potentially devastating complications.
Key words:
Heparin; Low molecular weight heparin; Heparin-induced thrombocytopenia; Isolated
heparin-induced thrombocytopenia; Heparin antibodies; Direct thrombin inhibitors; Fondaparinux;
Warfarin; Percutaneous coronary transluminal angioplasty; Percutaneous coronary intervention; Coronary
artery bypass surgery
From: Contemporary Cardiology: Antithrombotic Drug Therapy in Cardiovascular Disease
Edited by: A.T. Askari and A.M. Lincoff (eds.), DOI 10.1007/978-1-60327-235-3_23
© Humana Press, a part of Springer Science+Business Media, LLC 2010
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Antithrombotic Drug Therapy in Cardiovascular Disease
INTRODUCTION
Heparin induced thrombocytopenia is a common, transient, iatrogenic disorder that can occur in
any patient population exposed to UFH or LMWH. Cardiovascular patients are at increased risk
according to data from the Complication After Thrombocytopenia Caused by Heparin (CATCH)
registry. Approximately 25,000–50,000 of these patients will develop this complication annually in the
US with health care costs approaching $300 million (1). Patients undergoing endovascular procedures
percutaneous transluminal angioplasty (PTA), percutaneous coronary artery angioplasty (PTCA),
percutaneous coronary intervention (PCI), and coronary artery bypass (CABG) or vascular surgery
appear particularly vulnerable. The cause for its increased incidence in the cardiovascular patient
population is not known. However, it is speculated that it may be the result of an increase in the per-
centage of this population exposed to UFH or LWMH, greater use of UFH or LMWH during treat-
ment for the acute coronary syndromes (ACS), and an increase in the number of individuals who have
repeated exposures or undergo repeat coronary procedures (2).
INCIDENCE
The incidence of HIT varies depending on the type of heparin preparation- (bovine lung > porcine
intestine) and (UFH
> LMWH), patient population (surgical > medical), gender (women > men), dose
(treatment
> prophylaxis), and the definition of thrombocytopenia used (a > 50% decline in the platelet
count is more sensitive than an absolute count £150,000
mm
3
) (3)
The American College of Chest Physicians (ACCP) estimate the risk of HIT as 1–5% in patients
receiving UFH, but less than 1% in individuals exposed to LMWH
(4,5). The incidence is lower in
patients receiving thromboprophylaxis approaching 2.6% for UFH and 0.2% for LMWH
(6,7).
PATHOGENESIS
Heparin-induced thrombocytopenia is an immune-mediated disorder that develops following exposure
to UFH or LMWH. It is less common with LMWH, believed to be due to the smaller size of the
molecule, but both agents are capable of triggering the release of platelet factor 4 (PF4), a heparin-
neutralizing protein found in the alpha granules of platelets
(6). An immune response can develop in
susceptible individuals, forming IgG platelet activating antibodies. These “HIT antibodies” bind to
heparin-PF4 on the FcgIIa receptors of platelet surfaces forming immune complexes that are capable
of platelet activation and the release of procoagulant microparticles that promote thrombin generation.
These immune complexes can also bind to heparan sulfate on endothelial cells and monocytes where
they have the potential to initiate the release of tissue factor (TF) and contribute further to the hyper-
coagulable state (8–11) (Fig. 1).
CLINICAL FEATURES
Thrombocytopenia, defined as a platelet count less than 150,000 mm
3
is the most common clinical
finding of HIT, although most patients will have platelet counts well under this number. In a review
of 142 serologically confirmed cases, Warkentin et al reported the median figure as 59,000 mm
3
but
counts as low as 15,000 mm
3
were reported (12). Thrombocytopenia can occur in the absence of
thrombosis and is referred to as isolated HIT. Not all patients develop thrombocytopenia and a 50%
or greater drop in the platelet count from baseline in patients receiving UFH or LMWH is a more
sensitive marker (3,5,12–14).
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Heparin-Induced Thrombocytopenia
Patients are also at an increased risk of thrombosis. Approximately 30–75% develop a thrombotic
event (depending on the patient population) and four out of five events are venous. Deep vein throm-
bosis (DVT) of the lower extremity occurs in approximately 50% of patients and pulmonary embolism
(PE) is found in nearly 25% of individuals
(3,5). Deep vein thrombosis is also seen in the upper
extremity, more often associated with a central venous catheter or pacemaker wire. Other less commonly
reported events include mesenteric venous thrombosis, adrenal hemorrhagic infarction, and cerebral
venous (dural sinus) thrombosis.
Acute limb occlusion is the most common arterial event usually developing in areas of arterioscle-
rosis, at the site of a recent endovascular or surgical procedure, or following vascular trauma, and as
many as 10% of these patients will require amputation. HIT may also present as an acute thrombotic
stroke, myocardial infarction (MI), intracardiac thrombus, and thrombosis of an extracorporeal cir-
cuit, or rarely mesenteric or renal arteries. Occlusion of bypass conduits (saphenous veins more likely
than arterial grafts) may also result following open heart surgery (15). Despite recent advances in the
diagnosis and treatment of HIT, mortality rates approach 10–20%
(3,14,16).
There are a number of atypical manifestations of HIT including coumarin-induced venous limb
gangrene (VLG), coumarin-induced skin necrosis, heparin-induced skin necrosis, acute systemic
reaction following intravenous bolus of UFH or subcutaneous injection of UFH, or LMWH, and
disseminated intravascular coagulation (DIC) (17).
Coumarin-induced VLG is characterized by distal extremity necrosis, an ipsilateral limb DVT, and a
supratherapeutic international normalized ratio (INR). It differs from coumarin-induced skin necrosis,
which develops in areas of fatty tissue including breasts, buttocks, and thighs (17,18). Either condition
can develop when the vitamin K antagonist (VKA) warfarin is initiated during acute HIT prior to the
patient’s platelet count recovery. This depletes the vitamin-K dependent natural anticoagulant protein C,
and results in an additional prothrombotic condition. Both forms of coumarin-induced necrosis can also
occur if a VKA is administered unopposed (without a direct thrombin inhibitor (DTI) or given despite
the initiating of a DTI in the setting of persistent thrombocytopenia (17,18). Coumarin-induced skin
necrosis is 100 times more frequent in patients with HIT (5–10%) compared to the skin necrosis seen in
patients receiving a VKA in non-HIT conditions (0.001%) (19).
Heparin-induced Necrotizing skin lesions are found at the site of subcutaneous injections of UFH or
LMWH and erythematous plaques, nodules, or skin necrosis have also been reported. Necrotizing
lesions are characterized by an area of central ischemia surrounded by erythema and are characteristi-
cally extremely painful (20).
Additional immune complexes
are formed, leading to a vicious
cycle of
platelet
activation
The immune complex binds
to the platelet Fc receptor, resulting
in strong platelet activation and
release of more PF4
These immune complexes also bind
to the vascular endothelium,
creating a cascade of events that
accelerate platelet aggregation and
thrombus formation
Platelet Fcreceptors
Platelet
2
3
4
Immunoglobulin G (IgG)
forms immune complexes
with heparin and platelet
factor 4 (PF4)
PF4 (neutralizes heparin)
Heparin
1
IgG
The pathogenesis of heparin-induced thrombocytopenia
Fig. 1. The pathogenesis of heparin-induced thrombocytopenia (11,56).
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Antithrombotic Drug Therapy in Cardiovascular Disease
Acute systemic reactions develop anywhere from 5 to 30 min following an intravenous bolus of
UFH or up to 2
h after subcutaneous injections of UFH or LMWH (21). An abrupt fall in the platelet
count is observed followed by fever, tachycardia, hypertension, dyspnea, chest pain, or transient glo-
bal amnesia. Sudden cardiorespiratory collapse and death have also been reported
(5).
Disseminated intravascular coagulation (DIC) is characterized by hypofibrinogenemia, a transient
acquired deficiency of antithrombin and protein C, and a prolonged international normalized ratio
(INR) and activated partial thromboplastin time (aPTT). Schistocytes, livedo reticularis, renal failure,
and other signs of microvascular thrombosis may be observed.
TEMPORAL PATTERNS OF HIT
Three distinct temporal patterns of HIT are described - typical-onset, rapid-onset, and delaye-donset
(5,22). Approximately two thirds of HIT patients develop the typical-onset form that develops within
4–14 days after an initial exposure to either anticoagulant, but may occur several days later with the
LMWH preparations (5,20,22).
Rapid-onset HIT develops in 25–30% of all patients and occurs within hours to days after either
anticoagulant is initiated. In 243 serologically confirmed HIT cases, 30% of the individuals had this
type with a median time to onset of thrombocytopenia of 10.5
h. All patients had recent exposure,
commonly within the previous 30 days
(5,22). Rapid-onset HIT is due to residual heparin-platelet
factor 4 (PF4) antibodies that developed during a previous exposure.
Delayed-onset HIT is the least common pattern developing in 3–5% of all HIT patients. It usually
occurs within 7–40 days after either UFH or LMWH is discontinued, and often after discharge
(5).
Patients have very high titers of HIT IgG antibodies and are often readmitted with a new thrombosis.
Thrombo cytopenia may not be initially observed, but develops soon after UFH or LMWH is administered,
if this pattern is not recognized.
LABORATORY TESTING FOR HIT
Thrombocytopenia is a common finding in the hospital setting and possibilities other than HIT
must be considered in the differential diagnosis including: pseudothrombocytopenia, sepsis, throm-
botic thrombocytopenic purpura (TTP), idiopathic thrombocytopenic purpura (ITP), alcohol, aplastic
anemia, hypersplenism, DIC, drug-related (glycoprotein IIb/IIIa inhibitors and thienopyridines),
mechanically induced (intra-aortic balloon pump) or hemodilution from blood transfusions.
HIT should also be considered in the differential diagnosis of a new thrombosis or extension of an
existing thrombus in a patient receiving either anticoagulant and in patients resistant to UFH, defined
as individuals who require unusually high doses to attain a therapeutic aPTT.
The diagnosis of HIT is based on clinical presentation and laboratory testing. Warkentin et al developed
a scoring system to assess the pretest probability of HIT, known as the 4 T’s. This system is based on
four criteria - thrombocytopenia, timing of the platelet count fall, thrombosis, and exclusion of other
causes of thrombocytopenia. It appears to be most helpful in deciding which patient needs laboratory
testing as noted in Table 1 (3,5,23).
Two types of laboratory tests are available - functional tests that detect heparin-dependent platelet
activation in the presence of the patient’s sera and UFH or LMWH and immunoassays that measure
IgG, IgM, or IgA antibodies that bind PF4 to either anticoagulant. To avoid over diagnosis, laboratory
testing should only be ordered when there is a moderate to high clinical suspicion of HIT. Both tests
have high negative predictive values but only moderate positive predictive values (5,9,24).
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Several functional tests are available of which two are heparin induced platelet aggregation assay
(HIPA) and serotonin release assay (SRA). These assays have greater specificity but less sensitivity.
The HIPA uses platelet-rich plasma mixed with the patient’s plasma plus UFH, whereas the SRA uses
donor platelets labeled with radioactive
14
C serotonin. Although the latter is more sensitive and spe-
cific and the standard by which other tests are judged, it is not readily available at all hospitals because
it requires radioisotopes. It is also technically more demanding to perform (23).
Immunoassays have higher sensitivity but lower specificity and are technically easier to perform than
functional tests. Results are reported as optical density (OD) values, with results ³0.40 considered posi-
tive. Titers are generally higher in clinically confirmed cases as demonstrated by Zwicker and colleagues
in a retrospective review. They found that values (>1.0) were more likely to be associated with throm-
bosis (25). False positive results are more likely with the immunoassays because they detect all three
immunoglobulin classes, whereas only a minority of these anti-PF4 heparin antibodies (generally 196)
is pathogenic (9,24).
According to Arepally and Ortel, there are several approaches the clinician should take using the
pretest probability screening tool (4Ts), once HIT is suspected. If the clinical suspicion is low, no labora-
tory testing should be performed. If the clinical suspicion is intermediate or high however, an immu-
noassay should be performed. If the results are positive with an indeterminate pretest probability, a
functional assay should be obtained. If this test is positive, HIT is likely. If the functional test is negative,
however, HIT is considered indeterminate. If the pretest probability is high and the immunoassay posi-
tive, HIT is confirmed. If the pretest is high and the immunoassay negative, HIT is considered to be
indeterminate and repeating the test may be helpful (14). It must be remembered that HIT remains a
clinical diagnosis and results of laboratory testing may not always coincide with the clinical picture.
Management of HIT
Heparin and LMWH must be discontinued immediately once HIT is suspected and a thorough
search performed to identify either of these agents in unsuspected locations like; bound to UFH
coated-catheters, arterial line flushes, added to intravenous solutions for angiographic procedures,
administered during dialysis or added to total parenteral nutrition solutions. Low molecular weight
heparin should not be substituted for UFH because of the cross-reactivity of the HIT antibodies (5).
Table 1
Estimating pretest probability of HIT: The four T’s. (3,5)
2 points 1 point 0 points
Thrombocytopenia >50% fall or platelet nadir
20–100 mm
3
30–50% fall or platelet nadir
10–19 mm
3
<30% fall or platelet
nadir <10 mm
3
Timing of platelet drop
or other sequelae
Onset between day 5 and
10 or < 1 day if recent
exposure
Onset after day 10 or not
clear (missing counts)
Falls too early without
heparin exposure
Thrombosis or other
sequelae
New thrombosis; skin
necrosis; acute systemic
reaction
Progressive or recurrent
thrombosis; erythematous
skin lesions; suspected
thrombosis
None
Other causes of
thrombocytopenia
None evident Possible other causes Definite other causes
Pretest probability: 6–8 = high, 4–5 = intermediate, 0–3 = low
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Numerous studies have demonstrated that discontinuing UFH or LMWH is inadequate treatment
even if there is no evidence of acute thrombosis like isolated HIT, because of the potential risk of new
thrombosis, amputation or death (5,26–29). Treatment should not be delayed while waiting for labora-
tory confirmation as this delay only increases the risk of complications
(26,27). Physicians should
avoid platelet transfusions unless there is active bleeding; defer administration of a VKA until the
platelet count has recovered to ³100,000 mm
3
and preferably 150,000 mm
3
; and avoid placement of
an inferior vena cava filter (Table
2) (3).
DIRECT THROMBIN INHIBITORS
Currently, the Food and Drug Administration (FDA) has approved two DTI’s for treating HIT
(argatroban and lepirudin; one agent for the treatment of isolated HIT (argatroban) and two agents for
patients with HIT requiring PCI (argatroban and bivalirudin).
LEPIRUDIN
Lepirudin is a recombinant form of hirudin, the natural anticoagulant derived from the medicinal
leech, Hirudo Medicinalis. It irreversibly binds thrombin, has a half-life of approximately 1.3
h, and
is eliminated by the kidneys. It is given by intravenous infusion.
Three prospective trials (designated heparin-associated thrombocytopenia or HAT-1, 2, 3)
compared
403 patients treated with lepirudin to 120 historical controls - the latter group treated with the best
available therapy at the time (26,27). The reported combined outcome of new thrombosis, amputation,
and death was lower among patients receiving lepirudin, although after further analysis, only a statistical
difference in new thrombotic events was reached. Bleeding was significantly higher in the lepirudin
population (14,26,27).
In the initial HAT trials, patients with normal renal function received a weight-based bolus of
0.4
mg/kg followed by an infusion of 0.15 mg/kg/h. Based on data from the HAT trials however, the
manufacturer no longer recommends a bolus dose (unless there is life threatening thrombosis) and
advises lowering the initial infusion rate to between 0.05 and 0.10 mg/kg/h (26,27).
The aPTT (targeted to 1.5–2.5 times the baseline level) is used to monitor lepirudin. It should be
checked 4 h after initiating therapy, with necessary dose adjustments and daily, once a therapeutic
level is reached.
Table 2
Treatment guidelines for HIT
1. Discontinue heparin or low molecular weight heparin immediately once HIT is suspected
2. Remove any hidden source(s) of heparin or LMWH
3. Do not wait for laboratory confirmation to begin treatment
4. Initiate an alternative anticoagulant using a direct thrombin inhibitor
5. Do not start warfarin until the platelet count has recovered to 100,000 mm
3
and preferably to 150,000 mm
3
6. Begin with low doses of warfarin and overlap a DTI for a minimum of 5 days and until the INR is ³2.0 for
two consecutive days
7. Avoid placement of inferior vena cava filters
8. Avoid platelet transfusions unless the patient is actively bleeding
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Heparin-Induced Thrombocytopenia
Lepirudin does not cross-react with UFH or LMWH, but anti-hirudin antibodies develop in as
many as 60% of patients
(3,5,30). Although these antibodies are not associated with an increased risk
of thrombosis, they may extend lepirudin’s half-life and will require more frequent dose adjustments.
Anaphylaxis and death in patients re-exposed to lepirudin have been reported; therefore caution is
recommended when using it inpatients with a previous exposure
(14,31).
ARGATROBAN
Argatroban is a small synthetic molecule derived from l-arginine. It binds in a reversible fashion
to the catalytic site of thrombin, is eliminated via hepatobiliary excretion, and has a half-life of
39–51
min. Argatroban lacks cross reactivity with UFH and is currently approved for the prevention
(isolated HIT) and treatment of HIT, as well as for patients undergoing PCI.
Argatroban was used in two prospective trials (Arg 911 and Arg 915) involving 772 patients with
HIT or suspected HIT and compared to historical controls. The combined outcomes of death, amputa-
tion, and new thrombosis were lower in individuals receiving argatroban when compared to historical
controls (34% vs.43%)
(28,29,32). As in the HAT trials, fewer new thromboembolic events were
reported, but no differences in amputations or death rates were noted. Unlike the lepirudin trials however,
there was no increase in bleeding rates compared to the historical controls.
Argatroban does not require a loading dose for the treatment or prevention of HIT. It is given by
continuous infusion at a rate of 0.2 mg/kg/min. Lower doses of 0.05 µg/kg/min are recommended
for patients with moderate to severe liver disease or multisystem organ failure
(33). Argatroban is
monitored using the aPTT targeted to 1.5–3.0 times the baseline level. The aPTT should be evaluated
2 h after initiating therapy and once daily after therapeutic levels have been attained.
A bolus dose of 350
mg/kg is required for patients who undergo PCI followed by an infusion rate
of 25
mg/kg/min adjusted to achieve an activated clotting time (ACT) of 300–450 s. Argatroban does
not produce antibodies.
BIVALIRUDIN
Bivalirudin is a small synthetic 20-amino-acid peptide, which is a specific and reversible inhibitor
of thrombin. Currently, the major indications for bivalirudin are for use in patients with unstable
angina undergoing PTCA and or with provisional glycoprotein IIb/IIIa receptor inhibitor treatment to
reduce acute ischemic events in select patients undergoing PCI.
The FDA has approved bivalirudin for PCI in patients who have, or are at risk of HIT (34). A bolus
of 0.75 mg/kg/intravenously should be followed by a 1.75 mg/kg/h infusion for 4 h to attain a target
ACT of >300 s. It has also been used in several trials as an alternative anticoagulant to UFH in on-
pump or off-pump cardiac surgery in patients with HIT who require an alternative anticoagulant
(35,36). Bivalirudin has been used “off label” for the treatment of HIT patients in a number of small
studies, where the dose is much lower (0.1–0.2 mg/kg/h (37–39). Patients with moderate to severe
renal insufficiency may require dose adjustments.
Bivalirudin has several advantages including a shorter half-life (25
min), enzymic (80%) and renal
(20%) metabolism, low immunogenicity and a minimal effect on the INR (39). It shares an 11-amino
acid sequence with hirudin; therefore, it is possible that patients with antilepirudin antibodies resulting
from treatment with lepirudin could cross react with bivalirudin. For that reason caution extreme
should be exercised (39), if bivalirudin is used in patients previously treated with lepirudin.
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