US Pharm. 2008;33:10(Oncology suppl):24-26.
Heparin-induced thrombocytopenia (HIT) is a transient, prothrombotic state.
Patients with HIT are at increased risk of thrombosis with demonstrated risk
even after resolution of acute-phase HIT. Anticoagulation during acute-phase
HIT continuing for some time thereafter is generally accepted as the standard
of care. Anticoagulation with a direct thrombin inhibitor during acute phase
HIT with transition to an agent that can be used in an outpatient setting is
typically recommended. This article reviews the pathophysiology and provides
updates presented in the recently revised American College of Chest Physicians
practice guidelines with regard to management of HIT with and without
thrombocytopenia (HIT) is a transient, immune-mediated, life-threatening
prothrombotic syndrome that develops subsequent to the administration of a
heparinoid product. It has been estimated that 0.3% to 5% of patients treated
with unfractionated heparin (UFH) will develop HIT.1 Less commonly,
HIT occurs in association with the administration of low-molecular-weight
heparin (LMWH) products. The majority of patients who develop HIT are 60 years
or older.2 Patients treated with UFH who undergo orthopedic surgery
are associated with the highest frequency of developing HIT.3 Data
have suggested that females treated with UFH are at twice the risk of
developing HIT than males. Further, it has been demonstrated that a higher
percentage of surgical patients will be diagnosed with HIT secondary to a
thrombotic event when compared with medical patients.4
The primary adverse outcome of
concern with regard to HIT is thrombosis. Among patients with confirmed HIT,
38% to 76% will develop thromboembolic complications.5
HIT-associated thrombosis can be fatal and may lead to severe morbidity such
as limb amputations and tissue infarction.6 Although HIT has been
associated with both arterial and venous thrombosis, venous thrombosis is most
common; however, a higher incidence of venous thrombosis is likely
attributable to the patient population rather than the condition of HIT.7
Patients with confirmed HIT at highest risk for thrombosis include those who
undergo orthopedic surgery; those who experience a more pronounced
thrombocytopenia; and those with a greater immune response. Further, patients
treated with UFH have a higher likelihood of experiencing HIT with thrombosis
when compared to patients treated with LMWH.6
The syndrome known as HIT
became recognized as an immunologic phenomenon when researchers determined
that it was caused by a noncomplement-fixing, heparin-dependent antibody.8
In a patient with HIT, partial platelet activation leads to release from and
rebinding to of platelet-factor 4 (PF4) from the platelet. Subsequently, PF4
is bundled by the heparin glycosaminoglycan, inducing a conformational change.
The conformational change allows the binding of HIT-immunoglobulin-G (IgG) to
the PF4 bundle (HPF4-A), which subsequently binds the Fc receptor on adjacent
platelets, initiating platelet activation. Activation of platelets enhances
generation of thrombin resulting in a prothrombotic state.
HIT-IgG antibodies typically
develop on day 5 to day 7 postinitiation of heparinoid therapy.9
Patients who have been treated with a heparinoid in the preceding 100 days,
however, may develop antibodies more quickly. The median time to a negative
antibody test is up to 85 days. It is recognized that formation of HIT-IgG
antibodies is associated with morbidities such as heparin-induced skin
lesions, acute systemic anaphylactoid reactions following an IV bolus of UFH,
and warfarin-associated necrosis syndromes.10
Patients with HIT generally
present with thrombocytopenia.11 Onset of HIT will vary according
to the patient's history of heparinoid exposure. In patients who are
heparinoid naïve or who have had no exposure to heparin-based products in the
100 days prior to use, symptoms develop on average five to 10 days after
initial exposure to a heparinoid product.9
Diagnosis of HIT is
accomplished using both clinical and objective parameters.11 In
patients with observed thrombocytopenia, other potential etiologies must be
ruled out. Thrombocytopenia is defined as a platelet count of less than
150,000 per cubic millimeter or a relative decrease of 50% or more from
baseline. It should be noted that the definition of baseline is generally
accepted as the platelet count prior to initiation of the heparinoid in
medical patients or peak postoperative thrombocytosis in surgical patients.12
When HIT is clinically suspected, laboratory testing for heparin-dependent
antibodies is reasonable. In the setting of a clinical diagnosis of HIT, a
positive lab result translates into a likely probability of HIT. The
hypercoagulable nature of HIT gives rise to a high probability of thrombosis,
which may not be clinically apparent. As such, surveillance ultrasonography is
warranted upon, diagnosis as discovery of thromboembolic complications may the
govern the duration of anticoagulation therapy.13,14
Management of HIT
Upon diagnosis of
HIT, the antigenic agent, a heparinoid, should be discontinued. No heparinoid
products, including line flushes, should be used in patients with HIT to avoid
augmenting the immunogenic response. Thrombotic complications that occur in
the setting of HIT are associated with the excess production of thrombin as
well as activation of platelets in the syndrome.11 Approximately 5%
to 10% of patients with HIT develop disseminated intravascular coagulation.14
Further, generation of thromboses increases the risk for tissue infarction,
myocardial infarction, or stroke. Thus, despite a low platelet level, patients
diagnosed with HIT require immediate initiation of anticoagulation therapy.
Selection of a direct thrombin inhibitor (DTI) as an anticoagulant in the
setting of HIT is logical. DTI agents provide anticoagulation through blockade
of thrombin activity, thereby working to reduce the prothrombotic effects
associated with excess production of thrombin in HIT.
Two agents, argatroban and
lepirudin, are FDA approved for the treatment of HIT.15 Bivalirudin
is FDA approved for use in patients with or at risk of HIT who are undergoing
percutaneous coronary intervention (PCI).14 There are limited data
that suggest fondaparinux may be an appropriate agent for use in HIT.
Favorable results were observed in a recent open-label, prospective,
single-center study conducted in Memphis, Tennessee.16 In this
study, fondaparinux was given at higher doses when the patient was diagnosed
as having HIT with thrombosis. Patients received either 5 mg, 7.5 mg, or 10 mg
daily if they weighed less than 50 kg, between 50 and 100 kg, and more than
100 kg, respectively. If diagnosed as having HIT without thrombosis, the
patient received the FDA-approved prophylactic fondaparinux dose of 2.5 mg
daily. Seven patients met inclusion eligibility and were enrolled in the
present study. Six of these patients were diagnosed with HIT with thrombosis.
All subjects included in this study recovered their platelets with no new
thrombotic event, major bleeding event, or death reported. These data
represent an initial glimpse into the possibility that fondaparinux may be
useful in HIT; however, further studies, which should include dose-finding
trials, are warranted.
Evidence for the use of DTI
agents in HIT in the form of randomized, controlled trials is limited due to
the infrequency of serologically confirmed diagnoses and the variety of
patient populations.14 The majority of clinical experience with
regard to treatment of HIT has been with the use of argatroban and lepirudin.
It is noteworthy that the American College of Chest Physicians (ACCP)
recommends lower dosing than that which is FDA approved for lepirudin and,
with selected comorbid conditions, for argatroban. Further analyses of
lepirudin studies uncovered that higher doses were associated with increased
bleeding events without any increase in efficacy. In addition, many studies
used a mean dose comparable to the lower dosage recommended by the ACCP. Thus,
the ACCP recommends that a bolus of lepirudin is not necessary except in cases
where life- or limb-threatening thromboses occur. In this setting, the bolus
should be 0.2 mg/kg for patients with normal organ function. Further, infusion
rates should be initiated no higher than 0.1 mg/kg/h in patients with normal
organ function.17 Patient monitoring includes obtaining activated
partial thromboplastin time (aPTT) values every four hours upon infusion
completion until steady state at 1.5 to 2 times the patient's baseline is
achieved. Adjustment of lepirudin dosing is necessary in patients with renal
dysfunction. The ACCP also recommends that argatroban dosing be initiated at 2
mcg/kg/min with no bolus dose except for patients with heart failure, multiple
organ system failure, or severe anasarca. For these patients, a lower infusion
rate of 0.5 to 1.2 mcg/kg/min is recommended. Patients with significant
hepatic dysfunction who are receiving argatroban therapy require dose
Selecting a DTI Agent
DTI agent selection
can be suited to the clinical situation at hand by taking certain
pharmacokinetic parameters, in conjunction with clinical parameters, into
account. All three DTI agents used in HIT are only available by the parenteral
route of administration. Both lepirudin and bivalirudin are eliminated
renally; however, bivalirudin is also cleared via enzymic metabolism.14
Argatroban is eliminated through the hepatobiliary system. If organ function
is normal, bivalirudin demonstrates the shortest half-life (25 min) and
lepirudin has the longest half-life (80 min). DTI agents have no available
reversal agent for their anticoagulant effects. As such, these agents must be
dosed and monitored with extreme vigilance.
Once the patient has been
stabilized on a therapeutic dose of DTI and the platelet count has returned to
baseline or 150,000 platelets/mm3, transition to warfarin can be
initiated.18-20 Warfarin should never be used as monotherapy prior
to platelet recovery because of a concern for increased thrombin production in
the setting of HIT, combined with an acute reduction of activated protein C by
warfarin. This could cause a worsening of the condition for which the warfarin
is used and may even lead to limb gangrene. Warfarin should be given in modest
doses--recommended as no higher than 5 mg daily--to avoid overshooting the
international normalized ratio (INR), and both the DTI and warfarin should be
given concurrently for at least four or five days prior to discontinuation of
Treatment with DTI agents may
affect INR values, causing them to be artificially inflated. This phenomenon
is addressed in the package insert for argatroban, in which the manufacturer
recommends aiming for an INR greater than four to ensure a therapeutic dose of
warfarin prior to discontinuation of the DTI.21 Upon
discontinuation of argatroban, the INR should be reevaluated after four to six
hours have elapsed. If this evaluation demonstrates an INR below therapeutic
goal, the manufacturer recommends restarting anticoagulation with argatroban.
This procedure should be repeated daily until therapeutic INR values with
warfarin alone are seen.
Factor X Assays
elect to use the chromogenic factor X assay to assist with interpretation of
an artificially inflated INR value often observed when a patient receives
concomitant warfarin and DTI treatment. Accurate interpretation of
artificially inflated INR values allows confidence in therapeutic
anticoagulation of the patient upon discontinuation of the DTI and initiation
of warfarin monotherapy. The chromogenic factor X assay measures the amount of
clotting factor X, which is pharmacologically decreased with warfarin therapy.
Chromogenic factor X levels of 11% to 42% inversely correspond to therapeutic
INR values of 2 to 3.5.22 A study evaluating the ability of the
chromogenic factor X assay to predict the INR for patients receiving both
argatroban and warfarin found that a chromogenic factor X level of 45% or less
predicted an INR of two or greater with a sensitivity of 93%, a specificity of
78%, and an accuracy of 89%. Thus, this assay may provide a useful tool for
clinicians to interpret the therapeutic effects of warfarin in this setting.
Duration of Warfarin Therapy
directly addressing the optimal duration of therapy with warfarin in patients
diagnosed with HIT are not currently available; however, it is known
that risk of thrombosis remains high for weeks after diagnosis of HIT.9
The ACCP guidelines recommend three months of treatment with warfarin for
patients with a first episode of deep venous thrombosis or pulmonary embolism
secondary to a transient risk factor.14 Determination of a
reasonable duration of warfarin therapy is not quite as straightforward in
patients who have not developed thrombosis in the setting of HIT. Although no
thrombotic complication has occurred, there is substantial risk for
HIT-related thrombosis. For treatment of isolated HIT without thrombosis, many
clinicians initiate therapy with warfarin and transition to monotherapy once
platelet counts have recovered. Evidence suggests that risk of thrombosis
remains high in this patient population for at least 30 days. Therefore, it is
logical to treat patients with isolated HIT for at least 30 days. Prior to
discontinuation of warfarin therapy, surveillance ultrasonography can provide
data to assist with medical decision making. Further prospective, randomized
studies are necessary to concretely determine the optimal duration of warfarin
therapy post-HIT diagnosis for patients with and especially without thrombotic
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