Type II Heparin-Induced Thrombocytopenia:
New Treatment Options
Introduction:Heparin-induced thrombocytopenia (HIT) may develop in two distinct forms, type I and type
II (See Table 1). Type I HIT, also known as heparin-associated
thrombocytopenia (HAT), is a non-immunologic response to heparin therapy,
while type II HIT is an immunologic response to heparin therapy. Type
I is more common than type II, occurring in 10 to 20% of patients given
heparin, while type II occurs in 1 to 3% of patients receiving heparin.
The cause of type I HIT may be mediated by a direct interaction
between heparin and circulating platelets causing platelet
clumping or sequestration. This type of thrombocytopenia may
exist in patients receiving heparin in the presence of other
comorbid factors, such as other medications or sepsis, which
may complicate the diagnosis. Type I HIT usually occurs within
the first 48 to 72 hours after initiation of heparin therapy
and the platelet count usually does not fall below 100 X 103/mm3,
often returning to normal within 4 days despite continued
heparin use. No laboratory tests are required to diagnose
type I HIT, and it is not associated with an increased risk
Type II HIT occurs in approximately 1 to 3% of patients receiving
heparin and can occur at any dose or route of administration.
Clinically, type II HIT displays thrombocytopenia after 5
to 10 days of heparin therapy, and the platelet count decreases
approximately 30 to 50%, decreasing to less than 100 X 103/mm3,
but usually not falling below 10 to 20 X 103/mm3.
Type II HIT is more severe because of the increased risk of
thrombotic events, occurring in 30 to 80% of patients. Thrombotic
events may occur in both the arterial and venous systems.
These events occur primarily in the venous system and may
lead to deep venous thrombosis (DVT), pulmonary embolism (PE),
acute myocardial infarction, skin necrosis, venous limb gangrene,
and possibly death.
Type II HIT is caused by the formation of antibodies that activate
platelets following heparin administration. This leads to
an interaction with platelet factor 4 (PF4), which is normally
found on endothelial cells and platelets, and formation of
immunogenic heparin-PF4 complexes which cause an immunologic
response. Antibodies are generated resulting in a complex
forming between antibodies, heparin, and PF4 (mediated through
the FcyIIa portion of the platelet). This complex leads
to further platelet activation resulting in formation of microparticles
and thrombin generation. Antibodies also recognize PF4 bound
to heparin on the endothelial surface and this surface becomes
activated leading to another route of thrombin production.
These pathways of thrombin generation may ultimately lead
to thrombus formation and possible thromboembolic sequelae.
The antibodies that are formed may persist for weeks to months
following heparin administration; therefore, if a patient
develops type II HIT and is administered heparin at a later
date when circulating antibodies are still present, platelet
levels may decrease within hours.
Diagnosis: A number of diagnostic laboratory tests are available for
type II HIT. The 14C-serotonin-release assay (SRA)
combines serum from a suspected type II HIT patient with platelets
of normal donors and adds them to therapeutic concentrations
of heparin. A positive result detects if 14C-serotonin
is released from the serum of suspected type II HIT patients.
Another assay is the heparin-induced-platelet activation assay
(HIPAA). This test assesses aggregation of platelets induced
by the serum of patients in the presence of heparin. The platelet-rich
plasma (PRP) aggregation assay is another diagnostic test.
HIT-specific antibodies may also be assayed using the enzyme-linked
immunosorbent assay (ELISA) test. Antibodies detected include
IgG, IgM, and IgA. It is important to note that a patient
may have type II HIT with negative laboratory results. Therefore,
in patients with suspected type II HIT who have negative laboratory
tests, the diagnosis is usually made clinically. This is due
to the fact that adverse sequelae may occur with this condition
and an alternative anticoagulation strategy may need to be
Treatment: Treatment of type II HIT requires immediate discontinuation
of all heparin products, including heparin infusions, heparin
flushes, and heparin coated catheters used for hemodynamic
monitoring. The use of an effective alternative anticoagulant
also needs to be determined (See Table 2). Treatment options are focused on inhibiting thrombin formation or direct thrombin inhibition.
Hirudin is an anticoagulant unrelated to heparin and is a
direct thrombin inhibitor isolated from the salivary glands
of the medicinal leech, Hirudo medicinalis. Hirudin
binds with high affinity and specificity to the catalytic
and substrate binding sites of thrombin, forming a noncovalent,
irreversible complex that inhibits all proteolytic functions
of thrombin. Hirudin binds to plasma thrombin as well as fibrin-bound
thrombin. This is important because fibrin-bound thrombin
is able to activate platelets and increase fibrin formation.
Since it directly binds to thrombin, hirudin does not require
a plasma cofactor such as antithrombin III for its anticoagulant
properties, and it is not affected by PF4 or other substances
that can cause heparin resistance. Lepirudin (Refludan®)
is a recombinant form of hirudin and is FDA-approved for anticoagulation
for patients with heparin-induced thrombocytopenia and heparin-induced
thrombosis. The half-life of lepirudin is 40 to 120 minutes,
and it undergoes renal elimination (i.e., its half-life may
be increased in renal insufficiency).
Monitoring of lepirudin is done by measuring the aPTT, with a therapeutic
range of 1.5 to 3.0 times the median of normal range. The
recommended dose of lepirudin is 0.4 mg/kg as an intravenous
bolus, followed by a continuous infusion based on the body
weight and renal function of the patient. Since lepirudin
undergoes renal function of the patient. Since lepirudin undergoes
renal elimination, dose reductions are necessary when the
creatinine clearance of the patient is <45 to 60 ml/minute,
and the infusion should be avoided or stopped
in patients with a creatinine clearance of <15 ml/minute (See Table 3). There is no antidote for lepirudin, it is contraindicated
in patients with hypersensitivity to the agent, and it should
be used with caution in patients with active bleeding disorders.
As with all anticoagulants, the most common adverse reaction
with lepirudin is bleeding, occurring in 3 to 12% of patients,
but fever may also occur. Lepirudin prolongs the prothrombin
time making transition to warfarin therapy difficult. Antibody
formation to lepirudin develops in 40% patients on therapy
for >6 days and may lead to decreased clearance of the drug,
thereby increasing the risk of bleeding.
Bivalirudin: Bivalirudin (Angiomax®) is a direct thrombin
inhibitor and an analogue of the peptide fragment hirugen,
a compound derived from hirudin. Unlike lepirudin, the binding
of bivalirudin to thrombin is reversible. Bivalirudin specifically
binds to the catalytic site and substrate-binding site of
thrombin. Bivalirudin is FDA-approved for use in patients
undergoing coronary angioplasty with unstable angina and concomitant
aspirin therapy. The recommended dose of bivalirudin is 1
mg/kg as an intravenous bolus, followed by a continuous infusion
of 2.5 mg/kg/hour for 4 hours, and then 0.2 mg/kg/hour for
14 to 20 hours. Bivalirudin is metabolized in the kidneys
and blood, eliminated in the urine with 20% representing the
parent compound, and has a half-life of approximately 25 minutes.
Since a portion of bivalirudin is renally eliminated, dose
adjustments are required in patients with renal dysfunction.
When the creatinine clearance of the patient is 30 to 59 ml/min,
the dose should be reduced by 20%. If the creatinine clearance
is 10 to 29 ml/min, the dose should be decreased by 60%. If
the patient is on dialysis, the dose should be reduced by
90%. Bivalirudin is contra-indicated in patients with active
bleeding. Adverse reactions of bivalirudin include bleeding,
back pain, nausea, headache, and hypotension. Since bivalirudin
has similar pharmacology to lepirudin, it may be useful for
HIT. However, at this time, there are no data to support this
indication. At CCF, bivalirudin is restricted to the cardiac
catheterization lab for patients who have an allergy to heparin.
Argatroban: Argatroban (Argatroban®) is a direct and selective
thrombin inhibitor unrelated to heparin and is synthetically
derived from the amino acid arginine. Argatroban is a racemic
mixture with the S-isomer having twice the antithrombotic
activity. Argatroban reversibly binds to the active site of
thrombin, as well as soluble and clot-bound thrombin, to inhibit
thrombin-catalyzed or thrombin-induced reactions. Through
these reactions, argatroban inhibits fibrin formation, protein
C, activation of factors V, VIII, and XIII, as well as platelet
aggregation. Vascular smooth-muscle and endothelial-cell thrombin
are also inhibited through this pathway. Like other direct
thrombin inhibitors, argatroban does not require antithrombin
III as a cofactor, is not inactivated by PF4, and does not
cross-react with heparin-induced antibodies.
Argatroban is FDA-approved for prevention or treatment of
thrombosis in patients with type II HIT. The initial intravenous
dose of argatroban for type II HIT is 2 mcg/kg/min to maintain
an aPTT at 1.5 to 3.0 times the control, with the maximum
recommended dose of 10 mcg/kg/min. The aPTT is monitored 2
hours after the start of infusion, 2 hours after each dose
adjustment, and then daily.
Argatroban is metabolized hepatically via the cytochrome P450 enzyme
3A4/5 system. Approximately 65% of the agent is metabolized
resulting in four metabolites. The main metabolite has about
three- to five-fold less of an anticoagulant effect than the
parent compound. Elimination occurs mainly in the feces via
biliary secretion and the half-life of argatroban is approximately
24 to 50 minutes. Since argatroban is predominantly metabolized
in the liver, it may be useful in patients with type II HIT
who have renal impairment or are on renal replacement therapies.
Patients with moderate hepatic impairment should receive an
initial argatroban dose of 0.5 mcg/kg/min, since the clearance
of the drug is decreased four-fold in this patient population.
Although argatroban undergoes hepatic metabolism, no significant
drug interactions have been discovered in studies involving
healthy subjects receiving erythromycin, a potent inhibitor
of CYP 3A4/5 enzyme. Even though there is no reversal agent
for argatroban, one may not be necessary because the compound
has a relatively short half-life and does not undergo renal
Argatroban is contraindicated in patients with active bleeding or known
hypersensitivity to the agent. It should be used with caution
in patients on any other forms of anticoagulation or any conditions
that may increase the risk of bleeding. Bleeding is the major
adverse effect of argatroban occurring in 2.3 to 14.4% of
patients in clinical trials with other adverse effects including
dyspnea, hypotension, and fever.
Patients who require transition to warfarin therapy should also have
their international normalized ratio (INR) monitored while
they are receiving argatroban. After warfarin therapy is initiated,
argatroban should be continued until the INR is greater than
or equal to 4. If the patient is receiving argatroban at 2
mcg/kg/min, and the INR is greater than or equal to 4, the
argatroban infusion should be discontinued, and the INR rechecked
in 4 to 6 hours. If the INR is therapeutic, the argatroban
infusion does not need to be restarted. If the INR is subtherapeutic,
the argatroban infusion should be reinitiated at 2 mcg/kg/min.
If the patient is requiring >2 mcg/kg/min of argatroban, the
infusion should be titrated down to 2 mcg/kg/min, the INR
checked while the patient is receiving this dose for 4 to
6 hours, and adjusted as described above.
Danaparoid: Danaparoid (Orgaran®) is a heparinoid composed
of a heterogeneous mixture containing 84% heparan sulfate,
12% dermatan sulfate, and 4% chondroitin sulfate. However,
danaparoid does not contain heparin fragments and differs
from unfractionated heparin and low molecular weight heparins
(LMWHs) in its glycosaminoglycan backbone. The main activity
of danaparoid is against factor Xa with the anti-Xa to anti-IIa
ratio of >22:1 resulting in inhibition of fibrin formation.
Approximately 4% of the heparan sulfate portion of danaparoid
contains a pentasaccharide sequence that is found in heparin.
This binds to antithrombin and enhances its anti-factor Xa
activity. The remainder of the heparan sulfate has other anticoagulant
effects that are unknown. Other properties of danaparoid are
its anti-IIa effects, which are due to the dermatan sulfate
portion of the agent that enhances the activity of heparin
cofactor II and inhibits factor IIa (and its ability to specifically
inhibit platelet aggregation caused by the HIT antibody).
Danaparoid has a half-life of 18 to 28 hours and mainly undergoes
renal elimination. Therefore, dose adjustments are required
in renal impairment.
Danaparoid is FDA-approved for prophylaxis of postoperative DVT after
elective hip surgery although it is approved in some countries
for the treatment of type II HIT. Approximately 10 to 20%
of patients have demonstrated cross-reactivity in vitro but
<5% of patients have shown in vivo cross-reactivity to danaparoid.
Prior to initiating therapy with danaparoid, a negative in
vitro aggregation or serotonin release test result in response
to danaparoid should be obtained, but this is not always possible.
Dosing for danaparoid varies with the indication (See Table 4). The recommended dose for type II HIT is a loading
dose of 2,250 units as an intravenous bolus (which is adjusted
for body weight of the patient), followed by 400 units/hr
for 4 hours, then 300 units/hr for 4 hours, and then a maintenance
infusion of 150 to 200 units/hr (dosages based on anti-Xa
levels). Although not required, it is suggested that anti-Xa
levels be monitored in selected patients such as those weighing <55 kg or >90 to 95 kg, or patients with severe renal impairment (on days 1 to 3 of danaparoid therapy followed by every other day).
Danaparoid is contraindicated in patients with any active bleeding, medical
conditions that increase the risk of bleeding, or a positive
in vitro test for cross reactivity to type II HIT antibodies.
Bleeding may occur in all patients but is dependent on variables
such as weight and renal function. Other adverse effects include
fever, nausea, and constipation. This agent does not interfere
with the prothrombin time so bridging the patient to warfarin
therapy is not as complicated. When using danaparoid for alternative
anticoagulation, the goal of therapy is to maintain anti-Xa
levels between 0.5 and 0.8 units/ml (if these levels are measured).
Conclusion: A variety of treatment options have emerged in treating type
II HIT. Before starting any agents, clinicians must decide
which of these agents are safe and effective for the patient.
Lepirudin is an irreversible direct thrombin inhibitor that
has shown effectiveness in patients with type II HIT. It does
not cross react with heparin and can be readily monitored
using aPTT. Disadvantages of this agent include a prolonged
half-life, prolongation of the prothrombin time, possible
antibody formation, and dose adjustments in patients with
renal impairment. Argatroban is the newest agent used for
type II HIT. It reversibly binds to thrombin and is monitored
by using the aPTT. Patients who require anticoagulation and
have renal impairment may benefit from the use of argatroban
because of its hepatic metabolism. A disadvantage of this
agent is prolongation of the prothrombin time (requiring additional
monitoring in patients who are transitioned to warfarin) and
dose adjustment in patient with hepatic impairment. Since
danaparoid does not prolong the prothrombin time, it may be
useful in patients who will be transferred to warfarin therapy,
but monitoring is necessary in patients with extremes of weight
or those with renal dysfunction. However, this agent is not
FDA-approved for the treatment of type II HIT and may require
anti-Xa levels to be monitored. Bivalirudin may be useful
in type II HIT, but there are no data to support its use at
See related table: Formulary Status of Agents for Type II HIT