Heparin-Induced Thrombocytopenia - DOC by AEu192


									                          Management of Heparin-Induced Thrombocytopenia

          Heparin is widely used for prevention and treatment of thrombotic disorders. However, it can
cause serious adverse effects. One of these is heparin-induced thrombocytopenia (HIT), a common serious
and potentially life threatening condition. Often, the diagnosis can be difficult.
          Heparin was discovered in 1916, introduced clinically in 1935 and became firmly established as
an excellent agent for managing venous thromboembolism in 1960. Transient thrombocytopenia associated
with the administration of heparin was identified in animals in 1942 and in humans in 1962. However, the
relationship between HIT and thromboembolic complications was not clearly identified until 1973 (Shuster
et al., 2003). The thrombotic complications prove fatal in about 30% of patients and lead to amputation or
residual disability in about 20%.

          Clinically, HIT presents in 2 forms. The more common type I occurs in up to 30% of patients 1 to
3 days after the initiation of heparin therapy. The mechanism of type I is still unknown but it is likely not
immune mediated and is thought to occur in response to high doses of heparin causing platelet binding to
fibrinogen and increased platelet sequestration in the spleen, leading to a mild thrombocytopenia. It is
characterized by a transient decrease in platelet count, with clinically insignificant consequences. The
platelet count decline is mild and resolves during continued heparin therapy (Chong, 2003). For the
remainder of this paper, the term HIT will refer to the immune form, type II.
          Type II HIT, also known as heparin induced thrombocytopenia and thrombosis (HITT), and white
clot syndrome, was first described in 1973. It is an autoimmune reaction that is often associated with life or
limb threatening arterial or venous thromboembolic complications. Type II HIT typically occurs 4 to 10
days after the initiation of heparin therapy. Onset after two weeks is unusual. Thrombocytopenia due to
immune-mediated HIT is rarely severe, with platelet count typically above 20,000/uL and a median platelet
count nadir of about 60, 000/uL. As a result, spontaneous bleeding is unusual. Earlier onset is usually due
to type I HIT. But, earlier onset with a median time 10.5 hours after the start of heparin administration may
be seen in about 30% patients with persistent antibodies due to heparin therapy within the previous 3
months (Warkentin, 2003).
          Heparin is a negatively charged highly sulfated polysaccharide. Platelet factor 4 (PF4) is a small
cationic proinflammatory chemokine that is secreted when platelets are activated. Type II HIT is caused by
an antibody, usually IgG type, whose antigen is PF4 complex. PF4 binds heparin very strongly and PF4-
heparin complexes bind to platelets via the heparin binding sites. The immune complex reacts with the
platelet Fc gamma RIIA receptors, leading to platelet activation and further release of PF4, creating a
positive feedback loop. The activated platelets aggregate and are prematurely removed from the circulation
leading to thrombocytopenia and frequently thrombosis. The heparin-PF4-antibody complex also binds to
the same epitote on endothelial cells, which activates the release of tissue factor and produces
hypercoagulable state (Chong, 2003). Figure I represents a schematic depiction of pathogenesis of HIT.
HIT is uniquely associated with platelet activation. This may explain why HIT is uniquely associated with
thrombosis rather than bleeding.

Frequency of HIT
          All patients who receive any types of heparin are at risk for HIT. HIT has occurred after the
administration of porcine unfractionated heparin (UFH), beef UFH, and LMWHs. A meta-analysis of four
randomized trials performed in the 1980s showed that UH from bovine lung was more likely to cause HIT
than heparin derived from porcine intestinal mucosa (Warkentin, 2003). HIT can occur in patients who
receive small amounts of heparin (i.e. heparin flushes for IV catheters, PA catheters coated with heparin).
Thus, patient sensitization is not related to the heparin dose or to the route of administration. However,
studies have shown that LMWH induces antibody production with overt HIT less frequently than that of
UFH. For example, Warkentin et al in 1995 randomly assigned 665 patients to therapy with either UFH or
LMWH for prophylaxis after hip surgery. 7.8% of those treated with subcutaneous heparin developed
heparin antibodies without developing clinical syndrome, and 2.7% patients developed clinically manifest
HIT. Interestingly, none of those receiving LMWH developed heparin antibodies. Compared with
surgical patients, the incidence is lower in the medical patients (0-3.5% vs. 2.7-5.0%). Among cardiac
surgery patients, an even greater proportion form antibodies (20-50%) but only a few patients develop
thrombocytopenia (3.8%).
         Although it is widely assumed that previous heparin therapy increases the subsequent risk of HIT,
no evidence support this contention. Indeed, patients with prior history of HIT can safely receive heparin
following the disappearance of HIT antibodies. However, if heparin is given prior to the disappearance of
the antibodies, the syndrome of rapid onset HIT can occur where platelet count can abruptly fall as a
consequence of a recent immunizing exposure (Warkentin 2003).

          In any patient who develops thrombocytopenia while on heparin, HIT should always be
considered. Thrombocytopenia is considered as a drop of >50% in the patient’s platelet count from its
baseline as well as to a platelet decrease below 100,000 /uL. The diagnosis of HIT should be made firstly
on clinical basis, based on the following criteria: (1) thrombocytopenia occurs during heparin (including
LMWH) administration or on heparin within the preceding 5 to 10 days; (2) other causes of
thrombocytopenia have been excluded; (3) thrombocytopenia resolves after cessation of heparin. Although
criterion (3) is not applicable at the onset of thrombocytopenia, it is helpful subsequently for the
confirmation of diagnosis.
          Laboratory tests for HIT can be divided into two types: functional tests and immunoassays.
Unlike other platelet antibodies, the HIT antibody cause strong platelet activation, which results in many
platelet changes. Some of these, such as the serotonin release assays, heparin-induced platelet aggregation
assays, have been used as the end-points in laboratory tests for HIT.
          Serotonin release assay – The 14C-serontonin release assay remains the gold standard among the
diagnostic tests for HIT. Platelets from normal donors are radio labeled with 14C-serotonin. The platelets
are then washed and patient serum is added along with either high or low heparin concentrations. A
positive test is the release of 14C-seotonin when therapeutic (0.1U.mL) concentrations of heparin are used,
rather than high (100U/mL) concentrations, which can cause suppression of the reaction. The serotonin
release assay has been clinically validated in a prospective randomized trail (Warkenin et al., 1995)
          Heparin-induced platelet aggregation – In the platelet aggregation assay, either washed normal
donor platelets or platelet-rich plasma is added to serum or platelet-poor plasma from a patient suspected
HIT and platelet aggregation is measured. Aggregation is measured with no added heparin as one control
as well as with low (0.1 to 0.3 U/mL) heparin concentrations and high (10 to 100 U/mL) heparin
concentrations. A positive test would include low background aggregation with no added heparin,
aggregation with the addition of a low concentration of heparin, and absent aggregation with high heparin
concentrations. This test is quite specific (>90%) but suffers from lack of sensitivity. This is the preferred
test at North Carolina Baptist Hospital. Cost of the test is $128.50.
          Solid phase immunoassay – This test is different from the first two tests since it is not a functional
assay. Heparin-PF4 complexes are coated on a microtiter plate and patient serum is added. If heparin-
dependent antibodies are present in the serum sample, they will bind the complex , which can be identified
by adding a second antibody. This test is best used along with one of the functional assays rather than as a
single test, because up to 10 to 20% of samples result may be discordant between this assay and others.

          The diagnosis of HIT is initially made on clinical grounds, because the assays with the highest
sensitivity and specificity may not be readily available and have a slow turnaround time. The paradoxical
thromboembolic complications associated with HIT can be reduced in a patient with presumed HIT by
immediate cessation of heparin. And if necessary, an alternative anticoagulant started with out waiting for
the test results. Alternative anticoagulation regimens, including heparinoids, direct thrombin inhibitors, or
warfarin are offered when clinically indicated. Additionally, many patients require ongoing anticoagulation
for underlying medical conditions.
          Further evidence of the prothrombotic nature of the syndrome comes from clinical observations:
when patients with isolated HIT are treated by cessation of heparin therapy alone, at least 50% will
progress to a thrombotic event, typically within a week (Warkentin et al., 1996). This is evidenced by
several retrospective studies done between 1994 and 2003 (Warkentin et al., 1996, Wallis et al.,1999, Lewis
et al.,2001). These studies indicated that 25-50% of these patients develop clinically evident thrombosis
after stopping heparin (with or without substitution by warfarin), usually within the first week. Further, the
risk of fatal thrombosis is about 4-5%. A high rate (50%) of subclinical deep venous thrombosis has been
reported when patients with isolated HIT underwent routine compression ultrasonography (Tardy et al.,
1999). These clinical and laboratory observations have led most clinicians to conclude that patients with
HIT should be treated by discontinuation of heparin therapy and rapid initiation of an alternative
anticoagulant that does not resemble heparin or react with HIT antibodies.

Alternative anticoagulants to heparin
          A number of anticoagulants have been used in patients with HIT, including warfarin sodium,
dextran, ancrod, low-molecular weight heparin, and heparin-like agents such as danaparoid sodium.
During the past several years, a variety of approaches to anticoagulation of patients with HIT have been
reported in retrospective studies. Heparin and low-molecular-weight-heparins should not be used because
they often cross-react with the antibodies that cause HIT, which frequently worsens the syndrome. As high
as 50% in vivo cross reactivity has been reported if LMWH is used to teat HIT caused by unfractionated
heparin (Warkeintin, 2003). Dextran is a weak antithrombotic agent in the setting of acute venous or
arterial thrombosis. Ancrod, a snake venom extract, is no longer used in HIT patients, because it does not
have thrombin-inactivating activity (Hirsh et al., 2004).
          The use of warfarin sodium (vitamin K antagonist) in the absence of other anticoagulants should
be avoided in patients with HIT until the platelet count rises above 100,000/uL. Warfarin therapy alone is
contraindicated as an acute treatment because it can paradoxically worsen the thrombosis and cause venous
gangrene due to the transient hypercoagulable state induced by a decline in protein C levels. The length of
treatment is not well defined. But, in view of the high risk of thrombosis within 30 days of diagnosis of
HIT, warfarin anticoagulation should probably be continued for at least 2 to 3 months.
           Danaparoid (Orgaran, Roseland, NJ), a heparinoid derived from porcine intestinal mucosa, is
composed of a mixture of predominantly heparin sulfate (84%) and dermatan sulfate and condroitin sulfate
(12%). Its mechanism of action is the inhibition of the factor Xa, with lesser effects on factor IIa. It is
renally metabolized and requires dose reduction for patients with renal dysfunction. It does not prolong the
INR and has a long half-life, which makes it ideal for treating venous thromboembolism complicating HIT.
Danaparoid has been used successfully in some patients, but danaparoid cross-reacts with approximately
10%-20% of HIT antibodies. It was withdrawn from US market in April 2002 due to cross reactivity.
Although in EU, Canada and New Zealand, it is approved for the treatment and prevention of HIT-
associated thrombosis.
          At present, only 2 drugs are approved in the US for the treatment of HIT: lepirudin and argatroban.
Lepirudin (Refludan; Berlex Laboratories, Montville, NJ), a recombinant form of the medicinal leech
salivary protein hirudin, was approved by the US Food and Drug Administration for the treatment in
patients with HIT complicated by thrombosis in March 1998. Lepirudin is a direct thrombin inhibitor. It is
not inactivated by PF4. Moreover, it can inhibit thrombin bound within the clot and does not cross react
with heparin antibodies. Lepirudin is excreted by the kidneys; the dose must be reduced in patients with
renal insufficiency. The dose for patients with a normal renal function is a bolus of 0.4 mg/kg followed by
a continuous infusion at 0.15 mg/kg/hr. The anticoagulation effect is monitored by the activated partial
thromboplastin time (aPTT). Lepirudin has a circulation half-life of 80 minutes in patients with normal
renal function. The half-life extents to 2 days in patients with advanced renal failure. Although no antidote
for lepirudin exists, the relatively short half-life allows for correction of prolonged aPTTs. Side effects may
include, rash, allergic reaction (incidence 1%); anaphylactic reactions (1 in 400) resulting in fatality have
been reported in patients reexposed to lepirudin in a second or subsequent treatment course.
          Argatroban (Argatroban; Glaxo SmithKline Pharmaceuticals, Philadelphia, Penn), a synthetic
direct thrombin inhibitor derived from L-arginine, was approved by FDA in June 2000 for prophylaxis or
treatment of thrombosis in heparin induced thrombocytopenia. Argatroban is a direct thrombin inhibitor
that reversibly binds to the thrombin active site. Argatroban does not require the cofactor antithrombin III
for antithrombotic activity. Argatroban exerts its anticoagulant effects by inhibiting thrombin-catalyzed or -
induced reactions, including fibrin formation and activation of coagulation factors V, VIII, XIII. Argatroban
also inhibits the effect of thrombin on protein C activation and platelet aggregation. It is active against
both free and clot bound thrombin. Argatroban under goes hepatic metabolism and excretion. The standard
dose is 2 ug/kg/min IV, which is titrated to achieve an aPTT of 1.5 to 3.0 times the control. It is an
irreversible inhibitor of thrombin with a half-life of 40 to 50 minutes. There is no specific antidote for
argatroban and administration should be discontinued if hemorrhage occurs or if the aPTT becomes
excessively prolonged. Further, for unexplained reasons, argatroban causes greater prolongation of INR
values. This may complicate overlap with oral anticoagulants.

Treatment of Type II HIT with venous/arterial thrombosis
          When Type II is suspected clinically, heparin should be withdrawn. When an acute venous or
arterial thrombosis is present, an alternative anticoagulant should be initiated in its place. The clinician
should use the two drugs that have been shown to be effective in HIT, lepirudin or argatroban. These drugs
are immediately active and either inhibit thrombin directly or inhibit thrombin generation. Treatment with
this drug should continue for at least 5 days or until the thrombosis is under control. To prevent recurrence
of thrombosis, long term treatment (e.g. 6 months) with warfarin is usually required. The initiation of
warfarin should be delayed a few days as protein C and protein S deficiency induced by warfarin can lead
to thrombosis progression and limb gangrene. Treatment with lepirudin or argatroban should overlap
warfarin therapy for a few days until the INR is therapeutic. The following are pivotal studies evaluating
the treatment of HIT with lepirudin and argatroban.

  Recombinant Hirudin (Lepirudin) Provides Safe and Effective Anticoagulation in Patients with
                    Heparin Induced Thrombocytopenia. A Prospective Study.
                                    A. Greinacher et al (The HAT-1)
                                      Circulation 1999; 99: 73-80
Design: A prospective, multicenter historically controlled trial

Subjects: 82 German patients with a diagnosis of HIT based on clinical criteria (ie, a decrease in platelet
count by > 30% or < 109/L and/or new thromboembolic complications during heparin administration) and
with positive HIT antibodies were included in the study. Patients were required to have a definite need for
parenteral antithrombotic therapy or prophylaxis. Patients were excluded if they required hemodialysis,
were anticipated to comply poorly, had a known hypersensitivity to lepirudin, or were pregnant.

Methods: Patients with HIT or HIT with thrombosis (HITT) were treated with lepirudin based on 1 of 4
intravenous lepirudin regimens:

A1.   HITT (n=51)                            0.4mg/kg bolus and then 0.15mg/kg/hr
A2.   HITT receiving thrombolysis (n=5)      0.2mg/kg bolus and then 0.1mg/kg/hr
B.    HIT (n=18)                             0.1mg/kg/hr
C.    During CABG (n=8)                      0.25mg/kg bolus and then 5mg boluses as needed

The start of the treatment was defined as day 1. Scheduled duration of treatment was 2 to 10 days;
treatment could be prolonged if indicated. Conversion to oral anticoagulant began with phenprocoumon (a
coumadin derivative) until INR was 2. Lepirudin was then reduced by 50% and stopped when INR reached
2.5. Patient’s clinical course was followed for an additional two weeks after the discontinuation of

Response criteria were increase in platelet count by >30% to >10 9/L and aPTT values 1.5 to 3.0 times
baseline values achieved with a maximum of 2 dose increases. No placebo control was used for ethical
reasons. Clinical outcomes, including combined and individual incidences of death, amputations, new
thrombotic complications (TEC) and incidences of bleeding, were compared retrospectively with a
historical control group (n=120), i.e. patients with HIT, between 1989 and 1993, who had been treated with
the best possible care available, including danapariod sodium, phenprocoumon, no anticoagulation, LMWH,
ASA, thrombolytics.

Results: 82 patients were treated with lepirudin, and 74 (90.2%) completed the study according to the
protocol. The combined end point (TEC, limb amputation and death) at day 35 was 52.1% in the historical
control arm, while in the lepirudin arm, it was 25.4% (P=0.014; adjusted risk ratio 0.5; 95% CI 0.29-0.89).
Bleeding rate was slightly higher in lepirudin-treated patients, 39.6%, vs. 35.2% in the control patients
(P=0.60). No intracerebral or fatal hemorrhages were observed.

Conclusion: Lepirudin is effective in deceasing risk of death, limb amputation and new TECs in all HIT

          Lepirudin (Recombinant Hirudin) for Parenteral Anticoagulation in Patients With
                              Heparin-Induced Thrombocytopenia
                                 A. Greinacher et al (The HAT-2)
                                 Circulation 1999; 100: 587-593

Design: A Prospective, multicenter, historically controlled trial

Subjects: 112 German patients all tested positive for heparin-induced platelet aggregation test, and has a
decrease in platelet count by >50% or to values < 100g/L and/or new TECs during prestudy heparin
administration. Exclusion criteria included bleeding, pregnancy, alcohol, drug abuse and anticipated poor
compliance. Patients with renal dysfunction were enrolled in this trial but were excluded from HAT-1 study.

Methods: Patients with HIT or HITT were treated with lepirudin based on 1 of 3 parenteral lepirudin

A1. HITT (n=65)                               0.4mg/kg bolus and then 0.15mg/kg/hr
A2. HITT receiving thrombolysis (n=4)         0.2mg/kg bolus and then 0.1mg/kg/hr
B. HIT (n=43)                                 0.1mg/kg/hr

The primary objective of the study was to confirm the results of HAT-1 study of the clinical efficacy and
safety of lepirudin in HIT patients.

Results: The combined end point (new TECs, limb amputation and death) at day 35 was 52.1% in the
historical control arm, while in the lepirudin arm, it was 30.9% (P=0.15; adjusted risk ratio 0.7; 95% CI
0.44-1.14). Bleeding rate was higher in lepirudin-treated patients, 44.6%, vs. 27.2% in the control patients
(RR 2.57, P=0.0001). But, there was no statistically significant difference in bleeding events requiring
transfusion (cumulative incidence at 35 days, 12.9% vs 9.1%; RR 1.66, P=0.23).

Conclusion: HAT-2 showed a similar trend toward clinical events with lepirudin, however, the results did
not reach statistical significance. If confirmed in a larger population, this could be clinically important.
The authors noted that patients in the HAT-2 study presented with a poorer clinical condition than patients
in HAT-1 at study entry, which may have made it more difficult to detect differences with historical controls.
  Heparin-Induced Thrombocytopenia with Thromboembolic Complications: Meta-Analysis of 2
 Prospective Trials to Assess TheValue of Parenteral Treatment with Lepirudin and Its Therapeutic
                                            aPTT Range
                                      Andreas Greinacher et al.
                                      Blood 2000; 96:846-851

Design: A meta-analysis of HAT-1 and HAT-2 studies (n=204, total)

Objectives: To evaluate the clinical outcomes of patients with HIT and TEC who were treated with
lepirudin and to compare them with the clinical outcomes of historical control patients who did not receive
lepirudin. To evaluate the therapeutic aPTT ranges for lepirudin, and to assess potential cofactors
influencing the outcomes in these patients, such as sex, age, patient population (surgery vs medical vs
others) and comedications (aspirin, coumadin, thrombolytics).

Subjects: Patients (n=113) administered lepirudin were selected from HAT-1, 2 studies. Inclusion criteria
consisted of the presence of an arterial or venous thromboembolism and a diagnosis of HIT based on
clinical criteria and on laboratory-confirmed HIT antibodies. Exclusion criteria included age < 18 years, no
ongoing thrombosis, missing date of lab confirmation of HIT, > 21 days between onset of clinical
symptoms (thrombocytopenia or TEC during heparin therapy) and lab confirmation of HIT,
cardiopulmonary bypass, start of therapy > 60days after lab confirmation of HIT.

Control group (n=91) was selected from a registry of patients who did not receive lepirudin. The diagnosis
of all patients was made in the same lab using the same methods, and all patients were enrolled

Methods: Lepirudin treatment regimens used in the HAT-1, 2 were as follows:

A1. HITT (n=105)                                       0.4mg/kg bolus and then 0.15mg/kg/hr
A2. HITT receiving thrombolysis (n=8)                  0.2mg/kg bolus and then 0.1mg/kg/hr

The aPTT was used to monitor lepirudin treatment. Predefined therapeutic aPTT was 1.5 to 2.5 times
baseline. Lepirudin dosed was reduced in patients with creatinine levels >1.5mg/dL. Historical controls
were treated at the discretion of the treating physician.

Results: The primary endpoint (combined incidence of death, new TEC, and limb amputation) occurred in
25 lepirudin treated patients (22.1%): 11 died (9.7%), 7 underwent limb amputation (6.2%), and 12
developed new TEC (10.6%). The risk was highest in the period between diagnosis of HIT and the start of
lepirudin therapy (combined event rate per day 6.1%). It markedly decreased to 1.3% during lepirudin
treatment and to 0.7% in the post treatment period. From the start of the therapy to the end of follow up,
lepirudin treated patients had consistently lower incidences of the combined endpoint than historical control
group (P=.004), mainly due to a reduced risk of new TEC (P=.005).
During treatment with lepirudin, aPTT ratios of 1.5 to 2.5 produced optimal clinical efficacy with a
moderate risk for bleeding. aPTT ratios lower than 1.5 were subtherapeutic, and aPTT levels greater than
2.5 were associated with high bleeding risk. Bleeding events requiring transfusion were significantly more
frequent in patients on lepirudin than controls (P=.02).

Conclusion: Lepirudin offers clinical benefits for patients with HIT and ongoing thrombosis. Heparin
cessation alone is insufficient to prevent further thromboembolism in acute HIT. If there is a suspicion of
HIT, a patient with a recent thrombosis should be treated immediately with an anticoagulant other than
heparin. Awaiting lab confirmation of HIT before alternative anticoagulation is started would cause a
significant delay for most patients and substantially enhance the risk for the patient. Lepirudin appears to
have a narrow therapeutic window and a relatively high bleeding risk even when given in clinically
relevant doses in a patient with HIT. Even so, lepirudin remains an important therapeutic agent given the
dangerous course of HIT and the apparent low risk for fatal hemorrhage related to its use.
Overview of the Argatroban studies
Two clinical studies form the basis of the conclusion that Argatroban is an effective treatment of HIT with
or without thrombosis:
         1) ARG-911: A prospective, historically controlled efficacy and safety study
         2) ARG-915: A follow up-on efficacy and safety study that used the same historical control group
         from ARG-911 as the comparator
These studies were comparable with regard to study design, study objectives, dosing regimens as well as
study outline, conduct, and monitoring.

    Argatroban Anticoagulation Therapy on Patients with Heparin-Induced Thrombocytopenia
                      Bruce E Lewis et al (The Argatroban-911 Investigators)
                                Circulation 2001; 103:1838 -1843

Design: A multicenter, nonrandomized, open-label, historical-controlled trial

Subjects: 304 patients with either isolated HIT (n=160) or HITT (n=144) were enrolled. Inclusion criteria
consisted of the following:

1) Male or nonpregnant females between the ages of 18 and 80 years old
2) Clinical diagnosis of HIT with or without thrombosis. Isolated HIT – fall in platelet count < 100 x 109/L
or a 50% reduction in count after heparin therapy with no explanation besides HIT. HIT with thrombosis –
HIT with the presence of an arterial or venous thrombosis documented by appropriate imaging technique or
supported by clinical evidence such as acute myocardial infarction, stroke, pulmonary embolism or other
clinical indications of vascular occlusion.
3) Need for anticoagulation and a documented history of positive HIT antibody test ( in the absence of
current thrombocytopenia or heparin rechallenge). These “latent” HIT patients were analyzed together with
the isolated HIT patients.

Exclusion criteria included unexplained aPTT> 2 times control at baseline, coagulation disorder unrelated
to HITT, LP within last 7 days, or history of previous aneurysm, hemorrhagic stroke, or recent thrombotic
stroke unrelated to HITT.
 Control subjects (n=193) were selected based on review of lab logs (4 years before study initiation) of
patients who were tested for HIT and were thrombocytopenic. Control subjects were treated according to
the local standard of practice at the time of HIT diagnosis, with typical treatments being heparin
discontinuation and/or oral anticoagulation.

Methods: Patients with isolated HIT or HITT received 2 ug/kg/min IV argatroban, adjusted to maintain
aPTT 1.5 to 3.0 times baseline value. Argatroban was continued until the underlying condition clinically
resolved, appropriate anticoagulation was provided with other agents, or treatment was continued for 14
days. On average, treatment was maintained for 6 days. Clinical outcomes over 37 days were compared
with those of 193 historical control subjects with HIT or HITT.

Results: The primary efficacy analysis was a comparison of event rates for a composite endpoint that
included death (all causes), amputation (all cause) or new thrombosis through the study day 37. Additional
analysis included the evaluation of event rates for components of the composite endpoint, as well as time-
to-event-analysis. Secondary efficacy endpoints included achievement of adequate anticoagulation and
resolution of thrombocytopenia.

The incidence of the primary efficacy end point, a composite of all-cause death, all-cause amputation, or
new thrombosis, was reduced significantly in argatroban-treated patients vs control subjects with HIT
(25.6% vs 38.8%, P=.014). In HITT arm, the composite incidence in argatroban-treated patients was 43.8
vs 56.5% in control subjects (P=.13). Significant between-group differences by time-to-event analysis of
the composite end point favored argatroban treatment group. Argatroban significantly increase the time-to
first-event in patients with isolated HIT (P=.01) and HITT (P=.014). Resolution of thrombocytopenia
(defined as platelet count > 100,000/uL or to at least 1.5 fold greater than the platelet count at study
initiation) was also much faster in argatroban treated arm by day 3 (P=.0001). Major or minor bleeding
rates were not different between the two groups.

Conclusion: Argatroban anticoagulation, compared with historical control subjects, improves clinical
outcomes in patients who have isolated HIT, without increased bleeding risk. Although there is no
statistical difference between the argatroban HITT arm and historical control in the composite endpoint
(death, amputation or new thrombosis), argatroban reduces the risk of new thrombosis as the most severe
event among HIT and/or HITT patients.

          Argatroban Anticoagulation in Patients with Heparin-Induced Thrombocytopenia
                      Bruce E. Lewis et al (The Argatroban-915 Investigators)
                        Archive of Internal Medicine 2003; 163: 1849-1856

Design: A multicenter, prospective study with historical-controls (from ARG-911 study)

Subjects: 418 patients with HIT (n=189) or HITT (n=229) were enrolled based on ARG-911 inclusion and
exclusion criteria.

Methods: Same as ARG-911 study

Results: Results of ARG-915 were consistent with those from ARG-911. In the isolated HIT arm, the
composite end point was significantly reduced in argatroban-treated patients vs controls (28% vs 38%;
P=.04). In the HITT arm, the composite end point occurred in 41.5% of argatroban treated patients vs.
56.5% of controls (P=.07). By time-to-event analysis of the composite end point, argatroban therapy was
significantly better than historical controls in HIT (P=.02) and HITT (P=.008).
Among secondary endpoints, argatroban also markedly reduced new thrombosis in HIT (P<.001) and
HITT (P<.001) and death due to thrombosis in HIT (P=.04) HITT (P=.002). No significant difference
between the historical control and the argatroban treatment group were observed in the occurrence of death
or amputation among HIT or HITT patients.

Conclusion: Argatroban therapy, compared to historical controls, improves outcomes, particularly new
thrombosis and death due to thrombosis, in patients with HIT and HITT. But, there is no statistically
significant reduction in mortality or morbidity (limb amputation) in HITT patients treated with argatroban
at the end of 37 days as compared to historical controls.

Treatment of Isolated HIT without clinically obvious thrombosis
          HIT is a hypercoagulable state. In a retrospective study by Warkentin et al 1996, about 53% of
HIT patients who had only isolated thrombocytopenia initially, subsequently developed thrombosis in all
cases within 30 days. Despite the term heparin induced thrombocytopenia, the degree of thrombocytopenia
fails to correlate with either the rate of antibody development or the severity of the clinical outcome.
These patients may benefit from treatment with either argatroban or lepirudin given the unfavorable natural
history of isolated HIT and the evidence of benefit using a direct thrombin inhibitor as described above.
Hence, these agents should be considered for prophylactic therapy in HIT patients without thrombosis until
platelet counts recovered. Table I summarizes the alternative anticoagulants for treatment of HIT.
          In general, the best way to prevent HIT is the judicious use of UFH or the substitution of LMW
heparin, where appropriate. Limiting heparin duration to less than five days and starting warfarin early to
minimize the length of heparin use in patients requiring long-term anticoagulation are two often overlooked
strategies. Warfarin should not be given to patients who already have HIT until the thrombocytopenia
resolves, and LMWH should not be substituted for UH after HIT develops.
          On the bases of multiple observational studies in patients with untreated HIT and of the
experiences with the use of thrombin inhibitors in patients with HIT, the following recommendations are
suggested. When a diagnosis of HIT is suspected, heparin therapy should be stopped and replace with an
effective anticoagulant that does not cross-react with heparin antibodies. Awaiting laboratory confirmation
of HIT before alternative anticoagulation therapy is started would cause a significant delay for most
patients and substantially enhance the risk for the patient. Lepirudin and argatroban are effective parenteral
anticoagulants. In HITT patients, oral anticoagulants should not be started in acute HIT until the platelet
count has recovered to at least 100,000/uL and only if the patient is improving clinically and is adequately
anticoagulated. In isolated HIT patients, continue parenteral anticoagulants until the platelet count
normalizes. Platelet counts should be monitored closely and further signs of thrombosis should be
carefully investigated once the diagnosis of HIT is made.

Chong BH. Heparin-induced thrombocytopenia. J Tjromb Haemost 2003; 1: 1471-8.

Greinacher A, Volpel H, Janssens U, Hach-Wunderle V, Kemkes-Mattes B, Eichler P, et al. Recombinant
hirudin (lepirudin) in patients with heparin-induced thrombocytopenia. A prospective study. Circulation
1999; 99: 73-80.

Greinacher A, Janssens U, Berg G, Bock M, Kwasny H, Kemkes-Mattes B, et al. Lepirudin (recombinant
hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. Circulation
1999; 100: 587-93.

Greinacher A, Eichler P, Lubenow N, et al. Heparin-induced thrombocytopenia with thromboembolic
complications: meta-analysis of 2 prospective trials to assess the value of parenteral treatment with
lepirudin and its therapeutic aPTT range. Blood 2000; 96:846-851.

Hirsh J, Heddle N, and Kelton J. Treatment of heparin-induced thrombocytopenia. Arch Intern Med. 2004;
164: 361-369.

Lewis BE, Wallis, DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, et al. Argatroban anticoagulant
therapy in patients with heparin-induced thrombocytopenia. Circulation 2001; 103:1838-43.

Lewis BE, Wallis DE, Leya F, Husting MJ, Kelton JG. Argatroban anticoagulation in patients with heparin-
induced thrombocytopenia. Arch Intern Med 2003; 163: 1849-1856.

Shuster TA, Silliman WR, Coates, RD, et al. Heparin-induced thrombocytopenia: Twenty-nine years later.
J Vas Surg 2003; 38:1316-22.

Tardy B, Tardy-Poncet B, Fournel P, Venet C, Jospe R, Dacosta A. Lower limb veins should be
systematically explored in patients with isolated heparin-induced thrombocytopenia (letter). Thromb
Haemost 1999;82: 1199-200.

Wallis ED, Workman DL, Lewis BE, Steen L, Pifarre R, Moran JF. Failure of early heparin cessation as
treatment for heparin-induced thrombocytopenia. Am J Med 1999; 106:629-35.

Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-
molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332:1330.

Warkentin TE, Kelton JG. A 14-year study of heparin induced thrombocytopenia. Am J Med 1996;

Warkentin TE. Heparin-induced thrombocytopenia: pathogenesis and management. British J of
Haematology. 2003, 121, 535-555.
Management of Heparin-Induced

       I-Wen Chang, M.D.
         March 30, 2004
     Resident Grand Rounds
          Fig 1. Pathogenesis of HIT: a central role for thrombin generation. PF4/heparin complexes that
can express multiple neoepitope sites bind to platelet surfaces. HIT-IgG antibodies recognize neoepitope
sites on PF4, leading to formation of multimolecular PF4/heparin/IgG complexes on the platelet surface.
The IgG Fc regions bind and crosslink the platelet Fc IIa receptors, resulting in platelet activation,
including formation of procoagulant, platelet-derived microparticles, which provide altered membrane
surfaces that support coagulation reactions. Activated platelets release additional PF4 from -granules,
leading to a vicious cycle of progressive platelet and coagulation activation. PF4 also can bind to
endothelial heparin sulphate, leading to endothelial cell immunoinjury, with tissue factor expression.
Monocytes also can bind PF4/heparin-IgG immune complexes, potentially leading to tissue factor
expression on these cells. Ultimately, there results marked thrombin generation in vivo, which helps explain
the strong association between HIT and thrombotic events. Figure adapted from Greinacher, A. &
Warkentin, T.E. (2001) Treatment of heparin-induced thrombocytopenia: an Overview. In: Heparin-induced
Thrombocytopenia, 2nd edn.
Table I.Alternative anticoagulants for the treatment of HIT.
Anticoagulant       Dosing (therapeutic          Pharmacokinetics            Comment
                    range)                       (t   )
Agents approved for treatment of HIT
Danaparoid          Bolus: 2250 U; infusion,     Renal metabolism (25 h      Approved for treatment and prevention of
sodium (Orgaran)    400 U/h 4 h, then            [antifactor Xa activity],   HIT-associated thrombosis in the EU,
                    300 U/h 4 h, then            2-4 h [antifactor IIa       Canada, New Zealand, Australia;
                    200 U/h, with monitoring     activity])                  withdrawn from US market, April 2002;
                    by antifactor Xa levels                                  potential for in vivo crossreactivity (rare)
                    (0·5-0·8 anti-Xa units/ml)                               which is not predictable by in-vitro testing;
                                                                             thus, crossreactivity testing is not
                                                                             recommended prior to use
Lepirudin           Bolus: 0·4 mg/kg;            Renal excretion             Approved in USA, Canada and EU for
(Refludan)          infusion, 0·15 mg/kg/h       (80 min)                    treatment of HIT-associated thrombosis;
                    (target aPTT range, 1·5-                                 t1/2 rises considerably in renal failure; high
                    2·5 baseline)                                            rate of antihirudin antibodies (40-60%)
                                                                             that are usually not clinically significant;
                                                                             anaphylaxis reported post lepirudin bolus
                                                                             (rare), especially with repeat treatment
Argatroban          2 µg/kg/min, without         Hepato-biliary excretion Approved in the USA and Canada for both
(Novastan in        initial bolus (target aPTT   (40-50 min)              prevention and treatment of HIT-
some non-USA        range, 1·5-3·0                                        associated thrombosis (identical
jurisdictions)      baseline)                                             therapeutic-dose regimens used for both
                                                                          indications); argatroban increases the
                                                                          INR: thus, higher therapeutic range
                                                                          required during overlapping
                                                                          argatroban/warfarin (Sheth et al 2001)
Investigational agents for treatment of HIT
Bivalirudin         0.15-0.20 mg/kg/h,           Enzymic > renal             Approved in the U.SA for anticoagulation
(Angiomax)          without initial bolus        (25 min)                    during percutaneous coronary
                    (target aPTT range, 1·5-                                 interventions (non-HIT); anecdotal
                    2·5 x baseline)                                          experience in HIT; low t and enzymic
                                                                             metabolism are theoretical advantages
                                                                             over lepirudin for cardiac surgery in HIT
                                                                             (under current investigation)
Fondaparinux        Uncertain                    Renal 17-20 h               Approved for DVT prophylaxis following
(Arixtra)                                                                    orthopaedic surgery; theoretically, lack of
                                                                             in vitro crossreactivity with HIT antibodies
                                                                             suggests it may be efficacious in HIT (not
                                                                             yet studied for this indication)

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