Recent Advancements in the Management of Heparin-Induced Thrombocytopenia
Article orginally published in March 1998
 | Theodore E. Warkentin,
Guest Editor |
Thrombocytopenia is one of the most common laboratory abnormalities
among hospitalized patients. Although thrombocytopenia is caused by a wide
variety of factors, including hemodilution, septicemia, and hypersplenism,
increasing attention is being directed to the syndrome known as
heparin-induced thrombocytopenia (HIT). HIT is an immunoglobulin-mediated
adverse drug reaction that is characterized by platelet activation,
thrombocytopenia, and a high risk of thrombotic complications among
patients receiving or who have recently received heparin. HIT is one of
the most important immunologic drug reactions; however, despite the
frequency and severity of HIT, there is only one FDA-approved treatment
for this syndrome. This article provides a summary of information designed
to bring the clinician up to date on the topic of HIT. Information
presented here is based on published data, personal clinical experience,
and information presented at several scientific symposia and during
presentations dealing with HIT at the recent 1997 annual conference of the
American Society of Hematology.
Pathogenesis of HIT
The cause of HIT eluded clinicians for many
years. It was clear that an unusual syndrome occurred in relation to
heparin treatment, as was suggested by early descriptions of the syndrome
such as “white clot syndrome” or “heparin-associated thrombocytopenia
(HAT).” However, only recently has it been accepted that HIT is most
commonly caused by IgG antibodies (designated HIT-IgG) that activate
platelets through their Fc receptors.1,2
Drug-induced thrombocytopenia
Certain drugs, such as
quinine, quinidine, and sulfa antibiotics, link non-covalently to platelet
membrane glycoproteins. Very rarely, in some patients receiving these
drugs, IgG antibodies are produced that recognize these drug-glycoprotein
targets. Severe thrombocytopenia characteristically results because
macrophages of the reticuloendothelial system remove the IgG-sensitized
platelets from the circulation. Sometimes, drug metabolites, rather than
the parent drug, provide the primary immunogenic stimulus. Patients who
develop drug-induced immune thrombocytopenia typically present with
mucocutaneous bleeding, ranging from petechiae and ecchymoses to
life-threatening gastrointestinal and intracranial hemorrhage.
Heparin-induced thrombocytopenia
In contrast, other
mechanisms appear to explain thrombocytopenia associated with use of
heparin. Two clinical syndromes have been identified.3-5 HIT type I is
characterized by a mild decrease in platelet counts (rarely below 100 x
109/L), is caused by nonimmunologic mechanisms (likely, mild direct
platelet activation by heparin), and is not associated with any major
clinical sequelae.
HIT type II, by comparison, is induced by immunologic mechanisms and is
associated with clinical events that range from mild and asymptomatic to
life-threatening. By definition, affected patients can be shown to have
formed HIT antibodies. The platelet count fall is usually substantial,
generally 50% or more, and there is the potential for concomitant
development of thromboembolic complications. Although HIT type I occurs
primarily in patients treated with intravenous high-dose heparin, HIT type
II can occur in patients receiving heparin by any route at any dose,
including heparin flushes. However, the risk of HIT type II varies with
the dose of heparin, the type of heparin (unfractionated >
low-molecular-weight [LMW] heparin; bovine > porcine), and the clinical
situation (higher risk for surgical than medical patients). This syndrome
will be referred to by its common designation, heparin-induced
thrombocytopenia (HIT)2 in the remainder of this article.
Heparin/PF4: the target antigen of HIT
HIT is caused
by antibodies, typically of the immunoglobulin G (IgG) type. The antigen
in HIT is a multimolecular complex of heparin and platelet factor 4 (PF4)
that is formed when the highly negatively charged heparin polysaccharide
molecules bind to PF4, a positively charged protein tetramer. PF4 is
released from platelet storage granules during platelet activation.
High-molecular-weight (unfractionated) heparins that can readily wrap
around the PF4 molecule facilitate complex formation to a greater extent
than do shorter-chain LMW heparins. The anticoagulant activity of heparin
is neutralized in this process. Immune complexes composed of heparin, PF4,
and IgG bind to platelet Fc receptors, resulting in strong platelet
activation.
Two studies6,7 that were presented at the 1997 annual
meeting of the American Society of Hematology give insights into the
immunopathogenesis of HIT. Chong & Newman6 reported that HIT
antibodies recognize PF4 that is either bound to a solid phase or bound to
heparin (either on a solid or in aqueous phase). Further, HIT antibodies
could be depleted by adsorption with agarose beads coated with heparin/PF4
or PF4 alone. Thus, Chong and Newman suggest that the epitope recognized
by HIT antibodies is conformationally altered PF4, bound either to heparin
or to a solid surface. In an intriguing study of T-cell receptor
repertoire in an HIT patient reported by Bacsi and colleagues,7
the patient’s lymphocytes could be stimulated in vitro by heparin/PF4
complex. A T-cell receptor beta-chain variable gene clonotype was
identified that responded to stimulation with heparin/PF4 complexes.
Because this clonotype could be found in low frequency, even in
unstimulated peripheral blood mononuclear cells from the patient, a role
for T lymphocytes in the pathogenesis of HIT is indicated.
Effects on the coagulation system
Although platelet
activation, per se, is indeed an important aspect of the HIT syndrome,
associated events are important in triggering activation of the
coagulation system, ultimately producing an increase in thrombin
generation. Evidence of increased in vivo thrombin generation in patients
with HIT includes elevated levels of thrombin-antithrombin complexes
(directly showing increased thrombin generation) and increased
cross-linked d-dimer levels (indicative of fibrin formation, subsequent
cross-linking, and fibrinolysis).8,9 However, overt disseminated
intravascular coagulation with hypofibrinogenemia is seen in only 5% to
10% of patients.
Several theories explain why IgG-mediated platelet activation results
in increased thrombin generation in patients with HIT. First, HIT-IgG is a
potent platelet agonist. Consequently, large quantities of
platelet-derived microparticles that are also highly procoagulant are
generated.10 Second, HIT antibodies have been shown to
recognize complexes formed by PF4 and endothelial heparan
sulfate.11 (Heparan sulfate is an endogenous glycosaminoglycan
structurally resembling heparin that plays a role in normal anticoagulant
activity of endothelium.) Immunoinjury by HIT antibody results in
generation of tissue factor by endothelial cells, which initiates the
extrinsic coagulation pathway. Third, platelet activation leads to the
further release of heparin-neutralizing substances, such as PF4, from the
platelet a-granule. This could explain the “resistance” to heparin
observed in some patients with HIT. Further heparin/PF4 complexes are
produced, leading to a vicious cycle of progressive platelet activation
(Fig 1).
Figure 1:
Cascade of events leading to formation of HIT antibodies
and prothrombotic components
Figure 2: | In practice, patients with HIT are at high risk for otherwise typical venous and arterial thromboembolism. In addition, a unique aspect of HIT, as discussed below, is the propensity of affected patients to develop the unusual syndrome of warfarin-induced venous limb gangrene (Fig 2).8 Increased thrombin generation helps to explain the risk for this catastrophic complication in HIT patients. |
Frequency of HIT and HIT-associated thrombosis
The
frequency of HIT is variable and patient population-dependent. In
orthopedic patients, the frequency of HIT was 1% and 3% in a study of
patients who received unfractionated heparin for one and two weeks,
respectively.2,3,12
This relatively high frequency was also suggested by a review of 13
prospective studies that assessed 1,336 patients who received heparin,
wherein the risk of HIT was approximately 3%.3 The overall
frequency of HIT-associated thrombosis was 1%, that is, at least one-third
of patients with HIT developed thrombosis.
A lower frequency of HIT occurs in patients receiving LMW heparin. In a
prospective study of 665 patients treated with heparin, approximately 3%
of the 332 patients who received unfractionated heparin for 2 weeks
developed HIT.12 By comparison, there were no cases of HIT
among the 333 patients treated with the LMW heparin, enoxaparin. Patients
receiving enoxaparin developed HIT antibodies at a significantly (p=0.02)
lower rate than did those receiving unfractionated heparin (2.2% versus
7.8%). Such findings support the observation that the frequency of HIT
varies, depending on the type of heparin formulation. This study also
strongly indicates that HIT is prothrombotic: 8 of 9 patients (89%) with
HIT developed thrombosis, compared with 18% of the remaining patients who
did not develop HIT (p < 0.001).12
The iceberg model of HIT
Only about one-third of
patients who developed strong HIT antibodies in this study also developed
thrombocytopenia. However, the increased risk for thrombosis was seen only
in the patients who developed thrombocytopenia, and not in the patients
who developed HIT antibodies without thrombocytopenia. These findings have
led to the “iceberg model” of HIT (Fig 3).3 Current research is
attempting to determine those factors that influence the development of
thrombocytopenia or thrombotic events in patients who form HIT antibodies.
Figure 3:
The iceberg model of heparin-induced thrombocytopenia.
The syndrome ranges from asymptomatic HIT-IgG seroconversion to
disseminated venous and arterial thrombosis.
Diagnosis of HIT
Because thrombocytopenia among
hospitalized patients can be caused by many factors (Table 1), clinicians
should be aware of several characteristic features of HIT.
| Table 1. Causes of Thrombocytopenia in Adults |
|---|
|
In patients with HIT, platelet counts typically begin to fall 5 to 8
days after heparin therapy is started.12 A rapid drop in
platelets may also be indicative of HIT, particularly if the patient
received heparin within the previous 3 months (Fig 4).13 In
these patients, residual circulating antibodies react upon heparin
re-exposure, inducing the rapid fall in platelet count.
Figure 4:
Heparin-induced thrombocytopenia without a platelet
count fall to < 150x109/L
A.
Transient postoperative platelet count fall (hemodilution).
B.
Platelet count fall beginning on day 7 of heparin use, heparin-induced
cytopenia.
C. Onset of leg pain on day 12, subsequently proven
secondary to proximal deep vein thrombosis.
D. Abrupt fallin
platelet count, from 429 to 160×109, following two heparin
boluses.
E. Platelet count rise on anticoagulation with ancrod,
followed by warfarin.
Thrombocytopenia is usually mild to moderate, with platelet counts
ranging from 20 to 150 x 109/L. Similarly, a fall in platelet count of 50%
or more that begins later than 5 days after the start of heparin therapy,
but with the platelet count still above the usual threshold for
thrombocytopenia (150 x 109/L), should also raise the suspicion of
HIT.13 By comparison, thrombocytopenia induced by sulfa drugs
and quinine is typically much more severe (Table 2).
| Heparin-induced Thrombocytopenia | Quinine- or Sulfa-induced Thrombocytopenia | |
|---|---|---|
| Frequency | approx. 1/100
| approx. 1/10,000
|
| Onset after beginning treatment | 5-8 days
| greater than or equal to 7 days
|
| Platelet count | 20-150×109/L*
| < 20x109/L
|
| Sequelae | Thrombosis
| Bleeding
|
| Laboratory testing using patient serum | Heparin-dependent platelet activation; Immunoassay
| Drug-dependent increase in platelet-associated
|
| *Some patients have a fall in platelet count but platelet count remains > 150×109/L. | ||
Table 2.
Comparison of Characteristics of HIT and Other
Drug-Induced Thrombocytopenia
HIT as a clinicopathologic syndrome
HIT should be
viewed as a clinicopathologic syndrome, that is, the diagnosis should be
based on the presence of both adverse clinical events (most often,
thrombocytopenia) and positive laboratory tests for HIT antibodies.
clinical events during or shortly after heparin therapy,3 such
as:
thrombosis
minutes after an IV heparin bolus
the absence of thrombocytopenia (Fig 5)14
Figure 5:
Typical skin lesions associated with
HIT.4
TOP: Heparin-induced erythematous plaques.
BOTTOM: Heparin-induced
skin necrosis.
HIT is a prothrombotic state.12 Table 3 lists common
clinical events that are associated with HIT. Venous thrombotic events,
particularly deep venous thrombosis and pulmonary embolism, are the most
common complications of HIT.15 Among serologically confirmed
patients with HIT diagnosed over a 14-year period in Hamilton, Canada,
venous thrombotic events predominated over arterial events by a 4:1
ratio.15 These events usually involve large vessels. Skin
lesions may also develop at the heparin injection site, beginning 5 or
more days after the start of heparin use. About 75% of patients who
develop heparin-induced skin lesions do not develop thrombocytopenia.
Because thromboembolic events are common, HIT-associated mortality is high
(about 18%). Approximately 5% of affected patients require limb
amputation. Appropriate management can limit morbidity and mortality
attributable to this syndrome. Even when thrombocytopenia is severe, HIT
patients rarely experience overt bleeding or bruising.
Laboratory testing
Both functional and antigen assays
can be used to diagnose HIT (Table 4).16 Functional assays
exploit the ability of HIT antibodies to activate normal platelets in
vitro in the presence of therapeutic levels of heparin. Aggregation assays
that use washed donor platelets, such as the serotonin release assay (SRA)
and the heparin-induced platelet activation (HIPA) test, are more
sensitive and specific than those using platelets in citrated plasma. Both
sensitivity and specificity of the SRA and HIPA tests are > 90%. Both
of the assays are performed in a microtiter plate, allowing for
large-scale routine testing while maintaining a high level of specificity
and sensitivity.16 The predictive value of the SRA was assessed
in a large series of postoperative orthopedic patients undergoing a trial
of prophylactic heparin.12 A positive SRA test was strongly
associated (odds ratio, 78; p < 0.001) with the development of
thrombocytopenia after 5 or more days of heparin. The specificity of the
test was high (96%); however, its widespread use is limited by the need to
use radiolabeled material.
| Test | Advantages | Disadvantages |
|---|---|---|
| PAA | Rapid and simple | Low sensitivity – not suitable for testing multiple samples |
| 14C SRA | High sensitivity | Washed platelets (technically demanding), needs radiolabeled material |
| HIPA | Rapid, high sensitivity | Washed platelets (technically demanding) |
| ELISA | High sensitivity, detects IgA and IgM | High cost, lower specificity for clinically significant HIT |
Table 4.
Common Laboratory Tests for HIT (adapted from ref.
2)
Many laboratories perform the platelet aggregation assay (PAA) using
citrated platelet-rich plasma. Platelet-rich plasma obtained from normal
donors is incubated with patient plasma and heparin; the presence of HIT
antibodies may cause platelet aggregation under these circumstances. The
value of this test is limited by its poor sensitivity and specificity
because heparin can activate platelets under these conditions, even in the
absence of HIT antibodies. The sensitivity and specificity of PAAs can be
improved by using platelets derived from normal donors known to respond
well to HIT antibodies, by demonstrating inhibition of platelet
aggregation using very high heparin concentrations, and by including
negative and positive controls.17
Functional assays using flow cytometry to detect platelet activation
may also be useful in detecting HIT antibodies but require laboratories to
be equipped with special instrumentation. These tests detect
microparticles18 or other markers of platelet
activation.19
In antigen assays, antibodies against multimolecular heparin/PF4
complexes (the major antigen of HIT) are measured by colorimetric
absorbance. Two enzyme-linked immunosorbent assays (ELISAs) have been
developed (Stago and GTI) for the heparin/PF4 antibody. One assay that was
described at the 1997 American Society of Hematology meeting20
is a solid-phase PF4-based ELISA that uses polyvinyl sulfate (PVS) as a
substitute for heparin. The assay appeared to have greater sensitivity for
the detection of HIT antibodies than did a functional assay tested in
parallel (the serotonin release assay). The specificity of the newer assay
was less certain, however, as clinical evaluation for HIT in the patients
with discrepant functional and antigen assay results was incomplete.
Certain technical advantages were observed with the newer assay, (e.g.,
the PF4/PVS complexes were quite stable, and antibodies appeared to react
well against a variety of PF4/PVS ratios).
Certain biological explanations account for the occasional discrepant
results between functional and antigen assays in patients with
HIT.2 For example, a positive result with a functional assay
combined with a negative antigen assay can be explained by the presence of
platelet-activating HIT antibodies that recognize “minor” antigens that
are distinct from heparin/PF4 complexes.16 In this regard,
Amiral and colleagues have reported that some patient sera contain HIT
antibodies that recognize complexes between heparin and interleukin-8, or
between heparin and neutrophil-activating peptide-2.21
Conversely, a false-negative functional assay can be caused by
nonplatelet-activating IgA or IgM antibodies that recognize heparin/PF4
complexes. Whether these antibodies cause clinically significant
thrombocytopenia is uncertain. Nevertheless, it is important that
reference laboratories have access to both functional and antigen assays
to assist in the diagnosis of HIT.2
Management of HIT
Studies have shown that the risk for thrombosis
is high in patients with HIT.12,15 Heparin is contraindicated
in patients with HIT; most patients, therefore, will require treatment
with an alternate anticoagulant. Indications for further anticoagulation
include either the persistence of the initial clinical problem that first
prompted the use of heparin, or a new thrombosis that has occurred during
the initial period of HIT. To further complicate this issue, it is now
known that even patients who are first recognized with isolated HIT (i.e.,
thrombocytopenia without initial evidence of HIT-associated thrombosis),
and who are managed with discontinuation of the heparin with or without
substitution with warfarin, have a subsequent risk for thrombosis as high
as 50%.15 Thus, a role for prophylactic anticoagulation in
patients recognized with isolated HIT should be considered.
Caveats in the Treatment of Patients with HIT Complicated by
Thrombosis
A large number of antithrombotic treatments have been used
in patients with HIT. Recently, important disadvantages of some treatment
approaches have been recognized. For example, it was reported recently
that warfarin anticoagulation can be associated with progression of deep
venous thrombosis to venous limb gangrene, requiring limb amputation in
some patients treated with this agent.8 A characteristic laboratory
feature of this syndrome is an elevated INR (International Normalized
Ratio for oral anticoagulant monitoring), generally > 4. Laboratory
studies have shown that the high INR corresponds to a marked reduction in
protein C levels, suggesting that there is insufficient activity of the
protein C anticoagulant pathway to regulate the increased thrombin
generation found in HIT patients. Warfarin should be considered
contraindicated in patients with acute HIT.2
Ancrod is a defibrinogenating snake venom that has been used
successfully in uncontrolled studies to treat some patients with HIT.22
However, this agent does not reduce thrombin generation and may even be
associated with increased thrombin generation in vivo.9 This
may explain why some of the patients who developed warfarin-associated
venous limb gangrene were also receiving ancrod therapy8 (i.e.,
ancrod does not inhibit increased thrombin generation, which appears to be
important in the pathogenesis of venous limb gangrene). Other
disadvantages of ancrod include its relatively slow onset of action (it
must be given over 12 to 24 hours) and the fact that its use is not
rational in patients with HIT and severe disseminated intravascular
coagulation (DIC) who may even be hypofibrinogenemic when HIT is
diagnosed.
LMW heparins, such as enoxaparin and dalteparin, have been used to
treat HIT patients with thrombosis. However, laboratory studies using
sensitive assays for HIT antibodies show virtually 100% cross-reactivity
using these various LMW heparin preparations.12,23 Although
large, controlled studies are lacking, there is anecdotal evidence of
patients often developing persistent or recurrent thrombocytopenia during
treatment with LMW heparin.5
Treatment of HIT Complicated by Thrombosis: Drugs that Reduce Thrombin
Generation
Three agents that reduce or inhibit thrombin have undergone
evaluation for the treatment of HIT: danaparoid sodium, recombinant
hirudin, and argatroban.
Danaparoid, a mixture of anticoagulant glycosaminoglycans (heparan
sulfate, dermatan sulfate, and chondroitin sulfate) with predominant
anti-factor Xa activity, is an effective anticoagulant for most patients
with HIT.9,24 Rapid therapeutic anticoagulation can be achieved
following bolus administration of the drug. The anti-Xa effect of
danaparoid has a fairly long half-life (approx. 25 hours). This is useful
in patients in whom a gradual switch to oral anticoagulant therapy is
anticipated (e.g., postoperative HIT patients with deep vein thrombosis or
pulmonary embolism) but can be a drawback in patients in whom a surgical
or other invasive procedure is planned. Further, anywhere from 10% to 40%
of HIT patient serum will “cross-react” with danaparoid; that is, the
patient’s serum will produce greater platelet activation in the presence
of danaparoid than at baseline. Many patients whose serum exhibits this
type of in vitro cross-reactivity will not develop thrombocytopenia or
thrombosis when treated with danaparoid for HIT (i.e., they do not exhibit
in vivo cross-reactivity).9 Nevertheless, some physicians are
reluctant to use this agent for this reason.
These potential limitations of danaparoid have led to the evaluation of
a novel approach to the treatment of HIT, namely use of the direct
antithrombin, hirudin (lepirudin, Refludan™). Lepirudin is a recombinant
form of the leech anticoagulant, hirudin, that has been evaluated in over
200 patients with serologically proven HIT in clinical trials conducted in
Germany.25 Hirudin is one of the most potent thrombin inhibitors yet
identified. Because this polypeptide agent bears no structural
relationship with heparin, there is no risk for in vitro or in vivo
cross-reactivity with HIT antibodies. Therapeutic anticoagulation is
rapidly achieved following bolus administration. Further, hirudin has a
relatively short half-life (1.3 hours); thus, this agent has advantages in
patients in whom anticoagulation may need to be briefly discontinued
because of the need to undergo surgical or other invasive procedures. The
anticoagulant effect of hirudin can be readily monitored by its
prolongation of the activated partial thromboplastin time (aPTT), and the
target therapeutic range is 1.5 to 3.0 times the mean of the laboratory
normal range. Hirudin is predominantly metabolized by the kidney and
should be considered relatively contraindicated in patients with
significant renal failure.
Based on comparative studies against historical controls, lepirudin was
approved in the European Union in 1997 and in early 1998 by the US FDA as
a treatment for HIT complicated by thrombosis. In one study,25
treatment with lepirudin was associated with a significantly lower
frequency of a composite endpoint of mortality, limb amputation, and new
thrombotic complications compared with historical controls (10% vs 23%,
respectively, at day-7 follow-up, and 25% vs 52%, respectively, at day-35
follow-up).
Argatroban (Novastan®) is a synthetic antithrombin that has been
evaluated both for HIT and HIT complicated by thrombosis in
historically-controlled clinical trials in the US. The results of these
studies have not yet been published. In contrast to the clinical trials
involving lepirudin, entry into the argatroban studies did not require
initially demonstrating a positive assay for HIT antibodies. Likely, some
of the patients treated did not have HIT. Argatroban shares some of the
theoretical advantages of lepirudin, such as a relatively short half-life,
lack of cross-reactivity for HIT antibodies, and potent antithrombin
activity. Lepirudin, which is excreted renally, may be administered to
patients with hepatic failure without need for dosage adjustments.
However, because argatroban is metabolized predominantly by the liver,
dose reduction is required in patients with hepatic insufficiency.
Adjunctive Therapies for HIT
A number of other therapies can be
helpful for selected patients. For example, plasmapheresis can reduce the
concentration of HIT antibodies in patients with acute HIT. Another
potential benefit of this therapy is that replacement with plasma may be
efficacious in patients with acquired deficiencies of natural
anticoagulant factors, such as protein C or antithrombin. For example,
plasmapheresis can benefit patients with severe phlegmasia cerulea dolens
associated with warfarin-induced deficiency of protein C.8
Thromboembolectomy is another treatment that can be limb-saving in a
patient with acute arterial occlusion associated with HIT.
Some physicians also prescribe anti-platelet drugs such as aspirin for
HIT patients, particularly if they are at high risk for acute arterial
occlusions. Unfortunately, aspirin has only a modest inhibitory effect on
platelet activation by HIT antibodies. However, recent evidence suggests
that a novel class of platelet inhibitors that block ADP receptors are
very effective in inhibiting in vitro platelet activation by HIT
antibodies.26
An abstract published in association with the 1997 American Society of
Hematology meeting27 indicated that glycoprotein Iib/IIIa
inhibitors can also prevent platelet activation by HIT antibodies.
However, it remains to be seen whether these agents will be beneficial for
the treatment of HIT. Two caveats include the lack of any direct effect of
glycoprotein Iib/IIIa inhibitors on increased coagulation processes in HIT
and the potential for severe bleeding complications in patients treated
with both an effective anticoagulant and a potent platelet-inhibiting
drug.
Final Considerations
Although HIT remains one of the most
important adverse drug reactions in clinical medicine, increasing
consensus is emerging regarding its definition, frequency, pathogenesis,
laboratory testing, and treatment approaches.2 In particular,
the recent approval in the US of lepirudin and anticipated approval of
other novel agents with clinically significant anticoagulant effects in
HIT will be of value to patients with this life- and limb-threatening
problem, as well as to clinicians who are faced with these treatment
challenges.
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- Warkentin TE, Chong BH, Greinacher A. Heparin-induced
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- Warkentin TE, Kelton JG. Interaction of heparin with platelets,
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- Warkentin TE. Heparin-induced thrombocytopenia: pathogenesis,
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- Bacsi S, Geoffrey R, Gorksi J, Aster R. Antigen-specific expansion
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- Warkentin TE, Elavathil L, Hayward CPM, et al. The pathogenesis of
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- Warkentin TE. Danaparoid (Orgaran¨) for the treatment of
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- Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced
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- Warkentin TE, Kelton JG. Heparin-induced thrombocytopenia: know what
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- Warkentin TE. Heparin-induced skin lesions. Br J Haematol.
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- Amiral J, Marfaing-Koka A, Wolf M, et al. Presence of autoantibodies
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- Demers C, Ginsberg JS, Brill-Edwards P, et al. Rapid anticoagulation
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