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Home > About HIT > FAQs
What is the history of heparin induced thrombocytopenia?
In clinical use for over 50 years,[15,16]
heparin is an important and widely used anticoagulant for the prophylaxis
or treatment of thromboembolic disease as well as numerous other applications
(Table 1).[3] Unfortunately, heparin can cause serious adverse events, one
of the most important of which is heparin-induced thrombocytopenia (HIT).[9]
HIT was first identified in the 1970s[15]
and emerged in the 1990s as one of the most difficult immunohematologic
issues confronting physicians.[17,18]
Table 1. Uses of Heparin[19,20]
| • |
Deep vein thrombosis (DVT) and pulmonary embolism
(PE): treatment and prophylaxis |
| • |
Acute coronary syndromes |
| • |
percutaneous coronary intervention (PCI) |
| • |
Thromboembolic disorders |
| • |
Arterial embolization: treatment and prophylaxis
(atrial fibrillation) |
| • |
Vascular and cardiac surgery |
| • |
Extracorporeal circulation (hemodialysis,
hemofiltration, and cardiopulmonary bypass during cardiac surgery) |
| • |
Arterial and venous catheters, pulmonary artery
catheters (heparin flushes) |
| • |
Diagnostic and therapeutic interventional
radiologic procedures |
|
[19]
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What is the clinical importance of heparin-induced thrombocytopenia?
| The clinical importance of HIT is driven
by four factors[3,14]: |
| 1. |
Heparin use is widespread and on the rise[3] |
| 2. |
HIT is a devastating prothrombotic disease[3,14] |
| 3. |
HIT is a severe, immune-mediated drug reaction that
can occur in any patient exposed to heparin[3] |
| 4. |
HIT presents clinicians with a critical medical dilemma[3] |
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What is HIT, including its pathophysiology?
HIT, which usually develops after a patient has been on heparin for 5 or
more days, may develop sooner if there has been previous heparin exposure
(see Figure 1).[3,14]
Heparin binds to platelet factor 4 (PF4), forming a highly reactive antigenic
complex on the surface of platelets and on endothelial cell surfaces, thereby
increasing the number of targets for heparin-dependent antibodies.[3,14]
Susceptible patients then develop an antibody (IgG) to the heparin-PF4 antigenic
complex. Once produced, immunoglobulins, usually IgG, bind to the heparin-PF4
immune complex on the platelet surface. The Fc portion of the IgG then activates
the platelets by binding to platelet Fc receptors.[3,14]
Thrombocytopenia develops as the reticuloendothelial system consumes activated
platelets, platelet microaggregates, and IgG-coated platelets.[3,14]
Most devastating, however, is the thrombotic state that develops as a
result of platelet activation and the generation of procoagulant microparticles,
and an additional increase in thrombin generation.[3]
Figure 1. Pathogenesis of HIT[7,5,22,23]
[7]
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What are the risks associated with HIT?
In select patient populations (e.g., cardiac surgery) exposed to heparin,
up to 50% have developed heparin-dependent antibodies.[16]
Up to 5% of all patients exposed to heparin develop HIT.[21]
Thromboembolic complications have been reported to occur in half to two
thirds of patients with HIT, including those with and without thrombosis
at diagnosis.[3,21,25] The thrombotic
complications of HIT can be catastrophic (see Table
2).[7,10,18,21] Clinical data
have shown that approximately 20% of patients with thrombotic complications
lose a limb, and about 30% die without appropriate nonheparin therapy.[18,21]
Table 2. Complications of HIT[7,10,18,26-29]
| • |
Deep vein thrombosis |
| • |
Pulmonary embolism |
| • |
Myocardial infarction |
| • |
Occlusion of limb arteries (possibly resulting
in amputation) |
| • |
Cerebrovascular accidents (Stroke, TIA) |
| • |
Skin necrosis |
| • |
End-organ damage (e.g., adrenal, bowel, spleen,
gallbladder or hepatic infarction; renal failure) |
| • |
Death |
|
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Who is at risk for developing HIT?
HIT is a serious side effect of a drug that is widely used in clinical practice.[3,30]
All patients exposed to heparin, administered by any route or at any dose,
are at varying risk of developing HIT and its potentially devastating thrombotic
complications.[3] This includes
patients receiving UFH at full therapeutic doses and low prophylactic doses,
including the minute amounts in heparin flushes and on heparin-coated catheters.
Patients receiving LMWH are also at risk for HIT, although to a lower degree.[21,25,28-30]
With 12 million patients receiving either UFH or LMWH in the United States
each year, the clinical implications of HIT become readily apparent.[21]
HIT presents clinicians with a critical medical dilemma
Clinicians should have a high index of suspicion for HIT in any patient
receiving heparin, especially in those with previous exposure to heparin,
presence of heparin-dependent antibodies, history of HIT, or postoperative
cardiovascular or orthopedic patients.[7,28,29]
Unfortunately, HIT is generally underrecognized and underdiagnosed. In addition,
in many patients, there are often multiple possible causes of thrombocytopenia,
the hallmark for diagnosing the disease. Therefore, although there are clinical
criteria to assist in the diagnosis of HIT, the diagnosis remains difficult.[1]
Figure 2. Criteria for diagnosing HIT[9,21]
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What accounts for the frequent underdiagnosis of HIT?
Three factors may help explain the underdiagnosis of HIT:
| 1. |
There is a general lack of awareness[21,30]
that may be due, perhaps, to confusion created by the name of the
disease, since clinically significant thrombocytopenia (< 150,000/mcL
platelets) may not be present in all patients with HIT.[15,30] |
| 2. |
Thrombocytopenia in HIT is paradoxically associated
with thrombosis, not with bleeding. |
| 3. |
There are a large number of other causes of thrombocytopenia
in hospitalized patients (e.g., septicemia/sepsis, hemodilution, disseminated
intravascular coagulation, hypercoagulable states, hemodialysis therapies,
multisystem organ failure, primary bone marrow disorders, and other
concurrent drug therapies).[32] |
The diagnosis of HIT should be made first on clinical
findings.[17]
Laboratory tests for the diagnosis of HIT are
useful; however, they still have limitations. Some laboratory tests are
not routinely available for use in the clinical setting.[7,28]
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Why has the optimal treatment of HIT been difficult to attain?
Optimal treatment of HIT has, until recently, been elusive. The first step
of treatment is the elimination of all sources of heparin.[25,30]
However, heparin discontinuation itself can be dangerous since the underlying
condition, for which heparin was originally instituted, may not yet be resolved.[21]
In addition, HIT, a prothrombotic process, requires further anticoagulation
with a nonheparin, alternative anticoagulant.[4,25]
In HIT, the thrombotic process is amplified by immune complex formation,
platelet activation, and thrombin generation—even after heparin has
been withdrawn.[25] In fact, heparin
withdrawal alone results in thrombotic complications in this hypercoagulable
state.[25] Many patients, including
those without clinical evidence of thrombosis at presentation, go on to
develop thrombotic complications even after heparin is discontinued.[21]
Unfortunately, the following anticoagulants are not appropriate in patients
with HIT:
| • |
LMWH is contraindicated
in the treatment of HIT due to its nearly 100% cross-reactivity with
heparin-dependent antibodies[21,25] |
| • |
Danaparoid (a heparinoid)
has a rate of 10% to 15% cross-reactivity with heparin-dependent antibodies,
and is therefore contraindicated in the treatment of HIT[17]
(not currently available in the United States) |
| • |
Warfarin takes several
days for its onset of activity and therefore is not an appropriate
treatment for acute HIT.[35]
In addition, warfarin can induce a prothrombotic state due to the
suppression of natural anticoagulant protein C. In HIT patients, this
has been associated with the occurrence of DVT, PE, venous limb gangrene,
and warfarin-induced skin necrosis.[10,27] |
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How should HIT be treated and thrombotic complications reduced?
Completely discontinuing all use of heparin is mandatory.[7,25,28,30]
An optimal agent to treat HIT would not cross-react with heparin/PF4 antibodies
and would be a potent antithrombotic. In addition, it should be fast-acting,
reasonably well tolerated, easy to monitor, and have a short half-life.[1]
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