About Heparin-Induced Thrombocytopenia (HIT)

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).[15] 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

The clinical importance of heparin-induced thrombocytopenia (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]

1. Heparin use is widespread and on the rise

Heparin is the most widely used intravenous (IV) anticoagulant[19] and one of the most widely prescribed drugs in the United States. Approximately 12 million individuals, or 1/3 of hospitalized patients, have some heparin exposure yearly.[21] Indications for its use continue to increase.[3] Unfortunately, this increased use of heparin has the potential to increase the occurrence of HIT. Aggressive anticoagulation is a critical requirement during PCI and many other procedures to reduce the risk of thrombosis. Anticoagulation during these procedures is traditionally achieved with unfractionated heparin (UFH). However, heparin is contraindicated in HIT patients. Low-molecular-weight heparin (LMWH) and danaparoid are also contraindicated for HIT because both cross-react with HIT antibodies.

Argatroban, a direct thrombin inhibitor, offers benefits in this clinical setting, as it does not cross-react with HIT antibodies, inhibits both circulating and bound thrombin, is relatively easy to titrate, and has short-acting anticoagulant effects in healthy subjects.

2. HIT is a devastating prothrombotic disease

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 heparin-induced thrombocytopenia (HIT)[5,7,22,23]

Pathogenesis of heparin-induced thrombocytopenia (HIT)

In select patient populations (e.g., cardiac surgery) exposed to heparin, up to 50% can develop heparin-dependent antibodies.[24] 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 heparin-induced thrombocytopenia (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 alternative nonheparin therapy.[10,18]

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

3. Heparin-induced thrombocytopenia (HIT) is a severe, immune-mediated drug reaction that can occur in any patient exposed to heparin

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]

4. Heparin-induced thrombocytopenia (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.[24]

Figure 2. Criteria for Diagnosing HIT[9,21]
Criteria for Diagnosing Heparin-Induced Thrombocytopenia (HIT)

Criteria for Diagnosing Heparin-Induced Thrombocytopenia (HIT)

Important Safety Information

As with all anticoagulants, bleeding is a serious concern. Argatroban is contraindicated in patients with overt major bleeding or those with hypersensitivity to the product or any of its components. Argatroban should be used with extreme caution in disease states or other circumstances in which there is an increased risk of hemorrhage. Overall major bleeding was reported in 5.3% of Argatroban-treated patients with HIT versus 6.7% of the historical controls. Overall major bleeding was reported in 1.8% of Argatroban-treated patients undergoing PCI versus 3.1% of the historical controls. Intracranial bleeding was not observed in the 568 patients treated with Argatroban for HIT (with or without thrombosis) or in the 91 patients who underwent PCI. The most common nonhemorrhagic side effects in HIT patients, regardless of the relationship to treatment, were dyspnea, hypotension, and fever. In patients undergoing PCI, the nonhemorrhagic side effects, regardless of the relationship to treatment, included chest pain, hypotension, and back pain. Please see full Prescribing Information for additional safety information on Argatroban.