Introduction

According to data presented at a symposium held during the 2003 American College of Emergency Physicians Scientific Assembly, heparin-induced thrombocytopenia (HIT) is an under-diagnosed and under-treated condition that results in significant morbidity and mortality.¹ Long-recognized as a complication associated with heparin therapy, HIT continues to escape detection of even the most experienced physicians, setting the stage for potentially devastating adverse effects that include myocardial infarction, thrombotic stroke, pulmonary embolism, deep venous thrombosis, and limb artery occlusion requiring amputation.²

Often perceived as a rare disorder and overlooked in a differential diagnosis, HIT affects large numbers of hospitalized patients, who face a risk of potentially catastrophic complications. In a pooled analysis of several prospective studies, HIT occurred in 3% of patients exposed to heparin for 5 days or more.³ Other estimates typically place HIT incidence from 1% to 5% of heparin-treated patients.

Incidence estimates fail to capture the threat posed by an episode of HIT that is not promptly recognized and treated. Every case of HIT is "a disaster waiting to happen," advised Lawrence Rice, MD, Professor of Medicine, Department of Internal Medicine, Hematology-Oncology Section, Baylor College of Medicine, Houston, Texas.⁴ A 14-year study of HIT cases showed that 52.9% of episodes were followed by thrombotic events within 30 days, most occurring within the first 10 days.⁵ Dr. Rice cited data that indicate 30% to 75% of patients with HIT develop arterial or venous thromboembolic complications, which prove to be fatal in up to 5% of cases. In untreated cases of HIT, the risk of amputation increases to about 20% and mortality to 30%, according to Dr. Rice.

"Heparin-induced thrombocytopenia is not a rare problem," stated Dr. Rice. "We see one hundred cases, year after year, and this year the figure could reach one-hundred-fifty cases. At any given time, we typically have three or four patients with heparin-induced thrombocytopenia."

In an attempt to put the risks associated with heparin therapy into context, Dr. Rice noted that more than 1 trillion units of heparin are used each year in the United States, and a third of all hospitalized patients (12 million) are exposed to heparin at some point during their hospitalization. Importantly, the use of low-molecular-weight heparin reduces, but does not eliminate, the development of HIT (about 0.5%). Considering the widespread and growing use of low-molecular-weight heparin as an alternative to unfractionated heparin, the true incidence of HIT may not be known.

"When I consider the millions of patients exposed to low-molecular-weight heparin, it is not surprising that in many of the cases [of HIT] that I see, the only heparin exposure has been to low-molecular-weight heparin," indicated Dr. Rice.

Historical Perspective

The potential adverse effects of heparin on platelets have been known since heparin was introduced almost 60 years ago. Initial descriptions of HIT-like features were described in series of surgical patients in the late 1950s and early 1960s,^6,7 and the underlying immune mechanisms of HIT were elucidated beginning in the late 1960s.^8-10 The syndrome known as HIT and its clinical features were formally identified and defined in the 1970s.^11,12 Despite its lengthy history, HIT has attracted little attention in widely read medical textbooks, contributing to the lack of awareness among physicians, Dr. Rice indicated.

According to John L. Francis, PhD, Director, Clinical and Research Laboratories, Florida Hospital Cancer Institute, Orlando, Florida,¹³ HIT actually has three distinct presentations. The presentations are typical-onset HIT (within 4 to 14 days), rapid-onset HIT (usually involving patients with previous heparin exposure), and delayed-onset HIT (average of 9 days after cessation of heparin therapy).

Immune-mediated Basis of Heparin-induced Thrombocytopenia

Studies have shown that HIT is caused by immune complexes composed of IgG bound to a complex of heparin and platelet factor 4 (heparin-PF4).^14,15 These immune complexes activate platelets and endothelial cells.^14,15 The activated platelets release procoagulant microparticles that initiate thrombin generation activating the coagulation cascade. Antibody-mediated endothelial injury may also contribute to the development of thrombi.¹⁶ In 90% of cases, antibodies formed by heparin-PF4 complex cross-react with low-molecular-weight heparin, Dr. Rice indicated.

Onset of HIT might be marked by a sudden and dramatic decrease in platelet count, although in many cases, the thrombocytopenia can be moderate and associated with a platelet count of 80,000/mm³ to 110,000/mm³ (a 50% platelet drop from baseline (ie, from 400,000/mm³ to 200,000/mm³) should also be considered HIT).

"This type of moderate thrombocytopenia is easily overlooked," advised Dr. Rice. "Yet, it could be the only clue to heparin-induced thrombocytopenia and offers the only opportunity for intervention—before it's too late. And thus, prevent a catastrophe."

Early Detection Key to Prevention

Prevention of HIT-related catastrophic clinical events requires a combination of awareness, vigilance, and suspicion on the part of the clinician, followed by prompt and appropriate clinical intervention. The basic approach to management of HIT is elimination of all heparin exposures (including low-molecular-weight heparin) and use of an alternative anticoagulant, such a direct thrombin inhibitor.

Although prompt recognition and treatment are the keys to successful management of HIT, patient assessment is complicated by the fact that diagnosis and treatment are based primarily on clinical findings. In arriving at a diagnosis of HIT, a physician should consider and rule out other diagnostic possibilities, including severe infection or sepsis, drug-related reactions or interactions, mechanical causes (such as bypass surgery or intra-aortic balloon pump), dilutional factors (massive bleeding), and coagulopathies. Laboratory testing should include a complete blood count (CBC), and then if HIT is suspected, an enzyme-linked immunosorbent assay (ELISA) can be performed to confirm the diagnosis. However, available laboratory tests remain problematic. "ELISA has a high frequency of false-positive results," advised Dr. Rice.

Clinical recognition of HIT is made complicated by its easily overlooked association with incidental heparin exposure. Wishing to emphasize that point, Dr. Rice described the case of a 30-year-old woman with a pituitary tumor who was receiving chemotherapy through a portacath that was flushed daily with heparin. On Day 1 of chemotherapy, the patient had a platelet count of 170,000/mm³. On Day 9, she was admitted to the hospital for severe pleuritic chest pain, normal chest X-ray, and a CBC showed her platelet count had dropped to 55,000/mm³. On Day 11, spiral computed tomography revealed bilateral pulmonary emboli. Massive, painful swelling of the patient's right arm led to ultrasound assessment showing a subclavian-axillary thrombus.

The portacath was removed and the patient was treated with enoxaparin 1 mg/kg every 12 hours. The patient's platelet count dropped precipitously to 19,000/mm³. The patient developed bilateral severe arm swelling and pain, accompanied by worsening chest pain, oxygenation, facial edema, and headache.

During consultation, Dr. Rice made a preliminary diagnosis of HIT, which was confirmed (positive ELISA for HIT) upon the patient's transfer to his institution. All heparin was discontinued and anticoagulation was initiated with argatroban. Over the next 8 days, the patient had resolution of painful facial and arm swelling, chest pain and shortness of breath. Over the course of 5 days, the patient's platelet count rose from 17,000/mm³ to 120,000/mm³ and the patient was transitioned from argatroban to warfarin. The patient was subsequently discharged on warfarin and has continued to do well during outpatient follow-up.

"This patient had a huge clot in her right main pulmonary artery; yet, her only heparin exposure was a tiny amount used to keep her catheter open," observed Dr. Rice.

Delayed-onset Heparin-induced Thrombocytopenia

Drs. Rice and Francis recently published a retrospective series of 14 cases of delayed-onset HIT,¹⁷ which is increasingly being recognized. Delayed-onset HIT involves an initially uncomplicated heparin exposure and an unrecognized drop in platelet count (although levels might be only mildly decreased or even normal). Cases often arise after hospital discharge (up to 40 days after heparin exposure in their series), and patients usually present with arterial or venous thrombosis. Re-exposure to heparin invariably leads to another decline in platelet counts, and the patient's condition deteriorates. The condition is associated with a mortality of 25 to 30%, although most patients respond well to alternative anticoagulant therapy.

Emerging Evidence of Asymptomatic Heparin Antibodies

An aspect of HIT that has recently come to light is evidence that some patients have "asymptomatic" heparin antibody formation following heparin exposure. A number of studies have documented heparin antibody formation following cardiac surgery.^2,18-22 Although relatively few of the patients evolve to clinically diagnosed HIT, they do appear to have an increased risk for thromboembolic events, Dr. Francis indicated.

Dr. Francis cited one study where 124 patients with unstable angina were treated with unfractionated heparin for 5 days and then followed for one year.²³ Patients who had positive ELISA tests were twice as likely to experience major adverse cardiac events (death, myocardial infarction, recurrent angina, stroke) during follow-up as compared to patients who tested heparin-PF4-negative (66% vs 44%, respectively).

Data from the GUSTO-IV trial²⁴ of thrombolytic therapy for acute myocardial infarction has provided additional evidence of the hazards of asymptomatic heparin antibody production. Patients who were antibody-positive had almost a three-fold higher 30-day risk of death or myocardial infarction (30.4% vs 11.3%, P = .011) or myocardial infarction (21.7% vs 6.2%, P = .008) than patients who were antibody-negative.

Heparin-PF4 antibody formation might be especially hazardous to patients who are re-exposed to heparin during or after coronary bypass surgery (CABG). Dr. Francis indicated that patients who were antibody-positive after CABG faced the risk of clinical HIT when re-exposed to heparin 1 to 6 weeks after surgery. Dr. Francis stated the results corroborate similar findings from other studies, including his own unpublished work showing a longer hospitalization in CABG patients who were antibody-positive.

In an ongoing study, Dr. Francis and colleagues are testing the hypothesis that heparin-PF4 antibody formation might play a role in many of the patients who present in the emergency room with chest pain or thrombosis and have a recent (<6 months) history of hospital admission. If true, antibody-positive patients would have an increased risk of HIT if re-exposed to heparin.

The study involves prospective evaluation of patients who present with chest pain and have a recent history of hospital admission versus patients with chest pain and no recent hospitalization. Preliminary findings indicate that chest pain patients who were recently in the hospital are much more likely to be antibody-positive. Analysis of the combined endpoints of chest pain and venous thromboembolism also reveals a much higher prevalence of heparin-PF4 antibodies in recently hospitalized patients. Heparin-PF4 antibodies were found in approximately 10% of all patients presenting to the emergency room with chest pain and/or thrombosis with a higher risk in patients with a recent hospitalization.

"I think the take-home message from this study is that there is a high frequency of positive circulating heparin-PF4 antibodies in patients who present to the emergency department with chest pain or thrombosis, especially the group of patients that has a recent history of hospital admission," advised Dr. Francis.

Treatment Options for Heparin-induced Thrombocytopenia

Dr. Rice noted that physicians have a growing list of alternative anticoagulant treatment options to use in the management and prophylaxis of HIT. Among available direct thrombin inhibitors, argatroban is indicated as an anticoagulant for prophylaxis or treatment of thrombosis in patients with HIT and in patients with or at risk for HIT undergoing percutaneous coronary intervention.²⁵ Lepirudin is indicated for anticoagulation in patients with HIT and associated thromboembolic disease in order to prevent further thromboembolic complications.²⁶ Both argatroban and lepirudin have demonstrated efficacy in reducing the risk of death, amputation, and thromboembolism associated with HIT. The systemic clearance of lepirudin is proportional to the glomerular filtration rate or creatinine clearance. Therefore, the lepirudin rate of infusion must be reduced in patients with known or suspected renal insufficiency. Whereas argatroban is metabolized in the liver and no dosage adjustment is necessary in patients with renal dysfunction, making argatroban an appropriate treatment option for renally-compromised patients, Dr. Rice advised.

References

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