Based on Data Presented in the CME-symposium "The Incidence and Impact of Heparin-induced Thrombocytopenia (HIT) in the Critical Care Setting" held during the 33rd Critical Care Congress of the Society of Critical Care Medicine, February 22, 2004 in Orlando, Florida

Expert Commentary

Louis Guzzi, MD, FCCM, Assistant Professor of Anesthesia, Florida State University, Tallahassee, Florida

The critical care physician often stands at the forefront of recognizing new disease states, resistance trends and becomes an early management expert in unique clinicopathologic syndromes. The long standing discussion revolving on the myriad causes of thrombocytopenia has often been the topic of heated and often fruitless discussions. The recognition of heparin-induced thrombocytopenia (HIT) as a disease process with the paradox of thrombosis, not bleeding with decreasing platelet counts, once again leads the CCM physician into the forefront of complex disease management.

The intensive care unit is a perfect example where the clinician may see several manifestations of HIT including early and unexplained deep vein thrombosis (DVT), pulmonary emboli or stroke in a patient who has had a long and protracted hospital course. The realization that we may need to reassess the paradigms in DVT and thrombocytopenic management presents a real and unique challenge to the CCM physician. This Critical Care Express Report™ begins to explore the role our practices may play in defining diagnosis, treatment and management of this complicated and deadly process.

According to data presented in a CME-symposium at the 33rd Critical Care Congress of the Society of Critical Care Medicine, HIT continues to go unrecognized with potentially fatal consequences. However, treatment with a direct thrombin inhibitor such as argatroban provides effective treatment for HIT in addition to preventing further thromboembolic complications.

Introduced almost 60 years ago, heparin remains one of the most widely used therapeutic agents in medicine, particularly among hospitalized patients. Though offering unquestionable benefits for patients requiring anticoagulation, heparin confers the risk of HIT, a potentially catastrophic event that often goes unrecognized. The risk of thrombosis due to HIT exceeds 50% in selected patient populations with potential consequences that include myocardial infarction, pulmonary embolism, stroke, amputation, and death.

Depending on the source of heparin received, the incidence of HIT has been reported in up to 5% of patients.¹ However, substantially more patients develop asymptomatic antibodies to heparin-platelet factor 4 (H-PF4). It has been estimated that as many as half the patients exposed to heparin are heparin antibody-positive. Heparin antibody formation clearly presents a risk for HIT and related sequelae upon heparin re-exposure, but the magnitude of this risk has yet to be accurately defined.

Defying classic definitions of thrombocytopenia, HIT is often underdiagnosed and there is a challenge in identifying at-risk patients. Diagnosis relies primarily on a physician's awareness of the condition and ability to recognize the clinical signs. Although many patients do meet the classic definition of thrombocytopenia with a decline in platelet count to less than 150,000/mm³, HIT also occurs in patients who have platelet values above that threshold. As a result, a precipitous decline in baseline platelet count on the order of 30% to 50% must also be considered diagnostic. Therefore, a decline in platelet count from 400,000/mm³ to 150,000/mm³ in association with heparin exposure should heighten the suspicion of HIT.

One may view HIT as a paradoxical disorder, and the multiple paradoxes that characterize the condition can complicate its management. Caused by a reaction to an anticoagulant, HIT results in thrombosis, a clotting disorder rather than a bleeding disorder. Discontinuation of heparin, the cause of the disorder, does not eliminate the risk of thrombosis. Switching a patient to unopposed oral anticoagulant therapy, without transitional assistance from a direct thrombin inhibitor, also can increase the risk of venous limb gangrene due to decreased protein C levels.²

Heparin-induced Thrombocytopenia: Management Challenge

Despite the ubiquity of heparin use in hospitalized patients, the most potentially devastating adverse consequence of its use remains widely unrecognized. Heparin-induced thrombocytopenia (HIT) confers a 30-day risk of thrombotic events that exceeds 50%.³ Without prompt recognition and appropriate clinical intervention, including use of a direct thrombin inhibitor such as argatroban, HIT-related thrombosis can lead to a significant rate of amputation (20%) and also significant mortality of 10% to 30%, according to John L. Francis, PhD, Director, Clinical and Research Laboratories, Florida Hospital Cancer Institute; Director, Florida Hospital Center for Hemostasis and Thrombosis, Orlando, Florida.⁴

Characterized as an autoimmune, iatrogenic condition, HIT occurs in up to 5% of all patients exposed to heparin.¹ However, this statistic creates a misleading impression about the impact of HIT in relation to the extensive exposure to heparin. According to Dr. Francis, approximately 12 million patients are exposed to a cumulative total of one trillion units of heparin annually.

"Heparin is one of the most commonly administered parenteral therapies in the hospital setting," stated Dr. Francis, "and the indications for heparin use are increasing."

By extension, HIT is not nearly as uncommon as generally perceived, Dr. Francis continued. As awareness of HIT increases and clinicians become more vigilant in suspecting HIT, the number of cases increases. Using his institution as an example, Dr. Francis indicated that the number of patients screened for the presence of heparin-dependent antibodies has increased from 63 in 1995 to 3,255 in 2003.

"Heparin-induced thrombocytopenia falls under the category of 'seek and you shall find,'" observed Dr. Francis.

Importance of Monitoring Platelet Levels

"Heparin-induced thrombocytopenia poses a challenge to physicians' diagnostic and clinical management skills," stated Stanley A. Nasraway Jr., MD, FCCM, Associate Professor, Surgery, Medicine & Anesthesia, Tufts University of Medicine; Director, Surgical Intensive Care Unit, Co-Director, Cardiothoracic Intensive Care Unit, New England Medical Center, Boston, Massachusetts.⁵ Though laboratory tests (activation and antigen assays) are available to detect HIT, the tests' availability, results, and laboratory turnaround times vary widely. As a consequence, diagnosis rests largely on a physician's clinical judgment.

When a heparin-exposed patient has a decline in platelet count below 150,000/mm³ or a 30% to 50% decline in the baseline platelet count, HIT should be suspected. For many patients, the percent decline in platelets figures more prominently in the recognition and diagnosis of HIT.

In reviewing more than 2,000 open-heart surgical procedures performed annually at his institution, Dr. Francis found that HIT was typically associated with a platelet count of approximately 60,000/mm³. Interestingly, a number of cases occurred at platelet counts as high as 150,000/mm³, the threshold typically used for diagnosis of thrombocytopenia. These results are consistent with other data indicating that HIT can occur across a wide spectrum of platelet levels.

"If a patient starts with a platelet count of 500,000/mm³ and then has a decline to 200,000/mm³, that can be an indication of thrombocytopenia and should be suspected," advised Dr. Nasraway.

Commenting on the management of HIT, Dr. Nasraway stated, "Simply stopping heparin is not enough."

A retrospective study illustrates the inadequacy of heparin discontinuation or switching anticoagulant therapy to warfarin after the recognition of HIT.⁶ An analysis of 114 consecutive patients with diagnosed HIT revealed a 38% rate of thrombosis and 27% mortality rate. After heparin cessation, initiation of warfarin therapy (n = 51) reduced mortality to 8%, but the rate of thrombosis rate increased to 45%. For those patients who discontinued heparin and did not receive warfarin (n = 63), the rate of thrombosis rate was 32% but the mortality rate soared to 43%.

Three time-dependent presentations of HIT have been identified. Typical-onset HIT occurs within 4 to 14 days of heparin exposure (Figure 1). Rapid-onset HIT is associated with previous heparin exposure and can occur within 0 to 3 days of subsequent heparin re-exposure. Delayed-onset HIT can occur as late as 6 weeks after heparin discontinuation, but typically averages about 9 days after discontinuation, according to Dr. Francis.

Risk of Heparin-induced Thrombocytopenia from Incidental Heparin Exposure

Neither infusional delivery nor prolonged exposure to heparin is necessary to trigger HIT. As an example, Dr. Nasraway cited a recent case involving a 44-year-old woman undergoing gastric bypass surgery for morbid obesity.⁷ The patient received a single injection of unfractionated heparin (5,000 units) before surgery. Over the next two days, the patient's platelet count declined from 163,000/mm³ to slightly over 50,000/mm³ (Figure 2). After rebounding over the next several days, the platelet count again dropped precipitously to 23,000/mm³ (8 days post-surgery), reaching a nadir of 7,000/mm³ approximately 16 days post-surgery. The patient had suffered a stroke 7 days post-surgery confirmed by CT scan showing infarction in the right superior-parietal region (on Day 11). An enzyme immunoassay detecting H-PF4 antibodies was strongly positive on Day 10 post-surgery. Even though the patient's platelet count began to recover, the patient remained at high risk, as evidenced by the occurrence of venous thromboembolism on Day 23 post-surgery.

Dr. Francis noted that many exposures to heparin go unnoticed or are not considered of significant extent to be a potential source of HIT, such as heparin flushes. Moreover, incidental or minor exposures are often not noted in patient charts, Dr. Francis added. Nonetheless, such minor exposures can set in motion the cascade resulting in HIT. Acknowledging one economic "sequelae" of HIT, Dr. Francis cautioned, "Heparin-induced thrombocyto-penia is one of the most litigated sources of malpractice. Law firms now specialize in it."

Current Consensus on Treatment of Heparin-induced Thrombocytopenia

Guidelines for the clinical management of HIT are limited but continue to evolve. The College of American Pathologists recommends a baseline platelet count prior to initiation of heparin, particularly in patients with previous exposure to heparin, with routine monitoring focusing on the period of highest risk (5 to 10 days after heparin initiation).⁸

According to Dr. Nasraway, the current consensus for clinical management of HIT is to discontinue heparin and test for the presence of heparin antibodies. At this point, one question facing clinicians is whether to institute therapy with a direct thrombin inhibitor to prevent thrombosis. However, Dr. Nasraway indicated that studies showing high rates of thrombotic events in patients with HIT in the absence of treatment^3,6 provide support for the use of a direct thrombin inhibitor after discontinuation of heparin.

Once initiated, "Treatment with a direct thrombin inhibitor should continue until the patient's platelet level has stabilized," advised Dr. Francis. Continuing, Dr. Francis noted, "If the platelet count declined to less than 100,000/mm³, treatment should continue until the platelet count increases beyond that threshold. When a stable platelet count has been achieved, transition to an oral anticoagulant can be considered. However, the transition should include some overlap between the direct thrombin inhibitor and the oral anticoagulant. Unopposed warfarin can dramatically increase the risk of venous limb gangrene due to decreased protein C levels."

Asymptomatic Heparin Antibody Formation

The availability of heparin-dependent antibody assays has allowed investigation into the frequency of antibody formation. Recent studies have demonstrated that asymptomatic heparin antibody formation occurs in up to 50% of patients who have undergone cardiac surgery.^9-13 These data suggest that overt thrombosis and thrombocytopenia represent a small percentage of a potentially vast and ominous problem.

The clinical significance of asymptomatic heparin antibody formation remains unclear, but several investigations have provided intriguing data, Dr. Francis indicated. An evaluation of patients with unstable angina showed that those who tested positive for H-PF4 antibodies after heparin exposure had a major adverse cardiac event rate that was 50% higher than the rate seen in patients who were H-PF4 antibody-negative¹⁴ (Figure 3). For patients receiving heparin during treatment for acute coronary syndromes, H-PF4 positivity also predicted comparatively worse outcomes.¹⁵ At his own institution, Dr. Francis has found that H-PF4 positivity after coronary bypass surgery predicts an increased duration of hospitalization.

Evidence also suggests that re-exposure to heparin increases the risk of adverse outcomes in patients who have asymptomatic heparin antibodies. Dr. Francis indicated that heparin antibody-positive patients have been shown to have an increased risk of death or more prolonged hospitalization after coronary bypass surgery compared to patients who test heparin antibody-negative prior to surgery. Results from a recent study demonstrate an increased risk of delayed-onset HIT after coronary bypass in patients known to be heparin antibody-positive before surgery.¹⁶

Concerns about HIT are not limited to the post-surgical setting. Dr. Francis reported results from an ongoing study assessing the frequency of H-PF4 positivity in patients presenting to the emergency department with chest pain or overt thrombosis. The data was further stratified for patients with a recent hospitalization (<6 months). Among patients with chest pain and a recent hospitalization, 12.9% tested positive for H-PF4, compared to 3.6% without recent hospitalization (Figure 4). Among combined patients with chest pain and thrombosis, the rates of H-PF4 positivity were 11.7% in patients recently hospitalized and 5.0% in patients without recent hospitalization.

"A substantial number of patients presenting to the emergency department with chest pain or thrombosis have pre-existing antibodies," advised Dr. Francis. "Though weak, these antibodies are still reactive, and we are very convinced that having these antibodies proposes a major risk for heparin-induced thrombocytopenia."

Very little data exist on the frequency of HIT among intensive care unit patients. Two small studies have demonstrated HIT rates of 0.4% and 2.3%.^17,18 Dr. Francis suggested the studies might have underestimated the risk, noting that critical care patients typically have high rates of heparin pre-exposure and that heparin use is common in critical care facilities.

Regardless of the setting, when physicians recognize HIT and select therapy for clinical intervention, direct thrombin inhibitors have demonstrated efficacy for the management and prophylaxis of HIT. However, the available agents differ in several respects that should be considered when contem-plating a direct thrombin inhibitor for a patient, Dr. Francis stated.

Lepirudin is approved for anticoagulation in patients with HIT and associated thromboembolic disease in order to prevent further thromboembolic complications.¹⁹ 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. Dr. Francis observed that lepirudin appears to be highly antigenic, with approximately 40% of treated patients forming anti-hirudin antibodies. That observation has led to speculation that subsequent re-exposure could carry a risk of anaphylaxis.

Argatroban is approved 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.²⁰ Unlike lepirudin, argatroban is not associated with antibody formation. 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.

Bivalirudin, a direct thrombin inhibitor, is approved as an anticoagulant for use in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty, it is not indicated for HIT.²¹

Conclusion

Heparin-induced thrombocytopenia continues to go unrecognized, exposing patients to potentially deadly complications that include thrombotic events, amputation, and death. Due to the widespread use of heparin in a variety of clinical settings, heparin-induced thrombocytopenia is more common than generally assumed. Emerging data indicate that many patients develop heparin antibodies after heparin exposure. Due to limitations in laboratory testing, its diagnosis remains principally a clinical one. Treatment with a direct thrombin inhibitor such as argatroban has demonstrated safety and efficacy in the prophylaxis and treatment of heparin-induced thrombocytopenia.

References

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Disclosure
Louis Guzzi, MD, FCCM
Speakers Bureau-Abbott Laboratories, GlaxoSmithKline, Ortho Biotech, Pfizer

This report contains no information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

This report is supported by an educational grant from GlaxoSmithKline.

Critical Care Express Report™ is a product of Millennium Medical Communications, Inc. ("MMC, Inc."), an independent, third-party organization providing educational information concerning current medical data and opinions presented at worldwide medical meetings. The Critical Care Express Report™ is published in accordance with the Guidance for Industry: Industry Supported Scientific and Educational Activities, 62 Fed. Reg. 64,093, 64,096-99 (1997) adopted by the U.S. Department of Health and Human Services Food and Drug Administration. Pursuant to the foregoing standards, MMC, Inc. is solely responsible for selecting the topics discussed herein. This Critical Care Express Report™ may contain data on products, product uses, indications, and dosages which are not approved for use in the USA, Canada, and the European Union and no endorsement is hereby made or intended by coverage of any unapproved use. The content of this report is intended for educational purposes only, and merely conveys scientific data presented at medical meetings. Approved product labeling should always be consulted for prescribing information. The Critical Care Express Report™ is an independent and non-promotional report intended to provide accurate scientific and medical information for educational purposes. MMC, Inc. is not responsible for errors or omissions in reports. The production of this report was supported by a wholly unrestricted educational grant from GlaxoSmithKline. GlaxoSmithKline maintains no control, direct or indirect, over the content, substance, or distribution of this report.

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