Argatroban

When we compose medical school curricula, we choose what to stress to our students based on how common or how instructive the disease is. What are the common plagues of our society? Vascular disease, trauma, and some infectious diseases affect a large percentage of our population and rightfully assume an important place at the curriculum table. However, most diseases affect < 1% of the population. Based on what their pathophysiologic, mechanistic, or basic science processes can teach us, these uncommon diseases assume a role in our curriculum that is greater then their frequency would seem to warrant. Many genetic diseases and cancers fall into this category. Other diseases such as rabies or necrotizing fasciitis are so terrible that even though most physicians never treat a single case, we teach students about them and test for knowledge of these illnesses on national board and specialty examinations. But would we not be remiss if there was an illness that affected a large number of our patients and, if this illness caused disability and death in a majority of the patients it affected, we failed to teach about this illness? What if the haystack was full of needles, but we failed to even recognize the haystack?

Heparin-induced thrombocytopenia (HIT) may be just that haystack. The first case I failed to recognize was a patient on my service > 25 years ago. I was a medical student rotating on a surgical service that was consulted to remove an acute arterial thrombosis from an ischemic limb, which we did. Then, we removed it again, prior to removing the patient's limbs, sequentially, and prior to the patient's death. We never knew what the patient died from or why. Though it could possibly be the iatrogenic disease of the last 25 years, HIT still "gets no respect at all." For example, HIT is covered in just a few sentences in the 14th edition of Harrison's Principles of Internal Medicine, (1,2) in which it is noted to be a "rare complication," "usually of no clinical consequence" and for which "discontinuing heparin can promptly reverse the syndrome and may be life-saving." Most physicians think that they have never seen a case, and, if they have, the patient recovered just by stopping the heparin therapy. No big deal, right? In light of the significant body of knowledge that has accumulated in the past 15 years, Rice (3) points out that these dangerous "myths" and misconceptions about HIT need to be corrected.

Heparin is administered to > 12 million patients each year. (3) HIT is caused by antibodies that develop in up to 50% of patients following heparin exposure, against a complex of heparin and platelet factor 4.4 Its occurrence is more frequent with bovine vs porcine heparin, (5) unfractionated vs low-molecular-weight heparin, (6) and after surgery. (7) These antibodies, circulating for [greater than or equal to] 3 months in approximately 40% of patients, (8) can activate platelets, leading to the release of procoagulant microparticles. In turn, this may cause excessive thrombin generation, thrombocytopenia, and clinical thromboses. HIT, thrombocytopenia due to the interaction of heparin, platelets, and platelet antibodies, is a profoundly prothrombotic condition occurring in 1 to 5% of patients receiving heparin, (6) with up to 600,000 cases occurring yearly. With half of the patients in these cases developing HIT-related morbidity and mortality, (9) as many as 300,000 patients develop thrombotic complications, and 90,000 patients may die yearly. For perspective, there were 14,874 cases of tuberculosis reported to the Centers for Disease Control and Prevention in 2003, (10) an estimated 215,990 new cases of invasive breast cancer patients were reported in 2004 in the United States, (11) and cystic fibrosis affects 1 in 3,000 live births in the white population of North America (or about 3,200 babies) (12) yearly.

Clinically, HIT manifests as at least a 30 to 50% fall in the platelet count from pre-heparin values, often to < 150 x [10.sup.9] cells/L, typically 5 to 14 days after starting heparin therapy. (9) Less commonly, thrombocytopenia can occur within hours of therapy or conversely may be delayed for up to 20 days. (8,13-15) Though the thrombocytopenia is typically moderate, with a median platelet count of 50 to 70 x [10.sup.9] cells/L, platelet counts may range from < 15 x [10.sup.9] to > 150 x [10.sup.9] cells/L. (8,9)

Nineteen to 52% of patients affected by HIT will develop thrombosis within a month after the cessation of heparin therapy, in the absence of specific treatment. (9,16,17) Thrombotic complications may lead to the initial recognition of HIT, and may include deep venous thrombosis, pulmonary embolism, myocardial infarction, stroke, limb artery occlusion leading to amputation, and other thromboembolic events. These events are more frequently venous than arterial with approximately a 4:1 ratio. The mortality rate for patients with HIT-associated thrombosis is approximately 20 to 30%. (16,17)

When HIT is suspected, all heparin-related products must be avoided, including, for example, low-molecular-weight heparins, heparin flushes, and heparin-coated catheters. In addition, alternative nonheparin, nonwarfarm anticoagulation therapy must be initiated immediately. Two direct thrombin inhibitors, argatroban and lepirudin, that are administered by IV infusion have been approved in the United States for use in patients with HIT. Argatroban and lepirudin have been shown to improve the outcomes of patients with HIT, including reducing the number of eases of new thrombosis. (16-19) Anticoagulation therapy with argatroban or lepirudin should be continued until the platelet count has recovered, usually to at least 100 x [10.sup.9] cells/L. Occasionally, surgical thromboembolectomy, systemic or local thrombolysis is needed to treat life or limb-threatening arterial or venous occlusion.

Under the umbrella of adequate alternative parenteral anticoagulation therapy, after platelet counts have recovered sufficiently, warfarin therapy can be initiated for the long-term treatment of HIT. Warfarin should never be used as the sole short-term therapy for patients with HIT. The depletion of activated protein C can paradoxically worsen the thrombosis, causing venous limb gangrene. (20) Warfarin is administered for a minimum of 3 to 6 months, adjusted to maintain an international normalized ratio of 2 to 3.

So, what about the needles in the haystack? In this issue of CHEST (see page 1857), Warkentin et al add to the rich body of information that they have elucidated regarding HIT, showing that rare but clinically important manifestations of HIT, including erythematous and necrotic skin lesions, anaphylactoid reactions, and warfarin-associated venous limb gangrene, may be more common than previously suspected. Another important but rarely appreciated presentation is that of HIT in the emergency department (ED). Patients may present to the ED with HIT-related thromboses due to heparin that had been administered during a prior admission. (14,15,21) Failure to recognize these patients" subsequent re-exposure to heparin can be catastrophic. Complicating the picture, these patients may not be thromboeytopenie on representation to the hospital, making the diagnosis of HIT less likely to be considered.

These unusual presentations are important, but maintaining perspective is the key. Berkeley Breathed's comic-strip character Opus, who was famous for mixing metaphors, might say, "we shouldn't miss the forest for the trees, looking for needles in haystacks." It is important to recognize rare manifestations or presentations of common diseases. But, first we need to recognize the usual presentation of HIT and its clinical importance, and to avoid the pitfalls that persist in our texts and practice in regard to HIT. HIT is a common problem, it is not treated by the cessation of heparin therapy done, and it can kill our patients. Sir William Osler said that "we see what we know." Until we know HIT, it will continue to plague us. Perhaps it is time for heparin to be replaced by direct thrombin inhibitors or other more effective, less toxic agents. Then, HIT can appropriately be summarized in our textbooks in a few paragraphs.

Robert L. Levine, MD

Houston, TX

Dr. Levine is Associate Professor of Neurosurgery Emergency Medicine and Medicine The University of Texas School of Medicine at Houston.

Reproduction of this article is prohibited without written permission rom the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml).

Correspondence to: Robert L. Levine MD, Associate Professor of Neurosurgery, Emergency Medicine and Medicine, The University of Texas School of Medicine at Houston 6431 Fannin MSB 7.142, Houston, TX 77030; e-mail: rlevine@uth.tmc.edu

REFERENCES

(1) Handin RI. Anticoagulant, fibrinolytic, and antiplatelet therapy. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, eds. Harrison's principles of internal medicine. 14th ed. New York, NY: McGraw-Hill, 1998; 744-747

(2) Goldhaber SZ. Pulmonary thromboembolism. In: Fauci AS, Braunwald E, Isselbaeher KJ, et al, eds. Harrison's principles of internal medicine. 14th ed. New York, NY: McGraw-Hill, 1998; 1469-1472

(3) Rice L. Heparin-induced thrombocytopenia: myths and misconceptions (that will cause trouble for you and your patient). Arch Intern Med 2004; 164:1961-1964

(4) Warkentin TE. Heparin-induced thromboeytopenia. Curr Hematol Rep 2002; I:63-72

(5) Francis JL, Palmer GJ 3rd, Moroose R, et al. Comparison of bovine and porcine heparin in heparin antibody formation after cardiac surgery. Ann Thorac Surg 2003; 75:17-22

(6) Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular weight heparin or unfractionated heparin. N Engl J Med 1995; 332:1330-1335

(7) Warkentin TE, Sheppard JI, Horsewood P, et al. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000; 96:1703-1708

(8) Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 2001; 344:1286-1292

(9) Warkentin TE, Kelton JG. A 14 year study of heparin-induced thrombocytopenia. Am J Med 1996; 101:502-507

(10) Centers for Disease Control and Prevention. Reported tuberculosis in the United States, 2003. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, 2004

(11) American Cancer Society. Cancer facts and figures 2004. Atlanta, GA: American Cancer Society, 2004

(12) Mayo Clinic. Cystic fibrosis. Available at: MayoClinic.com. Accessed April 8, 2004

(13) Lubenow N, Kempf R, Eichner A, et al. Heparin-induced thrombocytopenia: temporal pattern of thrombocytopenia in relation to initial use or reexposure to heparin. Chest 2002; 122:37-42

(14) Rice L, Attisha WK, Drexler A, et al. Delayed-onset heparin-induced thrombocytopenia. Ann Intern Med 2002; 136:210-215

(15) Warkentin TE, Kelton JC. Delayed-onset heparin-induced thrombocytopenia and thrombosis. Ann Intern Med 2001; 135:502-506

(16) Greinacher A, Volpel H, Janssens U, et al. Recombinant hirndin (lepirudin) provides safe and effective anticoagulation in patients with the immunologic type of heparin-induced thrombocytopenia: a prospective study. Circulation 1999; 99:73-80

(17) Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001; 103:1838-1843

(18) Lewis BE, Wallis DE, Leya F, et al. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 2003; 163:1849-1856

(19) Greinacher A, Janssens u, Berg G, et al. Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thromboeytopenia. Circulation 1999; 100: 587-593

(20) Srinivasan AF, Rice L, Bartholomew JR, et al. Warfarin-induced skin necrosis and venous limb gangrene in the setting of heparin-induced thrombocytopenia. Arch Intern Med 2004; 164:66-70

(21) Levine RL, Hursting MJ, Drexler A, et al. Heparin-induced thrombocytopenia in the emergency department. Ann Emerg Med 2004; 44:511-515

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