Review Article
Management of heparin-induced thrombocytopenia: a critical comparison of lepirudin and argatroban

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Abstract

Heparin-induced thrombocytopenia (HIT) is a transient hypercoagulability state initiated, paradoxically, by the anticoagulant, heparin. It is characterized by antibody-induced activation of platelets, leading to thrombin generation. Many patients with HIT develop thrombosis; even when heparin is stopped because of “isolated HIT” detected during routine platelet count monitoring, 25–50% of patients subsequently develop symptomatic thrombosis. Thus, an alternative anticoagulant should be substituted for heparin when HIT is strongly suspected. Two direct thrombin inhibitors (DTIs), lepirudin and argatroban, have been studied for prevention and treatment of thrombosis in HIT patients. Lepirudin is a polypeptide that binds irreversibly to the fibrin-binding and catalytic sites on thrombin (bivalent inhibitor). In contrast, argatroban is a synthetic, small-molecule DTI that binds reversibly to the catalytic site alone (univalent inhibitor). Results of historically controlled clinical trials suggest both agents are effective for preventing and treating thrombosis in HIT. However, these agents have not been compared directly, and important differences in study design limit conclusions from indirect comparison. For example, lepirudin was given for 12–14 days (mean) in treatment studies of thrombosis complicating HIT, whereas argatroban was given only for 6–7 days, a difference that could explain apparent lower thrombosis rates (and greater bleeding) with lepirudin. Recently, the transition from DTI therapy to oral anticoagulation in patients with deep venous thrombosis (DVT) complicating HIT has been identified as a risk period for coumarin-induced venous limb gangrene. Thus, the DTI should be given alone during acute HIT, with oral anticoagulants deferred until substantial resolution of the thrombocytopenia has occurred.

Section snippets

Case presentation

A 62-year-old woman received heparin during coronary artery bypass surgery, but did not receive postoperative antithrombotic prophylaxis. On postoperative day 7, she developed symptomatic deep venous thrombosis (DVT) of the left common femoral vein, which was treated with unfractionated heparin in therapeutic doses. Additionally, warfarin (5 mg) was given on day 7, with a second 5-mg dose repeated the next day. However, the platelet count fell abruptly when heparin was given to treat the DVT,

What is the definition of HIT?

Thrombocytopenia, thrombosis, and heparin use are common in hospitalized patients. Not all patients who develop thrombocytopenia during heparin treatment have HIT. Nor do all patients who make HIT antibodies develop this disorder. In general, the features supporting a diagnosis of HIT include otherwise unexplained thrombocytopenia with a temporal onset consistent with heparin-induced immunization, together with a (usually “strong”) positive laboratory test for HIT antibodies.

In older studies of

How prothrombotic is HIT?

Table 1 lists studies that provide information on the magnitude of the association between HIT and thrombosis [3], [6], [7], [8], [9]. HIT is prothrombotic, with odd ratios for thrombosis ranging from 12 to 40. For more severe thrombotic events, such as bilateral DVT or pulmonary embolism, the association is most striking. There also appears to be a relation between the severity of thrombocytopenia and risk of thrombosis. When “less severe” cases of HIT are recognized using a more sensitive

What is the natural history of isolated HIT?

“Isolated HIT” indicates those patients suspected of having HIT because of thrombocytopenia alone, and not because a new thrombosis occurs that draws attention to the thrombocytopenia. Several retrospective cohort studies [10], [11], [12], [13], [14] indicate that 25–50% of these patients develop clinically evident thrombosis after stopping heparin (with or without substitution by warfarin), usually within the first week. Further, the risk of fatal thrombosis is about 4–5% [1].

In 1996, Kelton

Lepirudin and argatroban for treating isolated HIT

There is evidence that non-heparin anticoagulants, such as a DTI [12], [13], [15], [16], [17], [18], [19], [20] or danaparoid1 (a “heparinoid” with predominant anti-factor Xa activity) [21], [22], are effective in managing patients with HIT. This review will focus on lepirudin and argatroban, the two DTIs approved for treating HIT in the U.S. and

Lepirudin and argatroban for treating thrombosis complicating HIT

Lepirudin and argatroban have also been studied, in comparison with historical controls, in patients with HIT complicated by thrombosis. Although these studies used the identical efficacy endpoint (composite of all-cause mortality, new thrombosis, and limb amputation), important differences in the conduct of these studies limit their comparability (see Section 8).

In my opinion, the single endpoint of new thrombosis (when comparing patients receiving active treatment vs. controls) most likely

Pharmacologic differences between lepirudin and argatroban

Both lepirudin and argatroban inhibit fibrin clot-bound thrombin and soluble thrombin (in contrast, the indirect thrombin inhibitor, heparin, only inhibits soluble thrombin, as its catalysis of thrombin inhibition by antithrombin is blocked when thrombin is bound to fibrin). Despite this common feature of the two DTIs, they are otherwise distinct agents. Lepirudin is a polypeptide of 65 amino acids (6980 Da) obtained by recombinant technology that closely resembles hirudin, the natural

Differences in study design between the lepirudin and argatroban trials

The comparisons made in Table 2, Table 3, Table 4 and in Fig. 1 do not take into account important differences in the design of the lepirudin and argatroban trials. Table 5 summarizes several differences, beginning with those differences I believe could be most important in explaining apparent differences in efficacy and bleeding between these agents. Three key differences are the longer treatment duration with lepirudin, the higher likelihood of receiving oral anticoagulants in the lepirudin

The paradox of warfarin-induced venous limb gangrene

In 1997, a novel syndrome of limb loss in patients with acute HIT was reported [31]. Remarkably, these patients with warfarin-induced venous limb gangrene developed acral (distal extremity) necrosis in a limb with DVT, despite palpable pulses. Pathologically, these patients had combined large-vein thrombosis and microvascular thrombosis. We proposed this syndrome results from a profound disturbance in procoagulant–anticoagulant balance: HIT causes greatly increased thrombin generation, whereas

Venous limb gangrene during overlapping anticoagulation of DTI and warfarin

Recent reports suggest that the period of transition between DTI therapy and long-term anticoagulation with warfarin is a risk period for warfarin-induced venous limb gangrene [2], [34]. Several features of these cases can be summarized: (a) the patients were receiving treatment for HIT and DVT; (b) warfarin was started before resolution of thrombocytopenia (indeed, it sometimes had been started prior to HIT being recognized); (c) the DTI was stopped without five or more days of warfarin

Avoiding limb gangrene in management of HIT-associated DVT

Table 6 summarizes the draft recommendations of the 2003 American College of Chest Physicians Antithrombotic Consensus Conference [38] regarding warfarin anticoagulation during HIT. These were written with the aim of minimizing risk of coumarin-related complications.

Case discussion

The case described at the beginning of this review is one of the first patients [2] recognized with warfarin-induced venous limb gangrene complicating overlapping DTI and warfarin therapy. The correct answer is (E), that is, besides HIT, warfarin treatment, the presence of DVT, and cessation of argatroban all contributed to microvascular thrombosis. An additional consideration suggested by this case is that when HIT is clinically recognized in a patient who has already received warfarin, it is

Acknowledgements

Some of the studies [2], [3], [4], [6], [8], [10], [31], [32], [33], [35] and reviews [1], [5], [7], [38] described were funded by the Heart and Stroke Foundation of Ontario from 1993 until the present (grants A-2449, T-2967, B-3763, T-4502, T-5207). Jo-Ann I. Sheppard provided the artwork.

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