Argatroban

For patients with heparin-induced thrombocytopenia (HIT), reexposure to heparin is generally not recommended. However, these patients are likely to require anticoagulation therapy at some point in the future. During acute HIT, when thrombocytopenia and anti-heparin-platelet factor 4 antibodies (or HIT antibodies) are present, therapy with heparin must be avoided. In patients with subacute HIT, when platelets have recovered but HIT antibodies are still present, therapy with heparin should be avoided. In patients with a remote history of HIT, when HIT antibodies have cleared, heparin reexposure may be safe, although recurrent HIT has been described in some patients. For all of these patients, the use of alternate anticoagulant agents, including direct thrombin inhibitors and anti-Xa agents, is preferable. There is an increasing amount of data supporting the use of these alternative agents in a wide variety of clinical circumstances, including thromboprophylaxis and treatment of acute thrombosis. Except for a few clinical situations, it is generally possible to avoid heparin reexposure in patients with a history of HIT.

Key words: anticoagulation; direct thrombin inhibitor; factor Xa inhibitor; heparin-induced thrombocytopenia; heparin reexposure; thromboprophylaxis

Abbreviations: CPB = cardiopulmonary bypass; DVT = deep venous thrombosis; ELISA = enzyme-linked immunosorbent assay; HIT heparin-induced thrombocytopenia; IVC = interior vena cava; PCI = percutaneous coronary intervention

**********

Heparin is administered in a wide variety of clinical situations, exposing a large number of patients to the potential development of heparin-induced thrombocytopenia (HIT). Many of these same patients will require anticoagulation therapy in the future, especially those with underlying thrombophilia or cardiovascular disease. The safety of heparin reexposure in a patient with a history of HIT is unclear. The limited data regarding reexposure to heparin focus on short-term reexposure, often for cardiovascular procedures. However, some patients will require extended treatment with an anticoagulant, as in the treatment of venous thromboembolism and unstable angina, or in extended prophylaxis for orthopedic or other major surgeries. There have been few data reported and few guidelines established for anticoagulation therapy in patients with a history of HIT.

SELECTION OF ALTERNATIVE ANTICOAGULATION AGENTS

The use of alternative anticoagulant agents for the treatment of patients with HIT is based on the premise that these agents do not generate or cross-react with anti-heparin-platelet factor 4 antibodies (or HIT antibodies), and are effective and safe for the prophylaxis or treatment of thrombosis. Available agents include parenteral direct thrombin inhibitors and factor Xa inhibitors.

Direct Thrombin Inhibitors

Direct thrombin inhibitors are fundamentally different from heparin in structure, do not generate or cross-react with HIT antibodies, and are approved for the treatment of acute HIT. (1,2) These agents thus represent a treatment option for patients with a history of HIT in order to avoid heparin reexposure. In some cases, this approach requires reexposure to direct thrombin inhibitor therapy. The direct thrombin inhibitor lepirudin is a recombinant protein. Hypersensitivity reactions to lepirudin have been reported with initial exposure and reexposure, and a proportion of patients (44 to 74%) develop antibodies to lepirudin. (3) These antibodies do not interfere with the function of the drag, but in a small subset of patients may result in delayed clearance, which is associated with an increased half-life and reduced dose requirements. (4) It is not clear whether these antibodies will affect subsequent lepirudin dosing; however, and reexposure is generally well-tolerated. (5,6) Lepirudin antibodies may cross-react with bivalirudin, a synthetic hirudin analog, although the clinical significance of these antibodies is unknown. (7) Argatroban does not appear to be associated with antibody development, and reexposure is well-tolerated. (8)

Danaparoid

Danaparoid, which is composed of heparan, dermatan, and chondroitin sulfates, has been used extensively in the treatment of patients with HIT in a wide variety of clinical situations. Despite 15% in vitro cross-reactivity of HIT antibodies with danaparoid, it seldom causes a worsening of HIT. (9,10) Danaparoid, where available (it is unavailable in the United States), is commonly use to treat HIT patients, and there is extensive experience in both HIT and non-HIT patients.

Fondaparinux

Fondaparinux is a synthetic pentasaccharide that has been extensively studied for use in orthopedic and abdominal surgery prophylaxis, and the treatment of deep venous thrombosis (DVT) and pulmonary embolism. (11) Small studies (12,13) have demonstrated no cross-reactivity of fondaparinux with HIT antibodies by in vitro activation assays, but there is limited clinical experience in HIT patients. The development of HIT antibodies was observed in a small percentage of patients receiving fondaparinux for prophylaxis for orthopedic surgery, equal to the rate of antibody formation in the group receiving enoxaparin, but none of the patients in either group developed clinical HIT. (14) Given the low rate of de novo antibody formation and the apparent lack of cross-reactivity with HIT antibodies, fondaparinux may represent a relatively safe alternate anticoagulant agent for use in patients with a history of HIT.

The selection of an alternate anticoagulant agent should be based on demonstrated efficacy and safety (whether in HIT or non-HIT patients) for the intended use, familiarity with drug dosing, and the availability of monitoring techniques, when indicated. The clearance of these agents is affected by renal dysfunction (eg, lepirudin, danaparoid, fondaparinux, bivalirudin) or hepatic dysfunction (eg, argatroban), so baseline organ function must be assessed. (9) Most of these agents, especially when administered subcutaneously, are irreversible, so appropriate dosing and monitoring is essential. (9) As new agents become available, including oral thrombin inhibitors and factor Xa inhibitors, their applicability to the HIT population will depend on their safety, efficacy, and potential cross-reactivity with HIT antibodies.

Warfarin

Vitamin K antagonists, including warfarin, are commonly used for the long-term management of thrombotic disorders. The introduction of warfarin therapy in a patient with acute HIT should be deferred until the platelet count has recovered, in order to avoid venous limb gangrene. (9) Once the acute episode has passed, however, warfarin therapy can be used as for non-HIT patients when indicated.

PATIENT CLASSIFICATION

Patients with HIT requiring anticoagulation therapy can be divided into the following three groups: (1) those with active HIT (ie, thrombocytopenia and the presence of HIT antibodies); (2) those with recent or "subacute" HIT (ie, platelet recovery but detectable antibodies); and (3) those with a history of HIT (ie, antibodies no longer detectable). This characterization of patients, used by Warkentin and Greinacher (15) when discussing anticoagulation therapy for HIT patients undergoing cardiopulmonary bypass (CPB), is useful when considering an approach to broader anticoagulation issues.

ANTICOAGULATION THERAPY IN PATIENTS WITH ACTIVE HIT (LOW PLATELET LEVELS AND ANTIBODY PRESENT)

For patients with active HIT, with associated thrombocytopenia and the presence of HIT antibodies, therapy with all forms of heparin should be avoided. This includes all routes of administration of heparin, including heparin flushes, regional anticoagulation therapy, and the use of heparin-coated catheters. (16) The options for anticoagulant treatment for patients with active HIT include the use of the direct thrombin inhibitors (eg, lepirudin or argatroban) or danaparoid and have been reviewed elsewhere. (9,10,16) For active HIT patients requiring full-dose anticoagulation therapy for preexisting venous thromboembolism, unstable angina, or indwelling devices such as an intra-aortic balloon pump, IV direct thrombin inhibitor therapy should provide adequate anticoagulation. (17-20)

There are some procedures that are routinely performed with heparin that cannot be avoided during an episode of active HIT (Table 1). (21-43) In clinical situations in which CPB, percutaneous coronary intervention (PCI), chronic arteriovenous hemofiltration, or chronic venous-venous hemofiltration and hemodialysis are being performed, the ideal anticoagulant agent is uncertain. The most extensive attention has been directed at CPB, and a comprehensive review of the approach to a HIT patient requiring CPB recently was addressed by Warkentin and Greinacher. (15) Also, based on prospective studies, (32) argatroban has been approved for use in the United States in patients with or at risk for HIT who are undergoing PCI. There are fewer data but growing experience with the use of direct thrombin inhibitors and danaparoid for other procedures. The availability of appropriate monitoring modalities, including anti-Xa levels for danaparoid and ecarin clotting time for some direct thrombin inhibitors, and careful attention to the timing of administration and dose adjustments for each agent in each setting is critical to the safe administration of alternate anticoagulation therapy in these settings.

ANTICOAGULATION THERAPY IN PATIENTS WITH SUBACUTE HIT (NORMAL PLATELET LEVELS AND ANTIBODY PRESENT)

The recovery of the platelet count to a stable, usually normal, level is thought to be associated with the reduction in activity of HIT, although there remains an increased risk for thrombosis for several weeks. For example, once the platelet count has recovered, warfarin therapy may be safely introduced for long-term anticoagulation, when indicated, without increasing the risk of warfarin-induced limb gangrene. (16,44) However, the IgG HIT antibody often persists for [greater than or equal to] 100 days, (45) and usually well after the thrombocytopenia has resolved. Reexposure to heparin in patients who have preexisting antibodies may be associated with the rapid recurrence of thrombocytopenia, recurrent thrombosis, and acute systemic reactions when an IV heparin bolus is used. (45,46) Based on these data, reexposure to any form of heparin should be avoided until there is no evidence of HIT antibodies. However, as the antibody titer falls over time, in the absence of continued heparin exposure, it may at some point become relatively safe to reexpose the patient to heparin. Warkentin and Greinacher (15) have recently suggested that heparin might be used for CPB procedures if the result of a sensitive functional assay for HIT antibodies is negative and the result of an enzyme-linked immunosorbent assay (ELISA) is only weakly positive. There are no published clinical studies regarding reexposure to heparin in patients with an ELISA result that is positive for HIT antibodies, but the available data (47-49) suggest that activity assays may have better specificity than the ELISA for detecting antibodies associated with clinical manifestations. In addition, the strength of the antibody titer detected by ELISA may correlate with the likelihood of clinical HIT. (50) Thus, it may be reasonable to consider short-term heparin reexposure in patients with a negative activity assay result and only a weakly positive ELISA result. However, there are no data regarding the safety of longer term exposure to heparin in these patients, as in the treatment of patients with venous thromboembolism and unstable angina, or in those who require extended prophylaxis for major surgery. In these settings, in the presence of persistent HIT antibodies, the avoidance of heparin therapy is advised. For these patients, the use of alternative forms of anticoagulation therapy are listed in Tables 2, 3 and discussed further in the next sections.

Treatment of Venous Thromboembolism

Studies (1,2,51) using IV argatroban and lepirudin to treat patients with acute HIT with thrombosis have demonstrated successful control of venous thromboembolism. Thus, the substitution of an IV direct thrombin inhibitor for heparin for the treatment of acute venous thromboembolism can be considered for a patient with subacute or remote HIT. However, as the short-term management of patients with venous thromboembolism has moved into the outpatient setting, subcutaneous or oral alternatives to therapy with low-molecular-weight heparins would be desirable in a patient with a history of HIT. Danaparoid has been administered subcutaneously for the treatment of venous thrombosis in patients with and without HIT. (10) Subcutaneous lepirudin was used in small series of patients with recent HIT with thrombosis and in isolated HIT (without thrombosis). (52,53) A dose-finding study (54) using subcutaneous lepirudin, compared to heparin, demonstrated equivalent safety and efficacy in non-HIT patients with DVT. In two large studies, (55, 56) fondaparinux compared favorably with unfractionated heparin in the short-term treatment of pulmonary embolism, and with low-molecular-weight heparin in the short-term treatment of DVT. As listed in Table 2, these agents, in full therapeutic doses, represent alternatives to heparin therapy in the patients who have experienced a new venous thrombotic event.

Unstable Coronary Syndromes

Patients with unstable angina may require full-dose anticoagulation therapy for several days. In the course of therapy for acute HIT, successful treatment of unstable angina with IV argatroban was noted, (17) and therapy with IV lepirudin has been compared (18) to that with heparin for the treatment of unstable angina in the non-HIT population. Bivalirudin has been used for patients with PCI in the setting of unstable angina, (33) and studies (57) of fondaparinux in this setting are underway.

Surgical Prophylaxis

For patients with active or subacute HIT, procedures should be delayed, if possible, until the antibody has cleared, or at least until thrombocytopenia has resolved with the use of appropriate anticoagulant therapy. In non-HIT patients, the interruption of anticoagulation therapy during the first 1 to 3 months after experiencing an acute thrombosis is associated with a significant risk (10 to 40%) of recurrent thrombosis, and this risk is increased 100-fold in the perioperative setting. (58) This risk would be exacerbated in the setting of acute HIT and may be increased in patients with persistent levels of HIT antibodies.

Even if performed after this high-risk period, some procedures, including orthopedic and major abdominal surgery, result in a significant risk for perioperative venous thromboembolic events. (59) Other procedures, especially when associated with extended anesthesia time and/or prolonged postoperative immobility, may also put patients at increased risk of perioperative thrombosis. (59,60) As emphasis is placed on extended prophylaxis for high-risk procedures, the duration of exposure to anticoagulation therapy in the perioperative period is increasing. (61)

Independent of the type of surgery, patients with prothrombotic risk features, including a history of thrombosis, congestive heart failure, edema, obesity, paralysis/immobility, varicose veins, and age > 40 years, are at increased risk for perioperative thrombosis. (60,62) Heart valve patients, particularly those with valves in the mitral position or with concomitant atrial fibrillation, are also at significant risk. (60)

Whether because of a high-risk surgery, high-risk patient features, or both, prophylaxis against perioperative thrombosis is indicated for a variety of procedures. If surgery cannot be delayed in a patient who has recently experienced HIT until the antibody has cleared, then alternatives to heparin prophylaxis should be considered, especially if the prophylaxis will be extended, as it is for orthopedic procedures.

Mechanical prophylaxis should be considered using compression stockings, sequential compression devices, and/or foot pumps. The benefits of these options have been reviewed elsewhere. (60, 63) The use of inferior vena cava (IVC) filters in patients with and without HIT has been associated with significant thrombotic complications (64,65) and should be avoided, especially in patients who have recently experienced HIT. In addition, the permanent use of IVC filters is associated with an increased long-term risk of recurrent DVT in non-HIT patients. (66,67) Temporary IVC filters (68) could be considered for surgical prophylaxis once the hypercoagulability associated with recent HIT has resolved.

For pharmacologic prophylaxis, several alternative anticoagulant agents have been compared to heparins in studies of non-HIT patients, and have been demonstrated to have equal or better efficacy and safety. As detailed in Table 3, (10,55,60,69,70) there are data supporting the use of fondaparinux, danaparoid, and the hirudin analog desirudin in the perioperative setting. Warfarin prophylaxis is used by some surgeons and is an option once acute HIT has subsided. Patients with subacute HIT who have recently experienced thrombosis are likely to be at a significant risk of perioperative thrombosis, and the use of both mechanical and pharmacologic prophylaxis should be considered if a procedure cannot be delayed. If fill-dose bridging therapy, rather than prophylactic dosing, is required, then full doses of alternate anticoagulant agents, as listed in Table 2, can be used.

Medical Prophylaxis

Hospitalized patients, especially those with prothrombotic risk factors, are at significant risk for venous thromboembolism, and heparin prophylaxis is often recommended. (62,71) As listed in Table 3, prophylactic doses of several alternate anticoagulant agents have been studied. Subcutaneous danaparoid (10) and fondaparinux (57) have been studied in medical populations.

ANTICOAGULATION IN PATIENTS WITH A HISTORY OF HIT (NORMAL PLATELET LEVELS AND NONDETECTABLE ANTIBODY LEVELS)

In a patient with a distant history of HIT and no detectable antibodies (ie, HIT-IgG antibodies), there is no consensus about the risks of heparin reexposure. There have been case reports (72,73) of recurrent HIT and associated thrombosis in patients who have even a distant history of HIT. However, successful reexposure to heparin in antibody-negative patients has been accomplished, though usually in the context of short-term exposure while undergoing CPB, without the development of HIT. (74,75) In eases in which HIT has developed a second time, there does not appear to be an anamnestic response on reexposure. (45) In one case report, (76) a patient with a history of HIT was reexposed to heparin and developed first an IgM antibody, then an IgG antibody. This is characteristic of a primary immune response and is not a typical anamnestic response. This suggests that if heparin reexposure occurs, the onset of thrombocytopenia would be expected alter 4 to 5 days of therapy. Careful monitoring of the platelet count may allow the early recognition of a recurrent episode of HIT, the discontinuation of heparin therapy, and the institution of therapy with a direct thrombin inhibitor before the onset of severe thrombotic complications.

If heparin reexposure is considered, testing for the presence of HIT antibodies, generally by ELISA, is important to be sure that the antibody is not detectable. While most antibodies seem to clear within 100 days, recent data (77) have suggested that antibodies occasionally can persist for [greater than or equal to] 6 months in some patients. The significance and potential pathogenicity of these antibodies are unclear.

For patients with a history of HIT but no detectable antibodies, short-term heparin reexposure may be safe, as for patients undergoing CPB. Until the risks of longer term heparin reexposure are better defined, however, the use of alternative agents may be preferable for most long-term indications for anticoagulation therapy.

CHALLENGING AREAS

Anticoagulation Therapy During Pregnancy in Women With History of HIT

Some women with a history of HIT may become pregnant and require thromboprophylaxis and/or treatment for thrombosis. As in other patient populations, heparin should be avoided in women with active HIT or subacute HIT with persistent antibody levels. Danaparoid has been used to treat women with heparin sensitivity or a history of HIT. (78)The successful use of subcutaneous lepirudin (9, 79) and fondaparinux (80) has been reported in women with pregnancies complicated by HIT. It is not known whether direct thrombin inhibitors or fondaparinux cross the placenta.

Patients With Multiorgan Failure

In patients who have both compromised hepatic and renal function, the options for anticoagulation therapy are limited, as most of the alternate anticoagulant agents are cleared by either the liver or kidney. Reduced dosing is recommended for lepirudin in patients with renal dysfunction, and for argatroban in patients with hepatic dysfunction, (9,16) but the potential for drug accumulation and the lack of a specific antidote may discourage the use of these agents in the critically ill patient with multiorgan failure. In patients with a remote history of HIT and negative test results for antibodies, heparin reexposure with careful surveillance may represent an option for anticoagulation therapy. Recent preliminary data (81,82) have demonstrated the successful use of bivalirudin, which is cleared predominantly by enzymatic cleavage.

Given the widespread use of heparins and an increasing awareness of possible complications, an expanding group of patients is suspected or confirmed to have HIT. The implications of this diagnosis extend beyond the acute episode, given the potential for sudden severe complications with heparin reexposure while HIT antibodies are present and the redevelopment of HIT even after the antibody has been cleared. When possible, heparin reexposure should be avoided in patients with a history of HIT until studies can better characterize who may safely receive heparin again. Alternate agents are available and in development that will not induce or cross-react with HIT antibodies, and can provide safe and efficacious anticoagulation therapy for these patients.

* From the University of Colorado Health Sciences Center, Denver, CO.

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Dr. Hassell has been a consultant for GlaxoSmith Kline, Berlex, Medicines Company, Organon, and Sanofi. This research was supported by grants from Organon, Sanofi, and Texas Biotechnology (now known as Encysive).

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Kathryn Hassell, MD, University of Colorado Health Sciences Center, 4200 East Ninth Ave, C-222, Denver, CO 80262; e-mail: kathryn.hassell@uchsc.edu

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