(Chest. 2005;127:27S-34S.)
© 2005
American College of Chest Physicians
Transition to an Oral Anticoagulant in Patients With Heparin-Induced Thrombocytopenia*
John R. Bartholomew, MD
* From the Department of Cardiovascular Medicine, Section of Vascular Medicine, The Cleveland Clinic Foundation, Cleveland, OH.
Correspondence to: John R. Bartholomew, MD, The Cleveland Clinic Foundation, 9500 Euclid Ave, S-60, Cleveland, OH 44195; e-mail address: barthoj{at}ccf.org
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Abstract
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Recommendations for transitioning from therapy with heparin or a low-molecular-weight heparin preparation to therapy with an oral anticoagulant in patients with acute venous or arterial thromboembolism have undergone several changes during the last two decades. Physicians are now comfortable with beginning treatment with an oral anticoagulant once the diagnosis is confirmed, and loading doses are no longer considered to be necessary. Exceptions to early transition may be necessary in patients with an extensive iliofemoral or axillary-subclavian vein thrombosis or pulmonary embolism where thrombolytic agents may be indicated, or in individuals who require surgery or other invasive procedures, or if there are concerns about bleeding. The avoidance of early transition to oral anticoagulants in patients with acute heparin-induced thrombocytopenia also has been advised because of the potential for further thrombotic complications, including venous limb gangrene and warfarin-induced skin necrosis.
Key Words: coumarin derivative • direct thrombin inhibitors • heparin-induced thrombocytopenia • indanedione derivative • oral anticoagulants • venous limb gangrene • warfarin-induced skin necrosis
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Introduction
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A number of changes have occurred in the long-term management of patients with venous and arterial thromboembolism over the past 20 years. The use of loading doses of oral anticoagulants (ie, coumarin or the indanedione derivatives) is no longer recommended. In addition, most physicians do not delay transitioning to oral anticoagulants from heparin or a low-molecular-weight heparin (LMWH) preparation once the diagnosis is confirmed.1 Exceptions to the early initiation of therapy with an oral anticoagulant include the following: patients with pulmonary embolism or extensive iliofemoral or axillary-subclavian deep-vein thrombosis, in whom the use of thrombolytic agents may be considered; individuals who requires surgery or an invasive procedure; or patients in whom there is a concern about bleeding. More recently, it has been recognized234 that early transition to therapy with an oral anticoagulant in the setting of acute heparin-induced thrombocytopenia (HIT) also should be delayed because it can lead to further thrombotic complications, including venous limb gangrene and warfarin-induced skin necrosis.
HIT is a potentially devastating complication of therapy with heparin or the LMWH preparations, which develops between 5 and 14 days after the initial exposure to these agents. HIT may also occur more rapidly if the patient has had a recent exposure to these anticoagulants (generally, within 100 days), but it can also develop 
9 to 30 days after the discontinuation of therapy, at which time it often goes unrecognized.56 The cessation of therapy with heparin or LMWH in patients with HIT without substituting an alternative anticoagulant leads to an increased risk for additional thrombotic complications and is not recommended.789 Although the early initiation of therapy with an oral anticoagulant may help to prevent HIT by limiting a patient’s exposure time to heparin or LMWH, the early transition in patients with HIT has now been reported, paradoxically, to lead to the thrombotic complications of venous limb gangrene and warfarin-induced skin necrosis (Fig 1, 2
).23410
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Figure 1. This 72-year-old woman underwent open-heart surgery following hospital admission for an acute myocardial infarction. She developed atrial fibrillation postoperatively and began to receive warfarin therapy. Four days later, she developed pain and discoloration of her left breast (left, A), right leg, and left foot (right, B). Her INR was 6.4, and her platelet count was 68 x 109 platelets/L. She required a mastectomy, amputation of her right leg below the knee, and eventually a left transmetatarsal amputation. HIT, warfarin-induced skin necrosis, and venous limb gangrene were eventually recognized. From Srinivasan et al4 (copyright 2004, American Medical Association; all rights reserved).
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Figure 2. A 53-year-old woman was treated with heparin for an acute pulmonary embolism. Warfarin therapy was begun on the fourth day of hospital admission at a dose of 10 mg. On day 7, the patient’s platelet count dropped to 86 x 109 platelets/L, and heparin therapy was stopped. Three days later, discoloration of both breasts developed, and warfarin therapy was discontinued. An enzyme-linked immunosorbent assay was positive for HIT. She underwent extensive surgical debridement of both breasts. From Srinivasan et al4 (copyright 2004, American Medical Association; all rights reserved).
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Clinical Findings
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The major clinical manifestations of HIT had traditionally been recognized as arterial events and included limb ischemia, stroke, and myocardial infarction. This concept changed following a report published by Warkentin and Kelton7 in 1996, which found that more individuals developed venous thromboembolism than arterial thrombosis by approximately a 4:1 ratio.
Warkentin and colleagues2 also recognized that not all instances of limb ischemia in HIT patients were a result of arterial thrombosis. In a review of 158 patients with serologically confirmed HIT, 10 developed arterial thromboses, while 8 had venous limb gangrene. These authors observed that venous limb gangrene developed after the diagnosis of HIT was confirmed, and after treatment with heparin was discontinued and that with warfarin had been initiated. In contrast, arterial thrombosis developed as the initial manifestation of HIT.2
Venous limb gangrene is defined as acral necrosis that develops despite palpable or Doppler-identifiable pulses. This condition differs from phlegmasia cerulea dolens, in which patients present with extensive deep venous thrombosis and a swollen limb without palpable pulses. Patients with venous limb gangrene are found to have extensive thrombosis of both the large and small veins without large artery occlusion despite most having a supratherapeutic international normalized ratio (INR) and considered well-anticoagulated. Venous limb gangrene can affect the toes, feet, fingers, or hands but usually complicates an acute (ipsilateral) deep venous thrombosis of the leg. In the review by Warkentin et al,2 only one patient developed ischemia of the hand, although this resolved with treatment and was not reported. They also noted that venous limb gangrene appeared more frequently in women and younger patients, and resulted in a greater numbers of limbs lost when compared to patients with arterial thrombosis. Two of these patients died, two required below-the-knee amputations, two required amputations of the distal portions of one or both feet, and two had distal skin sloughing but did not require amputation. One of these patients also developed warfarin-induced skin necrosis of the abdomen.2
Warfarin-induced skin necrosis, sometimes referred to as coumarin-induced skin necrosis, is a rare but potentially devastating complication of oral anticoagulation therapy. The reported frequency ranges between 1:100 and 1:10,000 individuals, and generally occurs between days 3 and 7 after the initiation of treatment.11121314 Flood et al15 first described this phenomenon in 1943; however, it was not until 1954 that Verhagen16 associated this condition with oral anticoagulants. Warfarin-induced skin necrosis was originally associated with the administration of large loading doses of warfarin, although the exact etiology remains uncertain. It has been linked most frequently to hereditary deficiencies of protein C, but has also been reported to occur in patients with deficiencies of protein S and antithrombin, resistance to activated protein C (factor V Leiden), and the antiphospholipid antibody syndrome. Only in the past few years has it been recognized to occur in patients during treatment for HIT.234
An erythematous, painful, flushed area on the skin that evolves into petechiae and hemorrhagic bullae within the first 24 h develops in patients with warfarin-induced skin necrosis. This eventually progresses to skin infarction. The lesions are very painful, and the breasts, thighs, and buttocks are most frequently involved. Warfarin-induced skin necrosis also has been reported to involve the trunk, face, extremities, and penis. Obese, middle-aged women appear to be more frequently affected than men. Most patients are receiving oral anticoagulation for treatment of a deep venous thrombosis or pulmonary embolism when they develop this complication.14
Venous limb gangrene and warfarin-induced skin necrosis have now been described by a number of authors as complications of HIT during the transition from heparin to warfarin therapy.23410171819202122 Most of these reports (other than the series by Warkentin et al2) are limited to one or two patients, with the exception of the study by Srinivasan et al4 who described six additional patients. In that report, two patients developed venous limb gangrene, one required below-the-knee and transmetatarsal amputations, while the condition of the other patient improved with treatment. More of their patients developed warfarin-induced skin necrosis, which was found on the thighs, breasts, or calves in five of their six patients.
Raskob and George10 have suggested that venous limb gangrene may be a part of the continuum of warfarin-induced skin necrosis, as approximately 10% of patients with this complication have been reported21012 to develop necrosis of the feet or hands. These two complications, however, generally differ in their clinical presentation. Warfarin-induced skin necrosis classically involves the more central tissues, including the breasts, abdomen, thighs, and legs, and is more likely to be associated with a congenital abnormality of the protein C anticoagulant pathway or other hypercoagulable state. Venous limb gangrene affects the extremities distally, and most patients are not found to have a hereditary hypercoagulable condition, and there are some reports2324 linking this complication with malignancy. Venous limb gangrene also has been reported to occur with use of the oral anticoagulant phenoprocoumon, and in patients during the overlap period between therapy with warfarin and the direct thrombin inhibitors (DTIs) argatroban (GlaxoSmithKline; Research Triangle Park, NC) or lepirudin (Refludan; Berlex; Richmond, CA).41725
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Incidence of Venous Limb Gangrene and Warfarin-Induced Skin Necrosis
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Venous limb gangrene and warfarin-induced skin necrosis are uncommon complications of HIT. Towne et al26 reportedly described the first case of venous limb gangrene in a patient who developed phlegmasia cerulea dolens as a complication of HIT. No association with warfarin treatment was noted, however.
In the largest reported series involving venous limb gangrene and warfarin-induced skin necrosis in patients receiving warfarin transition therapy during treatment for acute HIT, Warkentin et al2 identified venous limb gangrene in 12.1% of their patients (8 of 66 patients), while warfarin-induced skin necrosis occurred in only 1 patient. In one other consecutive series, Greinacher and colleagues17 found venous limb gangrene in only 1 of 21 patients (4.8%). Most other reports3181920212225 of venous limb gangrene or warfarin-induced skin necrosis in HIT patients are limited to one or two cases. Srinivasan et al4 identified six patients; however, these came from three different academic centers.
In contrast, several reviews involving large numbers of patients with HIT have not reported venous limb gangrene or warfarin-induced skin necrosis. Wallis et al27 did not find either of these complications in their series of 114 consecutive HIT patients, 51 of whom received warfarin. Only 16 of the 51 patients received warfarin for HIT-associated venous thrombosis. Neither of these conditions was reported (or recognized) in other earlier series of HIT patients. Bell and Royall28 reviewed 149 consecutive patients receiving heparin therapy, identifying 21 who developed thrombocytopenia. All 21 patients had their heparin therapy discontinued, and most were started on treatment with warfarin. The thrombocytopenia resolved in all cases, and no patient developed a thromboembolic complication. Although the authors thought that these patients had HIT, no laboratory testing for the presence of heparin antibodies was performed and the time frame for developing thrombocytopenia varied between 3 and 16 days, suggesting that not all patients carried this diagnosis. Laster et al29 reviewed 162 patients with HIT who had been diagnosed by a positive aggregation test result. Patients were treated by discontinuing heparin therapy and were started on IV or oral warfarin therapy in doses of 10 to 15 mg. No mention of venous limb gangrene or warfarin-induced skin necrosis was made, although a higher incidence of death was reported in their patients with thrombotic complications due to HIT.29
It is unclear why venous limb gangrene or warfarin-induced skin necrosis has not been reported in these or other previous series of HIT patients. Warkentin et al2 suggested that clinicians may not recognize venous limb gangrene as a separate entity and may assume that it is part of the natural history of HIT. In addition, they thought that the atypical clinical and laboratory features of venous limb gangrene make an association between warfarin therapy and HIT less obvious, while the small number of patients developing these syndromes limit any one physician’s exposure (and experience) to these conditions.2
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Laboratory Studies in Patients With Venous Limb Gangrene or Warfarin-Induced Skin Necrosis
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In the two largest series24 of patients who developed venous limb gangrene and/or warfarin-induced skin necrosis, most patients had a supratherapeutic INR while receiving warfarin monotherapy. (As discussed below, because DTIs also prolong the INR, "traditional" interpretations of the INR may not be fully applicable during warfarin cotherapy with a DTI.) In the report by Warkentin and colleagues,2 the median peak INR was 5.8, with a range of 3.8 to 9.4, while in the six patients reported on by Srinivasan et al,4 the peak INRs ranged from 3.2 to 8.1, with an average of 5.0.24
Patients in the Warkentin et al2 series also were found to have lower protein C activity levels, elevated thrombin-antithrombin complex levels, and higher ratios of thrombin-antithrombin complex to protein C activity while receiving warfarin therapy (Fig 3 ). In the article by Srinivasan et al,4 two patients had elevated levels of anticardiolipin antibodies (IgG) and one had a low protein S level, while one patient reported by Warkentin and colleagues23 had significantly reduced antithrombin levels and one other had evidence of disseminated intravascular coagulation.
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Figure 3. This figure demonstrates several of the laboratory features of a patient with acute HIT who developed venous limb gangrene and central skin necrosis during the first of two courses of warfarin therapy. Note the thrombocytopenia, increased thrombin-antithrombin complex levels and decrease in prothrombin and protein C activities indicative of the prothrombotic state due to the introduction of warfarin during acute HIT. No further complications developed, however, when the patient was rechallenged with warfarin once the acute HIT had resolved as noted by the improvement in the thrombocytopenia. From Warkentin et al.2 The American College of Physicians is not responsible for the accuracy of this figure.
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Pathophysiology
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Venous limb gangrene and warfarin-induced skin necrosis are the result of a profound disturbance in the procoagulant-anticoagulant balance that occurs during the conversion to warfarin therapy (or other oral anticoagulants) in some patients with acute HIT and more recently has been identified in a few patients with cancer.2324
Patients who develop HIT generate large amounts of thrombin. This has been well-documented by Warkentin et al,2 who identified higher levels of thrombin-antithrombin complexes, a marker of in vivo thrombin generation, in patients treated for HIT and cancer.223
Normally, warfarin (or an equivalent oral anticoagulant) counteracts thrombin production by gradually decreasing the levels of procoagulant vitamin K-dependent factors II, VII, IX, and X over a period of 4 to 5 days. At the same time, warfarin also decreases levels of the natural anticoagulants proteins C and S. It now appears that, during the transition to oral anticoagulation therapy in patients with HIT, warfarin fails to control this increased thrombin generation and actually contributes to the development of venous limb gangrene and warfarin-induced skin necrosis.242324 In these individuals, warfarin reduces factor VII and protein C levels (shorter half-lives) more rapidly than the prothrombotic factors II, IX, and X (see Table 1
for the half-lives of vitamin K-dependent prothrombotic and natural anticoagulant factors).3031 This results in a supratherapeutic INR due to factor VII depletion and a transient hypercoagulable state induced by a decrease in protein C levels without a concomitant decrease in the levels of prothrombotic factors II and X. At the same time, there is continued ongoing thrombin production generated by the HIT. Venous limb gangrene and warfarin-induced skin necrosis develop as a result of the combination of these factors.
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Treatment
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It is now well-recognized that merely stopping heparin or LMWH therapy is inadequate treatment for HIT. Three studies789 have clearly demonstrated that patients are at a continued risk for thrombosis if this approach is taken. In addition, most patients will require anticoagulation for treatment of their original condition. Therefore, the use of an alternative anticoagulant is strongly recommended. Presently, there are three antithrombotic agents that have been approved in a number of countries for the treatment of HIT.32 Two of these agents are the DTIs argatroban and lepirudin, and one is the heparinoid danaparoid.
Argatroban, a small synthetic molecule with a molecular weight of 526, is derived from L-arginine and binds reversibly to thrombin. It is approved in the United States and Canada for the treatment and prophylaxis of thrombosis in HIT patients. It is also approved for patients with, or at risk for, HIT who require percutaneous coronary intervention. Lepirudin, a recombinant polypeptide originally derived from the medicinal leech, inhibits thrombin directly and is only approved for the treatment of HIT. Danaparoid, a mixture of heparan sulfate, dermatan sulfate, and chondroitin sulfate reduces thrombin generation in vivo by the inhibition of factor Xa. It is no longer available in the United States but is used as a treatment for HIT in a number of other countries. A third DTI, bivalirudin (Angiomax; The Medicines Company; Parsippany, NJ), has not been approved for the treatment of HIT but has been used "off-label" for this indication in two small series.3334
Early transition from therapy with heparin or LMWH to warfarin therapy (or an equivalent oral anticoagulant) is now considered standard therapy for the management of most patients with acute venous or arterial thromboembolism. This approach also may help to prevent HIT by minimizing a patient’s exposure time to these agents.210 Paradoxically, it is now recognized that early transition to therapy with an oral anticoagulant during acute HIT (and in some patients with cancer) may lead to further devastating thrombotic events.234101718192021222526 Venous limb gangrene and warfarin-induced skin necrosis are now well-recognized complications of this early transition.
A number of recommendations have been made to help prevent these devastating events (Table 2
). These include the following: the use of a DTI or equivalent anticoagulant once HIT has been recognized and therapy with heparin or an LMWH has been discontinued; ensuring adequate anticoagulation when using alternative anticoagulant agents and avoiding interruptions during their use; avoiding early transition to therapy with warfarin (or equivalent) until the patient’s platelet count has recovered to near-normal levels (generally, > 150 x 109 platelets/L); initiating modest does of warfarin (2.5 to 5.0 mg); avoiding overshooting the target INR; and not using warfarin for monotherapy in the initial treatment of patients with HIT.
Once an alternative anticoagulation therapy has been started, overlapping warfarin with a DTI or alternative anticoagulant should continue for a minimum of 4 to 5 days and until the INR is > 2.0 for 2 consecutive days. This is to ensure the adequate reduction of levels of the vitamin K-dependent procoagulant factors II, VII, IX, and X. Patients receiving the DTI argatroban (and, to a lesser extent, lepirudin) will observe that these agents prolong the level of the INR. This can lead to challenges during the transition to warfarin therapy.435 The argatroban package insert advises overlapping with warfarin for a minimum of 4 to 5 days, aiming for an INR of 4.0. Once this level is attained, argatroban therapy should be discontinued, and testing of the INR should be repeated approximately 4 to 6 h later to ensure that it remains within the therapeutic range. It also may be advisable to check an INR once lepirudin therapy has been discontinued, although no recommendation is made in the package insert. It must be stressed that the overlap of therapy with both a DTI and warfarin must occur for a minimum of 4 to 5 days. The failure to follow these guidelines could result in further thrombotic complications, as described above.
Warkentin et al2 also have advocated the administration of small doses of vitamin K if a patient develops a supratherapeutic INR in this clinical situation to try and prevent these complications. The addition of fresh-frozen plasma also may be indicated.
Venous limb gangrene and warfarin-induced skin necrosis are preventable complications of HIT treatment. Their prevention requires a better understanding of the pathophysiology of these devastating processes, the addition of alternative therapeutic agents (ie, DTIs) to our armamentarium, and adherence to the recommendations listed in Table 2.
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Footnotes
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The author has received an honorarium as a consultant for GlaxoSmithKline and The Medicines Company, and has served on the Speakers Bureau of Berlex Laboratories and Aventis.
Abbreviations: DTI = direct thrombin inhibitor; HIT = heparin-induced thrombocytopenia; INR = international normalized ratio; LMWH = low-molecular-weight heparin
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References
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- Smythe, MA, Warkentin, TE, Stephens, JL, et al Venous limb gangrene during overlapping therapy with warfarin and a direct thrombin inhibitor for immune heparin-induced thrombocytopenia. Am J Hematol 2002;71,50-52[CrossRef][ISI][Medline]
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- Bell, WR, Royall, RM Heparin-associated thrombocytopenia: a comparison of three heparin preparations. N Engl J Med 1980;303,902-907[Abstract]
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Abstract
Introduction
