Argatroban anticoagulation in patients with a history of heparin-induced thrombocytopenia

doi:10.1016/j.thromres.2004.11.006

Thrombosis Research

Volume 116, Issue 2, 2005, Pages 121-126

https://doi.org/10.1016/j.thromres.2004.11.006 Get rights and content

Abstract

Introduction

Heparin therapy is not recommended for patients with a history of heparin-induced thrombocytopenia (HIT), except in specialized situations, because this treatment can lead to severe reactions including thrombocytopenia and thrombosis. However, the optimal management of patients with a history of HIT requiring acute anticoagulation has not yet been clarified because of the lack of prospective studies. We evaluated the safety and efficacy of argatroban, a direct thrombin inhibitor, as an anticoagulant in patients with a history of HIT needing acute anticoagulation.

Methods

Thirty-six patients with a history of serologically confirmed HIT were treated prospectively with argatroban [median (5th–95th percentile) dose of 2.0 (1.0–4.3) μg/kg/min for 4.0 (0.7–8.4) days]. Prospectively defined endpoints included successful anticoagulation (therapeutic activated partial thromboplastin time), and bleeding, new thromboembolic events, or other adverse effects during therapy or within 30 days following its cessation.

Results

All patients required acute anticoagulation with the most common admission diagnoses being deep venous thrombosis or pulmonary embolism (n=13) and chest pain or acute coronary syndrome (n=12). Eleven patients had previously received argatroban therapy for HIT; one patient underwent two treatment courses of argatroban for a history of HIT. The median (5th–95th percentile) time between the past diagnosis of HIT and initiation of argatroban was 7.5 (0.4–114.6) months. All evaluable patients were successfully anticoagulated. No patient had major bleeding, new thromboembolic events, or other adverse effects. There were no adverse events related to reexposure.

Conclusions

Argatroban can provide safe and effective anticoagulation, on initial or repeat exposure, in patients with a history of HIT.

Section snippets

Methods

Patients with a past history of HIT, who required anticoagulation, were identified from the prospective, open-label, multicenter studies Argatroban-911 or Argatroban-915. For patients with a history of HIT, inclusion in these trials required that the prior episode of HIT be serologically confirmed. The protocols were approved by the Institutional Review Board at each participating center, and each patient provided written informed consent. The results of the first trial [10] and of the active

Patients

The study population included 36 individual patients with a history of HIT who were treated with argatroban (Table 1). One patient received argatroban for acute anticoagulation on two separate occasions occurring 10 months apart, for a total of 37 treatments of patients with a history of HIT. Eleven patients had previously received argatroban for the prophylaxis or treatment of thrombosis during HIT, for a total of 12 patients overall with argatroban reexposure. The median time lapse between

Discussion

HIT is a devastating syndrome triggered by the use of unfractionated or low-molecular-weight heparin and is associated with high morbidity and mortality. HIT typically develops after 5 days of heparin therapy, but may occur more rapidly in patients who have received heparin within the previous 3 months [3], [4]. HIT patients, managed before the introduction of direct thrombin inhibitors, had a mortality rate of 20–25%, and the incidence of the combined endpoint of death, amputation, and new

Acknowledgments

The studies described in this report were supported by grants from Texas Biotechnology (now known as Encysive Pharmaceuticals), Houston, TX and GlaxoSmithKline, Philadelphia, PA. Parts of the study were supported by a grant to JGK by the Heart and Stroke Foundation of Ontario.

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Diagnostic and treatment recommendations from the FACME ad-hoc expert working group on the management of cerebral venous sinus thrombosis associated with COVID-19 vaccination
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Se han reportado casos de trombosis venosas cerebrales en personas vacunadas frente a COVID-19 con vacunas vectorizadas con adenovirus no replicantes. Aportamos recomendaciones sobre el diagnóstico y manejo de pacientes con esta complicación.
El grupo de trabajo multidisciplinar, liderado por la Federación de Asociaciones Científico Médicas Españolas y representado por distintas sociedades científicas, revisó la evidencia disponible publicada en la literatura y en los informes de la Agencia Europea de Medicamentos. Se estableció una definición de caso sospechoso y recomendaciones diagnóstico-terapéuticas de la trombocitopenia trombótica inducida por la vacunación.
Se considera caso sospechoso aquella trombosis venosa cerebral ocurrida entre 3 y 21 días tras la administración de vacunas no replicantes de adenovirus que presenten un valor de plaquetas inferior a 150.000 plaquetas por μL o un descenso del 50% respecto de la cifra previa. Los datos indicativos de trombocitopenia trombótica inducida por la vacunación incluyen la presencia de anticuerpos antifactor plaquetario tipo 4, la elevación de dímero-D 4 veces por encima del límite superior de la normalidad o la ausencia de justificación de la trombosis. En su tratamiento, se recomienda administrar inmunoglobulina humana inespecífica intravenosa o realizar plasmaféresis en su defecto, evitar el uso de heparina, empleando como anticoagulantes argatroban, bivalirudina, fondaparinux, rivaroxabán o apixabán, y evitar la transfusión de plaquetas.
Las vacunas de vectores no replicantes de adenovirus pueden asociarse a trombosis venosas cerebrales con trombocitopenia, en cuyo manejo es importante el tratamiento del fenómeno disinmune y de la trombosis venosa cerebral.
Cases of cerebral venous sinus thrombosis have been reported in individuals vaccinated against COVID-19 with non-replicating adenoviral vector vaccines. We issue our recommendations on the diagnosis and management of patients presenting this complication.
The multidisciplinary working group, led by the Spanish Federation of Medical and Scientific Associations and including representatives of several scientific societies, reviewed the available evidence from the literature and reports of the European Medicines Agency. We establish a definition for suspected cases and issue diagnostic and treatment recommendations regarding vaccine-induced immune thrombotic thrombocytopaenia.
We define suspected cases as those cases of cerebral venous sinus thrombosis occurring between 3 and 21 days after the administration of non-replicating adenoviral vector vaccines, in patients with a platelet count below 150,000/μL or presenting a decrease of 50% with respect to the previous value. Findings suggestive of vaccine-induced immune thrombotic thrombocytopaenia include the presence of antibodies to platelet factor 4, D-dimer levels 4 times greater than the upper limit of normal, and unexplained thrombosis. The recommended treatment includes intravenous administration of non-specific human immunoglobulin or alternatively plasmapheresis, avoiding the use of heparin, instead employing argatroban, bivalirudin, fondaparinux, rivaroxaban, or apixaban for anticoagulation, and avoiding platelet transfusion.
Non-replicating adenoviral vector vaccines may be associated with cerebral venous sinus thrombosis with thrombocytopaenia; it is important to treat the dysimmune phenomenon and the cerebral venous sinus thrombosis.
Spontaneous heparin-induced thrombocytopenia presenting as bilateral adrenal hemorrhages and pulmonary embolism after total knee arthroplasty
2015, Arthroplasty Today
Citation Excerpt :
Nevertheless, heparin can still be used, for short term only, in patients who require cardiac surgery provided that repeat PF4/heparin antibodies are negative. DVT prophylaxis can be achieved with fondaparinux [3,13] in patients with creatinine clearance >30 mL/min or with argatroban in patients with creatinine clearance <30 mL/min [14]. In summary, we report a rare case of spontaneous HIT presenting as severe thrombocytopenia, recurrent PE, and BAH after TKA.
Heparin-induced thrombocytopenia syndrome is an acquired potentially life-threatening prothrombotic disorder caused by antibodies that recognize complexes of platelet factor 4 bound to heparin or heparin-like molecules. It typically occurs after exposure to unfractionated heparin, to a lesser extent after exposure to low-molecular-weight heparins, and rarely after exposure to fondaparinux. Herein, we report the case of a 48-year-old woman who developed severe thrombocytopenia, bilateral pulmonary embolism, and bilateral adrenal hemorrhages after total knee arthroplasty without evidence of heparin exposure. Antibodies to the heparin-platelet factor 4 complex and serotonin-release assay were positive. Spontaneous heparin-induced thrombocytopenia syndrome should be considered in patients with unexplained thrombocytopenia after knee replacement surgery even without heparin exposure, and a high index of suspicion for adrenal hemorrhage is needed in patients with fever, abdominal pain, and shock.
Management of intra-aortic balloon counterpulsation by argatroban anticoagulation in a patient with a history of heparin-induced thrombocytopenia
2012, Journal of Cardiology Cases
Citation Excerpt :
A prior clinical trial evaluated the efficacy and safety of argatroban in patients with HIT in reducing subsequent thrombotic events without increasing bleeding rates [7]. Another study reported that this agent had been successfully employed in patients with a history of HIT needing acute anticoagulation with no major bleeding, new thromboembolic events, or other adverse effects [8]. Our patient rapidly deteriorated into cardiogenic shock.
Intra-aortic balloon counterpulsation (IABP) has been used in various cardiovascular conditions including cardiogenic shock. Prophylactic systemic heparinization has been commonly utilized to prevent thrombotic complications. There are a number of anticoagulants in addition to heparin; however, there is little consensus and few data to support the safety of alternative anticoagulation during IABP management. We report here on the case of a 47-year-old woman with cardiogenic shock. She had a medical history of heparin-induced thrombocytopenia (HIT) type II and soon after admission she deteriorated into cardiogenic shock of unknown etiology. This patient survived by IABP circulatory support with alternative argatroban anticoagulant therapy; and there were no signs of thrombus or thromboembolism in this patient or on the catheter itself. Our report suggests that alternative anticoagulation by argatroban may be a safe and effective therapeutic option in seriously ill patients requiring IABP support and nonheparin anticoagulation.
Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition)
2008, Chest
This chapter about the recognition, treatment, and prevention of heparin-induced thrombocytopenia (HIT) is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patient values may lead to different choices. Among the key recommendations in this chapter are the following: For patients receiving heparin in whom the clinician considers the risk of HIT to be > 1.0%, we recommend platelet count monitoring over no platelet count monitoring (Grade 1C). For patients who are receiving heparin or have received heparin within the previous 2 weeks, we recommend investigating for a diagnosis of HIT if the platelet count falls by ≥ 50%, and/or a thrombotic event occurs, between days 5 and 14 (inclusive) following initiation of heparin, even if the patient is no longer receiving heparin therapy when thrombosis or thrombocytopenia has occurred (Grade 1C). For patients with strongly suspected (or confirmed) HIT, whether or not complicated by thrombosis, we recommend use of an alternative, nonheparin anticoagulant (danaparoid [Grade 1B], lepirudin [Grade 1C], argatroban [Grade 1C], fondaparinux [Grade 2C], or bivalirudin [Grade 2C]) over the further use of unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) therapy or initiation/continuation of vitamin K antagonists (VKAs) [Grade 1B]. The guidelines include specific recommendations for nonheparin anticoagulant dosing that differ from the package inserts. For patients with strongly suspected or confirmed HIT, we recommend against the use of vitamin K antagonist (VKA) [coumarin] therapy until after the platelet count has substantially recovered (usually, to at least 150 x 10⁹/L) over starting VKA therapy at a lower platelet count (Grade 1B); that VKA therapy be started only with low maintenance doses (maximum, 5 mg of warfarin or 6 mg of phenprocoumon) over higher initial doses (Grade 1B); and that the nonheparin anticoagulant (eg, lepirudin, argatroban, danaparoid) be continued until the platelet count has reached a stable plateau, the international normalized ratio (INR) has reached the intended target range, and after a minimum overlap of at least 5 days between nonheparin anticoagulation and VKA therapy rather than a shorter overlap (Grade 1B). For patients receiving VKAs at the time of diagnosis of HIT, we recommend use of vitamin K (10 mg po or 5 to 10 mg IV) [Grade 1C].
Comparison of the ecarin chromogenic assay and different aPTT assays for the measurement of argatroban concentrations in plasma from healthy individuals and from coagulation factor deficient patients
2008, Thrombosis Research
Citation Excerpt :
The direct thrombin inhibitor argatroban is known as an effective alternative to heparin for the anticoagulation of patients with heparin induced thrombocytopenia (HIT) [1–5] even if these patients suffer from additional hepatic dysfunction [6].
The aim of this study was to assess the usefulness of different aPTT assays and the ecarin chromogenic assay reaction time (ECA) for measurement of argatroban concentration in plasma from healthy persons as well as in different patient subgroups.
We spiked plasma samples from healthy individuals, patients under oral anticoagulation (OAT) or with liver dysfunction (LD) with increasing argatroban concentrations (0 – 2000 ng/ml) and performed 4 different aPTTs assays and the ECA.
Depending on argatroban concentrations aPTTs increased in a curvilinear fashion; in plasma from healthy individuals means of calculated argatroban concentration at 2-fold aPTT differed extensively depending on the aPTT reagent used (725 ng/ml to 1136 ng/ml) and were even more pronounced in plasma from coagulation factor deficient patients (460 ng/ml in patients with LD vs. 1172 ng/ml in patients with OAT), whereas ECA showed linear argatroban influence and reliable results in all subgroups.
Because of wide differences in aPTT measurements depending on the aPTT reagent used, interindividual variations and different clinical conditions the aPTT is not the method of choice for monitoring argatroban and the ECA should be preferred.
Reducing thrombotic complications in the perioperative setting: An update on heparin-induced thrombocytopenia
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Heparins are widely used in the perioperative setting. Immune heparin-induced thrombocytopenia (HIT) is a serious, antibody-mediated complication of heparin therapy that occurs in approximately 0.5%–5% of patients treated with heparin for at least 5 days. An extremely prothrombotic disorder, HIT confers significant risks of thrombosis and devastating consequences on affected patients: approximately 38%–76% develop thrombosis, approximately 10% with thrombosis require limb amputation, and approximately 20%–30% die within a month. HIT antibodies are transient and typically disappear within 3 mo. In patients with lingering antibodies, however, re-exposure to heparin can be catastrophic. In the perioperative setting, heightened awareness is important for the prompt recognition, diagnosis, and treatment of HIT. HIT should be considered if the platelet count decreases 50% and/or thrombosis occurs 5–14 days after starting heparin, with other diagnoses excluded. On strong clinical suspicion of HIT, heparin should be discontinued and a parenteral alternative anticoagulant initiated, even before laboratory confirmation of HIT is obtained. Subsequent laboratory test results may help with the decision to continue with nonheparin therapy or switch back to heparin. Heparin avoidance in patients with current or previous HIT is feasible in most clinical situations, except perhaps in cardiovascular surgery. If the surgery cannot be delayed until HIT antibodies have disappeared, intraoperative alternative anticoagulation is recommended.

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Regular ArticleArgatroban anticoagulation in patients with a history of heparin-induced thrombocytopenia

Abstract

Introduction

Methods

Results

Conclusions

Section snippets

Methods

Patients

Discussion

Acknowledgments

Blood

Chest

Blood

Chest

Am. J. Med.

Thromb. Res.

Ann. Thorac. Surg.

Ann. Thorac. Surg.

Ann. Thorac. Surg.

Kidney Int.

Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin

N. Engl. J. Med.

Temporal aspects of heparin-induced thrombocytopenia

N. Engl. J. Med.

Use of heparin during cardiopulmonary bypass in patients with a history of heparin-induced thrombocytopenia

N. Engl. J. Med.

Regular Article
Argatroban anticoagulation in patients with a history of heparin-induced thrombocytopenia