Argatroban For Heparin-Induced Thrombocytopenia Research Articles

How to dose and monitor argatroban for treatment of HIT.

Dosing and monitoring of argatroban for treatment of heparin-induced thrombocytopenia (HIT) remain uncertain. Marchetti and colleagues critically and systematically reviewed their institutional experience using this direct thrombin inhibitor to treat patients with laboratory-confirmed HIT, and have formulated several practical recommendations for managing this challenging clinical situation. Commentary on: Marchetti et al. Managing argatroban in heparin-induced thrombocytopenia: A retrospective analysis of 729 treatment days in 32 patients with confirmed heparin-induced thrombocytopenia. Br J Haematol. 2022;197:766-790.

PB2257 USE OF ARGATROBAN AS AN ANTICOAGULANT TREATMENT ALTERNATIVE IN CRITICAL PATIENTS WITH HEPARIN‐INDUCED THROMBOCYTOPENIA. EXPERIENCE IN A THIRD LEVEL HOSPITAL.

Background:Heparin is a widely used drug. The most frequent complication derived from its use is the haemorrhage. However, an uncommon but potentially serious adverse effect is heparin‐induced thrombocytopenia (HIT). The goal of treatment of HIT is to reduce platelet activation and thrombin formation to decrease the risk of thrombosis. Argatroban is the drug of choice in HIT patients as an alternative anticoagulant treatment in critically ill patients with high risk of haemorrhage, postoperative cardiac events or renal failure, since it allows close control of anticoagulation.Aims:To analyze the clinical, laboratory and therapeutic characteristics of patients treated with Argatroban by HIT in our hospitalMethods:Retrospective analysis or patients treated with Argatroban for diagnosed HIT during the last year.Results:Four patients have required treatment with Argatroban for HIT since they required maintenance of anticoagulation due to mitral prosthesis, unstable angina, DVT in the right lower extremity and acute ischemia in the left lower extremity. Median age 68 years (43‐79). All of them were diagnosed with HIT according to the 4T score during their admission to the Intensive Care Unit. PF4/Heparin antibody testing was positive in the four patients.The median number of days from the start of Heparin treatment (2 with unfractioned and 2 with low molecular weight) to the onset of thrombocytopenia was 6 days (1‐8). Median platelets at diagnosis were 73x109/L (49‐82). Median number of days from the start of Argatroban to platelet recovery was 6 days (3‐12). Median number of days of treatment with Argatroban was 9.5 days (2‐18). Argatroban dose was adjusted to maintain aPTT at 1.5‐3.0 times baseline. 3 patients presented thrombotic events, 2 directly related to HIT (1 ischemic stroke and 1 acute ischemia of right upper extremity) and 1 with worsening of reperfusion of the limb. 2 patients required amputation of the limb. No adverse events associated with Argatroban, including haemorrhage, were observed.Summary/Conclusion:HIT is a potentially catastrophic complication of heparin treatment which requires urgent detection and treatment with a non‐heparin anticoagulant such as Argatroban should be initiated. Even in critically ill patients, Argatroban anticoagulation improves clinical outcomes in patients who have HIT, without increasing bleeding risk.

Argatroban for Heparin-Induced Thrombocytopenia during Venovenous Extracorporeal Membrane Oxygenation with Continuous Venovenous Hemofiltration

Patients receiving extracorporeal membrane oxygenation (ECMO) are at risk of circuit thrombosis due to constant contact between blood and the extracorporeal components. Unfractionated heparin has traditionally been used in this setting as a systemic form of anticoagulation to prevent thrombosis of the circuit. However, if a patient develops heparin-induced thrombocytopenia (HIT), an alternative anticoagulant would be required while the patient is maintained on ECMO. Unfortunately, the pharmacokinetic changes induced by ECMO and critical illness may potentially affect optimal drug dosing. In addition, other modalities, such as continuous renal replacement therapy, may further complicate dosing strategies. We report the case of a 27-year-old man with severe acute respiratory distress syndrome who developed HIT while on venovenous ECMO with continuous venovenous hemofiltration. We describe the successful use of an argatroban infusion in this setting at much higher doses than what has previously been reported in the adult literature.

Argatroban in heparin-induced thrombocytopenia: rationale for use and place in therapy

Heparin-induced thrombocytopenia (HIT) is a recognized complication of heparin and requires urgent detection and treatment. HIT can be divided into two types, type I and type II, with type I being a transient decrease in platelet count without clinical consequence. For the purpose of this review, the term HIT refers to the immune-mediated type II that causes paradoxical thrombo-emboli. The aim of this review is to familiarize clinicians with a specific direct thrombin inhibitor, argatroban, in the treatment of HIT. Argatroban has been successfully employed in treating HIT in many different subsets of patients, including those with endstage renal disease on hemodialysis and in patients undergoing percutaneous coronary intervention and those with multiorgan dysfunction syndrome.

High-Dose Argatroban for Heparin-Induced Thrombocytopenia in a Child Using a Ventricular Assist Device

A 10-year-old boy who was receiving support from a ventricular assist device (VAD) experienced heparin-induced thrombocytopenia that was successfully treated with high-dose argatroban infusion to attain therapeutic activated partial thromboplastin time in spite of high serum argatroban levels. This case also highlights bolus argatroban dosing for VAD change in the setting of persistent ventricular fibrillation.

Implementation of an individualized argatroban protocol in an academic medical center

A retrospective evaluation of the prescribing, dispensing, administration, and monitoring of argatroban at the Medical College of Georgia identified numerous areas for improvement in the medication-use process. With regard to prescribing, areas for improvement included the addition of heparin to the allergy list to ensure discontinuation of all heparin products while ruling out heparin- induced thrombocytopenia (HIT), ordering appropriate laboratory tests, and adjusting the initial infusion rate based on patient characteristics, such as the presence of hepatic dysfunction and critical illness. Our evaluation revealed a need for standardized monitoring of activated partial thromboplastin time (aPTT) values and associated rate changes. Several calculation errors, errors in timing of blood draws for aPTT measurements, and inappropriate argatroban dosage adjustments occurred when no protocol or guidelines were used. The analysis also revealed variability in warfarin bridging practices and identified adverse events. Due to the potential high risk for medication errors with argatroban, we aimed to implement an individualized, weight-based protocol for the use of argatroban in HIT.

Clinical experience with argatroban for heparin-induced thrombocytopenia in a large teaching hospital.

Argatroban is a direct thrombin inhibitor approved for the prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT). The product monograph does not guide clinicians beyond specifying the initial dose of 2 μg/kg per minute (or 0.5 μg/kg per minute for patients with hepatic impairment). Some authors have suggested that in the intensive care unit (ICU) and for patients with acute cardiac disease and those with renal or hepatic dysfunction, this dose may result in a supratherapeutic activated partial thromboplastin time (aPTT). To evaluate the efficacy and safety of argatroban in adult patients with suspected HIT in a large teaching hospital, and to review dosing for patients in the ICU, patients with acute cardiac disease, and patients with renal or hepatic dysfunction. Charts of patients with suspected HIT who had received argatroban for at least 24 h between October 1, 2005, and October 1, 2007, at the Foothills Medical Centre, Calgary, Alberta, were examined retrospectively. Thirty patients met the inclusion criteria, with charts available for review. Of these, 21 (70%) patients had an initial argatroban dose of 2 μg/kg per minute and 4 (13%) had an initial dose of 0.5 μg/kg per minute. The median duration of therapy was 6 days, and the mean dose was 2.14 μg/kg per minute. There were 122 dosage adjustments, the most common change being 0.5 μg/kg per minute, followed by adjustments of 1 and 0.1 μg/kg per minute. Six patients had supratherapeutic aPTT values (above 100 s), and none experienced major bleeding. The results of this study suggest that an initial argatroban dose of 2 μg/kg per minute is appropriate for patients with no hepatic dysfunction. Patients with acute cardiac disease and critically ill patients may require lower doses of argatroban; however no dosage adjustments are required for patients with renal dysfunction.

Argatroban for heparin-induced thrombocytopenia therapy in ICU patients with sepsis or multiple organ dysfunction syndrome

Heparin-induced thrombocytopenia (HIT) is a serious, prothrombotic, immune-mediated adverse reaction triggered by heparin therapy. When HIT is diagnosed or suspected, heparins should be discontinued and an alternative, fast-acting, parenteral, nonheparin anticoagulation such as argatroban should be initiated. The recommended initial dose of argatroban in HIT is 2 μg/kg/minute with following adjustment to the activated partial thromboplastin times (aPTTs). There are limited and inconsistent data about dosing of argatroban therapy in ICU patients with multiple organ dysfunction syndrome [1,2].

Identification and treatment of arterial thrombophilia

Once the diagnosis of a thrombophilic state has been established, management must include one or more strategies designed to attenuate thrombotic risk and the likelihood of clinical events. In the case of drug-induced arterial thrombosis provoked by oral contraceptives, hormone replacement therapy, heparinoids, cocaine, or thienopyridine-related thrombotic thrombocytopenic purpura (TTP), the offending agent should be discontinued immediately. Anticoagulant therapy and platelet-directed therapies, either alone or in combination, should be considered for patients experiencing a single arterial or venous thrombosis (secondary prevention), with treatment duration determined by diagnostic studies and the persistence of a prothrombotic state. Other specific therapies should be directed at the underlying thrombophilic disorder. These treatments include direct thrombin inhibitors such as argatroban for heparin-induced thrombocytopenia (HIT), myelosuppressive drugs such as hydroxyurea for essential thrombocytosis, plasma exchange for thrombotic thrombocytopenic purpura, and phlebotomy for polycythemia vera. Additionally, the treating physician must seek input early from a hematologist or rheumatologist when managing patients with known or suspected HIT, TTP, and myeloproliferative disorders, or the antiphospholipid syndrome, respectively. This interdisciplinary interface is critical to ensure an optimal outcome when treating patients with arterial thrombophilia.

Effect of renal function on argatroban therapy in heparin-induced thrombocytopenia

Argatroban is considered to be an alternative anticoagulant of choice in patients with heparin-induced thrombocytopenia (HIT) and renal impairment. The recommended initial dose in HIT is 2 microg/kg/min (0.5 microg/kg/min in hepatic impairment), adjusted to achieve activated partial thromboplastin times (aPTTs) 1.5-3 times baseline. Although argatroban is predominantly hepatically metabolized with minimal renal clearance, recent limited data have suggested that a patient's renal function should also be considered when initiating argatroban therapy for HIT. We retrospectively evaluated the effect of renal function on argatroban therapy in HIT patients with normal hepatic function, with the goal of refining dosing guidance, if needed. From case records of previous prospective studies of argatroban in clinically diagnosed HIT, we identified patients who had baseline laboratory data on liver and renal function. Individuals with abnormal hepatic function (serum total bilirubin > 1.5 mg/dl or ALT or AST > 100 U/l) were excluded. Patients were stratified according to their estimated creatinine clearance (CL(cr)): normal or mild impairment (CL(cr) > 60 ml/min), moderate impairment (CL(cr) 30-60 ml/min), or severe impairment (CL(cr) < 30 ml/min). Argatroban doses, aPTTs, and clinical outcomes were summarized overall and by group. By-patient relationships between CL(cr) and dose or aPTT during therapy were explored using regression analyses. The analysis population included 260 patients with normal to mild (n = 144), moderate (n = 80), or severe (n = 36) renal impairment. Argatroban was initiated at a mean infusion dose of 1.8 +/- 0.7 microg/kg/min (overall), titrated to achieve aPTTs 1.5-3 times baseline. Among renal function groups, no significant differences occurred in argatroban dose during therapy (overall value, 1.9 +/- 1.1 microg/kg/min), duration of therapy (7 +/- 6 days), or aPTTs (63 +/- 17 s). Regression analyses showed a 0.1 microg/kg/min increase in dose (r2 = 0.02) for each 30 ml/min increase in CL(cr). Within a 37 day follow-up, 46 (17.7%) patients died, most often when severe renal impairment was present. New thrombosis (11.5% overall) and major bleeding (5.0%) did not differ among groups. In this large cohort of HIT patients with normal hepatic function and varying levels of renal function, argatroban administered in accordance with current recommendations provided adequate levels of anticoagulation and was well tolerated. Altered renal function did not clinically significantly affect argatroban doses, aPTT responses, or rates of thrombosis or bleeding. These findings further support argatroban as an alternative anticoagulant of choice, without need for initial dose adjustment, in most patients with HIT and renal impairment. We retrospectively evaluated the effect of renal function on argatroban therapy in HIT patients with normal hepatic function, with the goal of refining current dosing guidance, if needed. From previous prospective studies of argatroban in HIT, we identified 260 patients with clinically diagnosed HIT, normal hepatic function, and varying degrees of renal function. Among patients whose renal function was normal or mildly impaired (estimated creatinine clearance, CL(cr) > 60 ml/min); moderately impaired (CL(cr) 30-60 ml/min), or severely impaired (CL(cr) < 30 ml/min), no significant differences occurred in the argatroban dose, aPTT response, duration of therapy, or rates of thrombosis or major bleeding. By regression analysis, there was a clinically insignificant 0.1 microg/kg/min increase in dose for each 30 ml/min increase in CL(cr). Overall, argatroban administered in accordance with current recommendations provided adequate levels of anticoagulation and was well tolerated, supporting its use as an alternative anticoagulant of choice, without need for initial dose adjustment, in most patients with HIT and renal impairment.

Direct Thrombin Inhibitors

Direct thrombin inhibitors (DTIs) are a new class of anticoagulants that bind directly to thrombin and block its interaction with its substrates. Four parenteral DTIs have been approved by the FDA — hirudin and argatroban for heparin-induced thrombocytopenia, bivalirudin as an alternative to heparin in percutaneous coronary intervention, and desirudin as prophylaxis against venous thromboembolism in hip replacement. This article discusses the clinical data on this important new class of medications.