Monitoring and Dosing of Argatroban in a Patient With Antiphospholipid Syndrome

Abstract

Background: This case reports outlines argatroban dosing and necessary dose adjustments in a 56 year-old male with a past medical history of antiphospholipid syndrome and heparin-induced thrombocytopenia. Method: Argatroban was initiated as a fixed dose of 0.5 µg/kg/min with all initial aPTTs above goal. Argatroban was held for a procedure and re-initiated at 0.25 µg/kg/min. The dose was increased or decreased by 25% from the current rate based on supratherapeutic and subtherapeutic aPTTs, respectively. Results: The patient remained on argatroban for 6 total days, while achieving goal aPTT levels with no VTE or bleeding events. Conclusion: Our patient represents the first reported case of monitoring argatroban with aPTTs in an individual with APS.

Introduction

Antiphospholipid syndrome (APS) is an autoimmune condition characterized by antiphospholipid antibodies which target phospholipids on platelet membranes and increase adhesion and aggregation thus potentiating thrombotic events. ¹ The lupus anticoagulant is an antibody that binds to phospholipids on platelet membranes resulting in a prolonged activated partial thromboplastin time (aPTT). Despite prolonged aPTT, these patients are at an increased risk of venous thromboembolism (VTE) formation. ¹ When treating a VTE with heparin or direct thrombin inhibitors, monitoring of aPTTs can be difficult given the prolonged baseline aPTT. Our case describes a patient with APS and history of heparin-induced thrombocytopenia (HIT) requiring anticoagulation with argatroban utilizing aPTT to monitor and dose adjust accordingly.

Case Report

A 56 year-old male with a past medical history of APS, lupus, chronic kidney disease, chronic anemia, chronic thrombocytopenia, HIT as reported by patient, and multiple VTEs was admitted for shortness of breath associated with fevers and chills. The patient’s original diagnosis of HIT was unknown. Coagulation laboratory values on admission included the following: hemoglobin 9.4 g/dL, hematocrit 29.9%, platelets 77 × 10⁹/L, prothrombin time 14.5 seconds, international normalized ratio 1.24, and aPTT 76 seconds. He was intubated upon transfer to the intensive care unit. Imaging revealed extensive bilateral pneumonia with pulmonary fibrosis and interstitial processes. The patient continued on his home rivaroxaban upon admission as well as azathioprine and furosemide. Due to worsening renal function and a pending lumbar puncture, rivaroxaban was held and argatroban was initiated. Other medications, while the patient remained on argatroban, included: docusate sodium, methylprednisolone, insulin detemir, insulin aspart, ferrous sulfate, piperacillin/tazobactam, fluconazole, pantoprazole, linezolid, norepinephrine, and fentanyl.

Prior to argatroban initiation, a baseline aPTT resulted at 66 seconds which was likely prolonged secondary to APS. Of note, the patient’s last dose of rivaroxaban was administered greater than 72 hours prior to this aPTT result. The target aPTT range for argatroban is 1.5 to 3.0 times the baseline aPTT. ² The local lab was limited to aPTT reporting up to 130 seconds. As a result, the patient’s aPTT could only be monitored to a maximum of twice their baseline for a goal of approximately 100 to 130 seconds.

Argatroban was initiated as a fixed dose at 0.5 µg/kg/min based on evidence suggesting a less aggressive dose be started in patients with a suspicion of HIT and without an acute thrombotic complication to reduce the risk of bleeding. ³ All initial aPTTs were greater than 130 seconds, as reported in Figure 1. Following this, argatroban was held for approximately two days for a lumbar puncture. Argatroban was then resumed with a new baseline aPTT of 64 seconds. The dose was initiated at half the previous rate based on clinical judgment given the previous rate of 0.5 µg/kg/min resulted in consistently supratherapeutic aPTTs. The dose was decreased or increased by 25% from the initial rate based on supratherapeutic (>130 seconds) and subtherapeutic (<100 seconds) aPTTs, respectively. aPTTs were in goal until day four of therapy when the aPTT was subtherapeutic and the dose was increased accordingly. As noted in Figure 1, two blood transfusions occurred due to his chronic anemia and were not thought to be associated with a bleeding event. The patient remained on argatroban for six total days. At that time argatroban and linezolid were held due to profound thrombocytopenia. Prior to discontinuation, coagulation laboratory values included the following: hemoglobin 8.0 g/dL, hematocrit 25.6%, platelets 15 × 10⁹/L, and aPTT 105 seconds. Approximately 24 hours post discontinuation hemoglobin and hematocrit remained stable and the platelet count increased to 24 × 10⁹/L. The patient remained in the hospital for 6 more days without any anticoagulation before care was withdrawn. No VTE or bleeding events occurred during this admission.

Figure 1.

Observed aPTT levels (closed circles) and argatroban administration record-documented administered doses. A = One unit of packed red blood cells (PRBC) infused for hemoglobin 6.7 g/dL prior to initiation of argatroban at 0.5 µg/kg/min; B = Argatroban dose interruption pending a lumbar puncture; C = Argatroban was resumed at 0.25 µg/kg/min; D = One unit of PRBC infused for hemoglobin 6.3 g/dL on the day prior to argatroban discontinuation.

Discussion

Our patient represents the challenges of accurately monitoring the anticoagulant effect of argatroban in individuals with APS. It is unique from previously reported cases as our dose adjustments were based solely on aPTT results.^4-7 Although recommended argatroban dosing to achieve an aPTT of 1.5 to 3.0 times the patient’s baseline has been validated in patients without coagulopathies, this has not been validated in patients with an elevated baseline aPTT due to APS. ⁸ Therefore, although our aPTTs were within the goal range, it is unknown the clinical significance of an aPTT in a patient on argatroban with APS. Other monitoring options for argatroban include the utilization of ecarin clotting time, chromogenic anti-factor IIa, and dilute thrombin time which work in a phospholipid independent manner and are not affected in patients with APS.^4,9,10 However, these tests are unavailable at most sites.

Our case report is the first to highlight monitoring aPTTs in patients receiving argatroban with APS to guide efficacious and safe administration. With monitoring and appropriate dose adjustments, this patient did not have a VTE or bleeding event despite being at high risk for both of these. More research is needed to support the appropriateness of dose adjustment based on aPTTs in patients on argatroban with APS.