We report on the case of an 82-year-old female patient with traumatic arterial retroperitoneal bleeding under anticoagulation with dabigatran etexilate (Pradaxa, Boehringer Ingelheim Pharma GmbH & Co, Ingelheim, Germany), which was reversed by the new specific antidote idarucizumab (Praxbind, Boehringer Ingelheim Pharma GmbH & Co, Ingelheim, Germany).
Dabigatran etexilate is part of a group of drugs known as direct oral anticoagulants. It was approved and introduced to the market in 2008 for the prevention of thrombosis after hip and knee joint replacement. The approval was later extended to the prevention of stroke in elderly patients with atrial fibrillation and certain risk factors as well as the prevention and treatment of deep vein thrombosis and pulmonary embolism, respectively.1,2 Its anticoagulant effect relies on the direct inhibition of thrombin, the most important enzyme of the coagulation cascade. More than 80% of dabigatran etexilate is eliminated by the kidneys, and its half-life is approximately 12 to 17 hours. Compared with warfarin, the risk–benefit ratio has been shown to be favorable.2 In the past, bleeding complications under therapy with dabigatran etexilate had to be managed by symptomatic therapy, including the transfusion of blood products and the administration of recombinant factor VIIa, factor VIII inhibitor bypassing activity, prothrombin complex concentrate, and tranexamic acid as well as the use of hemodialysis.3–7 However, this symptomatic therapeutic approach was shown to be far from perfect, because (1) the administration of procoagulant drugs always comes along with an inherent risk of thrombotic complications8; and (2) the efficacy of this approach is restricted because of several reports of fatal bleeding events under dabigatran etexilate despite maximal therapy.9,10
Idarucizumab is a humanized antibody fragment antigen binding (Fab) that specifically binds to dabigatran etexilate. It is able to reverse the anticoagulant effect of dabigatran etexilate within minutes without increasing the risk of thrombotic complications.11 In November 2015, the U.S. Food and Drug Administration approved idarucizumab as a specific antidote for the reversal of dabigatran etexilate. Shortly thereafter, idarucizumab was approved by the European Commission after approval by the Committee for Medicinal Products for Human Use and the European Medicines Agency. Its use is recommended in patients treated with dabigatran etexilate who are in need of emergency surgery or who suffer from life-threatening bleeding.
An 82-year-old female patient was admitted to our hospital through the trauma room after a car accident. She was conscious and presented with stable vital signs; however, atrial fibrillation was recognized on the electrocardiogram with a heart rate of approximately 140 beats/min. According to the patient, atrial fibrillation had been recognized a long time ago and was being treated with 110 mg dabigatran etexilate twice a day. The last dose was taken approximately 4 to 5 hours before the accident. As to the rest of her medical history, the patient was healthy except for arterial hypertension and hypothyreosis. Hemoglobin at admission was 12.1 g/dL. Renal function was shown to be normal as assessed by the glomerular filtration rate (Chronic Kidney Disease Epidemiology Collaboration, CKD-EPI) and creatinine. The international normalized ratio (INR) was 1.47, activated partial thromboplastin time (aPTT) 46.2 seconds, and thrombin time (the most sensitive parameter for therapy success control in patients treated with dabigatran etexilate) >120 seconds, representing a state of therapeutic anticoagulation. Computed tomography revealed serial rib fractures on the left side with a concomitant seropneumothorax, an unstable lumbar vertebral body fracture as well as a displaced fracture of the iliac crest with active arterial bleeding into the retroperitoneal space (Figure 1). Although vital signs were still stable, the patient was transferred to our intensive care unit (ICU), where the pneumothorax was relieved with a chest tube without any bleeding complications. At that time, active retroperitoneal bleeding was identified to be the leading injury, so different therapeutic options including interventional arterial coiling, immediate laparotomy, and conservative observation were discussed; interventional coiling was discarded because of a relevant risk of consecutive ischemic lesions of the iliopsoas muscle. Taking into account the patient’s age and stable cardiovascular condition, an immediate laparotomy was discarded by the interdisciplinary trauma team. Watchful waiting was, therefore, considered to be the most preferable treatment strategy. At that point in time, hemoglobin had moderately dropped to 10.8 g/dL without being attributable to excessive fluid therapy. To optimize blood coagulation, we performed further analysis with a viscoelastic point-of-care device (rotational thromboelastometry [ROTEM]). Because of the use of dabigatran etexilate, ROTEM revealed impaired clotting in terms of markedly prolonged clotting times in the EXTEM, INTEM, and FIBTEM tests (Figure 2A). To stop the bleeding and to avoid administering an allogenic blood transfusion, we decided to reverse the anticoagulant effect of dabigatran etexilate by the use of idarucizumab. The recommended dose of 2 × 2.5 g was administered as a short-term infusion. During the administration of the first dose, the patient presented a sudden decrease in blood pressure (70/30 mm Hg) accompanied by an episode of tachycardia and nausea. We suspected a possible anaphylactic reaction, so the patient was immediately treated with glucocorticosteroids (250 mg prednisolone), antihistamine drugs (8 mg dimentidene and 100 mg ranitidine), and epinephrine (10 μg) intravenously. Afterward, blood pressure recovered quickly, and the patient felt well again. The second dose was, therefore, administered 45 minutes later very slowly and under vigilant monitoring of the patient’s vital signs without any further adverse event. At 60 minutes after the treatment, we determined the effect of idarucizumab by another blood analysis as well as an additional ROTEM. The thrombin time was now found to be normal (17.2 seconds) as were INR (1.15) and aPTT (24.1 seconds). Furthermore, clotting times in the EXTEM, INTEM, and FIBTEM tests were found to be normal (Figure 2B).
The patient was closely monitored in our ICU. Within the next 6 hours, hemoglobin further decreased to 9.5 g/dL with accompanying fluid therapy. However, the patient was clinically stable without any catecholaminergic support. The next morning, the patient was transferred to the ICU of the orthopedics department. More than 24 hours after the accident, given normalized blood coagulation and stable cardiovascular conditions, prophylactic anticoagulation was started by the use of unfractionated heparin (UFH; 10,000 international units/d intravenously), which did not lead to an increase in aPTT. Two days after the reversal of dabigatran etexilate, the patient suffered another drop in hemoglobin down to 7.3 g/dL, so the low-dose UFH regime was stopped immediately and 1 unit of packed red blood cells (PRBCs) was administered (Figure 3). Searching for a plausible explanation for this further drop in hemoglobin, plasma levels of dabigatran etexilate were measured by a clotting assay (recommended trough level during treatment with 110 mg twice a day: 0.043–0.102 μg/mL), which were shown to be significantly increased despite the treatment being paused for 2 days and unobtrusive renal function throughout the whole stay in the ICU (glomerular filtration rate CKD-EPI, 87.6 mL/min and serum creatinine, 0.55 mg/dL). This reincrease in the plasma levels of dabigatran etexilate was most probably because of a redistribution process of the tissue-bound fraction of the molecule into the plasma. Accordingly, thrombin time had increased again to 66.2 seconds on the same day and 109 seconds the day after. Moreover, clotting times in the EXTEM, INTEM, and FIBTEM tests were prolonged again. Fortunately, this reincrease in dabigatran plasma levels did not lead to uncontrolled bleeding, and no further decrease in hemoglobin was observed. Accordingly, prophylactic anticoagulation by the use of UFH (10,000 international units/d intravenously) was restarted.
Five days after the reversal of dabigatran etexilate and 3 days after the reincrease in dabigatran etexilate plasma levels, dabigatran etexilate levels dropped below the detection limit accompanied by a normalization in thrombin time and clotting times in ROTEM. At that point in time, the risk of new-onset bleeding was considered to be low, so the low-dose treatment regime with UFH was switched toward a therapeutic anticoagulation regime by the use of low-molecular-weight heparin. The patient was discharged from the ICU into a regular ward in good health 1 week after the accident, having received 1 unit of PRBCs and no emergency surgery. Treatment with dabigatran etexilate was restarted 10 days after the initial reversal, because plasma levels of hemoglobin had remained stable, the chest drain was removed, and the risk of another bleeding complication was considered to be low.
In this case, the humanized antibody fragment idarucizumab proved to be clinically effective for the reversal of the anticoagulant effect of the direct thrombin inhibitor dabigatran etexilate as assessed by thrombin time, aPTT, INR, and clotting times in viscoelastic point-of-care testing. It is worth mentioning that especially the use of viscoelastic point-of-care testing devices (eg, thromboelastometry) at the bedside seems to be suitable for the rapid detection of high plasma levels of dabigatran etexilate, resulting in the earliest possible administration of idarucizumab in patients with severe bleeding. However, this time advantage was wasted in our case, because there was a multifactorial conditioned time delay of approximately 2 hours between hospital admission and the start of the reversing procedure. This was most probably because of typical uncertainties dealing with the first time application of a new substance (eg, storage site, responsibility for the indication of treatment, etc.). Nevertheless, the administration of idarucizumab was able to save an 82-year-old female patient from emergency surgery and allogenic blood transfusion in the initial phase after trauma. However, it has to be taken into account that the effect of idarucizumab only lasts for approximately 12 to 24 hours. The anticoagulant effect of dabigatran etexilate can then be restored by redistribution processes from the tissue, necessitating the transfusion of 1 unit of PRBCs in our case. Within this context, especially the impact of renal function, needs to be discussed critically, because it is known to be a key player in the metabolism of dabigatran etexilate. More than 80% of this drug is eliminated by the kidneys, resulting in increased plasma levels and greater extravascular tissue deposits, especially in patients with renal insufficiency. Thus, renal insufficiency may lead to a quicker, stronger, and longer restoration of the anticoagulant effect of dabigatran etexilate, necessitating repetitive 2.5-g doses of idarucizumab. However, even in our case with unobtrusive renal function, a reincrease in dabigatran etexilate plasma levels was observed. Therefore, in all patients with bleeding complications (regardless of a reversing procedure with idarucizumab or pre-existing renal insufficiency), repetitive measurements of dabigatran etexilate plasma levels should be taken into account. The administration of a second dose of idarucizumab may have saved the patient from allogenic blood transfusion and should therefore also be considered in the event of reelevate dabigatran etexilate plasma levels. However, repetitive doses of idarucizumab have to be weighed against an increased risk of thromboembolic complications. This is because of the fact that data from the first 90 patients included in the Phase III trial (The Reversal Effects of Idarucizumab on Active Dabigatran) revealed 5 patients with thromboembolic complications. Most of them occurred >72 hours after reversal with idarucizumab without any accompanying anticoagulant therapy.11 Although these complications were most likely attributable to the underlying medical condition and did not result from an overshooting procoagulant effect of idarucizumab, the importance of an early anticoagulant bridging concept after a reversal procedure needs to be taken into account.12 In the presented case of minor bleeding with stable vital signs, a low-dose treatment regime with UFH was considered to be safe at >24 hours after the accident, because it allows anticoagulation in careful measured doses and can rapidly be stopped in the event of new bleeding. Moreover, it can easily be antagonized by the use of protamine if necessary.
An 82-year-old trauma patient presented with retroperitoneal arterial bleeding under anticoagulation with dabigatran etexilate, which was successfully stopped by the administration of 2 × 2.5 g idarucizumab. Within the course of this case, the following novelties were observed as compared with the current literature:
- A reincrease in dabigatran etexilate plasma levels was observed 2 days after the administration of idarucizumab, although the patient’s renal function was shown to be completely unimpaired.
- Rotational thromboelastometry was shown to be a suitable tool for the rapid assessment of the anticoagulant effect of dabigatran etexilate.
- Although the immunogenic fragment crystalline region of the idarucizumab molecule has been removed, and no hypersensitivity has been reported in clinical trials, a possible anaphylactic reaction was observed in our patient during the administration of the first dose of idarucizumab.
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