Activated prothrombin complex concentrate for dabigatran‐associated bleeding

A humanized antibody fragment to reverse the oral thrombin inhibitor dabigatran is currently under development (Schiele et al, 2013). The absence of a specific reversal agent has caused apprehension over the use of this anticoagulant (Cotton et al, 2011). Prothrombin complex concentrate (PCC) and activated factor VII seemed ineffective in recently reported cases (Lillo-Le Louet et al, 2012), and animal models and ex vivo studies have provided conflicting results Majeed & Schulman, 2013). Although dabigatran has a low degree of binding to plasma proteins and is dialyzable (Khadzhynov et al, 2013), it may take many hours to eliminate this drug from the circulation. We treated four patients with potentially life-threatening dabigatran-associated bleeding with activated PCC (FEIBA, Baxter AG, Vienna, Austria), two in Hamilton, Ontario and two in Edmonton, Alberta. The laboratory and transfusion data are shown in Fig 1. Creatinine clearance was estimated with the Cockroft-Gault formula. An 84-year-old male (Hamilton 1) with a medical history of atrial fibrillation, hypertension and chronic renal insufficiency was urgently referred to our tertiary care hospital with subdural haematoma. He had fallen at home 1 month earlier and, at the time of presentation, had a 3-day history of headache and progressive left sided weakness. Computed tomography (CT) showed acute on chronic right parietal subdural haematoma with associated midline shift (Fig 2). The last dose of dabigatran, 110 mg, was 2 d before transfer to our hospital. On admission the thrombin time (TT) was 127 s (normal range 20–30 s), activated partial thromboplastin time (aPTT) was 46 s (normal 22–35 s), prothrombin time – international normalized ratio (INR) was 1·2, dabigatran concentration (with Hemoclot®) was 50 ng/ml, and creatinine 135 μmol/l with calculated creatinine clearance of 45 ml/min. The neurosurgeon elected to defer haematoma drainage until dabigatran had been eliminated. The patient received 4600 units (50 units/kg) of aPCC, whereafter the weakness improved without immediate change in the coagulation profile. The thrombin time normalized 3 d later and he underwent uneventful craniotomy with evacuation of 100 ml of blood. Repeat imaging demonstrated resolution of the bleed and he was discharged home the next day. At 1-month follow-up, there was complete resolution of the weakness. An 81-year-old female (Hamilton 2) with atrial fibrillation and hypertension woke up in the morning, 12 h after her last dabigatran dose (110 mg), and felt normal but 1 h later she fell off the toilet and was disoriented, unsteady and had right-sided weakness and slurred speech. When the paramedics arrived, 20 min later, her blood pressure was 196/100. CT, 70 min after onset showed acute intra-axial haemorrhage in the left basal ganglia, 1·8 × 2·3 × 3·3 cm with mild perilesional oedema and chronic microangiopathy. Her creatinine was 84 μmol/l, corresponding to a calculated creatinine clearance of 43 ml/min, aPTT was 48 s (normal 22–35 s) and TT >150 s (normal 20–30 s). She received aPCC 2500 units (42 units/kg) starting 4 h after onset. Repeat imaging after 3 d showed a mild increase in the haematoma (2·2 × 3·0 × 3·8 cm). There was no further progression of her symptoms; her speech normalized on the day of admission but her motor function required 2 months of rehabilitation. At follow-up, 13 weeks after the event, she had normal mobility and strength but slight numbness on her right side. An 85-year-old female (Edmonton 1) with atrial fibrillation, hypertension, dyslipidaemia, chronic kidney disease and previous myocardial infarction required insertion of a dual-chamber pacemaker due to sinus node tachy-brady-dysfunction and 7s-pauses. The patient was on aspirin 81 mg. After the insertion, dabigatran was started at 75 mg b.i.d. due to a calculated creatinine clearance of 27 ml/min. The creatinine subsequently increased from 160 to 424 μmol/l, the patient became hypotensive and an echocardiogram demonstrated penetration of a pacemaker lead into the pericardium, where there was a circumferential effusion. The aPTT was 65 s but pericardiocentesis was of vital importance, so 100 units/kg of aPCC was infused, immediately followed by centesis, draining 700 ml of blood. The bleeding ceased but the thrombin time remained unmeasurable for three more days. An 83-year-old female (Edmonton 2) with atrial fibrillation was admitted for upper gastrointestinal bleeding; haemoglobin concentration (Hb) was 99 g/l and creatinine clearance 24 ml/min. Dabigatran, started 1 month earlier at 110 mg b.i.d. (creatinine clearance then 43 ml/min), was withheld but her Hb continued to decrease, to 70 g/l after 3 d. Upper endoscopy was performed to verify the bleeding, aPCC at a dose of 50 units/kg and 3 units of red cells were administered and the clinical condition stabilized. These cases illustrate how life-threatening dabigatran-associated bleeding might be controlled with aPCC, supported by another case (Dager et al, 2013). These reports are admittedly anecdotal but still of interest whilst awaiting specifically designed clinical studies. The mechanism of action is unclear but might entail boosting the prothrombinase complex on the platelet surface (Hoffman & Dargaud, 2012). Alternatively, high levels of prothrombin increase the velocity of thrombin generation (Hoffman & Dargaud, 2012). aPCC does not remove dabigatran, explaining the unchanged thrombin time. With the retrospective nature of data collection, our laboratory data are limited. Discrepant haemostatic and laboratory results were also seen in animal models (van Ryn et al, 2011), and in healthy volunteers receiving dabigatran, aPCC corrected all parameters of thrombin generation (Majeed & Schulman, 2013). In a study with another thrombin inhibitor, melagatran, aPCC reduced blood loss in the rat tail bleeding model (Elg et al, 2001a). In comparison with other haemostatic agents, aPCC seemed to be the most effective for shortening the bleeding time in animals exposed to high doses of melagatran (Elg et al, 2001b). Doses of aPCC corresponding to 80–160 units/kg corrected some of the thrombin generation parameters to supranormal levels in the above-mentioned ex vivo study ((Majeed & Schulman, 2013) and therefore it might be prudent to attempt reversal in clinical situations with only 50 units/kg, which is at the lower end of the dose range used in haemophilia with inhibitors. Further studies are required to confirm the benefits and identify harms of aPCC in dabigatran-associated major bleeding. BR, SN, MA and SG managed the cases and provided the data, SS and JKG wrote the manuscript, all co-authors read critically and revised the manuscript. SS has received honoraria from Boehringer Ingelheim for work in study committees.

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