Our case report describes the successful management of a rare case of massive dabigatran overdose using haemodialysis. There is limited literature and guidelines available to date about the toxicity of dabigatran, monitoring of anticoagulation effect, and treatment options. Symptoms of overdose may include excessive bleeding from various sites. Idarucizumab is used as an antidote to reverse the action of dabigatran in case of emergency procedures or uncontrolled bleeding but the dose required and utility in case of intentional overdose remains unclear. Immediate availability of this antidote in case of acute dabigatran overdose may be challenging in many centers. Hence haemodialysis can be used as a rescue measure to prevent life-threatening haemorrhagic complications. However, the threshold for initiating haemodialysis is not yet well defined in a patient with normal renal function.

• Dabigatran; Overdose; Idarucizumab; Haemodialysis; Bleeding; Antidote

Rai AV, Gala J (2024) Role of Haemodialysis in the Management of Dabigatran Overdose. J Pharmacol Clin Toxicol 12(1):1182.

INR: International Normalized Ratio; aPTT: activated Partial Thromboplastin Time; FDA: Food and Drug Administration; TT: Thrombin Time; ECT: Ecarin Clotting Time; dTT: Diluted Thrombin Time; ESRD: End-Stage Renal Disease.

Dabigatran is a newer oral anticoagulant which acts by direct thrombin inhibition (Figure 1).

Figure 1: Mechanism of action of Dabigatran and Idarucizumab

Symptoms of overdose may include excessive bleeding from various sites. There is limited literature and guidelines available to date about the toxicity of dabigatran, monitoring of anticoagulation effect, and treatment options. Idarucizumab is the available antidote for dabigatran overdose which may not be available at different institutes. Management in cases of associated renal dysfunction is always a challenge as dabigatran is cleared by renal route.

A 26-year-old woman, diagnosed with cerebral venous thrombosis with cerebellar venous infarct on a therapeutic dose of dabigatran for 3 months presented with alleged history of consumption of 50 tablets of dabigatran 150 mg (7.5 gram). She was treated in a nearby hospital with gastric lavage within an hour of consumption. Initial laboratory studies done outside hospital revealed hemoglobin of 12.6 g/dl and an international normalized ratio (INR) of 6.4. On arrival at our emergency department, her vital parameters and neurological examination were normal. She gave a history of black-coloured stools occasionally as she was on iron supplements. Other blood reports revealed normal electrolytes, liver, and renal function but activated partial thromboplastin time (aPTT) ratio of 2.82 and INR of 5.83 (Table 1).

Table 1: Laboratory values of the patient

INR: international normalized ratio; aPTT: activated partial thromboplastin time; TT: thrombin time; g/dL: gram/decilitre; s: seconds

Due to non-availability of Idarucizumab, and the coagulation parameters which could not accurately predict bleeding risk and with a suspicion of upper gastrointestinal bleeding, decision for haemodialysis was made. Haemodialysis sheath was placed under ultrasound guidance and dialysis was done for 6 hours. Subsequent hemogram and coagulation profile were within normal limits. On day 4, she was discharged home with advice to follow up in the neurology and psychiatry outpatient department.

Pharmacokinetic properties of dabigatran include peak plasma concentrations at 1 to 3 h after ingestion, protein-bound fraction of 35 %, half-life of 12-17 hours depending on patient’s glomerular filtration rate, and elimination primarily through renal excretion (~85 %)(Table 2).

Table 2: Renal clearance of Dabigatran

ml/min: millilitre/minute, h: hours

The drug is converted into active form by plasma and hepatic esterases and reversibly inhibits thrombin, which is the final step in the coagulation pathway [1,2].

United States Food and Drug Administration (FDA) has approved dabigatran for stroke prophylaxis in patients with non-valvular atrial fibrillation, prevention of venous thromboembolism after hip surgery, and treatment of deep venous thrombosis and pulmonary embolism. Pharmacologic strengths of dabigatran over Vitamin K antagonist include a rapid onset and offset of action, wide therapeutic index with no routine monitoring of coagulation parameters or therapeutic drug monitoring, and lesser drug–drug and drug–food interactions while weaknesses include the requirement of adequate renal function for the elimination of the drug. There are case reports of dabigatran-related bleeding complications such as intracranial bleed after mild traumatic brain injury, postoperative bleeding complications, spontaneous hemopericardium, and significant gastrointestinal bleeding after renal impairment seen in patients taking dabigatran regularly as a part of oral anticoagulation and not overdose [3-10].

Though routine monitoring of the anticoagulant effect of dabigatran is not required, a better understanding and availability of laboratory tests specific to dabigatran activity would prove beneficial in treating adverse bleeding events and in situations of intentional overdose. Standard coagulation tests such as prothrombin time and international normalized ratio have been considered unreliable in measuring anticoagulation levels of patients receiving dabigatran. As seen in our case,initial coagulation tests could not predict bleeding risk. Diluted thrombin time (TT) directly measures the activity of thrombin in a plasma sample and is the most sensitive test to assess the anticoagulant effect of dabigatran [11]. A normal thrombin time usually excludes an anticoagulant effect due to dabigatran [12]. The Ecarin clotting time is a specific assay for thrombin generation, but not available commercially [13,14]. Apart from these tests, activated partial thromboplastin time (aPTT), which is a measure of the intrinsic pathway of coagulation is useful for confirming the degree of anticoagulation [15]. We relied on aPPT and aPTT ratio to monitor anticoagulation due to overdose. There exists a linear relationship between plasma concentrations of dabigatran and the thrombin time, ecarin clotting time (ECT), and INR. Dabigatran prolongs the TT, ECT and INR in a concentrationdependent fashion over therapeutic concentrations but the aPTT concentration-response curve is curvilinear which gets flattened at higher concentrations (200 ng/ mL) [13,14]. The dabigatran blood levels are not available routinely and thus offer very minimal diagnostic utility in the acute setting.

FDA had approved Idarucizumab as the specific reversal agent for dabigatran which is indicated for rapid reversal for urgent and emergent procedures and for patients with lifethreatening or uncontrolled bleeding. The total dose of 5 g of intravenous Idarucizumab is administered as two 50-ml bolus infusions not more than 15 minutes apart. Diluted thrombin time (dTT) and ecarin clotting time (ECT) is successfully reversed by Idarucizumab within one hour of administration in all patients with elevated coagulation tests at baseline [15-17].The 5-g dose was calculated to reverse the total body load of dabigatran that was associated with the 99th percentile of the dabigatran levels [18]. Bleeding manifestations are strictly not related to dabigatran blood levels [19]. Administration of a second dose of Idarucizumab 5 grams may be considered in patients with clinically significant bleeding or who require a second emergency surgery/urgent procedure [20-22]. It doesn’t have thrombin-like activity, so no prothrombotic effects documented [23]. Rebound effect may be seen following reversal due to the redistribution of dabigatran from the extravascular to the intravascular compartment and the short half-life of idarucizumab (45 minutes). As per the recent International Society on Thrombosis and Haemostasis guidelines, Idarucizumab should not generally be used for high plasma levels of dabigatran or excessive anticoagulation without associated bleeding [24].

Given the bleeding risk that is associated with the placement of a dialysis catheter in a patient with severe coagulopathy, other strategies to reverse the anticoagulant effect of dabigatran will be necessary. Gastric decontamination with activated charcoal offers benefits if done early within two hours of overdose [25], and it was already done in our case from outside the hospital. Maintaining good renal perfusion and urine output can aid elimination of the drug. As it is less protein bound (~35%) and lipophilic, haemodialysis studies in patients with end-stage renal disease (ESRD) on dabigatran showed a drug blood level concentration decrease by 62 % at 2 h and an additional 68 % decrease at 4 h [26]. Haemodialysis is effective in enhancing dabigatran clearance. It was successful in reducing bleeding complications in a postoperative cardiac patient with therapeutic plasma levels of dabigatran [27]. However, the threshold for initiation of dialysis is not well defined in an asymptomatic patient with normal renal function and the decision to dialyze a patient with non-bleeding or minor bleeding dabigatran overdose is still controversial. In our case, haemodialysis was done as there was suspicion of gastrointestinal bleed. Due to a rebound increase in plasma concentration post dialysis, continuous venovenous hemofiltration has been suggested in one study [28].

To conclude, there is limited experience with the management of dabigatran overdose. The evidence for expectant management in asymptomatic patients with no or minimal bleeding manifestations and normal renal function is not strongly supported in the literature. It is a potential area of research.

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