Managing Life-Threatening Bleeding in Patient with High Plasma Concentration of Dabigatran with Thromboelastogram, Idarucizumab and Renal Replacement Therapy

Case Report

Austin Crit Care Case Rep. 2021; 5(2): 1024.

Managing Life-Threatening Bleeding in Patient with High Plasma Concentration of Dabigatran with Thromboelastogram, Idarucizumab and Renal Replacement Therapy

Ego A*, Lheureux O and Creteur Jacques J

Department of Intensive Care, University Libre de Bruxelles (ULB), Belgium

*Corresponding author: Amedee Ego, Department of Intensive Care, Erasme Hospital, University Libre de Bruxelles (ULB), Route de Lennik, 808, 1070 Brussels, Belgium

Received: January 23, 2021; Accepted: February 23, 2021; Published: March 02, 2021

Abstract

We present a case of patient with spontaneous cardiac tamponade related to a very high 2-plasma concentration of dabigatran, an oral direct-acting thrombin inhibitor. By selectively inhibiting thrombin alone, dabigatran may have antithrombotic efficacy while preserving some other hemostatic mechanisms in the coagulation system and thus potentially mitigating the risk of bleeding. Nonetheless, serious bleeding can occur with dabigatran. We illustrate the management of this life threatening hemorrhagic complication by the combination of cardiac surgery, antagonization of the anticoagulant effect (using Idarucizumab, an humanized monoclonal antibody fragment and continuous renal replacement therapy), and monitoring of the effects on coagulation by thromboelastogram.

Introduction

Dabigatran is a new oral direct-acting thrombin inhibitor effective in the prevention of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE) and stroke in patients with Atrial Fibrillation (AF). Dabigatran has interesting pharmacokinetic and pharmacodynamic properties: non-vitamin dependent, metabolism independent of liver function, and with a few drug interferences [1]. By selectively inhibiting thrombin alone, dabigatran may have antithrombotic efficacy while preserving some other hemostatic mechanisms in the coagulation system and thus potentially mitigating the risk of bleeding. These properties associated with the uselessness of biological monitoring explain the success of new oral anticoagulants.

Compared to warfarin, treatment with dabigatran (150 mg twice daily) for AF and for the treatment of PE and DVT was associated with a higher rate of gastrointestinal bleeding and a lower rate of intracranial bleeding [1-3]. Nonetheless, serious bleeding can occur with dabigatran. Dabigatran is mainly (80%) excreted by the kidneys (its serum half-life is between 12 and 17 hours), making its use more limited in cases of renal failure [1]. In case of severe and active bleeding, the anticoagulant effect cannot be reversed with vitamin K, unlike warfarin. Idarucizumab is a humanized monoclonal antibody fragment that has been developed as a specific reversal agent for dabigatran. Idarucizumab selectively and exclusively binds dabigatran with an affinity ≈350-fold higher than the affinity of dabigatran for thrombin and neutralizes its anticoagulant effect immediately, especially in case of uncontrollable bleeding [4]. We present a case of an 84-year-old patient with spontaneous tamponade in a context of high plasma concentration of dabigatran, who required idarucizumab, four-factor prothrombin complex concentrates and continuous renal replacement therapy to control this life-threatening situation.

Case Presentation

An 84-year-old male with history of hypertension, AF, hyperlipidemia, severe arteriopathy, usually taking dabigatran (150mg twice daily), ACE-inhibitor with hydrochlorothiazide, and ezetimibe, presented to the emergency department for asthenia and dyspnea worsening since several days. Physical examination and vital parameters showed poor skin perfusion, lethargy, jugular turgor, tachycardia with paradoxical pulse, and arterial hypotension. Cardiac tamponade characterized by a circumferential pericardial effusion with compression of the right cavities was diagnosed by the use of cardiac ultrasound. Admission blood tests showed lactic acidosis (3.6mEq/L), acute renal failure KDIGO I (creatinine: 208.5μmol/L, uremia: 39.2mmol/L) and a significant alteration of standard coagulation tests: Activated Partial Thromboplastin Time (APTT) at 127s (normal range from 30 to 40 s) and Prothrombin Time (PT) at 143s (normal range from 11 to 13, 5s). Fibrinogen concentration and platelets count were in the normal ranges. The plasma concentration of dabigatran at admission was 368ng/mL. The patient reported no medication error.

To allow a sub-xyphoid pericardial puncture in order to evacuate the pericardial effusion, a reversion of dabigatran was quickly started by the administration of 50U/Kg of four-factor prothrombin complex concentrates (COFACT®) and with a 5g dose of idarucizumab. 200 cc of bloody liquid were drained under ultrasound guidance, resulting in a rapid resolution of the shock. However, no drain could be left in place due to an excessively thick pericardium. Thereafter, cardiac ultrasound examinations showed a very gradual recurrence of pericardial without compression of cavities. Despite the administration of a first dose of idarucizumab, the plasma level of dabigatran was still higher than the initial concentration (490ng/mL). Standard coagulation tests Remained Altered and Thromboelastogram (ROTEM®) showed a significant extended clotting time. Renal function deteriorated to a grade KDIGO III (creatinine: 586.9μmol/L, uremia 91.7mmol/L). In this context, Renal Replacement Therapy (RRT) by continuous venovenous hemodiafiltration (blood flow: 180ml/min; dialysate flow: 2000ml/h; no fluid withdrawal) was started in order to increase the clearance of dabigatran. In the following hours, successive biological analyzes showed a significant decrease in the plasma concentration of dabigatran as well as a progressive resolution of the coagulopathy on all tests (Figure 1 and Table 1).

Figure 1: Evolution of coagulation parameters since admission. PPC: fourfactor prothrombin complex concentrates. CT: Clotting Time on Thromboelastogram; CVVHDF: Continuous Veno- Venous Hemodiafiltration; APTT: Activated Partial Thromboplastin Time; PT: Prothrombin Time.

    

    
    

    

    Figure 1: Evolution of coagulation parameters since admission. PPC: fourfactor
prothrombin complex concentrates.
CT: Clotting Time on Thromboelastogram; CVVHDF: Continuous Veno-
Venous Hemodiafiltration; APTT: Activated Partial Thromboplastin Time; PT:
Prothrombin Time.

Table 1: Evolution of coagulation parameters since admission.





  

    
    
APTT

      (second es)

    
PT

      (second es)

    
Extern CT

      (second es)

    
Dabigatran

      (ng/ml)

  

  

    
HO

    
127

    
143

    
    
368

  

  

    
H+8

    
556

    
217

    
486

    
490

  

  

    
H+30

    
61

    
344

    
427

    
  

  

    
H+40

    
483

    
224

    
272

    
378

  

  

    
H+50

    
388

    
192

    
179

    
  

  

    
H+52

    
228

    
154

    
68

    
<20

  

  

    
CT: Clotting Time on Thromboelastogram; APTT:    Activated Partial Thromboplastin Time; PT: Prothrombin Time. 

  










Table 1: Evolution of coagulation parameters since admission.

Nevertheless, on day 3, we observed a recurrence of cardiac tamponade that required surgical pericardial drainage 20 hours after the initiation of RRT. A second 5g dose of idarucizumab was administered before the incision in order to perform the surgery in the best coagulation conditions. The surgery was done without difficulty in hemostasis. Dabigatran plasma concentration was less than 20ng/ mL and APTT, PT and ROTEM® were in normal range. The patient no longer suffered from bleeding complications and was able to fully recover from his heart and kidney failure, without further dialysis. Finally, anatomopathological analyzes of the pericardial liquid identified a lymphoma.

Discussion

This clinical case illustrates the complexity of managing lifethreatening bleeding in a patient with high plasma concentration of dabigatran. In a prespecified analysis of the RE-LY study, the twice daily 150mg dose of dabigatran (taken by our patient) was associated with a more than 5-fold variation of plasma concentration, indicating a wide therapeutic range (median peak plasma concentrations of 184 ng/ml [10th-90th percentile 74.3-383 ng/mL) [4]. The risks of major bleeding after dosing 150mg dabigatran in patients with AF were related to trough concentrations of dabigatran [4]. As our patient did not make a mistake in taking his medication, it seems likely that other factors could have influenced his results. Indeed, significant factors influence dabigatran plasma concentrations such as age, renal function, and gender [4]. Indeed, there is a great variability in the blood concentration of dabigatran in the geriatric population, and levels above ≥243.9 ng/mL seem to be associated with a risk of bleeding [5].

Interestingly, we observed an increase in the plasma concentration of dabigatran during the first hours of hospitalization. The most likely explanation for a recurrent increase in dabigatran level, which was seen at 12 h from the admission, is redistribution of unbound dabigatran from the extravascular to the intravascular compartment [6].

Idarucizumab, a humanized monoclonal antibody fragment, has been developed for a specific reversal agent for dabigatran. Idarucizumab binds dabigatran with a high affinity and once dabigatran is complexed to idarucizumab, the anticoagulant effects of unbound and proteinbound dabigatran and its active metabolites are neutralized. In vitro and ex vivo studies have demonstrated that idarucizumab promptly restores dabigatran-prolonged coagulation parameters to baseline values [7]. In 503 patients who were receiving dabigatran, the REVERSE AD trial showed 5g idarucizumab reversed anticoagulation rapidly in more than 98% of the patients [8]. However, a single dose of 5g idarucizumab may not be sufficient to reverse the anticoagulant effects of dabigatran especially during circumstances favoring significant high concentration such as renal failure [9,10].

About 35% of dabigatran is bound to plasma protein and >80% of the drug is renally cleared; the rest is eliminated through biliary excretion [11]. The utility of RRT as a mechanism for expedited elimination of dabigatran may be an option for patients undergoing emergency surgery or in the setting of life-threatening bleeding [12,13]. Conventional dialysis is more effective, but rebounded up seem more important than with CVVH [14,15]. The extracorporeal therapy reduced the plasma concentration of dabigatran by more than 50% in 24 hours. The combination of RRT by CVVH and a second dose of 5g idarucizumab made it possible to perform the surgical intervention in good hemostasis conditions. It can be difficult to evaluate activity of dabigatran by a common coagulant test, such as INR or APTT, because may be within their normal ranges although important concentration [16]. ROTEM Clotting Time (CT) appears to be well correlated with circulating dabigatran, with the advantage of being a point-of-care and rapid response [17,18].

Conclusion

This clinical case illustrates the complexity of managing lifethreatening bleeding in a patient with very high plasma concentration of dabigatran and highlights the importance of monitoring the reversal effect of idarucizumab. A single dose may not be sufficient. Treatment should therefore be individualized.

Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

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Citation:Ego A, Lheureux O and Creteur Jacques J. Managing Life-Threatening Bleeding in Patient with High Plasma Concentration of Dabigatran with Thromboelastogram, Idarucizumab and Renal Replacement Therapy. Austin Crit Care Case Rep. 2021; 5(2): 1024.