Idarucizumab reverses dabigatran-induced anticoagulation in treatment of gastric bleeding:A case report

INTRODUCTION

Dabigatran is an oral direct-acting thrombin inhibitor that was initially approved by the US Food and Drug Administration for the prevention of stroke and systemic embolism caused by nonvalvular atrial fibrillation(AF)[1,2].It is considered safer and more effective than warfarin and does not require regular coagulation monitoring or dose adjustment,except for those with renal insufficiency(RI),advanced age,and low body weight[3].

However,even long-term dose-adjusted dabigatran therapy in older patients may also increase the risk of major bleeding such as the gastrointestinal(GI)hemorrhage described in this report or cerebral hemorrhage.Idarucizumab was introduced as a dabigatran antidote in December 2015,and its safety and efficacy have been proven in various studies[4];however,clinical data are still limited,especially in Asians.Here,we report a case of an older Asian woman whose coagulation function was timely and successfully restored by idarucizumab to rescue her from this life-threatening GI bleeding.

In December 1982, I had a job at a local bank. One afternoon, we were decorating the tree in the bank lobby5 and singing carols, getting ready for the Christmas season. One of my customers approached me with a sample of her handiwork: beautiful handmade dolls. She was taking orders for Christmas. I decided6 to get one for my daughter, Katie, who was almost five years old. Then I had an idea. I asked my customer if she could make me a special doll for my mother - one with gray hair and spectacles7（）: a grandmother doll.

CASE PRESENTATION

Chief complaints

On January 26,2021,a 76-year-old Asian woman was admitted to our hospital with hematemesis and melena,which she had never experienced before and began the previous day.

History of present illness

Four days prior to this reported incident,the patient experienced upper abdominal discomfort and appetite loss without any recognizable precipitating factors.

History of past illness

The patient was administered 2 U 400 mL packed red blood cells(PRBCs),a proton-pump inhibitor(PPI),and octreotide intravenously.On day 2,Hb level increased to 67 g/L and the chief complaints were nausea and retching,which appeared to be well controlled;the remaining concern was abnormal coagulation.On the next day,the patient defecated approximately 400 mL black stools with an Hb level,TT,PT and INR of 44 g/L,121.20 s,14.2 s,and 1.25,respectively and was immediately administered 2 U PRBCs.

Personal and family history

The patient had no other disease history and relevant family disease history.

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Physical examination

Idarucizumab is a humanized monoclonal antibody that specifically and efficiently inhibits the biological activity of dabigatran etexilate.After antibody-antigen binding,it irreversibly neutralizes the anticoagulant effect.The binding affinity of idarucizumab to dabigatran is 350 times higher than that of dabigatran to thrombin,and the reversal effect shows rapid onset and lasts 12 h,which is suitable for life-threatening bleeding,uncontrolled hemorrhage,or emergency surgery in patients administered dabigatran[14,15].A single dose of 5 g idarucizumab is reported to be sufficient to reverse the effect of dabigatran etexilate in 98% of patients,and the effect is maintained in most patients for 24 h[16].

Laboratory examinations

The patient had no recurrence of AF during hospitalization and her routine stool and occult blood test results were normal.Finally,she was discharged on hospitalization day 14,with Hb level of 104 g/L and TT of 17.7 s.

Imaging examinations

Computed tomography of the entire abdomen showed no obvious abnormalities and electrocardiography showed normal sinus rhythm and abnormal ST-T changes.The electronic gastroscopy showed acute erosive gastritis with extensive gastric mucosal bleeding(Figure 1).

FINAL DIAGNOSIS

Acute erosive gastritis with extensive gastric mucosal bleeding was diagnosed using an electronic gastroscope.

TREATMENT

The patient had a history of AF since 2019,and had been taking dabigatran(110 mg twice daily)to reduce her stroke risk.She had stopped taking dabigatran for at least 4 d before presenting to the hospital.In addition,she had a history of hypertension and coronary atherosclerotic heart disease for >20 years,type 2 diabetes for >5 years,and chronic RI(creatinine clearance 30-50 mL/min per 1.73 m)for 1 year.The present event occurred >12 years after she underwent surgery for bladder cancer and 7 years after thyroid nodule surgery.

Considering the extensive gastric mucosal bleeding experienced by this patient,endoscopic hemostasis was less efficient.The conventional therapeutic regimen of acid suppression,hemostasis,and blood transfusion did not achieve hemostasis in this patient and idarucizumab was administered to reverse the effect of dabigatran to rescue her from the second episode of life-threatening bleeding.Subsequently,the patient,whose coagulation function was normalized during hospitalization,was relieved of the symptoms of hematemesis and melena,and her Hb level increased to 104 g/L on day 14.Finally,the patient was discharged in stable conditions.

OUTCOME AND FOLLOW-UP

The routine blood tests of the patient showed a white blood cell count of 6890/μL and hemoglobin(Hb)level of 41 g/dL.The coagulation function test showed the following results: thrombin time(TT)>180 s;activated partial thromboplastin time,36.2 s;and international normalized ratio(INR),1.20.The biochemical parameters of the patient were as follows:Albumin,34.6 g/L;blood urea nitrogen,26.96 mmol/L;and serum creatinine,251.0 μmol/L(Table 1).The tumor markers -fetoprotein,carcinoembryonic antigen,cancer antigen(CA)199,and CA125 were all within the normal range.TheC urea breath test for detection of()was negative.

DISCUSSION

The authors have read the CARE Checklist(2016),and the manuscript was prepared and revised according to the CARE Checklist(2016).

When Friday arrived, we could hardly contain ourselves. After lunch, when we saw the delivery truck coming, we told “our family” about the surprise. It was like watching ecstatic children on Christmas morning.

But the young man told her all his sad tale, and how he possessed5 a wonderful snuff-box, and how it had been stolen from him, and how he had nothing left, now that he was parted from his wife and was in need of everything

Nevertheless,the elimination of dabigatran is highly dependent on the kidney,through which approximately 85% of plasma dabigatran is excreted,and the process can be prolonged with RI[7].The RE-LY study demonstrated that dabigatran could reduce all-cause mortality and intracranial hemorrhage,but increased GI bleeding compared with warfarin.The risk of dabigatran-related GI bleeding seems to be evenly distributed between the upper and lower canals(53%47%),whereaswarfarin-related upper canal bleeding dominated(75%25%).

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The mechanism by which bleeding is induced remains unclear.One possible theory suggests that the local metabolism of dabigatran etexilate increases the concentration of active dabigatran during transit through the GI tract8,9.Dabigatran-induced GI hemorrhage is also related to age and primarily occurs in patients aged ≥ 75 years.[10]

infection,liver cirrhosis,malignant tumors,genetic factors,history of major bleeding,peptic ulcers,and GI injury such as diverticulosis and intestinal vascular dysplasia can also increase the risk of bleeding11,12.A study showed that coadministration of a PPI and dabigatran not only markedly reduced the risk of upper GI hemorrhage,but also the dabigatran plasma levels in patients with AF[13].

In this case report,the patient was a 76-year-old Asian woman with a history of AF and concealed progressive RI.She had undergone long-term dabigatran therapy with dose adjustments for 1 year,regular blood coagulation function monitoring,and oral administration of a PPI.The massive hemorrhage from the gastric mucosa was likely induced by prolonged dabigatran excretion because of RI.

On arrival at the ward,the temperature,heart rate,respiratory rate,and blood pressure of the patient were 36.3 °C,90 bpm,18 breaths/min,and 105/80 mmHg,respectively.Her palpebral conjunctiva and complexion were pale,abdomen was soft,and middle and upper abdomen showed slight tenderness.In addition,the bowel sounds of the patient were 6/min.

Single doses of idarucizumab(2.5 g)were administered twiceintravenous infusion to reverse the effect of dabigatran,and the related commonly encountered adverse reactions such as fever,headache,hypokalemia,and delirium were not observed.Twelve hours later,the TT of the patient was 17.4 s,which was within the normal range.On day 4,she was administered an additional 2 U PRBCs for the third time,without symptoms of hematemesis and melena on the following days.

This study had the following limitations and shortcomings that are worth mentioning.(1)The serum level of dabigatran was not measured because of restricted laboratory conditions;(2)Colonoscopy was not performed because we could not obtain informed consent from the patient;and(3)We were unable to detect any possible intracardiac thrombus caused by AF because the transesophageal echocardiography technique was unavailable.

CONCLUSION

We report a case of safe and successful reversal of dabigatran-induced abnormal coagulation function by idarucizumab.In addition,we provide evidence to support recommendations for regular renal and coagulation function tests and dabigatran concentration monitoring for older patients where clinical conditions permit.This is to ensure that proper dose adjustments of dabigatran are instituted or the drug discontinuation is timely if unpredictable blood loss occurs.As mentioned in the discussion regarding dabigatran-induced GI-bleeding-related factors,especiallyinfection,there is currently no consensus on the benefits of coadministration of PPIs with dabigatran,which warrants further investigation.

ACKNOWLEDGMENTS

We would like to thank the attending physician Zhu Y and deputy chief physician Wang SH for their strong support for the publication of the manuscript.

FOOTNOTES

Jia Y and Zhu Y wrote and modified the manuscript;Wang SH performed the gastroscopy,confirmed the report,and provided the figures;Wang W and Li X collected the data;Cui N participated in the patient treatment;Zhu Y and Liu QX connected us to the pharmaceutical factory and purchased the idarucizumab;Gu YM and Wang SH reviewed the paper and provided suggestions for the revision;all authors have read and approved the final manuscript.

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All study participants,or their legal guardian,provided informed written consent prior to study enrollment.

We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted.

In this study,we presented the case of an older Asian woman whose coagulation function was effectively restored using idarucizumab to reverse the life-threatening GI bleeding experienced following administration of dabigatran.The prodrug of dabigatran,dabigatran etexilate,is rapidly converted to its active form following oral administration.It is an oral non-vitamin K antagonist anticoagulant that acts as a direct reversible and competitive inhibitor of both free and platelet-bound thrombin,thereby affecting the final step of blood clotting[5].Because of properties such as a short halflife,rapid onset of action,fewer effects on food and drugs,and no INR monitoring requirement[6],dabigatran is deemed a safer and more effective medicine for preventing stroke than some other available agents.

That night the boss came home to his 14-year-old son and sat him down. He said, The most incredible thing happened to me today. I was in my office and one of the junior executives came in and told me he admired me and gave me a blue ribbon for being a creative genius. Imagine. He thinks I m a creative genius. Then he put this blue ribbon that says Who I Am Makes A Difference on my jacket above my heart. He gave me an extra ribbon and asked me to find somebody else to honor. As I was driving home tonight, I started thinking about whom I would honor with this ribbon and I thought about you. I want to honor you.

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China

Yu Jia 0000-0002-1743-4943;Shao-Hua Wang 0000-0002-9085-5218;Na-Juan Cui 0000-0002-7867-6153;Quan-Xi Liu 0000-0002-6526-2840;Wei Wang 0000-0001-5057-5433;Xue Li 0000-0001-8880-1133;Ya-Mei Gu 0000-0001-7173-1183;Yan Zhu 0000-0001-5906-1412.

Wu YXJ

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Why did he cherish her portrait while he was so fatally indifferent to herself? At last she found an opportunity of asking him the name of the Princess whose picture he carried about with him always

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Wu YXJ