Idarucizumab for the Reversal of Dabigatran-induced Anticoagulation in the Treatment of Gastric Bleeding: a Case Report


 BACKGROUND:The drug instruction for dabigatran recommends the does adjustment 110 mg twice-a-day for the patient with bleeding risk, and at least 1 time of renal function test per year for moderate renal impairment. However, dabigatran still can be abnormal accumulation due to the chronic insidiously progressive renal insufficiency, which requiring idarucizumab to reverse the anticoagulation on account of acute erosive gastritis with extensive gastric mucosal bleeding.CASE SUMMARY: A 76-year-old female, with a history of Atrial Fibrillation (AF), took dabigatran 110 mg twice-a-day as recommended does adjustment to reduce the risk of stroke, and admitted to the hospital for the main complaints of hematemesis and melena. The laboratory findings showed severe life-threatening blood-loss anemia with hemoglobin (Hb) 41.0g/L, and significant coagulation abnormalities with thrombin time (TT) > 180s, most likely caused by dabigatran metabolic disorder. Aggressive acid suppressive, hemostatic and blood transfusion therapy brought out a short-time bleed-controlled misconception, which situation was exactly confirmed by re-bleeding. Idarucizumab was given timely to reverse the anticoagulation effect of dabigatran. 12 hours later, TT was tested as 17.4s which belonged to the normal range. Finally, she had no active bleeding signs, with labs showing Hb 104g/L and TT 17.7s.CONCLUSION:It is recommended to monitor renal function regularly, even coagulation function and dabigatran concentration, for the elder. There is at present no general agreement on the use of Proton Pump Inhibitor (PPI)–dabigatran coadministration to prevent upper gastrointestinal bleeding.


Introduction
Dabigatran is an oral direct thrombin inhibitor, initially approved by the Food and Drug Administration to prevent stroke and systemic embolism caused by non-valvular Atrial Fibrillation. [2] It is considered to be safer and more effective than warfarin, and no need for regular coagulation monitoring or dose adjustment, except for renal insu ciency (RI), advanced age and low body weight. [3] However, a longterm, even does adjustment, dabigatran therapy (DT) for the elder may also increases the risk of major bleeding, such as gastrointestinal hemorrhage described in this report or cerebral hemorrhage.
Idarucizumab, as a dabigatran antidote, was introduced in December 2015, of which safety and effectiveness have been proved in various experimental projects, [4] but the clinical data is still limited especially for Asians. This article reports a case that an elder Asian woman's coagulation function is timely and successfully reversed by idarucizumab to rescue a deadly gastric bleeding.

Case Presentation
Chief complaints On January 26 2021, a 76-year-old Asian female was admitted to our hospital because of hematemesis and melena, which symptoms never happened before and began in the past day.

History of present illness
Four days ago, she just felt upper abdominal discomfort and appetite loss without any recognizable precipitating factors.

History of past illness
She had a medical history of AF since 2019, and then dabigatran (110 mg twice daily) was given to reduce the stroke risk. She had stopped taking dabigatran at least for 4 days before sent to the hospital.
Apart from that, she had the history of hypertension and coronary atherosclerotic heart disease for more than 20 years, type 2 diabetes for more than 5 years, and chronic renal insu ciency (creatinine clearance 30-50 mL/min/1.73) for 1 year. It is more than 12 years after surgery for bladder cancer and 7 years after thyroid nodule surgery.

Physical examination
When arriving at the ward, the patient's temperature was 36.3°C, heart rate was 90 bpm, respiratory rate was 18 breaths per minute, blood pressure was 105/80 mmHg. Her palpebral conjunctiva and complexion were pale. The abdomen was soft and tenderness in the middle and upper abdomen was weakly positive.
Bowel sounds was 6 times/min.

Imaging examinations
No obvious abnormalities on computed tomography (CT) scan of the whole abdomen. The electrocardiogram (ECG) showed sinus rhythm, ST-T changes. Electronic gastroscope was made to show acute erosive gastritis with extensive gastric mucosal bleeding (Fig. 1).

FINAL DIAGNOSIS
Acute erosive gastritis with extensive gastric mucosal bleeding was made according to the electronic gastroscope.
TREATMENT Two units of packed red blood cells (PRBC) 400ml, PPI, and octreotide were administered intravenously.
On the 2ed day, The Hb rose to 67g/L and the chief complaints were nausea and retching, which condition appeared to be well controlled except the remaining concern about the abnormal coagulation.

Discussion
The prodrug of dabigatran -dabigatran etexilate, rapidly converted into its active form via per os, is a kind of non-vitamin K antagonist oral anticoagulant, acting as a direct reversible and competitive inhibitor for both free and platelet-bound thrombin, thereby affecting the nal step of blood clotting. [5] Since its short half-life, rapid onset of action, less effect on food and drugs, and no need to monitor the INR, etc. [6] , it is deemed to be a type of safer and more effective medicine to prevent stroke. Nevertheless, Dabigatran's elimination is highly dependent on the kidney function; about eighty-ve percent of plasma dabigatran is excreted through the kidneys, 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 gastrointestinal (GI) bleeding compared with warfarin. The risk of dabigatran-related GI bleeding seems to be evenly distributed between the upper and the lower canals (53 vs. 47%); whereas warfarin-related the upper dominated (75 vs. 25%). The mechanism of its bleeding remains unclear; one possible theory, as noted that local metabolism of dabigatran etexilate leads to an increase in active dabigatran concentrations during transit through the GI tract. [8,9] Dabigatran-induced GI hemorrhage is also related to the age, which chie y occurs among patients aged 75 years and older. [10] Helicobacter pylori (Hp) infection, liver cirrhosis, malignant tumors, genetic factors, and history of major bleeding, of peptic ulcer or of GI injury, such as diverticulosis and intestinal vascular dysplasia can also increase the risk of bleeding. [11,12] As the study shows PPI-dabigatran coadministration can not only signi cantly reduce the risk of upper GI hemorrhage, but also the dabigatran plasma levels in patients with AF. [13] The patient, in this case report, a 76-year-old Asian woman, has a history of AF and concealed progressive RI, with a long-term does-adjustment DT for one year, short of regular blood coagulation function monitoring and orally administered PPI. The massive hemorrhage from the gastric mucosal was likely affected by prolonged dabigatran excretion resulting from RI.
Idarucizumab is a sort of humanized monoclonal antibody that speci cally and e ciently inhibits the biological activity of dabigatran etexilate. After antibody-antigen binding, it neutralizes the anticoagulant effect irreversibly. The binding a nity of idarucizumab-dabigatran is 350 times higher than that of dabigatran-thrombin, and the reversal consequence shows a rapid onset and lasts for 12 hours, of which are suitable for life-threatening bleeding, uncontrolled hemorrhage, or emergency surgery of the patients with dabigatran. [14,15] It has been reported that a single dose of 5g idarucizumab for 98% of patients is su cient to reverse the effect of dabigatran etexilate, and most patients can maintain 24 hours. [16] Considering the extensive gastric mucosal bleeding, endoscopic hemostasis was less e cacious for her. The conventional therapy of acid suppressive, hemostatic and blood transfusion did not achieve hemostasis, and then idarucizumab was given to reverse the effect of dabigatran for rescuing the 2ed time life-threatening bleeding. Since then, the patient, whose coagulation function became normal during hospitalization, was deprived of the symptoms of hematemesis and melena, with Hb growing to 104g/L on the 14th day. Finally, she was discharged in a stable condition.

Conclusions
The purpose of this present paper is to report a case about idarucizumab's safe and successful reverse of dabigatran-induced abnormal coagulation function, and to make recommendations on regular renal function test, even coagulation function and dabigatran concentration monitor if clinical conditions permit, for the elder, so as to make proper dose adjustments or stop taking dabigatran in time, in case of producing unpredictable blood loss result. As discussed above on the dabigatran-induced gastrointestinal bleeding related factors, especially for the Hp infection, there is at present no general agreement on the use of PPI-dabigatran coadministration, and this issue warrants further investigation.
There still exits several limitations and shortcomings as follows: 1.the dabigatran's serum level is not measured due to restricted conditions in the laboratory; 2. the colonoscopy is undo resulting from the failure to obtain informed consent; 3. whether occurs intracardiac thrombus caused by AF is not observed because of the unavailable transesophageal echocardiography technic. Informed consent was obtained from the patient for the procedures.

List Of Abbreviations
-Consent for publication Written informed consent for publication was obtained from all participants.
-Availability of supporting data All data are fully available without restriction.

-Competing interests
There are no con icts of interests to declare. -Funding This manuscript is not under consideration elsewhere.
-Authors' contributions Yu Jia and Yan Zhu wrote and modi ed the manuscript. Shao-Hua Wang performed the Gastroscope operation, con rmed the report and provided the gure. Wei Wang and Xue Li collected the data. Na-Juan Cui participated in the therapy. Yan Zhu and Quan-Xi Liu helped connect the pharmaceutical factory and purchased the Idarucizumab. Ya-Mei Gu and Shao-Hua Wang reviewed the paper and put forward suggestions for revising. -Acknowledgements Not applicable -Supportive foundation acknowledgment This work receives no nancial support from any source.