Thrombocytopenia induced by dabigatran: two case reports

Abstract

Background: Vitamin K inhibitors (e.g. warfarin) and indirect thrombin inhibitors (e.g. heparin) are widely used to prevent thromboembolic disorders (e.g. myocardial infarction, venous thromboembolism, and stroke). These agents have been mainstays of anticoagulation for people older than 60 years. However, their administration is associated with a risk of bleeding and requires careful monitoring of patients. Novel oral anticoagulants (NOACs), such as dabigatran, are significantly safer in preventing thromboembolism than warfarin and heparin (sporadically causes thrombocytopenia) and are more specific for their target protein, thrombin. The major advantage of dabigatran, a direct thrombin inhibitor, is that it reversibly inhibits both free and clot-bound thrombin by tight binding affinity and the predictable pharmacodynamic effect. A few studies, however, reported that dabigatran can cause thrombocytopenia, although the underlying mechanism remains unclear. Thus, an antidote for dabigatran was developed to prevent thrombocytopenia.

Case presentation: In this report, we discuss two cases of thrombocytopenia and purpura after dabigatran treatment. A 73-year-old man showed hemorrhagic necrotic skin lesions on his neck and right hand. He was administered dabigatran (220 mg/day) for cerebral infarction for three days and his platelet count decreased abruptly (6000/μL). This suggested that dabigatran had caused thrombocytopenia and purpura; therefore, dabigatran administration was discontinued. The results of a blood test, performed 14 days after stopping dabigatran treatment, showed that the platelet count had recovered to the normal range of more than 150,000/μL. A 75-year-old woman had taken warfarin continuously for 8 years. However, she had a new cerebral infarction. Therefore, warfarin treatment was replaced with dabigatran (300 mg/day). Her platelet count decreased (41,000/μL) significantly and dabigatran treatment was discontinued. The blood test results show that platelet counts gradually recovered to the normal range.

Conclusions: Dabigatran application may cause bleeding; therefore, careful monitoring during dabigatran treatment is required to prevent thrombocytopenia. An explanation is that the interaction of dabigatran with thrombin, because of its strong binding affinity, may cause the observed thrombocytopenia.

Keywords: Dabigatran; Factor Xa inhibitor; Thrombin inhibitor; Thrombocytopenia.

Fig. 1

Bruising and multiple petechiae on the patient’s right hand (a) and chin (b) in patient 1 after 14 days treatment of dabigatran

Fig. 2

Course of thrombocytopenia caused by dabigatran in patient 1 and 2. Platelet counts were gradually recovered after discontinuation of dabigatran

Fig. 3

Active sites of (a) Dabigatran-thrombin (PDB accession: 4YHI) and (b) Apixaban-factor Xa (PDB accession: 2P16). These inhibitors generate specific interactions to their target enzymes to prevent anti-coagulation. The hydrophobic and hydrophobic pharmacophores interact to their target enzymes. Blue, red, and gray represent the nitrogen, oxygen, and carbon atoms