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Short-Term Cessation of Dabigatran Causes a Paradoxical Prothrombotic State

Authors
 Jiwon Kim  ;  Hee Jeong Jang  ;  Dawid Schellingerhout  ;  Su-Kyoung Lee  ;  Ha Kim  ;  Young Dae Kim  ;  Kyung-Yul Lee  ;  Hye-Yeon Choi  ;  Han-Jin Cho  ;  Seong-Soo Jang  ;  Sangmin Jeon  ;  Ick Chan Kwon  ;  Kwangmeyung Kim  ;  Wi-Sun Ryu  ;  Matthias Nahrendorf  ;  Seungbum Choi  ;  Dong-Eog Kim 
Citation
 ANNALS OF NEUROLOGY, Vol.89(3) : 444-458, 2021-03 
Journal Title
ANNALS OF NEUROLOGY
ISSN
 0364-5134 
Issue Date
2021-03
Keywords
Aged ; Aged, 80 and over ; Animals ; Antithrombins / adverse effects* ; Antithrombins / pharmacology ; Arachidonic Acid / blood ; Aspirin / pharmacology ; Carotid Artery Thrombosis / chemically induced ; Carotid Artery Thrombosis / diagnostic imaging* ; Carotid Artery Thrombosis / prevention & control ; Cerebral Infarction / diagnostic imaging ; Cerebral Infarction / etiology ; Cerebral Infarction / physiopathology ; Cerebral Infarction / prevention & control ; Chlorides / toxicity ; Computed Tomography Angiography ; Dabigatran / adverse effects* ; Dabigatran / pharmacology ; Deprescriptions* ; Factor Xa Inhibitors / adverse effects ; Female ; Ferric Compounds / toxicity ; Humans ; Ischemic Stroke / diagnostic imaging ; Ischemic Stroke / etiology ; Ischemic Stroke / physiopathology ; Ischemic Stroke / prevention & control ; Magnetic Resonance Angiography ; Male ; Mean Platelet Volume ; Mice ; Noxae / toxicity ; Pilot Projects ; Platelet Aggregation / drug effects* ; Platelet Aggregation Inhibitors / pharmacology ; Platelet Count ; Pyrazoles / adverse effects ; Pyridones / adverse effects ; Rivaroxaban / adverse effects ; Severity of Illness Index ; Substance Withdrawal Syndrome / blood* ; Substance Withdrawal Syndrome / etiology ; Substance Withdrawal Syndrome / prevention & control ; Thrombin / metabolism ; Thrombophilia / blood* ; Thrombophilia / etiology ; Thrombophilia / prevention & control ; X-Ray Microtomography
Abstract
Objective: It is unclear if stopping treatment with dabigatran, a new oral anticoagulant (NOAC), induces a paradoxical rebound prothrombotic state. We investigated if short-term (1-3 days) dabigatran cessation is associated with a higher thrombus volume than expected from a simple reversal of the anticoagulant effect.

Methods: Ten-week-old C57Bl/6 mice (n = 338) received one of the following oral treatments: phosphate-buffered saline (PBS), dabigatran for 7 days with or without 1 to 4 day cessation, and aspirin in either a single dose or daily for 7 days. Some of the animals that ceased dabigatran for 1 to 3 days received single-dose aspirin. Thereafter, we induced FeCl3 -mediated carotid thrombosis in 130 mice, after which we performed micro computed tomography thrombus imaging. The other 208 mice underwent coagulation assays or platelet function tests. As an explorative pilot study, we reviewed the medical records of 18 consecutive patients with NOAC cessation-related cerebral infarction in a large acute stroke cohort.

Results: We observed a ~ 40% higher volume of carotid thrombus after dabigatran cessation at 1 to 3 days than after vehicle treatment and showed that this effect could be prevented by single-dose aspirin pretreatment. Dabigatran cessation unduly increased platelet aggregability for 2 days after drug cessation, an effect mediated through thrombin or arachidonic acid, which effect was significantly attenuated by single-dose aspirin pretreatment. In patients, short-term (≤ 3 days) cessation of NOAC therapy, compared with longer-term (≥ 5 days) cessation, tended to be associated with relatively high stroke severity.

Interpretation: We provide the first preclinical evidence that a rebound prothrombotic state follows short-term cessation of dabigatran therapy.
Full Text
https://onlinelibrary.wiley.com/doi/10.1002/ana.25964
DOI
10.1002/ana.25964
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Neurology (신경과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Young Dae(김영대) ORCID logo https://orcid.org/0000-0001-5750-2616
Lee, Kyung Yul(이경열) ORCID logo https://orcid.org/0000-0001-5585-7739
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/185385
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