Short‐Term Cessation of Dabigatran Causes a Paradoxical Prothrombotic State

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. ANN NEUROL 2021;89:444–458

Relation of Pre‐Stroke Aspirin Use With Cerebral Infarct Volume and Functional Outcomes

“…Antiplatelet therapy is known to preferentially reduce the incidence of LAA stroke rather than CE or SVO stroke. 45 Yet, previous research has shown that platelet activation plays important roles in CE as well as in LAA stroke, 46,47 which may accord with results on aspirin-related lower thrombus burden (as was also demonstrated in our recent preclinical study on carotid artery thrombosis 48 ) and less frequent early neurological deterioration in CE stroke. On the other hand, platelet activation appears to be less important in SVO stroke, which mainly results from chronic hypertension-mediated lipohyalinosis of small arterioles.…”

Towards a biomarker for acute arterial thrombosis using complete blood count and white blood cell differential parameters in mice

“…Mice were anesthetized with an induction chamber using 2 ~ 2.5% isoflurane mixed with 30% oxygen (1.5 L/min), and in situ carotid thrombus was formed (n = 72) by an experienced researcher (J. Kim), as has been previously reported 37,38 , by applying a strip of 1 × 1 mm 2 filter paper (grade 42; Whatman, Oxon, UK) soaked in 4 μL 10% FeCl 3 to the left common carotid artery (CCA) for 10 min after exposing the vessel by a midline neck incision and dissection of the perivascular tissue. We previously demonstrated that similar-sized carotid thrombi can be consistently generated at the hands of a skillful researcher 39 . In sham-operated animals (n = 79), the left CCA was exposed to saline-soaked filter paper for 10 min.…”

Factors Associated with Platelet Activation-Recent Pharmaceutical Approaches

“…This platelet inhibitory effect appears to be dose-dependent [ 166 ]. Interestingly, cessation of dabigatran may induce a state of platelet activation [ 167 ]. Those antiplatelet effects have also been proposed for the factor Xa inhibitors [ 168 ].…”