Thrombus formation varies according to the type of drug

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Researchers in Japan examined several types of anticoagulants and found that the rates of thrombus formation are different according to the type of drug, which may link to the risk of side effects, especially intracranial bleeding.

Atrial fibrillation is an arrhythmia signified by rapid and irregular beating of the upper chambers of the heart (atria). Anticoagulant therapy is recommended for atrial fibrillation because thrombi formed by stagnated blood in the atrium can cause stroke. In addition to the conventional anticoagulant warfarin, direct oral anticoagulants (DOACs) have become widely used. DOACs can selectively inhibit coagulation factors, whereas warfarin cannot.

Anticoagulants, however, can cause bleeding complications as a side effect. Care should be taken to avoid intracranial bleeding in particular since it can cause severe neurological dysfunction. Fortunately, DOACs are known to have less incidence of intracranial bleeding and fewer incidents of haematoma than warfarin. Although the DOAC mechanisms responsible for reduced intracranial bleeding compared to warfarin have been investigated in animal experiments, they have not yet been fully elucidated.

To clarify these mechanisms, researchers from Kumamoto University, Japan used a Total Thrombus-Formation Analysis System (T-TAS) to analyse on- and off-treatment blood samples from 120 patients who underwent catheter ablation for atrial fibrillation and who were taking warfarin or DOACs. The T-TAS is a device that can monitor thrombus formation by using a microchip mimicking blood vessels, a pump that circulates collected blood, a pressure sensor, and a video microscope. The characteristic features of this device are that it only requires a small blood sample volume (500 ?L) for analysis and that collected blood can be measured easily without any complicated pretreatment. With the T-TAS, it is possible to observe the thrombus formation as the blood flows into the obstructed-blood-vessel microchip model, and quantitatively evaluate the speed and volume of thrombus formation.

Twenty-nine patients were treated with warfarin, 19 with dabigatran, 47 with rivaroxaban, and 25 with apixaban; the latter three being DOACs. The T-TAS analysis showed that the level of anticoagulation for patients on-treatment decreased by the same degree in all groups compared to those off-treatment, indicating that all of the anticoagulants were working sufficiently.

However, when observing thrombus formation over time with a microscope, the researchers found that thrombi adhering to the wall of the obstructed-blood-vessel microchip thickened earlier in the rivaroxaban and apixaban groups compared to those in the warfarin group. These DOACs can prevent stroke as well as warfarin. However, this observation suggests that DOACs may promptly form thrombi at the site of a vessel injury should one occur.

“We found that thrombus formation varies according to the type of drug even though the final anticoagulant effect is similar between warfarin and DOACs,” said study leaders, Dr Masanobu Ishii, and Associate Professor Koichi Kaikita of Kumamoto University. “Our work may help to clarify the differential mechanism between warfarin and DOACs for the prevention of intracranial bleeding. In the future, we hope our research can be used to effectively select medicines that suppress anticoagulant side effects.”

Abstract
Direct oral anticoagulants (DOACs) have low risk of intracranial hemorrhage compared to warfarin. We sought to clarify the different mechanisms responsible for suppression of bleeding events using the Total Thrombus-formation Analysis System (T-TAS), a flow-microchip chamber with thrombogenic surfaces. Blood samples were obtained at Off- and On-anticoagulant (trough) from 120 consecutive patients with atrial fibrillation (warfarin; n = 29, dabigatran; n = 19, rivaroxaban; n = 47, apixaban; n = 25), which were used for T-TAS to compute the area under the curve (AUC) (AR10-AUC30) in the AR chip, and to measure plasma concentrations of DOACs at On-anticoagulant. In addition, the two-dimensional area covered by thrombi (%) in the capillary was analyzed every 3 minutes after sample applications. The AR10-AUC30 correlated weakly and negatively with plasma concentrations of DOACs, and the levels at On-anticoagulant were lower in all groups than at Off-anticoagulant. AR10-AUC30 levels at Off- and On-anticoagulant were identical among the groups. The thrombi areas in early phase were significantly larger in rivaroxaban and apixaban than warfarin and dabigatran groups. The findings suggested that visual analysis of the AR-chip can identify the differential inhibitory patterns of warfarin and DOACs on thrombus formation under flow condition.

Authors
Masanobu Ishii, Koichi Kaikita, Miwa Ito, Daisuke Sueta, Yuichiro Arima, Seiji Takashio, Yasuhiro Izumiya, Eiichiro Yamamoto, Megumi Yamamuro, Sunao Kojima, Seiji Hokimoto, Hiroshige Yamabe, Hisao Ogawa, Kenichi Tsujita

Kumamoto University material
Scientific Reports


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