The clinical spectrum of intracranial hemorrhage is similar

The clinical spectrum of intracranial hemorrhage is similar for patients treated with warfarin and dabigatran [10]. Absolute rates of intracranial hemorrhage across all sites and of both fatal and traumatic intracranial hemorrhages are lower with dabigatran than with warfarin [10]. Concomitant aspirin use is the most important modifiable independent risk factor for intracranial hemorrhage. In a recent report, patients with atrial fibrillation who were at risk for stroke and were aged less than 75 years showed a lower incidence of intracranial and extracranial bleeding when treated with dabigatran than when treated with warfarin [15]. In patients aged 75 years or more, compared to warfarin treatment, dabigatran treatment was associated with lower risk of intracranial bleeding risk but similar or higher risk of extracranial bleeding [15]. Bleeding risk increased with age and degree of renal dysfunction, was inversely related to body weight, and increased with concomitant administration of antiplatelet therapy [15]. Caution is, therefore, required when administering anticoagulants to a patient who is aged 75 years or older or has low body weight or renal dysfunction or if the patient is concomitantly administered antiplatelets. A new bleeding risk index, called HAS-BLED, which is scored from to 9 for several factors, namely, hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly age (>65 years), and concomitant drug/alcohol use, has been proposed for NVAF patients [16]. This simple score provides a practical tool to assess the individual bleeding risk of an NVAF patient and can potentially support decision-making regarding antithrombotic therapy. The incidence of major bleeding was reported as 3.74%/year or more in patients with a HAS-BLED score of 3 or more, indicating that reference 4 attention should be given to major bleeding in these patients [16].
Intracranial bleeding Compared to warfarin, dabigatran, rivaroxaban, and apixaban have a much lower risk of inducing intracranial hemorrhage [2–4]. Intracranial bleeding during anticoagulation is often devastating, and the lower risk associated with these novel anticoagulants is, therefore, beneficial for patients requiring anticoagulation. The lower risk of intracranial bleeding with the novel anticoagulants may be explained on the basis of the tissue factor and VIIa complex formation, the first reaction in the coagulation cascade (Fig. 5). The concentration of tissue factor in the brain is same as that in the lungs and placenta and higher than that in other parts of the body [17]. However, warfarin suppresses vitamin K-dependent carboxylation of coagulation factor VII, resulting in low concentrations of VIIa and low production of tissue factor and VIIa complex. Thus, it is difficult for the coagulation cascade to start and for bleeding to stop.
Intermittent anticoagulation The plasma concentrations of the novel anticoagulants vary over the course of a day, with 1 or 2 peaks and troughs in their concentration vs. time curves [1–4]. In the peak phases, coagulation is suppressed by direct inhibition of thrombin or factor Xa. However, in the trough phases, it seems that the coagulation cascade is not fully inhibited. One potential explanation for the lack of thrombus formation during the trough phase is the presence of physiological coagulation inhibitors, such as antithrombin, protein C, and protein S, tissue factor pathway inhibitor, and the fibrinolytic system, which would suppress thrombus formation if they are active during the trough phase (Figs. 5 and 6). Continuous activation of thrombin may reduce the activity of physiological coagulation inhibitors and the fibrinolytic system by exhausting factors related to coagulation. Intermittent anticoagulation induced by the novel anticoagulants, as well as continuous anticoagulation induced by warfarin, is thought to suppress the continuous activation of thrombin, thus preventing thrombus formation in the cardiovascular system.