Aging　– The Great Impact on Coagulation State –

Risk stratification for stroke and thromboembolism in patients with non-valvular atrial fibrillation (NVAF) is very important to identify those patients requiring oral anticoagulation therapy. The simplest risk assessment scheme is the CHADS₂ score.¹ Recently, the CHA₂DS₂-VASc (Congestive heart failure/left ventricular dysfunction, Hypertension, Age ≥75 [doubled], Diabetes, Stroke [doubled]-Vascular disease, Age 65–74, and Sex category [female]) score has been developed, to essentially identify “truly low risk” patients.² The CHA₂DS₂-VASc score is inclusive of the most common stroke risk factors in everyday clinical practice. The characteristics of the CHA₂DS₂-VASc score, compared with the CHADS₂ score, is that either age 65–74 or female sex is counted as 1 point risk. Age ≥75 is doubly counted as 2 points. In fact, the ESC guideline proposed that previous stroke, transient ischemic attack (TIA) or systemic embolism, and age ≥75 should be regarded as “major” risk factors, while the other 6 are “clinically relevant non-major” risk factors.² Here, I would like to discuss the impact of aging and sex category in Japanese NVAF patients.

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In the J-RHYTHM Registry, consecutive patients with AF were recruited from the outpatient clinic of each participating institution from January 2009 to July 2009.³ A total of 7,937 patients with AF (mean age, 70 years) were enrolled. Subanalysis of the J-RHYTHM Registry has demonstrated that female sex is not a risk factor for thromboembolic events in those who were treated mostly with warfarin.⁴ Subsequently, the validity of risk scoring systems excluding female sex from CHA₂DS₂-VASc was reported.⁵ What about aging? Suzuki et al⁶ performed a pooled analysis of 3,588 patients from the Shinken Database, J-RHYTHM Registry, and Fushimi AF Registry to determine the incidence rate of ischemic stroke in Japanese NVAF patients without anticoagulation therapy. Their analysis revealed that the incidence of ischemic stroke increased with age from 6.9 per 1,000 person-years in patients aged <65 years to 9.8 per 1,000 person-years in those aged 65–74 years and 24.5 per 1,000 person-years in those aged ≥75 years. The hazard ratio (HR) in patients aged ≥75 years relative to those aged <65 years was 3.37 (95% CI: 1.83–6.22). In contrast, the HR in patients aged 65–74 years relative to those aged <65 years was 1.39 (95% CI: 0.67–2.89). Based on these observations, it is conceivable to say that the risk for those aged 65–74 years is not so high, but for those aged ≥75 years it is remarkably high.

In this issue of the Journal, Ochi et al⁷ report on their study in which they measured plasma levels of D-dimer, prothrombin-fragment1+2 (F1+2), plasmin-α2 plasmin inhibitor complex (PIC), and thrombomodulin (TM) in “real-world” cardiology outpatients. D-dimer is a byproduct of the degradation of fibrin, reflecting thrombin and fibrin turnover, and is a surrogate marker for a hypercoagulable state. F1+2, which arises from in vivo cleavage of prothrombin by factor Xa, is considered to be useful for diagnosis of thrombosis. PIC is a fibrinolytic marker that directly reflects the generation of plasmin in vivo. Soluble TM is considered to be a marker of plasma endothelial damage or dysfunction marker. Ochi et al⁷ demonstrate a significant correlation between aging and the levels of F1+2, D-dimer, and PIC. In contrast, there were no sex-associated differences in these markers of coagulation and fibrinolysis. When examining the determinants of high F1+2 and PIC levels, being older than 75 years was the most important factor among the components of the CHA₂DS₂-VASc score. A schematic of the main finding is illustrated in Figure 1. When patients were divided into 3 groups by age (<65, 65–74, ≥75 years), the levels of blood markers of coagulation and fibrinolysis were increased in association with the increase in age, without difference between males and females in all age populations.

Figure 1.

Schematic of the main findings by Ochi et al.⁷ Levels of blood markers of coagulation and fibrinolysis increase in association with increasing age, without differences between males and females in any age group.

How do we practically apply the results from Ochi et al⁷ in the clinical setting? Figure 2 shows the position of each risk factor comprising CHA₂DS₂-VASc. We may distinguish each risk factor by severity and controllability. As shown, age ≥75 and previous stroke/TIA are major and uncontrollable risk factors. The study by Ochi et al⁷ is very worthwhile, because it clearly demonstrates that aging, especially age ≥75, is strongly associated with hypercoagulable states. However, Ochi et al⁷ did not enroll patients with AF. The effect of aging on coagulation states is expected to be augmented in NVAF patients. Time passes by so quickly. A 68-year-old patient will be 73-year-old after 5 years, and 78 after the next 5 years. We should keep in mind that the coagulation state of individual patients is increasing year by year.

Figure 2.

Schematic of the position of each risk factor comprising the CHA₂DS₂-VASc score. Age ≥75 and previous stroke/transient ischemic attack (TIA) are major and incontrollable risk factors.

Conflict of Interest

None.

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