血漿プロトロンビンフラグメント1＋2濃度測定によるワルファリンや非ビタミンK拮抗経口抗凝固薬療法中の抗凝固作用の評価に関する検討

Measurement of Prothrombin Fragment 1＋2 for the Assessment of Anticoagulant Activity in Patients Treated with Warfarin or Non-vitamin K Antagonist Oral Anticoagulant

プロトロンビンフラグメント1＋2（PF1＋2）は鋭敏な凝固系分子マーカーである。ワルファリンや非ビタミンK拮抗経口抗凝固薬（NOAC）療法例で血漿中のPF1＋2値を測定し，それぞれの抗凝固作用を評価した。脳梗塞の二次予防を目的に経口抗凝固療法を受けている28例（77±6歳，男性比61％）を対象に，血漿中のPF1＋2値を測定した。ワルファリン療法群では血漿プロトロンビン時間（PT-INR）を同時に測定した。その結果，ワルファリン療法群ではPT-INR中央値は1.96［四分位範囲（IQR）1.8〜2.1］，PF1＋2中央値は111（IQR 95〜141）であった。そのPF1＋2値は5例12回（17％）で正常下限未満を呈し，そのうち3例8回はPT-INR 2.5未満で観察され，1例で脳出血を発症した。ワルファリン療法群でPF1＋2の正常上限を上回る症例は観察されなかった。NOAC療法群ではPF1＋2の中央値は116（IQR 99〜147）であり，いずれのNOACでもPF1＋2の正常下限を下回る症例は観察されなかった。NOAC療法群でPF1＋2の正常上限を上回る症例は3例3回（1.9％）で観察された。ワルファリン療法群では，17％でトロンビンを過剰に抑制していた。一方で，NOAC療法群ではトロンビンの過剰な抑制はみられなかった。

Abstract

【Background and purpose】Prothrombin fragment 1＋2 (PF1＋2) is a sensitive marker for blood coagulation system. In order to evaluate anticoagulant activity in patients treated with warfarin or non-vitamin K antagonist oral anticoagulant (NOAC), we measured plasma levels of PF1＋2 and evaluated anticoagulant activity by each anticoagulant agent.【Methods】Subjects were 28 patients, 17 men and 11 women, 77±6 year old, with oral anticoagulant therapy for secondary prevention of stroke. We measured plasma levels of PF1＋2 in 70 times in 7 patients treated with warfarin, and 154 times in 27 patients treated with NOAC. PT-INR was simultaneously measured in patients treated with warfarin.【Results】In warfarin treatment groups, PT-INR values were median 1.96 (IQR 1.8-2.1) and PF1＋2 levels were median 111 pmol/l (IQR 95-141). All PF1＋2 levels were below the upper limit of normal range, but 12 values (17%) of them in 5 patients were below the lower limit of normal range. 8 of the 12 values were at PT-INR below 2.5, and 1 of whom developed intracerebral hemorrhage. Plasma levels of PF1＋2 in patients treated with dabigatran 150mg BID, dabigatran 110mg BID, rivaroxaban 15mg QD, rivaroxaban 10mg QD, apixaban 5mg BID, apixaban 2.5mg BID, and edxaban 30mg QD were median 116 pmol/l (IQR 99-136), 132 pmol/l (IQR 99-162), 109 pmol/l (IQR 100-125), 133 pmol/l (IQR 100-177), 88 pmol/l (IQR 76-102), 148 pmol/l (IQR 93-167), 221 pmol/l (IQR 208-234). They were all above the lower limit of the normal range, 3 of which were above the upper limit of the normal range. Excessive suppression of thrombin production was more frequently seen in warfarin treatment than in NOAC treatment (p＜0.05).【Conclusion】In warfarin treatment, thrombin production was suppressed excessively in 17%, although it was not in NOAC treatment.

(Received September 21, 2016; Accepted December 26, 2016; Published May 1, 2017)