Hatzinikolaou-Kotsakou Eleni, Kartasis Zarifis, Tziakas Dimitrios, Hotidis Athanasios, Stakos Dimitrios, Tsatalas Konstantinos, Bourikas Georgios, Kotsakou Maria E, Hatseras Dimitrios I
Academic Cardiology Department, Demokritious University of Thrace, Greece.
J Thromb Thrombolysis. 2003 Dec;16(3):155-61. doi: 10.1023/B:THRO.0000024053.45693.fc.
It is well known that atrial fibrillation is associated with high incidence of thromboembolic events, propably due to a prothrombotic or hypercoagulable state. However, it is unclear whether or not there is any difference of this prothrombotic state in the clinical subgroups of atrial fibrillation patients, that is, in those with paroxysmal, persistent or permanent atrial fibrillation. From the other side the role of the arrhythmia duration on the changes of coagulative variables in atrial fibrillation patients is not clearly enough. The contribution of genetic and functional alterations in factors of the coagulation and fibrinolytic pathways (that is hemostatic risk factors) to the development of hypercoagulation state in atrial fibrillation requires clarification. We investigated therefore (1) if there are differences in the prothrombotic state between patients with different clinical status of the arrhythmia, (2) if the arrhythmia duration per se could be an independent determinant of the prothrombotic state in all atrial fibrillation patients and (3) if coexistent genetic alterations in haemostatic risk factors in patients with atrial fibrillation could contribute to the development of prothrombotic abnormalities.
Over a period of 23 months, we studied 55 patients with chronic non-valvular atrial fibrillation. We recruited 18 consecutive patients (13 men, mean age 59 +/- 10 years) with paroxysmal atrial fibrillation 17 patients (11 men, mean age 61 +/- 7 years) with persistent atrial fibrillation who underwent elective successful DC and remained in sinus rhythm at the 3 month visit and 20 patients (14 men mean age 64 +/- 9) with permanent atrial fibrillation. Blood results were compared to 17 age-sex- and race-matched controls. The prothrombotic state was quantified by measurement of plasma levels of fibrinogen, soluble P -selectin (an index of platelet activation) and von Willebrand factor (a marker of endothelial dysfunction). We assessed the frequencies of factor V Leiden and prothrombin variant G20210A to determine whether particular inherited haemostatic risk factors may have contribution to the development of prothrombotic state in atrial fibrillation patients.
Permanent atrial fibrillation was associated with significant raised levels of von Willebrand factor, fibrinogen levels and soluble P -selectin compared to matched controls (all p < 0.001) and matched patients with paroxysmal and permanent AF (all p ranged between <0.003 and <0.002). Patients with persistent atrial fibrillation had significantly elevated von Willebrand factor levels (p = 0.0064) and fibrinogen levels (p = 0.002), but not Soluble P -selectin (p = 0.509). when compared to controls. Patients with paroxysmal atrial fibrillation had significantly elevated levels of P -selectin (p = 0.005) and fibrinogen (p = 0.003), but not von Willebrand factor (p =.0.61) compared to controls. Stepwise multiple regression analyses demonstrated that the arrhythmia duration (approximately 3 years) was an independent predictor of abnormal von Willebrand factor, fibrinogen and soluble P -selectin levels. Restoration of sinus rhythm in paroxysmal atrial fibrillation subgroup and successful electrical cardioversion of patients with permanent fibrillation atrial fibrillation did not significantly alter levels of the affected factors. The frequency of factor V Leiden was 8.9 in all studied patients with atrial fibrillation, versus 2.4% in the control group (odds ratio [OR] 4.6 [95% confidence (CI) 1.4-17.5], p = 0.02). The frequency of the prothrombin variant G20210A was 6.4.% compared with control group 1.6% (OR 4.9 [95% confidence interval (CI) 1.2-2.9], p = 0.04). There was a trend towards an increased frequency of factor V Leiden and/or prothrombin variant G20210A in patients age <55 years and in patients living at a particular area of Thrace mountains.
Our results showed that there were significant differences in the prothrombotic state when patients with paroxysmal, and persistent atrial fibrillation were compared to matched that there were significant differences in the prothrombotic state when patients with paroxysmal, and persistent atrial fibrillation were compared to matched patients with permanent atrial fibrillation and controls in sinus rhythm. The duration of the arrhythmia (about 3 years) was an independent predictor of abnormal measured factors. We found for the first time that some genetic alterations in haemostatic risk factors could be coexist in atrial fibrillation patients and may be a contributor to the development of hypercoagulability in atrial fibrillation patients.
众所周知，心房颤动与血栓栓塞事件的高发生率相关，这可能是由于血栓前状态或高凝状态所致。然而，尚不清楚在心房颤动患者的临床亚组中，即阵发性、持续性或永久性心房颤动患者中，这种血栓前状态是否存在差异。另一方面，心律失常持续时间对心房颤动患者凝血变量变化的作用尚不够明确。凝血和纤维蛋白溶解途径（即止血危险因素）中的基因和功能改变对心房颤动高凝状态发展的贡献需要阐明。因此，我们研究了：（1）心律失常不同临床状态的患者之间血栓前状态是否存在差异；（2）心律失常持续时间本身是否可能是所有心房颤动患者血栓前状态的独立决定因素；（3）心房颤动患者中止血危险因素的共存基因改变是否可能导致血栓前异常的发展。
在23个月的时间里，我们研究了55例慢性非瓣膜性心房颤动患者。我们招募了18例连续的阵发性心房颤动患者（13例男性，平均年龄59±10岁）、17例持续性心房颤动患者（11例男性，平均年龄61±7岁），这些持续性心房颤动患者接受了择期成功的直流电复律，且在3个月随访时保持窦性心律，以及20例永久性心房颤动患者（14例男性，平均年龄64±9岁）。将血液检测结果与17例年龄、性别和种族匹配的对照者进行比较。通过测量血浆纤维蛋白原水平、可溶性P-选择素（血小板活化指标）和血管性血友病因子（内皮功能障碍标志物）来量化血栓前状态。我们评估了因子V莱顿突变和凝血酶原变异体G20210A的频率，以确定特定的遗传性止血危险因素是否可能对心房颤动患者血栓前状态的发展有影响。
与匹配的对照者（所有p<0.001）以及匹配的阵发性和持续性心房颤动患者（所有p值在<0.003至<0.002之间）相比，永久性心房颤动与血管性血友病因子水平、纤维蛋白原水平和可溶性P-选择素显著升高相关。与对照者相比，持续性心房颤动患者的血管性血友病因子水平（p=0.0064）和纤维蛋白原水平（p=0.002）显著升高，但可溶性P-选择素水平无显著变化（p=0.509）。与对照者相比，阵发性心房颤动患者的P-选择素水平（p=0.005）和纤维蛋白原水平（p=0.003）显著升高，但血管性血友病因子水平无显著变化（p=0.61）。逐步多元回归分析表明，心律失常持续时间（约3年）是血管性血友病因子异常、纤维蛋白原和可溶性P-选择素水平的独立预测因子。阵发性心房颤动亚组恢复窦性心律以及永久性心房颤动患者成功电复律并未显著改变受影响因子的水平。所有研究的心房颤动患者中因子V莱顿突变的频率为8.9%，而对照组为2.4%（比值比[OR]4.6[95%置信区间（CI）1.4 - 17.5]，p=0.02）。凝血酶原变异体G20210A的频率为6.4%，而对照组为1.6%（OR 4.9[95%置信区间（CI）1.2 - 2.9]，p=0.04）。年龄<55岁的患者以及居住在色雷斯山区特定区域的患者中，因子V莱顿突变和/或凝血酶原变异体G20210A的频率有增加趋势。
我们的结果表明，阵发性和持续性心房颤动患者与匹配的永久性心房颤动患者及窦性心律对照者相比，血栓前状态存在显著差异。心律失常持续时间（约3年）是所测异常因子的独立预测因子。我们首次发现，心房颤动患者中一些止血危险因素的基因改变可能共存，并且可能是心房颤动患者高凝状态发展的一个促成因素。
