Grünewald M, Siegemund A, Grünewald A, Konegan A, Koksch M, Griesshammer M
Department of Haematology, Haemostaseology Division, University of Ulm, Germany.
Haemophilia. 2002 Nov;8(6):768-75. doi: 10.1046/j.1365-2516.2002.00686.x.
To elucidate potential causes for differing bleeding phenotypes of haemophilic patients of identical degree of coagulation factor deficiency, we investigated 21 male patients with severe haemophilia. Median annual coagulation factor demand and the extent of haemophilic arthropathy were used to discriminate between intensely and less intensely haemorrhagic phenotypes. Haemophiliacs with a median annual coagulation factor demand of 800 IU per kg bodyweight or more and with three or more joints affected by haemophilic arthropathy represented the intensely haemorrhagic phenotype group; all other patients comprised the less intense group. The discriminator values represent the respective medians of the overall group. The results of activated partial thromboplastin time, endogenous thrombin potential, pro- and anticoagulant factor analysis did not differ between the two groups. Median tissue-type plasminogen activator concentration (TPA) was elevated significantly in haemophiliacs with an intensely haemorrhagic phenotype, as was the activity of the thrombin-activatable fibrinolysis inhibitor. Median activity of the plasminogen activator inhibitor 1 (PAI 1) and the concentration of TPA-PAI 1 complexes were increased to approximately double those in nonsevere haemophiliacs. Coexistent congenital thrombophilia was found significantly more often in the less intensely haemorrhagic group. Thus, increased stimulation of the fibrinolytic system was associated with a more intensely haemorrhagic phenotype in our patients. We hypothesize that ineffective haemophilic haemostasis in response to trauma evokes a protracted stimulation of the entire haemostatic system, including costimulation of fibrinolysis. The absence of coexistent congenital thrombophilia predisposes to excess stimulation of fibrinolysis, which cannot be downregulated effectively due to the dysfunctional intrinsic pathway. The association of a more intensely haemorrhagic phenotype with a paradoxical hyperstimulation of the fibrinolytic system resembles a vicious circle, where bleeding seems to cause predisposition to more bleeding.
为阐明相同凝血因子缺乏程度的血友病患者出血表型不同的潜在原因，我们研究了21例重度血友病男性患者。采用每年凝血因子需求中位数和血友病性关节病的程度来区分出血频繁型和出血不那么频繁型表型。每年凝血因子需求中位数为每公斤体重800国际单位或更多且有三个或更多关节受血友病性关节病影响的血友病患者代表出血频繁型表型组；所有其他患者组成出血不那么频繁型组。区分值代表整个组各自的中位数。两组之间活化部分凝血活酶时间、内源性凝血酶潜力、促凝血和抗凝血因子分析结果无差异。出血频繁型表型的血友病患者组织型纤溶酶原激活剂浓度（TPA）中位数显著升高，凝血酶激活的纤溶抑制物活性也是如此。纤溶酶原激活剂抑制剂1（PAI 1）的活性中位数和TPA - PAI 1复合物的浓度增加到非重度血友病患者的约两倍。在出血不那么频繁型组中，共存先天性血栓形成倾向的情况明显更常见。因此，纤溶系统的刺激增加与我们患者中更频繁出血的表型相关。我们推测，创伤后血友病性止血无效会引发整个止血系统的长期刺激，包括纤溶的协同刺激。不存在共存先天性血栓形成倾向会导致纤溶过度刺激，由于内源性途径功能障碍，这种刺激无法有效下调。出血更频繁的表型与纤溶系统反常的过度刺激之间的关联类似于一个恶性循环，即出血似乎会导致更易出血。
