GRAHAM J B, BARROW E M
J Exp Med. 1957 Aug 1;106(2):273-92. doi: 10.1084/jem.106.2.273.
It has been possible to duplicate in the hemophilic dog four of the major experiments which have suggested in humans an "anticephalin" hypothesis for the pathogenesis of hemophilia. The experiments in the dog have been considerably extended, as compared with the human experiments, by a variety of techniques. I. Asbestos was placed in contact with hemophilic dog plasma, and the clotting time became shorter. When transfused, this plasma had no effect on the defective prothrombin utilization of hemophilic dogs, in contrast to untreated normal plasma. II. The ionic strength of native dog plasma and dog plasma citrated (38 per cent sodium citrate) then recalcified (0.2 M CaCl(2)) were calculated. The ionic strength of the native plasma was approximately 0.15 while that of the citrated plasma was approximately 0.21. Conductivity and freezing point determinations on the plasmas described above were consistent with the idea that the ionic strength of the citrated plasma was significantly higher. The biphasic dilution curve, to which much significance has been attached in arriving at the "anticephalin" hypothesis, can be produced readily in the dog. Diluting dog plasma with "iso-ionic" or "hyper-ionic" NaCl solution abolished the biphasic phenomenon. Dilution with distilled water exaggerated the biphasic curve. These experiments suggest that the biphasic curve is an artifact of uncontrolled ionic strength. III. The prothrombin utilization rates of undiluted whole hemophilic dog blood and hemophilic dog blood diluted 1:2 with 0.85 per cent NaCl were found to be the same. IV. Ether extraction of both normal and hemophilic dog plasma removed fibrinogen and reduced somewhat the concentration of prothrombin. In treated normal plasma AHF was reduced to the level of untreated hemophilic plasma, thus producing a quasi-hemophilic plasma. Defibrination and ether extraction of both normal and hemophilic dog plasma "generated" clotting activity which shortened the clotting time of hemophilic plasma and was active in the thromboplastin generation test. The activity "generated" by defibrination and ether extraction of dog plasma was adsorbed by a BaSO(4) suspension and shown, therefore, not to be the anti-hemophilic factor (AHF). Transfusion of ether-extracted normal or hemophilic dog plasma into hemophilic dogs had no effect on the prothrombin utilization rate, unlike untreated normal plasma which had a marked effect. Thus, four of the main lines of evidence supporting the "anticephalin" hypothesis were duplicated in the dog. However, by extending the experiments it was found that all were explainable on bases other than the presence of "anticephalin." Such an hypothesis is not necessary, therefore, to explain the pathogenesis of canine hemophilia. The apparent identity of hemophilia in the two species suggests that the hypothesis is also not applicable to humans.
已经能够在血友病犬身上重复四项主要实验，这些实验在人类中提示了一种关于血友病发病机制的“抗脑磷脂”假说。与人类实验相比，通过各种技术，犬的实验得到了相当大的扩展。一、将石棉与血友病犬血浆接触，凝血时间变短。与未处理的正常血浆相比，输注这种血浆对血友病犬凝血酶原利用缺陷没有影响。二、计算了天然犬血浆和用枸橼酸盐（38%柠檬酸钠）处理后再重新钙化（0.2M氯化钙）的犬血浆的离子强度。天然血浆的离子强度约为0.15，而枸橼酸盐处理血浆的离子强度约为0.21。对上述血浆进行的电导率和冰点测定与枸橼酸盐处理血浆离子强度显著更高的观点一致。在得出“抗脑磷脂”假说时被赋予很大意义的双相稀释曲线，在犬身上很容易产生。用“等离子”或“高离子”氯化钠溶液稀释犬血浆消除了双相现象。用蒸馏水稀释则使双相曲线更加明显。这些实验表明双相曲线是离子强度未控制的人为现象。三、发现未稀释的血友病犬全血和用0.85%氯化钠按1:2稀释的血友病犬血的凝血酶原利用率相同。四、对正常和血友病犬血浆进行乙醚提取，去除了纤维蛋白原并使凝血酶原浓度有所降低。在处理后的正常血浆中，抗血友病因子（AHF）降至未处理的血友病血浆水平，从而产生了一种类似血友病的血浆。对正常和血友病犬血浆进行去纤维蛋白和乙醚提取“产生”了凝血活性，缩短了血友病血浆的凝血时间，并且在凝血活酶生成试验中具有活性。犬血浆去纤维蛋白和乙醚提取“产生”的活性被硫酸钡悬浮液吸附，因此表明不是抗血友病因子（AHF）。将乙醚提取的正常或血友病犬血浆输注到血友病犬体内对凝血酶原利用率没有影响，这与未处理的正常血浆有显著影响不同。因此，支持“抗脑磷脂”假说的四条主要证据线索在犬身上得到了重复。然而，通过扩展实验发现，所有这些都可以用“抗脑磷脂”不存在以外的其他依据来解释。因此，这样一种假说对于解释犬血友病的发病机制并非必要。这两个物种中血友病明显相同这一点表明，该假说也不适用于人类。
