Studies on the Nature of the Circulating Anticoagulant Directed against Antihemophilic Factor: With Notes on an Assay for Antihemophilic Factor

Fibrinolysis; its mechanism and significance

Acquired haemophilia is a rare but life-threatening acquired bleeding diathesis caused by autoimmune depletion of factor VIII. This occurs most frequently in elderly patients who lack disease associations. Acquired haemophilia may also arise in association with SLE rheumatoid arthritis, Sjogren's syndrome, other autoimmune conditions, lymphoproliferative malignancy, pregnancy and as a drug reaction. Acquired haemophilia has an equal sex distribution. The aims of treatment are to eliminate the inhibitor by immunosuppression and to treat the bleeding, which is the most common cause of death in patients with acquired haemophilia. The inhibitor is abolished in up to 70% of patients using prednisolone and cyclophosphamide, although other immunosuppressive regimens may also be used. These include azathioprine, vincristine and other cytotoxic agents, high-dose immunoglobulin and cyclosporin A. Bleeding may be controlled using porcine factor VIII or recombinant factor VIIa, although human factor VIII and prothrombin complex concentrates also have a limited role as haemostatic agents in this condition.

1 Acquired haemophilia

In a retrospective study 51 published cases of post-partum factor VIII inhibitors were analyzed with regard to the outcome according to treatment. The overall outcome was favorable with 97% survival at two years. The probability of complete remission (CR, absence of the inhibitor and normalization of factor VIII activity) was almost 100% at 30 months. Steroid treatment appears to be not superior to no treatment, but patients treated with immunosuppressive drugs (cyclophosphamide, azathioprine, 6-mercaptopurine) had a significantly shorter time to CR. In the absence of a randomized trial this analysis may be helpful for decision-making in women with factor VIII post-partum inhibitors. Because of the retrospective study design, conclusions have to be regarded with caution.

Post-partum factor VIII inhibitors. A review of the literature with special reference to the value of steroid and immunosuppressive treatment.

Some properties of purified prothrombin and its activation with sodium citrate.

ACCORDING to Quick1, prothrombin is composed of two components A and B, in combination with calcium. Nolf2 carried out experiments from which he formed a similar conclusion. On the other hand, Seegers, Loomis and Vandenbelt3 used purified preparations and concluded that prothrombin consists of a single substance which can act as thrombin precursor.

Acceleration of thrombin formation by a plasma component.

An acquired haemorrhagic disease in a female due to an inhibitor of blood coagulation.

children, owing to their upsetting experiences,are liable to become the troublesomepeople of tomorrow, and the community owes it to itself and to them to see that they get the best considerationpossible, from the moment the suit is instituted. I am awarethat any effective measures for better securing the welfare of these children might involve heavy public expense. However, as the public spendsfreely upon horsesand greyhoundsand the excitements which those animals provide, I regard with contemptany objection basedon expense. There is anothermatter to which I would like to refer. Every year there is an increasing tendency in the professionsto specializemore and more at the expenseof general knowledge. It is no longer considerednecessary, or even desirable, for a professional man to have broadened his general outlook or to have fortified his mind to withstand the narrowing tendency of having oBly one intellectual interest, by building the professional superstructure upon a sound and lastmg general education. I may be expressingan outmodedidea when I tell you that it is my clear conviction that an advancedbasiceducation, either in the classics or in modern languagesand comparativephilology, or in mathematics,or in history, or in psychology, makes the brain a better machine,and the mind more receptive over a wide field, and the judgementbetter balancedthan they are without the aid of an early 'comprehensivetraining. Let me take two instances to illustrate what I am stressing. One of the greatestand most Ilberal-minded Australian lawyers of all time was Leverrier. His legal knowledge was immense, his judgement perfectly balanced. But he was, as many of you may remember,not only a lawyer, but also a scientistof great attainments,a mathematician and a man possessedof wide general learning. All these contributed to his greatnessas a lawyer. Another great Australian, whom many of you will remember, was Edgeworth David. As a geologist he combined a great knowledge of detail of Australian geology with a remarkable capacity for evolving from detail a clear and comprehensivepicture of the geological structure and history of the continent as a whole. Edgeworth David before he became a geologist was a classical scholar of considerablelearning. Each one of you, no doubt, will readily call to mind from your own experienceprofessional men graced with the imprint of general learning; men who can leave the highroad of some specialized pursuit, and enjoy, with delight to themselvesand their friends, the broad and lovely fields and bushlandsof knowledge. I suggest,therefore,that the greatquestionof education, as it affects our two professions,is one which a society such as this might well examine. Let it be understood,however, that I am not attacking specialization; it is both desirableand inevitable. What I am suggestingis that there should be a proper foundation beneathit. At the risk of detaining you a little longer than I should, I pass to the last matter to which I invite your attention. We of the British race have developedover the centuries a form of constitutional government which particularly suits our character, our love of freedom and our deep dislike of anything savouring of autocracy. And we have developedconceptsof law, and of the rule of Jaw, which are admirably designed to secure us from invasion of our liberties, and to protect us from the dictatorship either of an individual or of any group of individuals claiming to exercise executive authority without responsibility either to the law or to the people. As a result of the last two world wars, those precious things which we have inherited, which are the envy of less fortunate peoples,are in grave danger of being lost. That danger exists because the people, having enjoyed liberty for so long, do not notice its existence,and tend to neglect their duty of understandingand preserving it for themselvesand for their children. The continuance of parliamentary government as we have known it, of the responsibilityof parliamentand the executive governmentto the people, and of the rule of law, dependsentirely upon a strong and articulate desire for their continuanceon the part of a substantialsection of the community. You may ask what this has to do with a medico-legal society. Just this: without leadershipno community can be anything but a decadent rabble. I use the word \"leadership\" in a large sense,as comprising not merely the active leaders of a State, but also the many who have a guiding or enlightening influence upon others. So far democracy has succeededin our land, because leadership, loyal to its principles, has not been lacking. This has happenedbecausea substantial portion of the people-andnote that I say \"portion' and not \"class\"has qualified itself for leadershipeither by a broad and liberal education gained scholastically, or by balanced wisdom acquired by wide experienceor wide reading. That is where we enter the picture. There is no longer any leisured class to provide part of the necessary leadership; because,say what you like about the leisured groups of the past, they provided many men who devoted their lives to the service of the community. More and more, the generalmassof the people will come to respect a man for his learning, be it learning in science, art, music, literature, or in one of the professions, or in anything else. These are the men upon whom depends the survival of democracy,of civil liberty, of the rule of law, of the responsibility of those who govern to those who are governed. Therefore do I stress the first and paramount duty of all professional men-particularly of the lawyers because of their understanding of constitutional principles-to hold their education and their knowledge of humanity in trust for the benefit of the people, just as much as they hold their professional skill in trust for thosewho seekit. In conclusion, I hope that such thoughtsas I have been tempted to utter in the course of this address, if not acceptable to Minerva, might possibly be provocative enough to stimulate useful ideas in others. As I said, humanity is only just beginning to understanditself and to study itself scientifically. This society has sprung into life at one of the greatest and most anxious periods of all history; at a time when it was never more necessary for all men of special learning to accept their responsibilities towards the community. Let us, therefore, following the example of other learned associationsin our land, proceed to fulflll our aims and ambitions of useful achievement.

The physiological activation of prothrombin.

THE prophylaxis against and the treatment of thromboembolism by drugs interfering with blood coagulation assumes that there is a primary relationship between thrombus formation and the clotting system. Evidence has been furnished that substances inhibiting the essential components of the coagulation system will prevent thrombus formation in laboratory animals. (1)(2) Although a number of compounds capable of delaying blood coagulation are available, it appears that only two have found practical application in the prevention and treatment of thrombotic conditions. These are heparin and 3,3'methylene-bis-4hydroxycoumarin or \"Dicumarol\". Heparin affects the whole blood coagulation time by inhibiting thrombin formation and thrombin action. It has the advantage of prompt action. The effect, however, is of short duration necessitating frequent parenteral injections. On the othe~ hand, \"Dicumarol\" acts after oral as well as parenteral administration by reducing prothrombin activity, and when applied in therapeutic doses has no effect on the coagulation time of whole blood. The latter is governed by the concentration of the essential factors involved. It appears that normal blood has a low concentration of thromboplastin, which therefore is the limiting factor. Its amount is sufficient to convert only a fraction of prothrombin. Theoretically, therefore, only severe hypoprothrombiruemia could be effective in preventing thrombus formation' but it has been shown that prothrombin concentration~ of approximately 25% of the normal are adequate, and at such a, concentration whole blood coagulation time

The hypoprothrombinaemic effect of 3,3'ethylidene-bis-4-hydroxycoumarin (E.D.C.) an experimental and clinical study.

SINCE the announcement by Peters, Stocken and Thompson1 of BAL as an antidote for lewisite, the compound finds increasing application in the treatment of poisoning due to arsenicals2, mercury salts3,4 and organic mercurials5 in humans and animals. Substances containing —SH groups are known to influence blood coagulation, for example, thiosulphate6, cysteine7,8 and glutathione9. In preliminary experiments it was observed that BAL was more active as an anticoagulant than cysteine. This made desirable a detailed study of the influence of BAL on the components of the clotting system.

Margaret H. Nance

Papers

Acceleration of thrombin formation by a plasma component.

An acquired haemorrhagic disease in a female due to an inhibitor of blood coagulation.

The physiological activation of prothrombin.

The hypoprothrombinaemic effect of 3,3'ethylidene-bis-4-hydroxycoumarin (E.D.C.) an experimental and clinical study.

Influence of 2,3-dimercaptopropanol (BAL) on blood coagulation.