Idiopathic Thrombocytopenic Purpura: Some Ideas on Its Pathogenesis and Treatment

Idiopathic Thrombocytopenic Purpura SOll1e Ideas on Its Pathogenesis and Treatm.ent WILLIAM DAMESHEK, M.D., F.A.C.P., * MARIO STEFANINI, M.D. **

"IDIOPATHIC thrombocytopenic purpura" is a sonorous but rather formidable term. Its meaning is sufficiently vague, however, to cover what is undoubtedly a rather wide group of disorders, more or less related by a low platelet level. Some cases of this disorder are by no means "idiopathic" and as time goes on most of them will probably be found to have more or less clearly defined pathogenetic patterns. When this happy time arrives doubtless a decided change in terminology will be made but for the present the well-established term used above seems desirable.

DEFINITION AND DIFFERENTIAL DIAGNOSIS

Idiopathic thrombocytopenic purpura has three features which are all-important from the standpoint of differential diagnosis and definition: 1. The platelet count is low but there is no apparent abnormality of the red cells or leukocytes. 2. The spleen is not ordinarily palpable, or if so, just slightly. 3. The bone marrow contains abundant megakaryocytes. It may be defined as a disorder of obscure causation characterized by an acute or chronic reduction in the blood platelet count, in the presence of otherwise essentially normal blood counts, a normal sized spleen, and a marrow containing normal or increased numbers of megakaryocytes. Occasional cases of bone marrow disease either following chemical or From the Ziskind Laboratories (Blood Research Laboratory) of the New England Center Hospital and the Department of Medicine, Tufts College M edical School, Boston. Aided by grants from the Atomic Energy Commission and the U. S. Public Health Service.

* Professor of Clinical Medicine, Tufts College Medical School; Senior Physician and Hematologist, New England Medical Center.

** Associate Professor of Medicine; Tufts College Medical School; Physician, New England Center Hospital; Damon Runyon Senior Clinical Research Fellow (195(}-1952) j Established Investigator J American Heart Association. 1395

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x-ray exposure or even in leukemia may show thrombocytopenia as the first hematologic abnormality. Thus it is always essential when confronted with a patient showing thrombocytopenia to note the various features of the blood count and to study an aspirate of the bone marrow. In bone marrow disorders of various types whether due to hypoplastic anemia, leukemia, leukosarcoma or metastatic carcinoma, the megakaryocytes are greatly reduced or are lacking completely. In idiopathic thrombocytopenic purpura on the other hand, these giant cells are usually increased in number, despite the paucity of the platelets in the blood. 1 Their platelet production, however, as judged by studies either with regular staining methods or with phase microscopy, is greatly reduced. Obviously, there is a great difference in the significance of a bone marrow depleted of megakaryocytes and one in which the megakaryocytes are numerous, albeit unproductive. Thus, thrombocytopenia can be divided into amegakaryocytic (secondary) and megakaryocytic forms. In idiopathic thrombocytopenic purpura perhaps the most useful characterization that one can make is between the acute and chronic forms of the disease. 2 Although this is a purely clinical differentiation it has important implications from the prognostic and therapeutic standpoints. The acute cases appear "out of a clear sky" in an individual never previously troubled with hemorrhagic disease. There is usually a history of an acute illness such as chickenpox, a sore throat, or an upper respiratory infection antedating the purpura by one to t"vo weeks. Suddenly there is the development of a more or less violent purpuric eruption often accompanied with bleeding from mucous membranes. Except for the presence of numerous petechiae and ecchymoses, the examination is usually negative. Such findings as lymphadenopathy and splenomegaly, so common in acute leukemia, are lacking. The blood shows an almost complete lack of platelets although the red cell, leukocyte and differential counts are essentially normal. Aspiration of the marrow reveals normal or slightly increased numbers of megakaryocytes which tend to be agranular; platelet formation is conspicuously lacking. Marked degenerative changes of the megakaryocytes, including some degree of vacuolization, may be present. In the early phases of the disease, bleeding manifestations are outstanding and the bleeding time greatly prolonged. This is perhaps due to an associated small blood vessel disturbance. In fact, multiple disturbances may be discriminated: 1. Degenerative changes of the megakaryocytes and lack of platelet production. 2. Thrombocytopenia and an extremely short survival time of transfused normal platelets indicating an extrinsic mechanism acting on the blood platelets, and 3. Increased capillary fragility.

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The acute hemorrhagic manifestations gradually subside and the bleeding time becomes lessened, although at first the platelet count remains low. Gradually, in the course of two weeks to three months the platelets increase and eventually there is a return to completely normal values within a period of three to four months in most cases. 'rhus, acute idiopathic thrombocytopenic purpura is a self-limited disease in which, when improvement takes place, the platelet count rises to normal and remains so throughout the patient's life. Chronic idiopathic thrombocytopenic purpura represents an entirely different situation. Here, there is a history of easy bruising over many years, bleeding from mucous membranes, such as menorrhagia and nosebleeds, and bleeding from small cuts and the like. Lengthy remissions are often present but these may be interrupted by sharp relapses. Even in remissions and even in the mildest cases, the platelet count is always lower than normal and rarely reaches values above 50 per cent of normal. In some of the chronic cases, purpura in the sense of confluent petechiae is never seen and the only manifestation of bleeding may be from the uterus in the form of marked menorrhagia. This may lead to the diagnosis of a uterine or ovarian disturbance. In many cases of this type various surgical procedures have been performed, including dilatation and curettage and even hysterectomy. Even the mildest eases are subject to relapses or hemorrhagic crisis during which purpura may be a striking feature. In such a circumstance, and for want of a good history it might be quite difficult to state categorically whether one was dealing with an acute case or an acute exacerbation of a chronic illness. rrhe distinction between the acute and chronic conditions from the standpoint of prognosis and therapy may be all-important. In a child who has previously been under careful observation and who suddenly develops thrombocytopenic purpura following an infectious disease the diagnosis is relatively easy. In a woman with a longstanding history of numerous ecchymoses with slightest trauma, menorrhagia and thrombocytopenia the diagnosis, this time of a chronic case, is also made with ease. However, in the case of an adult with acute bleeding showing rather marked purpura and thrombocytopenia and with a vague history of possible easy bruising in the past, the distinction between an acute condition and an acute exacerbation of the chronic disease may tax all one's best diagnostic effort. The points in differential diagnosis given in Table 1 have been found helpfu1. 2 It must be conceded that many of the differential points between the acute cases and those of the chronic variety are relatively vague and overlapping, and may not be helpful in a given case as it presents itself. Although the acute cases are generally self-limited, it is impossible to state at a given moment in their course that this event will indeed take place. This can only be learned ty continued observation which may

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take anywhere from two weeks to several months. However, if the physician can preserve his equanimity, be patient, and withstand the frequent Table 1 DIFFERENTIATION BETWEEN ACUTE SELF-LIMITED THROMBOCYTOPENIA AND CHRONIC IDIOPATHIC THROMBOCYTOPENIA ACUTE

Incidence: female/male. . .. Presenting symptom. . . . . .. Past history of bruising or other forms of abnormal bleeding. . . . . . . . . . . . . . . .. Physical findings. . . . . . . . ..

1/1 Purpura

CHRONIC

5/3

"Bleeding disorder"

Almost always None Skin rash may be present Spleen palpable in 10% in addition to purpura Etiological factors. . . . . . . .. Drugs; infections . Unknown Blood and/or marrow lymphocytosis and/or eosinophilia. . . . . . . . . . . . . . . .. Common Rare Course. . . . . . . . . . . . . . . . . .. Spontaneous recovery May recover clinically within 4 months but thrombocyte count always below normal Repeat attacks. . . . . . . . . . .. None spontaneously Spontaneous exacerbations Family history of bruising.. 15% 25% Familial thrombocytopenia None Occasional

Table 2 LABORATORY DIFFERENTIATION OF ACUTE FROM CHRONIC IDIOPATHIC THROMBOCYTOPENIA PURPURA ACUTE

Platelet count. . . . . . .. Extremely low Platelet morphology. .. Normal ~egakaryocytes in

bone marrow. . . . . .. Normal number Vacuolization and other evidences of degeneration Platelet transfusions. .. Very short survival time of 1 to 3 hrs. Patient's plasma transfused to normal persons. . . . . . . . . . . . . . . .. No change Platelet agglutinins in serum None Electrophoretic changes in serum. . . . . . . . . .. ax globulin present

CHRONIC

Low; usually above 25,000 to 50,000 and below 200,000 Large bizarre platelets common Greatly increased number Lack of platelet production but degenerative changes uncommon Shortened survival time of 1 to 2 days Usually causes platelet reduction, sometimes marked Often present Normal {32 globulin at times

pressure from many sources, this period of waiting is usually well repaid by the avoidance of unnecessary splenectomy. In the last few years, we have been able to set up some more objective laboratory criteria in the differentiation of the acute from the chronic case. These are listed in Table 2.

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PATHOGENESIS

Our concepts of the pathogenesis of idiopathic thrombocytopenic purpura have become greatly modified in the last few years. Kaznelson3 who proposed splenectomy for the disorder, based it on the idea that the spleen was actively destroying platelets and should, therefore, be removed. On the other hand, from a careful study of the megakaryocytes in the disorder, Frank4 concluded that the spleen exerted some sort of inhibitory activity upon platelet production. Thus, the issue was early joined and has continued to the present. Doan and his coworkers concluded that the disease was characterized by selective sequestration of platelets by the spleen, whereas we have been impressed by the lack of production of platelets by the marrow megakaryocytes, and by their extreme productivity following splenectomy.! The interpretation of these latter findings was that idiopathic thrombocytopenic purpura represented a form of hypersplenism in which a hypothetical and abnormal humoral factor in the spleen inhibited platelet production by the megakaryocytes. Recent developments have gone far to modify these views. Increasing knowledge concerning the auto-immune character of many cases of acquired hemolytic anemia led Evans 5 to speculate that idiopathic thrombocytopenic purpura might conceivably be on the same basis. In his hands, the presence of a frequently positive Coombs' test and of platelet agglutinins in the serum seemed to confirm this supposition, although some of these findings have not been confirmed. By the very direct method of injecting blood plasma from cases of idiopathic thrombocytopenic purpura into normals, Harrington and his associates 6 proved that a humoral factor of some sort was present in the disease resulting in a drastic lowering of the platelet count in some instances. Parallel observations of Stefanini and his co-workers' and of Hirsch and Gardner8 revealed that the survival time of transfused platelets in patients with idiopathic thrombocytopenic purpura was considerably shortened, particularly in the acute cases. This indicated an extrinsic destructive mechanism as a cause for the thrombocytopenia. That the destruction did not take place selectively in the spleen, at least in the acute cases, was shown in further experiments. By the use of specialized techniques for preparing platelet suspensions and by careful attention to such matters as prothrombin content, it was possible to develop methods for the accurate determination of platelet agglutinins. 9 These demonstrated that platelet agglutinins were present in about 50 per cent of the chronic cases, sometimes in very high concentration. lo Thus, the emphasis began to shift in our laboratory from a purely hypersplenic cause for idiopathic thrombocytopenic purpura to an auto-immune mechanism comparable to that seen in acquired hemolytic anemia. Further studies have indicated that the acute cases are for the most part "allergic" without

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demonstrable antibodies in the serum, and that the chronic cases are either on an immunologic basis with demonstrable antibodies, or due perhaps to the production of an abnormal.humoral substance by the spleen. The possibility also exists that platelets "sensitized" by autoantibody are readily phagocytosed by a normal spleen. In any event, the immuno-allergic approach to idiopathic thrombocytopenic purpura has been a fruitful one although it does not answer all the questions, particularly the reason for the rapid and striking increase in platelets following splenectomy in the chronic cases. As Evans pointed out, the dividing line between immuno-hemolytic and immuno-thrombocytopenic disease may be difficult to define, as some cases may show both processes simultaneously. In fact, diseases with multiple immunologic disturbances are becoming more readily recognizable as we can visualize the fundamental concept better. Thus, some cases of predominantly auto-immune hemolytic disease also show thrombocytopenia and leukopenia. The interesting disorder which is miscalled "thrombotic thrombocytopenic purpura" probably represents at least a triple immunologic disturbance in which the small blood vessels, platelets and red cells are involved. Clinically, it presents itself with the triad that Singerll has emphasized: (1) hemolytic anemia, (2) thrombocytopenia and (3) transitory cerebral symptoms. A better name for the condition might be "thrombohemolytic purpura" or "hemolytic thrombotic thrombocytopenia." The impression is gaining ground that this disorder may conceivably be related to periarteritis nodosa, which most people conceive of as a form of vascular allergy. The disease par excellence from the immunologic standpoint is, however, disseminated lupus. Here one can discriminate numerous disturbances, all of them perhaps based on immunologic abnormalities. These are: leukopenia, the L.E. phenomenon, arthritis, nephritis, hemolytic anemia and thrombocytopenia and even the occasional coagulation disorder based on the development of an anticoagulant. 12 The hemolytic anemia and the thrombocytopenia of disseminated lupus are often indistinguishable from similar disorders occurring "idiopathically." This is so important that it is essential in every instance of auto-immune hemolytic anemia and of idiopathic thrombocytopenic purpura to search for a possible underlying disorder. This may be likened to an iceberg (Fig. 190). Thrombocytopenic purpura or hemolytic anemia or arthritis or nephritis may be at the surface and thus readily recognizable, but the great mass of the' iceberg-disseminated lupus, periarteritis nodosa-may be submerged below water level and thus not recognized until it is perhaps too late for either diagnosis or proper therapy. A classification of idiopathic thrombocytopenic purpura based largely on one we have used for some years in hemolytic anemia is offered with

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the understanding and qualification that it may be altered at any time without notice (Table 3). DISEASES AND ICEBERGS ARTHRITIS

Fig. 190. (For explanation, see text.)

A

Table 3 CLASSIFICATION OF HEMOLYTIC ANEMIA AND THROMBOCYTOPENIC PURPURA HEMOLYTIC ANEMIA

Intrinsic ity

A.bnormal- Hereditary spherocytosis Leptocytosis Sickle cell anemia Others DisturbExtrinsic Bacterial viral, parasiances tic, chemical Auto-immune: idiopathic and symptomatic Hypersplenic

THROMBOCYTOPENIC PURPURA

Hereditary thrombocytopathic thrombocytopenia "Thrombasthenia"

Bacterial (?), viral (?), chemical Auto-immune: idiopathic and symptomatic. Hypersplenic

COMBINED HEMOLYTIC AND THROMBOCYTOPENIC TYPES

Auto-immune hemolytic anemia and thrombocytopenia "Thrombotic thrombocytopenic purpura" Disseminated lupus and periarteritis nodosa with hemolytic anemia and thrombocytopenia

TREATMENT I. ACUTE IDIOPATHIC THROMBOCYTOPENIC PURPURA

Acute cases vary greatly in their severity. In the mild cases only a few petechiae may be present and there is only a relatively minor reduction in platelet count. Therapeutically, these cases are best left alone. In the severe cases, there is bleeding from the nose and other mucous

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membranes and the body is covered with confluent petechiae lesions and many small ecchymoses. Blood blisters of the mouth and lips may be present and thus resemble the disorder described in South Africa as "Onyalai."13 These cases must be regarded as medical emergencies since (a) there is an almost complete lack of platelets; (b) with bleeding from one visible type of mucous membrane taking place, bleeding into other sites (retina, gastrointestinal tract, kidneys, brain) may also occur; and (c) the added factor of a simultaneous blood vessel disturbance may be present. It is, therefore, best to have the patient in the hospital where all possible facilities are available. For the acute cases two positive therapeutic principles and one negative one are offered. The negative one is to discard all thought of splenectomy, at least as an emergency or first procedure. 14 Splenectomy in an acutely bleeding patient is not only dangerous but usually unnecessary. Whether or not it has any effect in raising the platelet count is questionable. The important thing to realize is that the acute cases are almost always self-limited. The physician's job, therefore, is to tide the patient over the hemorrhagic crisis. Once this is done, there is relatively smooth sailing. To treat the hemorrhagic crisis, chief reliance is placed on (1) blood transfusions, and (2) ACTH or cortisone. Blood Transfusions

The blood must be fresh and preferably from a "walking donor." Bank blood should not be used under any circumstances because platelets are destroyed in glass containers in a matter of hours, most of them at the time of collection. From the standpoint of increasing the platelet level, the best results are obtained with the use of polycythemic, high platelet count donors, the blood being drawn into and given by means of completely siliconized apparatus or with the use of plastic bags containing A.C.D. solution. If polycythemic donors are not at hand the blood of normal individuals may be used. This may be concentrated as to platelets by the simple expedient of removing most of the red cells and combining the plasmas from 2 to 4 plastic bag samples. In the order of their relative value in increasing the platelet level, the various types of transfusions are listed below: The Best Methods 1. Direct transfusion of polycythemic (preferably) or normal blood with silicone-coated syringes and arquad Z-C coated needles. 2. Administration of polycythemic (preferably) or normal blood collected by gravity into plastic bags containing A.C.D. solution or other anticoagulant. 3. Administration of platelet-rich plasma obtained by slow speed centrifugation of blood collected in plastic bags or by spontaneous separation of red cells following addition to the blood of plasma volume expanders (dextran, glutamyl peptide).

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4. Administration of isolated platelets separated by differential centrifugation and resuspended in various fluids, or plasma; or collected on and eluted from ion-exchange resin columns.

The Worst Method Blood and plasma collected in vacuum glass bottles.

The beneficial effects of platelet transfusions are probably due not only to the introduction of intact and physiologically active platelets, but to the release of various chemical and enzymatic factors produced by platelet destruction. The number and frequency of transfusions given must be a matter of individual judgment, and will of course depend upon the degree of bleeding, the platelet level, and perhaps other factors. It is of course important not to overload the circulation in an adult. This can be guarded against by giving the blood in as small volumes as possible and by the appropriate spacing of the transfusions. ACTH and Cortisone

These hormones appear to have a definite value in reducing the acute bleeding manifestations, probably by decreasing the capillary permeability rather than by an effect on the platelet level. 16 With adequate hormone therapy, the bleeding time, the tourniquet test, and other indica'" tions of increased capillary permeability are usually diminished within a few hours. In a case with severe mucous membrane bleeding we have relied chiefly on ACTH in amounts of 80 to 100 mg. in children and up to 200 mg. in adults. This is given intramuscularly in divided dosages at six to twelve hour intervals according to whether the aqueous or gel material is used. It is also possible to give the ACTH by intravenous route in a dosage of 25 mg._ over an eight hour period. It is our impression that cortisone has somewhat less effect although it is of course more convenient to administer. We have, however, used cortisone chiefly for maintenance therapy after an initial course of ACTH. An adequate maintenance dose is about 100 mg. daily for adults. Although a transitory effect on the platelet count, and even a complete remission may follow the use of the steroid hormones, it is impossible to state whether they are responsible for these effects since remissions occur spontaneously. In a series of 6 consecutive cases of idiopathic thrombocytopenic purpura, 3 treated with the steroid hormones and 3 untreated, the results were very similar although it is possible that the treated cases showed a more rapid return to a normal platelet level. With the aid of proper transfusion therapy and adequate doses of the two hormones ACTH and cortisone, we have found it possible to maintain the acute cases in good physical condition until the active bleeding

William Dameshek, M ario Stejanini subsides. Once this has occurred, even though marked thrombocytopenia may still be present, the rest of the course is usually "plain sailing," and all one must do then is to observe the patient regularly in the expectation that the platelet count will eventually return to completely normal values. This may take a week or a month or four months but if the diagnosis of an acute self-limited disorder has been correctly made, the desired-for result should eventually take place. Three Questions Answered 1. Do some acute cases, with no previous history whatever, become chronic?

The answer to this must be "Yes, probably." In our experience, they are unusual and should a sufficient waiting period have elapsed (we have chosen four months as an arbitrary dividing line between the acute and chronic cases) then splenectomy can be carried out. Nothing has been lost; in fact, the reverse is often true since operation is now carried out in an individual no longer bleeding actively from mucous membranes and thus in a relatively quiescent stage of the disease. 2. Is there a risk to "watchful waiting" in the acute cases? There can be no question but that a real risk exists. In the face of severe mucous membrane bleeding, bleeding into a "vital" area is possible and cerebral hemorrhage is always a dread possibility. The period of active bleeding, presumably when there is not only thrombocytopenia but capillary injury as well, is a time of crisis. However, with the modern tools of the platelet transfusion and the steroid hormones, the physician is much better fortified than he used to be and the risk should be distinctly less than that of splenectomy. 3. Is there, therefore, any place for emergency splenectomy! We do not believe there is. 14 Analysis of our own cases indicates that there is far more risk from a hurried splenectbmy than from careful medical management. Splenectomy is best done in a "quiet" patient under the best of physical and psychological circumstances. To make the decision in a given case is, however, extremely difficult and requires all the judgment and experience one can muster. It must be admitted that whatever course is undertaken is subject to an unpredictable risk but the results of patient medical management in the past four or five years have been remarkably good and have not been marred with cerebral hemorrhage, although death has occurred in two cases not responding to every know~ measure including splenectomy. 11.

CHRONIC IDIOPATHIC THROMBOCYTOPENIC PURPURA

Splenectomy

Treatment of the chronic case is relatively simple. Splenectomy done at a favorable time as an elective operation is the treatment of choice

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and in fact the only method of treatment which offers a reasonably good prospect for success. Since, however, the chronic cases are subject to bouts of hemorrhagic crisis indistinguishable except on the basis of the history from the acute cases, they may have to be treated just like the acute cases, Le. with transfusions and steroid hormones, until the crisis is over, follo,ving which splenectomy can be done as an elective procedure. Again, we believe it is best to forego emergency splenectomy in favor of doing the operation as an elective operation later in a patient who is well prepared with a fairly adequate number of platelets and has as little bleeding tendency as possible. The unpredictable nature of the hemorrhagic crisis both as to time and severity make it necessary to recommend splenectomy in every case of chronic idiopathic thrombocytopenic purpura, however mild. Such cases may have only local bleeding such as menorrhagia but splenectomy should be done not only to stop local bleeding but to avoid a future hemorrhagic crisis. It is possible, of course, that future studies may make splenectomy unnecessary and that some chemical or immunologic method may be developed which will improve our present therapeutic results. However, at this writing the only reliable method for producing beneficial results in most cases is splenectomy. About 60 per cent of the chronic cases show an immediate and sustained rise in platelet level following operation and thus may be considered cured although it must be said that even some of these cases relapse after two to ten years. About 20 per cent of cases show a partial response both in platelets and in bleeding manifestations and about 20 per cent show no effect whatever to the operation. Some of these latter cases may be due to an underlying disease such as disseminated lupus or perhaps to a chronic immunologic disturbance which keeps smoldering despite splenectomy. What should one do with the case of the splenectomized patient who suffers a relapse? Is it advisable to search for accessory spleens? Our own experience indicates that nothing can be accomplished from this maneuver. Although it is possible in some cases to find accessory spleens either by Thorotrast visualization or at operation, their removal has in our hands been without effect. We do not therefore recommend a second operation in these cases even though some rather remarkable cures have been reported following the removal of accessory spleens. ACTH and cortisone, male sex hormones, the use of polycythemic donors and other methods have been used in our clinic but with at best very transient results. SUMMARY

Idiopathic thrombocytopenic purpura is probably a heterogeneous disease of many pathogenetic mechanisms. The hypersplenic explanation for its causation seems to be giving way to an immunologic one in which

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a violent allergic reaction (the acute case) or a sustained antibody disturbance (the chronic case) are implicated. From the standpoints of prognosis and treatment it is essential to make the distinction between the acute and chronic cases. The acute cases are self-limited and should be treated expectantly with fresh platelet transfusions and ACTH or cortisone. Splenectomy should be reserved for the chronic cases and in any event should not be done as an emergency procedure in a patient bleeding freely into the skin and from mucous membranes. The immunologic nature of the disease makes it possible that the operation of splenectomy may some day give way to less spectacular but more effective methods of control. Acknowledgments We wish to acknowledge the invaluable assistance of the following co-workers in the collection of the original material presented in this article: Drs. Leda Zannos, J. H. Silverberg, Jyoti B. Chatterjea, E. Perez Santiago, E. Adelson, A. V. Pisciotta, E. W. Campbell, G. 1. Plitman, Mrs. I. B. Mednicoff, Mrs. L. Salomon. The electrophoretic data were supplied by Dr. P. Bernfeld and Miss V. Donahue, Cancer Research Unit, Tufts College Medical School.

REFERENCES 1. Dameshek, W. and Miller, E. B.: The Megakaryocytes in Idiopathic Thrombocytopenic Purpura, a Form of Hypersplenism. Blood 1: 27-50, 1946. 2. IIirsch, E. O. and Dameshek, W.: "Idiopathic" Thrombocytopenia. Arch. Int. Med. 88: 701-728, 1951. 3. Kaznelson, P.: Verschwinden der haemorrhagischen Diathese bei einem Fallen von essentieller Thrombopenie (Frank) nach Milz Extirpation. Splenogene thrombolytische Purpura. Wien. klin. Wchnschr. ~9: 1451-1454, 1916. 4. Frank, E.: Die essentielle Thrombopenie. I. Klinisches Bild. Bed. klin. Wchnschr. 52: 454-458, 1915; II. Pathogenese. Berl. klin. Wchnschr. 52: 490-494, 1916. Frank, E.: Aleukia splenica (Splenogene Leuco-myelotoxikose) Ber!. klin. Wchnschr. 53: 555-559, 1916. 5. Evans, R. S., Takahashi, K., Duane, R. T., Payne, R. and Liu, C. K.: Primary Throlnbocytopenic purpura and acquired hemolytic anemia; evidence for a Common Etiology. Arch. Int. Med. 87: 48-65,1951. 6. I-Iarrington, W. J., Minnich, V., Hollingsworth, J. W. and Moore, C. V.: Deluonstration of a Thrombocytopenic Factor in the Blood of Patients with idiopathic thrombocytopenic purpura. J. Lab. & Clin. Med. 38: 1-10, 1951. 7. Stefanini, M., Chatterjea, J. B., Dameshek, W., Zannos, L. and Perez, S. E.: Studies on Platelets. II. The Effect of Transfusion of Platelet-Rich Polycythemic Blood on the Platelets and Hemostatic Function in "Idiopathic" and "Secondary" Thrombocytopenic Purpura. Blood 7: 53-76, 1952. 8. Hirsch, E. O. and Gardner, F. H.: The transfusion of Human Blood Platelets. J. Lab. & Clin. Med. 39: 556-569, 1952. 9. Stefanini, M. and Silverberg, J. H.: Studies on Platelets. I. The Relationship of Platelet Agglutination to the Blood Coagulation Mechanism. Am. J. Clin. Path. 21: 1030-1038, 1951. 10. Stefanini, M., Dameshek, W., Chatterjea, J. B., Adelson, E. and Mednicoff, I. B.: Studies on Platelets. IX. Observations on the Properties and Mechanism of Action of a Potent Platelet Agglutinin Detected in the Serum of

I diopathic Thrombocytopenic Purpura 11. 12. 13. 14. 15.

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a Patient with Idiopathic Thrombocytopenic Purpura (With a note on the pathogenesis of the disease). Blood 8: 26-64, 1953. Singer, K., Bornstein, F. P. and Wile, S. A.: Thrombotic Thrombocytopenic Purpura. Hemorrhagic Diathesis with Generalized Platelet Thrombosis. Blood 2: 542-554. 1947. Conley, L. C. and H~rtmann, R. C.: A Hemorrhagic Disorder Caused by Circulating Anticoagulant in Patients with Disseminated Lupus Erythromatosus. J. Clin. Investigation 31: 621, 1952 (Abstract). Gilkes, H. A.: Two Little Known Diseases of Northern Rhodesia: Onyalai and Chiufa. Tr. Roy. Soc. Trop. Med. & Hyg. 27: 491-498 (March) 1934. Welch, C. S. and Dameshek, W.: "Emergency" Splenectomy. Surg., Gynec. & Obst. 85: 521-524, 1952. Stefanini, M., Perez, E. S., Chatterjea, J. B., Dameshek, W. and Salomon, L.: Corticotropin (ACTH) and Cortisone in Idiopathic Thrombocytopenic Purpura. J.A.M.A. 149: 647-653, 1952.