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Chapter XIII

Contents

CHAPTER XIII

Byproducts of Plasma Fractionation

GENERAL CONSIDERATIONS

One of the truly important achievements of the plasma-blood program in World War II-and, indeed, one of the important scientific contributions of the century-was the development by Dr. Edwin J. Cohn and his group at the Department of Physical Chemistry, Harvard Medical School, of a practical physicochemical technique by which plasma could be separated into clinically usable fractions. The wartime work was an extension of previous work done in this laboratory on plasma fractionation, and was directly stimulated by the endeavor to find a purified preparation of bovine albumin. The fractions separated, particularly albumin, proved of great value during the war and have since affected many areas of medicine. The work that Dr. Cohn began is continuing and expanding under the auspices of the Protein Foundation, which was established in 1953.

By the Cohn technique, each plasma fraction is precipitated in ethyl alcohol, under specific conditions of temperature, pH, ionic strength, and protein concentration, in a coldroom, at a temperature of 23 F. (-5 C.). Since the processing is carried out below the freezing point of water, denaturation of the plasma proteins by alcohol does not occur. Bacterial growth is also inhibited. The dried fractions can be stored for an indefinite period before they are used.

The six major fractions of plasma were described in 1947 by Dr. Cohn as follows (1):

Fraction I contains most of the fibrinogen and the antihemophilic globulin.

Fraction II, obtained by subfractionation of II+III, contains the gamma-globulin antibodies of proven value in the prophylaxis of measles and probably also of infectious hepatitis.

Fraction III-1 contains other antibodies, including those to typhoid 0. The isoagglutinins, including the anti-Rh antibodies of value in blood typing, are also concentrated in this fraction.1

Fraction III-2 contains prothrombin and one of the components of complement. Prothrombin converted by thromboplastin to thrombin has proved of value in conjunction with fibrin foam or some other pledget as an hemostatic agent and, in conjunction with fibrinogen, in the formation of clots, films as dural substitutes, and tubes for other surgical uses.

Fraction III-3 contains plasminogen, the precursor of plasmin, which has sometimes been called the fibrinolytic enzyme.

Fraction III-0 is rich in lipoprotein, including the so-called X-protein of McFarlane, which interacts in the plasma in such a way as to suggest that the molecular weight varies with concentration. * * *

1Isoagglutinins and the Rh factor are discussed in the chapter on laboratory tests.


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CHART 7-Fractional distribution of various components of plasma, proportion separated in each fraction, and uses for each to 1947

Source: Cohn, E. J.: The Separation of Blood into Fractions of Therapeutic Value. Ann. Int. Med. 26: 341-352, March 1947.

Fraction IV-1 is lipoprotein in nature. * * *

Fraction V contains the human serum albumin that has been made available in such large amounts to the Armed Forces for use in the treatment of shock, hypoproteinemia and edema. As at present released for distribution under conditions that have been specified by George Scatchard, Laurence E. Strong and Walter L. Hughes, Jr., it is poor in salt and is so stable in the presence of nonpolar anions, developed for this purpose largely by J. Murray Luck, that it is heated in the final container for 10 hours at 60 C. That these conditions suffice for the destruction of the virus of infectious hepatitis has been demonstrated by Joseph Stokes, Jr.

Fraction VI consists of the large amount of salts, especially citrates, and the small amount of protein left in the mother liquors following the removal of these various precipitates. * * * Fraction VI deserves further exploration, as do fractions of proved therapeutic value.


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The distribution of the various components of plasma into fractions was indicated graphically in this same presentation (chart 7).

Aside from the specific value of the various plasma fractions, the plasma fractionation program had three general advantages:

1. Whole blood was conserved, since only the special component required in the special case was used.

2. Great economic savings were effected in the blood program.

3. Since plasma fractions were of human derivation, they possessed all the advantages of homologous substances. There was therefore no fear of sensitivity reactions.

The size of the plasma fractionation program is an indication of its importance. Up to May 1945, 1,218,531 units of plasma fractions had been produced, the largest production of a single fraction being 576,996 units of human serum albumin(2).

The Conference on Plasma Fractionation on 14 March 1945 (3) summarized the previous experience with plasma fractionation and indicated future trends. Reference to the minutes of this conference and to the minutes and appended reports of various meetings of the Subcommittee on Blood Substitutes is recommended for readers who desire more detailed information concerning this program than limitations of space permit here.

HEMOGLOBIN

Several research projects on hemoglobin solutions in replacement therapy were undertaken during the war, under the auspices of the Subcommittee on Blood Substitutes (4, 5), but their use was never seriously considered. Some studies were encouraging, but the careful work of Lamson and his associates (6) showed that such solutions would support life in shocked animals for only a few hours and that, to be effective at all, they must be given before severe shock developed. There were also other objections: The rise in blood pressure which they produced was extremely high in relation to the volume of fluid replacement. The metabolic rate rose more than 100 percent, an extremely undesirable reaction in patients in shock. The increase in pulse pressure was also considerable. Clinically, moderately severe reactions resulted even when only small testing amounts were injected. All of these phenomena were related to the established facts concerning the toxicity of hemoglobin.

GLOBIN

Although extensive studies were carried out with globin (3, 7, 8), the protein component that makes up about 96 percent of hemoglobin, nothing of practical value came of them during the war.

The first publication on globin, by Schulz in 1898 (9), which concerned its preparation and properties, was later invalidated when it was found that he was dealing with a denatured protein. Most subsequent investigations were


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concerned with modifications of his method in an attempt to obtain so-called native globin. The attempt was successful, but the material obtained was either toxic or antigenic.

Dr. Max M. Strumia's work with globin, which was begun in the spring of 1941, was first brought up in the Subcommittee on Blood Substitutes at the meeting of 13 May 1943 (8). The project he proposed-the derivation of globin from the hemoglobin of discarded erythrocytes and its use as a blood substitute-was recommended to the Committee on Medical Research, with the stipulation that Dr. Strumia use the facilities and advice of Dr. Cohn and Dr. Linus Pauling.

Reports on the progress of this project were made at various meetings of the Subcommittee on Blood Substitutes (2, 10-13), and at a special conference on globin on 21 April 1944 (14).

Globin production proved highly practical (15), for 700 gm. could be prepared with relative ease from about 3,000 cc. of packed red cells; this was the equivalent of 13,000 cc. of plasma or 53 blood donations. Globin, however, was never put to military use.

IMMUNE SERUM GLOBULIN

A conference on immune globulins was held on 8 February 1943 (16) to discuss possible uses for the globulin fractions containing immune bodies prepared by Dr. Cohn's group at Harvard, to evaluate the immunologic data already obtained on various preparations, and to consider criteria for further assay. At an earlier meeting (of the Albumin and By-Products Group), Dr. Cohn had emphasized the desirability of so fractionating human plasma that the greatest possible use might be made of its byproducts (7).

The data presented to, and the significant conclusions of, the conference may be summarized as follows:

1. Fraction II+III, obtained as a byproduct of processing human plasma and containing most of the beta and gamma globulins, was shown to contain antibodies that reacted with a variety of infectious agents and with the isoantibodies of the human blood groups.

2. Fraction II, obtained by further fractionation of fraction II+ III, and thus freed of prothrombin, thrombin, and much of the undesirable isoantibody, was shown to contain certain antibodies that were protective against the viruses of mumps and influenza A, as well as an antibody that inhibited the agglutination of chicken red cells by influenza A virus and another antibody that reacted with the H antigen of Eberthella typhosa.

3. The antibody content of fraction II represented a concentration of at least 14 to 16 times that of plasma, though not all the antibody of the plasma had yet been recovered.

4. Further investigations would include: (1) tests of the intravenous use of fraction II, to be run by Drs. Charles A. Janeway and Stokes; (2) tests to determine the cause of the immediate, painful reactions occasionally encountered, after modification of the final product in respect to salt concentration; and (3) further experiments on the effect of time and temperature on the activity of suitably resistant viruses or bacteriophage in the presence of albumin and globulin fractions, to determine whether inactivation by mild heating was practicable.

5. Preliminary clinical trials of the prophylactic and modifying effect of fraction II + III and of fraction II strongly suggested that both would be of value in the prevention or


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modification of measles, and further trials with fraction II among military personnel were considered warranted, especially for the protection of troops about to be sent overseas. The risk of inoculating soldiers with an unknown virus and producing infectious jaundice was recognized, but it was considered justified in order to achieve mass protection against measles.

For this purpose, 10,000 vials containing 5 cc. each of fraction II, prepared according to specifications already decided upon, would be produced as soon as possible and kept ready for immediate use by the Army and the Navy. On the authorization of the Acting Surgeon General, Navy, certain commercial firms were already proceeding with the preparation of fraction II from stocks of fraction II+III then available on their shelves. These preparations would be tested at the Harvard laboratory and would not be released for clinical use until physicochemical tests and tests for immune bodies had been satisfactory. The stocks of fraction II+III at the Harvard laboratory would also be converted to fraction II.

6. The possible value of fraction II against mumps, scarlatina, influenza, poliomyelitis and other diseases was discussed but definite conclusions were considered justified only in respect to measles.

The commercial production of immune globulin steadily improved. Some preparations, Dr. Cohn reported on 21 April 1944 (13), contained over 99 percent of gamma globulin, against 85 percent in some of the earlier preparations. Because of the improvement, the protein concentration was decreased from 20 to 16.5 percent in preparations containing over 96 percent gamma globulin, thus standardizing it at a concentration 25 times that of pooled plasma. After clinical tests proved satisfactory, 0.3 molar solution of glycine was employed as a diluent.

At the end of the war, gamma globulin was considered effective in preventing measles or in decreasing its severity (17-20). There had been enough experience with it in infectious hepatitis to warrant its consideration as a therapeutic agent (p. 679), but its preventive effect in this condition and in homologous serum jaundice had not been established. It was not successful as a preventive or therapeutic agent in mumps, scarlet fever, or other communicable diseases with the possible exception of anterior poliomyelitis.

FIBRIN FOAM AND FIBRIN FILM

The development of fibrin foam and fibrin film represented an extremely important neurosurgical advance, for these materials helped to solve two major problems outstanding in the field at the beginning of World War II, one connected with hemostasis and the other with the prevention of meningocerebral adhesions.

Prothrombin, which was obtained in the fractionation of plasma as a byproduct of fraction II, rapidly loses its activity. When it was converted into thrombin, the only form in which its potent coagulating properties could be exerted, it could be filtered and stored in the frozen state until facilities were available for preparing it in dry form (21, 22). When contracts were let for the preparation of immune globulin, a provision to this effect was included and thrombin was thus available in ample quantities.


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Preliminary studies by Dr. Orville T. Bailey, to determine the effect of thrombin on bleeding from the cut surface of the liver in guinea pigs, showed that oozing was reduced by 50 percent (7). The material was then tested as a hemostatic spray at Peter Bent Brigham Hospital, the Boston Children's Hospital, the Hospital of the University of Pennsylvania, and several other institutions, in neurosurgery, surgery of the spleen and gallbladder, tonsillectomy, and other operations. All reports (23) indicated that thrombin was a most effective agent in controlling oozing that could not be controlled by sutures. The experience of Lt. Col. (later Col.) R. Glen Spurling, MC, at Walter Reed General Hospital, Washington, D.C., was, however, generally confirmed, that neither human nor bovine thrombin gave more than temporary hemostatic results unless it was supported on some sort of matrix (17, 24).

At the 22 January 1943 meeting of the Albumin and By-Products Group (7), it was agreed that thrombin was now ready for extensive clinical testing. It was also proposed, on the basis of experimental evidence, that films of fibrinogen and thrombin might prove useful in the management of burns in the field because of the simplicity and speed of the technique and the small bulk of the material.

It was a great disappointment to find, shortly after the war, that thrombin harbored the virus of hepatitis and that the promising use of fibrin foam therefore had to be discontinued.

Fibrin Foam

At the 13 May 1943 meeting of the Subcommittee on Blood Substitutes (8), it was reported that soluble cellulose manufactured by the Eastman Kodak Co. had been saturated with thrombin, by the method developed by Dr. Tracy Putnam, and had proved satisfactory in a small number of clinical cases.

When thrombin first became available, Lt. Edgar A. Bering, Jr., MC, USN (25), and Dr. Bailey had applied it in solution to bleeding points in several cranial and spinal operations. It did no harm, even when it reached the lateral ventricle, but its effect was entirely transient. Lieutenant Bering then conceived the idea of using fibrinogen, converted into fibrin foam, as a matrix. The dry foam was a light, porous, slightly brittle material, in which the air spaces could easily be seen with the naked eye. When it was wet with thrombin solution, it became soft, pliable, and somewhat resilient.

In vitro testing of pledgets of fibrin foam and of soluble cellulose soaked in thrombin solution showed, on the basis of clotting of fibrinogen solution, that the foam was a much more effective matrix than cellulose. Solutions of only 10 thrombic units per cc. were necessary with it, against solutions of at least 40 thrombic units with cellulose.

Using monkeys (Macaca mulatta), these observers placed fibrin foam saturated with thrombin on traumatized and untraumatized areas of the cortex and into the cortical substance. Sulfadiazine and penicillin were used locally


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in some of the animals. Soluble cellulose was used in one control series and muscle in another, smaller series. The animals were sacrificed at intervals of 24 hours to 3 months.

The local reaction of the tissues to soluble cellulose and to fibrin film was insignificant. Most of the foam had disappeared at the end of a week, and no fragments of it could be identified at the end of 3 weeks. The speed of absorption and the nature of the tissue reaction were not influenced by the presence of antimicrobial agents. The reaction of the tissues to muscle was considerably greater.

The first applications of fibrin foam were made in cases in which bleeding was difficult to control and the application of muscle was not feasible. The hemostatic effect was evident even when large venous channels were opened. The technique was next extended to simple oozing from the cerebral surface or the outer surface of the dura. Finally, the foam was left in place. No traces of it were found on histologic examination or autopsy from 9 to 81 days after it was used.

At a conference of the Albumin and By-Products Group on 17 November 1943 (24), it was reported that fibrin foam had been used successfully on 60 neurosurgical patients at Walter Reed General Hospital and on the same number at Peter Bent Brigham Hospital, as well as in several smaller series. It was agreed that the material was of extraordinary value as a hemostatic agent in neurosurgery.

By the end of 1943, it had been used in well over 500 neurosurgical cases. It had also been used experimentally to control bleeding from the kidney, liver, spleen, lung, and heart, and in a few clinical cases. It had proved of great value in hemophiliacs, in controlling bleeding from traumatic lacerations, and in maintaining hemostasis during minor surgical procedures such as tooth extractions.

The demand for thrombin foam was not exceeding the supply in Dr. Cohn's laboratory, and the conference agreed that the next important step was to produce it on a scale sufficient to permit its widespread use. These arrangements were duly made (5). The first contracts, for appraisal purposes, were let by the Committee on Medical Research. The subsequent contracts were made by the Navy.

Demands for fibrin foam increased throughout the remainder of the war. When Lederle Laboratories reported that it had been successful in filtering contaminated plasma and expected, as a result, to reduce plasma losses from contamination, some anxiety was expressed that there would not be enough substandard plasma available for the production of fibrin foam and thrombin, which were being made from it. The war ended before any such shortages developed.

In February 1945, it was recommended that fibrin foam and thrombin, presently in use as nonstandard items, should be standardized. The length of the dating period had not been determined, but it was evident that no deterioration would occur as long as sterility was maintained.


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FIGURE 74.-Commercially prepared fibrin foam, thrombin, and sterile isotonic sodium chloride solution.

Fibrin foam was packaged with a small vial containing dried human thrombin, which, at the operating table, was dissolved in 50 cc. of physiologic salt solution (fig. 74). The solution was complete in less than a minute if the mixture was vigorously stirred. Portions of fibrin foam, cut in the desired shapes and sizes, were placed in it. As the foam became saturated with thrombin, a moderate amount of spontaneous shrinkage occurred. The porosity of the fibrin matrix permitted swift penetration of the thrombin solution into all parts of the mass.

The following case history is an illustration of the prompt and effective hemostasis accomplished by fibrin foam.

Case 1.-This patient was received at the 45th General Hospital after exploration for a thoracoabdominal wound. Several days later, when the large gauze pack in the liver was removed, a hemorrhage occurred. After several episodes of bleeding, the abdomen was reopened and a number of clots were removed, along with a necrotic portion of the liver. The wound, which was on the superior surface of the right hepatic lobe, had to be repacked to check bleeding.

Several additional episodes of bleeding occurred over the next several days, the blood losses ranging from 200 to 800 cc. each time. The longest period without bleeding was the 10 days immediately after the first laparotomy.

The patient gradually lost ground in spite of 38 blood transfusions. Attempts to pack the bleeding tract with dried blood plasma were not successful. Then, after some fibrin foam had been obtained, a third laparotomy was done. After clots and additional necrotic tissue had been removed, the wound in the liver was packed with the fibrin foam.

The gauze pack over the foam was removed without incident on the fourth postoperative day. The single hemorrhage after this operation, on the 10th day, was so slight that there


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was no change in pulse or blood pressure. With this exception, recovery was smooth. The patient was given 4 additional transfusions, making 42 in all, with a total of 21,000 cc. of blood.

Fibrin Film

Techniques developed at the Harvard laboratory made it possible to process fibrin clots into films of any desired size, shape, and thickness (26). These films were translucent, flexible, and elastic, and possessed of considerable tensile strength. Changes in preparation made it possible to vary the time required for absorption in situ from a few days to several months. The films were made in various weights and were of the following types:

P, plain fibrin film.
F, a fibrin film with a fabric backing.
W and WF, types P or F with a waterproof backing.

The fibrin film used in both clinical and experimental studies was prepared in flat sheets of various sizes and thickness. The films were sufficiently strong to be sutured without tearing. They could be trimmed to fit the defect and were so elastic that they could easily be fitted over rounded or irregular surfaces, whose contours they assumed. They were composed of two parts. The protein part, which made up 20 to 60 percent of the films by weight, was at least 90 percent fibrin. When the films were prepared, the remainder was composed of glycerol, but when they were immersed in water or physiologic salt solution, the glycerol was removed and the water taken up was regarded as the final plasticizer under these conditions.

The process of dipping fibrin film in hot glycerol required special handling by operators skilled in sterile techniques. In November 1944 (27), an alternative technique was worked out in the Harvard laboratory, by which the material was packaged in a flame-sealed glass tube and sterilized by steam. The final moisture content was not more than 10 percent. This method was suitable for large-scale production and yielded a product which could be given a much longer dating period.

Before fibrin film was used clinically as a cerebral covering for dural defects caused by either accident or surgery, Drs. F. D. Ingraham and Bailey (27) studied its use in monkeys (M. mulatta), applying it to replace the dura mater over both traumatized and untraumatized cerebral cortex, under bone flaps; after removal of the bone; and with and without the local application of sulfadiazine and penicillin. The animals were sacrificed at intervals ranging from 1 day to 6 months. There was no physiologic evidence of cortical irritation during any of these periods. Detailed histologic studies revealed no essential tissue changes and no adhesions. As time passed, the film was first surrounded by a small amount of fibrous tissue, from which it could easily be separated, and was then replaced by a layer of fibrous tissue about the thickness of the original film. Neither healing nor tissue reaction was influenced by the use of sulfadiazine or penicillin.


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Fibrin film was first used as a clinical dural substitute in a patient with lead encephalitis, who required two operations. The original film was replaced at the second operation. Nine months afterward, the patient was in excellent condition.

The original policy was to use fibrin film only in such cases as the one just described, in which multiple surgery was likely to be necessary, and in relatively hopeless conditions, such as brain tumors (26-28). Later, it was used in any condition in which dura had to be removed or the cortex was left unprotected because of the retraction of normal dura, as in decompression operations. The film was cut slightly larger than the defect, and the edges were passed underneath the cut dural margin.

By the end of 1943, Drs. Ingraham and Bailey had used fibrin film in 44 cases, including 25 intracranial and intraspinal tumors; 8 congenital anomalies; 6 lead encephalopathies; 3 cases of Jacksonian epilepsy; and 2 compound fractures. They had recovered the film for examination 18 times, at secondary surgery or autopsy, at intervals of 14 hours to 81 days after implantation. In no instance was the slightest evidence of an inflammatory reaction seen grossly, and there was a striking absence of adhesions. In 10 of these cases, the films were examined histologically. The tissue reactions, both in extent and character, were similar to those already described for experimental animals.

In 1945, Dr. Ingraham and his associates (28) reported a total of 94 cases in which fibrin film was used; glycerol-treated material was used in 59 cases, and steam-sterilized material in the remainder. No abnormalities of any kind were evident in the 33 patients followed 6 months or more, nor were there any instances of tissue reactions, adhesions, or retarded healing in 19 specimens recovered at a second operation or at autopsy.

Fibrin film was also used successfully in the treatment of a small number of second and third degree burns. Healing was rapid as in control areas covered with petrolatum-impregnated gauze.

Fibrin film was occasionally used in peripheral nerve suture but gave rise to foreign body reactions in practically every instance.

References

1. Cohn, E. J.: The Separation of Blood into Fractions of Therapeutic Value. Ann. Int. Med. 26: 341-352, March 1947.

2. Minutes, Conference on Resuspended Blood Cells, and meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 18 May 1945.

3. Minutes, Conference on Plasma Fractionation, Division of Medical Sciences, NRC, 14 Mar. 1945.

4. Minutes, Conference on Albumin and By-Products, Division of Medical Sciences, NRC, 24 June 1942.

5. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 2 June 1944.

6. Lamson, P. D., Robbins, B. H., and Greig, M. E.: Studies on Shock Induced by Hemorrhage. X. Hemoglobin Solutions as Blood Substitutes. J. Pharmacol. & Exper. Therap. 83: 225-234, March 1945.


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7. Minutes, meeting of Subcommittee on Albumin and By-Products, Division of Medical Sciences, NRC, 22 Jan. 1943.

8. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 13 May 1943.

9. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 5 Jan. 1944.

10. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 16 Mar. 1945.

11. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 3 Mar. 1944.

12. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 17 Nov. 1943.

13. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 21 Apr. 1944.

14. Minutes, Conference on Globin, Division of Medical Sciences, NRC, 21 Apr. 1944.

15. DeGowin, E. L., Hardin, R. C., and Alsever, J. B.: Blood Transfusion. Philadelphia and London: W. B. Saunders Co., 1949.

16. Minutes, Conference on Immune Globulins, Division of Medical Sciences, NRC, 8 Feb. 1943.

17. Minutes, Conference of Albumin and By-Products Group; meeting of Subcommittee on Blood Substitutes with Subcommittee on Neurosurgery, Division of Medical Sciences, NRC, 5 Oct. 1943.

18. Minutes, Conference on Production of Normal Human Serum Albumin and Its By-Products, Division of Medical Sciences, NRC, 19 July 1943.

19. Janeway, C. A.: Clinical Use of Products of Human Plasma Fractionation. I. Albumin in Shock and Hypoproteinemia. II. Gamma-Globulin in Measles. J.A.M.A. 126: 674-680, 11 Nov. 1944.

20. Blood Substitutes Report No. 18, Committee on Medical Research, Office of Scientific Research and Development, subject: Testing of Immune Serum Globulin (Human) in the Prophylaxis of Measles, 21 Apr. 1944.

21. Minutes, Conference of Albumin and By-Products Group, Division of Medical Sciences, NRC, 28 July 1943.

22. Minutes, meeting of Subcommittee on Blood Substitutes, Division of Medical Sciences, NRC, 24 Sept. 1943.

23. Minutes, Conference on Albumin and By-Products, Division of Medical Sciences, NRC, 15 Apr. 1942.

24. Minutes, Conference of Albumin and By-Products Group, Division of Medical Sciences, NRC, 17 Nov. 1943.

25. Bering, E. A., Jr.: Clinical Uses of Products Made From Human Fibrinogen and Human Thrombin. Work carried out between Office of Scientific Research and Development and Harvard University on products developed in the Department of Physical Chemistry, Harvard Medical School, from blood collected by the American Red Cross. 1943.

26. Ingraham, F. D., and Bailey, O. T.: The Use of Products Prepared From Human Fibrinogen and Human Thrombin in Neurosurgery. Fibrin Foams as Hemostatic Agents; Fibrin Films in Repair of Dural Defects and in Prevention of Meningocerebral Adhesions. J. Neurosurg. 1: 23-44, January 1944.

27. Ingraham, F. D., and Bailey, O. T.: Clinical Use of Products of Human Fractionation. III. The Use of Products of Fibrinogen and Thrombin in Surgery. J.A.M.A. 126: 680-685, 11 Nov. 1944.

28. Ingraham, F. D., Bailey, O. T., and Cobb, C. A.: The Use of Fibrin Film as a Dural Substitute. Further Studies and Clinical Results. J.A.M.A. 128: 1088-1091. 11 Aug. 1945.

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