Given healthy dogs, fed abundant iron and protein-free or low protein diets, with sustained anemia due to bleeding, we can study the capacity of these animals to produce simultaneously new hemoglobin and plasma protein. The reserve stores of blood protein producing materials in this way are very largely depleted, and levels of 6 to 8 gm. per cent for hemoglobin and 4 to 5 gm. per cent for plasma protein can be maintained for considerable periods of time. These dogs are very susceptible to infection and to injury by many poisons. Under such conditions, these anemic and hypoproteinemic dogs will use very efficiently a variety of digests (serum, hemoglobin, and casein) and the growth mixture (Rose) of pure amino acids. Nitrogen balance is maintained and considerable new blood proteins are produced. Dog plasma by vein is used freely in these doubly depleted dogs to make new hemoglobin in abundance (Table 1). Serum digests by vein are well utilized to make new hemoglobin and plasma protein in the same dogs (Table 1). Serum digests by mouth are effectively used to make new blood proteins (Table 5). Dog or sheep hemoglobin given in large amounts intraperitoneally are remarkably well utilized to form hemoglobin and plasma protein (Table 6). It must be obvious that the globin of the hemoglobin is saved in these protein-depleted dogs and used to make large amounts of hemoglobin and plasma protein. Hemoglobin digests are also well utilized whether given by mouth (Table 7) or by vein (Table 8) and liberal amounts of plasma protein are manufactured from digests presumably ideally suited for hemoglobin production. Casein digests are well used (Table 8) and form as much new plasma protein as any material tested—even serum digests. Amino acid mixtures are of especial interest. The growth mixture of 10 amino acids (Rose) is well utilized by mouth or by vein and favors new hemoglobin production more than any material tested (Table 2). Cystine replacing methionine in the amino acid mixture increases the plasma protein—hemoglobin output ratio, that is it favors plasma protein production. Digests of various sorts and amino acid mixtures or combinations of digests and amino acid mixtures can be used rapidly and effectively to build new hemoglobin or plasma protein, to maintain nitrogen equilibrium, and to replete reserve protein stores. These experiments point to clinical problems. The unexplained preference given to hemoglobin production in these hypoproteinemic dogs is observed under all conditions, even when whole plasma or serum digests are given by vein. In general, 2 to 4 gm. of hemoglobin are formed for every gram of plasma protein. This all adds up to a remarkable fluidity in the use of plasma protein or hemoglobin which can contribute directly to the body protein pool from which are evolved, without waste of nitrogen, the needed proteins, whether hemoglobin, plasma protein, or tissue proteins.

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Infection in human cases is often believed to be responsible for anemia. It is generally believed that lack of absorption and definite blood destruction are responsible for the anemia. Accelerated metabolism due to thyroid or dinitrophenol does not modify hemoglobin production in these standard anemic dogs. Endometritis lasting over many weeks will profoundly reduce the production of hemoglobin in the standard anemic dog. A sterile abscessalso will diminish the production of new hemoglobin in the anemic dog when liver is being fed but particularly during fasting periods when the usual abundant production of new hemoglobin is reduced to zero. Impaired absorption can be excluded as a factor of any significance in certain experiments given above. Destruction of red cells can likewise be excluded as of any significance in certain experiments given above. These experiments point to a disturbance of internal metabolism related to hemoglobin building in the body as responsible for the inhibition of hemoglobin production under these conditions. We believe this same factor is often of importance in human disease.

In long continued severe anemia due to bleeding in dogs we may observe all degrees of red marrow spread. The maximal red marrow spread takes in the total marrow area in ribs, vertebrae and long bones. The minimal red marrow spread may involve but 10 to 20 per cent of this maximal area. All gradations between these extremes are observed in this series. The extent of the red marrow spread is not dependent upon the length of the anemia period nor is it related to the capacity of the dog to produce new hemoglobin and red cells on standard diets. Evidence points to the liver as concerned with this hemoglobin production and liver function may set the limits for hemoglobin production on these standard diets. This in turn may determine the needful red marrow spread. During favorable diet periods there is a storage of hemoglobin or hemoglobin precursors which come out later in the control periods as finished red cells. This reserve of hemoglobin producing material is not stored as mature red cells in the marrow or elsewhere but as intermediates stored probably in the liver and red marrow but also perhaps in the kidney and spleen. Red marrow very rarely gives evidence of exhaustion even after many years of continuous severe anemia (Dog 18-114). This would seem to consist of a shrinkage of the red marrow area rather than a degenerative change of the red marrow cells. The spleen shows some evidence of erythrogenesis in these dogs. Megakaryocytes in some instances are conspicuous (Fig. 6) and nests of nucleated red cells are found in the spleen pulp but it is unlikely that the spleen contributes any large amount of red cells to the anemic circulation in these experiments. There is no evidence that erythrogenesis occurs in the liver or lymphatic tissue in these dogs.

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Dogs with sustained anemia and hypoproteinemia due to bleeding and a continuing low protein or protein-free diet with abundant iron will continue to produce much new hemoglobin and plasma protein for many weeks. The stimulus of double depletion (anemia and hypoproteinemia) leads to raiding of body and tissue protein to fill the demand for new hemoglobin and plasma protein. The blood proteins in these experiments take priority over the organ and tissue proteins. This is another illustration of the "ebb and flow" or dynamic equilibrium between organ or tissue protein and blood proteins. The average dog cannot tolerate this drain of double depletion for more than 7 to 11 weeks and during this time may lose 30 to 40 per cent of body weight. Some dogs are much more resistant to this raiding than others. Some dogs show a high blood protein output during every week up to the danger point. With the largest blood protein output one usually observes the most rapid weight loss. For every kilogram of weight loss we observe 50 to 140 gm. blood protein output. The weekly blood protein production ranges from 40 to 66 gm. These experiments make heavy demands on the body protein and we expected to record a "premortal rise" in urinary nitrogen. No such observations are noted, rather a most frugal use of all protein and minimum figures for urinary nitrogen. We suspect that "premortal rise" in many experiments means a terminal infection with the related catabolism of tissue protein and high urinary nitrogen.