Pathogenesis of Hemolysis Anemia
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MEDICAL INFORMATION H2, CH4 and CO2, and by these actions allow antibody, with or without the participation of for the diffusion of N2 from blood into the colonic complement. The basis for detecting the presence lumen. of such a reaction is the antiglobulin test, other- * Although attention to excessive air swallow- wise known as the Coombs' test.' Antiserum is ing and change in diet may help some patients produced by injecting rabbits with human im- with "too much gas," alteration of abnormal gut munoprotein, either antibody or complement. The motility may be of greater therapeutic benefit. animal makes antibody to whatever is injected. That antibody can be purified and then reacted REFERENCES 1. Levitt MD, Bond JH: Volume, composition, and source in vitro with a patient's washed red blood cells of intestinal gas. Gastroenterology 59:921-928, Dec 1970 (RBC). If the cells agglutinate, the test is positive. 2. Levitt MD: Volume and composition of human intestinal gas determined by means of an intestinal washout technique. N By serial dilutions the degree of positivity can Engl J Med 284:1394-1398, Jun 1971 3. Levitt MD, Lasser RB, Schwartz JE, et al: Studies of a be quantitated. flatulent patient. N Engl J Med 295: 260-262, Jul 1976 Rosse has classi- 4. Lasser RB, Bond JH, Levitt MD: The role of intestinal In a recent review,2 Wendell gas in functional abdominal pain. N Engl J Med 293:523-526 fied the Coombs' test results according to whether Sept 1975 5. Levitt MD, Berggren T, Hastings J, et al: Hydrogen (H.2) antibody alone is detected on the red cell, anti- catabolism in the colon of the rat. J Lab Clin Med 84:163-167, Aug 1974 body plus complement, complement alone, or 6. Levitt MD, Duane WC: Floating stools-flatus versus fat. This classifi- N Engl J Med 286:973-975, May 1972 neither antibody nor complement. cation is useful in understanding the pathophysi- ology of immune red cell destruction. Antibody Alone on RBC In 1967, LoBuglio and co-workers showed that red blood cells coated with IgG would bind to Refer to: Cohen JR: Pathogenesis of hemolysis in immune hemo- That this was inhibited by lytic anemia (Medical Information). West J Med 127: monocytes.3 binding 363-365, Oct 1977 excess IgG, and more specifically by excess Fc fragments, suggested that there was a binding site on monocytes for the Fc fragment of IgG. Elec- Pathogenesis of Hemolysis tronmicrography showed that the monocytes caused membrane injury to the red cells coated in Immune Hemolytic with IgG, causing them to become spherocytes. Spherocytes were subsequently sequestered in the Anemia spleen. In the absence of monocytes, IgG caused no membrane injury. Cells coated with IgM did JAMES R. COHEN, MD not bind to monocytes.4 Subsequent workers have Stanford shown that there are subclasses of IgG: IgG1, IgG2, IgG3 and IgG4. Monocyte receptors have AUTOIMMUNE HEMOLYTIC ANEMIA is not an un- been found only for subclasses IgG1, and IgG,.5 common problem in clinical medicine, and when IgG2 and IgG, will not inhibit monocyte binding it occurs it can be quite perplexing to the prac- of cells coated with IgG1 and IgG2 but these two titioner. In recent years our understanding of the subtypes will inhibit each other, suggesting that mechanisms involved in immune red cell destruc- there is only one binding site. Radiolabeling tion has advanced considerably. This discussion studies have showed in vivo that cells coated by will attempt to summarize some of these mech- IgG are sequestered in the spleen.7 The char- anisms and relate them to clinical decisions con- acteristic of autoimmune hemolytic anemia with cerning course and treatment. a Coombs' test positive for antibody alone (the Hemolysis due to immunologic mechanisms is "gamma Coombs'"), therefore, is an IgG anti- caused by a reaction between antigenic sites on body, spherocytes and splenic sequestration. the surface of the red blood cell and circulating Antibody Plus Complement on RBC From the Division of Hematology, Department of Medicine, showed that Stanford University School of Medicine. In 1968 Huber and co-workers8 Supported in part by: Public Health Service Grant CA-08122-10 there was a second monocyte receptor; this one and Hematology Small Gifts Fund. Reprint requests to: James R. Cohen, MD, Division of Hema- for the third component of complement. That this tology, Dept. of Medicine, Stanford University School of Medicine, Stanford, CA 94305. receptor was separate from the above described THE WESTERN JOURNAL OF MEDICINE 363 MEDICAL INFORMATION IgG receptor was concluded from the inability of No Antibody or Complement Detected free IgG to inhibit the binding. Cells coated with There are some patients who appear to have Cl, C1,4 and C1,4,2 did not bind, and the addi- all the signs and, symptoms of classic immune tion of C5,6,7 did not enhance the binding. It has hemolysis but in whom results of a Coombs' test been long known that IgM binds complement are negative. It has recently been shown by Gil- more readily than IgG.9 This is felt to be- due to liland and associates,1'12'1 using a sensitive com- the fact that complement fixation requires two plement-fixing antibody consumption test, that Fc fragments a specific distance apart. A single such red blood cells do indeed have a small in- molecule of IgM, which has five Fc fragments, crease in the number of IgG molecules adherent can accomplish this, whereas two molecules of to their red blood cells. Whereas normal red cells IgG must be adherent to the red blood cell at have approximately 35 molecules per red blood the correct distance apart to allow for the binding cell and commercial Coombs' antisera cannot de- of C3.1'0'1 Chromium51 studies have shown that tect less than 200 molecules, Gilliland has found red cells coated with IgM and complement, unlike hemolysis with as few as 70 molecules of IgG per those coated with only IgG, tend to be seques- red blood cell. tered in the liver preferentially, rather than the The treatment of immune hemolytic anemia spleen. It has been shown both in experimental depends both on the underlying cause and upon animals12 and in man,13 that some of these cells which of the above types of immunologic reactions are subsequently released from the liver. This is involved. Most drug or viral related hemolyses can be explained by looking at the fixation of are self-limited once the offending agent is re- C3 in somewhat greater detail. When adherent to moved or infection over. Hemolysis related to a red cell, C1,4,2 is able to cleave C3 into sub- lymphoma or connective tissue disease may im- fragments. The fragment known as C3b adheres prove with treatment of the disease. From the to the red blood cell, and the monocyte receptor above discussion, it is evident that the treatment is specific for C3b.11 A serum enzyme,' C3b inacti- of an IgG idiopathic hemolytic anemia should in- vator, can cleave C3b leaving a second subfrag- clude serious consideration of a splenectomy. This ment, C3d, adherent to the red cell. There is no gives up to 68 percent response in some series, monocyte receptor for C3d, hence the red cell is although some of these patients subsequently may protected from sequestration and destruction.14 5 require continuous steroid treatment.22 This explains the seemingly paradoxical finding Splenectomy clearly is not indicated in the that autologous red cells from some patients with hemolyses involving complement, since most se- cold agglutinin disease survive longer when re- questration and red blood cell destruction is here injected in vivo than infused matched donor occurring in the liver. Steroids are often of bene- cells.'6 fit. The mechanism of action of steroids in hemo- Alone on RBC lysis is not known, although they have been shown Complement to decrease cell bound IgG,23 and increase free Whereas IgM has been shown to readily fix IgG, implying a decrease in red cell-antibody complement, the IgM itself does not adhere well affinity. More important, steroids have been to the red cells at room temperature. The IgM shown to decrease monocyte binding of IgG- may come off the red cell in vivo, as when it is coated red blood cells.24 Steroids also are lympho- fixed in a cool extremity and removed at core lytic and may work partly by decreasing antibody temperature, or it may be removed in vitro when production. This should be a slow action, how- the red cells are washed at 37°C. Therefore, most ever, and the response to steroids is often fairly cases of "cold" hemolytic anemia are IgM medi- dramatic.25 Although up to 80 to 90 percent of ated, but only complement is detected when the patients with autoimmune idiopathic hemolytic Coombs' test is done. Such Coombs' tests are anemia may respond to therapy with steroids, in reported as "nongamma." Whereas, as discussed a number of these patients steroid administration above, these cells are subsequently sequestered will have to be maintained indefinitely. Although in the liver, complement can itself cause intra- cytotoxic agents have been used with some suc- vascular hemolysis. This requires the completion cess in patients refractory to steroids, these should of the complement sequence through C9, at which not be employed unless hemolysis cannot be con- point the red cell lyses.17"19 trolled by steroids and splenectomy.26 364 OCTOBER 1977 * 127 * 4 MEDICAL INFORMATION 10. Rosse WE: Fixation of the first component of complement This has been a brief attempt to present one la by human antibodies.