Transfusion Problems in Hemolytic Anemias*
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Transfusion Problems in Hemolytic Anemias* ALI A. HOSSAIN! Department of Pathdlogy, Medical College of Virginia, Richmond 23219 All hemolytic anemias feature shortened red cell Extrinsic Mechanisms survival due to premature hemolysis of the cell. For the Those hemolytic anemias which are due to extrinsic purposes of this presentation, we may classify the factors may be classified, further, as non-immune or hemolytic anemias, most broadly, according to the immune. Non-immune mechanisms include a) drugs mechanisms leading to hemolysis. and chemicals (phenylhydrazine, naphthalene, lead, snake venoms); b) physical agents (heat); c) bacteria Intrinsic Mechanisms and parasites (hemolytic streptococci, Clostridium Hemolytic anemias due to intrinsically defective welchii, Bartonella, plasmodia); and d) acquired sen erythrocytes are essentially of three types. First are sitivity to penicillin, methylodopa, Keftin®, or fava those anemias in which the red cells are defective due plant as examples. Some of the agents in this. last to lack of an essential factor, eg, pernicious anemia group serve to lyse the cells, either through duect in relapse. The second type includes those in which action or by formation of antibodies. the red cells have an abnormal shape because of an These hemolytic anemias due to extrinsic factors inherited error in the chemical makeup of the hemo of the non-immune variety present no transfusion globin molecules; eg, sickle cells, elliptocytes, sphero problem for the Blood Bank. However, it ~~st b.e cytes, and the target cells. Last are those anemias in realized that in those conditions where a positive di which the red cells are defective in their basic enzyme rect or indirect Coombs test is obtained (as in acquired systems, as in paroxysmal nocturnal hemoglobinuria sensitivity to methyldopa, penicillin, phenacetin) a (PNH) (bithermal auto-hemolysins) with acetylcho situation may arise whereby blood may be needed in linesterase deficiency, or primaquine sensitivity with an emergency; because of this incompatibility the re glucose-6-phosphate dehydrogenase ( G6PD) defi lease of blood may be delayed, to the detriment of ciency. the patient. Therefore, it is essential th~t such ~on Such anemias due to intrinsically defective erythro ditions be recognized within a short penod of time. cytes, including those in which the red cells are de The administration of blood thereafter becomes as fective in their basic enzyme systems as iq PNH, pose easy as the transfusion of any patient in the previous no problem for the Blood Bank. In these cases there category. is no antibody involved, and compatible group and In drug sensitivity cases, however, it must be re type specific blood is abundantly available and ef alized that the hemolytic anemia will cease once fective in raising the hemoglobin level of these pa the drug administration is stopped, and the DCT tients. However, should the reticulocyte count ex usually reverts to negative. Worrledge, Carstairs, ceed five percent, a direct Coombs test (DCT) may and Dacie (1966) studied 30 patients who developed be obtained which complicates matters for the Blood hemolytic anemia while taking methyldopa (Al Bank, unless the reticulocytosis is brought to the at domet®). Cessation of therapy led to immediate hema tention of the Blood Bank staff. tological remission. Peculiarly, the auto-antibo~ies Another complication may occur if the specimen had Rh specificity, instead of being directed. agamst sent for blood group, type, and crossmatch is obtained shortly after hemolysis has occurred. Should the methyldopa or one of its derivatives. In pat1ent.s. on serum contain hemolysins, they might not be de methyldopa, in which the DCT beco1!1-es pos1t1ve, warm auto-antibodies may be detected m the serum tected in the crossmatch unless certain precautions so that all donors appear to be incompatible. How are taken. If missed, incompatible blood may be issued ever, despite the presence of such incompat~bility, -adding insult to injury. infused red cells show normal survival. Revers10n to * Presented at the 23rd Annual Stoneburner Lecture a negative Coombs test enables the Blood Ban~ to Series, February 20, 1970, at the Medical College of obtain and prepare compatible blood for the patient Virginia, Richmond. without difficulty or worry. It is essential, therefore, MCV QUARTERLY 6(2): 87-92, i970 87 TRANSFUSION PROBLEMS that the drug causing the hemolytic anemia be with the protein moiety. If the drug attaches to the red held. cell membrane proteins first, the formed antibodies Sodium cephalothin (Keflin®) is another drug sensitize the red cells and lead to their destruction. which sometimes causes neutropenia and often a DCT According to Ackroyd ( 1952), this is the mechanism which appears to be causally related to hemolytic of immune hemolysis in penicillin sensitivity. A vari anemia. The clinical significance of the DCT in these ation of this scheme has been proposed which sug patients is primarily one of its complicating blood gests that cephalothin causes a positive OCT by bind banking-as high as 75 percent of such patients, de ing pre-existing plasma proteins to erythrocytes. An pending on the dose administered, may give an in other mechanism of cell destruction has been ad compatible minor crossmatch on a non-immunologic vanced by Miescher and Cooper (1960) who suggest basis. that drug and antibody combine in the plasma with Another antibiotic which complicates blood bank secondary and non-specific fixation to the cell. ing, and may be a cause of hemolytic anemia, is The hemolytic anemias of immune origin may be penicillin. In contrast to cephalothin, penicillin pro the result of the presence of a) iso-antibodies or iso duces both a DCT and indirect Coombs test (JCT). hemolysins, or b) auto-antibodies or autohemolysins. This means that the major crossmatch, in addition to Hemolytic anemias caused by auto-antibodies are the minor crossmatch, is incompatible. In a review of acquired. From the standpoint of mechanism they allergic drug-induced hemolysis, Dausset and Contu may be classified as primary idiopathic (occurs in ( 1967) found penicillin to be the offending drug in patients in whom no primary disease can be demon 14/ 34 cases. Another difference between these two strated), or secondary symptomatic (is associated related antibiotics is that an eluate which will react with some other disease; eg, malignant lymphomas, with penicillin as well as cephalothin-coated cells may leukemia, virus pneumonia, infectious mononucleosis, be prepared. No such eluates may be prepared from or collagen disease). From the standpoint of serology, the. sera of patients receiving cephalothin. the auto-antibodies may be classified as warm anti Another drug known to rarely cause hemolytic bodies, with best reactivity at 37 C; and cold anti anemia on an immunological basis is phenacetin bodies, with maximum reactivity at lower temperature. (acetophenetidin). This drug also produces a number In turn, the cold and warm antibodies may be sub of side effects: direct dose dependent hemolytic ane classified into normal and pathogenic. The presence of mia, methemoglobinemia, sulfhemoglobinemia, and both of these kinds of antibodies is shown best by (rarely) a severe hemolytic anemia in G-6-PD de the DCT, which is the distinguishing feature, and ficient individuals. Patients who develop sensitivity to by auto-agglutination. Patients with the pathogenic the drug produce antiphenacetin antibodies which can type of either the cold or warm type are said to have directly (although weakly) agglutinate red cells, and auto-immune hemolytic disease or anemia. Most anti produce and JCT and an active eluate. The addition bodies eluted from the cells of patients with the of phenacetin to the patient's serum neutralizes the warm type of auto-immune hemolytic anemia detect antibodies in the presence of complement after two an antigen associated with the Rh agglutinogen com hours of incubation. A basic difference between Keflin® plex. and penicillin sensitivity, and phenacetin sensitivity is Hemolytic anemias due to iso-antibodies and iso the failure of normal erythrocytes to absorb phen hemolysins are, in the majority of cases, easy to deal acetin. with; cells lacking the corresponding antigen are Quinidine, quinine, p-aminosalicylic acid, stibophen, usually relatively easy to find, and compatible blood and sulfomethrazine have been cited as rare causes of may therefore be transfused. However, certain iso hemolytic anemia. antibodies are directed against an antigen that is Varying mechanisms of action have been postulated present in a high percentage of the population; should for these drugs. The cause-effect relationship of these blood be requested, particularly in large amounts, it drugs is dependent on the in vitro demonstration of would be very difficult to obtain the required number enhancement of the JCT in the presence of the offend of units of compatible blood. For example, in order ing drugs. It seems that the mechanism of immuno to find two units of compatible blood for a patient logic hemolysis induced by some drugs may be dif with anti-k antibody, the blood of 1,000 donors ferent than that produced by others. In 1965, Levin must be crossmatched since the percentage of Cellano summarized the mechanism leading to drug sensitivity negative individuals is only 0.2 percent. Other ex with antibody formation as a drug or a drug degrada amples of this type of incompatibility