Lupus erythematosus with severe anemia, selective erythroid hypoplasia and multiple red blood cell isoantibodies

Clinicopathologic

Conference

Lupus Erythematosus

with Severe Anemia,

Selective Erythroid Hypoplasia Multiple

S

and

Red Blood Cell Isoantibodies

reports, edited by Richard Aach, M.D. and John Kissane, M.D. of weekly clinicopathologic conferences held in the Barnes and Wohl Hospitals, are published in each issue of the Journal.These conferences are participated in jointly by members of the Departments of Internal Medicine and Pathology of the Washington University School of Medicine and by Junior and Senior medical students.

A

TENOGRAPHIC

cent, alpha2 globulin 0.7 gm. per cent, beta globulin 0.8 gm. per cent and gamma globulins 1.1 gm. per cent. The Kahn test, serologic test for syphilis and the lupus erythematosus latex agglutination test were positive. Lupus erythematosus cells were demonstrated on lupus erythematosus preparation. Antibiotics were administered with good results and the patient was discharged ten days later. She was readmitted to the same hospital in February 1965 with a roentgenographic diagnosis of pneumonia in the lower lobe of the right lung. Biochemical and serologic test results were similar to those on the previous admission. The infection responded to penicillin therapy and the patient was discharged five days later. She did fairly well until May 11, 1967, when she complained of nausea, vomiting and easy fatiguability. Complete blood count disclosed a hemoglobin of 3.4 gm. per cent, hematocrit 10 per cent, red blood cells 1.9 million per cu. mm., white blood cell count 3,000 per cu. mm. The differential count revealed 89 polymorphonuclear leukocytes and 11 lymphocytes. Red blood cell indices included a mean corpuscular volume of 53 cu. p, mean corpuscular hemoglobin 18 ppg. per cent and mean corpuscular hemoglobin concentration 34 per cent. The erythrocyte sedimentation rate was 166 mm. after one hour (Westergren method). The serum iron was 145 pg. per cent with total iron-binding capacity of 200 pg. per cent. The urine gave a l+ reaction for protein ; stools were guaiac negative. The blood urea nitrogen was 21 mg. per cent, uric

year old white woman (J.K.) was admitted to the Barnes Hospital because of severe anemia on May 27, 1967 ; she died two days later. The past history revealed that the patient had had a blood transfusion at age five for “protection from measles.” At the time of her marriage a routine serologic test for syphilis was positive, but the same test on the cerebrospinal fluid was negative. In 1951 the patient had a miscarriage and a diagnosis of Rh incompatibility was made. In 1953 she had a spontaneous abortion after four months of pregnancy. In 1955 a uterine dilatation and curettage was performed because of a threatened abortion in the fourth month of pregnancy. On the following day she suffered a complete right-sided hemiparesis and aphasia. She recovered from this episode almost completely. In 1958 she was seen by a dermatologist because and a diagnosis of lupus of “skin troubles” erythematosus was made. Dexamethasone, 0.75 mg. daily, was prescribed which she continued to take until her death. On August 18, 1964, the patient was admitted to another hospital for treatment of bilateral pneumonia. Complete blood count yielded a hemoglobin of 12.6 gm. per cent, hematocrit 37 per cent, white blood cell count 3,700 per CU. mm. and 9,900 per cu. mm. with 90 polymorphonuclear leukocytes, 7 lymphocytes and 3 monocytes. Urinalysis was within normal limits. Blood urea nitrogen was 12 mg. per cent. On electrophoresis the serum proteins were albumin 3.1 pm. per cent, alpha1 globulin 0.4 gm. per FORTY-ONE

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acid 4.6 mg. per cent, bilirubin 0.3 mg. per cent, alkaline phosphatase 1.5 Bodansky units, serum glutamic oxaloacetic transaminase 20 units and lactate dehydrogenase 60 units. The prothrombin time by Quick’s one-stage method was sixteen seconds with a control of thirteen seconds. The serum albumin was 2.5 gm. per cent and globulin 3.4 gm. per cent. The serologic test for syphilis and rheumatoid arthritis factor were positive. A lupus erythematosus cell preparation was strongly positive but a serum latex test for antinucleoprotein antibodies was negative. The patient’s blood group was designated as A Rh (D) negative; the indirect Coombs’ test was positive. The patient was given a transfusion of 5 units of blood (4 units of packed red cells and 1 unit of whole blood) ; the hemoglobin value rose to 9.9 gm. per cent. A sternal bone marrow aspiration was performed on May 12 with scanty yield which was inadequate for diagnosis. Roentgenograms of the chest were unremarkable except for minimal cardiac enlargement. An electrocardiogram showed low voltage but was otherwise within normal limits. An x-ray series of the upper gastrointestinal tract was within normal limits. Further investigation of the abnormal blood antibodies revealed anti-D antibodies reacting at 37’c., an indirect Coombs’ phase and an autoimmune anti-1 antibody reacting at 4°C. Because of the severity of this patient’s disease she was referred to the Washington University Medical Center as an outpatient on May 26, 1967. She was found to be an extremely pale, well developed, well nourished, middle-aged white woman in no acute distress. Blood pressure was 122/80 mm. Hg, pulse 120 per minute and regular, and temperature 37”~. There were multiple ecchymoses on her arms, trunk and legs, but no petechiae. Marked livedo reticularis of hands and legs was noted. The lymph nodes were not enlarged. An exudate was seen in the left fundus. A grade 3 precordial systolic murmur and a grade 3 apical holosystolic murmur radiating into the axilla were heard on auscultation of the heart. Abdominal examination revealed no abnormalities. Complete blood counts were hemoglobin 4.0 gm. per cent, hematocrit 11 per cent, white blood cell count 6,600 per cu. mm. with 85 segmented neutrophils, 1 stab form, 1 myelocyte, 9 lymphocytes and 4 monocytes. Platelet count was 104,000 per cu. mm. and the reticulocyte count was zero. The red blood cell mean corpuscular volume was 79 cu. p, mean corpuscular VOL.

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hemoglobin 29 ppg. and mean corpuscular hemoglobin concentration 36 per cent. A sternal bone marrow aspiration revealed a normocellular marrow specimen with adequate megakaryocytes and granulocytic cells, and a slight increase in the plasma cells. There was almost complete absence of erythroid precursors in the bone marrow with an M: E ratio of 200: 1. Prussian blue stain of the marrow revealed adequate marrow iron with no ringed sideroblasts. After returning home that evening the patient noted the onset of fever, shaking chills, nausea and vomiting. She was hospitalized at a local hospital where blood and urine cultures were drawn. Penicillin and streptomycin were administered and she was given 2 units of blood without any immediate allergic reaction. However, the next morning the patient noted darkening of her urine and she was transferred to Barnes Hospital on the evening of May 27, 1967. Physical examination revealed an alert, pleasant white woman lying comfortably flat in bed. Vital signs included blood pressure 120/80 mm. Hg, pulse 120 per minute and body temperature 38.7”~. Icteric skin and scleras were noted; the remainder of the examination was unchanged. Blood counts included a hemoglobin of 3.3 gm. per cent and a hematocrit of 9 per cent. The serum was portwine in color. Urinalysis revealed a red-colored urine with a specific gravity of 1.013, pH 8.0, 2+ protein; 10 to 20 white blood cells with clumps, 3 to 5 red blood cells, occasional hyaline casts, 3f bacteria and 10 epithelial cells per high power field were seen on microscopic examination of the urinary sediment. Serum electrolytes were normal except for a carbon dioxide combining power of 19.5 mEq. per L. The serum albumin was 4.0 gm. per cent, globulin 3.8 gm. per cent, total bilirubin 4.2 mg. per cent, serum glutamic oxaloacetic transaminase 100 units and blood urea nitrogen 90 mg. per cent. Roentgenogram of the chest revealed an infiltrate in the left lower lung field. An electrocardiogram showed only sinus tachycardia. All attempts to cross match her blood failed. Further investigations by the blood bank demonstrated additional antibodies, probably anti-Kiddb isoantibody and anti-Kell isoantibody in addition to the previously established anti-D and anti-1 antibodies. Ampicillin and prednisone, 200 mg. per day were administered after blood cultures had been taken. Urine output remained adequate; the blood cultures were without growth of bacteria.

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Forty-eight hours after admission, the patient experienced moderate chest pain and respiratory distress developed with sudden onset of tachycardia. Her pulse was feeble and thready with a rate of 200 per minute. The neck veins were distended and auscultation of the chest revealed moist rales throughout both lung fields. The patient was treated with intermittent positive pressure breathing and oxygen, morphine sulfate, digitalis and ethacrynic acid. Her condition improved momentarily but subsequently cardiac arrest developed. Resuscitation was undertaken but the patient never regained consciousness and died three hours later. CLINICAL

DISCUSSION

DR. WILLIAM H. DAUGHADAY: It is clear from the protocol that this woman had manifestations of a disease for many years which, in retrospect, can be ascribed to lupus erythematosus. These included a positive serologic test for syphilis, a skin rash, antinuclear antibodies and later a positive Coombs’ test. The course was indolent until one year before her death when a severe anemia developed associated with erythrocytic hypoplasia of the bone marrow. The presence of several antibodies directed against erythrocyte antigens made cross matching diflicult and eventually led to a serious transfusion reaction. During the short time the patient was in Barnes Hospital, she demonstrated the circulatory consequences of severe anemia. Her terminal episode followed a period of increasing tachycardia and pulmonary congestion. Cardiac arrest developed and resuscitation was unsuccessful. Dr. Brinker, can you discuss the limited available films? DR. RAYMOND A. BRINKER: As an outpatient, this patient’s gastrointestinal and chest roentgenograms were within normal limits. Only three chest films were available. They demonstrated an area of pneumonitis in the lower lobe of the left lung posteriorly which was nonspecific. The heart was borderline enlarged; there was no evidence of increased vascularity in the lung fields. The bony thorax detail was normal. DR. DAUGHADAY: Until May 1967, this patient seemed to be having a rather smouldering, indolent course for lupus erythematosus. Dr. Osterland, would you review the features that can be attributed to lupus erythematosus and make any additional comments that you like

Conference concerning this patient’s subsequent course in relation to lupus erythematosus? DR. C. KIRK OSTERLAND: Until this patient’s last admission to Barnes Hospital, her clinical course was not only compatible with, but also almost classic for a case of systemic lupus erythematosus. The very early finding of a false positive serologic test for syphilis is not infrequently seen in early or latent systemic lupus erythematosus. The diagnosis was made initially by a dermatologist when a skin rash was the first clinical manifestation of her disease. This is not described completely in the protocol, but may well have been the typical butterfly type of skin eruption. At that time she was given dexamethasone, 0.75 mg. daily, a rather homeopathic dose, on which she was apparently maintained for some time. DR. DAUGHADAY: She might not have needed any treatment at all. DR. OSTERLAND : Yes, the dose used probably did not have much effect. The pneumonia in 1964 may have been viral, but it may also have been pulmonary involvement of active lupus. At that time she was leukopenic, had lupus erythematosus cells, anti-DNA antibodies and several positive serologic tests, giving the multiple autoantibody picture so often seen in serum from patients with lupus erythematosus. In 1967 the clinical picture was somewhat different. For the first time renal damage became apparent with proteinuria, abnormal urine sediment and an elevated blood urea nitrogen level. Her serologic tests for lupus erythematosus remained positive and her serum contained rheumatoid factor as well. Several different red cell antibodies including cold agglutinins and other indirect antibodies against red cell antigens were detected. The formation of these red cell antibodies with or without defined specificity is perfectly compatible with active systemic lupus erythematosus, although isoimmunization by transfused cells must also be considered. The terminal episode might have been an acute crisis of this disease or, alternatively, one of the more exotic complications of long-standing lupus erythematosus. In summary, the entire clinical course in this patient is perfectly compatible with chronic active systemic lupus erythematosus with terminal hematologic complications. DR. DAUGHADAY: There is a possibility that early in the course of this patient’s disease, the frequency of her abortions might have been reAMERICAN

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lupus erythematosus. We have emphasized so often that this disease is aggravated by pregnancy, but I do not think that there has been sufficient emphasis on the fact that lupus erythematosus leads to frequent abortions, if and when pregnancy occurs. Dr. Brown, beginning in February 1965 this patient had a severe anemia, and unusual bone marrow findings were observed in May 1967. This is a puzzling aspect of the case and I would like your thoughts about it. DR. ELMER BROWN: These findings cannot be put together in any definitive package since it is not known what happened in the period immediately preceding her admission in May 1967. However, when a pattern of selective red cell aplasia is seen in contrast to a pattern of diffuse hypoplasia of all bone marrow elements, the first association that must be thought of is a thymoma. Sixty or more cases have been reported in which pure red cell aplasia has preceded, been associated with or followed the occurrence of a thymoma. How a thymoma and red cell aplasia are related is not known but the association of various autoimmune phenomena, the response of some patients to corticosteroid therapy, splenectomy and immunosuppressive drugs, plus the recent observations reported by Krantz and his co-workers’ of antibodies in plasma directed toward erythroid precursors in normal bone marrow, all suggest a possible immune relationship between the thymoma and selective erythroid suppression. In this case the absence of roentgenographic evidence of a thymoma is against this possibility but does not eliminate it. DR. BRINKER: There was no indication of a thymoma on any of the chest films. On the other hand, a thymoma may not be demonstrable roentgenographically except by tomography. DR. BROWN: In the same vein as autoimmune phenomena associated with thymoma is the possibility of a chance development of an antibody to the erythroid precursors as a manifestation of augmented antibody-forming capacity associated with lupus erythematosus. This mechanism has been postulated in a few patients with lupus erythematosus and hemolytic anemia. A third consideration, which I favor somewhat more in this case, is the development of a transient aplastic crisis of red cell production in a pa-

tient with underlying chronic cotttpensated hemolytic anemia. The evidence for this phenomenon is incager here since we ha\e little antecedent hernatologic information. Howe\-rr, transient aplastic crises in children w-ith sickle cell anetnia and in patients with hereditary spherocytosis or thalassemia are well established. Often a mild respiratory tract infection is the only precipitating event associated with these crises ; their mechanism is entirely unknown. Other causes for selective red cell aplasia, such as an association with acute renal failure, tnali,qnancy or as an inherited disorder, hat-e no support in this case. DR. DAUGHADAY: One of the features on physical examination which puzzled me was the rather wide distribution of ecchymoses over the lower extremity and on the trunk. Would you comment on the possible explanations for these? DR. BROWN : The ecchymoses were probably due to vasculitis. The patient was not receiving a large enough dose of steroids to have steroid purpura develop. She did not have thrombocytopenia of significant degree, nor did she ha1.e petechiae. So, by elimination, I be1iei.e this was a vascular purpura. DR. DAUGHADAY: Have not anticoagulants been demonstrated in lupus erythematosus? Would this be a possibility? DR. BROWN: Yes, they have. Ordinarily these anticoagulants are directed to elements in the second stage of coagulation and result in mucous membrane bleeding more prominently than they do in isolated ecchymoses of the skin. DR. DAUGHADAY: One of the patient’s most complicated problems was the difficulty which followed blood transfusions. Dr. Chaplin, would you discuss this problem? DR. HUGH CHAPLIN: Before attacking the transfusion problems directly, I would like to suggest another feature in favor of the diagnosis of lupus erythematosus and that is the multiplicity of red cell antibodies formed in this patient. In patients with lupus erythematosus multiple antibodies are known to form; Drs. Callender and Race2 described one such patient in whom five different red cell isoantibodies were formed. I think the reason this woman died was that she became so anemic that heart failure ensued. Therefore, it is important to scrutinize the trans-

1KRANTZ, S. B. and KAO, V. Studies on red cell aplasia. I. Demonstration of a plasma inhibitor to heme synthesis and an antibody to erythroblast nuclei. Proc. .Vat.Acad. SC., 58: 493, 1967.

2 CALLENDER, S. T. and RACE, R. R. A serological and genetical study of multiple antibodies formed in response to blood transfusion by a patient with lupus erythematosus diffusus. Ann. Eugenics, 13: 102, 1946.

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594 TABLE ANTIGENIC

I

CHARACTERISTICS

OF DONOR

BLOOD

Antibody Date of Transfusion

Donor Unit No.

p$,

Jkb

S

Kell

5112 5/13 5/16 5/17 5/26 5/27

2-01811 I-16203 4-17972 4-18165 I-18670 86545

-

+ + T

-

-

;

+ -

-

fusion difficulties that arose and to examine the steps that were or might have been taken to delay or possibly even prevent her death. All told, four isoantibodies developed. Anti-Rh (D) and anti-1 antibodies were demonstrable in early May 1967. Although, on the basis of preliminary studies, the protocol states that anti-Kell antibodies developed, it was subsequently determined that the antibody was anti-S. This discrepancy is not going to prove relevant, as you will see. Most important was the formation of anti-Jkb antibodies. What were the opportunities that permitted the development of these antibodies? The first opportunity was the regrettable injection of blood at age five for protection against measles. The patient probably received whole blood because this was the form in which such prophylaxis was usually given. Although this practice has long since been abandoned, it was not particularly uncommon at the time. This almost certainly was the cause of her sensitization to the Rh (D) antigen, because with her first pregnancy she had a stillbirth, a rather late abortion during the sixth month of gestation, and evidently studies at that time were compatible with Rh hemolytic disease. DR. DAUCHADAY: Could her abortion be attributed to antibodies? DR. CHAPLIN : She could have aborted for some other reason, but the Rh antigen is certainly present long before the sixth month of gestation and babies may become acutely anemic and die in utero at that time. She had three pregnancies and these also could have served to stimulate production of the anti-Rh (D), the anti-S and the anti-Jkb antibodies. Her last pregnancy was in 1955. Twelve years later the only antibodies demonstrable were anti-Rh (D) and anti-I. This is a normal finding. The presence of anti-1 antibodies made this whole problem a little more difficult technically, but I

Conference do not think the I “sensitization” had anything to do with the rapid destruction of donor cells. Turning to the other isoantibodies, it is not at all uncommon for sensitization to the Kidd system and the S system to “disappear,” that is, for the antibodies to disappear from the serum within a relatively few months after their stimulation. Therefore, the fact that they were not demonstrable on May 11, 1967, does not necessarily mean that they were stimulated de nova after that date. When the patient entered the outside hospital, severely anemic, she was given 5 units of blood. Since her hemoglobin level rose almost the expected amount, immediate acute destruction of donor cells probably did not take place. However, within two weeks her hemoglobin had fallen to almost the pretransfusion level. This suggests that at least 4 of the 5 units of blood had been destroyed. Sensitization within the Jk system often gives rise to what are called “delayed” transfusion reactions. The patient has been sensitized in the past but detectable antibody has disappeared from the serum; cross matching is “compatible” and blood is given. Within a few days, rapid destruction of the donor cells takes place. I believe this is precisely what occurred here. At the time that the patient received the sixth and seventh units, the serum used for the cross match was shown on subsequent study to contain all four antibodies. However, the transfusions were given nonetheless. I learned through a telephone call to the other hospital that they had performed an indirect Coombs’ cross match test and that it had been incompatible. However, because of the severity of the clinical picture, the medical decision was to proceed with the transfusion. Up to that time the patient had not had any gross intravascular hemolysis. She went home and on the following day there was evidence of gross intravascular hemolysis. The hemoglobin concentration had fallen to pretransfusion levels and it can be assumed that both of the donor units had been destroyed. Thanks to the energy of Mrs. Dorner in our blood bank, pilot samples from six of the seven donors were obtained. Their relevant antigenic characteristics are summarized in Table I. At least three of the first five units were Jkb positive. In the case of the final 2 units, both were Jkb positive, one was S positive as well. In light of these findings it is not at all surprising that intravascular destruction of the red cells of these two donors took place. AMERICAN

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The situation faced by the Barnes Hospital blood bank was an extremely dangerous and difficult one. This woman had just had an acute intravascular helnolysis. She was in a precarious state of anemia and the blood bank was asked to provide blood which would be tolerated well. This was simply impossible to guarantee at that time. The actual specificity of the antibodies was not demonstrated antemortem because of the time required to work out the multiple isosensitization problems. Furthermore, shortly after an acute incompatibility reaction, an isoantibody may be absorbed by the donor cells and may not be detectable in the serum, and therefore not detectable by cross matching. Thirty-four units of Rh negative blood were cross matched. Three of these showed minimal incompatibility by the indirect Coombs’ technic. They were not completely compatible, but they appeared to be more compatible than the other thirty-one. One might have said, “Let’s take a chance on these; they are the best we have.” The only other avenue left was the in viuo cross match which can be performed in two ways. The easiest way, one which is not really hazardous when performed properly, is to start the transfusion cautiously, having obtained a pretransfusion sample for comparison, and search for the presence of heme pigments in subsequent samples taken at intervals during the transfusion. This approach was not feasible in this case because the patient’s serum was already portwine in color. The second approach, an extremely safe one, is to label 1 ml. of donor cells with chrotnium 51 (Cr51) and follow their in vivo survival for one hour. If dangerous incompatibility is present, all the cells will be destroyed in an hour. If at least 70 per cent of the cells survive after one hour, one can probably proceed with the transfusion without major risk. Because the present crisis arose on a Sunday night, the labeling technic was not immediately available. Since the patient was doing reasonably well, it was elected to observe her throughout the night and to initiate the Cr5l study first thing in the morning. One thing we can learn from this case is that someone should be prepared to carry out Cr51 labeled in vivo cross matching at any time of the day or night. In the present instance, it turned out that the 3 units that had minimal “incompatibility” were Jkb negative and S negative. Very likely, the minitnal “incompatibility” was due to the anti-1 antibody, which may have some activity at room temperature and therefore can cause a weak posVOL.

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itive indirect Coombs’ rraction. In SUI~IIIGW~, 6 units of donor blood were destroyed in the course of two weeks due to anti-Jk” incompatibility. The last 2 units were lysed intravascularly. DR. DAUGHADAY: 'IYe have been treated to an elegant discussion of this complicated problem. It is ob\?ous that the shock organ in this catastrophe was the cardiovascular systenl. Dr. Hellam, would you detail the physiologic compensations which occur with this degree of anemia and give us your best guess as to what went wrong in this particular patient? A question as reaDR. DUANE C. HELLAM: sonable as “Why did she die?” might be “How did she stay alive with anetnia of this severity?” In trying to answer the second question, we can obtain some clue to the cause of her death. With a hemoglobin level of about 3 gm. per cent, all the so-called cardiac reserves of this patient had been called into action: coronary blood flow was increased at least three to four times to increase myocardial oxygen supply and myocardial metabolism became more anaerobic. Myocardial function was maintained at a reduced efficiency and contractility was almost certainly reduced. A precarious functional balance was thus maintained and taxed seriously by a tachycardia of 120 per minute. Thus, it is reasonable to think that she might not tolerate either an insult to her coronary flow or a greater functional demand on her heart. However, some such demand was made. Although it could have been impairment of coronary flow by vascular obstruction, we have no direct evidence for this. The event could have been extracardiac. The clinical signs of chest pain, dyspnea and apparently increasing hypoxia suggest that the patient may have suffered a pulmonary embolus. One of the catastrophic events that her heart faced was the tachycardia of 200 per minute which followed. What caused the total electrical failure of her heart (since her heart arrested in diastole and was not fibrillating) is difficult to understand, for fibrillation might more commonly be expected to occur. A plausible, but not necessarily unique, explanation could be that the nausea and vomiting suffered by the patient throughout her hospitalization produced sufficient vagal tone that, added to hypoxia, arrest of the sinus node and the other pacemakers resulted. The heart was revived for a short time after the cardiac arrest ; other centers, however, had already received a fatal anoxic insult.

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Intrinsic heart disease such as valvular lesions or coronary artery disease cannot be excluded, but we have no direct evidence for these. Their presence is not required to explain her death. DR. DAUGHADAY: I came to very similar conclusions. Dr. Parker, have you given this problem your thoughts? DR. BRENT PARKER: The only other suggestion I have is the possibility of a myocardial infarct, the result of vasculitis in the coronary arteries, and a very severe anemia. An infarct could also result from a coronary embolus from Libman-Sacks endocarditis of one of the leftsided valves. DR. DAUGHADAY: I toyed with the idea of an acute hemopericardium, but it would not explain the pulmonary edema. I was unable to find any case of arteritis in lupus erythematosus that had produced a hemopericardium, although bleeding into the renal area or bleeding into the abdominal cavity due to hypersensitivity angiitis has been described. Dr. Brown, are thrombotic episodes frequent when a patient has a hemolytic reaction? DR. BROWN: There is the suggestion of a consumption coagulopathy in many patients undergoing a hemolytic reaction. With the rapid dissolution of several units of blood, one could expect an increased amount of “thromboplastic which might initiate intravascular substances” coagulation. Since we do not have the terminal platelet count or other more specific assays of coagulation factors, we are unable to assess this possibility. DR. DAUGHADAY: My interpretation of the case does not seem to differ much from that of the discussants. This patient did have lupus erythematosus and erythrocytic hypoplasia of the bone marrow. The transfusion reaction was related to the anti-Kibb B antibody. The terminal episode appeared to be the result of cardiovascular embarrassment due to severe anemia and I would go along with acute pulmonary embolus. The medical resident told me that there was a surprise here. Due to the development of anemia and lack of erythroid precursors, I think the surprise will be a thymoma not demonstrated on the roentgenogram. PATHOLOGIC DISCUSSION This case is fairly comDR. CHARLES KUHN: plex, anatomically as well as clinically. The appearance of the bone marrow at autopsy was similar to its appearance in the clinical aspirate.

Conference The over-all cellularity was normal. Megakaryocytes and granulocyte precursors were abundant, but there was an extreme reduction in the proportion of normoblasts. The prosector searched diligently for a thymoma, but was unable to find one. Among the many sections of thymus, several showed proliferation of the epithelial component, a finding which has frequently been described in patients with lupus erythematosus, but which is by no means specific for it.3 The lungs were edematous; they weighed twice the normal weight, and as noted on the roentgenograms there was a patch of bronchopneumonia in the lower lobe of the left lung. Clinically, the evidence for lupus erythematosus was strong. Both serologic and cutaneous manifestations were present. The only typical lesion of systemic lupus erythematosus at autopsy was a concentric pattern of perivascular fibrosis of a few splenic arterioles, the so-called onionskin lesion (Fig. 1). A number of other splenic arterioles were occluded by small thrombi (Fig. 2). The adrenal gland showed the effects of steroid therapy. There was a marked narrowing of the reticular and fascicular zones. Many of the adrenal cortical arterioles were filled with recent thrombi. The kidneys were of normal weight, but appeared swollen. The sectioned cortex appeared mottled with numerous petechiae. The prosector remarked about the resemblance of these kidneys to the kidneys in malignant hypertension. The reason for this resemblance was that the insult was directed at the same arteries that are involved most prominently in malignant hypertension. In this case the intralobular arteries, afferent arterioles and glomerular capillary loops contained thrombi, many of which showed some degree of organization (Fig. 3). Although the glomerular epithelial cells were swollen and the basement membranes thickened, neither the “wire-loops” nor focal glomerulitis, the most typical type of renal involvement for lupus erythematosus, was present. Thrombosis of small vessels was found at all levels of the nervous system including the vasa nervorum of peripheral nerves, the brain stem, cerebellum and cerebrum. Only one infarct was evident grossly, an old cystic lesion in the left frontal cortex and superior operculum which 3 HUTCHINS, G. M. and HARVEY, in systemic lupus erythematosus. Ho+, 115: 355, 1964. AMERICAN

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Fxa. 1. Concentric perivascular fibrosis around a follicular artcry of the pleen. Original magnification x 503

FIG. 2. arteriole.

must have been the cause of hemiparesis in 1955. Microscopically there were a small number of other minute old infarcts in the hemispheres. The heart, which was the immediate cause of death, had many small yellow flecks throughout the myocardium. Numerous small arteries and arterioles were occluded by organizing and recent thrombi (Fig. 4). Distal to some of the occluded arteries were small foci of recent necrosis or loss of myocardial fibers. On the posterior leaflet of the mitral valve were two vegetations approximately 5 mm. in diameter. No bacteria were demonstrable in these vegations. On the other hand, this is not the type of endocarditis described by Libman and Sacks.* In their cases there were numerous bead-like verrucae on the closing edges of the valves, extending into the valve pockets and onto the mural

endocardium. In the present case the lesion had the appearance of the nonbacterial thrombotic endocarditis which is not uncommonly found at autopsy in debilitated patients with all kinds of illnesses. In the liver a few portal vein branches in perilobular portal tracts were occluded by thrombi. This finding eliminates the possibility that all the vascular occlusions resuited from emboli from the mitral valve. Widespread thrombosis of small arteries, arterioles and capillaries is the typical anatomic finding of thrombotic thrombocytopenic purpura. The thrombi often have a characteristic granular appearance (Fig. 5), which originally lead to the conclusion that they are pure platelet thrombi, although in fact they contain fibrin.5

4 LIBMAN, carditis.

E. and

SACKS,

B. Atypical

verrucous

endo-

Arch. Int. Med., 33: 701, 1924.

Several glomerular capillary loops are filled by FIG. 3. granular eosinophilic thrombi. The basement membrane is diffusely thickened. Original magnification X 500. VOL.

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in a splenic

6 CRAIG, J. M. and GITLIN, D. The nature hyaline thrombi in thrombotic thrombocytopenic pura. Am. J. Path., 33: 251, 1957.

li.

Lt.

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artery m an n X 200.

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Clinicopathologic

FIG. 5. An arteriole in the pancreas occluded by a granular eosinophilic thrombus. Note proliferation of the endothelium. Original magnification X 500. The predominant localization is in kidney, heart and nervous system as seen in this case. In addition this patient had purpura and at least a modest reduction in her platelet count during her terminal illness. On the other hand her chronic course and other clinical and serologic findings were more in keeping with systemic lupus erythematosus. Anatomic evidence in support of this diagnosis was meager except for the “onion-skin” lesion in the spleen. We interpret this case as a mixed form of collagen disease with features of both lupus erythematosus and thrombotic thrombocytopenic purpura. The disease apparently began around 1955 with the hemiparesis. It is unlikely that the earlier abortions were directly related to the connective tissue disorder, since abortions in patients with lupus erythematosus occur mostly in those with the most active disease. I underDR. DAUGHADAY: Dr. Chaplin, stand that you knew the diagnosis before the dis-

Conference cussion. Would you like to comment on the pathologic interpretation of thrombotic thrombocytopenic purpura? DR. CHAPLIN : I had wanted to make a strong plea against the diagnosis of thrombotic thrombocytopenic purpura, hoping to persuade the pathologist that thrombotic complications associated with the destruction of 6 units of blood could possibly have produced the blocked vessels that were seen. However, it is quite evident that the occlusions, particularly in the brain and in the myocardium, must have antedated the hemolytic episodes. DR. DAUGHADAY: This association is not completely unknown. Dr. Reinhard, you had to wrestle with this problem first hand. Do you have any comments? I would accept DR. EDWARD H. REINHARD: this as a combination of these two disorders. It has been a rare combination in my experience. DR. KUHN: There have been several reports of one or two cases with both lupus erythematosus and thrombotic thrombocytopenia purpura.+* In one review of patients with thrombotic thrombocytopenia purpura, one quarter of them had features of lupus erythematosus.9

6 BARONDESS, J. A. Thrombotic thrombocytopenic purpura. Review of the literature and report .of three cases. Am. J. Med.. 13: 294, 1952. r BEIGELMAN,P. M. Variants of the platelet thrombosis syndrome and their relationship to disseminated lupus erythematosus. Arch. Path., 51: 213, 1951. 8 LASZLO, M. H., ALVAREZ, A. and FELDMAN, F. The association of thrombotic thrombocytopenic purpura and disseminated lupus erythematosus. Ann. Znt. Med., 42: 1308, 1955. 9 LEVINE, S. and STEARN, M. A. Thrombotic cytopenic

purpura

and systemic

lupus

thromboerythematosus.

Arch. Znt. Med., 113: 826, 1964.

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