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Anemia, thrombocytopenia, proteinuria and central nervous system dysfunction
CLINICOPATHOLOGIC CONFERENCE
Anemia, Thrombocytopenia, Proteinuria and Central Nervous System Dysfunction
Stenographic reports, edited by Philip E. Cryer, M.D. and John M. Kissane, M.D., of weekly clinicopathologic conferences held in 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, Radiology and Pathology of Washington University School of Medicine. A 43 year old woman was admitted to Barnes Hospital on February 23, 1976, because of weakness, anemia and thrombocytopenia. She died one week later. The patient was well until August 1975 when she began to tire easily. Because of persistent headaches, she discontinued taking an oral contraceptive in October. Fever and chills occurred on February 16, 1976. Petechiae appeared over the lower extremities on the following day, and an episode of epistaxis occurred. She noted lightheadedness upon standing. On February 23, 1977, she was seen by a physician who noted pallor and petechiae, and who found the hematocrit value to be 19 per cent and the platelet count to be 5,000/ mm3. Physical findings, in addition to pallor and petechiae, included bleeding from the uterine cervix and a grade 2/6 apical systolic murmur. The vital signs were normal aside from a pulse rate of 108/min. The mental status and neurologic examinations were within normal limits. The hemoglobin level was 6.2 g/100 ml, the hematocrit value 19 per cent and the platelet count 7,500/mm3. The white blood cell count was 11,600/mm3. Fragmented red blood ceils were seen on the blood smear. The reticulocyte count was 11 per cent. The total serum bilirubin was 1.6 mg/lOO ml and the serum lactic acid dehydrogenase (LDH) 1,120 mlU/ml. The direct Coombs’ test result was negative. Prothrombin and partial thromboplastin times were normal. The urine was positive for blood and protein; only occasional red blood cells were seen in the urine sediment. The serum creatinine was 0.9 mg/lOO ml and the 24-hour urinary protein excretion 5.8 g. A test for serum antinuclear antibody (ANA) was l+ positive with homogeneous nuclear staining. Anti-DNA binding was 2 1.4 per cent (normal less than 16.3 per cent). A bone marrow specimen demonstrated erythroid hyperplasia and increased numbers of megakaryocytes, The administration of prednisone, 60 mg daily, was begun, and blood transfusions were administered. On February 25, during a transfusion,
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patient passed dark urine. The hematocrit value was 24 per cent after the transfusion. The prothrombin and partial thromboplastin times were normal; the serum fibrinogen was 159 mg/lOO ml, and the fibrin degradation products were 32 pg/ml. The prednisone dose was increased to 100 mg daily. On February 26, the hematocrit value was 20 per cent and the platelet count 11,000/mm3. The following day the patient became lethargic and transiently dysarthric. A gingival biopsy was nondiagnostic. Therapy with aspirin and persantine was begun. On February 28, the patient complained of epigastric pain. An x-ray series of the upper gastrointestinal tract revealed no abnormalities. The hematocrit value was 16 per cent and the platelet count 7,000/mm3. Complement levels, tests for cold agglutinins and a sucrose hemolysis test were negative. Transfusions were given. Epigastric pain continued the following day. On March 1, the patient became agitated, confused and dysarthric, and a left hemiparesis was noted. Computerized tomographic scans of the head were within normal limits. The patient became hypotensive and bradycardic, with an increased central venous pressure, and cardiopulmonary arrest ensued. Resuscitative efforts were unsuccessful. the
CLINICAL DISCUSSION Dr. Richard Aach: This patient had a truly catastrophic illness that terminated fatally after approximately two weeks. The illness began following an acute febrile, “flu-like” episode which, in turn, was superimposed on a several month history of easy tiring. The main features of the patient’s illness were a marked anemia, without evidence of external blood loss, and thrombocytopenia. The anemia appeared to be hemolytic and microangiopathic in character, and despite multiple transfusions, large doses of steroids, aspirin and persantine, her anemia and profoundly low platelet count persisted. The patient was never febrile after her “flu-like” illness. Later in her course, she had unmistakable central nervous system abnormalities consisting of dysarthria and hemiparesis. In addition, she had at least two episodes of abdominal pain. One week after admission, she became hypotensive and had a cardiorespiratory arrest from which she could not be successfully resuscitated. Dr. Jost, will you review the patient’s roentgenologic findings? Dr. R. Gilbert Jost: The chest film was unremarkable at the time of the patient’s admission, and chest films taken later in her hospital course were also entirely within normal limits. The x-ray series of the upper gastrointestinal tract was originally interpreted as being within normal limits; however, the fluoroscopist com-
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mented on some prominent folds in the stomach. Diffuse, thickened folds in the stomach are often a nonspecific pattern and, indeed, can be normal, but they can also be seen in association with antral gastritis, with Menetrier’s disease or with lymphoma. The pattern is difficult to interpret roentgenographically, and endoscopy is often required for a precise diagnosis. The computerized tomographic scans of the head were unremarkable. Perhaps I can anticipate the direction of our discussion this afternoon and indicate that in a patient with thrombotic thrombocytopenic purpura, the pathologic findings in the brain would be small microhemorrhages. To my knowledge, we have not had an opportunity as yet to study this disease with computed tomography; however, I would expect the scans to be within normal limits. Dr. Aach: It seems to me that the most logical way to approach this patient’s medical problem is to consider those conditions that can give rise to acute thrombocytopenia and anemia. Dr. Rogers, would you discuss this? Dr. John Rogers: I thought it would be best to review the thinking of a hematologist seeing the patient for the first time. As was pointed out, she had no evidence of blood loss. Assuming that there was no bleeding into her retroperitoneal space or some other hidden place, her falling hematocrit value is evidence that her red blood cells were being destroyed. The initial problem in evaluating any patient with anemia is one of distinguishing increased peripheral destruction of red cells from decreased production of red cells: in her initial laboratory data, the LDH and bilirubin levels were elevated, findings which could be consistent with either possibility. The bone marrow aspirate showed erythroid hyperplasia; this is consistent with an attempt by the marrow to increase production, but it should be pointed out that a situation in which cells are made in the marrow but do not escape into the peripheral blood, that is, ineffective erythropoiesis, might also give this finding. However, this patient also had an increased reticulocyte count, meaning that she not only had the ability to produce red cells but also that they were effectively leaving the bone marrow. This, then, forms a logical basis to say that she had a hemolytic anemia. There were other findings to help us narrow the differential diagnosis of hemolysis. First, hemoglobinuria presumably was present on admission since the urine dip stick test was positive for blood in the absence of red cells in the urine sediment. In addition, after the transfusion, there was gross hemoglobinuria. I am not convinced that that was due to a transfusion reaction, although that was necessarily considered. Other important information was obtained by examining the peripheral blood smear; there were a lot of fragmented red cells, a finding which is caused by external trauma
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TABLE I
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Differential Diagnosis and Relevant Findings
Diagnosis Hypersplenism Intrinsic RBC defect (e.g., GGPD deficiency) Toxin (e.g.. arsine) Heart valve hemolysis Paroxysmal nocturnal hemoglobinuria Evans’ syndrome Disseminated intravascular coagulation Thrombotic thrombocytopenic purpura Vasculitis
NormalSized Spleen
Negative Coombs’ Test
Gross Hemoglobinurla
+ -
+
+ +
+
-
+
+
+
-
+
+
-
+
+
+
+
+ +
+ +
+/+
+ +
+
i-
+
+
+
+
+
+
-
Thrombocytopenia
Schistocytes
Negative Sucrose Hemolysis Test
Normal Coagulation Test -.
Shortened Survival of Transfused RBC
+ +
+ +
+ -
-
+
+
-
+
-t
+
+
+
-
+ +
+ -
+ +
+
+
+
+
+
+
+
+
NOTE: Data from oatient consistent with diaanoses listed at left are designated (+); data inconsistent are designated (--). RBC = red blood cells: GGPD = glucose-g-phosphate dehydrogenase.
damaging circulating erythrocytes. These two findings, hemoglobinuria and schistocytes, are evidence that red cell destruction was occurring within this patient’s vascular system rather than, for instance, occurring exclusively within the spleen. Two bits of evidence suggest that the source of this intravascular hemolysis was extrinsic rather than some intrinsic red ceil defect. First, the presence of schistocytes indicates external trauma. Second, transfusions were given and, apparently, the transfused cells did not survive. We are given the following data from the protocol: immediately after the transfusion, when the patient had the putative reaction, her hematocrit value was 24 per cent, the next day it was 20 per cent and two days later it was 16 per cent. One might argue that her own red cells were being destroyed while the transfused cells survived. We have insufficient data to absolutely exclude that possibility, but I think it most probable that both the transfused donor cells and the patient’s own cells were being destroyed in an indiscriminate fashion. In combination with the hemolytic anemia we also know that she had thrombocytopenia. Presumably, she had the means for making platelets because there were increased quantities of megakaryocytes in her bone marrow aspirate; that is about the only practical means we have of easily assessing whether thrombocytopenia is due to decreased production or to increased destruction of platelets. Our differential diagnosis, therefore, centers around conditions associated with accelerated destruction of both red blood cells and of platelets. I have provided a long list of things that should be considered and have tried to arrange information we have in a way that will allow us to settle on the most likely possibilities (Table I). The important bits of data
to note are thrombocytopenia, a normal-sized spleen, a negative Coombs’ test, gross hemoglobinuria, schistocytes in the peripheral smear, a negative sucrose hemolysis test and a normal coagulation profile on admission. First, in hypersplenism, red cells are destroyed and platelets sequestered in the spleen, but the patient had a normal-sized spleen. Intrinsic red cells defects such as glucose-6-phosphate dehydrogenase deficiency, which is rare in a female, cause hemolysis but are not accompanied by thrombocytopenia. As mentioned previously, an intrinsic defect does not cause schistocytes, and normal cells transfused into a person with such a defect would survive normally. A toxin may cause acute hemolysis; one of the best examples is arsine poisoning in which inhalation may result in catastrophic intravascular hemolysis. I would expect that massive hemolysis might trigger intravascular coagulation with resultant thrombocytopenia. However, this patient had no known exposure and her course was too prolonged. Heart valves may traumatize erythrocytes and destroy them. Our patient had a murmur but, with unusual exceptions, significant heart. valve hemolysis only occurs in patients with a prosthetic valve; this condition is not associated with thrombocytopenia and usually does not cause massive hemoglobinuria although hemoglobin is present in the urine. Now we approach more probable diagnostic possibilities. Paroxysmal nocturnal hemoglobinuria is something we all look for although it is quite rare. It is associated with thrombocytopenia, probably on the basis of decreased platelet production. Such patients may have a normal-sized spleen and also a negative Coombs’ test. They may have gross hemoglobinuria, particularly after receiving a blood transfusion. How-
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ever, they do not have fragmented red cells on the peripheral smear, and the diagnosis was excluded in our patient since her sucrose hemolysis test was negative. The next diagnostic consideration probably explains why prednisone therapy was started when she first came into the hospital, that of immune hemolytic anemia and immune thrombocytopenia or Evans’ syndrome. In this case, the destruction of both blood elements would have been mediated by autoantibodies. Patients may have a normal-sized spleen and the Coombs’ test may be negative if the antibody is present in rather low amounts on the red cells [ 11. Patients may have gross hemoglobinuria but fragmented cells are not seen; rather, classically, spherocytes are present in the peripheral smear. If a person who has autoimmune hemolytic anemia is given a transfusion, the donor cells also have a shortened survival since, in practical terms, the autoantibody would not discriminate between donor and recipient erythrocytes. I think this diagnosis can be ruled out by her subsequent course. Disseminated intravascular coagulation (DIC) triggered by any one of many possible mechanisms was also seriously considered by her physicians; as I have listed, most of her findings were consistent with this diagnosis except for the fact that her coagulation parameters were normal on admission in the face of brisk hemolysis and consumption of platelets. In our experience, thrombocytopenia and anemia of this severity due to the DIC syndrome are always accompanied by easily demonstrated coagulation abnormalities. Thrombotic thrombocytopenic purpura fits best with her presentation and course. I will return to that shortly. Vasculitis can be accompanied by a microangiopathic hemolytic anemia, schistocytes may be present on the peripheral smear, and transfused red cells also would be destroyed. I do not know about gross hemoglobinuria; I have never seen this in a patient with vasculitis. In addition, patients with vasculitis and hemolysis usually also have some derangement of their coagulation tests. Finally, I should include an entity called neoplastic angioendotheliomatosis [2,3] a rare, malignant, multifocal proliferation of the lining cells of small vessels. It is pertinent because we saw such a patient with hemolytic anemia and severe thrombocytopenia last year, and the correct diagnosis was not made until the time of autopsy. In this disease the malignant cells do not invade organs, but rather pile up in the vessels; hematologitally, it appears similar to a vasculitis syndrome. Dr. Aach: Thank you. Dr. Atkinson will consider the possibility of vasculitis shortly. It should be remembered that paroxysmal nocturnal hemoglobinuria may not present in a classic fashion with nocturnal episodes of hemolysis. Paroxysmal nocturnal hemoglobinuria should be considered in any patient with unexplained anemia, particularly when
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there is evidence of intravascular hemolysis. However, the anemia of paroxysmal nocturnal hemoglobinuria is due to a defect of the red cell membrane and does not appear microangiopathic in nature. I certainly agree with you that this patient most likely had thrombotic thrombocytopenia purpura (TTP). Would you review this disorder in greater detail concentrating on its clinical features? Dr. Rogers: Thrombotic thrombocytopenia purpura is a syndrome defined by a pentad of ,findings [4]: hemolytic anemia, thrombocytopenia, central nervous system dysfunction, renal abnormalities and fever. Most patients have these five signs during the course of their illness; the fact that our patient had no fever during her hospital course is somewhat against the diagnosis but would not exclude it [4]. Usually, the illness is preceded by some febrile episode having the appearance of a viral infection of the upper respiratory tract. In TTP, the defect seems to be primarily consumption of platelets since fibrinogen turnover is not accelerated; in disseminated intravascular coagulation, platelets are also consumed but in a parallel fashion fibrinogen turnover is markedly increased [5]. There is no consistent relationship between derangement of coagulation tests and the diagnosis or severity of lTP [6]. The underlying defect is thought to involve triggering of platelet aggregation or adhesion to vascular surfaces with plugging of small vessels. A gingival biopsy has been advocated as a means of diagnosing this process since one frequently can demonstrate small plugs of fibrin and platelets in the gingival small vessels. However these findings are not always present and are not specific for TTP [4], and the fact that her biopsy was unrevealing does not exclude the diagnosis. Another interesting fact is that the disease appears to be a relapsing one. There are reports of recurrences of the illness years after the original episode. In addition, the disease may appear in siblings, and it has been reported in husband and wife. All this suggests that perhaps it is the result of some unusual infectious disorder that alters the endothelium or platelets. Dr. Aach: The gingivae have a rich microcirculation and are an easy site for biopsy. Biopsy usually demonstrates the classic lesion of TTP. It is an important diagnostic procedure, but one should be aware that a gingival biopsy is not always positive. Among seven patients with well-documented TTP who had gingival biopsies, the findings in two were negative. Thus, a negative biopsy is unusual; it does not exclude the diagnosis of TTP. The absence of fever is disturbing to me although we do know that the patient was febrile for a brief period approximately one week before she was hospitalized, just prior to the time that purpura was first recognized. Her illness is certainly consistent with TTP in all other respects. She had renal involvement as indicated by
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proteinuria, central nervous system manifestations and a microangiopathic hemolytic anemia associated with thrombocytopenia. I would like next to turn to a consideration of the etiology of TTP. This has been a subject of much debate and controversy. I have asked Dr. Lawrence Sherman to help clarify
this area for us. Dr. Lawrence Sherman: As Dr. Rogers has indicated,
there has been speculation about infectious agents, none of which has been borne out. I think the major thing that can be said is that currently there is no clear-cut evidence for any specific etiologic agent or association. Similarly, TTP has not been established as being secondary to another disorder, such as malignancy. In those cases of malignancies which have been thought to be underlying TTP, the so-called TTP was really more like the picture of DIC or, occasionally, appeared to be nonbacterial thrombotic endocarditis. From the standpoint of pathogenesis, at the present time I think many people would say that a platelet abnormality may be primary [7] although its nature is unknown. There is no known primary disorder of endothelial cells or underlying structures of the vasculature. Platelet antibodies have not been demonstrated, which casts doubt on the therapeutic use of exchange transfusions [8]. It is difficult conceptually to see what would be accomplished by such exchange if there has been no evidence of an abnormal humoral element. But I think the fact that exchange transfusions have been advocated indicates our degree of ignorance about the pathogenesis of the disease, as well as our desperation. The purported success of the exchange is difficult to evaluate because of the rarity of the disease and other concomitant therapy. Dr. Aach: The earlier literature on TTP favored the hypothesis that the primary event was an injury to the endothelium of blood vessels, perhaps induced by a viral illness. The injury was believed to lead to the deposition of platelets and then fibrin in the form of hyaline occlusions of small blood vessels throughout the body, principally the heart, pancreas and adrenals. Environmental agents have been implicated, including toxins, hair dyes and, at least one report of a rarely described organism, a microtatobiote, a member of the rickettsiales family [9]. I was unable to find any subsequent documentation of an association of TTP with this microorganism normally carried by mites, which of course raises the question about whether or not there is any causal relationship at all. More recently, it has been proposed that the primary event is platelet activation and aggregation in the microcirculation with secondary injury to blood vessel endothelium. Some people consider this disease to be a varient of disseminated intravascular coagulation, although it appears that many experts in the field consider TTP and DIC to be different
PROTEINURIA AND CENTRAL NERVOUS SYSTEM
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conditions. The main argument for distinction is that clotting parameters, other than those associated with platelet activity, are normal early in the course in the majority of patients with TTP. There is a close relative of TTP called the hemolytic-uremic syndrome. This condition is seen primarily in children. It shares many of the clinical and pathologic features of TTP. In many instances, the hemolytic uremic syndrome follows an antecedent acute febrile illness which appears to be clearly distinguishable from the syndrome itself. Very frequently, the illness has been suggestive of a viral gastroenteritis. In most instances, a microorganism has not been identified. However, there are reports in which there has been recovery of the agent responsible for Argentine hemorrhagic fever and documentation of prior ECHO and coxsackie, group A, infection. The evidence of an infectious agent initiating the hemolytic uremic syndrome, therefore, is rather good. It raises what I think is a serious possibility that an infectious agent or agents may, at times, also trigger TTP in adults. Dr. Sherman: Most investigators who have looked for viral or rickettsial infections in adults with TTP have not found any evidence for such a cause. Microscopically, the vascular lesions look singularly bland as compared with the similar clinical picture of various vasculities, as Dr. Rogers noted. There does not seem to be a detectable structural lesion in the vessels. I think this is the major reason it is thought that the platelet event is primary. The fibrin deposition seems to be secondary. DIC can occur in TTP but appears to be a complication. Even in these patients, the response to heparin may be fortuitious as there are reports of DIC in TTP, which was not responsive to heparin [6]. As far as therapy is concerned, those patients who have a brisk DIC as manifested by laboratory tests seem to be the only ones who benefit from heparinization. Why, if this is just a secondary complication, the disease over-all may remit after heparinization in this particular set of patients is not known. But, DIC is worth looking for because one would not want to heparinize patients with TTP. Dr. Aach: As Dr. Rogers indicated earlier, TTP usually runs a very rapid downhill course with most deaths occurring within three months of onset. A variety of therapeutic approaches have been utilized in the treatment of TTP, and I have asked Dr. Sherman to discuss them for us. Dr. Sherman: Initially, most patients were treated with steroids. Other sorts of immunosuppressive therapy have been tried as well. There has been enthusiasm, a year or two ago, for the combined use of splenectomy, steroids and dextran. The use of dextran was related to its potential antiplatelet nature. It is uncertain as to what dextran exactly does. In vivo, it prolongs the bleeding time and also has a significant rheologic effect which
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may perhaps have something to do with its possible efficacy in TTP, unrelated to its effect on the platelets. It is not clear what the direct effect of dextran is on platelets. Aspirin, because of its action on the prostaglandin system, has been used. Dipyridamole, which affects cyclic AMP levels, is also being used. Sulfinpyrazone, which is not as potent a drug in vitro but has had in vivo effects in a number of experimental situations, has also been advocated. As far as the other thrombotic disorders, only dipyridamole has been convincingly described as being an efficacious antithrombotic agent, when artificial prosthetic surfaces are present. Some data have indicated that sulfinpyrazone seems to be of value in arteriovenous-shunt situations and with damaged endothelium, and also in one experimental model system in which a prosthesis was inserted. For that reason, some have tried sulfinpyrazone in TTP with a few successful reports. These successes again raise the possibility of the vascular lesion being primary. I think sulfinpyrazone must be considered therpeutically. The choice of the other agents depends on personal predilections. The wave of enthusiasm for splenectomy has decreased, particularly since a case was reported last year in which TTP developed after splenectomy for idiopathic thrombocytopenic purpura [lo]. Also, there is a surgical risk of splenectomy and that must be considered a more extreme measure as is an exchange transfusion. Lastly, it is very important in this syndrome to emphasize the problem of only successful cases being reported. We do not know how many failures there are with splenectomy or exchange transfusion. A registry has been advocated for TTP. Such would be very desirable as a means of evaluating therapy. Dr. Aach: There is a very nice editorial [7] in the Annals of internal Medicine which reviews the state of the art of therapy for TTP. It also makes a strong plea for a national registry. TTP occurs infrequently so that no one center can accumulate a sufficient number of patients to adequately evaluate the therapy used in the treatment of this condition. In 1971, Dr. Leon Zacharski tried to initiate a national cooperative clinical trial in an effort to determine which form of therapy was most effective. I spoke with Dr. Zacharski earlier this week. He indicated it was not possible to initiate the clinical trial, in large part, because of a natural reluctance on the part of physicians to enter patients with a highly lethal disease into a study which might deprive them of what could turn out to be a life-saving drug or form of therapy. However, a national registry is a very rational alternative for it would not only document the incidence of this disease, but also could still then be used to determine whether or not one form of therapy is clearly advantageous over another. Dr. Zacharski believes that between 50 and 100 new cases of TTP occur in the
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United States each year so that a national registry over a period of several years could provide information of considerable value. Dr. Zacharski” is willing to coordinate the Registry. All documented cases should be reported to him indicating the type of therapy and outcome. Dr. Atkinson, we have come out very strongly for TTP, yet there is some information such as the positive anti-DNA antibodies, which suggest another process, namely, systemic lupus erythematosus. Did this patient have lupus or some other form of systemic vasculitis rather than TTP? Dr. John Atkinson: I do not think this patient had a systemic vasculitis, in particular, systemic lupus erythematosus, for a variety of reasons. The hematologic evaluation by Dr. Rogers was excellent and, for the reasons he carefully delineated, rules out vasculitis as being the underlying cause of the cytopenias. In addition, the only nonhematologic findings this patient had to suggest the presence of lupus were proteinuria and a l+ homogeneous ANA with a slight increase in anti-DNA antibodies. For these reasons and the rapid clinical course, I strongly believe that a systemic collagen vascular disease is not the underlying problem. However, I do want to make a few brief comments regarding these laboratory studies. One relates to the interpretation of a weakly positive (1 -I- homogeneous) ANA and a mildly elevated titer of antibody to DNA. The rheumatology service is often asked for consultative advice regarding patients with similar laboratory data who are usually hospitalized for a diagnostic evaluation. The approach we utilize is to review the history, with particular attention to the major manifestations of lupus as outlined by the American Rheumatism Association. The areas sometimes missed in initial workups relate to the skin manifestations, especially alopecia and oral ulcers. We have also seen several patients in whom a faint butterfly rash was not observed because the patient covered it with makeup. A detailed review of the symptoms was obtained in this patient, and no additional findings were present. Weakly positive (li- at a 1:lO dilution) ANA tests, regardless of the pattern of fluorescence, can usually be disregarded. Weak reactions may be seen in “sick” patients with acute phase reactants. Of course, such a result should also encourage the physician to review the patient’s presentation, with a collagen vascular disease in mind, and also to reorder this test in three to six months as the clinical situation dictates. The ANA is a sensitive screening test but lacks specificity for the diagnosis of systemic lupus erythematosus. Interpretation of this patient’s positive test for anti-DNA antibodies is a little Dr. LeonZacharski, River Junction, Vermont l
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more difficult. The upper limit of normal on the day this patient’s value was increased was 16 per cent; this value is 2 standard deviations above the mean. Therefore, 21.4 per cent binding probably represents a real but slight increase. I do not know the cause of this laboratory finding, but this patient apparently had a modest increase in anti-DNA antibodies. Dr. Aach: It is of interest that a positive lupus erythematosus preparation is found in about 10 per cent of patients with TTP. Further, in some patients with longstanding lupus, lTP has also developed both processes being well-documented histologically [ 1 l]. The interrelationship between TTP and lupus is not understood, but it is intriguing to say the least. Let us now turn to the terminal event. The patient had severe recurrent abdominal pain with slight guarding for two days before she died. Two serum amylase determinations were normal, as were her stool guaiacs. A mild dysarthria and a left hemiparesis developed on the morning of her death. Because of the abdominal pain, an x-ray series of the upper gastrointestinal tract was obtained which essentially showed no abnormalities except for thickened gastric folds. The patient apparently tolerated the procedure without difficulty and on return to the floor, her neurologic status had not changed. She did not have papilledema. Because of the possibility of a subarachnoid bleed or some other form of a major cerebral vascular accident, she then had emergency CT scans of the head which were negative. She was agitated during the procedure and, therefore, received a very small dose of diazepam which calmed her but apparently did not change her vital signs. She was attended throughout this time by the housestaff which I consider to be imperative when an acutely ill patient leaves the medical floor for any diagnostic procedure. Later in the day, after she returned from the scans, she became hypotensive and tachypneic, and had a sinus tachycardia of 112/min. A central venous pressure of 28 cm was noted. Shortly thereafter, her blood pressure became inaudible, although spontaneous respirations continued for a short time. She was given pressors with poor response; an electrocardiogram showed low voltage in all leads. A respiratory arrest occurred and then sinus bradycardia developed followed by ventricular fibrillation, requiring electroshock. A pericardiocentesis was attempted. However, pericardial tamponade was not found and the patient died. Dr. Ruwitch with this information, how can we explain her terminal event? Dr. Joseph Ruwitch: I think that this lady’s terminal course of events did not represent a primary cardiac problem. There are many terminal situations in which it may be very difficult to make a distinction between a primary cardiac event, such as cardiac tamponade or massive pulmonary embolism, and a noncardiac or
PROTEINURIA AND CENTRAL NERVOUS SYSTEM DYSFUNCTION
secondary event. In this situation the sequence of events was relatively straightforward. This woman returned to her bed clearly hypotensive and somnolent, with a “thready” pulse and tachycardia. She had ample manifestations of acute central nervous system malfunction that day and earlier which may very well have altered her autonomic cardiac control mechanisms, which we are recognizing increasingly to exert profound influence on cardiac output and rhythm. Her sequence from this point was one of gradual deterioration, with increasingly shallow respirations and finally bradycardia followed rapidly by asystolic cardiac arrest. The most logical primary event initiating this terminal sequence was hypotension. There is little to suggest that she had an occult hemorrhage, although that is something of which one must be very much aware. Most convincingly against hemorrhagic shock is the high central venous pressure (if the central venous pressure was at all accurate). The small dose of diazepam may or may not have had an effect on her course. If she had acute central nervous system abnormalities affecting her medullary or perhaps hypothalamic autonomic control centers, it is entirely conceivable that what would have otherwise been a relatively innocuous dose of diazepam may have blunted sympathetic responses to some extent, limiting her capability to respond to the ongoing stress of hypotension. Her cardiac event, i.e., bradycardia, appeared relatively late in the sequence, clearly after cessation of respiration and after a period of hypotension, very likely with inadequate coronary circulation. Gradual bradycardiac arrest is the expected event with prolonged myocardial anoxia. I congratulate the housestaff for aggressively considering the possibility of pericardial tamponade. As you know, the triad of a very high venous pressure, tachycardia (at least early) and hypotension, particularly in a relatively comatose state not otherwise well explained, should call to mind the possibility of tamponade, especially when hemorrhage into the pericardium is a possibility. Interestingly, pericardial tamponade may lead to bradycardia, by a different mechanism than the late anoxic bradycardiac arrest. In canines with experimentally induced tamponade there is consistently a vagus-mediated reflex causing relatively sudden bradycardia with attendant rapid deterioration of ventricular function. The meaning of this reflex teleologitally is unclear. It apparently occurs when tamponade progresses to the point of reducing cardiac output below 20 per cent of normal. At this point, ,there is a sudden rapid burst of afferent parasympathetic activity, perhaps from receptors in the atria or coronary sinus. The reflex is abolished by prior vagotomy. The problem clinically with a patient like this is to make the distinction between pericardial tamponade and simply terminal failure of forward output due to
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circulatory shock and secondary depression of left ventricular function. Both of these are important causes of relative electromechanical dissociation due to inadequate ventricular preload, as nicely reviewed by Friedman [ 121. The signs of this terminal “cardiogenic shock” are essentially indistinguishable from the signs of tamponade. Given the inability to rapidly distinguish between these, the emergency attempt at pericardiocentesis was totally appropriate. If one has more time to evaluate the situation and is not immediately faced with a moribund patient, the echocardiogram is an excellent means of differentiating between these two entities. It is a simple, quick, noninvasive means of demonstrating the presence or absence of a pericardial effusion, and it may additionally reflect confirmatory hemodynamic changes one would expect with tamponade [ 131. Dr. Aach: Death due to myocardial infarction does occur in TTP. It is due to extensive involvement of the cardiac microcirculation, and one may not see classic electrocardiographic changes of infarction in this setting
[141. I also have trouble defining her terminal event. Abdominal pain followed by hypotension makes hemorrhagic shock a serious contender, but the central venous pressure should be low, not high, unless it is an agonal determination. However, there was no roentgenologic support for an intra-abdominal or retroperitoneal bleed and I suspect her abdominal pain was due to microinfarctions of the pancreas and/or the bowel, typical of TTP. Her blood gases were normal when she became hypotensive. So I do not think a pulmonary embolism or aspiration explains her terminal event either. In summary, we believe this patient had TTP with involvement of the microcirculation of multiple organs, including the central nervous system, kidneys, heart, pancreas and, quite likely, the bowel. We do not think she had a connective tissue disorder such as lupus. PATHOLOGIC DISCUSSION Dr. Dan Mckeel: I would like to discuss this patient as a classic example of TTP. She had the major findings that set this group of patients apart: thrombocytopenia, multiple organ thrombosis, microangiopathic hemolytic anemia, azotemia and fever (at least initially). Although these clinical features make TTP a very recognizable entity, an attempt to separate these patients as a group based on pathognomonic microscopic lesions is open to debate at this time [ 14,151. In fact, most of the original “pathognomonic” lesions are not confined to patients with l?P. Similar lesions occur in patients with the hemolytic-uremic syndrome and systemic lupus erythematosus; many people believe the lesions are an expression of DIC. The argument gets to be somewhat
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semantic because, in fact, the pathology of TTP is diffuse intravascular microthrombosis. The thrombi seen at autopsy are composed of platelets with a fibrin-fibrinogen component, so at least terminally there must be consumption of clotting factors other than platelets. However, the platelet abnormality may indeed be the primary etiologic defect. In TTP there is a very characteristic organ distribution of lesions. The brain is commonly affected as are the heart, pancreas, kidneys and adrenals. Only rarely are the lungs or the bone marrow involved. In our patient the brain, kidneys, adrenals and heart were the most severely involved organs. A section of the myocardium had three small vessels with various kinds of thrombi (Figure 1) almost completely occluding them. Many acute thrombotic lesions were noted, whereas others revealed recanalized channels and appeared to be more chronic. One of the features that I think separates TTP as a pathologic entity is the massive numbers of these thrombi that occur in any given organ. Commonly, patients with a strongly positive DIC profile come to autopsy, and the pathologist may have to search for thrombi. But, in TTP the involved organs often contain myriad microthrombi. Some portions of the myocardium surrounding occluded vessles showed eosinophilic fibers with hemorrhage denoting that the thrombi caused necrosis focally. These necrotic lesions were multiple, very small and discrete, and it is uncertain whether they actually contributed to death. The coronary arteries were fully patent. No large vessels throughout the body were involved, nor was there evidence of vasculitis. The lungs had only rare thrombi. Both lungs were quite heavy due to congestion and edema, indicating the terminal event possibly was assodiated with cardiac failure. Multiple pulmonary alveolar capillaries had lobulated nuclear masses (Figure 2). These chromatin masses could represent either circulating endothelium, indicating microvascular damage [ 161, or the nuclear profiles could represent circulating megakaryocytes which were increased in the bone marrow. The clumped nuclei of endothelial cells resemble the convoluted nuclei of megakaryocytes; however, the granular cytoplasm characterizing megakaryocytes was not present. Liver sinusoids contained hematopoietic cells. This cellularity could represent either increased marrow mobilization or extramedullary new blood formation. Splenic blood vessels contained platelet thrombi (Figure 3) which could be recognized in sections as granular eosinophilic masses. The pancreas contained more typical thrombi, appearing as hyaline masses which stained weakly or were negative for fibrin. Figure 4 illustrates a pancreatic islet with all the capillaries occluded by thrombotic masses. Other sections of pancreas showed multiple necrotic lesions near occluded
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Figure 1. Three myocardial capillaries (arrows) contain occlusive hyaline thrombi. Hematoxylin and eosin stain; original magnification X 100, reduced by 30 per cent.
Figure 2. Nuclear chromatin (arrow) of uncertain origin in a pulmonary alveolar capillary. Hematoxylin and eosin stain; original magnification X 200, reduced by 30 per cent.
Figure 3. A splenic artery is filled with a thrombus composed primarily of platelets. Hematoxylin and eosin stain; original magnification X 100, reduced by 30 per cent.
Figure 4. Pancreatic islet capillaries are massively occluded by thrombotic material. Hematoxylin and eosin stain; original magnification X 100, reduced by 30 per cent.
Figure 5. A renal,microaneurysm is filled withpartiallyrecanalized thrombus, perhaps representing the formative stage of a “glomeruloid” lesion. Hematoxylin and eosin stain; original magnification X 50, reduced by 30 per cent.
Figure 6. Striking cerebral capillary thrombosis and hemorrhage sparing the intervening brain tissue. Hematoxylin and eosin stain; original magnification X 200, reduced by 30 per cent.
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vessels; this may partially explain the abdominal pain which the patient experienced. The kidneys contained examples of lesions said by some to be pathognomonic of TTP, including glomeruloid lesions and microaneurysms. However, I believe it is now well established that patients with DIC of diverse etiologic origins commonly have microaneurysms of the occluded microvasculature. Figure 5 shows a blood vessel filled with a thrombus; you can appreciate that the wall is thin and dilated. The lesion represents a microaneurysm that is at least as large as the adjacent glomerulus which appears normal. Glomeruloid formations may evolve from microaneurysms, days to weeks later, due to reorganization and re-endothelialization of the thrombus. In the example displayed you can see spaces beginning to enlarge causing the structure to resemble a glomerulus whereas it actually represents a healing thrombosed vessel. The adrenals also contained many microthrombi and foci of necrosis.
Perhaps the most spectacular microscopic lesions were present in sections of the brain. This contrasted to the gross appearance which was entirely unremarkable except for rare petechiae in the cerebral cortex. Figure 6 illustrates a typical field with focal hemorrhage near occluded microvessels without necrosis of the surrounding tissue. The magnitude of the thrombi indicates that major interference with cerebral blood flow must have occurred, suggesting that cerebral microvascular compromise might have been an agonal event. The main final anatomic doses were thrombotic thrombocytopenic purpura with microvascular thrombi in brain, heart, lungs, kidneys, adrenals, spleen and pancreas; erythroid and megakaryocytic hyperplasia in bone marrow; focal myocardial, pancreatic and adrenal necrosis and hemorrhage secondary to the preceding events; extramedullary hematopoiesis; mild cardiomegaly; acute and chronic pulmonary congestion and edema: mild chronic hepatic congestion.
REFERENCES 1.
2.
7.
6.
9.
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Gilliland BC, Baxter E, Evans RS: Red cell antibodies in acquired hemolytic anemia with negative antiglobulin serum tests. N Engl J Med 285: 252, 1971. Braverman IM, Lerner AB: Diffuse malignant proliferation of vascular endothelium: a possible new clinical and pathologic entity. Arch Dermatol 84: 22, 1961. Strouth JC, Donahue S. Ross A, et al.: Neoplastic angioendotheliosis. Neurology 15: 644, 1965. Amarosi EL, Ultman JE: Thrombotic thrombocytopenic purpura. Medicine (Balt) 45: 139, 1966. Harker LA, Slichter SJ: Platelet and fibrinogen consumption in man. N Engl J Med 287: 999, 1972. Jaffe EA. Nachman RL. Merskey C: Thrombotic thrombocytopenic purpura-Coagulation parameters in 12 patients. Blood 42: 499, 1973. Amorosi EL, Karpatkin S: Antiplatelet treatment of thrombotic thrombocytopenic purpura. Ann Intern Med 86: 102, 1977. Bukowski RM, Hewlett JS, Harris JW, et al.: Exchange transfusions in the treatment of thrombotic thrombocytopenic purpura. Sem Hematol 13: 219, 1976. Mettler NE: Isolation of a microtatobiote from patients with
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10.
11.
12. 13.
14.
15. 16.
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hemolytic-uremic syndrome and thrombotic thrombocytopenia in the United States. N Engl J Med 281: 1023, 1969. Zarcharski LR, Lusted D, Glick JL: Thrombotic thrombocytopenic purpura in a previously splenectomized patient. Am J Med 60: 1061, 1976. Dekker A, O’Brien MD, Cammarata R: The association of thrombotic thrombocytopenic purpura with systemic lupus erythematosus. Am J Med Sci 267: 243. 1974. Friedman HS: Diagnostic considerations in electromechanical dissociation. Am J Cardiol 38: 268, 1976. D’Cruz IA, Cohen HC, Prablru R, et al.: Diagnosis of cardiac tamponade by echocardiography. Circulation 52: 460, 1975. Amorosi EL, Ultman JE: Thrombotic thrombocytopenic purpura. Report of 16 cases and review of the literature. Medicine (Balt) 45: 139, 1966. Umlas J, Kaiser J: Thrombohemolytic thrombocytopenic purpura (TTP). Am J Med 49: 723, 1970. Gaynor E, Bouvier C, Spaet TH: Vascular lesions: possible pathogenetic basis of the generalized Schwartzman reaction. Science 170: 986, 1970.
Anemia, Thrombocytopenia, Proteinuria and Central Nervous System Dysfunction
Stenographic reports, edited by Philip E. Cryer, M.D. and John M. Kissane, M.D., of weekly clinicopathologic conferences held in 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, Radiology and Pathology of Washington University School of Medicine. A 43 year old woman was admitted to Barnes Hospital on February 23, 1976, because of weakness, anemia and thrombocytopenia. She died one week later. The patient was well until August 1975 when she began to tire easily. Because of persistent headaches, she discontinued taking an oral contraceptive in October. Fever and chills occurred on February 16, 1976. Petechiae appeared over the lower extremities on the following day, and an episode of epistaxis occurred. She noted lightheadedness upon standing. On February 23, 1977, she was seen by a physician who noted pallor and petechiae, and who found the hematocrit value to be 19 per cent and the platelet count to be 5,000/ mm3. Physical findings, in addition to pallor and petechiae, included bleeding from the uterine cervix and a grade 2/6 apical systolic murmur. The vital signs were normal aside from a pulse rate of 108/min. The mental status and neurologic examinations were within normal limits. The hemoglobin level was 6.2 g/100 ml, the hematocrit value 19 per cent and the platelet count 7,500/mm3. The white blood cell count was 11,600/mm3. Fragmented red blood ceils were seen on the blood smear. The reticulocyte count was 11 per cent. The total serum bilirubin was 1.6 mg/lOO ml and the serum lactic acid dehydrogenase (LDH) 1,120 mlU/ml. The direct Coombs’ test result was negative. Prothrombin and partial thromboplastin times were normal. The urine was positive for blood and protein; only occasional red blood cells were seen in the urine sediment. The serum creatinine was 0.9 mg/lOO ml and the 24-hour urinary protein excretion 5.8 g. A test for serum antinuclear antibody (ANA) was l+ positive with homogeneous nuclear staining. Anti-DNA binding was 2 1.4 per cent (normal less than 16.3 per cent). A bone marrow specimen demonstrated erythroid hyperplasia and increased numbers of megakaryocytes, The administration of prednisone, 60 mg daily, was begun, and blood transfusions were administered. On February 25, during a transfusion,
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patient passed dark urine. The hematocrit value was 24 per cent after the transfusion. The prothrombin and partial thromboplastin times were normal; the serum fibrinogen was 159 mg/lOO ml, and the fibrin degradation products were 32 pg/ml. The prednisone dose was increased to 100 mg daily. On February 26, the hematocrit value was 20 per cent and the platelet count 11,000/mm3. The following day the patient became lethargic and transiently dysarthric. A gingival biopsy was nondiagnostic. Therapy with aspirin and persantine was begun. On February 28, the patient complained of epigastric pain. An x-ray series of the upper gastrointestinal tract revealed no abnormalities. The hematocrit value was 16 per cent and the platelet count 7,000/mm3. Complement levels, tests for cold agglutinins and a sucrose hemolysis test were negative. Transfusions were given. Epigastric pain continued the following day. On March 1, the patient became agitated, confused and dysarthric, and a left hemiparesis was noted. Computerized tomographic scans of the head were within normal limits. The patient became hypotensive and bradycardic, with an increased central venous pressure, and cardiopulmonary arrest ensued. Resuscitative efforts were unsuccessful. the
CLINICAL DISCUSSION Dr. Richard Aach: This patient had a truly catastrophic illness that terminated fatally after approximately two weeks. The illness began following an acute febrile, “flu-like” episode which, in turn, was superimposed on a several month history of easy tiring. The main features of the patient’s illness were a marked anemia, without evidence of external blood loss, and thrombocytopenia. The anemia appeared to be hemolytic and microangiopathic in character, and despite multiple transfusions, large doses of steroids, aspirin and persantine, her anemia and profoundly low platelet count persisted. The patient was never febrile after her “flu-like” illness. Later in her course, she had unmistakable central nervous system abnormalities consisting of dysarthria and hemiparesis. In addition, she had at least two episodes of abdominal pain. One week after admission, she became hypotensive and had a cardiorespiratory arrest from which she could not be successfully resuscitated. Dr. Jost, will you review the patient’s roentgenologic findings? Dr. R. Gilbert Jost: The chest film was unremarkable at the time of the patient’s admission, and chest films taken later in her hospital course were also entirely within normal limits. The x-ray series of the upper gastrointestinal tract was originally interpreted as being within normal limits; however, the fluoroscopist com-
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mented on some prominent folds in the stomach. Diffuse, thickened folds in the stomach are often a nonspecific pattern and, indeed, can be normal, but they can also be seen in association with antral gastritis, with Menetrier’s disease or with lymphoma. The pattern is difficult to interpret roentgenographically, and endoscopy is often required for a precise diagnosis. The computerized tomographic scans of the head were unremarkable. Perhaps I can anticipate the direction of our discussion this afternoon and indicate that in a patient with thrombotic thrombocytopenic purpura, the pathologic findings in the brain would be small microhemorrhages. To my knowledge, we have not had an opportunity as yet to study this disease with computed tomography; however, I would expect the scans to be within normal limits. Dr. Aach: It seems to me that the most logical way to approach this patient’s medical problem is to consider those conditions that can give rise to acute thrombocytopenia and anemia. Dr. Rogers, would you discuss this? Dr. John Rogers: I thought it would be best to review the thinking of a hematologist seeing the patient for the first time. As was pointed out, she had no evidence of blood loss. Assuming that there was no bleeding into her retroperitoneal space or some other hidden place, her falling hematocrit value is evidence that her red blood cells were being destroyed. The initial problem in evaluating any patient with anemia is one of distinguishing increased peripheral destruction of red cells from decreased production of red cells: in her initial laboratory data, the LDH and bilirubin levels were elevated, findings which could be consistent with either possibility. The bone marrow aspirate showed erythroid hyperplasia; this is consistent with an attempt by the marrow to increase production, but it should be pointed out that a situation in which cells are made in the marrow but do not escape into the peripheral blood, that is, ineffective erythropoiesis, might also give this finding. However, this patient also had an increased reticulocyte count, meaning that she not only had the ability to produce red cells but also that they were effectively leaving the bone marrow. This, then, forms a logical basis to say that she had a hemolytic anemia. There were other findings to help us narrow the differential diagnosis of hemolysis. First, hemoglobinuria presumably was present on admission since the urine dip stick test was positive for blood in the absence of red cells in the urine sediment. In addition, after the transfusion, there was gross hemoglobinuria. I am not convinced that that was due to a transfusion reaction, although that was necessarily considered. Other important information was obtained by examining the peripheral blood smear; there were a lot of fragmented red cells, a finding which is caused by external trauma
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TABLE I
PROTEINURIA AND CENTRAL NERVOUS SYSTEM DYSFUNCTION
Differential Diagnosis and Relevant Findings
Diagnosis Hypersplenism Intrinsic RBC defect (e.g., GGPD deficiency) Toxin (e.g.. arsine) Heart valve hemolysis Paroxysmal nocturnal hemoglobinuria Evans’ syndrome Disseminated intravascular coagulation Thrombotic thrombocytopenic purpura Vasculitis
NormalSized Spleen
Negative Coombs’ Test
Gross Hemoglobinurla
+ -
+
+ +
+
-
+
+
+
-
+
+
-
+
+
+
+
+ +
+ +
+/+
+ +
+
i-
+
+
+
+
+
+
-
Thrombocytopenia
Schistocytes
Negative Sucrose Hemolysis Test
Normal Coagulation Test -.
Shortened Survival of Transfused RBC
+ +
+ +
+ -
-
+
+
-
+
-t
+
+
+
-
+ +
+ -
+ +
+
+
+
+
+
+
+
+
NOTE: Data from oatient consistent with diaanoses listed at left are designated (+); data inconsistent are designated (--). RBC = red blood cells: GGPD = glucose-g-phosphate dehydrogenase.
damaging circulating erythrocytes. These two findings, hemoglobinuria and schistocytes, are evidence that red cell destruction was occurring within this patient’s vascular system rather than, for instance, occurring exclusively within the spleen. Two bits of evidence suggest that the source of this intravascular hemolysis was extrinsic rather than some intrinsic red ceil defect. First, the presence of schistocytes indicates external trauma. Second, transfusions were given and, apparently, the transfused cells did not survive. We are given the following data from the protocol: immediately after the transfusion, when the patient had the putative reaction, her hematocrit value was 24 per cent, the next day it was 20 per cent and two days later it was 16 per cent. One might argue that her own red cells were being destroyed while the transfused cells survived. We have insufficient data to absolutely exclude that possibility, but I think it most probable that both the transfused donor cells and the patient’s own cells were being destroyed in an indiscriminate fashion. In combination with the hemolytic anemia we also know that she had thrombocytopenia. Presumably, she had the means for making platelets because there were increased quantities of megakaryocytes in her bone marrow aspirate; that is about the only practical means we have of easily assessing whether thrombocytopenia is due to decreased production or to increased destruction of platelets. Our differential diagnosis, therefore, centers around conditions associated with accelerated destruction of both red blood cells and of platelets. I have provided a long list of things that should be considered and have tried to arrange information we have in a way that will allow us to settle on the most likely possibilities (Table I). The important bits of data
to note are thrombocytopenia, a normal-sized spleen, a negative Coombs’ test, gross hemoglobinuria, schistocytes in the peripheral smear, a negative sucrose hemolysis test and a normal coagulation profile on admission. First, in hypersplenism, red cells are destroyed and platelets sequestered in the spleen, but the patient had a normal-sized spleen. Intrinsic red cells defects such as glucose-6-phosphate dehydrogenase deficiency, which is rare in a female, cause hemolysis but are not accompanied by thrombocytopenia. As mentioned previously, an intrinsic defect does not cause schistocytes, and normal cells transfused into a person with such a defect would survive normally. A toxin may cause acute hemolysis; one of the best examples is arsine poisoning in which inhalation may result in catastrophic intravascular hemolysis. I would expect that massive hemolysis might trigger intravascular coagulation with resultant thrombocytopenia. However, this patient had no known exposure and her course was too prolonged. Heart valves may traumatize erythrocytes and destroy them. Our patient had a murmur but, with unusual exceptions, significant heart. valve hemolysis only occurs in patients with a prosthetic valve; this condition is not associated with thrombocytopenia and usually does not cause massive hemoglobinuria although hemoglobin is present in the urine. Now we approach more probable diagnostic possibilities. Paroxysmal nocturnal hemoglobinuria is something we all look for although it is quite rare. It is associated with thrombocytopenia, probably on the basis of decreased platelet production. Such patients may have a normal-sized spleen and also a negative Coombs’ test. They may have gross hemoglobinuria, particularly after receiving a blood transfusion. How-
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ever, they do not have fragmented red cells on the peripheral smear, and the diagnosis was excluded in our patient since her sucrose hemolysis test was negative. The next diagnostic consideration probably explains why prednisone therapy was started when she first came into the hospital, that of immune hemolytic anemia and immune thrombocytopenia or Evans’ syndrome. In this case, the destruction of both blood elements would have been mediated by autoantibodies. Patients may have a normal-sized spleen and the Coombs’ test may be negative if the antibody is present in rather low amounts on the red cells [ 11. Patients may have gross hemoglobinuria but fragmented cells are not seen; rather, classically, spherocytes are present in the peripheral smear. If a person who has autoimmune hemolytic anemia is given a transfusion, the donor cells also have a shortened survival since, in practical terms, the autoantibody would not discriminate between donor and recipient erythrocytes. I think this diagnosis can be ruled out by her subsequent course. Disseminated intravascular coagulation (DIC) triggered by any one of many possible mechanisms was also seriously considered by her physicians; as I have listed, most of her findings were consistent with this diagnosis except for the fact that her coagulation parameters were normal on admission in the face of brisk hemolysis and consumption of platelets. In our experience, thrombocytopenia and anemia of this severity due to the DIC syndrome are always accompanied by easily demonstrated coagulation abnormalities. Thrombotic thrombocytopenic purpura fits best with her presentation and course. I will return to that shortly. Vasculitis can be accompanied by a microangiopathic hemolytic anemia, schistocytes may be present on the peripheral smear, and transfused red cells also would be destroyed. I do not know about gross hemoglobinuria; I have never seen this in a patient with vasculitis. In addition, patients with vasculitis and hemolysis usually also have some derangement of their coagulation tests. Finally, I should include an entity called neoplastic angioendotheliomatosis [2,3] a rare, malignant, multifocal proliferation of the lining cells of small vessels. It is pertinent because we saw such a patient with hemolytic anemia and severe thrombocytopenia last year, and the correct diagnosis was not made until the time of autopsy. In this disease the malignant cells do not invade organs, but rather pile up in the vessels; hematologitally, it appears similar to a vasculitis syndrome. Dr. Aach: Thank you. Dr. Atkinson will consider the possibility of vasculitis shortly. It should be remembered that paroxysmal nocturnal hemoglobinuria may not present in a classic fashion with nocturnal episodes of hemolysis. Paroxysmal nocturnal hemoglobinuria should be considered in any patient with unexplained anemia, particularly when
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there is evidence of intravascular hemolysis. However, the anemia of paroxysmal nocturnal hemoglobinuria is due to a defect of the red cell membrane and does not appear microangiopathic in nature. I certainly agree with you that this patient most likely had thrombotic thrombocytopenia purpura (TTP). Would you review this disorder in greater detail concentrating on its clinical features? Dr. Rogers: Thrombotic thrombocytopenia purpura is a syndrome defined by a pentad of ,findings [4]: hemolytic anemia, thrombocytopenia, central nervous system dysfunction, renal abnormalities and fever. Most patients have these five signs during the course of their illness; the fact that our patient had no fever during her hospital course is somewhat against the diagnosis but would not exclude it [4]. Usually, the illness is preceded by some febrile episode having the appearance of a viral infection of the upper respiratory tract. In TTP, the defect seems to be primarily consumption of platelets since fibrinogen turnover is not accelerated; in disseminated intravascular coagulation, platelets are also consumed but in a parallel fashion fibrinogen turnover is markedly increased [5]. There is no consistent relationship between derangement of coagulation tests and the diagnosis or severity of lTP [6]. The underlying defect is thought to involve triggering of platelet aggregation or adhesion to vascular surfaces with plugging of small vessels. A gingival biopsy has been advocated as a means of diagnosing this process since one frequently can demonstrate small plugs of fibrin and platelets in the gingival small vessels. However these findings are not always present and are not specific for TTP [4], and the fact that her biopsy was unrevealing does not exclude the diagnosis. Another interesting fact is that the disease appears to be a relapsing one. There are reports of recurrences of the illness years after the original episode. In addition, the disease may appear in siblings, and it has been reported in husband and wife. All this suggests that perhaps it is the result of some unusual infectious disorder that alters the endothelium or platelets. Dr. Aach: The gingivae have a rich microcirculation and are an easy site for biopsy. Biopsy usually demonstrates the classic lesion of TTP. It is an important diagnostic procedure, but one should be aware that a gingival biopsy is not always positive. Among seven patients with well-documented TTP who had gingival biopsies, the findings in two were negative. Thus, a negative biopsy is unusual; it does not exclude the diagnosis of TTP. The absence of fever is disturbing to me although we do know that the patient was febrile for a brief period approximately one week before she was hospitalized, just prior to the time that purpura was first recognized. Her illness is certainly consistent with TTP in all other respects. She had renal involvement as indicated by
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proteinuria, central nervous system manifestations and a microangiopathic hemolytic anemia associated with thrombocytopenia. I would like next to turn to a consideration of the etiology of TTP. This has been a subject of much debate and controversy. I have asked Dr. Lawrence Sherman to help clarify
this area for us. Dr. Lawrence Sherman: As Dr. Rogers has indicated,
there has been speculation about infectious agents, none of which has been borne out. I think the major thing that can be said is that currently there is no clear-cut evidence for any specific etiologic agent or association. Similarly, TTP has not been established as being secondary to another disorder, such as malignancy. In those cases of malignancies which have been thought to be underlying TTP, the so-called TTP was really more like the picture of DIC or, occasionally, appeared to be nonbacterial thrombotic endocarditis. From the standpoint of pathogenesis, at the present time I think many people would say that a platelet abnormality may be primary [7] although its nature is unknown. There is no known primary disorder of endothelial cells or underlying structures of the vasculature. Platelet antibodies have not been demonstrated, which casts doubt on the therapeutic use of exchange transfusions [8]. It is difficult conceptually to see what would be accomplished by such exchange if there has been no evidence of an abnormal humoral element. But I think the fact that exchange transfusions have been advocated indicates our degree of ignorance about the pathogenesis of the disease, as well as our desperation. The purported success of the exchange is difficult to evaluate because of the rarity of the disease and other concomitant therapy. Dr. Aach: The earlier literature on TTP favored the hypothesis that the primary event was an injury to the endothelium of blood vessels, perhaps induced by a viral illness. The injury was believed to lead to the deposition of platelets and then fibrin in the form of hyaline occlusions of small blood vessels throughout the body, principally the heart, pancreas and adrenals. Environmental agents have been implicated, including toxins, hair dyes and, at least one report of a rarely described organism, a microtatobiote, a member of the rickettsiales family [9]. I was unable to find any subsequent documentation of an association of TTP with this microorganism normally carried by mites, which of course raises the question about whether or not there is any causal relationship at all. More recently, it has been proposed that the primary event is platelet activation and aggregation in the microcirculation with secondary injury to blood vessel endothelium. Some people consider this disease to be a varient of disseminated intravascular coagulation, although it appears that many experts in the field consider TTP and DIC to be different
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conditions. The main argument for distinction is that clotting parameters, other than those associated with platelet activity, are normal early in the course in the majority of patients with TTP. There is a close relative of TTP called the hemolytic-uremic syndrome. This condition is seen primarily in children. It shares many of the clinical and pathologic features of TTP. In many instances, the hemolytic uremic syndrome follows an antecedent acute febrile illness which appears to be clearly distinguishable from the syndrome itself. Very frequently, the illness has been suggestive of a viral gastroenteritis. In most instances, a microorganism has not been identified. However, there are reports in which there has been recovery of the agent responsible for Argentine hemorrhagic fever and documentation of prior ECHO and coxsackie, group A, infection. The evidence of an infectious agent initiating the hemolytic uremic syndrome, therefore, is rather good. It raises what I think is a serious possibility that an infectious agent or agents may, at times, also trigger TTP in adults. Dr. Sherman: Most investigators who have looked for viral or rickettsial infections in adults with TTP have not found any evidence for such a cause. Microscopically, the vascular lesions look singularly bland as compared with the similar clinical picture of various vasculities, as Dr. Rogers noted. There does not seem to be a detectable structural lesion in the vessels. I think this is the major reason it is thought that the platelet event is primary. The fibrin deposition seems to be secondary. DIC can occur in TTP but appears to be a complication. Even in these patients, the response to heparin may be fortuitious as there are reports of DIC in TTP, which was not responsive to heparin [6]. As far as therapy is concerned, those patients who have a brisk DIC as manifested by laboratory tests seem to be the only ones who benefit from heparinization. Why, if this is just a secondary complication, the disease over-all may remit after heparinization in this particular set of patients is not known. But, DIC is worth looking for because one would not want to heparinize patients with TTP. Dr. Aach: As Dr. Rogers indicated earlier, TTP usually runs a very rapid downhill course with most deaths occurring within three months of onset. A variety of therapeutic approaches have been utilized in the treatment of TTP, and I have asked Dr. Sherman to discuss them for us. Dr. Sherman: Initially, most patients were treated with steroids. Other sorts of immunosuppressive therapy have been tried as well. There has been enthusiasm, a year or two ago, for the combined use of splenectomy, steroids and dextran. The use of dextran was related to its potential antiplatelet nature. It is uncertain as to what dextran exactly does. In vivo, it prolongs the bleeding time and also has a significant rheologic effect which
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may perhaps have something to do with its possible efficacy in TTP, unrelated to its effect on the platelets. It is not clear what the direct effect of dextran is on platelets. Aspirin, because of its action on the prostaglandin system, has been used. Dipyridamole, which affects cyclic AMP levels, is also being used. Sulfinpyrazone, which is not as potent a drug in vitro but has had in vivo effects in a number of experimental situations, has also been advocated. As far as the other thrombotic disorders, only dipyridamole has been convincingly described as being an efficacious antithrombotic agent, when artificial prosthetic surfaces are present. Some data have indicated that sulfinpyrazone seems to be of value in arteriovenous-shunt situations and with damaged endothelium, and also in one experimental model system in which a prosthesis was inserted. For that reason, some have tried sulfinpyrazone in TTP with a few successful reports. These successes again raise the possibility of the vascular lesion being primary. I think sulfinpyrazone must be considered therpeutically. The choice of the other agents depends on personal predilections. The wave of enthusiasm for splenectomy has decreased, particularly since a case was reported last year in which TTP developed after splenectomy for idiopathic thrombocytopenic purpura [lo]. Also, there is a surgical risk of splenectomy and that must be considered a more extreme measure as is an exchange transfusion. Lastly, it is very important in this syndrome to emphasize the problem of only successful cases being reported. We do not know how many failures there are with splenectomy or exchange transfusion. A registry has been advocated for TTP. Such would be very desirable as a means of evaluating therapy. Dr. Aach: There is a very nice editorial [7] in the Annals of internal Medicine which reviews the state of the art of therapy for TTP. It also makes a strong plea for a national registry. TTP occurs infrequently so that no one center can accumulate a sufficient number of patients to adequately evaluate the therapy used in the treatment of this condition. In 1971, Dr. Leon Zacharski tried to initiate a national cooperative clinical trial in an effort to determine which form of therapy was most effective. I spoke with Dr. Zacharski earlier this week. He indicated it was not possible to initiate the clinical trial, in large part, because of a natural reluctance on the part of physicians to enter patients with a highly lethal disease into a study which might deprive them of what could turn out to be a life-saving drug or form of therapy. However, a national registry is a very rational alternative for it would not only document the incidence of this disease, but also could still then be used to determine whether or not one form of therapy is clearly advantageous over another. Dr. Zacharski believes that between 50 and 100 new cases of TTP occur in the
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United States each year so that a national registry over a period of several years could provide information of considerable value. Dr. Zacharski” is willing to coordinate the Registry. All documented cases should be reported to him indicating the type of therapy and outcome. Dr. Atkinson, we have come out very strongly for TTP, yet there is some information such as the positive anti-DNA antibodies, which suggest another process, namely, systemic lupus erythematosus. Did this patient have lupus or some other form of systemic vasculitis rather than TTP? Dr. John Atkinson: I do not think this patient had a systemic vasculitis, in particular, systemic lupus erythematosus, for a variety of reasons. The hematologic evaluation by Dr. Rogers was excellent and, for the reasons he carefully delineated, rules out vasculitis as being the underlying cause of the cytopenias. In addition, the only nonhematologic findings this patient had to suggest the presence of lupus were proteinuria and a l+ homogeneous ANA with a slight increase in anti-DNA antibodies. For these reasons and the rapid clinical course, I strongly believe that a systemic collagen vascular disease is not the underlying problem. However, I do want to make a few brief comments regarding these laboratory studies. One relates to the interpretation of a weakly positive (1 -I- homogeneous) ANA and a mildly elevated titer of antibody to DNA. The rheumatology service is often asked for consultative advice regarding patients with similar laboratory data who are usually hospitalized for a diagnostic evaluation. The approach we utilize is to review the history, with particular attention to the major manifestations of lupus as outlined by the American Rheumatism Association. The areas sometimes missed in initial workups relate to the skin manifestations, especially alopecia and oral ulcers. We have also seen several patients in whom a faint butterfly rash was not observed because the patient covered it with makeup. A detailed review of the symptoms was obtained in this patient, and no additional findings were present. Weakly positive (li- at a 1:lO dilution) ANA tests, regardless of the pattern of fluorescence, can usually be disregarded. Weak reactions may be seen in “sick” patients with acute phase reactants. Of course, such a result should also encourage the physician to review the patient’s presentation, with a collagen vascular disease in mind, and also to reorder this test in three to six months as the clinical situation dictates. The ANA is a sensitive screening test but lacks specificity for the diagnosis of systemic lupus erythematosus. Interpretation of this patient’s positive test for anti-DNA antibodies is a little Dr. LeonZacharski, River Junction, Vermont l
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more difficult. The upper limit of normal on the day this patient’s value was increased was 16 per cent; this value is 2 standard deviations above the mean. Therefore, 21.4 per cent binding probably represents a real but slight increase. I do not know the cause of this laboratory finding, but this patient apparently had a modest increase in anti-DNA antibodies. Dr. Aach: It is of interest that a positive lupus erythematosus preparation is found in about 10 per cent of patients with TTP. Further, in some patients with longstanding lupus, lTP has also developed both processes being well-documented histologically [ 1 l]. The interrelationship between TTP and lupus is not understood, but it is intriguing to say the least. Let us now turn to the terminal event. The patient had severe recurrent abdominal pain with slight guarding for two days before she died. Two serum amylase determinations were normal, as were her stool guaiacs. A mild dysarthria and a left hemiparesis developed on the morning of her death. Because of the abdominal pain, an x-ray series of the upper gastrointestinal tract was obtained which essentially showed no abnormalities except for thickened gastric folds. The patient apparently tolerated the procedure without difficulty and on return to the floor, her neurologic status had not changed. She did not have papilledema. Because of the possibility of a subarachnoid bleed or some other form of a major cerebral vascular accident, she then had emergency CT scans of the head which were negative. She was agitated during the procedure and, therefore, received a very small dose of diazepam which calmed her but apparently did not change her vital signs. She was attended throughout this time by the housestaff which I consider to be imperative when an acutely ill patient leaves the medical floor for any diagnostic procedure. Later in the day, after she returned from the scans, she became hypotensive and tachypneic, and had a sinus tachycardia of 112/min. A central venous pressure of 28 cm was noted. Shortly thereafter, her blood pressure became inaudible, although spontaneous respirations continued for a short time. She was given pressors with poor response; an electrocardiogram showed low voltage in all leads. A respiratory arrest occurred and then sinus bradycardia developed followed by ventricular fibrillation, requiring electroshock. A pericardiocentesis was attempted. However, pericardial tamponade was not found and the patient died. Dr. Ruwitch with this information, how can we explain her terminal event? Dr. Joseph Ruwitch: I think that this lady’s terminal course of events did not represent a primary cardiac problem. There are many terminal situations in which it may be very difficult to make a distinction between a primary cardiac event, such as cardiac tamponade or massive pulmonary embolism, and a noncardiac or
PROTEINURIA AND CENTRAL NERVOUS SYSTEM DYSFUNCTION
secondary event. In this situation the sequence of events was relatively straightforward. This woman returned to her bed clearly hypotensive and somnolent, with a “thready” pulse and tachycardia. She had ample manifestations of acute central nervous system malfunction that day and earlier which may very well have altered her autonomic cardiac control mechanisms, which we are recognizing increasingly to exert profound influence on cardiac output and rhythm. Her sequence from this point was one of gradual deterioration, with increasingly shallow respirations and finally bradycardia followed rapidly by asystolic cardiac arrest. The most logical primary event initiating this terminal sequence was hypotension. There is little to suggest that she had an occult hemorrhage, although that is something of which one must be very much aware. Most convincingly against hemorrhagic shock is the high central venous pressure (if the central venous pressure was at all accurate). The small dose of diazepam may or may not have had an effect on her course. If she had acute central nervous system abnormalities affecting her medullary or perhaps hypothalamic autonomic control centers, it is entirely conceivable that what would have otherwise been a relatively innocuous dose of diazepam may have blunted sympathetic responses to some extent, limiting her capability to respond to the ongoing stress of hypotension. Her cardiac event, i.e., bradycardia, appeared relatively late in the sequence, clearly after cessation of respiration and after a period of hypotension, very likely with inadequate coronary circulation. Gradual bradycardiac arrest is the expected event with prolonged myocardial anoxia. I congratulate the housestaff for aggressively considering the possibility of pericardial tamponade. As you know, the triad of a very high venous pressure, tachycardia (at least early) and hypotension, particularly in a relatively comatose state not otherwise well explained, should call to mind the possibility of tamponade, especially when hemorrhage into the pericardium is a possibility. Interestingly, pericardial tamponade may lead to bradycardia, by a different mechanism than the late anoxic bradycardiac arrest. In canines with experimentally induced tamponade there is consistently a vagus-mediated reflex causing relatively sudden bradycardia with attendant rapid deterioration of ventricular function. The meaning of this reflex teleologitally is unclear. It apparently occurs when tamponade progresses to the point of reducing cardiac output below 20 per cent of normal. At this point, ,there is a sudden rapid burst of afferent parasympathetic activity, perhaps from receptors in the atria or coronary sinus. The reflex is abolished by prior vagotomy. The problem clinically with a patient like this is to make the distinction between pericardial tamponade and simply terminal failure of forward output due to
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circulatory shock and secondary depression of left ventricular function. Both of these are important causes of relative electromechanical dissociation due to inadequate ventricular preload, as nicely reviewed by Friedman [ 121. The signs of this terminal “cardiogenic shock” are essentially indistinguishable from the signs of tamponade. Given the inability to rapidly distinguish between these, the emergency attempt at pericardiocentesis was totally appropriate. If one has more time to evaluate the situation and is not immediately faced with a moribund patient, the echocardiogram is an excellent means of differentiating between these two entities. It is a simple, quick, noninvasive means of demonstrating the presence or absence of a pericardial effusion, and it may additionally reflect confirmatory hemodynamic changes one would expect with tamponade [ 131. Dr. Aach: Death due to myocardial infarction does occur in TTP. It is due to extensive involvement of the cardiac microcirculation, and one may not see classic electrocardiographic changes of infarction in this setting
[141. I also have trouble defining her terminal event. Abdominal pain followed by hypotension makes hemorrhagic shock a serious contender, but the central venous pressure should be low, not high, unless it is an agonal determination. However, there was no roentgenologic support for an intra-abdominal or retroperitoneal bleed and I suspect her abdominal pain was due to microinfarctions of the pancreas and/or the bowel, typical of TTP. Her blood gases were normal when she became hypotensive. So I do not think a pulmonary embolism or aspiration explains her terminal event either. In summary, we believe this patient had TTP with involvement of the microcirculation of multiple organs, including the central nervous system, kidneys, heart, pancreas and, quite likely, the bowel. We do not think she had a connective tissue disorder such as lupus. PATHOLOGIC DISCUSSION Dr. Dan Mckeel: I would like to discuss this patient as a classic example of TTP. She had the major findings that set this group of patients apart: thrombocytopenia, multiple organ thrombosis, microangiopathic hemolytic anemia, azotemia and fever (at least initially). Although these clinical features make TTP a very recognizable entity, an attempt to separate these patients as a group based on pathognomonic microscopic lesions is open to debate at this time [ 14,151. In fact, most of the original “pathognomonic” lesions are not confined to patients with l?P. Similar lesions occur in patients with the hemolytic-uremic syndrome and systemic lupus erythematosus; many people believe the lesions are an expression of DIC. The argument gets to be somewhat
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semantic because, in fact, the pathology of TTP is diffuse intravascular microthrombosis. The thrombi seen at autopsy are composed of platelets with a fibrin-fibrinogen component, so at least terminally there must be consumption of clotting factors other than platelets. However, the platelet abnormality may indeed be the primary etiologic defect. In TTP there is a very characteristic organ distribution of lesions. The brain is commonly affected as are the heart, pancreas, kidneys and adrenals. Only rarely are the lungs or the bone marrow involved. In our patient the brain, kidneys, adrenals and heart were the most severely involved organs. A section of the myocardium had three small vessels with various kinds of thrombi (Figure 1) almost completely occluding them. Many acute thrombotic lesions were noted, whereas others revealed recanalized channels and appeared to be more chronic. One of the features that I think separates TTP as a pathologic entity is the massive numbers of these thrombi that occur in any given organ. Commonly, patients with a strongly positive DIC profile come to autopsy, and the pathologist may have to search for thrombi. But, in TTP the involved organs often contain myriad microthrombi. Some portions of the myocardium surrounding occluded vessles showed eosinophilic fibers with hemorrhage denoting that the thrombi caused necrosis focally. These necrotic lesions were multiple, very small and discrete, and it is uncertain whether they actually contributed to death. The coronary arteries were fully patent. No large vessels throughout the body were involved, nor was there evidence of vasculitis. The lungs had only rare thrombi. Both lungs were quite heavy due to congestion and edema, indicating the terminal event possibly was assodiated with cardiac failure. Multiple pulmonary alveolar capillaries had lobulated nuclear masses (Figure 2). These chromatin masses could represent either circulating endothelium, indicating microvascular damage [ 161, or the nuclear profiles could represent circulating megakaryocytes which were increased in the bone marrow. The clumped nuclei of endothelial cells resemble the convoluted nuclei of megakaryocytes; however, the granular cytoplasm characterizing megakaryocytes was not present. Liver sinusoids contained hematopoietic cells. This cellularity could represent either increased marrow mobilization or extramedullary new blood formation. Splenic blood vessels contained platelet thrombi (Figure 3) which could be recognized in sections as granular eosinophilic masses. The pancreas contained more typical thrombi, appearing as hyaline masses which stained weakly or were negative for fibrin. Figure 4 illustrates a pancreatic islet with all the capillaries occluded by thrombotic masses. Other sections of pancreas showed multiple necrotic lesions near occluded
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Figure 1. Three myocardial capillaries (arrows) contain occlusive hyaline thrombi. Hematoxylin and eosin stain; original magnification X 100, reduced by 30 per cent.
Figure 2. Nuclear chromatin (arrow) of uncertain origin in a pulmonary alveolar capillary. Hematoxylin and eosin stain; original magnification X 200, reduced by 30 per cent.
Figure 3. A splenic artery is filled with a thrombus composed primarily of platelets. Hematoxylin and eosin stain; original magnification X 100, reduced by 30 per cent.
Figure 4. Pancreatic islet capillaries are massively occluded by thrombotic material. Hematoxylin and eosin stain; original magnification X 100, reduced by 30 per cent.
Figure 5. A renal,microaneurysm is filled withpartiallyrecanalized thrombus, perhaps representing the formative stage of a “glomeruloid” lesion. Hematoxylin and eosin stain; original magnification X 50, reduced by 30 per cent.
Figure 6. Striking cerebral capillary thrombosis and hemorrhage sparing the intervening brain tissue. Hematoxylin and eosin stain; original magnification X 200, reduced by 30 per cent.
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vessels; this may partially explain the abdominal pain which the patient experienced. The kidneys contained examples of lesions said by some to be pathognomonic of TTP, including glomeruloid lesions and microaneurysms. However, I believe it is now well established that patients with DIC of diverse etiologic origins commonly have microaneurysms of the occluded microvasculature. Figure 5 shows a blood vessel filled with a thrombus; you can appreciate that the wall is thin and dilated. The lesion represents a microaneurysm that is at least as large as the adjacent glomerulus which appears normal. Glomeruloid formations may evolve from microaneurysms, days to weeks later, due to reorganization and re-endothelialization of the thrombus. In the example displayed you can see spaces beginning to enlarge causing the structure to resemble a glomerulus whereas it actually represents a healing thrombosed vessel. The adrenals also contained many microthrombi and foci of necrosis.
Perhaps the most spectacular microscopic lesions were present in sections of the brain. This contrasted to the gross appearance which was entirely unremarkable except for rare petechiae in the cerebral cortex. Figure 6 illustrates a typical field with focal hemorrhage near occluded microvessels without necrosis of the surrounding tissue. The magnitude of the thrombi indicates that major interference with cerebral blood flow must have occurred, suggesting that cerebral microvascular compromise might have been an agonal event. The main final anatomic doses were thrombotic thrombocytopenic purpura with microvascular thrombi in brain, heart, lungs, kidneys, adrenals, spleen and pancreas; erythroid and megakaryocytic hyperplasia in bone marrow; focal myocardial, pancreatic and adrenal necrosis and hemorrhage secondary to the preceding events; extramedullary hematopoiesis; mild cardiomegaly; acute and chronic pulmonary congestion and edema: mild chronic hepatic congestion.
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Gilliland BC, Baxter E, Evans RS: Red cell antibodies in acquired hemolytic anemia with negative antiglobulin serum tests. N Engl J Med 285: 252, 1971. Braverman IM, Lerner AB: Diffuse malignant proliferation of vascular endothelium: a possible new clinical and pathologic entity. Arch Dermatol 84: 22, 1961. Strouth JC, Donahue S. Ross A, et al.: Neoplastic angioendotheliosis. Neurology 15: 644, 1965. Amarosi EL, Ultman JE: Thrombotic thrombocytopenic purpura. Medicine (Balt) 45: 139, 1966. Harker LA, Slichter SJ: Platelet and fibrinogen consumption in man. N Engl J Med 287: 999, 1972. Jaffe EA. Nachman RL. Merskey C: Thrombotic thrombocytopenic purpura-Coagulation parameters in 12 patients. Blood 42: 499, 1973. Amorosi EL, Karpatkin S: Antiplatelet treatment of thrombotic thrombocytopenic purpura. Ann Intern Med 86: 102, 1977. Bukowski RM, Hewlett JS, Harris JW, et al.: Exchange transfusions in the treatment of thrombotic thrombocytopenic purpura. Sem Hematol 13: 219, 1976. Mettler NE: Isolation of a microtatobiote from patients with
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hemolytic-uremic syndrome and thrombotic thrombocytopenia in the United States. N Engl J Med 281: 1023, 1969. Zarcharski LR, Lusted D, Glick JL: Thrombotic thrombocytopenic purpura in a previously splenectomized patient. Am J Med 60: 1061, 1976. Dekker A, O’Brien MD, Cammarata R: The association of thrombotic thrombocytopenic purpura with systemic lupus erythematosus. Am J Med Sci 267: 243. 1974. Friedman HS: Diagnostic considerations in electromechanical dissociation. Am J Cardiol 38: 268, 1976. D’Cruz IA, Cohen HC, Prablru R, et al.: Diagnosis of cardiac tamponade by echocardiography. Circulation 52: 460, 1975. Amorosi EL, Ultman JE: Thrombotic thrombocytopenic purpura. Report of 16 cases and review of the literature. Medicine (Balt) 45: 139, 1966. Umlas J, Kaiser J: Thrombohemolytic thrombocytopenic purpura (TTP). Am J Med 49: 723, 1970. Gaynor E, Bouvier C, Spaet TH: Vascular lesions: possible pathogenetic basis of the generalized Schwartzman reaction. Science 170: 986, 1970.