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Clinicopathologic Conference*Presented at King Faisal Specialist Hospital and Research, Centre, 23 April 1984.

1985; King Faisal Specialist Hospital and Research Centre; Volume: 5; Issue: 2 Linguagem: Inglês

10.5144/0256-4947.1985.117

0975-4466

M. Andrew Padmos, William Cumming, Galal M. Ziady, Mohamed Ashraf Ali, Lucio Luzzatto, John T. Godwin,

Hematological disorders and diagnostics

Clinicopathologic ConferanceClinicopathologic Conference**Presented at King Faisal Specialist Hospital and Research, Centre, 23 April 1984. M. Andrew Padmos, MD, FRCP(C) William Cumming, MD Galal M. Ziady, MD, FCCP, FACC M. Ashraf Ali, MD Lucio Luzzatto, and MD John T. GodwinMD M. Andrew Padmos Staff Hematologist, Department of Oncology, King Faisal Specialist Hospital Search for more papers by this author , William Cumming Staff Radiologist, Department of Radiology, King Faisal Specialist Hospital Search for more papers by this author , Galal M. Ziady Staff Cardiologist, Department of Medicine, King Faisal Specialist Hospital Search for more papers by this author , M. Ashraf Ali Pathologist, Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital Search for more papers by this author , Lucio Luzzatto Visiting Professor, Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Department of Hematology, Royal Postgraduate Medical School, Hammersmith Hospital, Ducane Road, London W120HS, England Search for more papers by this author , and John T. Godwin Chairman, Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia Search for more papers by this author Published Online:1 Apr 1985https://doi.org/10.5144/0256-4947.1985.117SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutCASE PRESENTATIONA 22-year-old carpenter, resident in the United Kingdom for 15 years, but originally from Jamaica (West Indies) was admitted on 26 September 1974 because of pain in the right groin for three days. The pain had been of sudden onset and rapidly had become so severe that it confined the patient to bed. He remembered similar attacks of pain, mostly in the back but also in the thighs, lasting a week at a time, about six times a year for the last four years. He had never been hospitalized. His back pain was at one time thought to be due to a slipped disc. He took no drugs, and the pain was not brought on by exercise. His friends noticed that his eyes and fingers were intermittently very yellow, and he had noticed that his urine was sometimes beer-colored. At one time he was told he had an “African” disease. He had no past history of tuberculosis or rheumatic fever, and he never had an operation. His parents, two sisters, and one brother were alive and well; but one brother died in infancy of “blood disease.” Otherwise, he was fit and well and a nonsmoker.On physical examination, the patient was not acutely ill. Temperature was 37.2 °C. There was marked jaundice of sclerae and palms; he was slightly pale. Pulse was 96/min and regular, blood pressure 135/70 mmHg. Jugular venous pressure was not raised, and there was no evidence of heart failure. Peripheral pulses were present and feet warm. Chest was clear. Tonsils were possibly a little inflamed, and small cervical nodes were palpable. There were no masses in the abdomen. Central nervous system was normal. There was tenderness in the right groin, and the medial thigh movements of the hip were painful. Internal rotation was markedly limited. Active abduction of the right hip was weak.Laboratory investigation revealed hemoglobin 11.1 gm/dl, white cell count of 11,800/mm3 with 58% neutrophils, 34% lymphocytes, 8% monocytes, and occasional late normoblasts. Blood film revealed anisocytosis, poikilocytosis, and sickle cells. Reticulocytes were 19%, platelets 510,000. Hemoglobin electrophoresis revealed a major band in the position of HbS. HbF was 10.4%, and HbA2 was 1.6%. Other values were: urea, 29 mg/dl; creatinine, 0.8 mg/dl; sodium, 141 mmol/l; potassium, 5.2 mmol/l; bicarbonate, 27 mmol/l; uric acid, 5.0 mg/ml; calcium, 9.8 mg/dl; cholesterol, 118 mg/dl; total protein, 8.6 mg/dl; albumin, 4.4 gm/dl; SGOT, 17 U/l; alkaline phosphatase, 83 U/l; bilirubin, 3.51 gm/dl (33% conjugated). Urine was negative for protein, urobilinogen, and bile. A throat swab grew no pathogens, and blood cultures were sterile. Radiologic examination of the pelvis showed increased prominence of bone trabeculae, but no evidence of osteomyelitis.COURSEThe patient was given analgesics. Fever and pain settled rapidly, and jaundice decreased. The patient was discharged after six days in good condition. Over the next 8½ years the patient attended the Hematology Clinic. During this period, hemoglobin levels ranged from 7.4 to 11.0 gm/dl. He was admitted several times, briefly, because of painful episodes, and on three occasions received blood transfusions. On two occasions these episodes were described as “chest crises,” and in one of these a left lower lobe consolidation was seen radiologically. The patient had echocardiogram studies in 1978 and again in 1982. Some serial laboratory results for 1982–1983 are given in Table 1.Table 1. Selected serial laboratory findings over the last six monthsTable 1. Selected serial laboratory findings over the last six monthsOn 27 March 1983 the patient was admitted again because of sudden onset of back pain and some pleuritic chest pain. Four days prior to this he had had a flu-like illness and had developed a productive cough. On examination he was obviously in pain. He was not cyanotic. Respiratory rate was 32/min, and the chest was clinically clear. The rest of the examination was unremarkable. Laboratory investigations gave the results shown in the last lines of Table 1, and in addition a PO2 of 211 mmHg and a PCo2 of 46 mmHg. By the following day, although still in pain, the patient felt better, but coarse crackles were present on both sides of the chest. He was not obviously distressed in breathing. Later that day, however, the patient suddenly became tachypneic with widespread chest crepitations consistent with severe pulmonary edema. At this time his PO2 had fallen to 44 mmHg. The possibility of myocardial infarction secondary to severe anemia was raised, but before further investigative measures could be taken the patient had a cardiac arrest from which he could not be resuscitated.Dr. Padmos:This young Jamaican man presented in 1974 with severe disabling pain in his right groin. On the basis of the data presented, there is no easy alternative to the diagnosis of a sickle crisis in a sickle cell anemia patient. Certainly the patient has a sickle syndrome, as the presence of sickled cells in the peripheral blood film is diagnostic. It should be kept in mind that the patient could be presenting atypically with an acute abdomen as might happen with a retrocecal appendicitis or a psoas muscle abscess, but the described physical findings do not support these conclusions. His later clinical course effectively rules them out of further consideration. Transient consideration should also be given to bleeding disorders when patients present with pain localized in or around large joints. Direct infection or arthritis of the hip joint could have a similar clinical presentation, although the remainder of the findings do not point in that direction. Common things occur commonly, and I would propose the diagnosis of sickle cell anemia with a painful crisis due to local vaso-occlusive sickling causing bony infarction.Other hemoglobinopathies, such as hemoglobin SE and hemoglobin SD diseases, can be ruled out in this case. They are usually milder in their clinical expression and geographically do not pertain to West Indies or Black African or North American populations. Hemoglobin SD disease is common in northern India where hemoglobin D-Punjab is found. Hemoglobin E is common in the Far East, particularly in Thailand, and is becoming less unusual in America because of immigrants from the Far East. Because the gene for hemoglobin C is found in 3% of black North Americans and West Indians, hemoglobin SC disease should be kept in mind.The patient has sickle cell anemia syndrome and undoubtedly has hemoglobin SS disease, but the possibility of hemoglobin S/beta thalassemia cannot be excluded dogmatically. The latter diagnosis is unlikely because of the mild macrocytosis, the lack of palpable spleen, and the low level of hemoglobin A2. The basic pathophysiology in sickling disorders is like that described in the protocol.Of several types of crises in sickle cell anemia, the one presented here is the most common, a painful crisis due to bony infarction from local vaso-occlusive sickling. Hemolytic crises can also occur. In this regard it is prudent to remember associated conditions such as the G6PD deficiency common in the Middle East, which can be associated with brisk hemolysis from administered medications. Aplastic crises occur in children, who are almost routinely maintained on permanent folic acid supplementation. The fourth and last is a sequestration crisis, or sudden anemia associated with swelling of liver and spleen due to sequestration of large quantities of sickled cells in these organs.Once painful crises occur, supportive therapy is given with hydration and adequate analgesia, including anti-inflammatory agents such as aspirin or acetominophen along with adequate quantities of narcotic analgesics until the crisis has abated. We frequently use morphine intravenously or orally for this. Bicarbonate is commonly added, but the practice is of no defined value. In severe crises, exchange transfusion may be beneficial.It should be pointed out that the patient was nine years older when he was last admitted, in 1983, with pleuritic chest pain, cough, tachypnea, and back pain. His hemoglobin had fallen from its usual level, and he had a leukocytosis, which is not remarkable in the steady state of sickle cell anemia. The bilirubin, however, had doubled from 4 or 6 mg/dl to 9.1 mg/dl. The patient was hypoxemic and tachypneic. The second day, physical examination revealed crackles on both sides of the chest. The patient deteriorated suddenly and died of hypoxic cardiac arrest with widespread pulmonary edema without antecedent signs of any left ventricular failure. Perhaps the available x-rays should be reviewed at this time.Dr. Cumming:We have a chest film taken two years prior to the terminal admission. The chest appears almost normal, although the heart is a little enlarged. It does not appear to be cor pulmonale. Patients with anemia can have cardiomegaly due to anemia alone. I do not think this patient has congenital heart disease.The next chest film we have is anything but normal. We have a heart that is probably a little larger than the previous one and an almost complete “white-out” of both lungs with a little air at the apices and a homogeneous density elsewhere. Air bronchogram patterns show alveoli that are filled with something that is not air. It seems unlikely that the inflammatory exudate of pneumonia would give this appearance or be this extensive. I believe this is edema, although the cause of it is obscure. The changes we commonly see in sickle cell disease in the lungs are pulmonary infarcts, often multiple and relatively small. Sometimes they are due to actual sickling and occlusion of branches of the pulmonary artery in the lung and at other times to emboli from infarcted bone and other organs. A film of one shoulder shows osteolysis of the proximal humerus typical of what is seen in bone crises in sickle cell disease. It is difficult to know whether these lesions are due to osteomyelitis or infarct although they are usually due to infarction. A film of the abdomen showed calcification in the gallbladder (cholelithiasis is an expected feature of the disease). It is difficult to explain the pulmonary edema, since pulmonary emboli do not cause edema of this sort, although pulmonary venous obstruction or left ventricular failure might do so.Dr. Padmos:Although the patient's last 24 hours are not well documented, it should be emphasized that findings included pleuritic pain with cough and negative lung findings on admission and presumably on x-ray, a dramatic fall in the level of hemoglobin and a rise in the bilirubin suggesting increased hemolysis, and, sudden pulmonary edema leading to death.Many questions could be raised at this point. Was there a chest x-ray on admission and did it show any abnormalities? What were the results of cultures taken, remembering that this patient would have no splenic function and would be a candidate for overwhelming septicemia? Other infections, such as pneumonia, could be responsible, as Streptococcus can occasionally cause pneumonia, with pleurisy appearing before the lung infiltrate. Details of the cardiovascular examination would be important, specifically the jugular venous pressure. As it was not recorded, we assume it was not elevated. Was there a peristernal heave suggesting right ventricular hypertrophy or any change in heart sounds such as gallop or murmur? Many investigations would be retrospectively desirable and easy to order after the fact. Certainly a lung scan with or without nuclear venography would exclude pulmonary embolism. Swan–Ganz catheter data or data from pulmonary angiography would be helpful in reaching a firm diagnosis at this time, but I expect that the patient's sudden deterioration precluded time for these studies.The differential diagnosis should include: (1) pneumonia with overwhelming bacterial sepsis, probably pneumococcal; (2) pulmonary thromboembolism with or without infarction; (3) cor pulmonale with pulmonary hypertension and the “acute chest syndrome.” The data provided do not seem to point to pneumonia; one would expect more fever and evidence of cardiovascular collapse with hypotension rather than pulmonary edema and hypoxia.In a young man who has been previously well, deep venous thrombosis of the lower extremities leading to pulmonary embolism and infarction is a less likely explanation than others available to us. Of course, physical signs are absent in more than half of the documented cases of pulmonary embolism so that one cannot be dogmatic about its presence. Pulmonary embolism and infarction have been regarded as common in sickle cell disease. One study of 36 patients showed pulmonary embolism in two thirds of those who died with sickle cell anemia, including 10 of 12 adult patients.1 Cor pulmonale due to recurrent small thromboses in pulmonary arteries with recanalization and intimal proliferation leading to variable destruction and remodeling of pulmonary blood vessels has been postulated. Bone marrow or fat emboli precipitating right heart strain could also play a role in his sudden deterioration. A more topical explanation for this patient's final admission can be found in recent references to “acute chest syndrome.” In 25 episodes occurring in 13 adult patients treated at Central Middlesex Hospital in London, chest pain, which was almost always pleuritic, occurred in 23 of 25 cases.2 Cough occurred in 9 of 25; abnormal chest signs, usually basal crackles, were present in 11 episodes. Chest x-ray was abnormal on admission in only nine cases, but became abnormal later in 13 of the remainder. Only three patients had a normal chest x-ray throughout. These x-ray abnormalities were bilateral in 9 of 25, which correlated with the severity of hematologic findings and the clinical course.Laboratory features include a fall in the level of hemoglobin, leukocytosis, and a fall in the level of the platelet count from steady state value (in three cases); the two patients who died had platelet counts that fell below 100,000/mm3. Microbiologic studies were negative in 23 of 25 episodes, supporting the contention that actual documented bacterial infection is uncommon in sickle cell patients presenting with chest complaints. Ordinary treatment for a patient in crisis, including one with thoracic pain, includes hydration, adequate analgesia, and oxygen. In patients whose condition deteriorates, an exchange transfusion may be necessary. This was done in these patients on 12 occasions and was successful in all but two. The two deaths were a 50-year-old female with hemoglobin SC disease and pre-existing cardiomegaly and a 15-year-old male who had a normal chest x-ray on admission.I would like to suggest a final diagnosis of sickle cell anemia for the reasons referred to before. The patient probably had acute chest syndrome, and his death was due to a hypoxic arrest caused by sudden pulmonary edema, probably due to widespread sickling in the pulmonary circulation. The sudden anemia that occurs is probably due to sequestration of sickled red cells in the pulmonary circulation. I think this is what led to the pulmonary edema, which in this case would result in sufficient hypoxia to generate a cardiac arrhythmia from which the patient could not be resuscitated. He very likely had some element of right ventricular hypertrophy, and I would not be surprised if he had generalized small thromboembolic occlusions throughout the pulmonary vasculature. I strongly suspect he has normal coronary arteries and that there was no evidence of deep venous thrombosis that would lead to major pulmonary embolism.Perhaps Dr. Ziady would review the echocardiograms and give us his comments at this point.CARDIAC COMMENTSDr. Ziady:No clinical information regarding the patient's cardiac evaluation of 1982, about a year before the final episode, is available, but we have an echocardiogram [M-mode] and carotid pulse tracing and a phonocardiogram (Fig. 1). On the phono-cardiogram, the first and second heart sound were within normal limits, there was a loud S-4, and no murmurs. The carotid pulse tracing shows a normal upstroke with normal systolic time intervals. The M-mode echocardiogram revealed a normal aortic root and a normal aortic cusp excursion. The mitral valve was shown to be normal, cusp excursions were slightly exaggerated, but the cusps of the mitral valve were thin, and there was no evidence of vegetations (Fig. 2).Fig. 1. External carotid pulse tracing, a phonocardiogram, and an electrocardiographic lead; S1 = first heart sound, S2 = second heart sound, S4 = fourth heart sound.Download FigureFig. 2. M-mode echocardiogramn showing both right and left ventricular cavities as normal in size. Normal mitral value is also shown; RV = right ventricle, LV = left ventricle, MV = mitral valve.Download FigureThe interventricular septum moved normally and was normal in thickness. The right ventricular cavity, especially the ventricular outflow tract anterior to the aortic root and anterior to the interventricular septum, was mildly dilated and its diameter calculated to be 30 mm (normal up to 26 mm). There was a posterior pericardial effusion behind the left ventricular wall, and the amount of effusion appeared to be minimal.Although there is no clinical information about the episode from which the patient died one year later, on the chest x-ray it looked as though the patient had florid pulmonary edema. This pulmonary edema could be cardiogenic or noncardiogenic. Noncardiogenic pulmonary edema comes with adult pulmonary distress syndrome and could be for reasons other than cardiac problems. If this episode of acute pulmonary edema was cardiogenic in origin, there are few explanations for such florid acute pulmonary edema. The likelihood is that these patients develop sickling crisis and occlusion of the small vessels within the myocardium, thus producing a sort of global left ventricular ischemia causing a high filling pressure of the left ventricle which leads to acute pulmonary edema and the patient's death within a few hours. This acute pulmonary edema cannot be explained by the presence of multiple pulmonary arterial thrombi or by the presence of multiple small venule thrombi as it was massive, florid, and affected both lungs equally. A Swan–Ganz catheter would have helped delineate the underlying etiology of this acute pulmonary edema. Nothing on the echocardiogram suggests that the patient had a left ventricular dysfunction; also, looking at the study of his cardiovascular system, there is nothing to suggest a specific cardiomyopathy as was suggested by Oliveira et al.3 Acute pulmonary edema was present in six out of nine patients in another study by Uzsoy.4 In these six patients with acute pulmonary edema at the time of death, pathological studies showed evidence of diffuse intravascular sickling in the coronary vessels. Most pathological studies, in those who have died of sickle cell disease, show vacuolation of the myocardial fibers with interstitial edema and increased fibrous tissue, all of which may lead to repeated episodes of intravascular sickling in the small coronary vessels. In the last episode this was more massive than in previous episodes. In these patients it was shown that the papillary muscles of the left ventricle were severely fibrosed and the small coronary vessels within were thrombosed.In another study by Baroldi,5 of 53 patients with increased heart weights at postmortem examination, autopsy studies of the coronary arteries, especially the small vessel, revealed engorgement of all the arterioles and capillary beds by sickled red blood cells. The patient had conduction involvement for one year before the last episode, evidenced by a loud fourth heart sound, sinus tachycardia, and posterior pericardial effusion with beginning dilatation of the right ventricle. This could be the cardiac cause for his pulmonary edema. Another possible cause of his death could be some sort of cor pulmonale secondary to repeated showers of pulmonary thrombi and sickling of red blood cells in the small pulmonary vessels causing some form of acute cor pulmonale superimposed on chronic cor pulmonale that led to congestive heart failure.6 However, acute pulmonary edema in this situation will not be a feature of cor pulmonale.Sickle cell crises take various forms but are usually characterized by vascular occlusion and local hypoxia, and injury and necrosis of the tissues. It is likely that the last episode this patient had was production of vascular occlusion in his myocardium and lungs, and this was the cause of his death.The frequent occurrence of infarction in bone, lungs, and other tissues leads us to think that sickling in cardiac vessels may cause local ischemia and infarction in the form of global subendocardial infarction without actual necrosis, which leads to pulmonary edema and death. Covarrubias et al,7 in their noninvasive evaluation of patients with sickle cell disease published in Southern Medical Journal in 1980, found that cardiac enzymes and cardiac isoenzymes were normal in these patients. But, in patients dying from myocardial infarction or ischemia less than 12 hours after the acute episode, there was usually not enough time to observe the creatine phosphokinase isoenzyme (CPK–MB). This we know very well from patients dying from acute myocardial infarction early in the course of the infarction.Question: The last echocardiogram is from 1982, so it antedated the patient's terminal admission by a number of months. Dr. Ziady, would you not expect that he would have some physical signs at the time of his terminal admission that would indicate hypertrophy?Dr. Ziady:I would think so if his left ventricle were getting more and more impaired, but if he were getting into a type of cor pulmonale, maybe it would be missed. One of the most difficult clinical diagnoses would be a chronic type of cor pulmonale due to whatever cause. But I gather he must have had abnormal physical signs.Dr. Fawzy:I would like to mention something about the pulmonary edema. I do not think you can have such massive edema due to pulmonary embolism or cor pulmonale. I think the cause of the pulmonary edema here is most probably thrombosis of either the pulmonary arteries or pulmonary veins. The other alternative is a noncardiogenic pulmonary edema due to aspiration of the stomach contents or pulmonary infection. These can give the same x-ray picture as cardiogenic pulmonary edema. They are indistinguishable unless you place a Swan–Ganz catheter. In noncardiogenic pulmonary edema, one finds normal pressure, while in the cardiogenic pulmonary edema one finds a very high wedge pressure.Dr. Padmos:I think those are very relevant comments. I also feel that overwhelming sepsis and aspiration of the stomach contents are less likely. I think the patient could have massive bilateral embolism or thrombosis in his pulmonary veins causing sudden pulmonary edema. I think his extremities are going to be free of venous thrombosis.Dr. Norton:How does this acute chest syndrome differ from ARDS in the course of a severe sickle cell crisis?Dr. Padmos:I think the end results are similar. These patients are described as having acute chest syndrome. Really they are describing the pattern where the x-ray and physical findings may be delayed and the patient presents with pain, cough, and hypoxemia prior to developing many of these symptoms. The majority of patients recover from it which is better than in the ARDS. But presumably those infiltrates that do appear on an x-ray are similar in that they represent a capillary or alveolar leak leading to the localized fluid exudation in the lungs.Dr. Ali:At postmortem, this man appeared not chronically ill and wasted. Minimal jaundice was present. No skin ulcers were present. The body cavities were devoid of any effusions. The liver and kidney showed features of chronic passive congestion. Gallstones were present. The spleen showed hemosiderosis and fibrosis. The vertebrae showed a “fishbone” appearance, but there was no evidence of infarction in the bone. The bone marrow was hyperplastic, showing erythroid hyperplasia in addition to sickling. All of these findings are consistent with sickle cell anemia. The most salient features were found in the chest. The heart weighed 460 grams (slightly increased). There was minimal coronary arteriosclerosis. Scarring of the posterior papillary muscles of the left ventricle was present, which on microscopy revealed extensive fibrosis of the myocardium in addition to thrombosed and recanalized blood vessels (Figs. 3 and 4). This lesion is consistent with episodes of old thrombosis (at least several months).Fig. 3. Microscopic section of papillary muscle in the left ventricle, showing a thrombosed vessel and area of fibrosis.Download FigureFig. 4. Microscopic sections of papillary muscle in the left ventricle. At higher magnification, a vessel shows organized thrombus with recanalization. In between areas of fibrosis, the muscle fibres appear histologically normal.Download FigureThe weight of both lungs is increased (aggregate of 1265 grams). These lungs showed multiple small depressed scars on the pleural surface (Fig. 5) and edema. On microscopy, a scar area and pulmonary edema were present. There were no neutrophils to indicate pneumonia (Fig. 6). Also noted were blood vessels previously thrombosed and recanalized (Fig. 7). In addition to the above, thrombosis of small pulmonary veins with small amounts of edema fluid in the lung was also seen. These thrombi did not show well formed lines of Zahn (a well recognized occurrence in sickle cell anemia), but they did otherwise show characteristics of recent antemortem thrombi (Fig. 8).Fig. 5. Macroscopic view of the pleural surface of the right lung, showing multiple areas of scarring.Download FigureFig. 6. Microscopic section of lung showing alveoli distended by edema fluid, and an area of fibrosis with proliferation of bronchial epithelium and presence of chronic inflammation.Download FigureFig. 7. Microscopic section of lung showing thrombosed vessel of long-standing with some recanalization, surrounded by fibrotic tissue.Download FigureFig. 8. Microscopic section of the lung, showing two small veins completely obliterated by recent thrombus.Download FigureIn summary, we have a patient with sickle cell disease, multiple old small pulmonary micro-infarcts, old pulmonary thrombosis with recanalization, multiple recent pulmonary thrombosis in the pulmonary veins, and acute pulmonary edema. There were also fibrotic scars in the posterior papillary muscle of the left ventricle.Question: Is there anything in the material that you have seen—you didn't, of course have slides of the gross, but it would have been nice to cut through the lungs and see how extensive these pulmonary thromboses were. Did you get the impression they were major blood vessels, like massive emboli, or thrombosis?Dr. Ali:No. The cut surface of the lung which we saw in gross pictures did not show any thrombosis of the major blood vessels.Question: The findings are more consistent then with long-standing, repetitive thromboses in the smaller vessels. Probably the patient did have cor pulmonale.Dr. Fawzy:You can not have pulmonary edema due to cor pulmonale. For edema you must have high pressure in the pulmonary vein and pulmonary capillaries. This is caused by two things: either obstruction of the pulmonary vein or left atrium or high pressure in the left ventricle. The left ventricle, mitral valve, and left atrium are normal, so the problem has to be the pulmonary vein.Dr. Ziady:I think this is not conclusive, because this man has a history of a fourth heart sound that was demonstrated one year before, and he showed extensive fibrosis of the left ventricle. I think this man had an abrupt ischemic event of the left ventricle and this ischemic episode did not go to infarction, this is why there was no necrosis of the left ventricle—just fibrosis, which raised the left ventricular filling pressure and produced pulmonary edema.Dr. Ali:Whatever fibrosis and scarring are present affected the posterior papillary muscle of the left ventricle, nothing else. The heart is normal otherwise.Dr. Luzzatto:After this excellent discussion, I would just like to pick up a few points. First, there is the question of the primary condition in this patient. Dr. Padmos was correct in favoring homozygous sickle cell anemia rather than any of the other variants of sickle cell disease. Unfortunately, the family was not available for study, but on the grounds that the patient had only hemoglobin S, in addition to 10% HbF and about 2% HbA2, I think there is no doubt that S/S was his actual genotype. It might be relevant to the situation in Saudi Arabia that this patient had a relatively high level of HbF; on repeated determinations it ranged between 10% and 15%. This correlated fairly well with his steady state hemoglobin level, which was in the 9.5 to 10.5 gm range rather than 7 to 8 gm. Only because it was mentioned, I will add that we have in fact found the S/E hemoglobin combination in Jamaica, presumably as a result of East Asian input into the human genetic pool of the West Indies. In response to one of your questions, blood and sputum cultures were of course taken, and findings, which came back after the patient's death, were negative. Indeed, the postmortem did not show any evidence of overwhelming sepsis.As for what we can learn from this case, there is no doubt that in view of the abnormalities on the echocardiogram that it should have been repeated. As far as the terminal events are concerned, transaminases had shown intermittently modest elevations in the past. Aspartate aminotransferase (AST) was 71 U/ml the day before death and 134 U/ml on the last day, but bilirubin had also increased from 4.45 to 9.07 mg/dl. Regarding other investigations during the final episode, it must be realized that the onset of the patient's respiratory distress took place at 2000 hrs; the patient immediately had blood counts, blood chemistry, blood gases, and chest x-ray (Figs. 9 and 10); at 2215 he had cardiac arrest and the ECG showed asystole.Fig. 9. Chest, on 24 October 1981, showing cardiomegaly and clear lungs.Download FigureFig. 10. Chest, on 28 March 1983, showing bilateral pulmonary edema.Download FigureI think I am less fit than some of the cardiology discussants to give a final assessment as to the immediate cause of death. Upon reviewing the literature on the cardiopathy of sickle cell anemia for this CPC, I find it intriguing that it is vast but, if I may say so with all due respect, not very coherent. There are probably numerous reasons for this. There is, firstly, a considerable heterogeneity among the patients; secondly, a very high selection for those who come to postmortem; and thirdly, a shift, I think, in the age range of patients seen who come to postmortem. For a long time there was a loose concept of “sickle cell cardiomyopathy.” I was glad to read in a recent review by Falk and Hood8 that, by critical cardiologic assessment, they could not support this concept at all. In relatively rare instances, the myocardium may of course be affected by hemosiderosis. This would be expected mostly in multiply transfused patients, and this was not the case here. There was some evidence of iron overload at postmortem, but we certainly do not think he had a cardiomyopathy from that. So it seems to boil down to whether the number of microthrombi seen in the pulmonary circulation is sufficient to explain the final demise. Of course, the apparent inconsistency between the existence of diffuse thromboembolism or microthrombi in the lungs and the massive pulmonary edema observed clinically and radiologically was obvious to us, as it was pointed out here. I was very interested in Dr. Ziady's point on the possible consequences of multiple small vaso-occlusive phenomena in the myocardium due to sickling without thrombosis. If I understand correctly, the idea is that this would cause sufficient loss of myocardial function to cause left ventricular failure and pulmonary edema. There could have been no time for necrosis; thus no “infarction” would be seen at postmortem. This is reminiscent of the “sludge” described by Baroldi.5 The pressing, unsolved question seems to be what causes this sudden massive sludge, apparently out of a “blue sky.” From the evidence of the multiple scars in the lungs, it appears possible that this patient had survived much microthrombosis in the arterial pulmonary tree, but that he could not survive the combination of a much more recent thrombosis in the lungs and myocardial ischemia due to “sludging.”Dr. Ziady:Taking into consideration the small vessels—and this is well known from National Institutes of Health (NIH) studies 20 years ago—the patient who develops even myocardial infarction dies within the first eight hours. Sometimes with ordinary stains in the pathological studies, you will not find left ventricular necrosis. You do not need myocardial necrosis to get acute pulmonary edema, only a rise of the filling pressure of the left ventricle. Otherwise, this man should have another cause for his pulmonary edema which should be noncardiogenic. I do not believe that the four major pulmonary veins of the left atrium can be so involved at the same time, in spite of the fact that no major vessel was found to be thrombosed, neither the coronary or pulmonary arteries or pulmonary vein. These are microthrombi which will not give florid bilateral pulmonary edema.Final diagnosis: Sickle cell disease; pulmonary thrombosis with multiple pulmonary infarcts and acute pulmonary edema; thrombosis and scarring, myocardium; hemosiderosis.ARTICLE REFERENCES:1. Oppenheimer EH, Esterly JR: "Pulmonary changes in sickle cell diseases" . Am Rev Respir Dis 103: 858–91971. Google Scholar2. Davies SC, Luce PJ, Win AA, et al.: "Acute chest syndrome in sickle cell disease" . Lancet 1 (8367): 36–71984. Google Scholar3. Oliveira E, Gómez-Patiño N: "Falcemic cardiopathy: report of a case" . Am J Cardiol 11: 686–81963. Google Scholar4. Uzsoy NK: "Cardiovascular findings in patients with sickle cell anemia" . Am J Cardiol 13: 320–81964. Google Scholar5. Baroldi G: "High resistance of the human myocardium to shock and red blood cell aggregation (sludge)" . Cardiologia (Basel) 54: 271–71969. Google Scholar6. Gerry JL, Bulkley BH, Hutchins GM: "Clinicopathologic analysis of cardiac dysfunction in 52 patients with sickle cell anemia" . Am J Cardiol 42 (2): 211–61978. Google Scholar7. Covarrubias EA, Sheikh MU, Solanki DL, et al.: "Left ventricular function in sickle cell anemia: a noninvasive evaluation" . South Med J 73 (3): 342–41980. Google Scholar8. Falk RH, Hood WB: "The heart in sickle cell anaemia" . Arch Intern Med 142: 1680–91982. Google Scholar Previous article Next article FiguresReferencesRelatedDetails Volume 5, Issue 2April 1985 Metrics History Published online1 April 1985 ACKNOWLEDGMENTWe wish to thank Drs. Y. Chia and E. C. Gordon-Smith of the Royal Postgraduate Medical School, Hammersmith Hospital, London, for the case material.InformationCopyright © 1985, Annals of Saudi Medicine