Thrombotic Thrombocytopenic
D. C. WALLACE,
M.D.
Newcastle N.S. W., Australia A. LOVRIC, M.B., B.S. Camperdown N.S. W., Australia J. S. CLUBB. M.B., B.S. D. B. CARSELDINE, M.B. i&u/burn
A family is described in which four members of a sibship of seven have suffered from a hematologic and systemic disorder which has been fatal in three and has been proved at autopsy to have been thrombotic thrombocytopenic purpura. The fourth member has probably suffered the same disorder. The clinical, laboratory and genetic features of the family are discussed at length. No cause of the disorder has been determined.
N.S. W., Australia
From the Royal Newcastle Hospital, Newcastle N.S.W. 2300, Australia; the Royal Alexandra Hospital for Children, Camperdown N.S.W. 2050. Australia: and the Goulburn Base Hospital, Goulburn N.S.W. 2580, Australia. Requests for reprints should be addressed to Dr. D. C. Wallace, Royal Newcastle Hospital, Newcastle N.S.W. 2300, Australia. Manuscript received April 2, 1974.
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We describe this unfortunate family not only as a record of unusual rarity, but also in the knowledge that from study of such exceptional cases deductions can often be made that have wider application in the understanding and management of the underlying disease. Microangiopathic hemolytic anemia, a term introduced by Symmers [ 11, is perhaps the best generic name for a group of illnesses that have been described under a series of titles since the first annotation by Moschowitz in 1925 [2]. Of these, the best established is thrombotic thrombocytopenic purpura, but the related condition known as the hemolytic-uremic syndrome [3] is probably more widely recognized and may be a manifestation of the same pathologic process [ 41. Diagnosis depends upon the presence of characteristic pathologic lesions consisting of widespread hyaline occlusion of terminal arterioles and capillaries. The manifestations of such a process are naturally protean and involve many systems, thus accounting for the variety of clinical syndromes described in association with this disease [5]. Cases with the triad of thrombocytopenic purpura, hemolytic anemia and neurologic manifestations have become known as thrombotic thrombocytopenic purpura, whereas cases with mainly glomerular changes are known as the hemolytic-uremic syndrome. The etiology of the small vessel occlusions may or may not be unitary [4]. In the present complete uncertainty as to the cause of the condition, it is perhaps best to suspend judgement concerning its nature. That three of the four siblings we describe did indeed suffer from microangiopathic hemolytic anemia is proved by histologic data, and the evidence that the surviving fourth sibling has the same tendency is compelling. Elucidation of the nature of the illness in this family may also shed light on the etiology of this group of diseases in general. THE FAMILY The four affected siblings were born into a family of seven children. An abbreviated pedigree of this tragic family is shown in Figure 1. The brother and father come of Irish stock and are descended from the early settlers of the Southern Tablelands of New South Wales where they are moderately well-todo landholders of a grazing
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Xeroderma pigmentosum
0
Thrombotic Microangiopathy
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Glanzmann’s Thrombasthenia Rgure 1.
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An abbreviated family tree.
property. The original settlers multiplied rapidly and, until the human carrying capacity of the land they took over was saturated, they remained for the most part in the area of their adoption. This made possible the contacting and occasional examination of a very large kindred indeed, most of the information concerning whom does not at this stage appear relevant. Only those segments considered to be of possible interest have been included in the family tree. The sibship we describe in detail comprises the children of the union between IV-6 and IV-7. W-4, the sister of W-6, contracted a consanguineous marriage with her mother’s first cousin; from this marriage six children were born, two of whom have died of xeroderma pigmentosum. At a distance on the father’s side of the pedigree are members Ill-6 and IV-9 who have a bleeding disorder of moderate degree characterized by an abnormality of platelet morphology and function that conforms to the heterogeneous group of disorders classified as Glanzmann’s thrombasthenia. As far as can be determined, there is no evidence of this disorder in the direct line of descent of the father, IV-7. His platelets and that of his mother,
sus, he has taken antimalarials intermittently to control it over the years. He has a heavy alcohol consumption, but this is not greatly above average for his social contacts. His wife, IV-6, now aged 41, has no physical illness of any note. She does suffer from repeated attacks of endogenous depression for which she has received much psychiatric treatment over a period of many years. The presenting episode occurred 20 years ago when, after the birth of her second child, V-8, she suffered a severe puerperal depression, during which the unfortunate woman murdered the infant. The sibship under discussion consists of the seven children, V-7 through V-13. Of these, the eldest, V-7, a male now aged 2 1, has never shown any evidence of hematologic disorder, and the youngest, V-13, a girl now aged 11 years, has also been healthy. Three of the children, V-9, V-10 and V-l 1, have died from thrombotic thrombocytopenic purpura, and the other, V-12, has had diseases diagnosed as idiopathic thrombocytopenic purpura and acute glomerulonephritis but is now well. More detailed description of these cases follows.
111-4, have been described as having a normal appearance on microscopic examination of stained blood smear, and neither bore a spontaneous bleeding tendency. IV-7 is now (1973) aged 50. He is in good health except for a skin condition affecting his face, which developed while he was serving in Borneo in 19431944. Diagnosed as having discoid lupus erythemato-
Case 1. V-9, a male, born in 1954, died in 1963. He was normal at birth, but in early childhood suffered frequent epistaxes and was said to have always bruised easily. At the age of 5 years, he was admitted to the Royal Alexandra Hospital for Children in Sydney with a bleeding diathesis. For 2 days before admission he had been febrile, with anorexia, blood-stained vomitus and blood in his urine. On examination, he had scattered bruises and was bleeding
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slightly from his right nostril. There was no lymphadenopathy or hepatosplenomegaly. His urine contained free hemoglobin, the direct antiglobulin test was negative, and Heinz red blood cell inclusion bodies were not detected. Blood count showed a hemoglobin level of 7.2 g/100 ml, red blood cells mainly normocytic with marked polychromasia, many fragmented cells, moderate number of spherocytes and several nucleated red cells; platelet count was 18,000/mm3. White cells were normal. Clotting studies were normal. The hematuria and epistaxis persisted and a morbilliform rash developed. Bone marrow showed normoblastic erythroid hyperplasia, and the mature red cells showed evidence of spherocytosis and distortion of shape. Myeloid and lymphoid series were normal. Megakaryocytes were normal in number. It was thought that the patient had acute acquired hemolytic anemia and thrombocytopenia or thrombotic thrombocytopenic purpura. He was given a transfusion, and his condition improved. On discharge 10 days later, his hemoglobin level was 10.2 gl 100 ml, with IO per cent reticulocytes and 400,000 thrombocytes/mm3. Except for continuing bruising tendency, the patient was well until 3 l/2 years later when he vomited blood-stained material, his feces contained old blood and his urine was blood-stained. Nothing remarkable was found on physical examination. His hemoglobin level was 12.0 g/100 ml, reticulocytes were 4 per cent, numerous spherocytes and fragmented cells were present in the blood smear, and the platelet count was markedly reduced. Methemalbumin was present, and the serum bilirubin was 2.5 mg/lOO ml. No incomplete antibodies were detected by antiglobulin or enzyme tests. The blood urea was 98 mgl100 ml. During the next few days jaundice developed and the hemoglobin level fell to 6.6 g/100 ml; the platelet count was 80,0001 mm3. A few petechiae were noticed on his skin, and the patient became vague and complained of dizziness, but no objective central nervous system signs were noted. He died suddenly 6 days after admission. Autopsy was performed 4 l/2 hours after death. The body was that of a jaundiced, normally developed 9 year old boy with scattered ecchymoses on the arms and legs. There were regurgitated stomach contents in the pharynx, larynx, trachea and bronchi, with macroscopic evidence of areas of edema in the lungs related to this. There were multiple small hemorrhages in the myocardium, stomach wall, and throughout the length of the small and large intestine. There were numerous hemorrhagic lymph nodes in the mesentery. The kidneys and other viscera were of normal size and, macroscopically, of normal appearance. The histopathology was typical of thrombotic thrombocytopenic purpura with the thrombotic lesions affecting the capillaries and arterioles, and with the major lesions present in the myocardium without infarction but associated with numerous small hemorrhages. In other organs, there was a lesser and variable degree of vascular involvement, being pronounced in the pancreas and bowel, and less developed in the liver and kidneys. In these latter organs, there were abundant albuminous casts in the tubules, and some tubules were filled with blood. Only a small proportion of the glomeruli contained thrombotic lesions, with a rather larger number of the cor-
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tical capillaries and arterioles being affected. Scarring of glomeruli was very infrequent. No vascular lesions were present in the lungs. The bone marrow showed erythroid hyperplasia with a high proportion of very early erythroid cells. Sections of brain stem, cerebellum, basal ganglia and cerebral cortex were examined. The meningeal and cerebral vessels were devoid of any disease except in the region of the internal capsules where there was evidence of some anoxic change in the fibers; one occluded vessel was found. The final diagnosis was thrombotic thrombocytopenic purpura. Case 2. V-10, a male, was born in 1955. We observed this patient over the last 8 years of his life. He had been normal at birth, and early development had been normal, but from an early age he had suffered intermittently from asthma, hay fever and eczema. These had never been serious enough to cause undue concern, but at the age of 6 or 7 he became listless and purpuric spots were noted on his chest. His family practitioner had treated him for “anemia” with occasional cyanocobalamin injections. The patient was first brought to our attention in November 1965 when he was 10 years old, 2 weeks after an attack of measles, which had recently affected several of his siblings. He had not been unduly ill, but he had “bled more than the other children,” to use his mother’s expression. On examination, he was pale and febrile (temperature 38.0°C) with bilateral catarrhal otitis media. The spleen was enlarged. There was a fading measles rash which looked as though it had had a purpuric element, and Hess’s test was positive. Hematologic examination disclosed features suggestive of acute hemolytic anemia with marked thrombocytopenia, a mild leukocytosis and a moderate eosinophilia. The patient was treated with penicillin and a pholcodine cough linctus and made a rapid recovery, returning within a fortnight to apparent completely normal health. During the next 2 years he remained well, with no bleeding episodes, although he suffered from an almost constant low grade eczema and occasional attacks of asthma. He was able, however, to captain his school’s hockey team. He was investigated hematologically in February 1968 and other than a mild eosinophilia no abnormality was found. He remained well until August of that year when his parents reported a certain lack of drive, and a period when he had nosebleeds and the development of some petechial spots during a coryzal illness. At this time he had mild anemia and a marked thrombocytopenia. In October 1968 he had a moderately severe illness with fever, sore throat and cervical lymphadenopathy. Physical examination at this time showed generalized lymph node enlargement, hepatosplenomegaly, herpes simplex labialis, slight eczema and again a blood film with thrombocytopenia, hemolytic process and anemia, and, on this occasion, neutropenia and many immature cells in peripheral blood. Nevertheless, he made a rapid and clinically complete recovery once again, receiving penicillin as his only therapy. During this illness, evidence of renal involvement was noted for the first time in the form of albuminuria
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and red blood cells and casts on microscopic examination. By the end of December, his urine was clear on clinical and microscopic examination. The next record concerns psychiatric illness. From 1969 to 1!)72 he was well and made reasonable progress at school. By 1972 he was in his last year at high school. In June of that year he had a depressive episode and was admitted to the hospital where he received electroconvulsive therapy. In July and August he had two further short hospital admissions following suicidal attempts. During this period he was given chlorpromazine, 300 mg daily. “MelIaria” (thioridatine) had been given initially, but its administration was discontinued following the appearance of a facial rash. The final illness began on a hot day in January 1973 when, over a period of a few hours, the patient experienced three episodes, each lasting some minutes, consisting of right-sided paresthesia, incoordination and dysarthria, associated with a bitemporal headache of some hours’ duration. A fourth similar attack occurred some days later. There were at this stage no abnormal neurologic findings; the only obvious clinical signs were a palpable spleen and large ecchymoses on his left thigh and ankle, the result of a vigorous game of hockey. There was conjunctival p,allor. No lymphadenopathy was noted on this occasion. Following his initial admission to a country hospital, he was transferred to Sydney for more extensive investigation. Full blood count on admission included a hemoglobin level of 7.9 per cent and a hematocrit value of 21.2 per cent. Red cell morphology was abnormal, with anisocytosis, poikilocytosis, microcytes, fragmentation, spherocytes, polychromasia, nucleated red blood cells and rouleaux formation. There were also numerous teardrop cells. Reticulocytes were 32.2 per cent. The white blood cell count was 3,9001mm3, and the platelet count was 15,000/mm3 (Figure 2). Erythrocyte sedimentation rate was 50 mm/hour. Direct antiglobulin test was negative. Only occasional erythrocytes showed inclusion bodies. Thrombin time: patient 12 seconds, control 10 seconds. Fibrinogen was 206 mg/lOO ml. Sucrose hemolysis screening test was negative. Latex test for fibrin degradation products showed these to be in excess of 40 j&g/ml. Lupus erythematosus phenomenon was negative. Red blood cell glucose-&phosphate dehydrogenase was normal. Electrolytes were normal. The blood urea nitrogen was 37 mg/lOO ml, creatinine 2.1 mg/lOO ml, phosphorus 5 mg/lOO ml, uric acid 12 mg/iOO ml, calcium 9.6 mgl 100 ml, haptoglobins 0 to 30 mg/ 100 ml. Schumm’s test was negative. Serum alkaline phosphatase was 73. Albumin was 4.96 per cent and globulin 2.76 per cent. Bilirubin was 1.5 mg/ 100 ml, serum glutamic oxaloacetic transaminase (SGOT) 66 units, serum glutamic pyruvic transaminase (SGPT) 15 units, lactic dehydrogenase 2,700. Lactic dehydrogenase isoentymes were mainly peaks 1 and 2. Cerebrospinal fluid macroscopically was slightly pink, and opalescent. The supernatant was very slightly xanthochromic, ;and there was red blood cell deposit, with a total cell count per cubic millimeters of polymorphonuclear leukocytes 0, lymphocytes 1 and red cells 1,100/mm3. On
ET AL.
culture there was no growth. Cerebrospinal fluid protein was 95 mg/lOO ml, glucose 75 mg/ 100 ml, chloride 118 meq/liter. Lange curves 5 and 6; Pandy’s test was positive. Chest films disclosed no abnormality, and films of the skull did not show any lesions. On microscopic examination of the urine, there were less than 10 white cells/mm3, less than 10 red cells/m& and less than 10 epithelial cells/mm3. Bacterial count was less than 104/ml. There was no significant growth. Granular casts were I+ and amorphous urate crystals 3+. The serologic slide flocculation test for syphilis, Reiter protein complement fixation and Maltaner complement fixation were all nonreactive. No abnormality was seen in the cerebral studies. The electroencephalogram was generally abnormal and paroxysmal, but nonspecific. The electrocardiogram showed sinus rhythm with Wolff-Parkinson-White type trace. No abnormality was found in the serum protein electrophoretogram or immunoelectrophoretogram. Bone marrow sample obtained on January 30, 1973, showed hypercellular aspirate with marked erythroid hyperplasia, consistent with hemolysis. Myeloid precursors were plentiful and megakaryocytes were abundant, No diagnostic features were present. The diagnosis of thrombotic thrombocytopenic purpura was made. The patient was given a transfusion of 6 units of platelets followed by 2 units of whole blood, towards the end of which a marked widespread urticarial reaction developed. A febrile episode followed, considered to be the result of an infection at the site of the cannula. After this resolved, the patient was given high dosage corticosteroid therapy (prednisone 250 mg/day), and splenectomy was performed; the spleen weighed 455 g. Needle biopsy of one kidney was performed during the operation. Microscopic examination of the spleen showed congestion of the pulp, with prominent sinusoids. The vessels showed no abnormality and none of the changes sometimes described in idiopathic thrombocytopenic purpura. The appearances more closely resembled those of hemolytic anemia. They were, however, not diagnostic. Kidney biopsy showed thrombi within 3 or 4 small vessels. Two of these were surrounded by an unusual cellular proliferation which may be reactive to damaged vessel wall (Figure 2). These changes were thought to be consistent with those described in both disseminated intravascular coagulation and thrombotic thrombocytopenic purpura. Postoperatively the hematologic picture initially remitted rapidly, the hemoglobin level rising to 11.2 g, the white cell count to 21,700/mm3 and the platelet count to 405,000/ mm3 5 days after surgery, and corticosteroid therapy was reduced. However, 10 days postoperatively the platelet count had fallen to 60,000/mm3 and therapy with large doses of prednisone was again instituted: in addition, the patient was given dipyridamole, firstly 400 mg/day and later 800 mg/day. The peripheral blood picture continued to show marked fragmentation of erythrocytes with target cells, HowellJolly bodies and siderotic granules (Figure 3). The patient remained asymptomatic with no bleeding tendency. Hess
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Kidney biopsy specimen from V- 10 showing thrombus in an arteriole. Figure 2. lin and eosin stain; original magnification X 160, reduced by 20 per cent.
Hematoxy-
Figure 3. Peripheral blood picture in V- 10 showing typical appearance of microangiopathic hemolytic anemia with fragmentation of red cells and bizarre forms. 728
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test remained negative. Between 10 and 40 pug/mlof fibrin degradation products continued to be detected. Two weeks postoperatively, with hematologic status unchanged, Cushingoid appearance developed as well as oral candidiasis. Continuous intravenous infusion of heparin was given in a dose of 30,000 units/day for 5 days. The platelet c.ount continued to fall, with a lowest count of 13,000/mm3 on the 5th day of infusion. Serum complement at this time was not grossly abnormal. In view of the failure of all other forms of therapy, cyclophosphamide 150 mglday was commenced the day after the cessation of heparin therapy. This was not accompanied by any noticeable improvement in the patient’s general or hematologic condition. Five weeks postoperatively the patient was transferred to his hometown hospital. The dose of cyclophosphamide was gradually reduced and suspended after having been given for 3 months altogether. The administration of prednisone in lesser dosage was continued. The patient’s condition deteriorated steadily, he became cachectic and finally died 2 i/2 months after splenectomy, the final phase being one of progressive renal failure. Necropsy was performed 22 hours after death. Gross findings related to postsplenectomy. In addition, there were a few small petechiae in the myocardium, and more numerous petechiae in the walls of the large and small bowel. Scattered petechiae were present throughout the substance of the brain. The kidneys were engorged, but otherwise not abnormal except for the presence of an organizing thrombus at the site of the renal biopsy. No abnormality was noted in the larger blood vessels and no lymphadenopathy was found. Microscopically there were numerous and very widespread vascular lesions in most organs examined, the detailed findings are as follows: Kidney: Numerous capillaries containecl homogeneous and granular material within their lumens. In some there was endothelial cell proliferation. These vessels were enlarged due to aneurysmal dilatation. Other small vessels showed a thickened cellular wall (? healing). Some glomeruli were hemorrhagic. Capillary loops in some were distended by homogeneous material. There was no significant basement membrane thickening. These vascular changes are typical of thrombotic thrombocytopenic purpura but are also seen in disseminated intravascular thrombosis and generalized Shwartzman reaction. In addition to these, there was a larger vessel with a necrotic hemorrhagic wall. A large hemorrhagic cyst was a hematoma related to the previous needle biopsy. Liver: There was a severe autolysis but an occasional small vessel was similarly involved. Pituitary: There were many involved vessels in the posterior pituitary, but no other changes. Heart: The vessels in the myocardium and epicardium ‘were involved. There were very severe microinfarcts with myocardial cell fallout and some small hemorrhages. There was an unusual degree of myocardial involvement. Lung: Severe autolysis was present. The vessels were probably involved. Bowel: Submucosal vessels were involved in the small intestine. Severe mucosal autolysis was present, but there was no evidence of ulceration. Pancreas: Many vessels were involved. In addition, thrombosis of a large artery and a thrombosed recanalized large vein were evident. Brain: Occasional small vessels were
involved with minute areas of softening. Peripheral nerve: The vasa nervorum were involved. Adrenal cortex: Many vessels were involved. Tongue testis: No significant change was evident. Summary: (1) Vessels in most organs were occluded by homogeneous and granular material. (2) Larger vessels were involved in the pancreas and kidney. Pathologic diagnosls: Thrombotic thrombocytopenic purpura. Case 3. V-l 1, a female, was born in 1956. This chiki was well until the age of 19 months. She then had a sudden onset of anorexia and irritability. Three days later some small red spots were noted on her trunk which persisted for only 1 or 2 days. The parents then noted progressive pallor and lack of movement on her left side. She was admitted to the hospital on the 16th day of her illness; she was pale and listless and had a left flaccid hemiplegia. Spleen and liver were palpable. Hair was noted to be falling out. Her hemoglobin level was 4.6 g/100 ml, reticulocytes 9 per cent, platelet count 5,000/mm3. The white blood cell count was 10,000/mm3 with a normal differential. Blood smear showed macrocytic anemia with scattered spherocytes and nucleated red cells and marked polychromasia. The cerebrospinal fluid was a blood-stained specimen with 1,000 red blood cells/mm3; no other abnormality was detected. The electroencephalogram showed a gross right temporo-occipital focal abnormality. Serum proteins were normal. Lupus erythematosus preparations were not diagnostic on three separate occasions. An increased arsenic content was found in hair and nails on one occasion, and urinary lead content was normal. No thallium was found. The patient was given a transfusion on numerous occasions and large doses of corticosteroids up to 60 mg of prednisone/day. After finding the arsenic in her hair and nails, a course of dimercaprol therapy was also given. Her hemoglobin levels fell rapidly after each transfusion, and the platelet count remained very low throughout. The antiglobulin test was invariably negative. Bone marrow examination showed only an active erythropoietic marrow. The hemiparesis improved, but the child remained gravely ill and died following a sudden rise in temperature 3 months after her admission to the hospital. She had quite marked petechial hemorrhage on numerous occasions, but the Hess test was always recorded as negative. Only a partial necropsy was permitted, and the brain and spinal cord were not removed. The only gross abnormality was an enlarged fatty liver. Microscopic examination disclosed hyaline thrombi of varying stages of development in many of the arterioles and capillaries. They were most numerous in the vessels of the heart, in which they had produced occasional small infarcts, and least numerous in the lung. In the liver cells, there was marked fatty accumulation and in some cells an amount of unidentified waxy substance. In the kidney, many glomeruli were damaged as a result of occlusion of the glomerular capillaries and/or the afferent and efferent vessels. Diagnosis of thrombotic thrombocytopenic purpura was established. May 1975
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4. V-12, a female, was born in 1958. This girl is the only survivor among the siblings who has shown any evidence of hematologic or other disorder. At present she is well and has not had any serious illness for several years. She was born after a normal confinement and was healthy until the age of 4 years, although the parents report that in infancy and early childhood she bruised easily and had suffered an occasional mild epistaxis. At this time, a day after taking some Viprynium pamoate (Vanquine) she had a severe nose bleed and spontaneous bruising and petechiae developed., Initially, the spleen was impalpable, but it was felt 24 hours later. The ecchymoses became more marked for the first 48 hours, but no subsequent bleeding occurred. Investigation at this stage showed a hemoglobin level of 12.3 g/100 ml, and this did not subsequently vary. Platelets were initially 5,000/mm3 but rose over a period of 10 days to 138,000/mm3 without treatment. Peripheral blood smear showed a normal white cell picture. Marrow aspiration showed a slight eosinophilia, and an increased number of megakaryocytes, the majority of which had absence of budding. No treatment was given, and the patient made an uninterrupted recovery. In absence of other symptoms or signs, a diagnosis of idiopathic thrombocytopenia was made. The patient was subsequently seen 2 years later when she had an upper respiratory tract infection, following which she suffered a series of small epistaxes and one small, but definite hematemesis. She was admitted to the hospital, and routine testing of her urine revealed the presence of blood and albumin. Microscopic examination confirmed the presence of red blood cells and demonstrated the presence of granular casts. No evidence for streptococcal infection was found. The diagnosis of acute glomerulonephritis was made, and oral penicillin therapy was given. Blood count at this time was usual. No abnormality of clotting was demonstrated. The patient made a rapid clinical recovery, but measles developed 2 weeks after her admission to the hospital. Red blood cells were detectable for 2 months in her urine, which then became normal and has subsequently remained so. There was no biochemical evidence, at any stage, of impaired renal function. Since then she has not been ill, a period of 9 years. Case
COMMENTS This family appears to be unique. There can be little doubt that the three children who died suffered from thrombotic thrombocytopenic purpura. Although her illnesses are not well documented, there is reason to believe that the fourth child has had episodes of the same disorder. The presence of petechiae, anemia, thrombocytopenia and a glomerular lesion at various times follows the same pattern as that set by the fatal cases. From this emerges a pattern of disease that may be summarized as follows. The affected person is for the most part fit and healthy. He is subject at irregular intervals to the de-
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velopment of an acute hemolytic process associated with concurrent severe thrombocytopenia. No predisposing factor is obvious, although it is at least suggestive that on numerous occasions in three of the children attacks appeared to be ushered in by a febrile illness resembling a viral infection. The underlying pathologic process is that of thrombotic thrombocytopenic purpura, which has produced in these children evidence of impaired renal, hepatic, cerebral and cardiac function from involvement of these organs. The disease is remittent, some attacks being subclinical, and others lasting up to 2 or 3 months with subsequent complete remissions. No evidence to suggest an immune process has been found. The antiglobulin test has been consistently negative, and no definite abnormality of cellular or humoral immunity has ever been demonstrated. Yet the presence in one parent of an autoimmune disorder, and severe asthma, hay fever and eczema in one of the sufferers leaves this question open. Reappraisal of therapy suggested that the children have done best when treated symptomatically. There is no evidence that corticosteroid therapy, heparin or cyclophosphamide has been of any benefit. The etiology of the disorder is unknown, and this family does little to make the pattern any more clear. Certain features demand explanation. The histopathology is consistent in each case, and it should be noted that the appearances in V-10, who had repeated episodes over a period of years, were no different from those found in V-l 1 (Figure 4) in whom the disease had been present for a few months only. Indeed, it is the pertinent finding that in many areas the disease shows a startling lack of tissue reaction or of resolution of the occlusive process. Over-all, the microscopic pictures are remarkably similar to those seen in other cases of the disease already reported by us [6] in which the disease was of only a few days’ duration. There are only two possible explanations. Either the lesions once laid down are present permanently, or they are so evanescent as to disappear without leaving evidence of tissue reaction. There is a definite element of vessel wall damage in these sections. The hyaline intravascular material does not always occlude the whole of the vessel lumen. In some areas it is noted to be attached only to a section of the vessel wall. When that has occurred there is almost invariably a bulging of the vessel wall beneath the deposit with microaneurysm formation. When the vessel is completely occluded with the hyaline material, in longitudinal cuts it can be seen to be abnormally dilated. There is reaction in the form of round cell aggregation in some areas, chiefly in the kidney, but this is not a uniform feature in other tissues. Figures 5 and 6 illustrate these
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Figure 5.
Heart of V-I I showing thrombus in vessel with damaged wall. Hematoxyk eosin stain; original magnification X 200, reduced by 20 per cent
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Adrenal gland from V-9 showing dilated thrombosed vessels and normal vessels for comparison. Hematoxylin and eosin stain; original magnification X 63, reduced by 20 per cent.
Figure 6.
points. In Figure 5 the round cell aggregation is sufficient to mimic a glomerulus and is known as glomeruloid. From this we are inclined to deduce that the vessel wall changes represent primary disease and that the hyaline deposits are secondary. A feature of the cases was the degree of myocardial involvement. This was accompanied by thrombosis and hemorrhage (Figure 5). V-10 showed a considerably more intense reaction. We consider that the possible etiology can be discussed under four headings. The first is the obvious possibility of a genetic defect. At first sight one would think that there can be no other explanation in this family. Four affected children in a sibship of seven, with apparently normal parents, is very suggestive of a single mendelian autosomal recessive segregating in this family. But if so, why have similar families not been reported before? They are only a finite number of human loci, and mutation occurs at a rate averaging lo+ per locus per generation. Were we dealing with a single recessive mutation with startling phenotypic effects such as this, it is inconceivable that the disease would not have already been well described. Yet a careful search of the literature has not shown us many reports which would indicate a genetic basis for this disease [7- 131. There are several references to familial cases in which genetic causes would not have been present. For instance, the dis-
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ease has been documented as occurring in husband and wife [ 141, and the related hemolytic-uremic syndrome has been described as occurring simultaneously in nonrelated adopted siblings [ 151. The possibility of a common familial environment mimicking the effects of inheritance must always be kept in mind. Thus the fact that these children were siblings does not do more than indicate a possible genetic factor in the causation of their condition. Yet the presence of the allergic diathesis, with eczema of considerable severity in V-10, and the tendency to exacerbation with infections is reminiscent of the Wiskott-Aldrich syndrome [ 161. In this condition, characterized by the presence of immunologic disturbances and eczema, thrombocytopenia, proneness to infection and bloody diarrhea, sex-linked recessive transmission is established. Other types of sex-linked thrombocytopenia are also known [ 17,181. None of the laboratory investigations carried out in this family suggested a common factor with these disorders. The second possible cause of this familial aggregate of thrombotic thrombocytopenic purpura would be an environmental agent. One must bear in mind the history of maternal psychosis and the interesting intermittent nature of the disease in the children. But we are aware of no toxic agent which can produce a picture of thrombotic thrombocytopenic purpura and
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mention this possibility only to dismiss it. The hemolytic-uremic syndrome has been reported in small epidemics [ 19,201 from different parts of the world, and in some of the familial reports [9,14,15] the action of a common environmental factor is suggested. In this context the isolation by Mettler in 1969 [21] of a rickettsia-like microtatobiote from patients with the hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura, and from mites suspected of having bitten one of the patients warrants consideration, but in the absence of later confirmatory reports this association must be regarded as unproved. Disseminated intravascular coagulation is a recognized complication of many virus diseases [22], and a viral etiology may be the primary course in this family. Studies aimed at detecting infection as a cause in this family have not been rewarding, but the possibility remains. A third possible etiologic factor could be a disturbance of the immune mechanism in these children. The similarity of both thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome to the generalized Shwartzman reaction has been noted by many observers [3-5,231. This immune disease is produced in rabbits following two spaced injections of bacterial endotoxin, and results in intravascular coagulation and deposition of fibrin and platelet thrombi in small vessels, with consequent secondary changes in circulating blood and target organs. The clinical picture and pathologic condition are so similar to thrombotic thrombocytopenic purpura and hemolyticuremic syndrome as to make it difficult to deny that the two share common pathogenic pathways. Yet, and despite the presence at least in the two boys of evidence of an atopic diathesis, no abnormality of the immune mechanism in these children was *demonstrated. Their immunoglobulins were normal when measured, or almost so. The antiglobulin tests and lupus erythematosus tests and similar tests for abnormal antibodies were consistently negative. Their usual response to infection, in contrast to sufferers from the Wiskott-Aldrich syndrome [ 161, has been normal, and no specific pathologic change in the reticuloendothelial tissues has been demonstrated. Specific tests of immunofunction were not performed nor was immunofluorescence sought in biopsy or autopsy material. Specific therapy to the immune system in IV-9 was conspicuously unsuccessful, and IV-10 failed to respond to corticosteroid therapy. We believe that the balance of evidence at present does not favor an autoimmune etiology for this disease in this family. A final etiologic structure can be hypothesized. This is that there is present in this family a rare combination of genetic and environmental factors. The
ET AL.
episodic nature of the condition with remissions lasting up to several years between overt attacks strongly argues for an environmental factor which could be confined to the family or widely present in the community. The strong familial aggregation with four cases in a single sibship suggests the presence of genetic factors. It is difficult to envisage a single genetic locus exerting the only influence, for reasons already outlined. Discoid lupus in the father argues the presence of a deficiency of the immune mechanism, and this can be transmitted [24,25]. The defective allele responsible for the xeroderma pigmentosum in the consanguineous mating on the mother’s side could have been transmitted with a 50 per cent probability to her, and thus may play a part in the manner postulated by Swift [26] for carcinogenesis in the heterozygote in Fanconi’s anemia. The allele responsible for the thromboasthenia may be poorly penetrant and have escaped detection in the father’s pedigree. This highly speculative theory hardly enlightens, but surely must encompass, the true explanation for this unusually affected sibship. Several investigators have postulated a relationship between thrombotic thrombocytopenic purpura and systemic lupus erythematosus or other collagen diseases [8,26-281, and it is to be noted that the father of this sibship had discoid lupus. However, the relationship of the two conditions appears nebulous. Levine and Shearn [27] reported two cases of thrombotic thrombocytopenic purpura in one of which Libman-Sacks verrucous endocarditis was noted and in the other a positive lupus erythematosus precipitation test and some suggestive wire-looping in the glomeruli. From a survey of the literature, they found suggestive evidence of concomitant systemic lupus erythematosus in slightly less than one quarter of 151 cases of thrombotic thrombocytopenic purpura, and they postulated a distinct subgroup of cases of thrombotic thrombocytopenic purpura which show features of systemic lupus erythematosus. Familial concurrence of thrombotic thrombocytopenic purpura and systemic lupus erythematosus was reported some time ago [29-311. We were impressed with the severity of the capillary occlusion in the myocardium in this family, and it may well be that myocardial and other cardiac involvement plays a greater part in the fatal outcome of many of these cases than has been hitherto realized. Most of the cases adduced as evidence of a relationship between thrombotic thrombocytopenic purpura and systemic lupus erythematosus have had atypical verrucous endocarditis [27]. As prethrombotic subendothelial deposition of a hyaline substance in thrombotic thrombocytopenic purpura has been noted by several workers [6,32] it is reasonable to suppose that similar depo-
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sition, distinct from Libman-Sacks endocarditis, can occur on the leaflets of the heart valves in florid thrombotic thrombocytopenic purpura, and having no relation to systemic lupus erythematosus. Certainly in the family here described, apart from the skin lesions in the father, there was nothing to suggest any relationship with systemic lupus erythematosus in any case.
ACKNOWLEDGMENTS We wish to express our thanks to Dr. E. Hirst and Professor S. Posen of Sydney Hospital and the University of Sydney for their help with the preparation of the paper and its illustrations, and to Dr. K. Beck, the family practitioner, for his cooperation at all times in the management of these unfortunate people.
REFERENCES 1.
Symmers WStC: Thrombotic microangiopathic haemolytic anaemia. Br Med J 2: 897, 1952. Moschowitz E: An acute febrile pleiochromic anaemia with 2. hyaline thrombosis of terminal arterioles and capillaries; an undescribed disease. Arch Intern Med 36: 89, 1925. 3. Lieberman E: Haemolytic-uraemic syndrome. J Paediatr 80: 1. 1972. 4. Brain MC: Microangiopathic haemolytic anaemia. Ann Rev Med 21: 133. 1970. 5. Amorosi EL, Ultman JE: Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature. Medicine 45: 139, 1956. 6. Wallace DC: Diffuse disseminated platelet thrombosis (thrombotic thrombocytopenic purpura) with a report of two cases. Med J Aust 1: 9, 1951. Brunjes S, Zike K, Julian R: Familial systemic lupus erythe7. matosus: review of literature, with report of 10 additional cases in four families. Am J Med 30: 529, 1961. 8. Norkin SA, Freedman HH, Evans GW: Thrombotic thrombocytopenic purpura in siblings. Am J Med 43: 294, 1967. 9. Paz PA, Elijovich F, Barcat JA: Fatal simultaneous thrombocytopenic purpura in siblings. Br Med J 4: 727, 1969. 10. Hagge WW, Holley KE, Burlee EC, Stickler GB: Haemolytic uraemic syndrome in two siblings. N Engl J Med 277: 138, 1967. 11. Fison TN: Acute glomerulonephritis in infancy. Arch Dis Child 31: 301. 1956. 12. Anthony PP, Kaplan AB: Fatal haemolytic-uraemic syndrome in two siblings. Arch Dis Child 43: 316, 1968. 13. Campbell S, Carre IJ: Fatal haemolytic-uaemic syndrome and idiopathic hyperlipaemia in monozygotic twins. Arch Dis Child 40: 654, 1965. 14. Watson CG, Cooper WM: Thrombotic thrombocytopenic purpura. Concomitant occurrence of husband and wife. JAMA 215: 1821, 1971. 15. Chan JCM, Eleff MG, Campbell RA: The haemolytic-uraemic syndrome in nonrelated adopted siblings. J. Paediatr 75: 1050, 1969. 16. Wolff JA: Wiskott-Aldrich syndrome. Clinical, immunological and pathological observations. J Paediatr 70: 221, 1967. 17. Vestermark B, Vestermark S: Familial sex-linked thrombocytopenia. Acta Paediatr 53: 365, 1964. 18. Ata M, Fisher OD, Hobman CA: Inherited thrombocytope-
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19.
20.
21.
22.
23.
24. 25.
26. 27.
28. 29.
30.
31.
32.
nia. Lancet 1: 119, 1965. McLean MM, Jones CH, Sutherland DA: Haemolytic-uraemic syndrome. A report of an outbreak. Arch Dis Child 41: 76, 1966. Gianantonis C, Viatacco M, Mendilaharzu F, Rutty A, Mendilaharzu J: The haemolytic-uraemic syndrome. J Paediatr 64: 478, 1964. Mettler NE: Isolation of a microtatobiote from patients with haemolytic-uraemic syndrome and thrombotic thrombocytopenic purpura and from mites in the United States. N Engl J Med 281: 1023, 1969. McKay DB. Margaretten W: Disseminated intravascular coagulation in virus diseases. Arch Intern Med 120: 129, 1967. Taub RN, Rodriguez-Erdmann F, Dameshek W: Intravascular coagulation, the Shwartzman reaction and the pathogenesis of thrombotic thrombocytopenic purpura. Blood 24: 775, 1964. Pirofsky B, Shearn MA: Familial occurrence of disseminated lupus erythematosus. NY Med J 53: 3922, 1953. Kosloske AM, Pisiciotta AV: The syndrome of thrombotic thrombocytopenic purpura as the presenting manifestation of systemic lupus erythematosus. Marquette M Rev 27: 6, 1961. Swift M: Fanconi’s anaemia in the genetics of neoplasia. Nature (Lond) 230, 370, 197 1. Levine S. Shearn MA: Thrombotic thrombocytopenic purpura and systemic lupus erythematosus. Arch Intern Med 113: 826, 1964. Gitlow S, Gokfmark C: Generalised capillary and arteriolar thrombosis. Ann Intern Med 13: 1046, 1939. Antes EH: Thrombotic thrombocytopenic purpura. Review of literature with report of a case. Ann Intern Med 48: 512, 1958. Singer K, Bornstein FP, Wile SA: Thrombotic thrombocytopenic purpura haemorrhagic diatheses with generalised platelet thrombosis. Blood 2: 542. 1947. Singer K, Motulsky AG, Shauberge JN: Thrombotic thrombocytopenic purpura. II. Studies on haemolytic syndrome in this disease. Blood 5: 434, 1950. Dunea G, Muehrcke RC, Nakamoto S, Schwartz FD: Thrombotic thrombocytopenic purpura with acute anuric renal failure. Am J Med 41: 1000, 1966.
D. C. WALLACE,
M.D.
Newcastle N.S. W., Australia A. LOVRIC, M.B., B.S. Camperdown N.S. W., Australia J. S. CLUBB. M.B., B.S. D. B. CARSELDINE, M.B. i&u/burn
A family is described in which four members of a sibship of seven have suffered from a hematologic and systemic disorder which has been fatal in three and has been proved at autopsy to have been thrombotic thrombocytopenic purpura. The fourth member has probably suffered the same disorder. The clinical, laboratory and genetic features of the family are discussed at length. No cause of the disorder has been determined.
N.S. W., Australia
From the Royal Newcastle Hospital, Newcastle N.S.W. 2300, Australia; the Royal Alexandra Hospital for Children, Camperdown N.S.W. 2050. Australia: and the Goulburn Base Hospital, Goulburn N.S.W. 2580, Australia. Requests for reprints should be addressed to Dr. D. C. Wallace, Royal Newcastle Hospital, Newcastle N.S.W. 2300, Australia. Manuscript received April 2, 1974.
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We describe this unfortunate family not only as a record of unusual rarity, but also in the knowledge that from study of such exceptional cases deductions can often be made that have wider application in the understanding and management of the underlying disease. Microangiopathic hemolytic anemia, a term introduced by Symmers [ 11, is perhaps the best generic name for a group of illnesses that have been described under a series of titles since the first annotation by Moschowitz in 1925 [2]. Of these, the best established is thrombotic thrombocytopenic purpura, but the related condition known as the hemolytic-uremic syndrome [3] is probably more widely recognized and may be a manifestation of the same pathologic process [ 41. Diagnosis depends upon the presence of characteristic pathologic lesions consisting of widespread hyaline occlusion of terminal arterioles and capillaries. The manifestations of such a process are naturally protean and involve many systems, thus accounting for the variety of clinical syndromes described in association with this disease [5]. Cases with the triad of thrombocytopenic purpura, hemolytic anemia and neurologic manifestations have become known as thrombotic thrombocytopenic purpura, whereas cases with mainly glomerular changes are known as the hemolytic-uremic syndrome. The etiology of the small vessel occlusions may or may not be unitary [4]. In the present complete uncertainty as to the cause of the condition, it is perhaps best to suspend judgement concerning its nature. That three of the four siblings we describe did indeed suffer from microangiopathic hemolytic anemia is proved by histologic data, and the evidence that the surviving fourth sibling has the same tendency is compelling. Elucidation of the nature of the illness in this family may also shed light on the etiology of this group of diseases in general. THE FAMILY The four affected siblings were born into a family of seven children. An abbreviated pedigree of this tragic family is shown in Figure 1. The brother and father come of Irish stock and are descended from the early settlers of the Southern Tablelands of New South Wales where they are moderately well-todo landholders of a grazing
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Xeroderma pigmentosum
0
Thrombotic Microangiopathy
0
Glanzmann’s Thrombasthenia Rgure 1.
ET AL.
An abbreviated family tree.
property. The original settlers multiplied rapidly and, until the human carrying capacity of the land they took over was saturated, they remained for the most part in the area of their adoption. This made possible the contacting and occasional examination of a very large kindred indeed, most of the information concerning whom does not at this stage appear relevant. Only those segments considered to be of possible interest have been included in the family tree. The sibship we describe in detail comprises the children of the union between IV-6 and IV-7. W-4, the sister of W-6, contracted a consanguineous marriage with her mother’s first cousin; from this marriage six children were born, two of whom have died of xeroderma pigmentosum. At a distance on the father’s side of the pedigree are members Ill-6 and IV-9 who have a bleeding disorder of moderate degree characterized by an abnormality of platelet morphology and function that conforms to the heterogeneous group of disorders classified as Glanzmann’s thrombasthenia. As far as can be determined, there is no evidence of this disorder in the direct line of descent of the father, IV-7. His platelets and that of his mother,
sus, he has taken antimalarials intermittently to control it over the years. He has a heavy alcohol consumption, but this is not greatly above average for his social contacts. His wife, IV-6, now aged 41, has no physical illness of any note. She does suffer from repeated attacks of endogenous depression for which she has received much psychiatric treatment over a period of many years. The presenting episode occurred 20 years ago when, after the birth of her second child, V-8, she suffered a severe puerperal depression, during which the unfortunate woman murdered the infant. The sibship under discussion consists of the seven children, V-7 through V-13. Of these, the eldest, V-7, a male now aged 2 1, has never shown any evidence of hematologic disorder, and the youngest, V-13, a girl now aged 11 years, has also been healthy. Three of the children, V-9, V-10 and V-l 1, have died from thrombotic thrombocytopenic purpura, and the other, V-12, has had diseases diagnosed as idiopathic thrombocytopenic purpura and acute glomerulonephritis but is now well. More detailed description of these cases follows.
111-4, have been described as having a normal appearance on microscopic examination of stained blood smear, and neither bore a spontaneous bleeding tendency. IV-7 is now (1973) aged 50. He is in good health except for a skin condition affecting his face, which developed while he was serving in Borneo in 19431944. Diagnosed as having discoid lupus erythemato-
Case 1. V-9, a male, born in 1954, died in 1963. He was normal at birth, but in early childhood suffered frequent epistaxes and was said to have always bruised easily. At the age of 5 years, he was admitted to the Royal Alexandra Hospital for Children in Sydney with a bleeding diathesis. For 2 days before admission he had been febrile, with anorexia, blood-stained vomitus and blood in his urine. On examination, he had scattered bruises and was bleeding
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slightly from his right nostril. There was no lymphadenopathy or hepatosplenomegaly. His urine contained free hemoglobin, the direct antiglobulin test was negative, and Heinz red blood cell inclusion bodies were not detected. Blood count showed a hemoglobin level of 7.2 g/100 ml, red blood cells mainly normocytic with marked polychromasia, many fragmented cells, moderate number of spherocytes and several nucleated red cells; platelet count was 18,000/mm3. White cells were normal. Clotting studies were normal. The hematuria and epistaxis persisted and a morbilliform rash developed. Bone marrow showed normoblastic erythroid hyperplasia, and the mature red cells showed evidence of spherocytosis and distortion of shape. Myeloid and lymphoid series were normal. Megakaryocytes were normal in number. It was thought that the patient had acute acquired hemolytic anemia and thrombocytopenia or thrombotic thrombocytopenic purpura. He was given a transfusion, and his condition improved. On discharge 10 days later, his hemoglobin level was 10.2 gl 100 ml, with IO per cent reticulocytes and 400,000 thrombocytes/mm3. Except for continuing bruising tendency, the patient was well until 3 l/2 years later when he vomited blood-stained material, his feces contained old blood and his urine was blood-stained. Nothing remarkable was found on physical examination. His hemoglobin level was 12.0 g/100 ml, reticulocytes were 4 per cent, numerous spherocytes and fragmented cells were present in the blood smear, and the platelet count was markedly reduced. Methemalbumin was present, and the serum bilirubin was 2.5 mg/lOO ml. No incomplete antibodies were detected by antiglobulin or enzyme tests. The blood urea was 98 mgl100 ml. During the next few days jaundice developed and the hemoglobin level fell to 6.6 g/100 ml; the platelet count was 80,0001 mm3. A few petechiae were noticed on his skin, and the patient became vague and complained of dizziness, but no objective central nervous system signs were noted. He died suddenly 6 days after admission. Autopsy was performed 4 l/2 hours after death. The body was that of a jaundiced, normally developed 9 year old boy with scattered ecchymoses on the arms and legs. There were regurgitated stomach contents in the pharynx, larynx, trachea and bronchi, with macroscopic evidence of areas of edema in the lungs related to this. There were multiple small hemorrhages in the myocardium, stomach wall, and throughout the length of the small and large intestine. There were numerous hemorrhagic lymph nodes in the mesentery. The kidneys and other viscera were of normal size and, macroscopically, of normal appearance. The histopathology was typical of thrombotic thrombocytopenic purpura with the thrombotic lesions affecting the capillaries and arterioles, and with the major lesions present in the myocardium without infarction but associated with numerous small hemorrhages. In other organs, there was a lesser and variable degree of vascular involvement, being pronounced in the pancreas and bowel, and less developed in the liver and kidneys. In these latter organs, there were abundant albuminous casts in the tubules, and some tubules were filled with blood. Only a small proportion of the glomeruli contained thrombotic lesions, with a rather larger number of the cor-
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tical capillaries and arterioles being affected. Scarring of glomeruli was very infrequent. No vascular lesions were present in the lungs. The bone marrow showed erythroid hyperplasia with a high proportion of very early erythroid cells. Sections of brain stem, cerebellum, basal ganglia and cerebral cortex were examined. The meningeal and cerebral vessels were devoid of any disease except in the region of the internal capsules where there was evidence of some anoxic change in the fibers; one occluded vessel was found. The final diagnosis was thrombotic thrombocytopenic purpura. Case 2. V-10, a male, was born in 1955. We observed this patient over the last 8 years of his life. He had been normal at birth, and early development had been normal, but from an early age he had suffered intermittently from asthma, hay fever and eczema. These had never been serious enough to cause undue concern, but at the age of 6 or 7 he became listless and purpuric spots were noted on his chest. His family practitioner had treated him for “anemia” with occasional cyanocobalamin injections. The patient was first brought to our attention in November 1965 when he was 10 years old, 2 weeks after an attack of measles, which had recently affected several of his siblings. He had not been unduly ill, but he had “bled more than the other children,” to use his mother’s expression. On examination, he was pale and febrile (temperature 38.0°C) with bilateral catarrhal otitis media. The spleen was enlarged. There was a fading measles rash which looked as though it had had a purpuric element, and Hess’s test was positive. Hematologic examination disclosed features suggestive of acute hemolytic anemia with marked thrombocytopenia, a mild leukocytosis and a moderate eosinophilia. The patient was treated with penicillin and a pholcodine cough linctus and made a rapid recovery, returning within a fortnight to apparent completely normal health. During the next 2 years he remained well, with no bleeding episodes, although he suffered from an almost constant low grade eczema and occasional attacks of asthma. He was able, however, to captain his school’s hockey team. He was investigated hematologically in February 1968 and other than a mild eosinophilia no abnormality was found. He remained well until August of that year when his parents reported a certain lack of drive, and a period when he had nosebleeds and the development of some petechial spots during a coryzal illness. At this time he had mild anemia and a marked thrombocytopenia. In October 1968 he had a moderately severe illness with fever, sore throat and cervical lymphadenopathy. Physical examination at this time showed generalized lymph node enlargement, hepatosplenomegaly, herpes simplex labialis, slight eczema and again a blood film with thrombocytopenia, hemolytic process and anemia, and, on this occasion, neutropenia and many immature cells in peripheral blood. Nevertheless, he made a rapid and clinically complete recovery once again, receiving penicillin as his only therapy. During this illness, evidence of renal involvement was noted for the first time in the form of albuminuria
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and red blood cells and casts on microscopic examination. By the end of December, his urine was clear on clinical and microscopic examination. The next record concerns psychiatric illness. From 1969 to 1!)72 he was well and made reasonable progress at school. By 1972 he was in his last year at high school. In June of that year he had a depressive episode and was admitted to the hospital where he received electroconvulsive therapy. In July and August he had two further short hospital admissions following suicidal attempts. During this period he was given chlorpromazine, 300 mg daily. “MelIaria” (thioridatine) had been given initially, but its administration was discontinued following the appearance of a facial rash. The final illness began on a hot day in January 1973 when, over a period of a few hours, the patient experienced three episodes, each lasting some minutes, consisting of right-sided paresthesia, incoordination and dysarthria, associated with a bitemporal headache of some hours’ duration. A fourth similar attack occurred some days later. There were at this stage no abnormal neurologic findings; the only obvious clinical signs were a palpable spleen and large ecchymoses on his left thigh and ankle, the result of a vigorous game of hockey. There was conjunctival p,allor. No lymphadenopathy was noted on this occasion. Following his initial admission to a country hospital, he was transferred to Sydney for more extensive investigation. Full blood count on admission included a hemoglobin level of 7.9 per cent and a hematocrit value of 21.2 per cent. Red cell morphology was abnormal, with anisocytosis, poikilocytosis, microcytes, fragmentation, spherocytes, polychromasia, nucleated red blood cells and rouleaux formation. There were also numerous teardrop cells. Reticulocytes were 32.2 per cent. The white blood cell count was 3,9001mm3, and the platelet count was 15,000/mm3 (Figure 2). Erythrocyte sedimentation rate was 50 mm/hour. Direct antiglobulin test was negative. Only occasional erythrocytes showed inclusion bodies. Thrombin time: patient 12 seconds, control 10 seconds. Fibrinogen was 206 mg/lOO ml. Sucrose hemolysis screening test was negative. Latex test for fibrin degradation products showed these to be in excess of 40 j&g/ml. Lupus erythematosus phenomenon was negative. Red blood cell glucose-&phosphate dehydrogenase was normal. Electrolytes were normal. The blood urea nitrogen was 37 mg/lOO ml, creatinine 2.1 mg/lOO ml, phosphorus 5 mg/lOO ml, uric acid 12 mg/iOO ml, calcium 9.6 mgl 100 ml, haptoglobins 0 to 30 mg/ 100 ml. Schumm’s test was negative. Serum alkaline phosphatase was 73. Albumin was 4.96 per cent and globulin 2.76 per cent. Bilirubin was 1.5 mg/ 100 ml, serum glutamic oxaloacetic transaminase (SGOT) 66 units, serum glutamic pyruvic transaminase (SGPT) 15 units, lactic dehydrogenase 2,700. Lactic dehydrogenase isoentymes were mainly peaks 1 and 2. Cerebrospinal fluid macroscopically was slightly pink, and opalescent. The supernatant was very slightly xanthochromic, ;and there was red blood cell deposit, with a total cell count per cubic millimeters of polymorphonuclear leukocytes 0, lymphocytes 1 and red cells 1,100/mm3. On
ET AL.
culture there was no growth. Cerebrospinal fluid protein was 95 mg/lOO ml, glucose 75 mg/ 100 ml, chloride 118 meq/liter. Lange curves 5 and 6; Pandy’s test was positive. Chest films disclosed no abnormality, and films of the skull did not show any lesions. On microscopic examination of the urine, there were less than 10 white cells/mm3, less than 10 red cells/m& and less than 10 epithelial cells/mm3. Bacterial count was less than 104/ml. There was no significant growth. Granular casts were I+ and amorphous urate crystals 3+. The serologic slide flocculation test for syphilis, Reiter protein complement fixation and Maltaner complement fixation were all nonreactive. No abnormality was seen in the cerebral studies. The electroencephalogram was generally abnormal and paroxysmal, but nonspecific. The electrocardiogram showed sinus rhythm with Wolff-Parkinson-White type trace. No abnormality was found in the serum protein electrophoretogram or immunoelectrophoretogram. Bone marrow sample obtained on January 30, 1973, showed hypercellular aspirate with marked erythroid hyperplasia, consistent with hemolysis. Myeloid precursors were plentiful and megakaryocytes were abundant, No diagnostic features were present. The diagnosis of thrombotic thrombocytopenic purpura was made. The patient was given a transfusion of 6 units of platelets followed by 2 units of whole blood, towards the end of which a marked widespread urticarial reaction developed. A febrile episode followed, considered to be the result of an infection at the site of the cannula. After this resolved, the patient was given high dosage corticosteroid therapy (prednisone 250 mg/day), and splenectomy was performed; the spleen weighed 455 g. Needle biopsy of one kidney was performed during the operation. Microscopic examination of the spleen showed congestion of the pulp, with prominent sinusoids. The vessels showed no abnormality and none of the changes sometimes described in idiopathic thrombocytopenic purpura. The appearances more closely resembled those of hemolytic anemia. They were, however, not diagnostic. Kidney biopsy showed thrombi within 3 or 4 small vessels. Two of these were surrounded by an unusual cellular proliferation which may be reactive to damaged vessel wall (Figure 2). These changes were thought to be consistent with those described in both disseminated intravascular coagulation and thrombotic thrombocytopenic purpura. Postoperatively the hematologic picture initially remitted rapidly, the hemoglobin level rising to 11.2 g, the white cell count to 21,700/mm3 and the platelet count to 405,000/ mm3 5 days after surgery, and corticosteroid therapy was reduced. However, 10 days postoperatively the platelet count had fallen to 60,000/mm3 and therapy with large doses of prednisone was again instituted: in addition, the patient was given dipyridamole, firstly 400 mg/day and later 800 mg/day. The peripheral blood picture continued to show marked fragmentation of erythrocytes with target cells, HowellJolly bodies and siderotic granules (Figure 3). The patient remained asymptomatic with no bleeding tendency. Hess
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Kidney biopsy specimen from V- 10 showing thrombus in an arteriole. Figure 2. lin and eosin stain; original magnification X 160, reduced by 20 per cent.
Hematoxy-
Figure 3. Peripheral blood picture in V- 10 showing typical appearance of microangiopathic hemolytic anemia with fragmentation of red cells and bizarre forms. 728
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test remained negative. Between 10 and 40 pug/mlof fibrin degradation products continued to be detected. Two weeks postoperatively, with hematologic status unchanged, Cushingoid appearance developed as well as oral candidiasis. Continuous intravenous infusion of heparin was given in a dose of 30,000 units/day for 5 days. The platelet c.ount continued to fall, with a lowest count of 13,000/mm3 on the 5th day of infusion. Serum complement at this time was not grossly abnormal. In view of the failure of all other forms of therapy, cyclophosphamide 150 mglday was commenced the day after the cessation of heparin therapy. This was not accompanied by any noticeable improvement in the patient’s general or hematologic condition. Five weeks postoperatively the patient was transferred to his hometown hospital. The dose of cyclophosphamide was gradually reduced and suspended after having been given for 3 months altogether. The administration of prednisone in lesser dosage was continued. The patient’s condition deteriorated steadily, he became cachectic and finally died 2 i/2 months after splenectomy, the final phase being one of progressive renal failure. Necropsy was performed 22 hours after death. Gross findings related to postsplenectomy. In addition, there were a few small petechiae in the myocardium, and more numerous petechiae in the walls of the large and small bowel. Scattered petechiae were present throughout the substance of the brain. The kidneys were engorged, but otherwise not abnormal except for the presence of an organizing thrombus at the site of the renal biopsy. No abnormality was noted in the larger blood vessels and no lymphadenopathy was found. Microscopically there were numerous and very widespread vascular lesions in most organs examined, the detailed findings are as follows: Kidney: Numerous capillaries containecl homogeneous and granular material within their lumens. In some there was endothelial cell proliferation. These vessels were enlarged due to aneurysmal dilatation. Other small vessels showed a thickened cellular wall (? healing). Some glomeruli were hemorrhagic. Capillary loops in some were distended by homogeneous material. There was no significant basement membrane thickening. These vascular changes are typical of thrombotic thrombocytopenic purpura but are also seen in disseminated intravascular thrombosis and generalized Shwartzman reaction. In addition to these, there was a larger vessel with a necrotic hemorrhagic wall. A large hemorrhagic cyst was a hematoma related to the previous needle biopsy. Liver: There was a severe autolysis but an occasional small vessel was similarly involved. Pituitary: There were many involved vessels in the posterior pituitary, but no other changes. Heart: The vessels in the myocardium and epicardium ‘were involved. There were very severe microinfarcts with myocardial cell fallout and some small hemorrhages. There was an unusual degree of myocardial involvement. Lung: Severe autolysis was present. The vessels were probably involved. Bowel: Submucosal vessels were involved in the small intestine. Severe mucosal autolysis was present, but there was no evidence of ulceration. Pancreas: Many vessels were involved. In addition, thrombosis of a large artery and a thrombosed recanalized large vein were evident. Brain: Occasional small vessels were
involved with minute areas of softening. Peripheral nerve: The vasa nervorum were involved. Adrenal cortex: Many vessels were involved. Tongue testis: No significant change was evident. Summary: (1) Vessels in most organs were occluded by homogeneous and granular material. (2) Larger vessels were involved in the pancreas and kidney. Pathologic diagnosls: Thrombotic thrombocytopenic purpura. Case 3. V-l 1, a female, was born in 1956. This chiki was well until the age of 19 months. She then had a sudden onset of anorexia and irritability. Three days later some small red spots were noted on her trunk which persisted for only 1 or 2 days. The parents then noted progressive pallor and lack of movement on her left side. She was admitted to the hospital on the 16th day of her illness; she was pale and listless and had a left flaccid hemiplegia. Spleen and liver were palpable. Hair was noted to be falling out. Her hemoglobin level was 4.6 g/100 ml, reticulocytes 9 per cent, platelet count 5,000/mm3. The white blood cell count was 10,000/mm3 with a normal differential. Blood smear showed macrocytic anemia with scattered spherocytes and nucleated red cells and marked polychromasia. The cerebrospinal fluid was a blood-stained specimen with 1,000 red blood cells/mm3; no other abnormality was detected. The electroencephalogram showed a gross right temporo-occipital focal abnormality. Serum proteins were normal. Lupus erythematosus preparations were not diagnostic on three separate occasions. An increased arsenic content was found in hair and nails on one occasion, and urinary lead content was normal. No thallium was found. The patient was given a transfusion on numerous occasions and large doses of corticosteroids up to 60 mg of prednisone/day. After finding the arsenic in her hair and nails, a course of dimercaprol therapy was also given. Her hemoglobin levels fell rapidly after each transfusion, and the platelet count remained very low throughout. The antiglobulin test was invariably negative. Bone marrow examination showed only an active erythropoietic marrow. The hemiparesis improved, but the child remained gravely ill and died following a sudden rise in temperature 3 months after her admission to the hospital. She had quite marked petechial hemorrhage on numerous occasions, but the Hess test was always recorded as negative. Only a partial necropsy was permitted, and the brain and spinal cord were not removed. The only gross abnormality was an enlarged fatty liver. Microscopic examination disclosed hyaline thrombi of varying stages of development in many of the arterioles and capillaries. They were most numerous in the vessels of the heart, in which they had produced occasional small infarcts, and least numerous in the lung. In the liver cells, there was marked fatty accumulation and in some cells an amount of unidentified waxy substance. In the kidney, many glomeruli were damaged as a result of occlusion of the glomerular capillaries and/or the afferent and efferent vessels. Diagnosis of thrombotic thrombocytopenic purpura was established. May 1975
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4. V-12, a female, was born in 1958. This girl is the only survivor among the siblings who has shown any evidence of hematologic or other disorder. At present she is well and has not had any serious illness for several years. She was born after a normal confinement and was healthy until the age of 4 years, although the parents report that in infancy and early childhood she bruised easily and had suffered an occasional mild epistaxis. At this time, a day after taking some Viprynium pamoate (Vanquine) she had a severe nose bleed and spontaneous bruising and petechiae developed., Initially, the spleen was impalpable, but it was felt 24 hours later. The ecchymoses became more marked for the first 48 hours, but no subsequent bleeding occurred. Investigation at this stage showed a hemoglobin level of 12.3 g/100 ml, and this did not subsequently vary. Platelets were initially 5,000/mm3 but rose over a period of 10 days to 138,000/mm3 without treatment. Peripheral blood smear showed a normal white cell picture. Marrow aspiration showed a slight eosinophilia, and an increased number of megakaryocytes, the majority of which had absence of budding. No treatment was given, and the patient made an uninterrupted recovery. In absence of other symptoms or signs, a diagnosis of idiopathic thrombocytopenia was made. The patient was subsequently seen 2 years later when she had an upper respiratory tract infection, following which she suffered a series of small epistaxes and one small, but definite hematemesis. She was admitted to the hospital, and routine testing of her urine revealed the presence of blood and albumin. Microscopic examination confirmed the presence of red blood cells and demonstrated the presence of granular casts. No evidence for streptococcal infection was found. The diagnosis of acute glomerulonephritis was made, and oral penicillin therapy was given. Blood count at this time was usual. No abnormality of clotting was demonstrated. The patient made a rapid clinical recovery, but measles developed 2 weeks after her admission to the hospital. Red blood cells were detectable for 2 months in her urine, which then became normal and has subsequently remained so. There was no biochemical evidence, at any stage, of impaired renal function. Since then she has not been ill, a period of 9 years. Case
COMMENTS This family appears to be unique. There can be little doubt that the three children who died suffered from thrombotic thrombocytopenic purpura. Although her illnesses are not well documented, there is reason to believe that the fourth child has had episodes of the same disorder. The presence of petechiae, anemia, thrombocytopenia and a glomerular lesion at various times follows the same pattern as that set by the fatal cases. From this emerges a pattern of disease that may be summarized as follows. The affected person is for the most part fit and healthy. He is subject at irregular intervals to the de-
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velopment of an acute hemolytic process associated with concurrent severe thrombocytopenia. No predisposing factor is obvious, although it is at least suggestive that on numerous occasions in three of the children attacks appeared to be ushered in by a febrile illness resembling a viral infection. The underlying pathologic process is that of thrombotic thrombocytopenic purpura, which has produced in these children evidence of impaired renal, hepatic, cerebral and cardiac function from involvement of these organs. The disease is remittent, some attacks being subclinical, and others lasting up to 2 or 3 months with subsequent complete remissions. No evidence to suggest an immune process has been found. The antiglobulin test has been consistently negative, and no definite abnormality of cellular or humoral immunity has ever been demonstrated. Yet the presence in one parent of an autoimmune disorder, and severe asthma, hay fever and eczema in one of the sufferers leaves this question open. Reappraisal of therapy suggested that the children have done best when treated symptomatically. There is no evidence that corticosteroid therapy, heparin or cyclophosphamide has been of any benefit. The etiology of the disorder is unknown, and this family does little to make the pattern any more clear. Certain features demand explanation. The histopathology is consistent in each case, and it should be noted that the appearances in V-10, who had repeated episodes over a period of years, were no different from those found in V-l 1 (Figure 4) in whom the disease had been present for a few months only. Indeed, it is the pertinent finding that in many areas the disease shows a startling lack of tissue reaction or of resolution of the occlusive process. Over-all, the microscopic pictures are remarkably similar to those seen in other cases of the disease already reported by us [6] in which the disease was of only a few days’ duration. There are only two possible explanations. Either the lesions once laid down are present permanently, or they are so evanescent as to disappear without leaving evidence of tissue reaction. There is a definite element of vessel wall damage in these sections. The hyaline intravascular material does not always occlude the whole of the vessel lumen. In some areas it is noted to be attached only to a section of the vessel wall. When that has occurred there is almost invariably a bulging of the vessel wall beneath the deposit with microaneurysm formation. When the vessel is completely occluded with the hyaline material, in longitudinal cuts it can be seen to be abnormally dilated. There is reaction in the form of round cell aggregation in some areas, chiefly in the kidney, but this is not a uniform feature in other tissues. Figures 5 and 6 illustrate these
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Figure 5.
Heart of V-I I showing thrombus in vessel with damaged wall. Hematoxyk eosin stain; original magnification X 200, reduced by 20 per cent
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Adrenal gland from V-9 showing dilated thrombosed vessels and normal vessels for comparison. Hematoxylin and eosin stain; original magnification X 63, reduced by 20 per cent.
Figure 6.
points. In Figure 5 the round cell aggregation is sufficient to mimic a glomerulus and is known as glomeruloid. From this we are inclined to deduce that the vessel wall changes represent primary disease and that the hyaline deposits are secondary. A feature of the cases was the degree of myocardial involvement. This was accompanied by thrombosis and hemorrhage (Figure 5). V-10 showed a considerably more intense reaction. We consider that the possible etiology can be discussed under four headings. The first is the obvious possibility of a genetic defect. At first sight one would think that there can be no other explanation in this family. Four affected children in a sibship of seven, with apparently normal parents, is very suggestive of a single mendelian autosomal recessive segregating in this family. But if so, why have similar families not been reported before? They are only a finite number of human loci, and mutation occurs at a rate averaging lo+ per locus per generation. Were we dealing with a single recessive mutation with startling phenotypic effects such as this, it is inconceivable that the disease would not have already been well described. Yet a careful search of the literature has not shown us many reports which would indicate a genetic basis for this disease [7- 131. There are several references to familial cases in which genetic causes would not have been present. For instance, the dis-
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ease has been documented as occurring in husband and wife [ 141, and the related hemolytic-uremic syndrome has been described as occurring simultaneously in nonrelated adopted siblings [ 151. The possibility of a common familial environment mimicking the effects of inheritance must always be kept in mind. Thus the fact that these children were siblings does not do more than indicate a possible genetic factor in the causation of their condition. Yet the presence of the allergic diathesis, with eczema of considerable severity in V-10, and the tendency to exacerbation with infections is reminiscent of the Wiskott-Aldrich syndrome [ 161. In this condition, characterized by the presence of immunologic disturbances and eczema, thrombocytopenia, proneness to infection and bloody diarrhea, sex-linked recessive transmission is established. Other types of sex-linked thrombocytopenia are also known [ 17,181. None of the laboratory investigations carried out in this family suggested a common factor with these disorders. The second possible cause of this familial aggregate of thrombotic thrombocytopenic purpura would be an environmental agent. One must bear in mind the history of maternal psychosis and the interesting intermittent nature of the disease in the children. But we are aware of no toxic agent which can produce a picture of thrombotic thrombocytopenic purpura and
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mention this possibility only to dismiss it. The hemolytic-uremic syndrome has been reported in small epidemics [ 19,201 from different parts of the world, and in some of the familial reports [9,14,15] the action of a common environmental factor is suggested. In this context the isolation by Mettler in 1969 [21] of a rickettsia-like microtatobiote from patients with the hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura, and from mites suspected of having bitten one of the patients warrants consideration, but in the absence of later confirmatory reports this association must be regarded as unproved. Disseminated intravascular coagulation is a recognized complication of many virus diseases [22], and a viral etiology may be the primary course in this family. Studies aimed at detecting infection as a cause in this family have not been rewarding, but the possibility remains. A third possible etiologic factor could be a disturbance of the immune mechanism in these children. The similarity of both thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome to the generalized Shwartzman reaction has been noted by many observers [3-5,231. This immune disease is produced in rabbits following two spaced injections of bacterial endotoxin, and results in intravascular coagulation and deposition of fibrin and platelet thrombi in small vessels, with consequent secondary changes in circulating blood and target organs. The clinical picture and pathologic condition are so similar to thrombotic thrombocytopenic purpura and hemolyticuremic syndrome as to make it difficult to deny that the two share common pathogenic pathways. Yet, and despite the presence at least in the two boys of evidence of an atopic diathesis, no abnormality of the immune mechanism in these children was *demonstrated. Their immunoglobulins were normal when measured, or almost so. The antiglobulin tests and lupus erythematosus tests and similar tests for abnormal antibodies were consistently negative. Their usual response to infection, in contrast to sufferers from the Wiskott-Aldrich syndrome [ 161, has been normal, and no specific pathologic change in the reticuloendothelial tissues has been demonstrated. Specific tests of immunofunction were not performed nor was immunofluorescence sought in biopsy or autopsy material. Specific therapy to the immune system in IV-9 was conspicuously unsuccessful, and IV-10 failed to respond to corticosteroid therapy. We believe that the balance of evidence at present does not favor an autoimmune etiology for this disease in this family. A final etiologic structure can be hypothesized. This is that there is present in this family a rare combination of genetic and environmental factors. The
ET AL.
episodic nature of the condition with remissions lasting up to several years between overt attacks strongly argues for an environmental factor which could be confined to the family or widely present in the community. The strong familial aggregation with four cases in a single sibship suggests the presence of genetic factors. It is difficult to envisage a single genetic locus exerting the only influence, for reasons already outlined. Discoid lupus in the father argues the presence of a deficiency of the immune mechanism, and this can be transmitted [24,25]. The defective allele responsible for the xeroderma pigmentosum in the consanguineous mating on the mother’s side could have been transmitted with a 50 per cent probability to her, and thus may play a part in the manner postulated by Swift [26] for carcinogenesis in the heterozygote in Fanconi’s anemia. The allele responsible for the thromboasthenia may be poorly penetrant and have escaped detection in the father’s pedigree. This highly speculative theory hardly enlightens, but surely must encompass, the true explanation for this unusually affected sibship. Several investigators have postulated a relationship between thrombotic thrombocytopenic purpura and systemic lupus erythematosus or other collagen diseases [8,26-281, and it is to be noted that the father of this sibship had discoid lupus. However, the relationship of the two conditions appears nebulous. Levine and Shearn [27] reported two cases of thrombotic thrombocytopenic purpura in one of which Libman-Sacks verrucous endocarditis was noted and in the other a positive lupus erythematosus precipitation test and some suggestive wire-looping in the glomeruli. From a survey of the literature, they found suggestive evidence of concomitant systemic lupus erythematosus in slightly less than one quarter of 151 cases of thrombotic thrombocytopenic purpura, and they postulated a distinct subgroup of cases of thrombotic thrombocytopenic purpura which show features of systemic lupus erythematosus. Familial concurrence of thrombotic thrombocytopenic purpura and systemic lupus erythematosus was reported some time ago [29-311. We were impressed with the severity of the capillary occlusion in the myocardium in this family, and it may well be that myocardial and other cardiac involvement plays a greater part in the fatal outcome of many of these cases than has been hitherto realized. Most of the cases adduced as evidence of a relationship between thrombotic thrombocytopenic purpura and systemic lupus erythematosus have had atypical verrucous endocarditis [27]. As prethrombotic subendothelial deposition of a hyaline substance in thrombotic thrombocytopenic purpura has been noted by several workers [6,32] it is reasonable to suppose that similar depo-
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sition, distinct from Libman-Sacks endocarditis, can occur on the leaflets of the heart valves in florid thrombotic thrombocytopenic purpura, and having no relation to systemic lupus erythematosus. Certainly in the family here described, apart from the skin lesions in the father, there was nothing to suggest any relationship with systemic lupus erythematosus in any case.
ACKNOWLEDGMENTS We wish to express our thanks to Dr. E. Hirst and Professor S. Posen of Sydney Hospital and the University of Sydney for their help with the preparation of the paper and its illustrations, and to Dr. K. Beck, the family practitioner, for his cooperation at all times in the management of these unfortunate people.
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Symmers WStC: Thrombotic microangiopathic haemolytic anaemia. Br Med J 2: 897, 1952. Moschowitz E: An acute febrile pleiochromic anaemia with 2. hyaline thrombosis of terminal arterioles and capillaries; an undescribed disease. Arch Intern Med 36: 89, 1925. 3. Lieberman E: Haemolytic-uraemic syndrome. J Paediatr 80: 1. 1972. 4. Brain MC: Microangiopathic haemolytic anaemia. Ann Rev Med 21: 133. 1970. 5. Amorosi EL, Ultman JE: Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature. Medicine 45: 139, 1956. 6. Wallace DC: Diffuse disseminated platelet thrombosis (thrombotic thrombocytopenic purpura) with a report of two cases. Med J Aust 1: 9, 1951. Brunjes S, Zike K, Julian R: Familial systemic lupus erythe7. matosus: review of literature, with report of 10 additional cases in four families. Am J Med 30: 529, 1961. 8. Norkin SA, Freedman HH, Evans GW: Thrombotic thrombocytopenic purpura in siblings. Am J Med 43: 294, 1967. 9. Paz PA, Elijovich F, Barcat JA: Fatal simultaneous thrombocytopenic purpura in siblings. Br Med J 4: 727, 1969. 10. Hagge WW, Holley KE, Burlee EC, Stickler GB: Haemolytic uraemic syndrome in two siblings. N Engl J Med 277: 138, 1967. 11. Fison TN: Acute glomerulonephritis in infancy. Arch Dis Child 31: 301. 1956. 12. Anthony PP, Kaplan AB: Fatal haemolytic-uraemic syndrome in two siblings. Arch Dis Child 43: 316, 1968. 13. Campbell S, Carre IJ: Fatal haemolytic-uaemic syndrome and idiopathic hyperlipaemia in monozygotic twins. Arch Dis Child 40: 654, 1965. 14. Watson CG, Cooper WM: Thrombotic thrombocytopenic purpura. Concomitant occurrence of husband and wife. JAMA 215: 1821, 1971. 15. Chan JCM, Eleff MG, Campbell RA: The haemolytic-uraemic syndrome in nonrelated adopted siblings. J. Paediatr 75: 1050, 1969. 16. Wolff JA: Wiskott-Aldrich syndrome. Clinical, immunological and pathological observations. J Paediatr 70: 221, 1967. 17. Vestermark B, Vestermark S: Familial sex-linked thrombocytopenia. Acta Paediatr 53: 365, 1964. 18. Ata M, Fisher OD, Hobman CA: Inherited thrombocytope-
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