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Nonthrombocytopenic purpura with eosinophilia
Volume 105 Number 2
Clinical and laboratory observations
277
Nonthrombocytopenic purpura with eosinophilia Eiiel Bayever, M.R.C.P., Michael H. Rosove, M.D., and Carl Lenarsky, M.D. Los Angeles, Calif.
A SYNDROME of n o n t h r o m b o c y t o p e n i c purpura associated with m a r k e d eosinophilia has been reported to occur only in children or young adults living in S o u t h e a s t Asia. t-3 The s y n d r o m e is usually self-limiting and resolves within 6 months of onset. A n occasional patient has been described to have improved after a course of antihelminthics, indicating a possible association with intestinal parasites. This syndrome, a l t h o u g h well-recognized in S o u t h e a s t Asia, has never been reported in the United States. W e report a patient with n o n t h r o m b o c y t o p e n i c p u r p u r a with eosinophilia, and review the literature concerning this syndrome. CASE REPORT This I2-year-old Philippino boy, born in the United Statcs, had been living in the Philippines for several years. He was referred to us with a history of easy bruising for 6 months, which began just before his return to the United States. He recalled an episode of high fever associated with a rash prior to the onset of the easy bruising. The rash, which was macular, was confined largely to the trunk. Two months previously, an episode of trauma to the face had led to excessive bleeding. There was no recent history of weight loss, night sweating, vomiting, diarrhea, or drug ingestion. There was no personal or family history of a bleeding tendency. Physical examination revealed multiple ecchymoses, 2 to 5 cm in diameter and of varying ages, on the lower limbs and trunk. No petechiae were seen. There was no lymphadenopathy or hepatosplenomegaly. Laboratory tests revealed the following values: WBC count 11,300/mm 3, with 43% eosinophils (4860/mm3), 3% basophils (340/mm3), 29% polymorphonuclear cells, 21% lymphocytes, and 4% monocytes; hemoglobin 13.9 gm/dl; and platelet count 233,000/mm 3. Examination of the peripheral blood smear showed normochromic normocytic red cells, and normal white cell and platelet form and structure. Prothrombin time was 13.1 seconds (control 11.6 seconds), and activated partial thromboplastin time 35.2 seconds (control 32.5 seconds). Factor Vlllc was 69% (normal >50%), factor Vlll:ristocetin eofactor 50% (normal >55%), and factor VIII:antigen 65% (normal >50%).
From the Departments of' Pediatrics (Division of Hematology/ Oncology and Gwynne Hazen Cherry Memorial Laboratories) and Medicine (Division of Hematology/Oncology), UCLA School of Medicine. Submitted for publication Oct. 12, 1983; accepted Feb. 10, 1984. Reprint requests: Carl Lenarsky, M.D., Department of Pediatrics, Division of l-lematology/Oncology, MDCC A2-410, UCLA School of Medicine, Los Angeles, CA 90024.
The Ivy bleeding time was >30 minutes (normal 2.3 to 9.5 minutes) on two separate occasions (Simplate I1, General Diagnostics, Morris Plains, N.J.). Prothrombin consumption was 17.5 scconds (control 37.0 seconds). Platelet aggregation studies performed on 25 mM citrated platelet-rich plasma with a platelet count of 150,000#1 showed only a weak primary wave (30% change in optical transmission) in response to adenosine diphosphate (16 #m). There was no secondary wave in response to epinephrine. There was a markcdly reduced collagen response, and normal aggregation responses to arachidonic acid and ristocetin. Platelet-bound IgG, determined by a modification of the antiglobulin absorption technique on washed, frozen-thawed platelets,4 was 14 fg/platelet (normal < 15 fg/platelet). A bone marrow aspirate revealed eosinophilia, but was otherwise normal. Chromosome analysis showed a normal 46,XY karyotype. Six separate stool specimens were negative for ova and parasites. The sedimentation rate was 15 mm/hr (Wintrobe, normal 0 to 9 mm/hr). Serum lgE was 1510 U/ml (normal 100 U/ml). The blood group was O positive, with isohemagglutinin titers of anti-A I : 1024 and anti-B 1 : 1024 (normal values <1:400 and 1:200, respectively). The chest radiograph showed normal lindings. Five months after hc was first seen, the patient was noted to be less susceptible to spontaneous bruising, with only a few unexplained bruises, 1 to 2 cm in diameter, on the lower limbs. There were no pctechiae, and no history of bleeding was elicited. His bleeding time was 10.5 minutes, and platelet aggregation, although not normal, had improved from the last study. The cosinophil count had dropped to 1504/mm 3. At I1 months the clinical findings had resolved further. There was only an isolated ecchymosis over the anterior tibia related to trauma. The eosinophil count at that time was 830/ram ~. DISCUSSION T h e syndrome of n o n t h r o m b o c y t o p e n i c purpura associated with eosinophilia is well-recognized in children living in Southeast Asia. MitrakuP studied 24 children from T h a i l a n d who had widespread spontaneous bruising of the limbs, trunk, and face and no previous history of bleeding tendency. These children all had normal platelet counts, and all but one were reported to have eosinophilia. Suvatte et al. 2 reported the largest series of patients with this syndrome, and found a variety of abnormalities, including prolonged bleeding time, defective platelet adhesion, diminished platelet factor III availability, and a b n o r m a l platelet aggregation responses to A D P , thrombin, collagen, and ristocetin. In addition, intestinal parasites were
278
Clinical and laboratory observations
detected in the stool of 36 of 62 (58%) patients. The most common parasites isolated were Ascaris (28%), Enterobius (22%), and hookworm (4%). Recently, Kueh 3 reported a 19-year-old man from Singapore with multiple ecchymoses, absolute eosinophil count of 2320/mm 3, platelet count of 170,000/ram 3, and stool examination positive for ova of Ancylostoma duodenale. Although the bleeding time was reported to be normal, abnormal platelet aggregation was observed. The clinical and laboratory abnormalities improved several days after the patient was given a single dose of an antihelminthic. Typical features of this syndrome are the combination of a bleeding tendency in an otherwise healthy child, a normal platelet count, prolonged bleeding time, platelet function abnormalities, and eosinophilia. The syndrome appears to be self-limiting, spontaneous recovery occurring in 6 months (range 5 months to 1 year). ~, Parasitic infections may be responsible for this syndrome. Parasites are the most common cause of eosinophilia worldwide, with visceral larva migrans producing the most profound elevations of eosinophil counts? Failure to demonstrate larvae or eggs in the feces does not rule out parasitic infection, but a significant rise in isohemagglutinin titers, 6 as well as an elevated serum level of IgE, 7 both detected in our patient, is highly suggestive of infestation with Toxocara. Suvatte et al? have suggested that an immune response to parasitic infection might result in the production of antibodies and the formation of immune complexes, which could bind to platelets and interfere with their function. Clarification of the role of parasitic infection in the syndrome of acquired platelet dysfunction and eosinophilia awaits careful study in future patients. If
The Journal of Pediatrics August 1984
parasites are responsible for this syndrome, it is unclear why this syndrome has not yet been reported in the United States, because parasitic infection is common worldwide. An awareness of this syndrome by physicians may lead to an increased recognition of cases. The role of eosinophils, or basophils, inasmuch as these were also higher than normal in our patient, is unclear. Production of some as yet unknown platelet inhibiting substance may well account for the platelet abnormalities observed. We thank Dr. Hurwitz of the Naval Regional Medical Clinic, Port Hueneme, California, for referring this patient; and Ms. Donna Lopez for preparation of the manuscript. REFERENCES 1. Mitrakul C: Transient, spontaneous bruising with long bleeding time and normal platclet count. Am J Clin Pathol 63:81, 1975. 2. Suvatte V, Mahasandana C, Tanpaichitr U, Tuchinda S: Acquired platelet dysfunction with eosinophilia: Study of platelet function in 62 cases. Southeast Asian J Trop Med Public Health 10:358, t979. 3. Kneh YK: The syndrome of non-thrombocytopenic purpura with eosinophilia: An acquired platelet dysfunction (Letter). N Engl J Med 306:365, 1982. 4. Dixon R, Rosse W, Ebbert L: Quantitative determination of antibody in idiopathic thrombocytopenic purpura: Correlation of serum and platelet-bound antibody with clinical response. N Engl J Med 5:230, 1975. 5. LukensJN: Eosinophiliain children. Pediatr Clin North Am 19:969, 1972. 6. Heiner DC, Kcvy SV: Visceral larva migrans: Report of the syndrome in three siblings. N Engl J Med 254:629, 1956. 7. Butterworth AE, David JR: Eosin0phil function. N Engl J Mcd 304:t54, 1981.
Treatment of a spontaneous intracerebral hematoma with exchange transfusions in an infant with hemophilia B Jane E. Striegel, M.D., and J. Roger Edson, M.D. Minneapolis, Minn.
IN PATIENTS WITH HEMOPHILIA, a spontaneous hemorrhage is unusual in the first year of life, and a spontaneous intracranial hemorrhage is rare at any age. We report an infant with factor IX deficiency who had a spontaneous intracerebral hemorrhage as a complication of hemophilia From the Departments of Pediatrics and Laboratory Medicine and Pathology. University of Minnesota School of Medicine. Submitted for publication Oct. 24, 1983; accepted Feb. 3, 1984. Reprints not available.
B at 5 weeks of age. The infant was given frequent single-volume exchange transfusions as an alternative to using prothrombin complex concentrate, with a successful long-term outcome. FFP PRBC PT PTT TT
Fresh frozen plasma Packedred blood cells Prothrombin time Partial thrombop[astin time Thrombin time
Clinical and laboratory observations
277
Nonthrombocytopenic purpura with eosinophilia Eiiel Bayever, M.R.C.P., Michael H. Rosove, M.D., and Carl Lenarsky, M.D. Los Angeles, Calif.
A SYNDROME of n o n t h r o m b o c y t o p e n i c purpura associated with m a r k e d eosinophilia has been reported to occur only in children or young adults living in S o u t h e a s t Asia. t-3 The s y n d r o m e is usually self-limiting and resolves within 6 months of onset. A n occasional patient has been described to have improved after a course of antihelminthics, indicating a possible association with intestinal parasites. This syndrome, a l t h o u g h well-recognized in S o u t h e a s t Asia, has never been reported in the United States. W e report a patient with n o n t h r o m b o c y t o p e n i c p u r p u r a with eosinophilia, and review the literature concerning this syndrome. CASE REPORT This I2-year-old Philippino boy, born in the United Statcs, had been living in the Philippines for several years. He was referred to us with a history of easy bruising for 6 months, which began just before his return to the United States. He recalled an episode of high fever associated with a rash prior to the onset of the easy bruising. The rash, which was macular, was confined largely to the trunk. Two months previously, an episode of trauma to the face had led to excessive bleeding. There was no recent history of weight loss, night sweating, vomiting, diarrhea, or drug ingestion. There was no personal or family history of a bleeding tendency. Physical examination revealed multiple ecchymoses, 2 to 5 cm in diameter and of varying ages, on the lower limbs and trunk. No petechiae were seen. There was no lymphadenopathy or hepatosplenomegaly. Laboratory tests revealed the following values: WBC count 11,300/mm 3, with 43% eosinophils (4860/mm3), 3% basophils (340/mm3), 29% polymorphonuclear cells, 21% lymphocytes, and 4% monocytes; hemoglobin 13.9 gm/dl; and platelet count 233,000/mm 3. Examination of the peripheral blood smear showed normochromic normocytic red cells, and normal white cell and platelet form and structure. Prothrombin time was 13.1 seconds (control 11.6 seconds), and activated partial thromboplastin time 35.2 seconds (control 32.5 seconds). Factor Vlllc was 69% (normal >50%), factor Vlll:ristocetin eofactor 50% (normal >55%), and factor VIII:antigen 65% (normal >50%).
From the Departments of' Pediatrics (Division of Hematology/ Oncology and Gwynne Hazen Cherry Memorial Laboratories) and Medicine (Division of Hematology/Oncology), UCLA School of Medicine. Submitted for publication Oct. 12, 1983; accepted Feb. 10, 1984. Reprint requests: Carl Lenarsky, M.D., Department of Pediatrics, Division of l-lematology/Oncology, MDCC A2-410, UCLA School of Medicine, Los Angeles, CA 90024.
The Ivy bleeding time was >30 minutes (normal 2.3 to 9.5 minutes) on two separate occasions (Simplate I1, General Diagnostics, Morris Plains, N.J.). Prothrombin consumption was 17.5 scconds (control 37.0 seconds). Platelet aggregation studies performed on 25 mM citrated platelet-rich plasma with a platelet count of 150,000#1 showed only a weak primary wave (30% change in optical transmission) in response to adenosine diphosphate (16 #m). There was no secondary wave in response to epinephrine. There was a markcdly reduced collagen response, and normal aggregation responses to arachidonic acid and ristocetin. Platelet-bound IgG, determined by a modification of the antiglobulin absorption technique on washed, frozen-thawed platelets,4 was 14 fg/platelet (normal < 15 fg/platelet). A bone marrow aspirate revealed eosinophilia, but was otherwise normal. Chromosome analysis showed a normal 46,XY karyotype. Six separate stool specimens were negative for ova and parasites. The sedimentation rate was 15 mm/hr (Wintrobe, normal 0 to 9 mm/hr). Serum lgE was 1510 U/ml (normal 100 U/ml). The blood group was O positive, with isohemagglutinin titers of anti-A I : 1024 and anti-B 1 : 1024 (normal values <1:400 and 1:200, respectively). The chest radiograph showed normal lindings. Five months after hc was first seen, the patient was noted to be less susceptible to spontaneous bruising, with only a few unexplained bruises, 1 to 2 cm in diameter, on the lower limbs. There were no pctechiae, and no history of bleeding was elicited. His bleeding time was 10.5 minutes, and platelet aggregation, although not normal, had improved from the last study. The cosinophil count had dropped to 1504/mm 3. At I1 months the clinical findings had resolved further. There was only an isolated ecchymosis over the anterior tibia related to trauma. The eosinophil count at that time was 830/ram ~. DISCUSSION T h e syndrome of n o n t h r o m b o c y t o p e n i c purpura associated with eosinophilia is well-recognized in children living in Southeast Asia. MitrakuP studied 24 children from T h a i l a n d who had widespread spontaneous bruising of the limbs, trunk, and face and no previous history of bleeding tendency. These children all had normal platelet counts, and all but one were reported to have eosinophilia. Suvatte et al. 2 reported the largest series of patients with this syndrome, and found a variety of abnormalities, including prolonged bleeding time, defective platelet adhesion, diminished platelet factor III availability, and a b n o r m a l platelet aggregation responses to A D P , thrombin, collagen, and ristocetin. In addition, intestinal parasites were
278
Clinical and laboratory observations
detected in the stool of 36 of 62 (58%) patients. The most common parasites isolated were Ascaris (28%), Enterobius (22%), and hookworm (4%). Recently, Kueh 3 reported a 19-year-old man from Singapore with multiple ecchymoses, absolute eosinophil count of 2320/mm 3, platelet count of 170,000/ram 3, and stool examination positive for ova of Ancylostoma duodenale. Although the bleeding time was reported to be normal, abnormal platelet aggregation was observed. The clinical and laboratory abnormalities improved several days after the patient was given a single dose of an antihelminthic. Typical features of this syndrome are the combination of a bleeding tendency in an otherwise healthy child, a normal platelet count, prolonged bleeding time, platelet function abnormalities, and eosinophilia. The syndrome appears to be self-limiting, spontaneous recovery occurring in 6 months (range 5 months to 1 year). ~, Parasitic infections may be responsible for this syndrome. Parasites are the most common cause of eosinophilia worldwide, with visceral larva migrans producing the most profound elevations of eosinophil counts? Failure to demonstrate larvae or eggs in the feces does not rule out parasitic infection, but a significant rise in isohemagglutinin titers, 6 as well as an elevated serum level of IgE, 7 both detected in our patient, is highly suggestive of infestation with Toxocara. Suvatte et al? have suggested that an immune response to parasitic infection might result in the production of antibodies and the formation of immune complexes, which could bind to platelets and interfere with their function. Clarification of the role of parasitic infection in the syndrome of acquired platelet dysfunction and eosinophilia awaits careful study in future patients. If
The Journal of Pediatrics August 1984
parasites are responsible for this syndrome, it is unclear why this syndrome has not yet been reported in the United States, because parasitic infection is common worldwide. An awareness of this syndrome by physicians may lead to an increased recognition of cases. The role of eosinophils, or basophils, inasmuch as these were also higher than normal in our patient, is unclear. Production of some as yet unknown platelet inhibiting substance may well account for the platelet abnormalities observed. We thank Dr. Hurwitz of the Naval Regional Medical Clinic, Port Hueneme, California, for referring this patient; and Ms. Donna Lopez for preparation of the manuscript. REFERENCES 1. Mitrakul C: Transient, spontaneous bruising with long bleeding time and normal platclet count. Am J Clin Pathol 63:81, 1975. 2. Suvatte V, Mahasandana C, Tanpaichitr U, Tuchinda S: Acquired platelet dysfunction with eosinophilia: Study of platelet function in 62 cases. Southeast Asian J Trop Med Public Health 10:358, t979. 3. Kneh YK: The syndrome of non-thrombocytopenic purpura with eosinophilia: An acquired platelet dysfunction (Letter). N Engl J Med 306:365, 1982. 4. Dixon R, Rosse W, Ebbert L: Quantitative determination of antibody in idiopathic thrombocytopenic purpura: Correlation of serum and platelet-bound antibody with clinical response. N Engl J Med 5:230, 1975. 5. LukensJN: Eosinophiliain children. Pediatr Clin North Am 19:969, 1972. 6. Heiner DC, Kcvy SV: Visceral larva migrans: Report of the syndrome in three siblings. N Engl J Med 254:629, 1956. 7. Butterworth AE, David JR: Eosin0phil function. N Engl J Mcd 304:t54, 1981.
Treatment of a spontaneous intracerebral hematoma with exchange transfusions in an infant with hemophilia B Jane E. Striegel, M.D., and J. Roger Edson, M.D. Minneapolis, Minn.
IN PATIENTS WITH HEMOPHILIA, a spontaneous hemorrhage is unusual in the first year of life, and a spontaneous intracranial hemorrhage is rare at any age. We report an infant with factor IX deficiency who had a spontaneous intracerebral hemorrhage as a complication of hemophilia From the Departments of Pediatrics and Laboratory Medicine and Pathology. University of Minnesota School of Medicine. Submitted for publication Oct. 24, 1983; accepted Feb. 3, 1984. Reprints not available.
B at 5 weeks of age. The infant was given frequent single-volume exchange transfusions as an alternative to using prothrombin complex concentrate, with a successful long-term outcome. FFP PRBC PT PTT TT
Fresh frozen plasma Packedred blood cells Prothrombin time Partial thrombop[astin time Thrombin time