Idiopathic Thrombocytopenic Purpura in Two Children With Graves Disease Chifumbe Chintu, MD, Peter McClure, MD, CM
Chronic idiopathic thrombocytopenic purpura (ITP) and hyperthyroidism coexisted in two children. In one, hyperthyroidism developed nine years after the onset of purpura. In the other, the two diseases appeared concomitantly. It is important to distinguish the thrombocytopenia due to ITP from that due to antithyroid drugs.
Idiopathi(ITP)c thrombocytopenic
purpu¬
associated with Graves disease is rare in adults1-2 and rarer still in children.3 It is important to distinguish ITP from the thrombo¬ ra
cytopenic purpura produced by tithyroid drugs.4 We report here
an-
two
of Graves disease associated with ITP in children. cases
REPORT OF CASES Case l.-For three months this 8-yearold girl appeared excitable, tired easily, lost weight, and bruised easily. A triiodothyronine (T,) uptake of 43% (normal, 25% to 35%) and a thyroxine (T4) level of 18.4fig/100 ml (normal, 4Mg/100 ml to ll/i g/100 ml) indicated that she had hyperthy¬ roidism. Her platelet count was 40,000/cu mm. She was given methimazole, 10 mg orally four times a day, but after five Received for publication Jan 31,1974;
May 5.
accepted
From the Department of Pediatrics, Hospital for Sick Children; and the University of Toronto. Reprint requests to Hospital for Sick Children, 555 University Ave, Toronto, Ontario M5G 1X8, Canada (Dr. McClure).
weeks of treatment she developed migra¬ tory arthritis. When the arthritis did not improve on a reduced dose of 5 mg four times a day, she was transferred to our
hospital.
On admission she looked well. Her pulse was 88 beats per minute; respirations, 20 per minute; and blood pressure, 110/55 mm Hg. Her eyes were "starey," her skin was warm and suffused, and she had a slight tremor of the hands. Her thyroid was diffusely enlarged and smooth, but no bruit was heard over it. She had bruises on the arms and legs and a petechial rash on the chest and neck. Her spleen was just rate
palpable.
Results of a laboratory investigation showed that the hemoglobin level, white blood cell count, and differential cell count were normal. The platelet count, which on admission was 50,000/cu mm, fell to 5,000/cu mm three days later. A weak platelet antibody was detected in the blood by a complement fixation test. Tests for lupus erythematosus cells, heterophil anti¬ bodies, antinuclear factor, and direct Coombs test were all negative. Her bone marrow contained adequate numbers of all cellular elements, including megakaryocytes. Her T, uptake was 35% and T, level was 16.1/ig/100 ml. After starting on a regimen of propylthiouracil, 100 mg orally every eight hours, her T4 level and T3 uptake returned to nor¬ mal. On a regimen of prednisone, 5 mg ev¬ ery six hours, the platelet count rose to 120,000/cu mm. During the next two years she remained euthyroid while receiving
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Iowa User on 06/05/2015
propylthiouracil,
50 mg daily. Platelet counts have fluctuated between 16,000 and
85,000/cu mm while receiving prednisone, 5 to 10 mg daily. Case 2.—A 12-year-old girl had had epi¬ sodes of purpura and mild bruising for nine years. She received no specific ther¬ apy. Three years before admission, these episodes became more frequent and more severe. Every few months her platelet count decreased, sometimes to zero, re¬ mained low about two weeks, then in¬ creased in response to short courses of prednisone therapy. Neither a six-month course of azathioprine (Imuran) therapy nor splenectomy altered the course of her recurrent thrombocytopenia. Results of routine blood cell counts, ex¬ cept for platelets, were always normal, and megakaryocytes were plentiful in the bone marrow. A platelet antibody was detected in the blood by CFT. Tests for LE cells, heterophil antibodies, latex fixation, antinuclear factor, and VDRL test for syphilis were all negative. Serum IgG and IgA lev¬ els were normal, but the IgM level was ele¬ vated to 570 mg/100 ml (normal, 31 to 170 mg/100 ml). The direct Coombs test was weakly positive on two occasions and then became negative. At 12 years of age her eyes were proptosed, she sweated excessively, was irri¬ table and had a fine tremor of the hands. The thyroid was diffusely enlarged and smooth, but no bruit was heard. The plate¬ let count was 140,000/cu mm; T3 uptake, 39%; and T4 level 14.1/ig/100 ml. The 24hour radioactive iodine uptake was 37.2%
(normal, 9% to 26%). Propylthiouracil, 350 mg/day, controlled her hyperthyroidism. During the year af¬ ter this treatment began, she had two bouts of purpura that
were
treated with
prednisone.
COMMENT There are a few reports1·2-5·6 of ITP associated with hyperthyroidism in adults, but in some of these2-5·6 the mechanism producing the thrombo¬ cytopenia is confused because the pa¬ tients received iodine therapy. In chil¬ dren the association is rare, although recently Takeda et al3 described such an association in a 16-year-old girl. Papadopoulos et al7 described a child with hyperthyroidism, lupus erythematosus, and ITP. Among 30 children with hyperthy¬ roidism examined in our hospital, only the two described here developed purpura or thrombocytopenia. Since 1950 we have seen 413 children with ITP and, again, only the two reported above had associated hyperthyroid-
ism. However, as Marshall et al1 pointed out, the interval between the onset of the two syndromes may be up to ten years, which may account for the paucity of cases reported.
Idiopathic thrombocytopenic pur¬ pura may occur in association with other autoimmune disorders, such as hemolytic anemia8 and lupus erythematosus.7·910 Graves disease is an autoimmune disorder.11·12 The finding of antibodies directed against plate¬ lets in our patients suggests that their thrombocytopenia is another manifestation of autoimmunity. In case 2 there was evidence of an addi¬ tional antibody directed against red blood cells. Thrombocytopenic pur¬ pura in association with other auto¬ immune syndromes including Graves disease would be more accurately called autoimmune thrombocytopenic purpura. The thrombocytopenia is not likely secondary to increased thyroid hor¬ mone as suggested by Paulin and Gonzalez,2 since, in this case, the
platelet count should have risen when the patients became euthyroid. Sim¬ ilarly, the rise in platelet count dur¬ ing prednisone therapy is likely due to a direct action on platelet survival
rather
indirect
action
or aza-
necessary to control the purpura. In one, splenectomy failed to control it. Treatment of the hyperthyroidism with antithyroid drugs had no effect on the thrombocy¬ topenic purpura and treatment of the purpura had no effect on the hyper¬ thyroidism. It is important not to at¬ tribute the thrombocytopenia to antithyroid drugs, since this may lead to unnecessarily discontinuing useful
thioprine
were
therapy.
Drs. Eva Papadouris, MD; Mark Greenberg, MD; Neville Howard, MB; Harry Bain, MD; and Fred Saunders, MD, cooperated in studying the patients and reviewing the manuscript.
1. Marshall JS, Weisberger AS, Levy RP, et al: Coexistent idiopathic thrombocytopenic purpura and hyperthyroidism. Ann Intern Med 67:411-414, 1967. 2. Paulin C, Gonzalez T: Purpura thrombocytop\l=e'\niquesecondaire \l=a`\hyperthyroidie. Can Med Assoc J 97:229-231, 1967. 3. Takeda R, Funazu T, Odake K, et al: Idiopathic thrombocytopenic purpura associated with hyperthyroidism. South Med J 66:553-556, 1973. 4. Fewell RA, Engel EF, Zimmerman SL: Acute thrombopenic purpura associated with administration of propylthiouracil. JAMA 143:891-892, 1950. 5. Jackson AS: Acute hemorrhagic purpura associated with exophthalmic goiter. JAMA 96:38-39, 1931. 6. Toland CG, Askey JM: Atypical hemorrhagic purpura occurring with toxic adenoma of the thyroid gland. Mayo Clin Proc 6:597-598, 1931. 7. Papadopoulos C, Jiji R, Maher E: Lupus erythematosus and 1969. hyperthyroidism. Am J Dis Child 118:621-625, 8. Evans RS, Takahashi K, Duane RT, et al: Primary thrombocytopenic purpura and acquired hemolytic anemia: Evidence for a common etiology. Arch Intern Med 87:48-65, 1951. 9. Rabinowitz Y, Dameshek W: Systemic lupus erythematosus after "idiopathic" thrombocytopenic purpura: A review. Ann Intern Med 52:1-28, 1960. 10. MacKay IR, Perry BT: Autoimmunity in human thyroid disease. Australas Ann Med 9:84-92, 1960. 11. Kriss J: The nature and significance of the long-acting thyroid stimulator. Adv Metab Disord 3:209-230, 1968. 12. Kendall-Taylor P: Hyperthyroidism. Br Med J 2:337-341,
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Iowa User on 06/05/2015
on
chronic, and corticosteroids
References
1972.
than
through improved thyroid function. In both patients reported here the course of the thrombocytopenia was
Chronic idiopathic thrombocytopenic purpura (ITP) and hyperthyroidism coexisted in two children. In one, hyperthyroidism developed nine years after the onset of purpura. In the other, the two diseases appeared concomitantly. It is important to distinguish the thrombocytopenia due to ITP from that due to antithyroid drugs.
Idiopathi(ITP)c thrombocytopenic
purpu¬
associated with Graves disease is rare in adults1-2 and rarer still in children.3 It is important to distinguish ITP from the thrombo¬ ra
cytopenic purpura produced by tithyroid drugs.4 We report here
an-
two
of Graves disease associated with ITP in children. cases
REPORT OF CASES Case l.-For three months this 8-yearold girl appeared excitable, tired easily, lost weight, and bruised easily. A triiodothyronine (T,) uptake of 43% (normal, 25% to 35%) and a thyroxine (T4) level of 18.4fig/100 ml (normal, 4Mg/100 ml to ll/i g/100 ml) indicated that she had hyperthy¬ roidism. Her platelet count was 40,000/cu mm. She was given methimazole, 10 mg orally four times a day, but after five Received for publication Jan 31,1974;
May 5.
accepted
From the Department of Pediatrics, Hospital for Sick Children; and the University of Toronto. Reprint requests to Hospital for Sick Children, 555 University Ave, Toronto, Ontario M5G 1X8, Canada (Dr. McClure).
weeks of treatment she developed migra¬ tory arthritis. When the arthritis did not improve on a reduced dose of 5 mg four times a day, she was transferred to our
hospital.
On admission she looked well. Her pulse was 88 beats per minute; respirations, 20 per minute; and blood pressure, 110/55 mm Hg. Her eyes were "starey," her skin was warm and suffused, and she had a slight tremor of the hands. Her thyroid was diffusely enlarged and smooth, but no bruit was heard over it. She had bruises on the arms and legs and a petechial rash on the chest and neck. Her spleen was just rate
palpable.
Results of a laboratory investigation showed that the hemoglobin level, white blood cell count, and differential cell count were normal. The platelet count, which on admission was 50,000/cu mm, fell to 5,000/cu mm three days later. A weak platelet antibody was detected in the blood by a complement fixation test. Tests for lupus erythematosus cells, heterophil anti¬ bodies, antinuclear factor, and direct Coombs test were all negative. Her bone marrow contained adequate numbers of all cellular elements, including megakaryocytes. Her T, uptake was 35% and T, level was 16.1/ig/100 ml. After starting on a regimen of propylthiouracil, 100 mg orally every eight hours, her T4 level and T3 uptake returned to nor¬ mal. On a regimen of prednisone, 5 mg ev¬ ery six hours, the platelet count rose to 120,000/cu mm. During the next two years she remained euthyroid while receiving
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Iowa User on 06/05/2015
propylthiouracil,
50 mg daily. Platelet counts have fluctuated between 16,000 and
85,000/cu mm while receiving prednisone, 5 to 10 mg daily. Case 2.—A 12-year-old girl had had epi¬ sodes of purpura and mild bruising for nine years. She received no specific ther¬ apy. Three years before admission, these episodes became more frequent and more severe. Every few months her platelet count decreased, sometimes to zero, re¬ mained low about two weeks, then in¬ creased in response to short courses of prednisone therapy. Neither a six-month course of azathioprine (Imuran) therapy nor splenectomy altered the course of her recurrent thrombocytopenia. Results of routine blood cell counts, ex¬ cept for platelets, were always normal, and megakaryocytes were plentiful in the bone marrow. A platelet antibody was detected in the blood by CFT. Tests for LE cells, heterophil antibodies, latex fixation, antinuclear factor, and VDRL test for syphilis were all negative. Serum IgG and IgA lev¬ els were normal, but the IgM level was ele¬ vated to 570 mg/100 ml (normal, 31 to 170 mg/100 ml). The direct Coombs test was weakly positive on two occasions and then became negative. At 12 years of age her eyes were proptosed, she sweated excessively, was irri¬ table and had a fine tremor of the hands. The thyroid was diffusely enlarged and smooth, but no bruit was heard. The plate¬ let count was 140,000/cu mm; T3 uptake, 39%; and T4 level 14.1/ig/100 ml. The 24hour radioactive iodine uptake was 37.2%
(normal, 9% to 26%). Propylthiouracil, 350 mg/day, controlled her hyperthyroidism. During the year af¬ ter this treatment began, she had two bouts of purpura that
were
treated with
prednisone.
COMMENT There are a few reports1·2-5·6 of ITP associated with hyperthyroidism in adults, but in some of these2-5·6 the mechanism producing the thrombo¬ cytopenia is confused because the pa¬ tients received iodine therapy. In chil¬ dren the association is rare, although recently Takeda et al3 described such an association in a 16-year-old girl. Papadopoulos et al7 described a child with hyperthyroidism, lupus erythematosus, and ITP. Among 30 children with hyperthy¬ roidism examined in our hospital, only the two described here developed purpura or thrombocytopenia. Since 1950 we have seen 413 children with ITP and, again, only the two reported above had associated hyperthyroid-
ism. However, as Marshall et al1 pointed out, the interval between the onset of the two syndromes may be up to ten years, which may account for the paucity of cases reported.
Idiopathic thrombocytopenic pur¬ pura may occur in association with other autoimmune disorders, such as hemolytic anemia8 and lupus erythematosus.7·910 Graves disease is an autoimmune disorder.11·12 The finding of antibodies directed against plate¬ lets in our patients suggests that their thrombocytopenia is another manifestation of autoimmunity. In case 2 there was evidence of an addi¬ tional antibody directed against red blood cells. Thrombocytopenic pur¬ pura in association with other auto¬ immune syndromes including Graves disease would be more accurately called autoimmune thrombocytopenic purpura. The thrombocytopenia is not likely secondary to increased thyroid hor¬ mone as suggested by Paulin and Gonzalez,2 since, in this case, the
platelet count should have risen when the patients became euthyroid. Sim¬ ilarly, the rise in platelet count dur¬ ing prednisone therapy is likely due to a direct action on platelet survival
rather
indirect
action
or aza-
necessary to control the purpura. In one, splenectomy failed to control it. Treatment of the hyperthyroidism with antithyroid drugs had no effect on the thrombocy¬ topenic purpura and treatment of the purpura had no effect on the hyper¬ thyroidism. It is important not to at¬ tribute the thrombocytopenia to antithyroid drugs, since this may lead to unnecessarily discontinuing useful
thioprine
were
therapy.
Drs. Eva Papadouris, MD; Mark Greenberg, MD; Neville Howard, MB; Harry Bain, MD; and Fred Saunders, MD, cooperated in studying the patients and reviewing the manuscript.
1. Marshall JS, Weisberger AS, Levy RP, et al: Coexistent idiopathic thrombocytopenic purpura and hyperthyroidism. Ann Intern Med 67:411-414, 1967. 2. Paulin C, Gonzalez T: Purpura thrombocytop\l=e'\niquesecondaire \l=a`\hyperthyroidie. Can Med Assoc J 97:229-231, 1967. 3. Takeda R, Funazu T, Odake K, et al: Idiopathic thrombocytopenic purpura associated with hyperthyroidism. South Med J 66:553-556, 1973. 4. Fewell RA, Engel EF, Zimmerman SL: Acute thrombopenic purpura associated with administration of propylthiouracil. JAMA 143:891-892, 1950. 5. Jackson AS: Acute hemorrhagic purpura associated with exophthalmic goiter. JAMA 96:38-39, 1931. 6. Toland CG, Askey JM: Atypical hemorrhagic purpura occurring with toxic adenoma of the thyroid gland. Mayo Clin Proc 6:597-598, 1931. 7. Papadopoulos C, Jiji R, Maher E: Lupus erythematosus and 1969. hyperthyroidism. Am J Dis Child 118:621-625, 8. Evans RS, Takahashi K, Duane RT, et al: Primary thrombocytopenic purpura and acquired hemolytic anemia: Evidence for a common etiology. Arch Intern Med 87:48-65, 1951. 9. Rabinowitz Y, Dameshek W: Systemic lupus erythematosus after "idiopathic" thrombocytopenic purpura: A review. Ann Intern Med 52:1-28, 1960. 10. MacKay IR, Perry BT: Autoimmunity in human thyroid disease. Australas Ann Med 9:84-92, 1960. 11. Kriss J: The nature and significance of the long-acting thyroid stimulator. Adv Metab Disord 3:209-230, 1968. 12. Kendall-Taylor P: Hyperthyroidism. Br Med J 2:337-341,
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Iowa User on 06/05/2015
on
chronic, and corticosteroids
References
1972.
than
through improved thyroid function. In both patients reported here the course of the thrombocytopenia was
