BRIEF COMMUNICATIONS 1
ALLAN M. SEIDENFELD, MD, FRCP[C]; JOHN OWEN, MD, FIMLS; JAROSLAV F. PRCHAL, MD, FRCPIIC]; MICHAEL F.X. GLYNN, MD, D PHIL, FRCP[C], MRCP (LOND) Pure red cell aplasia is a rare hematologic disorder in which there is selective hypoplasia of erythroid tissue. It is characterized by normocytic, normochromic anemia, often severe, and absolute reticulocytopenia. The bone marrow contains intact myeloid tissue and adequate megakaryocytes, but almost no erythroid tissue.1 Acute transient pure red cell aplasia has been reported most frequently in association with hemolytic anemia, a circumstance in which the aplastic episode would be most noticeable.' These episodes have also been reported in association with vitamin deficiency, infections (particularly viral) and exposure to drugs or chemicals.3 Although a marrow toxin has frequently been suggested, no mechanism common to these cases has been found. Reversible pure red cell aplasia in pregnancy has been reported infrequently.34 Two of the reported cases were clearly instances of red cell aplasia4'5 but the remaining two were less well established.3 The pattern and kinetics of in vitro erythropoiesis were not studied in these cases. Our report describes a patient in whom acute transient From the departments of hematology and medicine, Toronto General Hospital and University of Toronto Reprint requests to: Dr. Michael F.X. Glynn, Coagulation laboratory, College wing, Toronto General Hospital, 101 College St., Toronto, Ont. MSG 1L7
red cell aplasia developed post partum in association with an inhibitor to erythropoiesis. Case report
A 21-year-old woman was admitted to hospital in the 35th week of her second pregnancy because of pruritus of 6 weeks' duration. Fifteen months previously, at another hospital, she had been delivered of a stillborn infant at 33 weeks' gestation. The pregnancy had been unsupervised, but no history of bleeding or distress was given. The hemoglobin value at the time of admission was 12 g/dl. By the third day post partum the value had fallen to 7 g/dl. No reticulocytes were seen. Serum values included: iron 23.7 .mol/l, total iron binding capacity 71.4 ..tmol/l, folic acid 11.3 nmol/l (5.0 ng/l), vitamin B12 420 pg/l and haptoglobin normal. The next day the patient complained of some discomfort in her abdomen, especially at the right lower costal margin. Examination revealed moderate right upper quadrant tenderness; the liver edge was not felt, and the percussed span was 13 cm. The sclera were not icteric. The direct serum bilirubin value was 23.9 .mol/l (1.4 mg/dl) and testing for hepatitis B antigen gave negative results. Later that day the patient abruptly discharged herself from hospital against medical advice. Ten days before the present ad-
188 CMA JOURNAL/JULY 21, 1979/VOL 121
mission she consulted a local physician because of pruritus. The physician established the presence of a living fetus that was in no distress, but in view of her complaint and previous history she was advised to enter hospital. The patient had noticed dark brown, clear urine for 2 weeks. Passing urine was not painful, and the urine did not "burn"; nocturia had been noticed as the pregnancy progressed. Fever, chills and night sweats were denied. She estimated she had gained about "10 pounds" during the pregnancy. Slight ankle swelling was admitted, but hand and face swelling, headaches, nausea and vomiting were all denied. There was a history of "minimal" alcohol intake. The temperature was 370C, the pulse rate 84/mm and the respiratory rate 20/mm. The blood pressure was 128/70 mm Hg. She appeared to be well nourished. Excoriations were seen on the trunk. The nails and hair appeared normal. The sclera were mildly icteric. The jugular venous pressure was about 4 cm, and some shotty nodes were palpable in the left anterior cervical area and the right axilla. The lungs were clear. The heart was not enlarged; a systolic ejection murmur was heard along the left sternal border and a third heart sound was heard. The abdomen was not tender. The liver edge was palpable and the percussed span was 13 cm. The spleen was not felt. The uterus was en-
larged to a size consistent with 33 weeks' gestation. No costovertebral angle tenderness was noted. The extremities were normal, except for a trace of pitting ankle and pretibial edema. The hemoglobin value was 13.2 g/dl, the leukocyte count was 7.3 x 10'/l and the platelet count was normal. Serum values included: total bilirubin 63.3 .mol/l (3.7 mg/dl), direct bilirubin 51.3 .mol/l (3.0 mg/dl), glutamic oxaloacetic transaminase 124 IU/l and alkaline phosphatase 347 lU/i. The urine contained a trace of protein, a moderate amount of urobilinogen and no bilirubin. An occasional leukocyte was seen but no bacteria or casts were detected. She was given cholestyramine, 10 g each day in divided doses; the pruritus was greatly relieved. On the 12th hospital day the woman gave birth to a healthy boy weighing 4.3 kg. The presentation was occipital. Forceps delivery was not required. The placenta was delivered intact. Bleeding was judged to be excessive, but appeared to stop with uterine packing. After delivery the vaginal bleeding persisted and began to increase. Questioning of the woman revealed her diet to be devoid of fresh vegetables and restricted to "snack foods"; she admitted to drinking "a lot" of alcohol. The infant was not jaundiced. His hemoglobin value was 15.8 g/dl and many nucleated erythrocytes were seen in the peripheral blood. The woman's hemoglobin value was 10 g/dl. The erythrocytes were normocytic and normochromic: no reticulocytes were seen. The platelet count was 220 x 1 0'/l. The prothrombin time was 37 seconds (control time 10 seconds), the activated partial thromboplastin time was 68 seconds (control time 27 seconds), the plasma fibrinogen value was 20.6 .mol/l (0.7 g/dl), the thrombin time with heparin neutralization was 30 seconds (control time 24 seconds) and the fibrin degradation products value was 40 to 80 .ig/ml. Factor V activity was greater than 200%, factor VII activity 12%, factor VIII coagulant activity greater than 200 mg/dl and factor
IX activity 9% of the activity in reference standard plasma. Treatment with vitamin K and four units of stored plasma decreased the bleeding, and the coagulation values returned to within the standard reference range. On the 18th hospital day vaginal bleeding increased and clots were passed. Dilation and curettage revealed a few small pieces of tissue, "probably placental", but mainly old blood clots. The vaginal bleeding slowed. The hemoglobin value continued to fall, with no reticulocyte response. On the 21st hospital day the value was 5.6 g/dl and three units of packed cells were transfused. Aspiration of the bone marrow was performed on the 24th hospital day. Examination of the aspirate revealed complete absence of erythrocyte precursors, good cellularity, intact granulopoiesis, sufficient normal megakaryocytes and abundant iron stores. Folic acid, 5 mg/d, vitamin B12, 50 p.g/d, and supplemental vitamin C and pyridoxine were given. Reticulocytes still did not appear. The hemoglobin value 3 days after transfusion was 6.8 g/dl. There was no evidence of hemolysis: the hydroxybutyrate dehydrogenase value was 150 lU/l (normal range of values 120 to 250 IU/l) and haptoglobin was present in adequate amounts. Bloody vaginal discharge persisted, and two additional units of packed erythrocytes were given. The total serum bilirubin value was now 50.0 .mol/l (2.9 mg/dl). Hepatitis B antigen, direct and indirect Coombs', serum acidification and sugar water tests gave negative results, and the glucose-6phosphate dehydrogenase value was normal. Antimitochondrial antibody, anti-smooth-muscle antibody and hepatitis B antibody were not detected. Examination of a specimen of bone marrow aspirated that day again showed no erythrocyte precursors. The bone marrow was cultured with methods previously described.6 Abundant erythroid colony-forming cells were harvested. The response to erythropoietin was normal and the serum erythropoietin value was normal. The presence of abundant ery-
throid colonies and erythropoietin suggested an inhibitor to erythropoiesis. Samples of the patient's serum were sent to Dr. S.B. Krantz, director of the division of hematology and professor of medicine, Vanderbilt University, Nashville, Tennessee. The serum was treated and added to normal erythropoietic cell cultures.7 The patient's serum exhibited pronounced inhibition of normal erythropoiesis: colonyforming cells developed in cultures of cells from control subjects after exposure to the patient's serum. Three days later the hemoglobin value began to rise and reticulocytes appeared in the peripheral blood. Examination of the bone marrow now revealed the presence of all stages of erythrocyte precursors. The total serum bilirubin value had fallen to 30.8 ..tmol/l (1.8 mg/dl) and the patient was no longer jaundiced. In accordance with her wishes the patient was discharged. The hemoglobin value was 12 g/dl and the proportion of reticulocytes was 5.5%. A chest roentgenogram and mediastinal tomograms were normal. Discussion In 1968 Massart and Bishop' reported the case of a 19-year-old pregnant woman with aregenerative anemia and hypogammaglobulinemia. That case was not clear-cut since the patient also had a thymoma, and 50% of all adults with pure red cell aplasia have a thymoma.' In 1976 Skikne and colleagues3 described two women who had well documented pure red cell aplasia when not pregnant; remission occurred with treatment. Subsequently the women became anemic while pregnant and, although the authors considered them to have pure red cell aplasia, there was no bone marrow evidence of this disorder. More recently Aggio and Zunini4 have described a well documented case of pure red cell aplasia occurring during pregnancy and resolving after delivery. In our patient pure red cell aplasia was documeated during the puerperium of the second pregnancy. There was no evidence of hemolytic anemia or infection. The patient's serum greatly inhibited
OMA JOURNAL/JULY 21, 1979/VOL 121
189
erythropoiesis in normal marrow, but studies could not be done to determine if the inhibition was due to an autoantibody. The inhibiting factor could have been related to the patient's pregnancy. None of the drugs used by the patient has been described as being associated with pure red cell aplasia. In 1953 Holly10 reported on 101 patients with anemia during pregnancy. Eight had normoblastic hypoplasia of the bone marrow. The mean normoblast count was 11.4% and the range was 5.4% to 14.6%, in comparison with counts of 19% during normal pregnancy and approximately 35% in pregnant women with untreated iron deficiency anemia. After delivery the anemia in each of the eight patients disappeared. Bone marrow aspirates obtained post partum from four of the patients showed normoblastic hyperplasia. In two of the patients anemia was observed in subsequent pregnancies. Holly suggested that some substance elaborated during pregnancy has a depressing or toxic effect on the bone marrow in a sensitive individual, and that the effect may be generalized and produce thrombocytopenia and leukopenia. At least 33 cases of aplastic anemia during pregnancy have been reported,11'1' and Ehrlich's1' first reported case of aplastic anemia, in 1888, was associated with an intrauterine pregnancy. Although some believe that the association of aplastic anemia and pregnancy is coincidental,14 no instance of remission of aplastic anemia during pregnancy has been reported to date. It seems that there is a subgroup of these patients in whom the anemia remits with delivery, which suggests that the primary defect may be humoral and related to the pregnancy. The jaundice and biochemical abnormalities or the hepatic dysfunction could have signalled underlying hepatitis in our patient despite the negative results of immunologic tests and the clinical picture characteristic of recurrent jaundice of pregnancy. Because permission for a biopsy of the liver was refused, cholestatic jaundice of pregnancy remains the most likely diagnosis.
Transient pure red cell aplasia has been observed in one patient with hepatitis following exposure to halothane15 and in two siblings with viral hepatitis.16 Although there is no evidence for the production of marrow toxins in hepatitis, the poorer prognosis of aplastic anemia following hepatitis in females as compared with males (proportion of survivors 8.5% and 28% respectively) raises the question of a possible suppressive effect on bone marrow by estrogens or other hor17 mones. Studies in dogs but not in humans have shown that large doses of estrogen are toxic to the bone marrow.18 The development of an inhibitor to erythropoiesis and concomitant red cell aplasia with anemia and their prompt disappearance after delivery strongly suggest a causal relation to pregnancy. The literature suggests that different degrees of marrow depression might exist, producing a continuum of clinical hematopoietic dysfunctions, including normoblastic hypoplasia, pure red cell hypoplasia and complete marrow aplasia. More studies are needed to see if a single humoral mechanism with various degrees of expression underlies these disorders, or if they are diseases of distinctly different origins. References 1. KRANTZ SB: Diagnosis and treatment of pure red cell aplasia. Med Clin North Am 60: 945, 1976
8. MASSART JJ, BISHOP WA: Thymoma occurring during pregnancy: a case report. Obstet Gynecol 32: 490, 1968 9. Hms.r E, ROBERTSON TI: The syndrome of thymoma and erythroblastopenic anemia. Medicine (Balti-
more) 46: 225, 1967 10. HOLLY RG: Hypoplastic anemia in pregnancy. Obstet Gynecol 1: 535, 1953 11. FLEMING AF: Hypoplastic anemia in pregnancy, in Haematological
Disorders in Pregnancy (Cliii Hacmatol vol 2, no 3), JEPSON JH (ed), Saunders, Philadelphia, 1973, pp 477, 496 12. GOLDSTEIN TM, COLLER RS: Aplastic anemia in pregnancy: recovery
after normal Spontaneous delivery. Ann intern Med 82: 537, 1975 13. EHRLICH P: Uber einen Fall von Anjimie mit Bemerkungen iiber regenerative Veranderungen des
Knochenmarks. Charite A nii 300, 1888
13:
14. KNISPEL JW, LYNCH VA, VIELE BD: Aplastic anemia in pregnancy: a case report, review of the literature, and a re-evaluation of manage-
ment. Obstet Gynecol Surv 31: 523, 1976 15. JURGENSEN JC, ABRAHAM JP, HARDY WW: Erythroid aplasia after halothane hepatitis: report of a case.
Am J Dig Dis 15: 577, 1970 16. SEARS DA, GEORGE JN, GOLD MS: Transient red blood cell aplasia in association with viral hepatitis. Oc-
currence four years apart in siblings. Arch intern Med 135: 1585, 1975 17. HAGLER L, PASTORE RA, BERGIN JJ: Aplastic anemia following viral hepatitis. Report of two fatal cases and literature review. Medicine
(Baltimore) 54: 139, 1975 18. CRAFTS RC: The effects of estrogens on the bone marrow of adult female
dogs. Blood 3: 276, 1948
2. CONKLIN GT, GEORGE JN, SEARS
DA: Transient erythroid aplasia in hemolytic anemia: a review of the literature with two case reports. Tex Rep Bid Med 32: 391, 1974 3. SKiKNE BS, LYNCH SR, BEZWODA WR, et al: Pure red cell aplasia.
S Air Med J 50: 1353, 1976 4. AGGIo MC, ZUNINI C: Reversible pure red-cell aplasia in pregnancy (C). N Engi J Med 297: 221, 1977 S. Mwosm I, HnuT. T, Koi B, et al: Reversible pure red-cell aplasia in pregnancy (C). N Engi J Med 299: 777, 1978 6. MCLEOD DL, SHREEvE MM, AXELRAD AA: Improved plasma culture system for production of erythrocytic colonies in vitro: quantitative assay method for CFU-E. Blood 44: 517, 1974 7. KRANTZ SB, KAO V: Studies on red cell aplasia. II. Report of a second patient with an antibody to erythroblast nuclei and a remission after immunosuppressive therapy. Blood 34: 1, 1969
190 CMA JOURNAL/JULY 21, 1979/VOL. 121
BOOKS continued from page 164 THE HANDBOOK OF CRITICAL CARE MEDICINE. Edited by Max Harry Well and Robert J. Henning. 205 pp. lIlust. EM Books, New York; Fischer Medical Publications, Inc., New York, 1979. $19.95 IT'S YOUR MONEY. The Complete Canadian Guide to Personal Financial Planning. New edition, revised and expanded. Edited by J. Christopher Snyder. Written by Brian E. Anderson, William Scott, W.D. Glenn McLean and others. 195 pp. lIlust. Methuen Publica. tions, Agincourt, Ont., 1979. $7.95, paperbound. ISBN 0-438-93950-1
LONDON PRIDE. The Story of a Voluntary Hospital. A.E. Clarke-Kennedy. 254 pp. Illust. Hutchinson Benham Limited, London, 1979. Price not stated, paperbound. ISBN 0-09-136541-4
continued on page 202
ALLAN M. SEIDENFELD, MD, FRCP[C]; JOHN OWEN, MD, FIMLS; JAROSLAV F. PRCHAL, MD, FRCPIIC]; MICHAEL F.X. GLYNN, MD, D PHIL, FRCP[C], MRCP (LOND) Pure red cell aplasia is a rare hematologic disorder in which there is selective hypoplasia of erythroid tissue. It is characterized by normocytic, normochromic anemia, often severe, and absolute reticulocytopenia. The bone marrow contains intact myeloid tissue and adequate megakaryocytes, but almost no erythroid tissue.1 Acute transient pure red cell aplasia has been reported most frequently in association with hemolytic anemia, a circumstance in which the aplastic episode would be most noticeable.' These episodes have also been reported in association with vitamin deficiency, infections (particularly viral) and exposure to drugs or chemicals.3 Although a marrow toxin has frequently been suggested, no mechanism common to these cases has been found. Reversible pure red cell aplasia in pregnancy has been reported infrequently.34 Two of the reported cases were clearly instances of red cell aplasia4'5 but the remaining two were less well established.3 The pattern and kinetics of in vitro erythropoiesis were not studied in these cases. Our report describes a patient in whom acute transient From the departments of hematology and medicine, Toronto General Hospital and University of Toronto Reprint requests to: Dr. Michael F.X. Glynn, Coagulation laboratory, College wing, Toronto General Hospital, 101 College St., Toronto, Ont. MSG 1L7
red cell aplasia developed post partum in association with an inhibitor to erythropoiesis. Case report
A 21-year-old woman was admitted to hospital in the 35th week of her second pregnancy because of pruritus of 6 weeks' duration. Fifteen months previously, at another hospital, she had been delivered of a stillborn infant at 33 weeks' gestation. The pregnancy had been unsupervised, but no history of bleeding or distress was given. The hemoglobin value at the time of admission was 12 g/dl. By the third day post partum the value had fallen to 7 g/dl. No reticulocytes were seen. Serum values included: iron 23.7 .mol/l, total iron binding capacity 71.4 ..tmol/l, folic acid 11.3 nmol/l (5.0 ng/l), vitamin B12 420 pg/l and haptoglobin normal. The next day the patient complained of some discomfort in her abdomen, especially at the right lower costal margin. Examination revealed moderate right upper quadrant tenderness; the liver edge was not felt, and the percussed span was 13 cm. The sclera were not icteric. The direct serum bilirubin value was 23.9 .mol/l (1.4 mg/dl) and testing for hepatitis B antigen gave negative results. Later that day the patient abruptly discharged herself from hospital against medical advice. Ten days before the present ad-
188 CMA JOURNAL/JULY 21, 1979/VOL 121
mission she consulted a local physician because of pruritus. The physician established the presence of a living fetus that was in no distress, but in view of her complaint and previous history she was advised to enter hospital. The patient had noticed dark brown, clear urine for 2 weeks. Passing urine was not painful, and the urine did not "burn"; nocturia had been noticed as the pregnancy progressed. Fever, chills and night sweats were denied. She estimated she had gained about "10 pounds" during the pregnancy. Slight ankle swelling was admitted, but hand and face swelling, headaches, nausea and vomiting were all denied. There was a history of "minimal" alcohol intake. The temperature was 370C, the pulse rate 84/mm and the respiratory rate 20/mm. The blood pressure was 128/70 mm Hg. She appeared to be well nourished. Excoriations were seen on the trunk. The nails and hair appeared normal. The sclera were mildly icteric. The jugular venous pressure was about 4 cm, and some shotty nodes were palpable in the left anterior cervical area and the right axilla. The lungs were clear. The heart was not enlarged; a systolic ejection murmur was heard along the left sternal border and a third heart sound was heard. The abdomen was not tender. The liver edge was palpable and the percussed span was 13 cm. The spleen was not felt. The uterus was en-
larged to a size consistent with 33 weeks' gestation. No costovertebral angle tenderness was noted. The extremities were normal, except for a trace of pitting ankle and pretibial edema. The hemoglobin value was 13.2 g/dl, the leukocyte count was 7.3 x 10'/l and the platelet count was normal. Serum values included: total bilirubin 63.3 .mol/l (3.7 mg/dl), direct bilirubin 51.3 .mol/l (3.0 mg/dl), glutamic oxaloacetic transaminase 124 IU/l and alkaline phosphatase 347 lU/i. The urine contained a trace of protein, a moderate amount of urobilinogen and no bilirubin. An occasional leukocyte was seen but no bacteria or casts were detected. She was given cholestyramine, 10 g each day in divided doses; the pruritus was greatly relieved. On the 12th hospital day the woman gave birth to a healthy boy weighing 4.3 kg. The presentation was occipital. Forceps delivery was not required. The placenta was delivered intact. Bleeding was judged to be excessive, but appeared to stop with uterine packing. After delivery the vaginal bleeding persisted and began to increase. Questioning of the woman revealed her diet to be devoid of fresh vegetables and restricted to "snack foods"; she admitted to drinking "a lot" of alcohol. The infant was not jaundiced. His hemoglobin value was 15.8 g/dl and many nucleated erythrocytes were seen in the peripheral blood. The woman's hemoglobin value was 10 g/dl. The erythrocytes were normocytic and normochromic: no reticulocytes were seen. The platelet count was 220 x 1 0'/l. The prothrombin time was 37 seconds (control time 10 seconds), the activated partial thromboplastin time was 68 seconds (control time 27 seconds), the plasma fibrinogen value was 20.6 .mol/l (0.7 g/dl), the thrombin time with heparin neutralization was 30 seconds (control time 24 seconds) and the fibrin degradation products value was 40 to 80 .ig/ml. Factor V activity was greater than 200%, factor VII activity 12%, factor VIII coagulant activity greater than 200 mg/dl and factor
IX activity 9% of the activity in reference standard plasma. Treatment with vitamin K and four units of stored plasma decreased the bleeding, and the coagulation values returned to within the standard reference range. On the 18th hospital day vaginal bleeding increased and clots were passed. Dilation and curettage revealed a few small pieces of tissue, "probably placental", but mainly old blood clots. The vaginal bleeding slowed. The hemoglobin value continued to fall, with no reticulocyte response. On the 21st hospital day the value was 5.6 g/dl and three units of packed cells were transfused. Aspiration of the bone marrow was performed on the 24th hospital day. Examination of the aspirate revealed complete absence of erythrocyte precursors, good cellularity, intact granulopoiesis, sufficient normal megakaryocytes and abundant iron stores. Folic acid, 5 mg/d, vitamin B12, 50 p.g/d, and supplemental vitamin C and pyridoxine were given. Reticulocytes still did not appear. The hemoglobin value 3 days after transfusion was 6.8 g/dl. There was no evidence of hemolysis: the hydroxybutyrate dehydrogenase value was 150 lU/l (normal range of values 120 to 250 IU/l) and haptoglobin was present in adequate amounts. Bloody vaginal discharge persisted, and two additional units of packed erythrocytes were given. The total serum bilirubin value was now 50.0 .mol/l (2.9 mg/dl). Hepatitis B antigen, direct and indirect Coombs', serum acidification and sugar water tests gave negative results, and the glucose-6phosphate dehydrogenase value was normal. Antimitochondrial antibody, anti-smooth-muscle antibody and hepatitis B antibody were not detected. Examination of a specimen of bone marrow aspirated that day again showed no erythrocyte precursors. The bone marrow was cultured with methods previously described.6 Abundant erythroid colony-forming cells were harvested. The response to erythropoietin was normal and the serum erythropoietin value was normal. The presence of abundant ery-
throid colonies and erythropoietin suggested an inhibitor to erythropoiesis. Samples of the patient's serum were sent to Dr. S.B. Krantz, director of the division of hematology and professor of medicine, Vanderbilt University, Nashville, Tennessee. The serum was treated and added to normal erythropoietic cell cultures.7 The patient's serum exhibited pronounced inhibition of normal erythropoiesis: colonyforming cells developed in cultures of cells from control subjects after exposure to the patient's serum. Three days later the hemoglobin value began to rise and reticulocytes appeared in the peripheral blood. Examination of the bone marrow now revealed the presence of all stages of erythrocyte precursors. The total serum bilirubin value had fallen to 30.8 ..tmol/l (1.8 mg/dl) and the patient was no longer jaundiced. In accordance with her wishes the patient was discharged. The hemoglobin value was 12 g/dl and the proportion of reticulocytes was 5.5%. A chest roentgenogram and mediastinal tomograms were normal. Discussion In 1968 Massart and Bishop' reported the case of a 19-year-old pregnant woman with aregenerative anemia and hypogammaglobulinemia. That case was not clear-cut since the patient also had a thymoma, and 50% of all adults with pure red cell aplasia have a thymoma.' In 1976 Skikne and colleagues3 described two women who had well documented pure red cell aplasia when not pregnant; remission occurred with treatment. Subsequently the women became anemic while pregnant and, although the authors considered them to have pure red cell aplasia, there was no bone marrow evidence of this disorder. More recently Aggio and Zunini4 have described a well documented case of pure red cell aplasia occurring during pregnancy and resolving after delivery. In our patient pure red cell aplasia was documeated during the puerperium of the second pregnancy. There was no evidence of hemolytic anemia or infection. The patient's serum greatly inhibited
OMA JOURNAL/JULY 21, 1979/VOL 121
189
erythropoiesis in normal marrow, but studies could not be done to determine if the inhibition was due to an autoantibody. The inhibiting factor could have been related to the patient's pregnancy. None of the drugs used by the patient has been described as being associated with pure red cell aplasia. In 1953 Holly10 reported on 101 patients with anemia during pregnancy. Eight had normoblastic hypoplasia of the bone marrow. The mean normoblast count was 11.4% and the range was 5.4% to 14.6%, in comparison with counts of 19% during normal pregnancy and approximately 35% in pregnant women with untreated iron deficiency anemia. After delivery the anemia in each of the eight patients disappeared. Bone marrow aspirates obtained post partum from four of the patients showed normoblastic hyperplasia. In two of the patients anemia was observed in subsequent pregnancies. Holly suggested that some substance elaborated during pregnancy has a depressing or toxic effect on the bone marrow in a sensitive individual, and that the effect may be generalized and produce thrombocytopenia and leukopenia. At least 33 cases of aplastic anemia during pregnancy have been reported,11'1' and Ehrlich's1' first reported case of aplastic anemia, in 1888, was associated with an intrauterine pregnancy. Although some believe that the association of aplastic anemia and pregnancy is coincidental,14 no instance of remission of aplastic anemia during pregnancy has been reported to date. It seems that there is a subgroup of these patients in whom the anemia remits with delivery, which suggests that the primary defect may be humoral and related to the pregnancy. The jaundice and biochemical abnormalities or the hepatic dysfunction could have signalled underlying hepatitis in our patient despite the negative results of immunologic tests and the clinical picture characteristic of recurrent jaundice of pregnancy. Because permission for a biopsy of the liver was refused, cholestatic jaundice of pregnancy remains the most likely diagnosis.
Transient pure red cell aplasia has been observed in one patient with hepatitis following exposure to halothane15 and in two siblings with viral hepatitis.16 Although there is no evidence for the production of marrow toxins in hepatitis, the poorer prognosis of aplastic anemia following hepatitis in females as compared with males (proportion of survivors 8.5% and 28% respectively) raises the question of a possible suppressive effect on bone marrow by estrogens or other hor17 mones. Studies in dogs but not in humans have shown that large doses of estrogen are toxic to the bone marrow.18 The development of an inhibitor to erythropoiesis and concomitant red cell aplasia with anemia and their prompt disappearance after delivery strongly suggest a causal relation to pregnancy. The literature suggests that different degrees of marrow depression might exist, producing a continuum of clinical hematopoietic dysfunctions, including normoblastic hypoplasia, pure red cell hypoplasia and complete marrow aplasia. More studies are needed to see if a single humoral mechanism with various degrees of expression underlies these disorders, or if they are diseases of distinctly different origins. References 1. KRANTZ SB: Diagnosis and treatment of pure red cell aplasia. Med Clin North Am 60: 945, 1976
8. MASSART JJ, BISHOP WA: Thymoma occurring during pregnancy: a case report. Obstet Gynecol 32: 490, 1968 9. Hms.r E, ROBERTSON TI: The syndrome of thymoma and erythroblastopenic anemia. Medicine (Balti-
more) 46: 225, 1967 10. HOLLY RG: Hypoplastic anemia in pregnancy. Obstet Gynecol 1: 535, 1953 11. FLEMING AF: Hypoplastic anemia in pregnancy, in Haematological
Disorders in Pregnancy (Cliii Hacmatol vol 2, no 3), JEPSON JH (ed), Saunders, Philadelphia, 1973, pp 477, 496 12. GOLDSTEIN TM, COLLER RS: Aplastic anemia in pregnancy: recovery
after normal Spontaneous delivery. Ann intern Med 82: 537, 1975 13. EHRLICH P: Uber einen Fall von Anjimie mit Bemerkungen iiber regenerative Veranderungen des
Knochenmarks. Charite A nii 300, 1888
13:
14. KNISPEL JW, LYNCH VA, VIELE BD: Aplastic anemia in pregnancy: a case report, review of the literature, and a re-evaluation of manage-
ment. Obstet Gynecol Surv 31: 523, 1976 15. JURGENSEN JC, ABRAHAM JP, HARDY WW: Erythroid aplasia after halothane hepatitis: report of a case.
Am J Dig Dis 15: 577, 1970 16. SEARS DA, GEORGE JN, GOLD MS: Transient red blood cell aplasia in association with viral hepatitis. Oc-
currence four years apart in siblings. Arch intern Med 135: 1585, 1975 17. HAGLER L, PASTORE RA, BERGIN JJ: Aplastic anemia following viral hepatitis. Report of two fatal cases and literature review. Medicine
(Baltimore) 54: 139, 1975 18. CRAFTS RC: The effects of estrogens on the bone marrow of adult female
dogs. Blood 3: 276, 1948
2. CONKLIN GT, GEORGE JN, SEARS
DA: Transient erythroid aplasia in hemolytic anemia: a review of the literature with two case reports. Tex Rep Bid Med 32: 391, 1974 3. SKiKNE BS, LYNCH SR, BEZWODA WR, et al: Pure red cell aplasia.
S Air Med J 50: 1353, 1976 4. AGGIo MC, ZUNINI C: Reversible pure red-cell aplasia in pregnancy (C). N Engi J Med 297: 221, 1977 S. Mwosm I, HnuT. T, Koi B, et al: Reversible pure red-cell aplasia in pregnancy (C). N Engi J Med 299: 777, 1978 6. MCLEOD DL, SHREEvE MM, AXELRAD AA: Improved plasma culture system for production of erythrocytic colonies in vitro: quantitative assay method for CFU-E. Blood 44: 517, 1974 7. KRANTZ SB, KAO V: Studies on red cell aplasia. II. Report of a second patient with an antibody to erythroblast nuclei and a remission after immunosuppressive therapy. Blood 34: 1, 1969
190 CMA JOURNAL/JULY 21, 1979/VOL. 121
BOOKS continued from page 164 THE HANDBOOK OF CRITICAL CARE MEDICINE. Edited by Max Harry Well and Robert J. Henning. 205 pp. lIlust. EM Books, New York; Fischer Medical Publications, Inc., New York, 1979. $19.95 IT'S YOUR MONEY. The Complete Canadian Guide to Personal Financial Planning. New edition, revised and expanded. Edited by J. Christopher Snyder. Written by Brian E. Anderson, William Scott, W.D. Glenn McLean and others. 195 pp. lIlust. Methuen Publica. tions, Agincourt, Ont., 1979. $7.95, paperbound. ISBN 0-438-93950-1
LONDON PRIDE. The Story of a Voluntary Hospital. A.E. Clarke-Kennedy. 254 pp. Illust. Hutchinson Benham Limited, London, 1979. Price not stated, paperbound. ISBN 0-09-136541-4
continued on page 202
