Thrombocytopenia with Decreased Megakaryocytes

Transcription

1 Thrombocytopenia with Decreased Megakaryocytes Evaluation and Prognosis DAVID B. STOLL, M.D.; STUART BLUM, M.D.; DOMINIC PASQUALE, M.D.; and SCOTT MURPHY, M.D.; Philadelphia, Pennsylvania; Camden, New Jersey; and Bethesda, Maryland The presenting clinical pictures and courses of seven patients with thrombocytopenia, decreased megakaryocytes in the marrow, and minimal changes in other hematopoietic cell lines are described. Little information exists in the literature on such patients. Initial bone marrow aspiration and biopsy in all patients showed decreased megakaryocytes with an otherwise normal marrow. Erythrocyte mean corpuscular volume was elevated in five of seven patients. Bone marrow karyotypes of six of the seven patients were normal. Chromium-51 platelet survival studies with platelet sizing, done in five of the seven patients, showed normal results. In two patients the course progressed to aplastic anemia. One of these died 9 months after presentation, and one responded dramatically to lithium. One patient developed preleukemia and died. The other four patients have remained thrombocytopenic but clinically stable. No useful therapy was identified. The differential diagnosis of such patients should include idiopathic thrombocytopenic purpura with misinterpretation of morphologic findings, hereditary and acquired aplastic anemia, preleukemia, and systemic lupus erythematosus. From the Cardeza Foundation for Hematologic Research and the Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania; Cooper Medical Center, Camden, New Jersey; and The National Naval Medical Center; Bethesda, Maryland. THROMBOCYTOPENIA with decreased megakaryocytes in the marrow may be seen in adults with such disorders as aplastic anemia and acute leukemia, and after chemotherapy and radiotherapy for malignancies. In the vast majority of such cases, there are also gross abnormalities in the erythroid and granulocytic lines. To our knowledge, the problem of evaluation of adult patients with thrombocytopenia, decreased megakaryocytes, and only minimal changes in other cell lines has not been discussed in the literature. We have seen seven such patients over the past 7 years and suggest that the problem is not as rare as the literature implies. The cases we present illustrate the approach we have taken toward such patients, the differential diagnostic possibilities that must be considered, and the clinical course as the patients have been observed over time. Materials and Methods Patients who presented with thrombocytopenia and decreased megakaryocytes between 1973 and 1979 were evaluated. Routine blood counts and bone marrow aspiration with biopsy were done in all patients. Six of the seven had marrow karyotype determinations with methods previously described (1). Chromium-51 ( 51 Cr) platelet survival studies, done by previously described methods (2), were obtained in five of the seven. All studies were done with ABO-matched platelets from normal donors except for one (Patient 5) who was studied with his own platelets. In three of these five patients, platelet size was estimated by ascertaining the percentage of platelets greater than 3 jam in diameter on peripheral smear using methods of Zeigler and associates (3). Normal values are less than 14%. For the other two, size estimates were made by ascertaining mean platelet volumes using a Coulter Counter (Coulter Electronics, Inc., Hialeah, Florida)(4). Normal range is 6 to 9 jam. 170 Annals of Internal Medicine. 1981;94: American College of Physicians

2 Case Reports Table 1 presents the initial clinical and hematologic values, marrow chromosome examination, and 51 Cr platelet survival results. Initial therapy and the patient's clinical course are also summarized. PATIENT 1 A 73-year-old white man had a chief complaint of progressive weakness associated with tarry bowel movements and ecchymoses. A test for blood in the stools was strongly positive. There was no family history of hematologic disorders. He was pale and had multiple ecchymotic lesions over the thighs and forearms. There was no splenomegaly, lymphadenopathy, or physical deformities. Initial hematologic values were hemoglobin, 4.4 g/dl; hematocrit, 12.9%; leukocyte count, 6700/mm 3 with 33% neutrophils, 60% lymphocytes, 4% monocytes, and 3% eosinophils; reticulocyte count, 8.2%; and platelet count, 6000/mm 3. Erythrocyte indexes were normal except for mean corpuscular volume, 100 jum. Peripheral smear showed some target cells, a few tear-drop forms, and occasional ovalocytes. Bone marrow aspirate and biopsy showed normal cellularity and absent megakaryocytes. The myeloid-to-erythroid ratio was increased. Erythroid and myeloid lines showed normal maturation. Iron stores were present, and there was no increase in sideroblasts. A bone marrow karyotype was normal. Intravenous pyelogram, skeletal survey, liver-spleen scan, antinuclear antibody, sucrose and acid hemolysis test, direct and indirect Coombs' test, serum B12 and folate, serum muramidase, hemoglobin electrophoresis, and leukocyte alkaline phosphatase were all normal. There was no increase in hemoglobin F. The initial hospital course lasted 18 days, during which the patient was given packed erythrocyte and platelet transfusions. He was discharged on prednisone and androgens. He was readmitted 1 month later with recurrent weakness and gastrointestinal bleeding. Hematologic values were hemoglobin, 3.8 g/dl; hematocrit, 12.5%; leukocyte count, 4400/mm 3 with 34% neutrophils, 62% lymphocytes, and 4% monocytes; reticulocyte count, 9.2%; and platelet count, 4000/mm 3. A bone marrow aspirate now showed a myeloid-to-erythroid ratio of 1:10 with overall cellularity decreased. Megakaryocytes continued to be absent. Six days after admission the patient had a repeat bone marrow aspiration that showed further decrease in cellularity and granulocytic precursors. The patient appeared to have developed typical aplastic anemia with involvement of all three precursor lines. He was treated with transfusions, corticosteroids, and vincristine without response. Two months after presentation he was readmitted with severe upper gastrointestinal bleeding followed by bacterial sepsis. Hematologic values were hemoglobin, 11.0 g/dl; leukocyte count, 1800/mm 3 with 2% neutrophils; and platelet count, /mm 3. The patient died 2 days later. No autopsy was done. PATIENT 2 A 58-year-old white woman presented with a chief complaint of cutaneous purpura of 2 years' duration. There was no further evidence of hemorrhage. On physical examination, there was no evidence of lymphadenopathy, hepatosplenomegaly, or congenital deformities. Initial hematologic values were hemoglobin, 12.0 g/dl; hematocrit, 34.2%; leukocyte count, 5200/mm 3 with 58% neutrophils and 42% lymphocytes; reticulocyte count, 1%; and platelet count, /mm 3. Red cell indexes were normal except for a mean corpuscular volume of 95 jam. Peripheral smear showed only thrombocytopenia. Bone marrow aspirate and biopsy showed normal cellularity and decreased megakaryocytes. There was a normal myeloid-to-erythroid ratio. Maturation of the erythroid and granulocytic lines was normal. Iron stores were present, and there was no increase in sideroblasts. Serum B12 and folate, antinuclear antibody, sucrose hemolysis test, leukocyte alkaline phosphatase, and hemoglobin electrophoresis were all normal. There was no increase in hemoglobin F. The patient was treated with androgens and prednisone without improvement. One year after presentation, the patient's hematologic values were hemoglobin, 8.1 g/dl; hematocrit, 24.7%; leukocyte count, 3400/mm 3 with 51% neutrophils, 5% bands, and 44% lymphocytes; platelet count, 9000/mm 3 ; and mean corpuscular volume, 112 /xm. Bone marrow biopsy showed hypoplasia of all cell lines and continued decrease of megakaryocytes. A 5l Cr platelet survival study done with platelets from a normal donor showed the in-vivo recovery to be 33% with a half-life of 5.3 days. The percentage of platelets greater than 3 jam in diameter on peripheral smear was normal, 5.6%. Further treatment with vincristine and steroids resulted in no improvement. Two years after presentation her hematologic values were hemoglobin, 7.5 g/dl, hematocrit, 22%; leukocyte count, 2100/mm 3 with 27% neutrophils, 56% lymphocytes, 4% eosinophils, and 5% monocytes; reticulocyte count, 1.3%; and platelet count, 1000/mm 3. A bone marrow biopsy showed persistent hypoplasia and absent megakaryocytes. She was now considered to have aplastic anemia and treated with 900 mg/d of lithium. Two months later her hematologic values were hemoglobin, 11.6 g/dl, hematocrit, 34%; leukocyte count, 5000/mm 3 ; and platelet count, /mm 3. A bone marrow aspirate and biopsy showed normal cellularity, adequate megakaryocytes, decreased myeloid-to-erythroid ratio, and normal maturation of the erythroid and myeloid cell lines. A bone marrow karyotype at this time was normal except for a balanced translocation involving chromosomes 13 and 14. Phytohemagglutinin-stimulated lymphocytes also contained this abnormality, suggesting that it was a constitutional abnormality. (Of interest is that Goh and colleagues (5) recently reported a similar translocation, also believed to be constitutional, in a woman with a myeloproliferative disorder.) This patient has been described previously (6). PATIENT 3 A 62-year-old white woman was initially evaluated for abdominal pain. She gave no family history of hematologic disorders. There were no signs of hemorrhage, lymphadenopathy, splenomegaly, or physical deformities. A possible mass extrinsic to the stomach was found on gastroscopy. A laparotomy that showed apparent chronic pancreatitis was accompanied by excessive bleeding. Initial hematologic values were hemoglobin, 11.0 g/dl; hematocrit, 39%; leukocyte count, 6200/mm 3 with 65% neutrophils, 30% lymphocytes, 3% band forms, and 2% monocytes; reticulocyte count, 2.5%; and platelet count, /mm 3. Erythrocyte indexes were normal except for mean corpuscular volume, 105 jam. Peripheral smear snowed only thrombocytopenia. Bone marrow aspirate and biopsy showed normal cellularity and decreased megakaryocytes. The myeloidto-erythroid ratio was normal. There was normal maturation of erythroid and myeloid cell lines. Iron stores were present, and there was no increase in sideroblasts. A bone marrow karyotype showed no abnormalities. Antinuclear antibody, direct Coomb's test, leukocyte alkaline phosphatase, serum B12 and folate, liver-spleen scan, rheumatoid factor, intravenous pyelogram, and hemoglobin electrophoresis were all normal. There was no increase in hemoglobin F. The patient was discharged from the hospital on prednisone and androgens. She began, shortly thereafter, to notice increasing numbers of petechiae over her extremities. She was readmitted 2 months later. There were petechiae and ecchymoses distributed over her body. There was no lymphadenopathy or hepatosplenomegaly. Hemoglobin was 7.5 g/dl; hematocrit, 22%; leukocyte count, 2700/mm 3 with 22% neutrophils, 70% lymphocytes, and 6% monocytes; reticulocyte count, 0.3%; and platelet count, /mm 3. Bone marrow aspirate and biopsy showed slightly increased cellularity with erythroid hyperplasia and decreased megakaryocytes. The erythroid series showed normal maturation. The granulocytic series was quantitatively decreased but demonstrated maturation. There was no increase in sideroblasts. Erythrokinetic studies showed 5, Cr half-life, 17 days (normal = 28 days); 59 Fe clearance, 154 minutes (normal, 60 to 120 min); plasma iron turnover, 1.0 mg/d. dl blood (normal, 0.4 to 0.6 mg); and 59 Fe utilization, 43.4% (normal, greater than 75%). She was treated with androgens, prednisone, pyridoxine, folate, and lithium without improvement. Two months later a bone marrow aspiration showed a marked increase in cellularity and erythroid hyperplasia with prominent megaloblastic changes. The granulocytic series was normal except for 6% blast forms. There was Stolletal. Thrombocytopenia 171

3 Table 1. Summary of Initial Hematologic Values and Clinical Courses Patient Age Sex Hemoglobin Mean Corpuscular Volume Reticulocytes Leukocyte Count (% Neutrophils) yrs g/dl pm % /mm z 1 73 M (33) 2 58 M (Later 112.0) (58) 3 62 F (65) 4 29 M (62) 5 22 M (32) 6 62 M (72) 7 27 F (60) Normal values no increase in sideroblasts. The best diagnosis seemed to be a preleukemic state. Nine months after prescription, because of progressive hemorrhagic phenomena and transfusion requirements, the patient was treated with doxorubicin, 6-thioguanine, and cytarabine. Shortly thereafter, she died of hemorrhage and infection. PATIENT 4 A 29-year-old white man was admitted to the hospital for trauma suffered during an automobile accident. There was no family history of any hematologic disorders. Findings on physical examination were normal. Initial hematologic values were hemoglobin, 13.1 g/dl; hematocrit, 41%; leukocyte count, 8000/mm 3 with 63% neutrophils, 2% band forms, 28% lymphocytes, and 7% monocytes; reticulocyte count, 0.8%; and platelet count, /mm 3. Erythrocyte indexes were normal except for mean corpuscular volume, 104 jmm. Peripheral smear showed only thrombocytopenia. Bone marrow aspiration and biopsy demonstrated normal cellularity, normal myeloid-toerythroid ratio, and decreased megakaryocytes. Myeloid and erythroid maturation were normal. Iron stores were present, and there was no increase in sideroblasts. A liver-spleen scan, intravenous pyelogram, skeletal survey, direct Coombs' test, serum protein electrophoresis, and antinuclear antibody were normal. The patient failed to respond to a course of prednisone. A 5, Cr platelet survival study using platelets from a normal donor snowed the in-vivo recovery to be 52% with a half-life of 3.0 days. The percentage of platelets greater than 3 jum in diameter on peripheral smear was normal, 12%. The patient has now been followed for 3! / 2 years with no significant change in his clinical or laboratory status. PATIENT 5 A 22-year-old white man was found to have a platelet count of /mm 3 after platelets were noted to be decreased on the smear of a routine blood count. He gave no history to suggest a hemorrhagic tendency. His family history was unremarkable although there were two distant cousins with a history of Fanconi's anemia. Findings on physical examination were normal. Initial hematologic values were hemoglobin, 13.4 g/dl; hematocrit, 39%; leukocyte count, 3000/mm J with 32% neutrophils, 60% lymphocytes, and 8% monocytes; and reticulocyte count, 1.8%. Erythrocyte indexes were normal except for mean corpuscular volume, 95 ju,m. Peripheral smear showed only thrombocytopenia. Bone marrow aspirate and biopsy showed normal cellularity with decreased megakaryocytes. The myeloid-toerythroid ratio was slightly reduced. The maturation of both these lines was normal. No increase in sideroblasts was seen, 172 February 1981 Annals of Internal Medicine Volume 94 Number 2

4 Table 1. (continued) Plate Marrow 51 Cr Platelet Survival Therapy and Patient lets Karyotype (^linipal f nnrsp V.11111C&1 VUUISC Recovery Platelet Half-Life /mm 3 % d 6000 Normal Not done Not done Patient developed aplastic anemia 2 months after presentation and was unresponsive to therapy. Died 9 months after presentation Normal After 2 years, condition progressed to aplastic anemia that responded well to lithium therapy Normal Not done Not done Patient developed progressive transfusion therapy requirement and eventually pancytopenia with a picture of preleukemia. There was no response to therapy Not done Patient did not respond to steroids. No change in hematologic status after 3i years with no therapy Normal Patient did not respond to steroids or androgens. No change in hematologic status after 5 years Normal No therapy instituted. No change in hematologic status after 2 years Normal No response to steroids. No change in hematologic status after 2 years. Normal values and iron stores were normal. A bone marrow karyotype was normal. Antinuclear antibody, direct Coombs' test, intravenous pyelogram, skeletal survey, and liver-spleen scan were all normal. A 5, Cr platelet survival study using platelets from a normal donor showed the in-vivo recovery to be 54% with half-life of 3.0 days. The percentage of platelets greater than 3 /mm in diameter on peripheral smear was normal, 5.2%. He has now been followed for 5 years, and there has been no change in his hematologic or clinical status. PATIENT 6 A 62-year-old white man presented with petechiae of the lower extremities. There was no evidence of hemorrhage elsewhere. He had a history of hypertension treated with methyldopa and ethacrynic acid. There was no family history of hematologic disorder. Findings on physical examination were normal except for petechiae. Initial hematologic values were hemoglobin, 14.9 g/dl; hematocrit, 44.5%; leukocyte count, 8900/mm 3 with 72% neutrophils, 20% lymphocytes, and 8% monocytes; reticulocyte count, 0.6%; and platelet count, /mm 3. Erythrocyte indexes were normal; mean corpuscular volume was 91 fxm. Peripheral smear showed only thrombocytopenia. Bone marrow aspirate and biopsy demonstrated normal cellularity with decreased megakaryocytes. The myeloid-to-erythroid ratio was normal, and there was normal maturation of all cell lines. Iron stores were present, and there was no increase in sideroblasts. A bone marrow karyotype was normal. Antinuclear antibody, serum B12 and folate, direct Coombs' test, intravenous pyelogram, liver-spleen scan, and skeletal survey were normal. A 51 Cr platelet survival study using the patient's own platelets showed an in-vivo recovery of 55.9% with half-life 3.3 days. The mean platelet volume measured by Coulter Counter was normal, 5.8 urn. The patient has been followed for 2 years with no change in clinical or hematologic status. PATIENT 7 A 27-year-old white woman gave a history of easy bruising. There was no family history of hematologic abnormalities. Her physical examination was unremarkable except for several large ecchymoses on the upper extremities. There was no evidence of any other hemorrhagic signs. Initial hemoglobin values were hemoglobin, 14.5 g/dl; hematocrit, 43%; leukocyte count, 8000/mm 3 with 60% neutrophils, 12% lymphocytes, and 3% monocytes; reticulocyte count, 2.1%; and platelet count, /mm 3. Erythrocyte indexes were normal except for mean corpuscular volume, 108 urn. The peripheral smear was normal except for thrombocytopenia. Bone marrow aspirate and biopsy showed normal cellularity and a decrease in megakaryocytes. Stolletal. Thrombocytopenia 173

5 Myeloid-to-erythroid ratio was normal, and there was normal maturation of these lines. Iron stores were present with no increase in sideroblasts. A bone marrow karyotype was normal. Antinuclear antibody, serum B12 and folate, serum protein electrophoresis, direct Coombs' test, and hemoglobin electrophoresis were all normal. There was no increase in hemoglobin F. A 51 Cr platelet survival study with platelets from a normal donor showed the in-vivo recovery to be 56.2% and half-life, 5.1 days. The mean platelet volume measured by Coulter Counter was normal, 5.4 /urn. The patient was treated with prednisone with no response. She has been followed for 2 years with no change in clinical or hematologic status. Discussion The patients presented here do not represent a single clinical entity; rather they represent a hematologic problem with which the clinician must deal. All patients had thrombocytopenia with decreased megakaryocytes in the marrow and minimal changes in other hematopoietic cell lines. Of the seven patients, Patient 1 had a very low hemoglobin on presentation that appeared to be secondary to gastrointestinal bleeding. There was a vigorous reticulocyte response. Of the others, only Patient 3 had minimal anemia. Patient 5 had a minimal reduction in leukocyte count, and this patient and Patient 1 had a reduction in the percentage of neutrophils. Six of the patients had an elevated mean corpuscular volume, with five patients having values greater than 100 /xm. Marrow examination showed only decreased megakaryocytes. The differential diagnosis of such a patient includes idiopathic thrombocytopenia purpura with misinterpretation of morphologic findings; aplastic anemia, hereditary or acquired; preleukemia; and systemic lupus erythematosus. The first consideration should be that the patient has idiopathic thrombocytopenia purpura and that the marrow morphologic findings have been misinterpreted. In fact, this was the initial impression in most of these cases, and all but one received a trial of prednisone therapy. Harker and Finch (7) have devised a method for measuring total body megakaryocyte mass, but the method is laborious and has not been used widely. Without such a quantitative technique, marrow smears and biopsies can be interpreted only qualitatively and they will be misinterpreted frequently. Where possible, we have used 51 Cr survival studies as a supportive measurement. Current concepts suggest that idiopathic thrombocytopenic purpura results from accelerated platelet destruction mediated by the attachment of antibody to the platelet surface (8). Thus, the survival of patient's platelets and transfused normal platelets should be shortened. When the patient's platelet count is reduced, it is often difficult to obtain enough platelets for labeling. In this setting, platelets from normal persons can be used, recognizing that a short survival of normal platelets may be the result of alloantibodies related to previous pregnancy or transfusion. For this reason that we did not attempt survival studies in Patients 1 and 3, who had been transfused extensively before our evaluation. Platelet survival was normal in Patients 4 to 7. Two other types of measurement hold promise for the future to aide in this differential diagnosis. First, several methods have been described for measuring platelet-associated immunoglobulins (8, 9). We anticipated that this measurement would be normal in our patients and increased in patients with idiopathic thrombocytopenic purpura. Second, increased percent of large platelets and mean cell volume are characteristic of idiopathic thrombocytopenia purpura (3, 4). In five of our patients (Patients 2, 4, 5, 6, and 7) these measurements were normal. Aplastic anemia typically presents with thrombocytopenia as part of pancytopenia. However, a small percent of patients have been described as initially presenting with isolated thrombocytopenia (10). Patients 1 and 2 appear to be examples of this phenomenon. The progression to complete pancytopenia may occur over a variable period as illustrated by these two patients, 2 months and 2 years, respectively. In addition, thrombocytopenia with decreased megakaryocytes may occur on a hereditary basis as part of Fanconi's anemia (11) or as an isolated phenomenon in the thrombocytopenia with absent radius syndrome (12). However, none of our patients had histories dating to childhood or evidence of other congenital abnormalities suggesting Fanconi's anemia or the thrombocytopenia with absent radius syndrome. In the large series of patients with preleukemia described by Saarni and Linman (13), pancytopenia was present in 45%, and the marrow was hypercellular in 76%. However, in their series, the marrow had normal cellularity in 20%, and 3% presented with an isolated thrombocytopenia. In addition, 24% had decreased megakaryocytes. Our Patient 3 appears to fall into this category. Her condition progressed from a normocellular marrow with decreased megakaryocytes to a hyperplastic picture with erythroid hyperplasia and erythrokinetic evidence of ineffective erythropoiesis. Because of concern that some of our patients might be in an early phase of hematologic malignancy, marrow karyotypes were obtained in six of seven. In several series of patients with preleukemia, 30% to 50% have had clones of cells with chromosome abnormalities in their hematopoietic tissues (1, 14). None of our patients had such a clone, although one had a constitutional chromosome alteration. When thrombocytopenia occurs in the course of systemic lupus erythematosus, accelerated platelet destruction is almost invariably present. However, there has been one report of thrombocytopenia with decreased megakaryocytes (15). In this case, other characteristic features of systemic lupus erythematosus were present. We were struck that six of our seven patients had increased mean corpuscular volume. This is a recognized phenomenon in preleukemia (13) and aplastic anemia (10). Three of our four patients who remained stable clinically and hematologically over follow-up periods of 2 to 5 years showed this. Although evolution of a more severe hematologic condition may not be inevitable, the increased mean corpuscular volume may prove important, and acute leukemia or aplastic anemia may still occur. Recently, Koeffler and Golde (16) have emphasized the frequent occurrence of elevated hemoglobin F levels and ringed sideroblasts in the marrow of patients with preleukemia. Although neither of these phenomena occurred in our patients, this does not preclude the later develop- 174 February 1981 Annals of Internal Medicine Volume 94 Number 2

6 ment of this condition. The cause of the decrease in megakaryocyte proliferation in Patients 4 to 7 is unknown. One could theorize that there was decreased production of a poietic hormone (thrombopoietin) (17). In a recent case report of a patient similar to ours, such a hypothesis was advanced (18). There could also be an immunologic attack on that cell or its progeny. In experimental animals, techniques for measuring thrombopoietin and for determining megakaryocyte colony-forming units in marrow are being developed (19, 20). When these techniques are developed for human studies, the pathogenetic mechanisms in our patients can be explored. In summary, we have tried to define the approach that a physician might take toward a patient with thrombocytopenia who has decreased megakaryocytes and minimal changes in other cell lines. A common initial impression is that the patient has idiopathic thrombocytopenia purpura with atypical marrow morphologic findings. An increased mean corpuscular erythrocyte volume and slight abnormalities of the leukocyte count and differential are clues that this is not the case. Confirmatory evidence can be obtained from 51 Cr platelet survival study and platelet size measurements. With accurate diagnosis, the hazards of steroid therapy and splenectomy can be avoided. In this small series, eventual outcome was variable and unpredictable. Longer follow-up of a larger group or patients will be needed to define this group of disorders more exactly. ACKNOWLEDGMENT: The authors thank J. R. Kim, Charles Smith, Charles Lusch and Raymond Vivacqua for referring patients, Dr. Peter Nowell for performing the marrow karyotyping and for constructive criticism; and Ms. Geraldine Moore for preparing the manuscript. Grant support: by grant HL from the National Institutes of Health. This paper was presented at the American College of Physicians Associates Session, 5 October 1980, in Philadelphia, Pennsylvania. Requests for reprints should be addressed to Scott Murphy, M.D.; Cardeza Foundation for Hematologic Research, Thomas Jefferson University Hospital; Philadelphia, Pennsylvania. References 1. NOWELL P, FIN AN J. Chromosome studies in preleukemic states: IV. Myeloproliferative versus cytopenic disorders. Cancer. 1978;42: MURPHY S, OSKI FA, NAIMAN JL, LUSCH CJ, GOLDBERG S, GARD NER FH. Platelet size and kinetics in hereditary and acquired thrombocytopenia. W Engl J Med. 1972;286: ZEIGLER Z, MURPHY S, GARDNER FH. Microscopic platelet size and morphology in various hematologic disorders. Blood. 1978;51: MURPHY S. Intrinsic platelet defects in hereditary thrombocytopenia. Ann NY Acad Sci. 1972;201: GOH K-O, BAUMAN AW, TOWNES PL. Myeloproliferative disorder in a t (13ql4q) carrier. Cancer. 1980;45: BLUM SF. Lithium therapy of aplastic anemia. N Engl J Med. 1979;300: HARKER LA, FINCH CA. Thrombokinetics in man. / Clin Invest. 1969;48: 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. 1975;292: MCMILLAN R, LONGMIRE RL, YELENOSKY R, DONNELL RL, ARM STRONG S. Quantitation of platelet-binding IgG produced in vitro by spleens from patients with idiopathic thrombocytopenic purpura. N Engl J Med. 1974;291: WILLIAMS DM, LYNCH RE, CARTWRIGHT GE. Drug-induced aplastic anemia. Semin Hematol. 1973;10: FANCONI G. Familial constitutional panmyelocytopathy, Fanconi's anemia (F.A.). Semin Hematol. 1967;4: HALL JG, LEVIN J, KUHN JP, OTTENHEIMER EJ, VANBERKUM KAP, MCKUSICK VA. Thrombocytopenia with absent radius (TAR). Medicine (Baltimore). 1969;48: SAARNI MI, LINMAN JW. Preleukemia: the hematologic syndrome preceding acute leukemia. Am J Med. 1973;55: PIERRE, RV. Preleukemic syndromes. Virchows Arch [Cell Pathol]. 1978;29: GRINER PF, HOYER LW. Amegakaryocytic thrombocytopenia in systemic lupus erythematosus. Arch Intern Med. 1970;125: KOEFFLER HP, GOLDE DW. Human preleukemia. Ann Intern Med. 1980;93: MCDONALD TP. Assays for thrombopoietin. Scand J Haematol. 1977;18: HIRSH EH, VOGLER WR, MCDONALD TP, STEIN SF. Acquired hypomegakaryocytic thrombocytopenic purpura: occurrence in a patient with absent thrombopoietic stimulating factor. Arch Intern Med. 1980;140: WILLIAMS N, JACKSON H, SHERIDAN APC, MURPHY MJ JR, ELSTE A, MOORE MAS. Regulation of megakaryopoiesis in long-term murine bone marrow cultures. Blood. 1978;51: BURSTEIN SA, ADAMSON JW, THORNING D, HARKER LA. Characteristics of murine megakaryocytic colonies in vitro. Blood. 1979;54: Stolletal. Thrombocytopenia 175