A 20-Year-Old Man With a History of Hemoptysis and Purpura.

Pathologic Diagnosis: Thrombotic Thrombocytopenic Purpura Associated With Myelodysplastic Syndrome

A 20-year-old white man was admitted with an 8- to 10-month history of rash, fatigue, intermittent hemoptysis, and purpura, culminating in a seizure. He had received steroids intermittently for presumed vasculitis. On admission, widespread petechiae and purpura with scleral icterus were noted. No lymphadenopathy or splenomegaly was present. The patient had been intubated and sedated, but no focal neurologic deficit was apparent.

On evaluation in the emergency room, he was found to have a platelet count of 3 X [10.sup.9]/L with a hemoglobin level of 55 g/L; hematocrit, 0.154; mean corpuscular volume, 93 fL; red blood cell count, 2.65 X [10.sup.12]/L; and white blood cell count, 19.6 X [10.sup.9]/L with neutrophils at 0.67 and without myeloid blasts. Review of the peripheral smear revealed notable red cell morphology (Figure 1) and 24 nucleated red blood cells per 100 white blood cells, many of which were dysplastic. The patient's reticulocyte count was 0.21. Laboratory values included a serum urea nitrogen level of 15.4 mmol/L (43 mg/dL); creatinine, 239 [micro]mol/ L (2.7 mg/dL); lactate dehydrogenase (LDH), 2505 U/L; direct bilirubin, 10.3 [micro]mol/L (0.6 mg/dL); total bilirubin, 79 [micro]mol/L (4.6 mg/dL); and haptoglobin, 6 g/L. Antibodies to human immunodeficiency virus were negative.

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The patient was treated with plasma exchange. He also received methylprednisolone sodium succinate, 200 mg intravenously daily, plus phenytoin sodium and antibiotics. The patient's platelet count rose to 79 X [10.sup.9]/L by day 5, and his LDH fell to 625 U/L. Schistocytes persisted on the peripheral smear The patient was alert and essentially asymptomatic. Bone marrow biopsy showed evidence of hyperplasia (Figure 2), and a bone marrow aspirate revealed erythroid dysplasia (Figure 3). The bone marrow karyotype demonstrated an inversion of chromosome 16. Iron stain on the bone marrow smear showed the abnormality seen in Figure 4. On day 7, however, the platelet count fell to 18 X [10.sup.9]/L, and the LDH value was 1142 U/ L. High-dose intravenous immunoglobulin (Ig) G (100 g daily) was started; plasma exchange and steroids continued. On day 8, the patient's platelet count was 5 X [10.sup.9]/L, and he complained of substernal pain radiating down both arms. Cardiac enzymes showed a troponin level of 0.71 [micro]g/mL; creatine kinase-MB (CK-MB), 6.3 [micro]g/mL; and CK-MB index, 3.1. Subsequently, the patient developed irrational behavior, had a seizure, and died.

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What is your diagnosis?

To our knowledge, this is the second reported case of thrombotic thrombocytopenic purpura (TTP) associated with myelodysplastic syndrome. The only other case that we could find was published as a letter to the editor in American Journal of Hematology in 1992.[1]

When the patient was admitted, a presumptive diagnosis of thrombotic thrombocytic purpura was made in the presence of severe thrombocytopenia (platelet count, 3 X [10.sup.9]/L), microangiopathic hemolytic anemia, neurologic changes, and renal impairment, with the underlying inciting incident unknown. The peripheral blood at admission showed numerous nucleated red cells, many of which were prominently dysplastic. There was moderate anisocytosis, moderate to marked polychromasia, and slight to moderate poikilocytosis, predominantly schistocytes (Figure 1). Plasmapheresis was subsequently initiated, as well as high-dose steroids, which elicited a good response; the platelet count came up to 79 X [10.sup.9]/L. Bone marrow biopsy showed evidence of moderate hyperplasia of the erythroid cell line (Figure 2). The bone marrow aspirate smear revealed moderate erythroid hyperplasia with severe dysplasia, suggesting a refractory anemia type of myelodysplastic syndrome. The red cell nuclei were multilobulated and very irregular (Figure 3). Iron stain on the clot section showed increased +3 bone marrow iron stores. Iron stain on the smear showed numerous siderocytes with occasional ring sideroblasts present (Figure 4). A tentative diagnosis of myelodysplasia, type refractory anemia, was made at this time in the presence of the following characteristics: cytopenias (platelet count, 3 X [10.sup.9]/L; red blood cell count, 2.65 X [10.sup.12]/L), severely dysplastic red blood cells (peripheral smear and bone marrow), cytogenetic abnormality inv(16), and occasional ring sideroblasts in the bone marrow. Despite treatment with steroids and plasmapheresis, the TTP did not completely remit. The patient had no extensive bleeding, but his hemoglobin level dropped from 103 g/L to 87 g/L after transfusion. His LDH level increased to 1200 U/L, and his platelet count continued to drop. He subsequently developed substernal pain radiating to the arm and neck. Cardiac enzymes were positive for myocardial infarction. He was placed on a nitroglycerin drip, beta-blocker, and intravenous IgG therapy. The next day he became acutely agitated and somewhat confused with no focal neurologic signs. Shortly thereafter he became tachycardic and tachypneic, and within several minutes became aphasic and suffered a seizure with subsequent apnea and death. No autopsy was performed.

Myelodysplastic syndromes are a heterogeneous group of hemopoietic stem cell disorders characterized by dysplastic and ineffective hemopoiesis that usually accompany cytopenias and often progress to leukemia. Two different types of stem cells may be involved in the clonal process: a pluripotent stem cell with the capabilities of both self-renewal and differentiation into all cell lineages (myeloid and lymphoid), and a pluripotent stem cell that has lost its capacity for self-renewal and is already engaged specifically toward myeloid differentiation. Benzene, chemotherapeutic agents, particularly alkylating agents, and radiation are initiating factors that can induce a preleukemic disorder Simultaneous presentation of myelodysplastic syndrome and multiple myeloma has been described in the literature.[2] Chromosomal abnormalities are present in about 50% of patients with myelodysplastic syndrome. The most common numerical aberrations include monosomy 5 and 7, trisomy 8, loss of the Y chromosome, and structural abnormalities such as deletion of the long arm of chromosome 5 (5q-syndrome), 7, or 8.[3,4] However, other chromosomal aberrations have been described.[5] Different gene rearrangements have been reported in the literature, including M-bcr, Ig-JH, T-cell receptor beta (TCR[Beta]), IL-3, or granulocyte-macrophage colony-stimulating factor genes.[3] Based on the percentage of blasts ([is less than] 5%, 5%-20%, 20%-30%) or the presence of more than 15% ringed sideroblasts in bone marrow with less than 5% blasts, the French-American-British classification puts myelodysplastic syndrome into 4 morphologic categories: refractory anemia, refractory anemia with excess of blasts, refractory anemia with excess of blasts in transformation, and refractory anemia with ringed sideroblasts. The fifth morphologic type is chronic myelomonocytic leukemia, characterized by peripheral blood monocytosis ([is greater than] 1 X [10.sup.9]/L).

Thrombotic thrombocytopenic purpura is a rare, life-threatening, multisystem disorder of unknown etiology, which is potentially fatal and is characterized by widespread platelet thrombi in the microcirculation. The onset of the disease is indolent, and the symptoms are generally related to severe thrombocytopenia, microangiopathic hemolytic anemia, and neurologic changes (including headache, confusion, paresis, and dysphasia); renal dysfunction (including hematuria, proteinuria, and azotemia); and fever However, involvement of the heart, pancreas, spleen, adrenal glands, and other organs is well described. Cardiac involvement, in particular, may lead to conduction defects or signs and symptoms of coronary artery occlusion. An elevated serum LDH level is a characteristic finding in patients with TTP. It is widely accepted that total serum LDH principally rises due to the release of red blood cell LDH as a consequence of intravascular hemolysis.[6] Most cases of TTP are idiopathic, but different triggering factors may be involved, such as bacterial or viral infection (human immunodeficiency virus), autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis), exposure to certain drugs (sulfonamides, quinine, interferon alfa, etc), chemotherapy, pregnancy, and bone marrow transplantation. Thrombotic thrombocytopenic purpura has been associated with cancer, either as a result of the underlying disease or its treatment. Association with chronic myelogenous leukemia has been described.[7]

Deficiency of a recently identified enzyme, the von Willebrand factor-cleaving protease, seems to play a major role in the development of TTP. An abnormal interaction between the vascular endothelium and platelets that occurs in certain organs leads to thrombosis, endothelial proliferation, minimal inflammation, and microangiopathic hemolysis. Recent studies suggest that endothelial cell perturbation and apoptosis caused by as yet unknown plasma factors may lead to the release of abnormal von Willebrand factor, which facilitates the deposition of platelet microthrombi.[8]

Recent reports suggest that nonfamilial TTP may be caused by an IgG antibody directed against a plasma von Willebrand factor-cleaving enzyme. Nonfamilial TTP may be considered an autoimmune process, as either a distinct entity or part of another autoimmune syndrome. Familial forms are due to a congenital lack of the protease enzyme. Deficiency of the enzyme leads to accumulation of high-molecular-weight multimers that cause spontaneous platelet aggregation under high-shear-stress conditions.

A high degree of awareness to the possibility of TTP and careful examination of the peripheral blood film may obviate the need for invasive investigations and facilitate the prompt institution of specific and life-saving treatment in this deadly condition.

References

[1.] Leone G, Sica S, DeStefano V, et al. Acute onset of juvenile myelodysplastic syndrome mimicking thrombotic thrombocytopenic purpura and rapidly evolving in overt myeloid leukemia. Am J Hematol. 1992;41:64-65.

[2.] Tsiara S, Economou G, Panteli A, et al. Coexistence of myelodysplastic syndrome and multiple myeloma. J Exp Clin Cancer Res. 1999;18:565-571.

[3.] Schmetzer HM, Poleck B, Duell T, et al. Cytogenetic and Southern blot analysis to demonstrate clonality and to estimate prognosis in patients with myelodysplastic syndrome. Ann Hematol. 2000;79:20-29.

[4.] Schmitt-Graeff A, Mattern D, Kohler H, et al. Myelodysplastic syndromes (MDS): aspects of hematopathologic diagnosis. Pathologe. 2000;21:1-15.

[5.] Acar H, Caliskan U, Cora T. Paediatric myelodysplastic syndrome (MDS) and juvenile chronic myelogenous leukemia (JCML) detected by cytogenetic and FISH techniques. Clin Lab Haematol. 1999;21:403-409.

[6.] Cohen JA, Brecher ME, Bandarenko N. Cellular source of serum lactate dehydrogenase elevation in patients with thrombotic thrombocytopenic purpura. J Clin Apheresis. 1998;13:16-25.

[7.] Rachmani R, Avigdor A, Youkla M, et al. Thrombotic thrombocytopenic purpura complicating chronic myelogenous leukemia treated with interferon-alpha. Acta Haematol. 1998;100:204-206.

[8.] Eldor A. Thrombotic thrombocytopenic purpura: diagnosis, pathogenesis and modern therapy. Baillieres Clin Haematol. 1998;11:475-495.

Accepted for publication November 8, 2000.

From the Department of Pathology, Medical College of Ohio, Toledo.

Reprints not available from the authors.