Cryoprecipitate poor plasma does not improve early response in primary adult thrombotic thrombocytopenic purpura (TTP).

Thrombotic thrombocytopenic purpura (TTP) is a potentially fatal disease that is treated with plasma exchange and typically with replacement with fresh frozen plasma (FFP). This approach results in an approximate 50% response rate following 1 week of therapy and 80% survival. Cryoprecipitate poor plasma (CPP) is plasma from which the cryoprecipitate fraction is removed. CPP has been reported to be successful as salvage therapy in refractory TTP and has been suggested to be superior to FFP in retrospective studies. The present report compares initial therapy of TTP with exchange using replacement with either FFP or CPP in a multi-institutional prospective randomized study performed by the North American TTP Group (NATG Group) from 1993 to 1995. Initial therapy also included corticosteroids. Antiplatelet drugs or vinca alkaloids were not employed. A severity score index, response score, and individual clinical parameters (platelet count, LDH x upper limit of normal, hemoglobin level, and creatinine) were compared at their nadir or peak values, baseline, and days +6 and +13 of therapy. Thirteen patients were randomized to FFP exchange and 14 to CPP exchange. Results were equivalent for all parameters. Survival was equal with three deaths in each group. These data indicate that the efficacy of FFP and CPP are the same in the initial treatment of TTP in adults.

Hypotetraploidy in a patient with small cell carcinoma.

While numerical and structural chromosomal abnormalities characterize many hematopoietic and nonhematopoietic malignancies, the occurrence of polyploidy is by and large rare. We report here an interesting patient with small cell carcinoma (SCC) and hypotetraploidy initially referred to us because of a question of acute nonlymphocytic leukemia, M3 subtype, with a question of a 15;17 translocation characteristic of acute promyelocytic leukemia. However, the patient did not have a 15;17 translocation and the final hematopathologic analysis of the bone marrow aspirates and immunohistochemistry studies subsequently revealed the patient to have SCC. Small cell carcinoma is a highly malignant and a very aggressive neoplasm. A review of the literature, using Medline, Cancerlit, and the Science Citation Index, revealed that in most, if not all, reports, the presence of polyploidy is noted as a rare entity. In leukemia, reports of polyploidy point to a distinct category of patients with a poor risk for which more intensive treatment is needed. Limited information is currently available to assess the risk of polyploidy in small cell carcinoma. Our case is important not only because of the relative rarity of polyploidy, but also because insights gained from the study of this and other similar patients may help shed additional light on the mechanism of carcinogenesis, which is not fully known to date. As polyploidization is a manifestation of genetic instability and as genetic instability has been implicated in the genesis and progression of many cancers, it is perhaps not too surprising that polyploidy in our case was associated with a poor disease outcome. The patient has since expired.

Plasminogen activator inhibitor (PAI-1) antigen levels in primary TTP and secondary TTP post-bone marrow transplantation.

Our objectives were to measure and compare plasminogen activator inhibitor levels (PAI-1) in primary adult thrombotic thrombocytopenic purpura (TTP) and in secondary TTP associated with bone marrow transplantation (BMT)-TTP. PAI-1 antigen levels were measured by an enzyme linked immunosorbent assay on platelet poor plasma samples obtained from patients at the time of diagnosis of the TTP disorder and from a group of normal volunteers. The samples were frozen at -70 degrees C. Patients with TTP secondary to bone marrow transplantation had their grade determined by percentage fragmented cells and lactate dehydrogenase levels. The primary TTP samples were contributed by investigators in the multi-institutional North American TTP Group, and the bone marrow transplant samples were obtained from an adult bone marrow transplant program. Nineteen patients with adult TTP, and 47 patients with bone marrow transplant-TTP were evaluated. Of the latter, 14 had Grade 2, 13 had Grade 3, and 20 had Grade 4 BMT-TTP. PAI-1 levels were elevated compared to control volunteers in both primary adult TTP and BMT-TTP, P < 0.001. Levels did not differ from normal in Grade 2 BMT-TTP (median = 16 ng/ml; quartiles = 9-20). PAI-1 levels were similar in primary TTP (median = 32 ng/ml; quartiles = 25-51) and Grade 3 BMT-TTP (median = 35 ng/ml; quartiles = 19-48 ng/ml), P = 0.7. However, PAI-1 levels were significantly higher in Grade 4 BMT-TTP (median = 83 ng/ml; quartiles = 60-143) than Grade 3 BMT-TTP, and primary TTP, P < 0.001. PAI-1 levels are high in primary TTP and secondary bone marrow transplant-TTP (Grades 3-4). In contrast, normal levels are seen in Grade 2 BMT-TTP, which is a self-limited disorder. Therefore, high PAI-1 levels may contribute to hypofibrinolysis in the pathogenesis of primary TTP and of moderate to severe TTP (Grades 3-4) following bone marrow transplantation.

Trisomy 10 in leukemia.

Previous studies had raised questions about whether the relatively rare finding of trisomy 10 in leukemia is nonrandomly associated with a specific immunophenotype or ethnic origin. To shed light on the above questions and to obtain additional clinical and pathologic information on this unique class of leukemic patients, we conducted a retrospective study of leukemia cases at our laboratory from July 1, 1990, to July 31, 1996. The results not only support the rarity of trisomy 10, but they also reject the hypotheses that all trisomy 10 cases are CD7-positive, or found in Orientals.

Translocation 2;19 in a patient with probable relapsed acute myeloid leukemia.

We report the cytogenetic and hematopathologic results from a patient diagnosed with acute myeloid leukemia. Although the initial specimen revealed an apparently normal male karyotype, a translocation, t(2;19)(q21;p13), was detected in the second specimen. It is not clear whether this was a primary or secondary and possibly chemotherapy-induced abnormality. In an extensive search of the recent medical literature database (Medline, 1966 to the present; CancerLit, 1983 to the present, MDX Health Digest, 1988 to the present; HealthSTAR, 1975 to the present, and CINAHL, 1982 to the present), we found no previous report of this specific translocation. This case is of interest not only because of its cytogenetic rarity and its unique clinical features, but also because of the fact that this patient worked in construction management, performing offshore drilling in oil fields for several years, and also worked with plastics and polymer film for about 4 years, although this past history of possible genotoxic exposure may or may not be of relevance. In addition, it is also of interest that one of the translocation breakpoints, 19p13, is apparently identical to that found in the 1;19 translocation associated with pre-B cell acute lymphocytic leukemia.

Plasma von Willebrand Factor Antigen (vWF:AG) and thrombomodulin (TM) levels in Adult Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndromes (TTP/HUS) and bone marrow transplant-associated thrombotic microangiopathy (BMT-TM).

Endothelial damage is thought to be a contributing factor in the pathogenesis of Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndromes (TTP/HUS). The present studies measured two markers of endothelial cell stimulation and/or activation [von Willebrand Factor (vWF:Ag) and thrombomodulin (TM)] in patients with TTP/HUS disorders and compared them to controls. The patient groups consisted of adults with TTP/HUS, with (n = 13) and without (n = 14) peak Cr levels >2.0 mg/dl. Additionally, 52 patients with Bone Marrow Transplant-associated Thrombotic Microangiopathy (BMT-TM) following allogeneic BMT were evaluated. Both vWF:Ag and TM were elevated in all patient groups compared to controls. TTP/HUS patients with peak Cr >2.0 mg/dl had higher TM levels (P < 0.001) than did those with peak Cr levels below 2 mg/dl. However, thrombomodulin/ creatinine (TM/Cr) ratios did not differ in these two groups nor did they differ from controls. BMT-TM pts had higher vWF:Ag levels and higher TM/Cr ratios than controls and TTP/ HUS, P < 0.001. The median TM/Cr ratio in BMT-TM was 91 (range = 34-229) compared to 38 (range = 29-50) in controls, P < 0.001 and 38 (range = 6 to 156) in TTP/HUS, P < 0.001. Additionally both TM (P < 0.001) and TM/Cr (P < 0.02) were higher in patients with Grades 3 and 4 BMT-TM compared to those with Grade 2 BMT-TM. These results suggest that endothelial cell activation occurs in TTP/HUS and BMT-TM. Since TM/Cr ratios were higher in BMT-TM compared to TTP/HUS, these findings suggest that the mechanism of elevated TM in BMT-TM cannot be explained solely by altered renal excretion. Taken together, these findings strongly indicate a role of endothelial cell damage in BMT-TM.

Chronic myeloid leukemia manifested during megakaryoblastic crisis.

We describe a 38-year-old man with a chronic myeloproliferative syndrome characterized by elevated white blood cell and platelet counts and increased blasts in the peripheral blood. Bone marrow aspiration was a "dry tap" and the biopsy specimen was hypercellular with numerous blasts, atypical megakaryocytes, and increased reticulin fibrosis. The blasts exhibited cytochemical reactivity for nonspecific esterase and PAS and immunohistochemically were positive for factor VIII, supporting megakaryoblastic lineage. Cytogenetic studies of peripheral blood revealed the t(9;22)(q34;q11). We interpreted these findings to be most consistent with chronic myeloid leukemia (CML) manifested at the time of megakaryoblastic crisis. Although the initial complete blood count showed leukocytosis and thrombocytosis, the patient subsequently had pancytopenia with clinical and pathologic findings consistent with acute myelofibrosis (AMF). Cytosine arabinoside and etoposide chemotherapy induced remission of the acute leukemia. We conclude that CML infrequently presents itself in megakaryoblastic crisis and that such cases may result in the clinicopathologic syndrome of AMF. The success of chemotherapy in this case also suggests that intensive antileukemic therapy may be useful in other patients with either CML-blast crisis or the clinicopathologic syndrome of AMF.

Management of persistent B19 parvovirus infection in AIDS.

An HIV+ 26-year-old white man with a CD4 count of 0.06 x 10(9)/l was found to have red blood cell aplasia secondary to B19 parvovirus infection. Regular infusions of intravenous immunoglobulin (IVIG) were begun and resulted in marked reticulocytosis and correction of anaemia. The patient has been followed for over 4 years and has become anaemic and reticulocytopenic whenever IVIG was interrupted. Serial dot blot analysis of the patient's sera for B19 parvovirus DNA showed absence of DNA immediately following IVIG treatments but reappearance within 3-6 weeks. Regular IVIG was effective in controlling but not eradicating B19 parvovirus infection in this HIV+ patient.

Plasma cell myeloma associated with eosinophilia.

The association of plasma cell myeloma and eosinophilia is rare. The authors describe a 49-year-old man with plasma cell myeloma and marked absolute peripheral blood eosinophilia, 109.7 x 10(9)/L. Analysis of his bone marrow revealed cytologically atypical plasma cells that expressed monotypic IgG lambda and marked eosinophilia with normal maturation. A combination of steroids and chemotherapy resulted in a significant and sustained decrease in his absolute eosinophil count and bone marrow plasma cells. Analysis of the patient's pre-therapy serum revealed immunoreactive interleukin-3 (IL-3), but not IL-5 or granulocyte/macrophage colony stimulating factor (GM-CSF). The post-therapy serum sample was negative. Immunohistochemical analysis of the plasma cells for IL-3 and IL-5 was negative. This review of the literature has revealed five cases of plasma cell myeloma associated with eosinophilia described previously. In two patients, the eosinophilia was attributed to drug therapy. In the remaining cases, the pathogenesis of the eosinophilia was unexplained. In this case, IL-3 secreted either by the neoplastic cells at a level below detection by immunohistochemistry or by other cells in response to the presence of plasma cell myeloma may have played a role in causing the eosinophilia.

Therapeutic support of the patient with thrombocytopenia.

This article provides an update on the methods of collection, preservation, storage, and administration of platelet concentrates. The current indications for platelet transfusions are reviewed, and current knowledge concerning alloimmunization and its prevention is summarized. In addition, the ongoing controversies related to prophylactic administration of platelets versus therapeutic administration are reviewed.

Lactoferrin gene promoter: structural integrity and nonexpression in HL60 cells.

Lactoferrin is a member of the transferrin family of iron-binding proteins. It is found in several glandular epithelial tissues and human neutrophils, where it is localized to secondary granules. To examine the mechanisms controlling lactoferrin gene expression in neutrophils and defects in its expression in acute leukemia, we have cloned a lactoferrin cDNA from a chronic myelogenous leukemia library, and used it to obtain genomic clones representing the chromosomal lactoferrin gene. Using polymerase chain reaction, primer extension, and S1 analysis, we have identified the 5' end of the lactoferrin mRNA. We have defined a putative promoter region for the gene, and characterized its first two exons. In addition, we have examined the structure of these regions in DNA from HL60 cells. HL60 is a leukemic cell line that undergoes phenotypic neutrophil maturation on exposure to dimethyl sulfoxide (DMSO). However, the cells cannot be induced to express any secondary granule protein genes. We have shown that the 5' end of the lactoferrin gene, including the putative promoter region, is entirely normal in HL60. By Northern analysis, nuclear run-on studies, and primer extension assays we have shown that the gene is not transcribed in DMSO-induced HL60 cells. This supports the hypothesis that the defect in HL60 is an abnormality in the production or activity of a transacting regulator of lactoferrin gene expression.