Kidney-limited thrombotic microangiopathy in patients with SLE treated with romiplostim.

We present the case of a 19 year-old Caucasian female with history of systemic lupus erythematosus (SLE) and normal baseline kidney function who developed severe acute renal failure following treatment of thrombocytopenia with the thrombopoietic agent romiplostim. Percutaneous kidney biopsy revealed thrombotic microangiopathy (TMA) without immune complex lupus glomerulonephritis. We discuss pathogenesis and differential diagnosis of TMA in patients with SLE and raise concerns regarding the use of thrombopoietic agents in such patients. Based on favorable long-term outcome in our case aggressive treatment and in particular prolonged use of plasma exchange in these patients are advocated.

Autologous bone marrow transplant in a patient with sickle cell disease and diffuse large B-cell lymphoma.

As the life expectancy of patients with homozygous sickle cell anemia (SCA) improves, SCA care providers are confronted with diseases of the adult SCA population rarely seen before. We report here a 40-year-old woman with SCA who developed diffuse large B-cell non-Hodgkin's lymphoma (NHL) that was treated with eight cycles of chemotherapy consisting of cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE), without complete remission. She subsequently underwent high-dose cyclophosphamide and total-body irradiation followed by autologous bone marrow transplantation (BMT). To reduce the risk of sickle cell crisis precipitated by G-CSF, she underwent hypertransfusion to maintain a low % hemoglobin S throughout her treatment course. Although she has required iron chelation therapy and shows no sign of modification of her underlying SCA, she remains in remission from NHL 12 years posttransplant. To our knowledge, this is the first reported case of autologous BMT in a patient with SCA. Our patient illustrates that SCA in itself does not preclude autologous stem cell transplantation for lymphoma in selected patients, and this report should encourage others to consider autologous BMT in adults with SCA where it represents a lifesaving therapy for malignant diseases.

Mesenteric vein thrombosis secondary to protein S deficiency.

Mesenteric vein thrombosis is an uncommon condition. Diagnosis is often difficult because of the nonspecific clinical presentation and findings on routine laboratory and radiological evaluation. Endoscopy is usually unrevealing. An underlying hypercoagulable state is often present, but protein S deficiency has rarely been implicated. We describe a case in which chronic inferior mesenteric vein thrombosis, with remarkable endoscopic findings, occurred as the initial presentation of type I protein S deficiency.

Primary hepatic B-cell lymphoma of mucosa-associated lymphoid tissue.

Mucosa-associated lymphoid tissue (MALT) lymphomas are low-grade B-cell lymphomas that occur in a variety of extranodal sites but rarely as a primary hepatic lymphoma. We describe the histological findings, immunophenotype, and immunohistochemistry of one such lymphoma found incidentally in a 69-year-old woman. The lymphoid infiltrate invaded the liver in a serpiginous configuration with entrapment of nodules of normal liver. Reactive follicles were surrounded by intermediate-sized lymphoid cells with slightly irregular nuclei and pale cytoplasm. Only a few scattered lymphoepithelial lesions were identified since most of the bile ducts were destroyed. The immunophenotype determined by flow cytometry identified the lymphoid cells as being CD19, CD20 positive and exhibiting lambda light chain restriction. CD5, CD10, and CD23 were negative. Immunohistochemistry showed the neoplastic cells to be positive for CD20 (L-26) and bcl-2. The reactive follicles were negative for bcl-2. CD3 showed only a few scattered T cells. Cyclin D1 did not stain the neoplastic cells. Cytokeratin (AE1/AE3) highlighted the lymphoepithelial lesions and residual bile ducts. MALT lymphomas need to be recognized and distinguished from other B-cell lymphomas, particularly mantle cell lymphomas, because of the difference in behavior and treatment.

Systemic mast cell disease with marrow and splenic involvement associated with chronic myelomonocytic leukemia.

Systemic mast cell disease (SMCD) has a highly variable clinical expression and course. That SMCD is associated with hematologic disorders has been widely described. We report an unusual case of systemic mast cell disease and concurrent chronic myelomonocytic leukemia in a 60 year old male.

Factor V inhibitor in a liver transplant patient associated with porcine xenoperfusion.

The development of a high-titer factor V inhibitor is described in a patient who underwent orthotopic liver transplantation followed by porcine xenoperfusion after an acute rejection episode. The inhibitor showed no cross-reactivity to either porcine or bovine factor V, nor was it accessible to human platelet factor V. The limitations of treatment modalities including intravenous immunoglobulin, steroids, cytotoxic therapy, intense plasmapheresis and platelet transfusions are discussed.

HLA-Dr negative acute non-lymphocytic leukemia.

Absent or diminished HLA-Dr antigen representation on the cell surface of both normal and leukemic promyelocytes is a hallmark of this stage of myeloid maturation. In order to document the specificity of this finding for acute promyelocytic leukemia, flow cytometric analysis of leukemic blasts was utilized on 36 cases of acute non-lymphocytic leukemia. All 15 of the promyelocytic leukemias (FAB-M3) studied showed absent or markedly decreased HLA-Dr antigen on their cell surface. However, the majority of cases (21) in which this finding was noted were other than promyelocytic leukemias and included all FAB subtypes, most particularly FAB-M2, i.e., myeloblastic leukemia with maturation. It is concluded that absent to decreased HLA-Dr antigen representation on leukemic blasts lacks specificity and can be seen in all acute myeloid/monocytic leukemic subtypes.

Myelodysplasia associated with Turner syndrome.

PURPOSE: This study reports the association of myelodysplasia with Turner syndrome. PATIENT AND METHODS: An 11-year-old girl with Turner syndrome was found to have mild macrocytic anemia that persisted during 2 years. RESULTS: Examination of the bone marrow revealed dyserythropoietic features with multinucleation consistent with refractory anemia. Levels of hemoglobin F were also markedly elevated (57%). She also had transient neutropenia and thrombocytopenia, as well as abnormal platelet function studies. The hematopoietic abnormalities were mild and may have been missed were she not followed for her hypertension and aortic coarctation. CONCLUSIONS: Myelodysplastic syndromes in children are frequently associated with chromosomal abnormalities, but an association with Turner syndrome has not been previously described. This could be due to the fact that mild hematopoietic abnormalities in these patients may not be investigated.

Acquired von Willebrand's disease following bone marrow transplantation.

A 41-year-old male underwent allogeneic bone marrow transplantation for the treatment of acute myelogenous leukemia. Six months later, he was admitted to a hospital with signs and symptoms consistent with worsening chronic graft-vs-host disease. Despite a negative past history for a bleeding diathesis, the patient was found to have absent factor VIII procoagulant and ristocetin cofactor activities with markedly reduced von Willebrand factor antigen, all consistent with a diagnosis of acquired von Willebrand's disease. Successful treatment of this disorder with aggressive apheresis and von Willebrand factor replacement therapy is noted.

Intrapleural streptokinase in experimental empyema.

Intrapleural streptokinase has been used in multiloculated empyemas to enhance pleural space drainage, presumably by causing fibrinolysis of the interlocular septae. We evaluated the efficacy and safety of daily administration of 10,000 U intrapleural streptokinase or equal volumes of saline to enhance resolution of experimental empyema in the rabbit pleural space. Seventy-two hours after intrapleural turpentine, 10(8) colony-forming units each of Escherichia coli, Peptostreptococcus anaerobius, and Bacteroides fragilis were injected into the sterile pleural effusion of all animals. Immediately after bacterial inoculation, and daily for 3 days, animals received 10,000 U streptokinase or saline intrapleurally. Animals that achieved a pleural fluid pH < 7.30 and either glucose < 50 mg/dl or LDH > 500 IU/L were included for data analysis. At Day 4 after bacterial inoculation, the streptokinase-treated empyemic rabbits had more pleural fluid (18.8 +/- 5.1 ml) (mean +/- SEM) than did saline-treated control animals (4.8 +/- 1.7 ml) (p = 0.015), fewer interpleural adhesions (8.2 +/- 2.7) than did saline-treated control animals (25.1 +/- 3.6) (p = 0.002), and comparable amounts of visceral and parietal pleural plaque than did saline-treated control animals (p = NS). No evidence of systemic fibrinolysis was observed at 1 h after intrapleural streptokinase administration. We conclude that intrapleural streptokinase decreases interpleural adhesion numbers but fails to reduce the amount of pleural plaque observed in experimental empyema in rabbits. The increases in pleural fluid volume observed after streptokinase administration may be due to mechanisms other than fibrinolytic activity.

Alterations in von Willebrand factor antigen in premature infants with respiratory distress syndrome and chronic lung disease.

Elevated levels of von Willebrand Factor Antigen (vWF:Ag) may occur in the presence of endothelial injury, a component in the pathology of acute pulmonary insufficiency. The vWF:Ag levels were examined in 13 well infants (controls) and 20 infants with respiratory distress syndrome (RDS), nine of whom developed bronchopulmonary dysplasia (BPD). All infants were very low birth weight (730 to 1500 g) and premature (25 to 34 weeks estimated gestational age). Plasma samples were obtained at birth and weekly through 28 days of age and frozen at -70 degrees C. The vWF:Ag was quantified by the enzyme linked immunosorbent assay (ELISA) method for 138 plasma specimens; in addition, 77 samples were analyzed for multimer pattern by SDS-agarose (1.7 percent) electrophoresis and densitometric scanning. All groups had elevated mean levels of vWF:Ag, compared to adults. Although levels remained stable over the four week period, the group of infants with BPD had a significantly high mean level of vWF:Ag at 21 days than those groups without BPD (p < 0.05). Visual examination of vWF multimer patterns revealed absence of unusually large vWF multimers and triplet patterns suggestive of increased proteolytic degradation of von Willebrand factor. However, densitometer scanning revealed that samples with higher vWF:Ag levels (> 200 percent) had increased amounts of moderate to smaller sized multimers, regardless of presence or absence of BPD. It is our conclusion that von Willebrand factor antigen levels are nonspecifically elevated in premature infants and that chronic lung disease is associated with even higher plasma values, possibly owing to pulmonary endothelial injury.

Platelet dysfunction in Noonan's syndrome. A case with a platelet cyclooxygenase-like deficiency and chronic idiopathic thrombocytopenic purpura.

Individuals with Noonan's syndrome are likely to have one or more coagulation abnormalities: complex platelet function defects, partial Factor XI deficiency, or von Willebrand's disease. A distinctive platelet function defect has not been identified. The authors describe a 24-year-old women with Noonan's syndrome, chronic idiopathic thrombocytopenic purpura (ITP), and a platelet function defect characterized by a greater than 15-minute bleeding time, failure of aggregation and release with 10 microM ADP, 10 microM epinephrine, 750 microM arachidonic acid or 0.019 g/L collagen. A mixture of aspirin-treated platelets with the patient's platelets failed to correct the defect. Addition of 2.5 microM U46619 (a PGG2 analogue) corrected the aggregation and release defect. An electron microscopic analysis failed to reveal structural abnormalities. Thus, the platelet function defect in this patient appears to be a functional deficiency of cyclooxygenase. The presence of autoantiplatelet antibodies in a clinical setting consistent with chronic ITP raises the possibility that the defect may be acquired.

Acquired von Willebrand's syndrome associated with an extranodal pulmonary lymphoma.

A case of acquired von Willebrand's syndrome associated with an extranodal pulmonary lymphoma is reported in a 58-year-old man. His initial factor VIII-von Willebrand factor (vWF) complex parameters included a factor VIII activity of 29 U/dL, a vWF protein of 17 U/dL, and a ristocetin cofactor of less than 10 U/dL. A specific factor VIII inhibitor could not be demonstrated in mixtures of his plasma and normal pooled plasma nor could immune complexes of IgG-factor VIII be detected in similar mixtures using protein A in a solid phase. Following surgical removal of the patient's tumor, all factor VIII-vWF complex parameters returned to normal. Immunoperoxidase stains of the lymphoid tumor cells were negative for von Willebrand protein. The patient's acquired von Willebrand's syndrome recurred approximately one year later, presumably indicative of recurrent lymphoma.

The role of apheresis in the support of life-threatening ITP relapse.

A 14-year-old girl with chronic idiopathic thrombocytopenic purpura (ITP) presented in relapse with a platelet count of 1,000/microL and a high-level serum antiplatelet IgG antibody. She previously had been unresponsive to courses of therapy with steroids, vincristine, and splenectomy. When treatment with danazol and purified immunoglobulins was unsuccessful in controlling her rapidly progressive course, an 8-day plasma exchange procedure was initiated in combination with platelet transfusion therapy and immunosuppression with cyclophosphamide and vincristine. Within 2 days, her clinical state improved markedly, correlating with a drop in her serum antiplatelet antibody level. She continued to improve and was discharged on a regimen of cyclophosphamide and danazol. Her antiplatelet antibody level had fallen to within the normal range, despite a typical platelet count of 5,000/microL during the 8-day period. Two weeks later her platelet count rose to 65,000/microL. This case suggests that a course of therapeutic plasma exchange may have a temporizing role in the acute management of life-threatening chronic ITP relapse, generating time for the more definitive therapy of immunosuppression to take effect.

Mean platelet volume and platelet distribution width in the neonate.

Normal values for mean platelet volume (MPV) and platelet distribution width (PDW) have not been firmly established for term and preterm neonates. Cord blood samples from 143 healthy newborns (78 full term and 65 premature) were analyzed with the Coulter counter. Platelet count and MPV were significantly greater (p less than 0.05 and p less than 0.001, respectively) in term versus preterm infants, while PDW was significantly less in term infants (p less than 0.001). Platelet count and MPV correlated with gestational age, and platelet count also correlated with birth weight. There was a significant (p less than 0.001) negative correlation of PDW with gestational age and birth weight. These data represent normal reference ranges for neonates and demonstrate significant variation with gestational age.

Acquired dysfibrinogenemia secondary to mithramycin toxicity.

A 58-year-old black woman with IgD multiple myeloma developed a hemorrhagic diathesis within 48 hours after receiving mithramycin (20 micrograms/kg/day) for therapy of hypercalcemia. Her coagulation studies were characterized by prolonged prothrombin, partial thromboplastin, thrombin, and reptilase clotting times. Her plasma and partially purified fibrinogen were inhibitory to the clotting of normal plasma and fibrinogen. The patient's isolated fibrinogen showed a normal rate of fibrinopeptide release, but her fibrin monomer aggregation was markedly abnormal. These studies document the development of a dysfibrinogenemia secondary to mithramycin toxicity.

Factor V inhibitor associated with immune complex formation.

A 72-year-old man was noted, shortly after surgery, to have a bleeding diathesis secondary to the development of a high-titer anti-factor V inhibitor. We documented the presence of factor V:anti-factor V IgG immune complexes and their disappearance following a short course of steroid therapy.

Acquired von Willebrand syndrome due to an inhibitor specific for von Willebrand factor antigens.

A patient with acquired von Willebrand syndrome associated with polycythemia rubra vera is described. Her plasma factor VIII procoagulant activity (67 U/dl) and factor VIII-related antigen (117 U/dl) were normal but no von Willebrand factor activity could be detected. Factor VIII crossed immunoelectrophoresis revealed decreased levels of less anodic polymeric forms of factor VIII. Mixture of her plasma or immunoglobulin G (IgG) fraction with normal plasma resulted in complete recovery of factor VIII activity and related antigen but no measurable von Willebrand factor activity, confirming the presence of an unique inhibitor. The limited specificity of this inhibitor to antigenic sites solely on the von Willebrand portion of the factor VIII bimolecular complex is distinct from all previous reports of this syndrome. This unique inhibitor offers a molecular probe to examine the von Willebrand factor: platelet interaction.